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US20130315994A1 - Modified-release dosage forms of 5-ht2c agonists useful for weight management - Google Patents

Modified-release dosage forms of 5-ht2c agonists useful for weight management Download PDF

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US20130315994A1
US20130315994A1 US13/820,107 US201113820107A US2013315994A1 US 20130315994 A1 US20130315994 A1 US 20130315994A1 US 201113820107 A US201113820107 A US 201113820107A US 2013315994 A1 US2013315994 A1 US 2013315994A1
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Prior art keywords
methyl
salt
tetrahydro
chloro
benzazepine
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Inventor
Zezhi Jesse Shao
Anthony C. Blackburn
Andrew J. Grottick
Michael Morgan
Jaimie Karyn Rueter
Anna Shifrina
Scott Stirn
Libo Yang
Woo Hyun Yoon
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Arena Pharmaceuticals Inc
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Arena Pharmaceuticals Inc
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Priority to US13/820,107 priority Critical patent/US20130315994A1/en
Assigned to ARENA PHARMACEUTICALS, INC. reassignment ARENA PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: STIRN, SCOTT, YANG, LIBO, GROTTICK, ANDREW J, RUETER, JAIMIE KARYN, BLACKBURN, ANTHONY C, MORGAN, MICHAEL, SHAO, ZEZHI JESSE, YOON, WOO HYUN, SHIFRINA, ANNA
Publication of US20130315994A1 publication Critical patent/US20130315994A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23P—SHAPING OR WORKING OF FOODSTUFFS, NOT FULLY COVERED BY A SINGLE OTHER SUBCLASS
    • A23P20/00—Coating of foodstuffs; Coatings therefor; Making laminated, multi-layered, stuffed or hollow foodstuffs
    • A23P20/10—Coating with edible coatings, e.g. with oils or fats
    • A23P20/12—Apparatus or processes for applying powders or particles to foodstuffs, e.g. for breading; Such apparatus combined with means for pre-moistening or battering
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid

Definitions

  • the present invention relates to methods for weight management that utilize modified-release dosage forms comprising (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine salts and crystalline forms thereof.
  • the present invention further relates to (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine salts, crystalline forms thereof and modified-release dosage forms comprising them.
  • Obesity is a life-threatening disorder in which there is an increased risk of morbidity and mortality arising from concomitant diseases such as type II diabetes, hypertension, stroke, cancer and gallbladder disease.
  • Obesity is now a major healthcare issue in the Western World and increasingly in some third world countries.
  • the increase in numbers of obese people is due largely to the increasing preference for high fat content foods but also the decrease in activity in most people's lives.
  • Currently about 30% of the population of the USA is now considered obese.
  • BMI body mass index
  • BMI body mass that is muscle in relation to fat (adipose tissue).
  • obesity can also be defined on the basis of body fat content: greater than 25% in males and greater than 30% in females.
  • Kidney disease also called nephropathy
  • Diabetes occurs when the kidney's “filter mechanism” is damaged and protein leaks into urine in excessive amounts and eventually the kidney fails. Diabetes is also a leading cause of damage to the retina at the back of the eye and increases risk of cataracts and glaucoma.
  • diabetes is associated with nerve damage, especially in the legs and feet, which interferes with the ability to sense pain and contributes to serious infections. Taken together, diabetes complications are one of the nation's leading causes of death.
  • the first line of treatment is to offer diet and life style advice to patients such as reducing the fat content of their diet and increasing their physical activity.
  • patients find this difficult and need additional help from drug therapy to maintain results from these efforts.
  • Orlistat a drug that prevents absorption of fat by the inhibition of pancreatic lipase
  • Sibutramine ReductilTM
  • XenicalTM a drug that prevents absorption of fat by the inhibition of pancreatic lipase
  • Sibutramine ReductilTM
  • side effects associated with these products may limit their long-term utility.
  • Treatment with XenicalTM is reported to induce gastrointestinal distress in some patients, while Sibutramine has been associated with raised blood pressure in some patients.
  • Serotonin (5-HT) neurotransmission plays an important role in numerous physiological processes both in physical and in psychiatric disorders.
  • 5-HT has been implicated in the regulation of feeding behavior. 5-HT is believed to work by inducing a feeling of satiety, such that a subject with enhanced 5-HT stops eating earlier and fewer calories are consumed. It has been shown that a stimulatory action of 5-HT on the 5-HT 2C receptor plays an important role in the control of eating and in the anti-obesity effect of d-fenfluramine. As the 5-HT 2C receptor is expressed in high density in the brain (notably in the limbic structures, extrapyramidal pathways, thalamus and hypothalamus i.e.
  • a selective 5-HT 2C receptor agonist can be a more effective and safe anti-obesity agent. Also, 5-HT 2C knockout mice are overweight with cognitive impairment and susceptibility to seizure.
  • the 5-HT 2C receptor may play a role in obsessive compulsive disorder, some forms of depression, and epilepsy. Accordingly, agonists can have anti-panic properties, and properties useful for the treatment of sexual dysfunction.
  • the 5-HT 2C receptor is a receptor target for the treatment of obesity and psychiatric disorders, and it can be seen that there is a need for selective 5-HT 2C agonists which safely decrease food intake and body weight.
  • the salts and formulations of the present invention comprise the selective 5-HT 2C -receptor agonist (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound 1), and are useful for, inter alia, weight management, including weight loss and the maintenance of weight loss.
  • Compound 1 is disclosed in PCT patent publication WO2003/086303, which is incorporated herein by reference in its entirety.
  • provisional application 61/402,611 and Attorney Reference Number 192.WO1, a PCT application which claims priority to U.S. provisional applications 61/402,565 and 61/403,185; each of which is incorporated herein by reference in its entirety.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (lorcaserin hydrochloride) is an agonist of the 5-HT 2C receptor and shows effectiveness at reducing obesity in animal models and humans.
  • Arena Pharmaceuticals submitted a New Drug Application, or NDA, for lorcaserin to the FDA.
  • the NDA submission is based on an extensive data package from lorcaserin's clinical development program that includes 18 clinical trials totaling 8,576 patients.
  • the pivotal phase 3 clinical trial program evaluated nearly 7,200 patients treated for up to two years, and showed that lorcaserin consistently produced significant weight loss with excellent tolerability. About two-thirds of patients achieved at least 5% weight loss and over one-third achieved at least 10% weight loss.
  • Modified-release dosage forms elevate trough plasma levels and are suitable for use in once-a-day (q.d.) dosing regimens. Furthermore, modified-release dosage forms reduce the drug plasma concentration peak:trough ratio and can thereby decrease the incidence and severity of the adverse effects of intermittent dosing.
  • modified-release technology depends upon the plasma concentration profile desired and the active pharmaceutical ingredient (API) solubility.
  • the drug molecule must have appropriate pharmacokinetics and sufficient solubility, permeability, and stability throughout the GI tract for a successful modified-release formulation.
  • the salts and formulations described herein help meet these and other needs.
  • One aspect of the present invention pertains to modified-release dosage forms comprising a therapeutically effective amount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • One aspect of the present invention pertains to methods for weight management, comprising administering to an individual in need thereof, the modified-release dosage form of the present invention.
  • One aspect of the present invention pertains to a salt selected from: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydroiodide salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine maleate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine fumarate salt; and (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemifumarate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-acetamidobenzoate salt-cocrystal; (R)-8-chloro-1-methyl-2
  • One aspect of the present invention pertains to a pharmaceutical composition
  • a pharmaceutical composition comprising a salt of the present invention, and a pharmaceutically acceptable carrier.
  • One aspect of the present invention pertains to processes for preparing a pharmaceutical composition comprising admixing a salt of the present invention, and a pharmaceutically acceptable carrier.
  • One aspect of the present invention pertains to methods for weight management, comprising administering to an individual in need thereof, a therapeutically effective amount of a salt or a pharmaceutical composition of the present invention.
  • One aspect of the present invention pertains to uses of salts or pharmaceutical compositions of the present invention, in the manufacture of a medicament for weight management in an individual.
  • One aspect of the present invention pertains to salts, and pharmaceutical compositions of the present invention, for use in a method of treatment of the human or animal body by therapy.
  • One aspect of the present invention pertains to modified-release dosage forms, salts, and pharmaceutical compositions of the present invention, for use in a method of weight management.
  • One aspect of the present invention pertains to modified-release dosage forms, salts, and pharmaceutical compositions of the present invention, for use in a method of weight management; wherein the weight management comprises one or more of: weight loss, and maintenance of weight loss.
  • One aspect of the present invention pertains to modified-release dosage forms, salts, and pharmaceutical compositions of the present invention, for use in a method of weight management; wherein the weight management comprises one or more of: weight loss, maintenance of weight loss, decreased food consumption, increasing meal-related satiety, reducing pre-meal hunger, and reducing intra-meal food intake.
  • One aspect of the present invention pertains to modified-release dosage forms, salts, and pharmaceutical compositions of the present invention, for use as an adjunct to diet and exercise for weight management.
  • One aspect of the present invention pertains to modified-release dosage forms, salts, and pharmaceutical compositions of the present invention, for use in a method of weight management; wherein the individual in need of weight management is selected from: an obese patient with an initial body mass index ⁇ 30 kg/m 2 ; an overweight patient with an initial body mass index ⁇ 27 kg/m 2 in the presence of at least one weight related comorbid condition; and an overweight patient with an initial body mass index ⁇ 27 kg/m 2 in the presence of at least one weight related comorbid condition; wherein the weight related co-morbid condition is selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
  • One aspect of the present invention pertains to modified-release dosage forms, salts, and pharmaceutical compositions of the present invention, for use in a method of weight management in combination with a second anti-obesity agent.
  • One aspect of the present invention pertains to modified-release dosage forms, salts, and pharmaceutical compositions of the present invention, for use in a method of weight management in combination with a second anti-obesity agent selected from: chlorphentermine, clortermine, phenpentermine, and phentermine, and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • a second anti-obesity agent selected from: chlorphentermine, clortermine, phenpentermine, and phentermine, and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • One aspect of the present invention pertains to modified-release dosage forms, salts, and pharmaceutical compositions of the present invention, for use in a method of weight management in combination with an anti-diabetes agent.
  • One aspect of the present invention pertains to modified-release dosage forms, salts, and pharmaceutical compositions of the present invention, for use in a method of weight management in combination with metformin.
  • One aspect of the present invention pertains to methods of manufacturing a pharmaceutical composition
  • a pharmaceutical composition comprising: admixing a compound selected from: a salt of the present invention and pharmaceutically acceptable solvates and hydrates thereof, with a pharmaceutically acceptable excipient.
  • One aspect of the present invention pertains to methods of manufacturing a modified-release dosage form comprising: providing a compound selected from: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, and pharmaceutically acceptable salts, solvates, and hydrates thereof; and formulating the compound into a modified-release dosage form.
  • One aspect of the present invention pertains to methods for weight management, comprising administering to an individual in need thereof, a modified-release dosage form comprising a therapeutically effective dose of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • One aspect of the present invention pertains to modified-release dosage forms comprising a therapeutically effective dose of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate or hydrate thereof.
  • One aspect of the present invention pertains modified-release dosage forms comprising a therapeutically effective dose of a salt selected from: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and pharmaceutically acceptable salts, solvates, and hydrates thereof, for use in a method of weight management in an individual.
  • a salt selected from: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and pharmaceutically acceptable salts, solvates, and hydrates thereof, for use in a method of weight management in an individual.
  • One aspect of the present invention pertains to certain salts of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound 1) and pharmaceutically acceptable solvates and hydrates thereof.
  • One aspect of the present invention pertains to certain salts of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound 1).
  • One aspect of the present invention pertains to crystalline forms of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydroiodide salt.
  • One aspect of the present invention pertains to crystalline forms of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine maleate salt.
  • One aspect of the present invention pertains to crystalline forms of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine fumarate salt.
  • One aspect of the present invention pertains to crystalline forms of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemifumarate salt.
  • One aspect of the present invention pertains to crystalline forms of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt.
  • One aspect of the present invention pertains to crystalline forms of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt hydrate.
  • One aspect of the present invention pertains to crystalline forms of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate.
  • One aspect of the present invention pertains to crystalline forms of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine trans-cinnamate salt.
  • One aspect of the present invention pertains to crystalline forms of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine heminapadisilate salt.
  • One aspect of the present invention pertains to crystalline forms of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine heminapadisilate salt solvate 1.
  • One aspect of the present invention pertains to crystalline forms of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine heminapadisilate salt solvate 2.
  • One aspect of the present invention pertains to crystalline forms of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine( ⁇ )-mandelate salt hydrate.
  • One aspect of the present invention pertains to crystalline forms of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemipamoate salt hydrate.
  • One aspect of the present invention pertains to pharmaceutical compositions comprising a salt of the present invention.
  • One aspect of the present invention pertains to processes for preparing pharmaceutical compositions comprising admixing a salt of the present invention, and a pharmaceutically acceptable carrier.
  • One aspect of the present invention pertains to bulk pharmaceutical compositions suitable for the manufacture of dosage forms for weight management, comprising a salt of the present invention, and a pharmaceutically acceptable carrier.
  • One aspect of the present invention pertains to processes for preparing a bulk pharmaceutical composition suitable for the manufacture of dosage forms for weight management, comprising admixing a salt of the present invention, and a pharmaceutically acceptable carrier.
  • One aspect of the present invention pertains to methods for weight management, comprising administering to an individual in need thereof, a therapeutically effective amount of a salt, or a pharmaceutical composition of the present invention.
  • One aspect of the present invention pertains to the use of a salt of the present invention in the manufacture of a medicament for weight management in an individual.
  • One aspect of the present invention pertains to salts and pharmaceutical compositions of the present invention, for use in a method of treatment of the human or animal body by therapy.
  • FIG. 1 PXRD of Compound 1 Hydrochloride Salt, Hemihydrate Form III.
  • FIG. 2 DSC of Compound 1 Hydrochloride Salt, Hemihydrate Form III.
  • FIG. 3 TGA of Compound 1 Hydrochloride Salt, Hemihydrate Form III.
  • FIG. 4 DMS of Compound 1 Hydrochloride Salt, Hemihydrate Form III.
  • FIG. 5 PXRD of Compound 1 Hydroiodide Salt, Form I.
  • FIG. 6 DSC and TGA of Compound 1 Hydroiodide Salt, Form I.
  • FIG. 7 DMS of Compound 1 Hydroiodide Salt, Form I.
  • FIG. 8 PXRD of Compound 1 Maleate Salt, Form I.
  • FIG. 9 DSC and TGA of Compound 1 Maleate Salt, Form I.
  • FIG. 10 DMS of Compound 1 Maleate Salt, Form I.
  • FIG. 11 PXRD of Compound 1 Fumarate Salt, Form I.
  • FIG. 12 DSC and TGA of Compound 1 Fumarate Salt, Form I.
  • FIG. 13 DMS of Compound 1 Fumarate Salt, Form I.
  • FIG. 14 PXRD of Compound 1 Hemifumarate Salt, Form I.
  • FIG. 15 DSC and TGA of Compound 1 Hemifumarate Salt, Form I.
  • FIG. 16 DMS of Compound 1 Hemifumarate Salt, Form I.
  • FIG. 17 PXRD of Compound 1 Orotate Salt, Form I.
  • FIG. 18 DSC and TGA of Compound 1 Orotate Salt, Form I.
  • FIG. 19 DMS of Compound 1 Orotate Salt, Form I.
  • FIG. 20 PXRD of Compound 1 Orotate Salt Hydrate, Form I.
  • FIG. 21 DSC and TGA of Compound 1 Orotate Salt Hydrate, Form I.
  • FIG. 22 DMS of Compound 1 Orotate Salt Hydrate, Form I.
  • FIG. 23 PXRD of Compound 1 Di-4-acetamidobenzoate Salt-Cocrystal Methyl Ethyl Ketone Solvate, Form I.
  • FIG. 24 DSC and TGA of Compound 1 Di-4-acetamidobenzoate Salt-Cocrystal Methyl Ethyl Ketone Solvate, Form I.
  • FIG. 25 DMS of Compound 1 Di-4-acetamidobenzoate Salt-Cocrystal Methyl Ethyl Ketone Solvate, Form I.
  • FIG. 26 PXRD of Compound 1 trans-Cinnamate Salt, Form I.
  • FIG. 27 DSC and TGA of Compound 1 trans-Cinnamate Salt, Form I.
  • FIG. 28 DMS of Compound 1 trans-Cinnamate Salt, Form I.
  • FIG. 29 PXRD of Compound 1 Heminapadisilate Salt, Form I.
  • FIG. 30 DSC and TGA of Compound 1 Heminapadisilate Salt, Form I.
  • FIG. 31 DMS of Compound 1 Heminapadisilate Salt, Form I.
  • FIG. 32 PXRD of Compound 1 Heminapadisilate Salt Solvate 1, Form I.
  • FIG. 33 DSC and TGA of Compound 1 Heminapadisilate Salt Solvate 1, Form I.
  • FIG. 34 PXRD of Compound 1 Heminapadisilate Salt Solvate 2, Form I.
  • FIG. 35 DSC and TGA of Compound 1 Heminapadisilate Salt Solvate 2, Form I.
  • FIG. 36 PXRD of Compound 1 ( ⁇ )-Mandelate Salt Hydrate, Form I.
  • FIG. 37 DSC and TGA of Compound 1 ( ⁇ )-Mandelate Salt Hydrate, Form I.
  • FIG. 38 DMS of Compound 1 ( ⁇ )-Mandelate Salt Hydrate, Form I.
  • FIG. 39 PXRD of Compound 1 Hemipamoate Salt Hydrate, Form I.
  • FIG. 40 DSC and TGA of Compound 1 Hemipamoate Salt Hydrate, Form I.
  • FIG. 41 DMS of Compound 1 Hemipamoate Salt Hydrate, Form I.
  • FIG. 42 Upper Limit of Release of Compound 1 Hydrochloride Salt Hemihydrate, Form III from Modified-release Formulation.
  • FIG. 43 Pharmacokinetics Simulation of 20-mg Modified-release Formulation and 10-mg Immediate-release (IR) Tablets of Compound 1 Hydrochloride Salt Hemihydrate, Form III.
  • FIG. 44 Dissolution Profile of Compound 1 Hydrochloride Salt Hemihydrate, Form III Tablets Coated with Surelease®/Opadry® (85/15).
  • FIG. 45 Effect of the Surelease®/Opadry® Ratio on Compound 1 Hydrochloride Salt Hemihydrate, Form III Release.
  • FIG. 46 Effect of HPMC K4M Level on Compound 1 Hydrochloride Salt Hemihydrate, Form III Release.
  • FIG. 47 Effect of Surelease®/Opadry® Coating Level on Compound 1 Hydrochloride Salt Hemihydrate, Form III Release.
  • FIG. 48 Effect of Compound 1 Hydrochloride Salt Hemihydrate, Form III Loading.
  • FIG. 49 Day 26 Efficacy of Compound 1 after PO dosed at 24 mg/kg/day or Osmotic Pump Infusion at 15.1 mg/kg/day (Infusion Rate, 0.63 mg/kg/h) in Fed Male SD Rats.
  • FIG. 50 Mean Plasma Concentration of Compound 1 after PO dosed at 24 mg/kg/day or Osmotic Pump Infusion at 15.1 mg/kg/day (Infusion Rate, 0.63 mg/kg/h) in Fed Male SD Rats.
  • FIG. 51 Mean AUC last of Compound 1 after PO dosed at 24 mg/kg/day or Osmotic Pump Infusion at 15.1 mg/kg/day (Infusion Rate, 0.63 mg/kg/h) in Fed Male SD Rats.
  • FIG. 52 Mean C max of Compound 1 after PO dosed at 24 mg/kg/day or Osmotic Pump Infusion at 15.1 mg/kg/day (Infusion Rate, 0.63 mg/kg/h) in Fed Male SD Rats.
  • FIG. 53 Individual Compound 1 Exposure Values after PO (24 mg/kg/day) or SC Osmotic Pump Infusion (15.1 mg/kg/day, Infusion Rate, 0.63 mg/kg/h) in Fed Male SD Rats.
  • FIG. 54 Days 1-26 Efficacy of Compound 1 after PO dosed at 24 mg/kg/day or Osmotic Pump Infusion at 15.1 mg/kg/day (Infusion Rate, 0.63 mg/kg/h) in Fed Male SD Rats.
  • FIG. 55 Dissolution Profiles of Compound 1 Hydrochloride Salt Hemi-hydrate, Form III 20-mg Modified-release Formulations with Soluble Coating.
  • FIG. 56 Dissolution Profiles of Compound 1 Hydrochloride Salt Hemi-hydrate, Form III 20-mg Modified-release Formulations with Functional Polymer Coating.
  • FIG. 57 Immediate-Release Mean Plasma Compound 1 Concentrations Versus Time on Day 1 in Humans.
  • FIG. 58 Immediate-Release Mean Plasma Compound 1 Concentrations Versus Time on Day 14 in Humans.
  • agonist refers to a moiety that interacts with and activates a receptor, such as the 5-HT 2C serotonin receptor, and initiates a physiological or pharmacological response characteristic of that receptor.
  • AUC refers to the area under a plasma concentration versus time curve.
  • AUC 0-t refers to the area under a plasma concentration versus time curve from the time of dosing to time t.
  • AUC 0-inf refers to the area under a plasma concentration versus time curve from the time of dosing extrapolated to infinity.
  • AUC tau refers to the area under a plasma concentration versus time curve for a given dosing interval (tau).
  • AUC last refers to the area under the plasma concentration versus time curve from the time of dosing to the last sampling time. In some embodiments AUC last refers to the area under the plasma concentration versus time curve from the time of dosing to the last sampling time of a particular compound during the interval between any two consecutive doses of a medicament comprising the compound or a salt, solvate, or hydrate thereof, up to the last sampling time.
  • the compound is Compound 1.
  • the medicament is a modified-release dosage form.
  • C refers to the maximum (peak) plasma concentration of a particular compound during the interval between any two consecutive doses of a medicament comprising the compound or a salt, solvate, or hydrate thereof.
  • the compound is Compound 1.
  • the medicament is a modified-release dosage form.
  • C min refers to the minimum (trough) plasma concentration of a particular compound during the interval between any two consecutive doses of a medicament comprising the compound or a salt, solvate, or hydrate thereof.
  • the compound is Compound 1.
  • the medicament is a modified-release dosage form.
  • the term “functional coating” refers to a film coating on a tablet that provides a mechanism to restrict water ingress into the tablet and subsequent diffusion of the API.
  • Non-human mammals include but are not limited to rodents such as mice and rats, etc. rabbits, dogs, cats, swine, cattle, sheep, horses, and non-human primates such as monkeys and apes, etc.
  • immediate-release dosage form refers to a formulation which rapidly disintegrates upon oral administration to a human or other animal releasing an active pharmaceutical ingredient (API) from the formulation.
  • immediate release dosage forms comprising Compound 1 include, but are not limited to, the immediate-release formulation of Example 5 herein.
  • the T80% of the immediate-release dosage form is less than 3 hours. In some embodiments the T80% of the immediate-release dosage form is less than 1 hour. In some embodiments the T80% of the immediate-release dosage form is less than 30 minutes. In some embodiments the T80% of the immediate-release dosage form is less than 10 minutes.
  • An “immediate-release method for weight management” comprises administering to an individual in need thereof an immediate-release dosage form.
  • modified-release dosage form refers to any formulation that, upon oral administration to a human or other animal, releases an API at a slower rate over an extended period of time when compared to an immediate-release dosage-form of the API.
  • a modified-release tablet comprising Compound 1 administered orally to a human or other animal releases Compound 1 more slowly and over a longer period of time than does an immediate-release tablet comprising Compound 1 administered orally to a human or other animal
  • a modified-release suspension comprising Compound 1 administered orally to a human or other animal releases Compound 1 more slowly and over a longer period of time than an immediate-release suspension comprising Compound 1 administered orally to a human or other animal.
  • total plasma exposure refers to the total area under a drug plasma concentration versus time curve over a specified time period
  • composition refers to a composition comprising at least one active ingredient; including but not limited to Compound 1 and pharmaceutically acceptable salts, solvates, and hydrates thereof, whereby the composition is amenable to investigation for a specified, efficacious outcome in a mammal (for example, without limitation, a human).
  • a mammal for example, without limitation, a human
  • Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.
  • rate-controlling membrane refers to an inert membrane barrier through which a drug diffuses at a controlled rate.
  • rate-controlling polymer refers to an excipient which upon administration as a component of a modified-release tablet, becomes hydrated and forms a gel layer on the periphery of the tablet which modulates further water penetration and subsequent drug diffusion and release.
  • T80% refers to the time needed to achieve 80% cumulative release of an API from a particular formulation comprising the API.
  • t max refers to the time to maximum concentration of a particular compound during the interval between any two consecutive doses of a medicament comprising the compound or a salt, solvate, or hydrate thereof.
  • the compound is Compound 1.
  • the medicament is a modified-release dosage form.
  • terapéuticaally effective amount refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician or caregiver or by an individual, which includes one or more of the following:
  • Preventing the disease for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;
  • Inhibiting the disease for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology);
  • Ameliorating the disease for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
  • treatment refers to one or more of the following:
  • prevention of a disease for example, prevention of a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;
  • inhibition of a disease for example, inhibition of a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology);
  • amelioration of a disease for example, amelioration of a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology).
  • Whether an individual is in need of treatment is a judgment made by a caregiver (e.g. nurse practitioner, physician, physician assistant, nurse, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals) that an individual or animal requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of a caregiver's expertise, but that includes the knowledge that the individual or animal is ill, or will become ill, as the result of a disease, condition or disorder that is treatable by Compound 1 and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • a caregiver e.g. nurse practitioner, physician, physician assistant, nurse, etc. in the case of humans; veterinarian in the case of animals, including non-human mammals
  • Compound 1 and pharmaceutically acceptable salts, solvates, and hydrates thereof can be used in a protective or preventive manner; or Compound 1 and pharmaceutically acceptable salts, solvates, and hydrates thereof can be used to alleviate, inhibit or ameliorate a disease, condition or disorder.
  • weight management refers to controlling body weight and in the context of the present invention is directed toward weight loss and the maintenance of weight loss (also called weight maintenance herein).
  • weight management includes controlling parameters related to body weight, for example, BMI, percent body fat and waist circumference.
  • BMI body weight
  • percent body fat and waist circumference For example, weight management for an individual who is overweight or obese can mean losing weight with the goal of keeping weight in a healthier range.
  • weight management for an individual who is overweight or obese can include losing body fat or circumference around the waist with or without the loss of body weight.
  • weight maintenance refers to preventing, reducing or controlling weight gain after weight loss. It is well known that weight gain often occurs after weight loss. Weight loss can occur, for example, from dieting, exercising, illness, drug treatment, surgery or any combination of these methods, but often an individual that has lost weight will regain some or all of the lost weight. Therefore, weight maintenance in an individual who has lost weight can include preventing weight gain after weight loss, reducing the amount of weigh gained after weight loss, controlling weight gain after weight loss or slowing the rate of weight gain after weight loss.
  • modified-release dosage forms including but not limited to extended-release dosage forms
  • Immediate release tablets can be simulated by dosing via oral gavage.
  • Dose comparisons can be made based upon exposure or absolute dose. Studies can be run chronically or sub-chronically with an ultimate endpoint of body weight change.
  • Modified-release dosage forms comprising Compound 1 will decrease the incidence and severity of adverse effects associated with intermittent treatment by reducing the drug peak-to-trough concentration differences, while maintaining the AUC.
  • C max and/or the rate at which drug concentration increases in order to decrease adverse effects it is desirable to reduce C max and/or the rate at which drug concentration increases in order to decrease adverse effects, while maintaining therapeutic effects.
  • a reduction in C max or a reduction in the rate of drug concentration increase in plasma results in a greater corresponding reduction in the brain. This greater reduction is important for decreasing adverse effects linked to brain drug-concentration, for example, headache.
  • CSF cerebrospinal fluid
  • Modified-release dosage forms comprising Compound 1 will decrease the incidence and severity of adverse effects associated with intermittent treatment, by lowering the C max and/or the rate at which drug concentration increases in the plasma and in the brain, while maintaining the AUC.
  • t max it is desirable to increase t max to decrease adverse effects, while maintaining therapeutic effects.
  • a clinical trial was performed to evaluate the safety and pharmacokinetic profile of a single oral dose of Compound 1 (10 mg) administered to healthy male and female subjects aged 18 to 60 years (inclusive) under fed and fasted conditions.
  • Administration of Compound 1 after a high-fat breakfast resulted in a statistically significant delay to the time of maximum plasma concentrations compared to administration in the fasted state.
  • C max was reduced by approximately 10% in the fed compared to fasted state, but a lack of food effect was not proven. There was no food effect on overall exposure to Compound 1.
  • Compound 1 was generally well tolerated when dosed in the fasted state and after a high-fat breakfast.
  • Modified-release dosage forms comprising Compound 1 will decrease the incidence and severity of adverse effects associated with intermittent treatment, by increasing the t max , while maintaining the AUC.
  • One aspect of the present invention pertains to methods for weight management, comprising administering to an individual in need thereof, a modified-release dosage form comprising a therapeutically effective dose of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • One aspect of the present invention pertains to methods for weight management, comprising administering to an individual in need thereof, the modified-release dosage form of the present invention.
  • the method comprises a plurality of administrations of the modified-release dosage form, with a frequency wherein the average interval between any two sequential the administrations is: at least about 24 hours; or about 24 hours.
  • the method comprises a plurality of administrations of the modified-release dosage form, and the modified-release dosage form is administered once-a-day.
  • the plurality of administrations is: at least about 30; at least about 180; at least about 365; or at least about 730.
  • the method is more efficacious than an immediate-release method for weight management; wherein the immediate-release method for weight management comprises administering to an individual in need thereof, at the frequency, the plurality of administrations of an immediate-release dosage form comprising the therapeutically effective amount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the method is more efficacious than an immediate-release method for weight management; wherein the immediate-release method for weight management comprises administering to an individual in need thereof, an immediate-release dosage form comprising (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and wherein the total plasma exposure of the individual to (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine over the course of the immediate-release method is equal to or greater than the total plasma exposure of the individual to (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine over the course of the method.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a C max of: less than about 60 ng/mL; less than about 40 ng/mL; less than about 20 ng/mL; or less than about 10 ng/mL.
  • the C max divided by the therapeutically effective amount is equal to: less than about 1 ⁇ 10 ⁇ 5 mL ⁇ 1 ; less than about 5 ⁇ 10 ⁇ 6 mL ⁇ 1 ; less than about 1 ⁇ 10 ⁇ 6 mL ⁇ 1 ; or less than about 5 ⁇ 10 ⁇ 7 mL ⁇ 1 .
  • the C max occurs: more than 30 minutes after the administering; more than 1 hour after the administering; or more than 2 hours after the administering.
  • the C max occurs: more than 3 hours after the administering; more than 6 hours after the administering; or more than 12 hours after the administering.
  • the average peak to trough ratio of the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual is: less than about 3:1; less than about 2:1; less than about 1.5:1; or less than about 1.1:1.
  • the modified-release dosage form comprises a salt selected from: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride and pharmaceutically acceptable solvates and hydrates thereof.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate, Form III.
  • the modified-release dosage form further comprises (hydroxypropyl)methyl cellulose.
  • the modified-release dosage form further comprises one or more ingredients selected from: microcrystalline cellulose, mannitol, and magnesium stearate.
  • the modified-release dosage form further comprises a film coating.
  • the film coating comprises a water-soluble film coating.
  • the film coating comprises ethyl cellulose.
  • the film coating further comprises (hydroxypropyl)methyl cellulose.
  • the ratio of the ethyl cellulose to the (hydroxypropyl)methyl cellulose is: about 75:25; about 80:20; or about 85:15.
  • the modified-release dosage form comprises a core tablet and a film coating; wherein the core tablet comprises: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate, Form III; mannitol; (hydroxypropyl)methyl cellulose; microcrystalline cellulose; and magnesium sterate; and the film coating comprises a water-soluble film coating.
  • the modified-release dosage form comprises a core tablet and a film coating, wherein the weight to weight ratio of the core tablet to the coating is about 20:1; and wherein the core tablet comprises: about 7% (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate, Form III; about 22.5% mannitol; about 50% (hydroxypropyl)methyl cellulose; about 20% microcrystalline cellulose; and about 0.5% magnesium sterate; and the film coating comprises a water-soluble film coating.
  • the modified-release dosage form comprises a core tablet and a film coating; wherein the core tablet comprises: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate, Form III; mannitol; (hydroxypropyl)methyl cellulose; microcrystalline cellulose; and magnesium sterate; and the film coating comprises: ethyl cellulose; and (hydroxypropyl)methyl cellulose.
  • the modified-release dosage form comprises a core tablet and a film coating, wherein the weight to weight ratio of the core tablet to the coating is about 20:1; and wherein the core tablet comprises: about 7% (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate, Form III; about 22.5% mannitol; about 50% (hydroxypropyl)methyl cellulose; about 20% microcrystalline cellulose; and about 0.5% magnesium sterate; and the film coating comprises: about 85% ethyl cellulose; and about 15% (hydroxypropyl)methyl cellulose; or about 75% ethyl cellulose; and about 25% (hydroxypropyl)methyl cellulose.
  • the modified-release dosage form has a T80% of: at least 3 h; at least 6 h; at least 9 h; or at least 12 h.
  • the modified-release dosage form comprises a salt selected from: a pharmaceutically acceptable salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and pharmaceutically acceptable solvates and hydrates thereof, and wherein the salt has an aqueous solubility of: less than about 200 mg/mL at about room temperature; less than about 100 mg/mL at about room temperature; less than about 50 mg/mL at about room temperature; less than about 25 mg/mL at about room temperature; less than about 10 mg/mL at about room temperature; or less than about 5 mg/mL at about room temperature.
  • a salt selected from: a pharmaceutically acceptable salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and pharmaceutically acceptable solvates and hydrates thereof, and wherein the salt has an aqueous solubility of: less than about 200 mg/mL at about room temperature; less than about 100 mg/mL at
  • the modified-release dosage form comprises a salt selected from: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydroiodide salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine maleate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine fumarate salt; and (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemifumarate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-acetamidobenzoate salt-cocrystal; (R)-8-chloro-1-
  • the method comprises a plurality of administrations of the modified-release dosage form, with a frequency wherein the average interval between any two sequential administrations is at least about 24 hours.
  • the method comprises a plurality of administrations of the modified-release dosage form, with a frequency wherein the average interval between any two sequential administrations is about 24 hours.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a C max of less than about 60 ng/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a C max of less than about 40 ng/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a C max of less than about 20 ng/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a C max of less than about 10 ng/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a C max of about 60 ng/mL to about 5 ng/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a C max of about 60 ng/mL to about 10 ng/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a C max of about 60 ng/mL to about 20 ng/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a C max of about 60 ng/mL to about 40 ng/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a C max of about 40 ng/mL to about 5 ng/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a C max of about 40 ng/mL to about 10 ng/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a C max of about 40 ng/mL to about 20 ng/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a C max of about 20 ng/mL to about 5 ng/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a C max of about 20 ng/mL to about 10 ng/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a C max of about 10 ng/mL to about 5 ng/mL.
  • the C max is an average over a plurality of treated individuals.
  • the C max divided by the therapeutically effective amount is equal to less than about 1 ⁇ 10 ⁇ 5 mL ⁇ 1 .
  • the C max divided by the therapeutically effective amount is equal to less than about 5 ⁇ 10 ⁇ 6 mL ⁇ 1 .
  • the C max divided by the therapeutically effective amount is equal to less than about 1 ⁇ 10 ⁇ 6 mL ⁇ 1 .
  • the C max divided by the therapeutically effective amount is equal to less than about 5 ⁇ 10 ⁇ 7 mL ⁇ 1 .
  • the C max divided by the therapeutically effective amount is equal to between about 1 ⁇ 10 ⁇ 5 mL ⁇ 1 and about 1 ⁇ 10 ⁇ 7 mL ⁇ 1 .
  • the C max divided by the therapeutically effective amount is equal to between about 1 ⁇ 10 ⁇ 5 mL ⁇ 1 and about 5 ⁇ 10 ⁇ 7 mL ⁇ 1 .
  • the C max divided by the therapeutically effective amount is equal to between about 1 ⁇ 10 ⁇ 5 mL ⁇ 1 and about 1 ⁇ 10 ⁇ 6 mL ⁇ 1 .
  • the C max divided by the therapeutically effective amount is equal to between about 1 ⁇ 10 ⁇ 5 mL ⁇ 1 and about 5 ⁇ 10 ⁇ 6 mL ⁇ 1 .
  • the C max divided by the therapeutically effective amount is equal to between about 5 ⁇ 10 ⁇ 6 mL ⁇ 1 and about 1 ⁇ 10 ⁇ 7 mL ⁇ 1 .
  • the C max divided by the therapeutically effective amount is equal to between about 5 ⁇ 10 ⁇ 6 mL ⁇ 1 and about 5 ⁇ 10 ⁇ 7 mL ⁇ 1 .
  • the C max divided by the therapeutically effective amount is equal to between about 5 ⁇ 10 ⁇ 6 mL ⁇ 1 and about 1 ⁇ 10 ⁇ 6 mL ⁇ 1 .
  • the C max divided by the therapeutically effective amount is equal to between about 1 ⁇ 10 ⁇ 6 mL ⁇ 1 and about 1 ⁇ 10 ⁇ 7 mL ⁇ 1 .
  • the C max divided by the therapeutically effective amount is equal to between about 1 ⁇ 10 ⁇ 6 mL ⁇ 1 and about 5 ⁇ 10 ⁇ 7 mL ⁇ 1 .
  • the C max divided by the therapeutically effective amount is equal to between about 5 ⁇ 10 ⁇ 7 mL ⁇ 1 and about 1 ⁇ 10 ⁇ 7 mL ⁇ 1 .
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of at least about 1 ⁇ 10 ⁇ 3 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of at least about 1 ⁇ 10 ⁇ 2 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of at least about 0.1 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of at least about 1 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of at least about 10 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of at least about 100 h ⁇ g/mL.
  • the AUC last is an average over a plurality of treated individuals.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of between about 1 ⁇ 10 ⁇ 3 h ⁇ g/mL and about 200 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of between about 1 ⁇ 10 ⁇ 3 h ⁇ g/mL and about 100 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of between about 1 ⁇ 10 ⁇ 3 h ⁇ g/mL and about 10 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of between about 1 ⁇ 10 ⁇ 3 h ⁇ g/mL and about 1 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of between about 1 ⁇ 10 ⁇ 3 h ⁇ g/mL and about 0.1 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of between about 1 ⁇ 10 ⁇ 3 h ⁇ g/mL and about 1 ⁇ 10 ⁇ 2 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of between about 1 ⁇ 10 ⁇ 2 h ⁇ g/mL and about 200 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of between about 1 ⁇ 10 ⁇ 2 h ⁇ g/mL and about 100 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of between about 1 ⁇ 10 ⁇ 2 h ⁇ g/mL and about 10 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of between about 1 ⁇ 10 ⁇ 2 h ⁇ g/mL and about 1 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of between about 1 ⁇ 10 ⁇ 2 h ⁇ g/mL and about 0.1 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of between about 0.1 h ⁇ g/mL and about 200 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of between about 0.1 h ⁇ g/mL and about 100 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of between about 0.1 h ⁇ g/mL and about 10 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of between about 0.1 h ⁇ g/mL and about 1 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of between about 1 h ⁇ g/mL and about 200 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of between about 1 h ⁇ g/mL and about 100 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of between about 1 h ⁇ g/mL and about 10 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of between about 10 h ⁇ g/mL and about 200 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of between about 10 h ⁇ g/mL and about 100 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of between about 100 h ⁇ g/mL and about 200 h ⁇ g/mL.
  • the AUC last divided by the therapeutically effective amount is equal to at least about 1 ⁇ 10 ⁇ 6 h/mL.
  • the AUC last divided by the therapeutically effective amount is equal to at least about 1 ⁇ 10 ⁇ 5 h/mL.
  • the AUC last divided by the therapeutically effective amount is equal to at least about 1 ⁇ 10 ⁇ 4 h/mL.
  • the AUC last divided by the therapeutically effective amount is equal to at least about 1 ⁇ 10 ⁇ 3 h/mL.
  • the AUC last divided by the therapeutically effective amount is equal to at least about 1 ⁇ 10 ⁇ 2 h/mL.
  • the AUC last divided by the therapeutically effective amount is equal to between about 1 ⁇ 10 ⁇ 6 h/mL and about 0.1 h/mL.
  • the AUC last divided by the therapeutically effective amount is equal to between about 1 ⁇ 10 ⁇ 6 h/mL and about 1 ⁇ 10 ⁇ 2 h/mL.
  • the AUC last divided by the therapeutically effective amount is equal to between about 1 ⁇ 10 ⁇ 6 h/mL and about 1 ⁇ 10 ⁇ 3 h/mL.
  • the AUC last divided by the therapeutically effective amount is equal to between about 1 ⁇ 10 ⁇ 6 h/mL and about 1 ⁇ 10 ⁇ 4 h/mL.
  • the AUC last divided by the therapeutically effective amount is equal to between about 1 ⁇ 10 ⁇ 6 h/mL and about 1 ⁇ 10 ⁇ 5 h/mL.
  • the AUC last divided by the therapeutically effective amount is equal to between about 1 ⁇ 10 ⁇ 5 h/mL and about 0.1 h/mL.
  • the AUC last divided by the therapeutically effective amount is equal to between about 1 ⁇ 10 ⁇ 5 h/mL and about 1 ⁇ 10 ⁇ 2 h/mL.
  • the AUC last divided by the therapeutically effective amount is equal to between about 1 ⁇ 10 ⁇ 5 h/mL and about 1 ⁇ 10 ⁇ 3 h/mL.
  • the AUC last divided by the therapeutically effective amount is equal to between about 1 ⁇ 10 ⁇ 5 h/mL and about 1 ⁇ 10 ⁇ 4 h/mL.
  • the AUC last divided by the therapeutically effective amount is equal to between about 1 ⁇ 10 ⁇ 4 h/mL and about 0.1 h/mL.
  • the AUC last divided by the therapeutically effective amount is equal to between about 1 ⁇ 10 ⁇ 4 h/mL and about 1 ⁇ 10 ⁇ 2 h/mL.
  • the AUC last divided by the therapeutically effective amount is equal to between about 1 ⁇ 10 ⁇ 4 h/mL and about 1 ⁇ 10 ⁇ 3 h/mL.
  • the AUC last divided by the therapeutically effective amount is equal to between about 1 ⁇ 10 ⁇ 3 h/mL and about 0.1 h/mL.
  • the AUC last divided by the therapeutically effective amount is equal to between about 1 ⁇ 10 ⁇ 3 h/mL and about 1 ⁇ 10 ⁇ 2 h/mL.
  • the AUC last divided by the therapeutically effective amount is equal to between about 1 ⁇ 10 ⁇ 2 h/mL and about 0.1 h/mL.
  • the AUC last divided by the C max is equal to at least about 5 h.
  • the AUC last divided by the C max is equal to at least about 10 h.
  • the AUC last divided by the C max is equal to at least about 15 h.
  • the AUC last divided by the C max is equal to at least about 25 h.
  • the AUC last divided by the C max is equal to between about 5 h and about 50 h.
  • the AUC last divided by the C max is equal to between about 5 h and about 25 h.
  • the AUC last divided by the C max is equal to between about 5 h and about 15 h.
  • the AUC last divided by the C max is equal to between about 5 h and about 10 h.
  • the AUC last divided by the C max is equal to between about 10 h and about 50 h.
  • the AUC last divided by the C max is equal to between about 10 h and about 25 h.
  • the AUC last divided by the C max is equal to between about 10 h and about 15 h.
  • the AUC last divided by the C max is equal to between about 15 h and about 50 h.
  • the AUC last divided by the C max is equal to between about 15 h and about 25 h.
  • the AUC last divided by the C max is equal to between about 25 h and about 50 h.
  • the administering results in a C min of at least about 5 ng/mL and a C max of less than about 60.
  • the administering results in a C min of at least about 5 ng/mL and a C max of less than about 40 ng/mL.
  • the administering results in a C min of at least about 5 ng/mL and a C max of less than about 20 ng/mL.
  • the administering results in a C min of at least about 5 ng/mL and a C max of less than about 10 ng/mL.
  • C min and C max are averages over a plurality of treated individuals.
  • the average peak to trough ratio of the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual is less than about 3:1.
  • the average peak to trough ratio of the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual is less than about 2:1.
  • the average peak to trough ratio of the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual is less than about 1.5:1.
  • the average peak to trough ratio of the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual is less than about 1.1:1.
  • the peak to trough ratio of the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine is an average over a plurality of treated individuals.
  • the C max occurs more than 30 minutes after the administering.
  • the C max occurs more than 1 hour after the administering.
  • the C max occurs more than 2 hours after the administering.
  • the C max occurs more than 3 hours after the administering.
  • the C max occurs more than 6 hours after the administering.
  • the C max occurs more than 12 hours after the administering.
  • the C max occurs more than 30 minutes but less than 1 hour after the administering.
  • the C max occurs more than 30 minutes but less than 2 hours after the administering.
  • the C max occurs more than 30 minutes but less than 3 hours after the administering.
  • the C max occurs more than 30 minutes but less than 6 hours after the administering.
  • the C max occurs more than 30 minutes but less than 12 hours after the administering.
  • the C max occurs more than 1 hour but less than 2 hours after the administering.
  • the C max occurs more than 1 hour but less than 3 hours after the administering.
  • the C max occurs more than 1 hour but less than 6 hours after the administering.
  • the C max occurs more than 1 hour but less than 12 hours after the administering.
  • the C max occurs more than 2 hours but less than 3 hours after the administering.
  • the C max occurs more than 2 hours but less than 6 hours after the administering.
  • the C max occurs more than 2 hours but less than 12 hours after the administering.
  • the C max occurs more than 3 hours but less than 6 hours after the administering.
  • the C max occurs more than 3 hours but less than 12 hours after the administering.
  • the C max occurs more than 6 hours but less than 12 hours after the administering.
  • the C max is an average over a plurality of treated individuals.
  • the plurality of administrations is at least about 30.
  • the plurality of administrations is at least about 180.
  • the plurality of administrations is at least about 365.
  • the plurality of administrations is at least about 730.
  • the method is more efficacious than an immediate-release method for weight management; wherein the immediate-release method for weight management comprises administering to an individual in need thereof, at the frequency, the plurality of administrations of an immediate-release dosage form comprising the therapeutically effective dose of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the method is more efficacious than an immediate-release method for weight management; wherein the immediate-release method for weight management comprises administering to an individual in need thereof, an immediate-release dosage form comprising (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and wherein the AUC last of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the immediate-release method is equal to or greater than the AUC last of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the method.
  • the weight management comprises weight loss.
  • the weight management further comprises maintenance of weight loss.
  • the weight management comprises decreased food consumption.
  • the weight management comprises increasing meal-related satiety.
  • the weight management comprises reducing pre-meal hunger.
  • the weight management comprises reducing intra-meal food intake.
  • the weight management further comprises a reduced-calorie diet.
  • the weight management further comprises a program of regular exercise.
  • the weight management further comprises both a reduced-calorie diet and a program of regular exercise.
  • the individual in need of weight management is an obese patient with an initial body mass index ⁇ 30 kg/m 2 .
  • the individual in need of weight management is an overweight patient with an initial body mass index ⁇ 27 kg/m 2 in the presence of at least one weight related comorbid condition.
  • the weight related co-morbid condition is selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
  • the method further comprises administering phentermine to the individual.
  • the individual in need of weight management has an initial body mass index ⁇ 30 kg/m 2 .
  • the individual in need of weight management has an initial body mass index ⁇ 27 kg/m 2 .
  • the individual in need of weight management has an initial body mass index ⁇ 27 kg/m 2 in the presence of at least one weight related comorbid condition.
  • the individual in need of weight management has an initial body mass index ⁇ 27 kg/m 2 in the presence of at least one weight related comorbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
  • the individual in need of weight management has an initial body mass index ⁇ 25 kg/m 2 .
  • the individual in need of weight management has an initial body mass index ⁇ 25 kg/m 2 in the presence of at least one weight related comorbid condition.
  • the individual in need of weight management has an initial body mass index ⁇ 25 kg/m 2 in the presence of at least one weight related comorbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
  • the method for weight management further comprises administering phentermine to the individual.
  • One aspect of the present invention pertains to methods for the treatment of a disorder related to 5-HT 2C receptor activity in an individual, comprising administering to an individual in need thereof, a modified-release dosage form of the present invention.
  • One aspect of the present invention pertains to methods for the treatment of obesity, comprising administering to an individual in need thereof, a modified-release dosage form of the present invention.
  • the method for the treatment of obesity further comprises the administration or prescription of phentermine.
  • the method for the treatment of obesity further comprises gastric electrical stimulation.
  • One aspect of the present invention pertains to methods for inducing weight loss, BMI loss, waist circumference loss or body fat percentage loss, comprising administering to an individual in need thereof, a modified-release dosage form of the present invention.
  • One aspect of the present invention pertains to methods for inducing weight loss, BMI loss, waist circumference loss or body fat percentage loss in an individual in preparation of the individual for bariatric surgery, comprising administering to an individual in need thereof, a modified-release dosage form of the present invention.
  • One aspect of the present invention pertains to methods for maintaining weight loss, BMI loss, waist circumference loss or body fat percentage loss in an individual, comprising administering to an individual in need thereof, a modified-release dosage form of the present invention.
  • One aspect of the present invention pertains to methods for maintaining weight loss, BMI loss, waist circumference loss or body fat percentage loss in an individual following bariatric surgery, comprising administering to an individual in need thereof, a modified-release dosage form of the present invention.
  • One aspect of the present invention pertains to methods for inducing satiety in an individual, comprising administering to an individual in need thereof, a modified-release dosage form of the present invention.
  • One aspect of the present invention pertains to methods for decreasing food intake in an individual, comprising administering to an individual in need thereof, a modified-release dosage form of the present invention.
  • One aspect of the present invention pertains to methods for decreasing hunger in an individual, comprising administering to an individual in need thereof, a modified-release dosage form of the present invention.
  • One aspect of the present invention pertains to methods for decreasing food cravings in an individual, comprising administering to an individual in need thereof, a modified-release dosage form of the present invention.
  • One aspect of the present invention pertains to methods for increasing intermeal interval in an individual, comprising administering to an individual in need thereof, a modified-release dosage form of the present invention.
  • One aspect of the present invention pertains to methods for the treatment of a disorder selected from: schizophrenia, anxiety, depression, psychoses, and alcohol addiction, comprising administering to an individual in need thereof, a modified-release dosage form of the present invention.
  • the disorder is schizophrenia.
  • the disorder is anxiety.
  • the disorder is depression.
  • the disorder is psychoses.
  • the disorder is alcohol addiction.
  • the modified-release dosage form comprises (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride or a pharmaceutically acceptable solvate or hydrate thereof.
  • the modified-release dosage form comprises (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate.
  • the modified-release dosage form comprises (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate, Form III.
  • the modified-release dosage form further comprises an excipient selected from: (hydroxypropyl)methyl cellulose, Kollidon® SR, sodium carboxymethyl cellulose, Carbopol®, wax, and xanthan gum.
  • the modified-release dosage form further comprises (hydroxypropyl)methyl cellulose.
  • the (hydroxypropyl)methyl cellulose comprises Methocel® K4M.
  • the modified-release dosage form further comprises one or more ingredients selected from: microcrystalline cellulose, mannitol, and magnesium stearate.
  • the modified-release dosage form further comprises a film coating.
  • the film coating comprises Opadry® II Blue.
  • the film coating comprises ethyl cellulose, Kollicoat® SR30D, Eudragit®, or cellulose acetate.
  • the film coating comprises ethyl cellulose.
  • the ethyl cellulose comprises Surelease®.
  • the film coating further comprises (hydroxypropyl)methyl cellulose.
  • the (hydroxypropyl)methyl cellulose comprises Opadry®.
  • the ethyl cellulose to the (hydroxypropyl)methyl cellulose is about 75:25.
  • the ethyl cellulose to the (hydroxypropyl)methyl cellulose is about 80:20.
  • the ethyl cellulose to the (hydroxypropyl)methyl cellulose is about 85:15.
  • the modified-release dosage form comprises a core tablet and a coating; wherein the core tablet comprises: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate, Form III; mannitol; (hydroxypropyl)methyl cellulose; microcrystalline cellulose; and magnesium sterate; and the coating comprises Opadry® II Blue.
  • the modified-release dosage form comprises a core tablet and a coating, wherein the weight to weight ratio of the core tablet to the coating is about 20:1; and wherein the core tablet comprises: about 7% (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate, Form III; about 22.5% mannitol; about 50% (hydroxypropyl)methyl cellulose; about 20% microcrystalline cellulose; and about 0.5% magnesium sterate; and the coating comprises Opadry® II Blue.
  • the modified-release dosage form comprises a core tablet and a coating; wherein the core tablet comprises: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate, Form III; mannitol; (hydroxypropyl)methyl cellulose; microcrystalline cellulose; and magnesium sterate; and the coating comprises: ethyl cellulose; and (hydroxypropyl)methyl cellulose.
  • the modified-release dosage form comprises a core tablet and a coating, wherein the weight to weight ratio of the core tablet to the coating is about 20:1; and wherein the core tablet comprises: about 7% (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate, Form III; about 22.5% mannitol; about 50% (hydroxypropyl)methyl cellulose; about 20% microcrystalline cellulose; and about 0.5% magnesium sterate; and the coating comprises: about 85% ethyl cellulose; and about 15% (hydroxypropyl)methyl cellulose.
  • the modified-release dosage form comprises a core tablet and a coating, wherein the weight to weight ratio of the core tablet to the coating is about 20:1; and wherein the core tablet comprises: about 7% (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate, Form III; about 22.5% mannitol; about 50% (hydroxypropyl)methyl cellulose; about 20% microcrystalline cellulose; and about 0.5% magnesium sterate; and the coating comprises: about 75% ethyl cellulose; and about 25% (hydroxypropyl)methyl cellulose.
  • the modified-release dosage form has a T80% of at least 3 h.
  • the modified-release dosage form has a T80% of at least 6 h.
  • the modified-release dosage form has a T80% of at least 9 h.
  • the modified-release dosage form has a T80% of at least 12 h.
  • the modified-release dosage form comprises a salt selected from: a pharmaceutically acceptable salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and pharmaceutically acceptable solvates and hydrates thereof, wherein the salt has an aqueous solubility of less than about 200 mg/mL at about room temperature.
  • the salt has an aqueous solubility of less than about 100 mg/mL at about room temperature.
  • the salt has an aqueous solubility of less than about 50 mg/mL at about room temperature.
  • the salt has an aqueous solubility of less than about 25 mg/mL at about room temperature.
  • the salt has an aqueous solubility of less than about 10 mg/mL at about room temperature.
  • the salt has an aqueous solubility of less than about 5 mg/mL at about room temperature.
  • the salt has an aqueous solubility of less than about 200 mg/mL but more than about 0.0001 mg/mL at about room temperature.
  • the salt has an aqueous solubility of less than about 100 mg/mL but more than about 0.0001 mg/mL at about room temperature.
  • the salt has an aqueous solubility of less than about 50 mg/mL but more than about 0.0001 mg/mL at about room temperature.
  • the salt has an aqueous solubility of less than about 25 mg/mL but more than about 0.0001 mg/mL at about room temperature.
  • the salt has an aqueous solubility of less than about 10 mg/mL but more than about 0.0001 mg/mL at about room temperature.
  • the salt has an aqueous solubility of less than about 5 mg/mL but more than about 0.0001 mg/mL at about room temperature.
  • the salt is selected from: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydroiodide salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine maleate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine fumarate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemifumarate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt
  • the salt is selected from: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydroiodide salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine maleate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine fumarate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemifumarate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine trans-cinnamate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine trans
  • the salt is selected from: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydroiodide salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine maleate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine fumarate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemifumarate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt hydrate; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine oro
  • the salt is selected from: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt hydrate; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine heminapadisilate salt solvate 1; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine heminapadisilate salt solvate 2; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine( ⁇ )-mandelate salt hydrate; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydroiodide salt.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine maleate salt.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine fumarate salt.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemifumarate salt.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt hydrate.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine trans-cinnamate salt.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine heminapadisilate salt.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine heminapadisilate salt solvate 1.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine heminapadisilate salt solvate 2.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine( ⁇ )-mandelate salt hydrate.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemipamoate salt hydrate.
  • Compound 1 has been evaluated in three randomized, double-blind, placebo-controlled trials, one of 2 years duration (“BLOOM” trial) and two of 1 year duration (“BLOSSOM” and “BLOOM-DM” trials).
  • BLOOM 2 years duration
  • BLOSSOM 1 year duration
  • BLOOM-DM placebo-controlled trials
  • the BLOOM-DM study included only patients with type 2 diabetes mellitus; BLOOM and BLOSSOM excluded patients with diabetes.
  • the discontinuation rate due to adverse reaction was 7.1% for non-diabetic patients and 8.6% for patients with type 2 diabetes receiving Compound 1.
  • the most common adverse reactions leading to discontinuation more often among Compound 1 treated patients than placebo were headache (1.3% vs. 0.8%), depression (0.9% vs. 0.5%) and dizziness (0.7% vs. 0.2%).
  • One aspect of the present invention pertains to methods of treatment of the present invention wherein the individual to whom the modified-release dosage form of the present invention is administered experiences at least one adverse event selected from the adverse events shown in Table A and Table B.
  • One aspect of the present invention pertains to methods of treatment of the present invention wherein the individual to whom the salt or a pharmaceutical composition of the present invention is administered experiences at least one adverse event selected from the adverse events shown in Table A and Table B.
  • One aspect of the present invention pertains to the use of salts or pharmaceutical compositions of the present invention in the manufacture of a medicament for weight management in an individual, wherein the individual to whom the salt or a pharmaceutical composition of the present invention is administered experiences at least one adverse event selected from the adverse events shown in Table A and Table B.
  • One aspect of the present invention pertains to modified-release dosage forms, salts, or pharmaceutical composition of the present invention for use in a method of treatment, wherein the individual to whom the modified-release dosage form, salt or pharmaceutical composition of the present invention is administered experiences at least one adverse event selected from the adverse events shown in Table A and Table B.
  • the adverse event is selected from headache, fatigue, nausea, constipation, dry mouth, and dizziness.
  • the adverse event is headache.
  • the adverse event is upper respiratory tract infection.
  • the adverse event is dizziness.
  • the adverse event is nausea.
  • the adverse event is fatigue.
  • the adverse event is urinary tract infection.
  • the adverse event is diarrhea.
  • the adverse event is back pain.
  • the adverse event is constipation.
  • the adverse event is dry mouth.
  • the adverse event is nasopharyngitis.
  • the adverse event is hypoglycemia (including asymptomatic).
  • the adverse event is cough.
  • the adverse event is hypoglycemia, symptomatic.
  • the adverse event is gastroenteritis viral.
  • the adverse event is influenza.
  • the adverse event is procedural pain.
  • the adverse event is hypertension.
  • the present invention is directed, inter alia, to certain solid, stable, and readily isolable salts of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and crystalline forms thereof.
  • the solid state properties of the crystalline forms of the present invention are summarized infra.
  • salts of the present invention In the course of preparing the salts of the present invention, many counterions commonly used in the pharmaceutical industry (see e.g. Berge, et al., Journal of Pharmaceutical Sciences, 66:1-19 (1977)) were investigated. Acetate, DL-lactate, ascorbate, D-gluconate, besylate, napsylate, tosylate, isethionate, dichloroacetate, benzoate, esylate, gentisate, hippurate, lactobionate, xinafoate, and sebacate salts of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine were prepared, but in contrast to the crystalline salts of the present invention, all of these failed to crystallize.
  • One aspect of the present invention pertains to a salt selected from: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydroiodide salt, (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine maleate salt, (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine fumarate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemifumarate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-
  • One aspect of the present invention pertains to a salt selected from: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydroiodide salt, (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine maleate salt, (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine fumarate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemifumarate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine trans-cinnamate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1
  • One aspect of the present invention pertains to a salt selected from: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydroiodide salt, (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine maleate salt, (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine fumarate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemifumarate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt hydrate; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H
  • One aspect of the present invention pertains to (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt hydrate; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine heminapadisilate salt solvate 1; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine heminapadisilate salt solvate 2; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine( ⁇ )-mandelate salt hydrate; (R)-8-chloro-1-methyl-2,3,4,5-te
  • One aspect of the present invention pertains to (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydroiodide salt.
  • One aspect of the present invention pertains to (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine maleate salt.
  • One aspect of the present invention pertains to (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine fumarate salt.
  • One aspect of the present invention pertains to (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemifumarate salt.
  • One aspect of the present invention pertains to (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt.
  • One aspect of the present invention pertains to (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt hydrate.
  • One aspect of the present invention pertains to (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate.
  • One aspect of the present invention pertains to (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine trans-cinnamate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine heminapadisilate salt.
  • One aspect of the present invention pertains to (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine heminapadisilate salt solvate 1.
  • One aspect of the present invention pertains to (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine heminapadisilate salt solvate 2.
  • One aspect of the present invention pertains to (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine( ⁇ )-mandelate salt hydrate.
  • One aspect of the present invention pertains to (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemipamoate salt hydrate.
  • the terms “(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof” and “(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, and pharmaceutically acceptable salts, solvates, and hydrates thereof” as used herein encompass any one of the following salts, or a Markush group comprising any combination of the following salts:
  • the terms “(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof” and “(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, and pharmaceutically acceptable salts, solvates, and hydrates thereof” as used herein encompass any one of the following salts, or a Markush group comprising any combination of the following salts:
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemi-L-malate salt was prepared by the dropwise addition of L-malic acid (0.5 eq.), either in solution in hot MeOH or as a solid, to a solution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in isopropyl acetate. The mixture was heated to ⁇ 60° C. and held at that temperature for ⁇ 1 h. The mixture was then allowed to cool to room temperature and stirred for 1-3 days. The solid product was isolated by vacuum filtration and dried on the filter or in an oven at 40° C. (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemi-L-malate salt had an extrapolated melting onset temperature by DSC of 155-156° C.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-glutamate salt was prepared by addition of L-glutamic acid (0.5-1 eq.) in hot EtOH/H 2 O ( ⁇ 2:1) to a solution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in isopropyl acetate, followed by evaporation of the solvent overnight to produce a solid. The solid was slurried in isopropyl acetate and then isolated by filtration.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-glutamate salt was prepared by addition of a solution of L-glutamic acid (1 eq.) in hot H 2 O to a solution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
  • the product crystallized without the need for evaporation of the solvent.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-glutamate salt had an extrapolated melting onset temperature by DSC of about 187° C.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-aspartate salt was prepared by addition of a solution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in either acetone or acetonitrile to one equivalent of aspartic acid solid. The mixture was heated to 50° C. then slow-cooled and stirred overnight. (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine L-aspartate salt had an extrapolated melting onset temperature by DSC of about 174° C.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemimucate salt was synthesized from (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2 equivalents) and mucic acid (1 equivalent) in THF, acetone or IPA ( ⁇ 10 mg/mL) with 4% water.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemimucate salt had an extrapolated melting onset temperature by DSC of about 208° C.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine glucuronate salt was prepared by addition of a molar equivalent of D-glucuronic acid to a solution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in isopropanol, acetonitrile, ethyl acetate, or acetone at 60° C.
  • D-glucuronic acid dissolved in the corresponding solvent at 60° C., was added dropwise with vigorous stirring. Precipitation occurred immediately and the suspension was allowed to cool and stir overnight. The resulting solid was recovered by filtration and dried in a fume hood overnight.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine glucuronate salt had an extrapolated melting onset temperature by DSC of about 164° C.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine pyroglutamate salt was prepared by combining one equivalent of pyroglutamic acid with (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in ethyl acetate at 60° C. then cooling slowly and stirring overnight. The resulting white solid was isolated by filtration and dried.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine pyroglutamate salt had an extrapolated melting onset temperature by DSC of about 139° C.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-camphorate salt solvate was prepared by combining equal molar amounts of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and (1R,3S)-(+)-camphoric acid in ethyl acetate with 4% water. The solution was heated to 50° C. then slowly cooled. Upon cooling the sample was a clear solution and did not change after addition of MTBE. The sample was evaporated to a clear oil which formed a white solid after standing at room temperature. (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-camphorate salt had an extrapolated melting onset temperature by DSC of about 90° C.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine bisulfate salt was prepared by drop-wise addition of 1 mole equivalent of concentrated sulfuric acid to a solution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine free base in either isopropyl acetate or acetonitrile with vigorous stirring. Precipitation occurred immediately and the suspension was allowed to stir for 1 to 2 days. The resulting solid was recovered by filtration.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine bisulfate salt had an extrapolated melting onset temperature by DSC of about 162° C.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemisulfate salt was prepared by the drop-wise addition of 0.5 mole equivalent of concentrated sulfuric acid to a solution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine free base in either isopropyl acetate or acetonitrile with vigorous stirring. Precipitation occurred immediately and the suspension was allowed to stir for 1 to 2 days. The resulting yellow solid was recovered by filtration. Acetone was added to the solid followed by sufficient water to cause dispersal ( ⁇ 5%).
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine mesylate salt was prepared by the dropwise addition of one equivalent of methanesulfonic acid (99.5%) to a solution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine free base in acetonitrile, or isopropyl acetate with vigorous stirring. Crystallization occurred either immediately or within 24 hours after the solution was heated to ⁇ 60° C. and then allowed to cool to RT while stirring.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine mesylate salt had an extrapolated melting onset temperature by DSC of about 178° C.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine nitrate salt was prepared by dropwise addition of aqueous HNO 3 to a solution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine free base in isopropyl acetate or acetonitrile with vigorous stirring.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine nitrate salt had an extrapolated melting onset temperature by DSC of about 124° C.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine sesqui-oxalate salt-cocrystal was prepared by addition of oxalic acid (0.5 eq.) to a solution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in isopropyl acetate.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine sesqui-oxalate salt-cocrystal had an initial endotherm with an extrapolated onset temperature by DSC of about 105° C. and a second endotherm with an extrapolated melting onset temperature by DSC of about 111° C.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine adipate salt was prepared by addition of adipic acid (0.5-1 eq.) in acetone to a solution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine at ⁇ 62° C. Precipitation occurred within 5 min and the suspension was allowed to cool to ambient temperature with stirring.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine adipate salt had multiple endothermic events by DSC starting at onset temperatures between 104° C. and 107° C.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine malonate salt was prepared by addition of malonic acid (1 eq.) to a solution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in isopropyl acetate.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine malonate salt had an extrapolated melting onset temperature by DSC of about 143° C.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemimalonate salt was prepared by addition of malonic acid (0.5 eq.) to a solution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in isopropyl acetate.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemimalonate salt had an extrapolated melting onset temperature by DSC of 135-136° C.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine glycolate salt was prepared by the addition of one equivalent of glycolic acid to a solution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in ethyl acetate or acetone at 60° C. Glycolic acid, at 60° C., was added dropwise, in the corresponding solvent, with vigorous stirring. Precipitation occurred immediately and the suspension was allowed to cool and stir overnight. The resulting solid was recovered by filtration and air-dried in a fume hood overnight.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine glycolate salt had an extrapolated melting onset temperature by DSC of about 138° C.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemi-edisylate salt was prepared by the dropwise addition of 0.5 equivalents of aqueous 1,2-ethanedisulfonic acid dihydrate ( ⁇ 3.7 M) to a solution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine free base in either acetonitrile or isopropyl acetate with vigorous stirring. Immediate precipitation was observed. The solid obtained was washed with isopropyl alcohol and allowed to dry on the filter.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemi-edisylate salt had an extrapolated melting onset temperature by DSC of about 298° C.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine phosphate salt was prepared by dropwise addition of ortho-phosphoric acid (85%) (0.5-1 mole equivalent) to a solution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine free base in isopropyl acetate or acetonitrile with vigorous stirring. Immediate precipitation was observed in all experiments. Initially amorphous material was slurried in acetone; initially crystalline material was slurried/ripened in n-propanol for 3 days. (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine phosphate salt had an extrapolated melting onset temperature by DSC of about 208° C.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine citrate salt hemihydrate was prepared by dropwise addition of 1 mole equivalent of citric acid in hot MeOH to a solution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in isopropyl acetate. Precipitation occurred spontaneously.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine citrate salt hemihydrate had a dehydration onset temperature by DSC of about 80° C.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemi-oxalate salt was prepared by dropwise addition of 1 mole equivalent of oxalic acid as a solid or as a solution in MeOH ( ⁇ 2.5 M) to a solution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in isopropyl acetate.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemi-oxalate salt had an extrapolated melting onset temperature by DSC of about 212° C.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine succinate salt was prepared by the addition of succinic acid (0.5-1 eq.) in hot EtOH to a solution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in isopropyl acetate. After overnight stirring, a solid was recovered by suction filtration and washed in isopropyl acetate.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine succinate salt had an extrapolated melting onset temperature by DSC of about 179.1° C.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine oxoglutarate salt was prepared by addition of one equivalent of ⁇ -oxo-glutaric acid to a solution of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in ethyl acetate at 60° C.
  • ⁇ -Oxo-glutaric acid in ethyl acetate at 60° C. was added dropwise with vigorous stirring. Precipitation occurred immediately and the suspension was allowed to cool and stir overnight. The resulting solid was recovered by filtration and air-dried in a fume hood overnight.
  • (R)-8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine oxoglutarate salt had an extrapolated melting onset temperature by DSC of about 115° C.
  • One aspect of the present invention pertains to methods for weight management comprising administering to an individual in need thereof, a therapeutically effective amount of a salt of the present invention.
  • One aspect of the present invention pertains to uses of salts or pharmaceutical compositions of the present invention, in the manufacture of a medicament for weight management in an individual.
  • the weight management comprises one or more of: weight loss, and maintenance of weight loss.
  • the weight management comprises one or more of: weight loss, maintenance of weight loss, decreased food consumption, increasing meal-related satiety, reducing pre-meal hunger, and reducing intra-meal food intake.
  • the medicament is used as an adjunct to diet and exercise.
  • the individual in need of weight management is selected from: an obese patient with an initial body mass index ⁇ 30 kg/m 2 ; an overweight patient with an initial body mass index ⁇ 27 kg/m 2 in the presence of at least one weight related comorbid condition; and an overweight patient with an initial body mass index ⁇ 27 kg/m 2 in the presence of at least one weight related comorbid condition; wherein the weight related co-morbid condition is selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
  • the medicament is used in a method of the present invention.
  • the medicament is a modified-release dosage form of the present invention.
  • the medicament is used in combination with a second anti-obesity agent.
  • the second anti-obesity agent is selected from: chlorphentermine, clortermine, phenpentermine, and phentermine, and pharmaceutically acceptable salts, solvates, and hydrates thereof.
  • the medicament is used in combination with an anti-diabetes agent.
  • the medicament is used in combination with metformin.
  • One aspect of the present invention pertains to the use of salts of the present invention in the manufacture of a medicament for weight management in an individual.
  • One aspect of the present invention pertains to salts of the present invention for use in a method of treatment of the human or animal body by therapy.
  • One aspect of the present invention pertains to salts of the present invention for use in a method of weight management.
  • One aspect of the present invention pertains to salts of the present invention for use in a method of weight loss.
  • One aspect of the present invention pertains to salts of the present invention for use in a method of maintenance of weight loss.
  • One aspect of the present invention pertains to salts of the present invention for use in a method of decreasing food consumption
  • One aspect of the present invention pertains to salts of the present invention for use in a method of increasing meal-related satiety.
  • One aspect of the present invention pertains to salts of the present invention for use in a method of reducing pre-meal hunger.
  • One aspect of the present invention pertains to salts of the present invention for use in a method of reducing intra-meal food intake.
  • One aspect of the present invention pertains to salts of the present invention for use in a method of weight management further comprising a reduced-calorie diet.
  • One aspect of the present invention pertains to salts of the present invention for use in a method of weight management further comprising a program of regular exercise.
  • One aspect of the present invention pertains to salts of the present invention for use in a method of weight management further comprising a reduced-calorie diet and a program of regular exercise.
  • One aspect of the present invention pertains to salts of the present invention for use in a method of weight management in an obese patient with an initial body mass index ⁇ 30 kg/m 2 .
  • One aspect of the present invention pertains to salts of the present invention for use in a method of weight management in an overweight patient with an initial body mass index ⁇ 27 kg/m 2 in the presence of at least one weight related co-morbid condition.
  • One aspect of the present invention pertains to salts of the present invention for use in a method of weight management in an overweight patient with an initial body mass index ⁇ 27 kg/m 2 in the presence of at least one weight related co-morbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
  • One aspect of the present invention pertains to salts of the present invention for use in a method of weight management in a patient with an initial body mass index ⁇ 30 kg/m 2 .
  • One aspect of the present invention pertains to salts of the present invention for use in a method of weight management in a patient with an initial body mass index ⁇ 27 kg/m 2 .
  • One aspect of the present invention pertains to salts of the present invention for use in a method of weight management in a patient with an initial body mass index ⁇ 27 kg/m 2 in the presence of at least one weight related co-morbid condition.
  • One aspect of the present invention pertains to salts of the present invention for use in a method of weight management in a patient with an initial body mass index ⁇ 27 kg/m 2 in the presence of at least one weight related co-morbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
  • One aspect of the present invention pertains to salts of the present invention for use in a method of weight management in a patient with an initial body mass index ⁇ 25 kg/m 2 .
  • One aspect of the present invention pertains to salts of the present invention for use in a method of weight management in a patient with an initial body mass index ⁇ 25 kg/m 2 in the presence of at least one weight related co-morbid condition.
  • One aspect of the present invention pertains to salts of the present invention for use in a method of weight management in a patient with an initial body mass index ⁇ 25 kg/m 2 in the presence of at least one weight related co-morbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
  • One aspect of the present invention pertains to salts of the present invention for use in a method of weight management in combination with phentermine.
  • the dosing frequency can be reduced by designing a formulation that reduces the drug-release rate and thereby the rate of input of the drug into systemic circulation in order to produce the desired pharmacokinetic profile.
  • modified-release dosage forms offer the advantages of enhancing therapeutic efficacy, reducing adverse effects, and enabling product differentiation. Therefore, over the past few decades, modified-release technology has been increasingly used in clinical development as an enabling technology for drug-candidate progression. It has been reported that patients' adherence to the prescribed dosing regimen is inversely related to the dosing frequency, especially for the management of chronic diseases (Saini S. D. et al. Effect Of Medication Dosing Frequency On Adherence In Chronic Diseases. Am. J. Managed Care. 2009; 15 (6):e22-e33).
  • modified-release technologies include hydrophilic/hydrophobic matrices; polymer-coated pellets and beads pre-loaded with API; and multilayer tablets. Osmotic pump tablets can achieve much more consistent pump-like release profiles. These may use POLYOXTM (The Dow Chemical Company) in the drug layer and push layer and may be coated with cellulose acetate and PEG.
  • POLYOXTM The Dow Chemical Company
  • Drug release from these technologies is controlled by one or a combination of the following mechanisms: diffusion (through the pores of a barrier coating layer or a viscous gel layer of entangled polymer chains), osmosis, and polymer swelling/erosion.
  • diffusion through the pores of a barrier coating layer or a viscous gel layer of entangled polymer chains
  • osmosis a viscous gel layer of entangled polymer chains
  • polymer swelling/erosion are different with regard to the in vivo performance, release-controlling mechanism, development time and cost, manufacturability, applicability to the inherent biopharmaceutical properties of the API. Selection of modified-release technology for a particular drug will depend on the dose, solubility, pharmacokinetics, desired in vitro release profile, as well as clinical and marketing requirements (e.g., dosage form type, size, number of strengths).
  • Pharmacokinetics simulation can be used in the design and assessment of modified-release formulation development. If the therapeutic dose and human pharmacokinetics parameters are available for the drug molecule of interest, the release profile from modified-release formulation can be projected through simulation, which facilitates the selection of modified-release delivery technology, formulation, and expected release profile.
  • the hydrophilic polymer matrix is especially widely used due to the thorough understanding of its release-control mechanism, robust formulation, conventional manufacturing process, availability of a wide range of polymers, and flexibility to tailor desired release profiles.
  • Commonly used polymers include HPMC, high-molecular weight polyethylene oxides, polyvinylpyrrolidone, and polysaccharides of natural origin such as xanthan gum and locust bean gum.
  • hydrophilic polymer matrix system consists of drug, rate-controlling polymers, and other excipients which are homogenously mixed and compressed into a tablet.
  • the polymer Upon exposure to aqueous medium, the polymer becomes hydrated and forms a gel layer on the periphery of the tablet which modulates further water penetration and subsequent drug diffusion and release. It has been demonstrated that the drug release rate and kinetics are predominantly dependent on the rate of gel formation and erosion, gel layer thickness and strength, the solubility of added excipients, as well as the solubility of the drug to be delivered. (Siepmann J. and Peppas N. A., Modeling Of Drug Release From Delivery Systems Based On Hydroxypropyl Methylcellulose (HPMC). Adv. Drug Deliv. Rev., 2001; 48, 139-157). Drug release from HMPC tablets is controlled by diffusion through the gel layer surrounding the tablet. The gel layer thickness and strength are determined by the viscosity and concentration of HPMC. Increase in HPMC level leads to the formation of a stronger gel layer, thus retarding water ingress and drug diffusion.
  • hydrophilic polymer matrix tablets When exposed to aqueous medium, water penetration into hydrophilic polymer matrix tablets is modulated only by swelling of the hydrophilic polymer. The release of highly soluble APIs may not be adequately controlled by the swelling and diffusion mechanism alone. An additional mechanism may be needed to restrict water ingress into the tablet and subsequent diffusion of the API.
  • Commonly used strategies include compression coating, multilayer tablet, and functional film coating (such as enteric coating, insoluble coating, and pH-dependent polymer coating).
  • Functional film coating offers the advantages of robust formulation and processing, proven in vivo performance in other commercial products (e.g., Wellbutrin XL®).
  • the coating regulates water penetration, core tablet hydration, and API diffusion.
  • Additives such as low-viscosity HPMC can be added to the coating as pore former. The additive dissolves and leaches out of the coating membrane when exposed to aqueous media, thus generating pores in the coating membrane. These pores allow water to penetrate through the coating and be in contact with the core tablet.
  • APIs active pharmaceutical ingredients having more than adequate aqueous solubility throughout the GI-tract pH range
  • dissolution of the API inside a modified-release dosage form will be rapid, per the Noyes-Whitney equation:
  • dW/dt is the dissolution rate (mg/s); D is the diffusion coefficient (cm 2 /s); A is the surface area of the API (cm 2 ); C S is the saturated concentration (or solubility) in the diffusion layer around the API; C is the bulk solvent concentration (mg/mL); and L is the diffusion layer thickness (cm).
  • C S >>C, since drug molecules that diffuse into the GI bulk media are rapidly absorbed. In this case, C can be ignored in the Noyes-Whitney equation and dissolution rate becomes proportional to the solubility of the API.
  • Salt forms with high aqueous solubility may be used in modified-release dosage forms when formulated with a hydrophilic swelling excipient.
  • a polymer coating may also be used to further modify the release of the API from these dosage forms.
  • An immediate-release, film-coated 10-mg tablet was developed for the phase 3 clinical trials and commercialization of Compound 1 (Example 5).
  • a drug substance is considered highly soluble when the highest dose strength is soluble in 250 mL or less of aqueous media over the pH range of 1-7.5.
  • Compound 1, hydrochloride salt hemihydrate, Form III is further classified under the Biopharmaceutics Classification System as “highly permeable”.
  • a drug substance is considered to be highly permeable when the extent of absorption in humans is determined to be 90% or more of an administered dose based on a mass balance determination or in comparison to an intravenous reference dose.
  • C max peak plasma concentration
  • One aspect of the present invention pertains to modified-release dosage forms comprising a therapeutically effective amount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the modified-release dosage form is a tablet.
  • the modified-release dosage form is for use in a method of weight management in an individual.
  • the method comprises a plurality of administrations of the modified-release dosage form, with a frequency wherein the average interval between any two sequential the administrations is: at least about 24 hours; or about 24 hours.
  • the plurality of administrations is: at least about 30; at least about 180; at least about 365; or at least about 730.
  • the method is more efficacious than an immediate-release method for weight management; wherein the immediate-release method for weight management comprises administering to an individual in need thereof, at the frequency, the plurality of administrations of an immediate-release dosage form comprising the therapeutically effective amount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the method is more efficacious than an immediate-release method for weight management; wherein the immediate-release method for weight management comprises administering to an individual in need thereof, an immediate-release dosage form comprising (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and wherein the total plasma exposure of the individual to (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine over the course of the immediate-release method is equal to or greater than the total plasma exposure of the individual to (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine over the course of the method.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a C max of: less than about 60 ng/mL; less than about 40 ng/mL; less than about 20 ng/mL; or less than about 10 ng/mL.
  • the C max divided by the therapeutically effective amount is equal to: less than about 1 ⁇ 10 ⁇ 5 mL ⁇ 1 ; less than about 5 ⁇ 10 ⁇ 6 mL ⁇ 1 ; less than about 1 ⁇ 10 ⁇ 6 mL ⁇ 1 ; or less than about 5 ⁇ 10 ⁇ 7 mL ⁇ 1 .
  • the C max occurs: more than 30 minutes after the administering; more than 1 hour after the administering; or more than 2 hours after the administering.
  • the C max occurs: more than 3 hours after the administering; more than 6 hours after the administering; or more than 12 hours after the administering.
  • the average peak to trough ratio of the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual is: less than about 3:1; less than about 2:1; less than about 1.5:1; or less than about 1.1:1.
  • the modified-release dosage form comprises a salt selected from: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride and pharmaceutically acceptable solvates and hydrates thereof.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate, Form III.
  • the modified-release dosage form further comprises (hydroxypropyl)methyl cellulose.
  • the modified-release dosage form further comprises one or more ingredients selected from: microcrystalline cellulose, mannitol, and magnesium stearate.
  • the modified-release dosage form further comprises a film coating.
  • the film coating comprises a water-soluble film coating.
  • the film coating comprises ethyl cellulose.
  • the film coating further comprises (hydroxypropyl)methyl cellulose.
  • the ratio of the ethyl cellulose to the (hydroxypropyl)methyl cellulose is: about 75:25; about 80:20; or about 85:15.
  • the modified-release dosage form comprises a core tablet and a film coating; wherein the core tablet comprises: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate, Form III; mannitol; (hydroxypropyl)methyl cellulose; microcrystalline cellulose; and magnesium sterate; and the film coating comprises a water-soluble film coating.
  • the modified-release dosage form comprises a core tablet and a film coating, wherein the weight to weight ratio of the core tablet to the coating is about 20:1; and wherein the core tablet comprises: about 7% (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate, Form III; about 22.5% mannitol; about 50% (hydroxypropyl)methyl cellulose; about 20% microcrystalline cellulose; and about 0.5% magnesium sterate; and the film coating comprises a water-soluble film coating.
  • the modified-release dosage form comprises a core tablet and a film coating; wherein the core tablet comprises: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate, Form III; mannitol; (hydroxypropyl)methyl cellulose; microcrystalline cellulose; and magnesium sterate; and the film coating comprises: ethyl cellulose; and (hydroxypropyl)methyl cellulose.
  • the modified-release dosage form comprises a core tablet and a film coating, wherein the weight to weight ratio of the core tablet to the coating is about 20:1; and wherein the core tablet comprises: about 7% (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate, Form III; about 22.5% mannitol; about 50% (hydroxypropyl)methyl cellulose; about 20% microcrystalline cellulose; and about 0.5% magnesium sterate; the film coating comprises: about 85% ethyl cellulose; and about 15% (hydroxypropyl)methyl cellulose; or about 75% ethyl cellulose; and about 25% (hydroxypropyl)methyl cellulose.
  • the modified-release dosage form has a T80% of: at least 3 h; at least 6 h; at least 9 h; or at least 12 h.
  • the modified-release dosage form comprises a salt selected from: a pharmaceutically acceptable salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and pharmaceutically acceptable solvates and hydrates thereof, and wherein the salt has an aqueous solubility of: less than about 200 mg/mL at about room temperature; less than about 100 mg/mL at about room temperature; less than about 50 mg/mL at about room temperature; less than about 25 mg/mL at about room temperature; less than about 10 mg/mL at about room temperature; or less than about 5 mg/mL at about room temperature.
  • a salt selected from: a pharmaceutically acceptable salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and pharmaceutically acceptable solvates and hydrates thereof, and wherein the salt has an aqueous solubility of: less than about 200 mg/mL at about room temperature; less than about 100 mg/mL at
  • the modified-release dosage form comprises a salt selected from: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydroiodide salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine maleate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine fumarate salt; and (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemifumarate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-acetamidobenzoate salt-cocrystal; (R)-8-chloro-1-
  • One aspect of the present invention pertains to modified-release dosage forms comprising a therapeutically effective dose of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • One aspect of the present invention pertains to modified-release dosage forms comprising a therapeutically effective dose of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof, for use in a method of weight management in an individual.
  • One aspect of the present invention pertains to modified-release dosage forms comprising a therapeutically effective amount of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the modified-release dosage form is a tablet.
  • the method comprises a plurality of administrations of the modified-release dosage form, with a frequency wherein the average interval between any two sequential administrations is at least about 24 hours.
  • the method comprises a plurality of administrations of the modified-release dosage form, with a frequency wherein the average interval between any two sequential administrations is about 24 hours.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a C max of less than about 60 ng/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a C max of less than about 40 ng/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a C max of less than about 20 ng/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a C max of less than about 10 ng/mL.
  • the C max divided by the therapeutically effective amount is equal to less than about 1 ⁇ 10 ⁇ 5 mL ⁇ 1 .
  • the C max divided by the therapeutically effective amount is equal to less than about 5 ⁇ 10 ⁇ 6 mL ⁇ 1 .
  • the C max divided by the therapeutically effective amount is equal to less than about 1 ⁇ 10 ⁇ 6 mL ⁇ 1 .
  • the C max divided by the therapeutically effective amount is equal to less than about 5 ⁇ 10 ⁇ 7 mL ⁇ 1 .
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of at least about 1 ⁇ 10 ⁇ 3 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of at least about 1 ⁇ 10 ⁇ 2 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of at least about 0.1 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of at least about 1 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of at least about 10 h ⁇ g/mL.
  • the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual has a AUC last of at least about 100 h ⁇ g/mL.
  • the AUC last is an average over a plurality of treated individuals.
  • the AUC last divided by the therapeutically effective amount is equal to at least about 1 ⁇ 10 ⁇ 6 h/mL.
  • the AUC last divided by the therapeutically effective amount is equal to at least about 1 ⁇ 10 ⁇ 5 h/mL.
  • the AUC last divided by the therapeutically effective amount is equal to at least about 1 ⁇ 10 ⁇ 4 h/mL.
  • the AUC last divided by the therapeutically effective amount is equal to at least about 1 ⁇ 10 ⁇ 3 h/mL.
  • the AUC last divided by the therapeutically effective amount is equal to at least about 1 ⁇ 10 ⁇ 2 h/mL.
  • the AUC last divided by the C max is equal to at least about 5 h.
  • the AUC last divided by the C max is equal to at least about 10 h.
  • the AUC last divided by the C max is equal to at least about 15 h.
  • the AUC last divided by the C max is equal to at least about 25 h.
  • the administering results in a C min of at least about 5 ng/mL and a C max of less than about 60.
  • the administering results in a C min of at least about 5 ng/mL and a C max of less than about 40 ng/mL.
  • the administering results in a C min of at least about 5 ng/mL and a C max of less than about 20 ng/mL.
  • the administering results in a C min of at least about 5 ng/mL and a C max of less than about 10 ng/mL.
  • C min and C max are averages over a plurality of treated individuals.
  • the average peak to trough ratio of the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual is less than about 3:1.
  • the average peak to trough ratio of the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual is less than about 2:1.
  • the average peak to trough ratio of the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual is less than about 1.5:1.
  • the average peak to trough ratio of the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the individual is less than about 1.1:1.
  • the peak to trough ratio of the plasma concentration of the (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine is an average over a plurality of treated individuals.
  • the C max occurs more than 30 minutes after the administering.
  • the C max occurs more than 1 hour after the administering.
  • the C max occurs more than 2 hours after the administering.
  • the C max is an average over a plurality of treated individuals.
  • the plurality of administrations is at least about 30.
  • the plurality of administrations is at least about 180.
  • the plurality of administrations is at least about 365.
  • the plurality of administrations is at least about 730.
  • the method is more efficacious than an immediate-release method for weight management; wherein the immediate-release method for weight management comprises administering to an individual in need thereof, at the frequency, the plurality of administrations of an immediate-release dosage form comprising the therapeutically effective dose of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
  • the method is more efficacious than an immediate-release method for weight management; wherein the immediate-release method for weight management comprises administering to an individual in need thereof, an immediate-release dosage form comprising (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and wherein the AUC last of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the immediate-release method is equal to or greater than the AUC last of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the method.
  • the weight management comprises weight loss.
  • the weight management further comprises maintenance of weight loss.
  • the weight management further comprises decreasing food consumption
  • the weight management further comprises increasing meal-related satiety.
  • the weight management further comprises reducing pre-meal hunger.
  • the weight management further comprises reducing intra-meal food intake.
  • the weight management further comprises a reduced-calorie diet.
  • the weight management further comprises a program of regular exercise.
  • the weight management further comprises both a reduced-calorie diet and a program of regular exercise.
  • the individual in need of weight management is an obese patient with an initial body mass index ⁇ 30 kg/m 2 .
  • the individual in need of weight management is an overweight patient with an initial body mass index ⁇ 27 kg/m 2 in the presence of at least one weight related comorbid condition.
  • the weight related co-morbid condition is selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
  • the individual in need of weight management has an initial body mass index ⁇ 30 kg/m 2 .
  • the individual in need of weight management has an initial body mass index ⁇ 27 kg/m 2 .
  • the individual in need of weight management has an initial body mass index ⁇ 27 kg/m 2 in the presence of at least one weight related comorbid condition.
  • the individual in need of weight management has an initial body mass index ⁇ 27 kg/m 2 in the presence of at least one weight related comorbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
  • the individual in need of weight management has an initial body mass index ⁇ 25 kg/m 2 .
  • the individual in need of weight management has an initial body mass index ⁇ 25 kg/m 2 in the presence of at least one weight related comorbid condition.
  • the individual in need of weight management has an initial body mass index ⁇ 25 kg/m 2 in the presence of at least one weight related comorbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
  • the method for weight management further comprises administering phentermine to the individual.
  • One aspect of the present invention pertains to modified-release dosage forms of the present invention, for use in a method of treatment of a disorder related to 5-HT 2C receptor activity in an individual.
  • One aspect of the present invention pertains to modified-release dosage forms of the present invention, for use in a method of treatment of obesity in an individual.
  • the method for the treatment of obesity further comprises the administration or prescription of phentermine.
  • the method for the treatment of obesity further comprises gastric electrical stimulation.
  • One aspect of the present invention pertains to modified-release dosage forms of the present invention, for use in a method for inducing weight loss, BMI loss, waist circumference loss or body fat percentage loss in an individual.
  • One aspect of the present invention pertains to modified-release dosage forms of the present invention, for use in a method for inducing weight loss, BMI loss, waist circumference loss or body fat percentage loss in an individual in preparation of the individual for bariatric surgery.
  • One aspect of the present invention pertains to modified-release dosage forms of the present invention, for use in a method for maintaining weight loss, BMI loss, waist circumference loss or body fat percentage loss in an individual.
  • One aspect of the present invention pertains to modified-release dosage forms of the present invention, for use in a method for maintaining weight loss, BMI loss, waist circumference loss or body fat percentage loss in an individual following bariatric surgery.
  • One aspect of the present invention pertains to modified-release dosage forms of the present invention, for use in a method for inducing satiety in an individual.
  • One aspect of the present invention pertains to modified-release dosage forms of the present invention, for use in a method for decreasing food intake in an individual.
  • One aspect of the present invention pertains to modified-release dosage forms of the present invention, for use in a method for decreasing hunger in an individual.
  • One aspect of the present invention pertains to modified-release dosage forms of the present invention, for use in a method for decreasing food cravings in an individual.
  • One aspect of the present invention pertains to modified-release dosage forms of the present invention, for use in a method for increasing intermeal interval in an individual.
  • One aspect of the present invention pertains to modified-release dosage forms of the present invention, for use in a method for the treatment of a disorder selected from: schizophrenia, anxiety, depression, psychoses, and alcohol addiction in an individual.
  • the disorder is schizophrenia.
  • the disorder is anxiety.
  • the disorder is depression.
  • the disorder is psychoses.
  • the disorder is alcohol addiction.
  • the modified-release dosage form comprises (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride or a pharmaceutically acceptable solvate or hydrate thereof.
  • the modified-release dosage form comprises (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate.
  • the modified-release dosage form comprises (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate, Form III.
  • the modified-release dosage form further comprises an excipient selected from: (hydroxypropyl)methyl cellulose, Kollidon® SR, sodium carboxymethyl cellulose, Carbopol®, wax, and xanthan gum.
  • the modified-release dosage form further comprises (hydroxypropyl)methyl cellulose.
  • the (hydroxypropyl)methyl cellulose comprises Methocel® K4M.
  • the modified-release dosage form further comprises one or more ingredients selected from: microcrystalline cellulose, mannitol, and magnesium stearate.
  • the modified-release dosage form further comprises a film coating.
  • the film coating comprises Opadry® II Blue.
  • the film coating comprises ethyl cellulose, Kollicoat® SR30D, Eudragit®, or cellulose acetate.
  • the film coating comprises ethyl cellulose.
  • the ethyl cellulose comprises Surelease®.
  • the film coating further comprises (hydroxypropyl)methyl cellulose.
  • the (hydroxypropyl)methyl cellulose comprises Opadry®.
  • the ratio of the ethyl cellulose to the (hydroxypropyl)methyl cellulose is about 75:25.
  • the ratio of the ethyl cellulose to the (hydroxypropyl)methyl cellulose is about 80:20.
  • the ratio of the ethyl cellulose to the (hydroxypropyl)methyl cellulose is about 85:15.
  • the modified-release dosage form comprises a core tablet and a coating; wherein the core tablet comprises: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate, Form III; mannitol; (hydroxypropyl)methyl cellulose; microcrystalline cellulose; and magnesium sterate; and the coating comprises Opadry® II Blue.
  • the modified-release dosage form comprises a core tablet and a coating, wherein the weight to weight ratio of the core tablet to the coating is about 20:1; and wherein the core tablet comprises: about 7% (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate, Form III; about 22.5% mannitol; about 50% (hydroxypropyl)methyl cellulose; about 20% microcrystalline cellulose; and about 0.5% magnesium sterate; and the coating comprises Opadry® II Blue.
  • the modified-release dosage form comprises a core tablet and a coating; wherein the core tablet comprises: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate, Form III; mannitol; (hydroxypropyl)methyl cellulose; microcrystalline cellulose; and magnesium sterate; and the coating comprises: ethyl cellulose; and (hydroxypropyl)methyl cellulose.
  • the modified-release dosage form comprises a core tablet and a coating, wherein the weight to weight ratio of the core tablet to the coating is about 20:1; and wherein the core tablet comprises: about 7% (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate, Form III; about 22.5% mannitol; about 50% (hydroxypropyl)methyl cellulose; about 20% microcrystalline cellulose; and about 0.5% magnesium sterate; and the coating comprises: about 85% ethyl cellulose; and about 15% (hydroxypropyl)methyl cellulose.
  • the modified-release dosage form comprises a core tablet and a coating, wherein the weight to weight ratio of the core tablet to the coating is about 20:1; and wherein the core tablet comprises: about 7% (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate, Form III; about 22.5% mannitol; about 50% (hydroxypropyl)methyl cellulose; about 20% microcrystalline cellulose; and about 0.5% magnesium sterate; and the coating comprises: about 75% ethyl cellulose; and about 25% (hydroxypropyl)methyl cellulose.
  • the modified-release dosage form has a T80% of at least 3 h.
  • the modified-release dosage form has a T80% of at least 6 h.
  • the modified-release dosage form has a T80% of at least 9 h.
  • the modified-release dosage form has a T80% of at least 12 h.
  • the modified-release dosage form comprises a salt selected from: a pharmaceutically acceptable salt of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and pharmaceutically acceptable solvates and hydrates thereof, and wherein the salt has an aqueous solubility of less than about 200 mg/mL at about room temperature.
  • the salt has an aqueous solubility of less than about 100 mg/mL at about room temperature.
  • the salt has an aqueous solubility of less than about 50 mg/mL at about room temperature.
  • the salt has an aqueous solubility of less than about 25 mg/mL at about room temperature.
  • the salt has an aqueous solubility of less than about 10 mg/mL at about room temperature.
  • the salt has an aqueous solubility of less than about 5 mg/mL at about room temperature.
  • the salt is selected from: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydroiodide salt, (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine maleate salt, (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine fumarate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemifumarate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt
  • the salt is selected from: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydroiodide salt, (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine maleate salt, (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine fumarate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemifumarate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine trans-cinnamate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine trans
  • the salt is selected from: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydroiodide salt, (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine maleate salt, (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine fumarate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemifumarate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt hydrate; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine oro
  • the salt is selected from: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt hydrate; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine heminapadisilate salt solvate 1; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine heminapadisilate salt solvate 2; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine( ⁇ )-mandelate salt hydrate; (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydroiodide salt.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine maleate salt.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine fumarate salt.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemifumarate salt.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt hydrate.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt hydrate.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine trans-cinnamate salt.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine heminapadisilate salt.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine heminapadisilate salt solvate 1.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine heminapadisilate salt solvate 2.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine( ⁇ )-mandelate salt hydrate.
  • the salt is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemipamoate salt hydrate.
  • the modified-release dosage form further comprises one or more pharmaceutically acceptable excipients.
  • the modified-release dosage form is for oral administration to an individual.
  • the modified-release dosage form is selected from the group consisting of: tablets, capsules, pills, cachets, and lozenges.
  • the modified-release dosage form is a tablet.
  • the modified-release dosage form is for administration in combination with phentermine.
  • One aspect of the present invention pertains to methods of manufacturing a modified-release dosage form comprising: providing a compound selected from: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, and pharmaceutically acceptable salts, solvates, and hydrates thereof; and formulating the compound into a modified-release dosage form.
  • the method of manufacturing a modified-release dosage form of the present invention comprises, for example, one or more of the following: dispersing a compound selected from: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, and pharmaceutically acceptable solvates and hydrates thereof, in a rate-controlling polymer matrix; coating a tablet comprising a compound selected from: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, and pharmaceutically acceptable solvates and hydrates thereof, with a functional coating; alternating layers comprising a compound selected from: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, and pharmaceutically acceptable solvates and hydrates thereof, with layers of functional coating; loading a bead with a compound selected from: (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H
  • modified-release dosage forms of the present invention can be further limited by any of the specific formulation characteristics anywhere in this application.
  • Drug release from a swellable hydrophilic matrix is a complex phenomenon involving a number of physical processes, such as water or biological fluid penetration into the matrix, polymer chain relaxation and disentanglement, matrix geometry variation, and polymer gel dissolution/erosion (Hopfenberg H B, Hsu K C Swelling - controlled, constant rate delivery systems Polym. Eng. Sci. 1978; 18 (15):1186-1191; Lee P I Diffusional release of a solute from a polymeric matrix—approximate analytical solutions J. Membrane Sci. 1980; 7 (3):255-275; Lee P I, Peppas N A Prediction of polymer dissolution in swellable controlled - release systems J. Control. Release.
  • the gel layer grows with time as water permeates continuously into the core of the matrix, thereby increasing the thickness of the gel layer and providing a diffusion barrier to drug release.
  • concentration gradient-driven diffusion and polymer relaxation are the most important rate-limiting steps in regulating drug release, although the presence of drugs and additional excipients may enhance or suppress the swelling osmotic pressure at the swelling front and thus modify the mechanical integrity of polymer gel depending on the solubility of the additives.
  • diffusion and polymer relaxation compete in controlling drug release, leading to the usually observed non-Fickian release kinetics.
  • Equation 1 is one of the most widely used equations in modeling drug release from a swellable hydrophilic matrix:
  • M t is the amount of drug released at time t
  • M ⁇ is the total drug loading
  • M t /M ⁇ is the fraction of drug released at time t
  • Equation 1 k is a constant incorporating the structural and geometric characteristic of a matrix system, and n is an exponent that characterizes the release mechanism. Generally, this equation is only applicable for M t /M ⁇ ⁇ 80%.
  • Polymorphism is the ability of a substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice.
  • Polymorphs show the same properties in the liquid or gaseous state but they may behave differently in the solid state.
  • drugs can also exist as salts and other multicomponent crystalline phases.
  • solvates and hydrates may contain an active pharmaceutical ingredient (API) host and either solvent or water molecules, respectively, as guests.
  • API active pharmaceutical ingredient
  • the guest compound is a solid at room temperature, the resulting form is often called a cocrystal.
  • Salts, solvates, hydrates, and cocrystals may show polymorphism as well. Crystalline phases that share the same API host, but differ with respect to their guests, may be referred to as pseudopolymorphs of one another.
  • Solvates contain molecules of the solvent of crystallization in a definite crystal lattice. Solvates, in which the solvent of crystallization is water, are termed hydrates. Because water is a constituent of the atmosphere, hydrates of drugs may be formed rather easily. Recently, polymorph screens of 245 compounds revealed that about 90% of them exhibited multiple solid forms. Overall, approximately half the compounds were polymorphic, often having one to three forms. About one-third of the compounds formed hydrates, and about one-third formed solvates. Data from cocrystal screens of 64 compounds showed that 60% formed cocrystals other than hydrates or solvates. (G. P. Stahly, Crystal Growth & Design (2007), 7(6), 1007-1026.)
  • the present invention is directed, inter alia, to crystalline forms of salts of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and hydrates and solvates thereof.
  • the crystalline forms of the present invention can be identified by unique solid state signatures with respect to, for example, differential scanning calorimetry (DSC), X-ray powder diffraction (PXRD), and other solid state methods. Further characterization with respect to water or solvent content of the crystalline forms of the present invention can be gauged by any of the following methods for example, thermogravimetric analysis (TGA), DSC and the like.
  • the temperatures observed will depend upon sample purity, the rate of temperature change, as well as sample preparation technique and the particular instrument employed.
  • the values reported herein relating to DSC thermograms can vary by about ⁇ 6° C.
  • the values reported herein relating to DSC thermograms can also vary by about ⁇ 20 joules per gram.
  • the relative intensities of the peaks can vary, depending upon the sample preparation technique, the sample mounting procedure and the particular instrument employed. Moreover, instrument variation and other factors can often affect the 2 ⁇ values. Therefore, the peak assignments of diffraction patterns can vary by about ⁇ 0.2° 2 ⁇ .
  • the relative intensities of the reported peaks can also vary.
  • TGA the features reported herein can vary by about ⁇ 5° C.
  • the TGA features reported herein can also vary by about ⁇ 2% weight change due to, for example, sample variation. Further characterization with respect to hygroscopicity of the crystalline form can be gauged by, for example, dynamic moisture sorption (DMS).
  • the DMS features reported herein can vary by about ⁇ 5% relative humidity.
  • the DMS features reported herein can also vary by about ⁇ 5% weight change.
  • the deliquescence relative humidity (DRH) measurements by water activity meter are sensitive to sample quality and quantity.
  • the DRH measurements reported herein can vary by about ⁇ 5% RH.
  • FIG. 1 Peaks at 13.7° , 14.9° , 15.4° , 15.8° , 16.7° , 18.9 °2 ⁇ DSC
  • FIG. 2 95° C. (dehydration); 200° C. (melt)
  • FIG. 3 3.7% water loss DMS
  • FIG. 4 non-hygroscopic
  • Compound 1 hydrochloride salt hemihydrate, Form III displays a dehydration feature calculated as a 3.7% weight loss which is consistent with the theoretical weight loss of 3.7% for a hemihydrate. Analysis by DSC further confirms the TGA results, where Compound 1 hydrochloride salt hemihydrate, Form III shows a dehydration event at about 95° C. and a melting/decomposition endotherm at about 200-201° C.
  • DMS data shows that Compound 1 hydrochloride salt hemihydrate, Form III is substantially non-hygroscopic, adsorbing less than 0.5 wt % water out to and including the 90% RH hold at 25° C. and the XRPD pattern showed no change in crystalline form after the DMS cycle.
  • Form III of Compound 1 hydrochloride salt hemihydrate can be prepared as described in Example 4.
  • One aspect of the present invention pertains to a crystalline form of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydroiodide salt (Compound 1 hydroiodide salt).
  • the crystalline form of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydroiodide salt is Form I (Compound 1 hydroiodide salt, Form I).
  • Table 3 The physical properties of Form I of Compound 1 hydroiodide salt are summarized in Table 3 below.
  • FIG. 5 Peaks of ⁇ 30% relative intensity at 13.32, 15.35, 17.19, 18.46, 19.62, 23.07, 23.73, 26.70, 28.91, 29.37, 29.70, and 29.87 °2 ⁇ TGA
  • FIG. 6 anhydrous with significant weight loss after melting DSC
  • FIG. 6 extrapolated onset temperature about 121° C.
  • FIG. 7 non-hygroscopic
  • the TGA showed Compound 1 hydroiodide salt to be anhydrous, which was confirmed by Karl Fischer analysis. Melting onset by DSC was 121° C.; melting was accompanied by the beginning of large weight loss (>30%) out to about 200° C.
  • One aspect of the present invention is directed to a crystalline form of Compound 1 hydroiodide salt having an X-ray powder diffraction pattern comprising a peak, in terms of 2 ⁇ , at about 23.73°.
  • the crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2 ⁇ , at about 19.62°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 23.73° and about 19.62°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 23.73° and about 18.46°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 23.73 ⁇ , about 19.62° and about 18.46°. In some embodiments, the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 23.73°, about 19.62°, about 18.46°, about 17.19°, about 26.70°, about 28.91°, and about 23.07°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 23.73°, about 19.62°, about 18.46°, about 17.19°, about 26.70°, about 28.910, about 23.07°, about 13.32°, about 29.87°, and about 29.37°.
  • One aspect of the present invention is directed to a crystalline form of Compound 1 hydroiodide salt having an X-ray powder diffraction pattern comprising one or more peaks listed in Table 4.
  • the crystalline form has an X-ray powder diffraction pattern substantially as shown in FIG. 5 , wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2° 2 ⁇ , and also that the relative intensities of the reported peaks can vary.
  • the crystalline form of Compound 1 hydroiodide salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 105° C. and about 135° C. In some embodiments, the crystalline form of Compound 1 hydroiodide salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 121° C. In some embodiments, the crystalline form of Compound 1 hydroiodide salt has a differential scanning calorimetry thermogram comprising an endotherm with an associated heat flow of about 88 joules per gram.
  • the crystalline form of Compound 1 hydroiodide salt has a thermogravimetric analysis profile substantially as shown in FIG. 6 , wherein by “substantially” is meant that the reported TGA features can vary by about ⁇ 5° C. and by about ⁇ 2% weight change.
  • the crystalline form of Compound 1 hydroiodide salt has a differential scanning calorimetry thermogram substantially as shown in FIG. 6 , wherein by “substantially” is meant that the reported DSC features can vary by about ⁇ 6° C. and by about ⁇ 20 joules per gram.
  • the crystalline form of Compound 1 hydroiodide salt has a dynamic moisture sorption profile substantially as shown in FIG. 7 , wherein by “substantially” is meant that the reported DMS features can vary by about ⁇ 5% relative humidity and by about ⁇ 5% weight change.
  • Form I of Compound 1 hydroiodide salt can be prepared by any of the suitable procedures known in the art for preparing crystalline polymorphs. In some embodiments Form I of Compound 1 hydroiodide salt can be prepared as described in Example 3.1. In some embodiments, Form I of Compound 1 hydroiodide salt can be prepared by slurrying crystalline Compound 1 hydroiodide salt containing one or more crystalline forms other than Form I. In some embodiments, the crystalline form of Compound 1 hydroiodide salt can be prepared by recrystallizing crystalline Compound 1 hydroiodide salt containing one or more crystalline forms other than Form I.
  • One aspect of the present invention pertains to a crystalline form of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine maleate salt (Compound 1 maleate salt).
  • the crystalline form of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine maleate salt is Form I (Compound 1 maleate salt, Form I).
  • the physical properties of Form I of Compound 1 maleate salt are summarized in Table 5 below.
  • FIG. 8 Peaks of ⁇ 6% relative intensity at 11.93, 15.07, 16.23, 17.95, 19.32, 22.04, 23.88, 24.46, 26.31, 26.58, 27.07, and 28.29 °2 ⁇ TGA
  • FIG. 9 ⁇ 0.2% weight loss up to about 150° C.
  • DSC FIG. 9: extrapolated onset temperature about 166° C.; enthalpy of fusion 81 J/g DMS
  • FIG. 10 0.15% weight gain at 90% RH
  • Form I of Compound 1 maleate salt had a melting onset temperature about 166° C.
  • the TGA was consistent with an anhydrous salt. It was not hygroscopic, picking up just 0.15% weight out to and including the 90% RH hold at 25° C.
  • One aspect of the present invention is directed to a crystalline form of Compound 1 maleate salt having an X-ray powder diffraction pattern comprising a peak, in terms of 2 ⁇ , at about 11.93°.
  • the crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2 ⁇ , at about 23.88°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 11.93° and about 23.88°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 11.93° and about 26.31°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 11.93°, about 23.88°, and about 26.31°. In some embodiments, the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 11.93°, about 23.88°, about 26.31°, about 24.46°, about 19.32°, about 15.07°, and about 16.23°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 11.93°, about 23.88°, about 26.31°, about 24.46°, about 19.32°, about 15.07°, about 16.23°, about 26.58°, about 22.04°, and about 17.95°.
  • One aspect of the present invention is directed to a crystalline form of Compound 1 maleate salt having an X-ray powder diffraction pattern comprising one or more peaks listed in Table 6.
  • the crystalline form has an X-ray powder diffraction pattern substantially as shown in FIG. 8 , wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2° 2 ⁇ , and also that the relative intensities of the reported peaks can vary.
  • the crystalline form of Compound 1 maleate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 150° C. and about 180° C. In some embodiments, the crystalline form of Compound 1 maleate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 166° C. In some embodiments, the crystalline form of Compound 1 maleate salt has a differential scanning calorimetry thermogram comprising an endotherm with an associated heat flow of about 81 joules per gram. In some embodiments, the crystalline form of Compound 1 maleate salt has a thermogravimetric analysis profile substantially as shown in FIG. 9 , wherein by “substantially” is meant that the reported TGA features can vary by about ⁇ 5° C. and by about ⁇ 2% weight change.
  • the crystalline form of Compound 1 maleate salt has a differential scanning calorimetry thermogram substantially as shown in FIG. 9 , wherein by “substantially” is meant that the reported DSC features can vary by about ⁇ 6° C. and by about ⁇ 20 joules per gram.
  • the crystalline form of Compound 1 maleate salt has a dynamic moisture sorption profile substantially as shown in FIG. 10 , wherein by “substantially” is meant that the reported DMS features can vary by about ⁇ 5% relative humidity and by about ⁇ 5% weight change.
  • Form I of Compound 1 maleate salt can be prepared by any of the suitable procedures known in the art for preparing crystalline polymorphs. In some embodiments Form I of Compound 1 maleate salt can be prepared as described in Example 3.2. In some embodiments, Form I of Compound 1 maleate salt can be prepared by slurrying crystalline Compound 1 maleate salt containing one or more crystalline forms other than Form I. In some embodiments, the crystalline form of Compound 1 maleate salt can be prepared by recrystallizing crystalline Compound 1 maleate salt containing one or more crystalline forms other than Form I.
  • One aspect of the present invention pertains to a crystalline form of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine fumarate salt (Compound 1 fumarate salt).
  • the crystalline form of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine fumarate salt is Form I (Compound 1 fumarate salt, Form I).
  • the physical properties of Form I of Compound 1 fumarate salt are summarized in Table 7 below.
  • FIG. 11 Peaks of ⁇ 10% relative intensity at 11.59, 13.08, 17.11, 17.99, 18.36, 19.82, 23.21, 23.67, 25.40, 25.50, 25.89, 26.98, 27.36, and 28.78 °2 ⁇ TGA
  • FIG. 12 No significant weight loss up to about 150° C.; 16.85% weight between about 147° C. and about 210° C., prior to the melt onset
  • FIG. 12 extrapolated onset temperature about 219° C.
  • DMS FIG. 13 non-hygroscopic up to 90% RH
  • Compound 1 fumarate salt, Form I showed a very high melting onset of 218-219° C. depending on the sample analyzed. TGA showed the salt to be anhydrous, with significant weight loss prior to the melting onset, likely due to vaporization of the salt of components thereof.
  • Compound 1 fumarate salt, Form I was non-hygroscopic by DMS analysis out to and including the 90% RH hold at 25° C. and the DRH by water activity meter was 99% RH at 25° C.
  • One aspect of the present invention is directed to a crystalline form of Compound 1 fumarate salt having an X-ray powder diffraction pattern comprising a peak, in terms of 2 ⁇ , at about 13.08°.
  • the crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2 ⁇ , at about 17.99°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 13.08° and about 17.99°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 13.08° and about 19.82°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 13.08°, about 17.99°, and about 19.82°. In some embodiments, the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 13.08°, about 17.99°, about 19.82°, about 26.98°, about 25.89°, about 25.50°, and about 18.36°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 13.08°, about 17.99°, about 19.82°, about 26.98°, about 25.89°, about 25.50°, about 18.36°, about 17.11°, about 27.36°, and about 23.21°.
  • One aspect of the present invention is directed to a crystalline form of Compound 1 fumarate salt having an X-ray powder diffraction pattern comprising one or more peaks listed in Table 8.
  • the crystalline form has an X-ray powder diffraction pattern substantially as shown in FIG. 11 , wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2° 2 ⁇ , and also that the relative intensities of the reported peaks can vary.
  • the crystalline form of Compound 1 fumarate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 205° C. and about 235° C. In some embodiments, the crystalline form of Compound 1 fumarate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 219° C. In some embodiments, the crystalline form of Compound 1 fumarate salt has a thermogravimetric analysis profile substantially as shown in FIG. 12 , wherein by “substantially” is meant that the reported TGA features can vary by about ⁇ 5° C. and by about ⁇ 2% weight change.
  • the crystalline form of Compound 1 fumarate salt has a differential scanning calorimetry thermogram substantially as shown in FIG. 12 , wherein by “substantially” is meant that the reported DSC features can vary by about ⁇ 6° C. and by about ⁇ 20 joules per gram.
  • the crystalline form of Compound 1 fumarate salt has a dynamic moisture sorption profile substantially as shown in FIG. 13 , wherein by “substantially” is meant that the reported DMS features can vary by about ⁇ 5% relative humidity and by about ⁇ 5% weight change.
  • Form I of Compound 1 fumarate salt can be prepared by any of the suitable procedures known in the art for preparing crystalline polymorphs. In some embodiments Form I of Compound 1 fumarate salt can be prepared as described in Example 3.3. In some embodiments, Form I of Compound 1 fumarate salt can be prepared by slurrying crystalline Compound 1 fumarate salt containing one or more crystalline forms other than Form I. In some embodiments, the crystalline form of Compound 1 fumarate salt can be prepared by recrystallizing crystalline Compound 1 fumarate salt containing one or more crystalline forms other than Form I.
  • One aspect of the present invention pertains to a crystalline form of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemifumarate salt (Compound 1 hemifumarate salt).
  • the crystalline form of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemifumarate salt is Form I (Compound 1 hemifumarate salt, Form I).
  • Table 9 The physical properties of Form I of Compound 1 hemifumarate salt are summarized in Table 9 below.
  • FIG. 14 Peaks of ⁇ 10% relative intensity at 11.21, 13.12, 14.41, 14.60, 18.00, 19.85, 20.54, 21.47, 22.15, 23.24, 25.34, 25.57, 25.98, and 27.60 °2 ⁇ , TGA FIG. 15: about 27% weight loss up to about 160° C.
  • DSC FIG. 15 extrapolated onset temperature about 158° C.; enthalpy of fusion 51 J/g DMS
  • FIG. 16 ⁇ 8% weight gain at about 50% RH
  • Compound 1 hemifumarate salt, Form I had a melting onset of 158° C. by DSC, however, significant weight loss occurred prior to this melting onset based on TGA data. The weight loss was slightly more than the theoretical amount of fumaric acid for an anhydrous hemifumarate salt (27.0% vs. 22.9%).
  • One aspect of the present invention is directed to a crystalline form of Compound 1 hemifumarate salt having an X-ray powder diffraction pattern comprising a peak, in terms of 2 ⁇ , at about 20.54°.
  • the crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2 ⁇ , at about 11.21°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 20.54° and about 11.21°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 20.54° and about 18.00°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 20.54°, about 11.21°, and about 18.00°. In some embodiments, the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 20.54°, about 11.21°, about 18.00°, about 25.98°, about 22.15°, about 14.41°, and about 14.60°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 20.54°, about 11.21°, about 18.00°, about 25.98°, about 22.15°, about 14.41°, about 14.60°, about 25.57°, about 13.12°, and about 19.85°.
  • One aspect of the present invention is directed to a crystalline form of Compound 1 hemifumarate salt having an X-ray powder diffraction pattern comprising one or more peaks listed in Table 10.
  • the crystalline form has an X-ray powder diffraction pattern substantially as shown in FIG. 14 , wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2° 2 ⁇ , and also that the relative intensities of the reported peaks can vary.
  • the crystalline form of Compound 1 hemifumarate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 140° C. and about 170° C. In some embodiments, the crystalline form of Compound 1 hemifumarate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 158° C. In some embodiments, the crystalline form of Compound 1 hemifumarate salt has a differential scanning calorimetry thermogram comprising an endotherm with an associated heat flow of about 51 joules per gram.
  • the crystalline form of Compound 1 hemifumarate salt has a thermogravimetric analysis profile substantially as shown in FIG. 15 , wherein by “substantially” is meant that the reported TGA features can vary by about ⁇ 5° C. and by about ⁇ 2% weight change.
  • the crystalline form of Compound 1 hemifumarate salt has a differential scanning calorimetry thermogram substantially as shown in FIG. 15 , wherein by “substantially” is meant that the reported DSC features can vary by about ⁇ 6° C. and by about ⁇ 20 joules per gram.
  • the crystalline form of Compound 1 hemifumarate salt has a dynamic moisture sorption profile substantially as shown in FIG. 16 , wherein by “substantially” is meant that the reported DMS features can vary by about ⁇ 5% relative humidity and by about ⁇ 5% weight change.
  • Form I of Compound 1 hemifumarate salt can be prepared by any of the suitable procedures known in the art for preparing crystalline polymorphs. In some embodiments Form I of Compound 1 hemifumarate salt can be prepared as described in Example 3.4. In some embodiments, Form I of Compound 1 hemifumarate salt can be prepared by slurrying crystalline Compound 1 hemifumarate salt containing one or more crystalline forms other than Form I. In some embodiments, the crystalline form of Compound 1 hemifumarate salt can be prepared by recrystallizing crystalline Compound 1 hemifumarate salt containing one or more crystalline forms other than Form I.
  • One aspect of the present invention pertains to a crystalline form of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt (Compound 1 orotate salt).
  • the crystalline form of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt is Form I (Compound 1 orotate salt, Form I).
  • the physical properties of Form I of Compound 1 orotate salt are summarized in Table 11 below.
  • FIG. 17 Peaks of ⁇ 20% relative intensity at 6.30, 12.44, 14.59, 14.86, 16.96, 19.62, 19.71, 24.07, 24.55, 25.02, 26.64, and 28.64 °2 ⁇ TGA
  • FIG. 18 no significant weight loss up to about 200° C.
  • DSC FIG. 18 extrapolated onset temperature for initial endotherm about 236° C., followed by multiple thermal events
  • DMS FIG. 19 ⁇ 0.15% weight gain at about 90% RH
  • Compound 1 orotate salt, Form I was an anhydrous salt by TGA.
  • the initial melting onset by DSC was 236° C.
  • the initial endotherm was small and followed immediately by a small exotherm which was followed immediately by larger endothermic events. Based on TGA results, there was significant weight loss occurring throughout these thermal events, indicating that the salt melted with decomposition.
  • Compound 1 orotate salt was non-hygroscopic by DMS analysis, picking up about 0.15% out to and including the 90% RH hold at 25° C.
  • One aspect of the present invention is directed to a crystalline form of Compound 1 orotate salt having an X-ray powder diffraction pattern comprising a peak, in terms of 2 ⁇ , at about 24.07°.
  • the crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2 ⁇ , at about 6.30°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 24.07° and about 6.30°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 24.07° and about 19.71°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 24.07°, about 6.30°, and about 19.71°. In some embodiments, the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 24.07°, about 6.30°, about 19.71°, about 19.62°, about 12.44°, about 28.64°, and about 16.96°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 24.07°, about 6.30°, about 19.71°, about 19.62, about 12.44°, about 28.64°, about 16.96°, about 25.02°, about 24.55°, and about 14.86°.
  • One aspect of the present invention is directed to a crystalline form of Compound 1 orotate salt having an X-ray powder diffraction pattern comprising one or more peaks listed in Table 12.
  • the crystalline form has an X-ray powder diffraction pattern substantially as shown in FIG. 17 , wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2° 2 ⁇ , and also that the relative intensities of the reported peaks can vary.
  • the crystalline form of Compound 1 orotate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 220° C. and about 250° C. In some embodiments, the crystalline form of Compound 1 orotate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 236° C. In some embodiments, the crystalline form of Compound 1 orotate salt has a thermogravimetric analysis profile substantially as shown in FIG. 18 , wherein by “substantially” is meant that the reported TGA features can vary by about ⁇ 5° C. and by about ⁇ 2% weight change.
  • the crystalline form of Compound 1 orotate salt has a differential scanning calorimetry thermogram substantially as shown in FIG. 18 , wherein by “substantially” is meant that the reported DSC features can vary by about ⁇ 6° C. and by about ⁇ 20 joules per gram.
  • the crystalline form of Compound 1 orotate salt has a dynamic moisture sorption profile substantially as shown in FIG. 19 , wherein by “substantially” is meant that the reported DMS features can vary by about ⁇ 5% relative humidity and by about ⁇ 5% weight change.
  • Form I of Compound 1 orotate salt can be prepared by any of the suitable procedures known in the art for preparing crystalline polymorphs. In some embodiments Form I of Compound 1 orotate salt can be prepared as described in Example 3.5. In some embodiments, Form I of Compound 1 orotate salt can be prepared by slurrying crystalline Compound 1 orotate salt containing one or more crystalline forms other than Form I. In some embodiments, the crystalline form of Compound 1 orotate salt can be prepared by recrystallizing crystalline Compound 1 orotate salt containing one or more crystalline forms other than Form I.
  • One aspect of the present invention pertains to a crystalline form of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt hydrate (Compound 1 orotate salt hydrate).
  • the crystalline form of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine orotate salt hydrate is Form I (Compound 1 orotate salt hydrate, Form I).
  • the physical properties of Form I of Compound 1 orotate salt hydrate are summarized in Table 13 below.
  • FIG. 20 Peaks of ⁇ 28% relative intensity at 7.43, 7.6774, 13.35, 15.25, 16.28, 18.31, 21.47, 22.60, 24.31, 24.61, and 26.67 °2 ⁇ TGA
  • FIG. 21 about 2.7% weight loss up to about 147° C. and about 0.9% between about 147° C. and about 179° C.
  • DSC FIG. 21 extrapolated onset temperature about 173° C. corresponding to a melt/recrystallization; extrapolated onset temperature about 234° C. corresponding to a melt decomposition
  • FIG. 22 ⁇ 0.14% weight gain at about 90% RH
  • Compound 1 orotate salt hydrate had weight loss observed in two steps, the first (2.7%) measured out to ⁇ 147° C., and the second (0.9%) occurring out to ⁇ 179° C.
  • the total weight loss ( ⁇ 3.6%) was close to the theoretical amount for a 0.75 (3:4) hydrate (3.7%).
  • the two step weight loss was consistent with two H 2 O molecules having similar binding energies that are different than the third H 2 O molecule in the crystal lattice.
  • One aspect of the present invention is directed to a crystalline form of Compound 1 orotate salt hydrate having an X-ray powder diffraction pattern comprising a peak, in terms of 2 ⁇ , at about 16.28°.
  • the crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2 ⁇ , at about 21.47°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 16.28° and about 21.47°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 16.28° and about 7.43°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 16.28°, about 21.47°, and about 7.43°. In some embodiments, the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 16.28°, about 21.47°, about 7.43°, about 26.67°, about 13.35°, about 7.6774°, and about 18.31°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 16.28°, about 21.47°, about 7.43°, about 26.67°, about 13.35°, about 7.6774°, about 18.31°, about 15.25°, about 24.31°, and about 24.61°.
  • One aspect of the present invention is directed to a crystalline form of Compound 1 orotate salt hydrate having an X-ray powder diffraction pattern comprising one or more peaks listed in Table 14.
  • the crystalline form has an X-ray powder diffraction pattern substantially as shown in FIG. 20 , wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2° 2 ⁇ , and also that the relative intensities of the reported peaks can vary.
  • the crystalline form of Compound 1 orotate salt hydrate has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 160° C. and about 190° C. In some embodiments, the crystalline form of Compound 1 orotate salt hydrate has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 173° C. In some embodiments, the crystalline form of Compound 1 orotate salt hydrate has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 220° C. and about 250° C.
  • the crystalline form of Compound 1 orotate salt hydrate has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 234° C.
  • the crystalline form of Compound 1 orotate salt hydrate has a thermogravimetric analysis profile substantially as shown in FIG. 21 , wherein by “substantially” is meant that the reported TGA features can vary by about ⁇ 5° C. and by about ⁇ 2% weight change.
  • the crystalline form of Compound 1 orotate salt hydrate has a differential scanning calorimetry thermogram substantially as shown in FIG. 21 , wherein by “substantially” is meant that the reported DSC features can vary by about ⁇ 6° C. and by about ⁇ 20 joules per gram.
  • the crystalline form of Compound 1 orotate salt hydrate has a dynamic moisture sorption profile substantially as shown in FIG. 22 , wherein by “substantially” is meant that the reported DMS features can vary by about ⁇ 5% relative humidity and by about ⁇ 5% weight change.
  • Form I of Compound 1 orotate salt hydrate can be prepared by any of the suitable procedures known in the art for preparing crystalline polymorphs. In some embodiments Form I of Compound 1 orotate salt hydrate can be prepared as described in Example 3.6. In some embodiments, Form I of Compound 1 orotate salt hydrate can be prepared by slurrying crystalline Compound 1 orotate salt hydrate containing one or more crystalline forms other than Form I. In some embodiments, the crystalline form of Compound 1 orotate salt hydrate can be prepared by recrystallizing crystalline Compound 1 orotate salt hydrate containing one or more crystalline forms other than Form I.
  • One aspect of the present invention pertains to a crystalline form of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate (Compound 1 di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate).
  • the crystalline form of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate is Form I (Compound 1 di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate, Form I).
  • the physical properties of Form I of Compound 1 di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate are summarized in Table 15 below.
  • FIG. 23 Peaks of ⁇ 7% relative intensity at 5.19, 6.38, 7.46, 10.98, 12.31, 15.92, 16.92, 17.11, 19.60, 22.73, 23.84, and 24.26 °2 ⁇ TGA
  • FIG. 24 about 2.7% weight loss up to about 115° C.
  • DSC extrapolated melting/desolvation onset temperature about 113° C.; enthalpy of fusion 89 J/g DMS
  • FIG. 25 ⁇ 9% weight gain at about 90% RH
  • One aspect of the present invention is directed to a crystalline form of Compound 1 di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate having an X-ray powder diffraction pattern comprising a peak, in terms of 2 ⁇ , at about 10.98°.
  • the crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2 ⁇ , at about 5.19°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 10.98° and about 5.19°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 10.98° and about 7.46°. In some embodiments, the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 10.98°, about 5.19°, and about 7.46°. In some embodiments, the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 10.98°, about 5.19°, about 7.46°, about 12.31°, about 6.38°, about 22.73°, and about 23.84°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 10.98°, about 5.19°, about 7.46°, about 12.31°, about 6.38°, about 22.73°, about 23.84°, about 24.26°, about 17.11°, and about 19.60°.
  • One aspect of the present invention is directed to a crystalline form of Compound 1 di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate having an X-ray powder diffraction pattern comprising one or more peaks listed in Table 16.
  • the crystalline form has an X-ray powder diffraction pattern substantially as shown in FIG. 23 , wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2° 2 ⁇ , and also that the relative intensities of the reported peaks can vary.
  • the crystalline form of Compound 1 di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 100° C. and about 130° C. In some embodiments, the crystalline form of Compound 1 di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 113° C.
  • the crystalline form of Compound 1 di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate has a differential scanning calorimetry thermogram comprising an endotherm with an associated heat flow of about 89 joules per gram.
  • the crystalline form of Compound 1 di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate has a thermogravimetric analysis profile substantially as shown in FIG. 24 , wherein by “substantially” is meant that the reported TGA features can vary by about ⁇ 5° C. and by about ⁇ 2% weight change.
  • the crystalline form of Compound 1 di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate has a differential scanning calorimetry thermogram substantially as shown in FIG. 24 , wherein by “substantially” is meant that the reported DSC features can vary by about ⁇ 6° C. and by about ⁇ 20 joules per gram.
  • the crystalline form of Compound 1 di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate has a dynamic moisture sorption profile substantially as shown in FIG. 25 , wherein by “substantially” is meant that the reported DMS features can vary by about ⁇ 5% relative humidity and by about ⁇ 5% weight change.
  • Form I of Compound 1 di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate can be prepared by any of the suitable procedures known in the art for preparing crystalline polymorphs. In some embodiments Form I of Compound 1 di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate can be prepared as described in Example 3.7.
  • Form I of Compound 1 di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate can be prepared by slurrying crystalline Compound 1 di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate containing one or more crystalline forms other than Form I.
  • the crystalline form of Compound 1 di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate can be prepared by recrystallizing crystalline Compound 1 di-4-acetamidobenzoate salt-cocrystal methyl ethyl ketone solvate containing one or more crystalline forms other than Form I.
  • One aspect of the present invention pertains to a crystalline form of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine trans-cinnamate salt (Compound 1 trans-cinnamate salt).
  • the crystalline form of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine trans-cinnamate salt is Form I (Compound 1 trans-cinnamate salt, Form I).
  • Table 17 The physical properties of Form I of Compound 1 trans-cinnamate salt are summarized in Table 17 below.
  • FIG. 26 Peaks of ⁇ 15% relative intensity at 8.10, 12.30, 13.02, 16.20, 17.81, 18.85, 20.14, 21.13, 23.51, 24.05, 24.44, and 27.21 °2 ⁇ TGA
  • FIG. 27 minimal weight loss below about 106° C.
  • DSC FIG. 27: extrapolated onset temperature about 106° C.; enthalpy of fusion 106 J/g DMS
  • FIG. 28 ⁇ 1.2% weight gain at about 90% RH
  • Compound 1 trans-cinnamate salt, Form I exhibited a melting onset at 106° C. and a heat of fusion of 106 J/g. Prior to the melting onset there was minimal weight loss and upon melting there was a gradual and complete weight loss, indicating the isolated crystal phase is not solvated.
  • Compound 1 trans-cinnamate salt was non-hygroscopic up to 80% RH and picked up only 1.2% water out to and including the 90% RH hold at 25° C., although it was still picking up water after 2 h at 90% RH. The sample subsequently lost nearly all of the absorbed water at 80% RH.
  • One aspect of the present invention is directed to a crystalline form of Compound 1 trans-cinnamate salt having an X-ray powder diffraction pattern comprising a peak, in terms of 2 ⁇ , at about 17.81°.
  • the crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2 ⁇ , at about 20.14°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 17.81° and about 20.14°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 17.81° and about 24.44°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 17.81°, about 20.14°, and about 24.44°. In some embodiments, the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 17.81°, about 20.14°, about 21.13°, about 8.10°, about 24.44°, about 16.20°, and about 13.02°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 17.81°, about 20.14°, about 24.44°, about 21.13°, about 8.10°, about 16.20°, about 13.02°, about 12.30°, about 27.21°, and about 23.51°.
  • One aspect of the present invention is directed to a crystalline form of Compound 1 trans-cinnamate salt having an X-ray powder diffraction pattern comprising one or more peaks listed in Table 18.
  • the crystalline form has an X-ray powder diffraction pattern substantially as shown in FIG. 26 , wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2° 2 ⁇ , and also that the relative intensities of the reported peaks can vary.
  • the crystalline form of Compound 1 trans-cinnamate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 90° C. and about 120° C. In some embodiments, the crystalline form of Compound 1 trans-cinnamate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 106° C. In some embodiments, the crystalline form of Compound 1 trans-cinnamate salt has a differential scanning calorimetry thermogram comprising an endotherm with an associated heat flow of about 106 joules per gram.
  • the crystalline form of Compound 1 trans-cinnamate salt has a thermogravimetric analysis profile substantially as shown in FIG. 27 , wherein by “substantially” is meant that the reported TGA features can vary by about ⁇ 5° C. and by about ⁇ 2% weight change.
  • the crystalline form of Compound 1 trans-cinnamate salt has a differential scanning calorimetry thermogram substantially as shown in FIG. 27 , wherein by “substantially” is meant that the reported DSC features can vary by about ⁇ 6° C. and by about ⁇ 20 joules per gram.
  • the crystalline form of Compound 1 trans-cinnamate salt has a dynamic moisture sorption profile substantially as shown in FIG. 28 , wherein by “substantially” is meant that the reported DMS features can vary by about ⁇ 5% relative humidity and by about ⁇ 5% weight change.
  • Form I of Compound 1 trans-cinnamate salt can be prepared by any of the suitable procedures known in the art for preparing crystalline polymorphs. In some embodiments Form I of Compound 1 trans-cinnamate salt can be prepared as described in Example 3.8. In some embodiments, Form I of Compound 1 trans-cinnamate salt can be prepared by slurrying crystalline Compound 1 trans-cinnamate salt containing one or more crystalline forms other than Form I. In some embodiments, the crystalline form of Compound 1 trans-cinnamate salt can be prepared by recrystallizing crystalline Compound 1 trans-cinnamate salt containing one or more crystalline forms other than Form I.
  • One aspect of the present invention pertains to a crystalline form of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine heminapadisilate salt (Compound 1 heminapadisilate salt).
  • the crystalline form of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine heminapadisilate salt is Form I (Compound 1 heminapadisilate salt, Form I).
  • Table 19 The physical properties of Form I of Compound 1 heminapadisilate salt are summarized in Table 19 below.
  • FIG. 29 Peaks of ⁇ 12% relative intensity at 6.89, 11.47, 11.96, 13.20, 15.37, 16.35, 17.79, 20.56, 22.96, 23.19, 23.50, and 24.16 °2 ⁇ TGA
  • FIG. 30 negligible weight loss up to about 250° C.
  • DSC differential temperature measuring unit
  • FIG. 30 extrapolated onset temperature about 266° C.
  • FIG. 31 ⁇ 0.68% weight gain at about 90% RH
  • Compound 1 heminapadisilate, Form I was an anhydrous salt by TGA.
  • the melting onset by DSC was 266° C.
  • Compound 1 heminapadisilate was non-hygroscopic by DMS analysis, picking up about 0.68% out to and including the 90% RH hold at 25° C. A small amount of hysteresis was observed.
  • One aspect of the present invention is directed to a crystalline form of Compound 1 heminapadisilate salt having an X-ray powder diffraction pattern comprising a peak, in terms of 2 ⁇ , at about 23.50°.
  • the crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2 ⁇ , at about 15.37°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 23.50° and about 15.37°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 23.50° and about 11.47°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 23.50°, about 15.37°, and about 11.47°. In some embodiments, the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 23.50°, about 15.37°, about 11.47°, about 11.96°, about 23.19°, about 16.35°, and about 13.20°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 23.50°, about 15.37°, about 11.47°, about 11.96°, about 23.19°, about 16.35°, about 13.20°, about 6.89°, about 20.56°, and about 22.96°.
  • One aspect of the present invention is directed to a crystalline form of Compound 1 heminapadisilate salt having an X-ray powder diffraction pattern comprising one or more peaks listed in Table 20.
  • the crystalline form has an X-ray powder diffraction pattern substantially as shown in FIG. 29 , wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2° 2 ⁇ , and also that the relative intensities of the reported peaks can vary.
  • the crystalline form of Compound 1 heminapadisilate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 250° C. and about 280° C. In some embodiments, the crystalline form of Compound 1 heminapadisilate salt has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 266° C. In some embodiments, the crystalline form of Compound 1 heminapadisilate salt has a differential scanning calorimetry thermogram comprising an endotherm with an associated heat flow of about 90 joules per gram.
  • the crystalline form of Compound 1 heminapadisilate salt has a thermogravimetric analysis profile substantially as shown in FIG. 30 , wherein by “substantially” is meant that the reported TGA features can vary by about ⁇ 5° C. and by about ⁇ 2% weight change.
  • the crystalline form of Compound 1 heminapadisilate salt has a differential scanning calorimetry thermogram substantially as shown in FIG. 30 , wherein by “substantially” is meant that the reported DSC features can vary by about ⁇ 6° C. and by about ⁇ 20 joules per gram.
  • the crystalline form of Compound 1 heminapadisilate salt has a dynamic moisture sorption profile substantially as shown in FIG. 31 , wherein by “substantially” is meant that the reported DMS features can vary by about ⁇ 5% relative humidity and by about ⁇ 5% weight change.
  • Form I of Compound 1 heminapadisilate salt can be prepared by any of the suitable procedures known in the art for preparing crystalline polymorphs. In some embodiments Form I of Compound 1 heminapadisilate salt can be prepared as described in Example 3.9. In some embodiments, Form I of Compound 1 heminapadisilate salt can be prepared by slurrying crystalline Compound 1 heminapadisilate salt containing one or more crystalline forms other than Form I. In some embodiments, the crystalline form of Compound 1 heminapadisilate salt can be prepared by recrystallizing crystalline Compound 1 heminapadisilate salt containing one or more crystalline forms other than Form I.
  • One aspect of the present invention pertains to a crystalline form of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine heminapadisilate salt solvate 1 (Compound 1 heminapadisilate salt solvate 1).
  • the crystalline form of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine heminapadisilate salt solvate 1 is Form I (Compound 1 heminapadisilate salt solvate 1, Form I).
  • Table 21 The physical properties of Form I of Compound 1 heminapadisilate salt solvate 1 are summarized in Table 21 below.
  • FIG. 32 Peaks of ⁇ 18% relative intensity at 9.81, 17.39, 17.89, 19.62, 21.82, 23.56, 23.72, 23.96, 24.77, 25.03, and 28.56 °2 ⁇ TGA
  • FIG. 33 about 5.7% weight loss up to about 140° C.
  • DSC FIG. 33 extrapolated desolvation onset temperature about 101° C.
  • Compound 1 heminapadisilate salt solvate 1 had a weight loss of ⁇ 5.7% by TGA scanned at 10° C./min out to ⁇ 140° C. This weight loss was slightly lower than the theoretical value (6.1%) for a 0.25 ethyl acetate solvate. The desolvation was followed by further weight loss due to degradation.
  • One aspect of the present invention is directed to a crystalline form of Compound 1 heminapadisilate salt solvate 1 having an X-ray powder diffraction pattern comprising a peak, in terms of 2 ⁇ , at about 17.39°.
  • the crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2 ⁇ , at about 17.89°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 17.39° and about 17.89°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 17.39° and about 19.62°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 17.39°, about 17.89°, and about 19.62°. In some embodiments, the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 17.39°, about 17.89°, about 19.62°, about 21.82°, about 23.56°, about 23.96°, and about 23.72°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 17.39°, about 17.89°, about 19.62°, about 21.82°, about 23.56°, about 23.96°, about 23.72°, about 9.81°, about 25.03°, and about 24.77°.
  • One aspect of the present invention is directed to a crystalline form of Compound 1 heminapadisilate salt solvate 1 having an X-ray powder diffraction pattern comprising one or more peaks listed in Table 22.
  • the crystalline form has an X-ray powder diffraction pattern substantially as shown in FIG. 32 , wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2° 2 ⁇ , and also that the relative intensities of the reported peaks can vary.
  • the crystalline form of Compound 1 heminapadisilate salt solvate 1 has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 85° C. and about 115° C. In some embodiments, the crystalline form of Compound 1 heminapadisilate salt solvate 1 has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 101° C. In some embodiments, the crystalline form of Compound 1 heminapadisilate salt solvate 1 has a thermogravimetric analysis profile substantially as shown in FIG. 33 , wherein by “substantially” is meant that the reported TGA features can vary by about ⁇ 5° C. and by about ⁇ 2% weight change.
  • the crystalline form of Compound 1 heminapadisilate salt solvate 1 has a differential scanning calorimetry thermogram substantially as shown in FIG. 33 , wherein by “substantially” is meant that the reported DSC features can vary by about ⁇ 6° C. and by about ⁇ 20 joules per gram.
  • Form I of Compound 1 heminapadisilate salt solvate 1 can be prepared by any of the suitable procedures known in the art for preparing crystalline polymorphs. In some embodiments Form I of Compound 1 heminapadisilate salt solvate 1 can be prepared as described in Example 3.10. In some embodiments, Form I of Compound 1 heminapadisilate salt solvate 1 can be prepared by slurrying crystalline Compound 1 heminapadisilate salt solvate 1 containing one or more crystalline forms other than Form I.
  • the crystalline form of Compound 1 heminapadisilate salt solvate 1 can be prepared by recrystallizing crystalline Compound 1 heminapadisilate salt solvate 1 containing one or more crystalline forms other than Form I.
  • One aspect of the present invention pertains to a crystalline form of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine heminapadisilate salt solvate 2 (Compound 1 heminapadisilate salt solvate 2).
  • the crystalline form of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine heminapadisilate salt solvate 2 is Form I (Compound 1 heminapadisilate salt solvate 2, Form I).
  • Table 23 The physical properties of Form I of Compound 1 heminapadisilate salt solvate 2 are summarized in Table 23 below.
  • FIG. 34 Peaks of ⁇ 7% relative intensity at 12.35, 12.62, 13.40, 14.61, 16.17, 22.10, 23.01, 24.65, 24.72, 24.87, 24.99, 25.90, and 27.89 °2 ⁇ TGA
  • FIG. 35 about 4.6% weight loss up to about 175° C.
  • DSC extrapolated desolvation onset temperature about 129° C.; extrapolated melt onset temperature about 264° C., approximately matching that of the non-solvated salt
  • One aspect of the present invention is directed to a crystalline form of Compound 1 heminapadisilate salt solvate 2 having an X-ray powder diffraction pattern comprising a peak, in terms of 2 ⁇ , at about 12.35°.
  • the crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2 ⁇ , at about 12.62°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 12.35° and about 12.62°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 12.35° and about 14.61°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 12.35°, about 12.62°, and about 14.61°. In some embodiments, the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 12.35°, about 12.62°, about 14.61°, about 24.87°, about 13.40°, about 24.99°, and about 24.72°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 12.35°, about 12.62°, about 14.61°, about 24.87°, about 13.40°, about 24.99°, about 24.72°, about 23.01°, about 24.65°, and about 22.10°.
  • One aspect of the present invention is directed to a crystalline form of Compound 1 heminapadisilate salt solvate 2 having an X-ray powder diffraction pattern comprising one or more peaks listed in Table 24.
  • the crystalline form has an X-ray powder diffraction pattern substantially as shown in FIG. 34 , wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2° 2 ⁇ , and also that the relative intensities of the reported peaks can vary.
  • the crystalline form of Compound 1 heminapadisilate salt solvate 2 has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 110° C. and about 140° C. In some embodiments, the crystalline form of Compound 1 heminapadisilate salt solvate 2 has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 129° C. In some embodiments, the crystalline form of Compound 1 heminapadisilate salt solvate 2 has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 250° C. and about 280° C.
  • the crystalline form of Compound 1 heminapadisilate salt solvate 2 has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 264° C. In some embodiments, the crystalline form of Compound 1 heminapadisilate salt solvate 2 has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 110° C. and about 140° C., and an endotherm with an extrapolated onset temperature between about 250° C. and about 280° C.
  • the crystalline form of Compound 1 heminapadisilate salt solvate 2 has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 129° C., and an endotherm with an extrapolated onset temperature at about 264° C.
  • the crystalline form of Compound 1 heminapadisilate salt solvate 2 has a thermogravimetric analysis profile substantially as shown in FIG. 35 , wherein by “substantially” is meant that the reported TGA features can vary by about ⁇ 5° C. and by about ⁇ 2% weight change.
  • the crystalline form of Compound 1 heminapadisilate salt solvate 2 has a differential scanning calorimetry thermogram substantially as shown in FIG. 35 , wherein by “substantially” is meant that the reported DSC features can vary by about ⁇ 6° C. and by about ⁇ 20 joules per gram.
  • Form I of Compound 1 heminapadisilate salt solvate 2 can be prepared by any of the suitable procedures known in the art for preparing crystalline polymorphs. In some embodiments Form I of Compound 1 heminapadisilate salt solvate 2 can be prepared as described in Example 3.11. In some embodiments, Form I of Compound 1 heminapadisilate salt solvate 2 can be prepared by slurrying crystalline Compound 1 heminapadisilate salt solvate 2 containing one or more crystalline forms other than Form I.
  • the crystalline form of Compound 1 heminapadisilate salt solvate 2 can be prepared by recrystallizing crystalline Compound 1 heminapadisilate salt solvate 2 containing one or more crystalline forms other than Form I.
  • One aspect of the present invention pertains to a crystalline form of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine( ⁇ )-mandelate salt hydrate (Compound 1 ( ⁇ )-mandelate salt hydrate).
  • the crystalline form of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine( ⁇ )-mandelate salt hydrate is Form I (Compound 1 ( ⁇ )-mandelate salt hydrate, Form I).
  • Table 25 The physical properties of Form I of Compound 1 ( ⁇ )-mandelate salt hydrate are summarized in Table 25 below.
  • FIG. 36 Peaks of ⁇ 18% relative intensity at 5.97, 11.91, 12.13, 15.26, 16.15, 19.49, 21.45, 22.06, 22.29, 23.90, 24.76, 36.13, and 36.21 °2 ⁇ , TGA FIG. 37: about 4.8% weight loss up to about 100° C.
  • DSC FIG. 37 extrapolated desolvation onset temperature about 74° C.
  • DMS FIG. 38 Non-hygroscopic
  • One aspect of the present invention is directed to a crystalline form of Compound 1 ( ⁇ )-mandelate salt hydrate having an X-ray powder diffraction pattern comprising a peak, in terms of 2 ⁇ , at about 11.91°.
  • the crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2 ⁇ , at about 22.29°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 11.91° and about 22.29°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 11.91° and about 5.97°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 11.91°, about 22.29°, and about 5.97°. In some embodiments, the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 11.91°, about 22.29°, about 5.97°, about 23.90°, about 16.15°, about 24.76°, and about 22.06°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 11.91°, about 22.29°, about 5.97°, about 23.90°, about 16.15°, about 24.76°, about 22.06°, about 15.26°, about 12.13°, and about 21.45°.
  • One aspect of the present invention is directed to a crystalline form of Compound 1 ( ⁇ )-mandelate salt hydrate having an X-ray powder diffraction pattern comprising one or more peaks listed in Table 26.
  • the crystalline form has an X-ray powder diffraction pattern substantially as shown in FIG. 36 , wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2° 2°, and also that the relative intensities of the reported peaks can vary.
  • the crystalline form of Compound 1 ( ⁇ )-mandelate salt hydrate has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 60° C. and about 90° C. In some embodiments, the crystalline form of Compound 1 ( ⁇ )-mandelate salt hydrate has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 74° C. In some embodiments, the crystalline form of Compound 1 ( ⁇ )-mandelate salt hydrate has a thermogravimetric analysis profile substantially as shown in FIG. 37 , wherein by “substantially” is meant that the reported TGA features can vary by about ⁇ 5° C. and by about ⁇ 2% weight change.
  • the crystalline form of Compound 1 ( ⁇ )-mandelate salt hydrate has a differential scanning calorimetry thermogram substantially as shown in FIG. 37 , wherein by “substantially” is meant that the reported DSC features can vary by about ⁇ 6° C. and by about ⁇ 20 joules per gram.
  • the crystalline form of Compound 1 ( ⁇ )-mandelate salt hydrate has a dynamic moisture sorption profile substantially as shown in FIG. 38 , wherein by “substantially” is meant that the reported DMS features can vary by about ⁇ 5% relative humidity and by about ⁇ 5% weight change.
  • Form I of Compound 1 ( ⁇ )-mandelate salt hydrate can be prepared by any of the suitable procedures known in the art for preparing crystalline polymorphs. In some embodiments Form I of Compound 1 ( ⁇ )-mandelate salt hydrate can be prepared as described in Example 3.12. In some embodiments, Form I of Compound 1 ( ⁇ )-mandelate salt hydrate can be prepared by slurrying crystalline Compound 1 ( ⁇ )-mandelate salt hydrate containing one or more crystalline forms other than Form I. In some embodiments, the crystalline form of Compound 1 ( ⁇ )-mandelate salt hydrate can be prepared by recrystallizing crystalline Compound 1 ( ⁇ )-mandelate salt hydrate containing one or more crystalline forms other than Form I.
  • One aspect of the present invention pertains to a crystalline form of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemipamoate salt hydrate (Compound 1 hemipamoate salt hydrate).
  • the crystalline form of (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hemipamoate salt hydrate is Form I (Compound 1 hemipamoate salt hydrate, Form I).
  • Table 27 The physical properties of Form I of Compound 1 hemipamoate salt hydrate are summarized in Table 27 below.
  • FIG. 39 Peaks of ⁇ 11% relative intensity at 12.30, 14.29, 14.61, 15.70, 16.60, 17.63, 18.68, 20.16, 22.46, 22.88, 24.19, and 24.52 °2 ⁇ TGA
  • FIG. 40 about 5.3% weight loss below about 160° C.; extrapolated desolvation onset temperature about 101° C.; DSC
  • FIG. 40 extrapolated melt/decomposition onset temperature about 244° C.
  • DMS FIG. 41 ⁇ 1.472% weight gain at about 90% RH
  • Compound 1 hemipamoate salt hydrate, Form I had a weight loss of ⁇ 5.3% (desolvation onset ⁇ 101° C. by TGA) out to ⁇ 160° C. This weight loss was slightly higher than, but in fair agreement with the theoretical value (4.4%) for a monohydrate. The desolvation was followed by degradation. The melting/decomposition onset was ⁇ 244° C. by DSC.
  • One aspect of the present invention is directed to a crystalline form of Compound 1 hemipamoate salt hydrate having an X-ray powder diffraction pattern comprising a peak, in terms of 2 ⁇ , at about 14.29°.
  • the crystalline form has an X-ray powder diffraction pattern comprising a peak, in terms of 2 ⁇ , at about 12.30°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 14.29° and about 12.30°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 14.29° and about 24.52°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 14.29°, about 12.30°, and about 24.52°. In some embodiments, the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 14.29°, about 12.30°, about 24.52°, about 22.88°, about 14.61°, about 16.60°, and about 17.63°.
  • the crystalline form has an X-ray powder diffraction pattern comprising peaks, in terms of 2 ⁇ , at about 14.29°, about 12.30°, about 24.52°, about 22.88°, about 14.61°, about 16.60°, about 17.63°, about 18.68°, about 15.70°, and about 22.46°.
  • One aspect of the present invention is directed to a crystalline form of Compound 1 hemipamoate salt hydrate having an X-ray powder diffraction pattern comprising one or more peaks listed in Table 28.
  • the crystalline form has an X-ray powder diffraction pattern substantially as shown in FIG. 39 , wherein by “substantially” is meant that the reported peaks can vary by about ⁇ 0.2° 2 ⁇ , and also that the relative intensities of the reported peaks can vary.
  • the crystalline form of Compound 1 hemipamoate salt hydrate has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 85° C. and about 115° C. In some embodiments, the crystalline form of Compound 1 hemipamoate salt hydrate has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 101° C. In some embodiments, the crystalline form of Compound 1 hemipamoate salt hydrate has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 230° C. and about 260° C.
  • the crystalline form of Compound 1 hemipamoate salt hydrate has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 244° C. In some embodiments, the crystalline form of Compound 1 hemipamoate salt hydrate has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 85° C. and about 115° C., and an endotherm with an extrapolated onset temperature between about 230° C. and about 260° C.
  • the crystalline form of Compound 1 hemipamoate salt hydrate has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature at about 101° C. and an endotherm with an extrapolated onset temperature at about 244° C.
  • the crystalline form of Compound 1 hemipamoate salt hydrate has a thermogravimetric analysis profile substantially as shown in FIG. 40 , wherein by “substantially” is meant that the reported TGA features can vary by about ⁇ 5° C. and by about ⁇ 2% weight change.
  • the crystalline form of Compound 1 hemipamoate salt hydrate has a differential scanning calorimetry thermogram substantially as shown in FIG. 40 , wherein by “substantially” is meant that the reported DSC features can vary by about ⁇ 6° C. and by about ⁇ 20 joules per gram.
  • the crystalline form of Compound 1 hemipamoate salt hydrate has a dynamic moisture sorption profile substantially as shown in FIG. 41 , wherein by “substantially” is meant that the reported DMS features can vary by about ⁇ 5% relative humidity and by about ⁇ 5% weight change.
  • Form I of Compound 1 hemipamoate salt hydrate can be prepared by any of the suitable procedures known in the art for preparing crystalline polymorphs. In some embodiments Form I of Compound 1 hemipamoate salt hydrate can be prepared as described in Example 3.13. In some embodiments, Form I of Compound 1 hemipamoate salt hydrate can be prepared by slurrying crystalline Compound 1 hemipamoate salt hydrate containing one or more crystalline forms other than Form I. In some embodiments, the crystalline form of Compound 1 hemipamoate salt hydrate can be prepared by recrystallizing crystalline Compound 1 hemipamoate salt hydrate containing one or more crystalline forms other than Form I.
  • One aspect of the present invention pertains to pharmaceutical compositions comprising a crystalline form of the present invention, and a pharmaceutically acceptable carrier.
  • One aspect of the present invention pertains to processes for preparing a pharmaceutical composition comprising admixing a crystalline form of the present invention, and a pharmaceutically acceptable carrier.
  • One aspect of the present invention pertains to modified-release dosage forms comprising a crystalline form of the present invention.
  • One aspect of the present invention pertains to methods for weight management comprising administering to an individual in need thereof a crystalline form of the present invention.
  • One aspect of the present invention pertains to the use of crystalline forms of the present invention in the manufacture of a medicament for weight management in an individual.
  • One aspect of the present invention pertains to crystalline forms of the present invention for use in a method of treatment of the human or animal body by therapy.
  • One aspect of the present invention pertains to crystalline forms of the present invention for use in a method of weight management.
  • One aspect of the present invention pertains to crystalline forms of the present invention for use in a method of weight loss.
  • One aspect of the present invention pertains to crystalline forms of the present invention for use in a method of maintenance of weight loss.
  • One aspect of the present invention pertains to crystalline forms of the present invention for use in a method of decreasing food consumption
  • One aspect of the present invention pertains to crystalline forms of the present invention for use in a method of increasing meal-related satiety.
  • One aspect of the present invention pertains to crystalline forms of the present invention for use in a method of reducing pre-meal hunger.
  • One aspect of the present invention pertains to crystalline forms of the present invention for use in a method of reducing intra-meal food intake.
  • One aspect of the present invention pertains to crystalline forms of the present invention for use in a method of weight management further comprising a reduced-calorie diet.
  • One aspect of the present invention pertains to crystalline forms of the present invention for use in a method of weight management further comprising a program of regular exercise.
  • One aspect of the present invention pertains to crystalline forms of the present invention for use in a method of weight management further comprising a reduced-calorie diet and a program of regular exercise.
  • One aspect of the present invention pertains to crystalline forms of the present invention for use in a method of weight management in an obese patient with an initial body mass index ⁇ 30 kg/m 2 .
  • One aspect of the present invention pertains to crystalline forms of the present invention for use in a method of weight management in an overweight patient with an initial body mass index ⁇ 27 kg/m 2 in the presence of at least one weight related co-morbid condition.
  • One aspect of the present invention pertains to crystalline forms of the present invention for use in a method of weight management in an overweight patient with an initial body mass index ⁇ 27 kg/m 2 in the presence of at least one weight related co-morbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
  • One aspect of the present invention pertains to crystalline forms of the present invention for use in a method of weight management in a patient with an initial body mass index ⁇ 30 kg/m 2 .
  • One aspect of the present invention pertains to crystalline forms of the present invention for use in a method of weight management in a patient with an initial body mass index ⁇ 27 kg/m 2 .
  • One aspect of the present invention pertains to crystalline forms of the present invention for use in a method of weight management in a patient with an initial body mass index ⁇ 27 kg/m 2 in the presence of at least one weight related co-morbid condition.
  • One aspect of the present invention pertains to crystalline forms of the present invention for use in a method of weight management in a patient with an initial body mass index ⁇ 27 kg/m 2 in the presence of at least one weight related co-morbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
  • One aspect of the present invention pertains to crystalline forms of the present invention for use in a method of weight management in a patient with an initial body mass index ⁇ 25 kg/m 2 .
  • One aspect of the present invention pertains to crystalline forms of the present invention for use in a method of weight management in a patient with an initial body mass index ⁇ 25 kg/m 2 in the presence of at least one weight related co-morbid condition.
  • One aspect of the present invention pertains to crystalline forms of the present invention for use in a method of weight management in a patient with an initial body mass index ⁇ 25 kg/m 2 in the presence of at least one weight related co-morbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
  • a further aspect of the present invention pertains to pharmaceutical compositions comprising one or more salts according to any of the salt embodiments disclosed herein and one or more pharmaceutically acceptable carriers. Some embodiments pertain to pharmaceutical compositions comprising a salt according to any of the salt embodiments disclosed herein and a pharmaceutically acceptable carrier. Some embodiments pertain to pharmaceutical compositions comprising any subcombination of salts according to any of the salt embodiments disclosed herein.
  • Another aspect of the present invention pertains to methods of producing pharmaceutical compositions comprising admixing one or more salts according to any of the salt embodiments disclosed herein and one or more pharmaceutically acceptable carriers. Some embodiments pertain to a method of producing a pharmaceutical composition comprising admixing a salt according to any of the salt embodiments disclosed herein and a pharmaceutically acceptable carrier. Some embodiments pertain to a methods of producing pharmaceutical compositions comprising admixing any subcombination of salts according to any of the salt embodiments disclosed herein and a pharmaceutically acceptable carrier.
  • One aspect of the present invention pertains to methods of manufacturing a pharmaceutical composition
  • a pharmaceutical composition comprising: admixing a compound selected from: a salt of the present invention and pharmaceutically acceptable solvates and hydrates thereof, with a pharmaceutically acceptable excipient.
  • the salts and crystalline forms of the present invention can be used as active ingredients in pharmaceutical compositions, specifically as 5-HT 2C -receptor modulators.
  • active ingredient as defined in the context of a “pharmaceutical composition” and is intended to mean a component of a pharmaceutical composition that provides the primary pharmacological effect, as opposed to an “inactive ingredient” which would generally be recognized as providing no pharmaceutical benefit.
  • the dose when using the salts of the present invention can vary within wide limits and as is customary and is known to the physician, it is to be tailored to the individual conditions in each individual case. It depends, for example, on the nature and severity of the illness to be treated, on the condition of the patient, on the salt employed or on whether an acute or chronic disease state is treated or prophylaxis conducted or on whether further active compounds are administered in addition to the salts of the present invention.
  • Representative doses of the present invention include, but are not limited to, about 0.001 mg to about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg to about 1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg, about 0.001 mg to 100 mg, about 0.001 mg to about 50 mg and about 0.001 mg to about 25 mg.
  • Multiple doses may be administered during the day, especially when relatively large amounts are deemed to be needed, for example 2, 3 or 4 doses. Depending on the individual and as deemed appropriate from the patient's physician or caregiver it may be necessary to deviate upward or downward from the doses described herein.
  • Some embodiments of the present invention include a method of producing a pharmaceutical composition for “combination-therapy” comprising admixing at least one salt according to any of the salt embodiments disclosed herein, together with at least one known pharmaceutical agent as described herein and a pharmaceutically acceptable carrier.
  • salts of the present invention are utilized as active ingredients in a pharmaceutical composition, these are not intended for use only in humans, but in other non-human mammals as well. Indeed, recent advances in the area of animal health-care mandate that consideration be given for the use of active agents, such as 5-HT 2C -receptor modulators, for the treatment of a 5-HT 2C -receptor-associated disease or disorders in companionship animals (e.g., cats, dogs, etc.) and in livestock animals (e.g., cows, chickens, fish, etc.). Those of ordinary skill in the art are readily credited with understanding the utility of such salts in such settings.
  • active agents such as 5-HT 2C -receptor modulators
  • One aspect of the present invention pertains to pharmaceutical compositions comprising a salt of the present invention.
  • One aspect of the present invention pertains to processes for preparing pharmaceutical compositions comprising admixing a salt of the present invention, and a pharmaceutically acceptable carrier
  • One aspect of the present invention pertains to pharmaceutical compositions of the present invention for use in a method of treatment of the human or animal body by therapy.
  • One aspect of the present invention pertains to pharmaceutical compositions of the present invention for use in a method of weight management.
  • One aspect of the present invention pertains to pharmaceutical compositions of the present invention for use in a method of weight loss.
  • One aspect of the present invention pertains to pharmaceutical compositions of the present invention for use in a method of maintenance of weight loss.
  • One aspect of the present invention pertains to pharmaceutical compositions of the present invention for use in a method of decreasing food consumption
  • One aspect of the present invention pertains to pharmaceutical compositions of the present invention for use in a method of increasing meal-related satiety.
  • One aspect of the present invention pertains to pharmaceutical compositions of the present invention for use in a method of reducing pre-meal hunger.
  • One aspect of the present invention pertains to pharmaceutical compositions of the present invention for use in a method of reducing intra-meal food intake.
  • One aspect of the present invention pertains to pharmaceutical compositions of the present invention for use in a method of weight management further comprising a reduced-calorie diet.
  • One aspect of the present invention pertains to pharmaceutical compositions of the present invention for use in a method of weight management further comprising a program of regular exercise.
  • One aspect of the present invention pertains to pharmaceutical compositions of the present invention for use in a method of weight management further comprising a reduced-calorie diet and a program of regular exercise.
  • One aspect of the present invention pertains to pharmaceutical compositions of the present invention for use in a method of weight management in an obese patient with an initial body mass index ⁇ 30 kg/m 2 .
  • One aspect of the present invention pertains to pharmaceutical compositions of the present invention for use in a method of weight management in an overweight patient with an initial body mass index ⁇ 27 kg/m 2 in the presence of at least one weight related co-morbid condition.
  • One aspect of the present invention pertains to pharmaceutical compositions of the present invention for use in a method of weight management in an overweight patient with an initial body mass index ⁇ 27 kg/m 2 in the presence of at least one weight related co-morbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
  • One aspect of the present invention pertains to pharmaceutical compositions of the present invention for use in a method of weight management in a patient with an initial body mass index ⁇ 30 kg/m 2 .
  • One aspect of the present invention pertains to pharmaceutical compositions of the present invention for use in a method of weight management in a patient with an initial body mass index ⁇ 27 kg/m 2 .
  • One aspect of the present invention pertains to pharmaceutical compositions of the present invention for use in a method of weight management in a patient with an initial body mass index ⁇ 27 kg/m 2 in the presence of at least one weight related co-morbid condition.
  • One aspect of the present invention pertains to pharmaceutical compositions of the present invention for use in a method of weight management in a patient with an initial body mass index ⁇ 27 kg/m 2 in the presence of at least one weight related co-morbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
  • One aspect of the present invention pertains to pharmaceutical compositions of the present invention for use in a method of weight management in a patient with an initial body mass index ⁇ 25 kg/m 2 .
  • One aspect of the present invention pertains to pharmaceutical compositions of the present invention for use in a method of weight management in a patient with an initial body mass index ⁇ 25 kg/m 2 in the presence of at least one weight related co-morbid condition.
  • One aspect of the present invention pertains to pharmaceutical compositions of the present invention for use in a method of weight management in a patient with an initial body mass index ⁇ 25 kg/m 2 in the presence of at least one weight related co-morbid condition selected from: hypertension, dyslipidemia, cardiovascular disease, glucose intolerance, and sleep apnea.
  • the dosage forms described herein may comprise, as the active component, either a salts or crystalline form thereof as described herein, or a solvate or hydrate thereof.
  • various hydrates and solvates of the salts or crystalline form thereof described herein will find use as intermediates in the manufacture of pharmaceutical compositions.
  • Typical procedures for making and identifying suitable hydrates and solvates, outside those mentioned herein, are well known to those in the art; see for example, pages 202-209 of K. J. Guillory, “Generation of Polymorphs, Hydrates, Solvates, and Amorphous Solids,” in: Polymorphism in Pharmaceutical Solids, ed. Harry G. Britain, Vol. 95, Marcel Dekker, Inc., New York, 1999.
  • one aspect of the present invention pertains to methods of administering hydrates and solvates of salts or crystalline forms thereof described herein and/or their pharmaceutically acceptable salts, that can be isolated and characterized by methods known in the art, such as, thermogravimetric analysis (TGA), TGA-mass spectroscopy, TGA-Infrared spectroscopy, powder X-ray diffraction (XRPD), Karl Fisher titration, high resolution X-ray diffraction, and the like.
  • TGA thermogravimetric analysis
  • TGA-mass spectroscopy TGA-mass spectroscopy
  • TGA-Infrared spectroscopy powder X-ray diffraction (XRPD)
  • Karl Fisher titration high resolution X-ray diffraction

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