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WO2012123325A1 - Nouvelles formes cristallines du sel de trans-5-chloro-2-méthyl-2,3,3a,12b-tétrahydro-1h-dibenzo[2,3:6,7] oxépino[4,5-c]pyrrole avec l'acide maléique - Google Patents

Nouvelles formes cristallines du sel de trans-5-chloro-2-méthyl-2,3,3a,12b-tétrahydro-1h-dibenzo[2,3:6,7] oxépino[4,5-c]pyrrole avec l'acide maléique Download PDF

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Publication number
WO2012123325A1
WO2012123325A1 PCT/EP2012/053988 EP2012053988W WO2012123325A1 WO 2012123325 A1 WO2012123325 A1 WO 2012123325A1 EP 2012053988 W EP2012053988 W EP 2012053988W WO 2012123325 A1 WO2012123325 A1 WO 2012123325A1
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Prior art keywords
asenapine maleate
mixture
temperature
antisolvent
asenapine
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English (en)
Inventor
Mingli Xu
Ernesto DURÁN LÓPEZ
Mónica BENITO VÉLEZ
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Medichem SA
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Medichem SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

Definitions

  • MALEIC ACID This invention relates to new crystal forms of the salt of frans-5-chloro-2-methyl- 2,3,3a, 12b-tetrahydro-1 /-/-dibenzo[2, 3:6, 7]oxepino[4,5-c]pyrrole with maleic acid.
  • Asenapine (compound trans-( ⁇ )) is the international commonly accepted nonproprietary name (INN) for frans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1 /-/- dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole, and has an empirical formula of Ci 7 H 16 CINO and a molecular weight of 285.77.
  • the molecule has two chiral centers but the name asenapine is used to designate the racemic mixture of the trans isomer.
  • the maleic acid salt (1 :1) of asenapine (designated in this specification as asenapine maleate) is known to be therapeutically useful and is commercially marketed for the treatment of schizophrenia and acute manic or mixed episodes associated with bipolar 1 disorder.
  • Asenapine maleate exhibits high affinity and potency for blocking dopamine, serotonin, a-adrenergic and histamine receptors, and no appreciable activity at muscarinic and cholinergic receptors.
  • the rank order of receptor affinity for asenapine maleate reveals a unique human receptor binding signature, characterized by strong serotonergic properties, when compared to other antipsychotic drugs.
  • asenapine maleate is marketed under the name SaphrisTM.
  • asenapine maleate is marketed under the name SycrestTM.
  • Asenapine maleate was first disclosed in U.S. Patent No. 4, 145,434 ("the '434 patent").
  • Example IV of the '434 patent described asenapine maleate to have a melting point of 141 °C.
  • solid asenapine maleate shows polymorphism. Polymorphism is the existence of different crystal forms of the same chemical compound. The different crystal polymorphs of a molecule may differ (and frequently do) in their chemical and physical properties, such as their melting point, solubility, and crystal habit. These properties in turn may influence the stability, bioavailability and flow behaviour of the compound.
  • Arzneim.-Forsch. Drug Res. 1990, 40, 536 described the physicochemical properties of a monoclinic crystalline form of asenapine maleate having a melting point in the range of 141 to 145 °C (form H) which comprised crystalline particles over 100 ⁇ in size.
  • Aqueous solubility of this monoclinic form is described to be 3 g/L (at 21 °C).
  • This patent application also describes that a micronization step is applied to reduce the particle size of the crystals, but that it is difficult to obtain a drug substance with high polymorph purity by micronization of the monoclinic form (form H) of asenapine maleate, since the outcome of the micronization process is very unpredictable when crystals of the monoclinic form of asenapine maleate are subjected to such a process.
  • analyses of the crystals following micronization of the monoclinic form revealed the presence of a second polymorph (orthorhombic form L) in addition to the known monoclinic form in the starting material.
  • This second polymorph (form L) has a melting point in the range of 138 to 142 °C.
  • European Patent EP 1 710 245 A1 also discloses that the orthorhombic form of asenapine maleate (form L) is obtainable with a smaller particle size (based on d 95 ) than the monoclinic form (form H) by means of crystallization techniques. Furthermore, it is said that micronization of the orthorhombic form of asenapine maleate reproducibly results in microcrystalline asenapine maleate of the orthorhombic form. Therefore, the teaching from EP 1 710 245 A1 is that a suitable and stable composition of crystalline asenapine maleate for sublingual or buccal administration can only be obtained from the orthorhombic form of asenapine maleate (form L) which shows high polymorphic purity after micronization.
  • European Patent EP 1 710 245 A1 describes the preparation of the monoclinic form of asenapine maleate (form H) by crystallization from ethanolic solutions and the preparation of the orthorhombic form of asenapine maleate (form L) by crystallization from 9: 1 v/v ethanol:water solutions.
  • this patent and International patent application number WO 2008/003460 A1 describe the preparation of the orthorhombic form of asenapine maleate (form L) by seeding a solution of asenapine maleate in a 3: 1 v/v acetone/heptane mixture with the desired orthorhombic form, followed by the addition of more heptane up to a solvent ratio of 1 :1.2 v/v acetone/heptane.
  • EP 1 710 245 A1 A teaching from EP 1 710 245 A1 is that asenapine maleate form H is obtained by crystallization from ethanol and that asenapine maleate form L is obtained by crystallization from mixtures of ethanol/water.
  • Patent application WO 201 1/159903 A2 relates to a monoclinic form of asenapine maleate, which is stable to micronization. This asenapine maleate monoclinic form apparently matches with previously described monoclinic form H.
  • This patent application discloses the preparation of this asenapine maleate monoclinic form by crystallization from 1-propanol or 2-propanol, optionally seeding with asenapine maleate monoclinic form.
  • This patent application also describes the micronization of this asenapine maleate monoclinic form using a Midas Micronizer 50, using nitrogen gas with pressures of 4-6 kg/cm 2 .
  • This micronization conditions are very similar to those reported in EP 1 710 245 A1 : Chrispro MC200 stainless steel JetMill, using nitrogen as the gas carrier and a micronization pressure of 7 bars.
  • asenapine maleate used herein as starting material to obtain asenapine maleate form M and/or form T as disclosed herein can be obtained by any of the processes described in the prior art.
  • Research Disclosure 523012 discloses solvent / anti-solvent recrystallization processes for the preparation of monoclinic asenapine maleate (form H).
  • the mixtures of solvents used for the preparation of monoclinic asenapine maleate are: acetone: methyl tert- butyl ether (MTBE) (1 : 10 v/v, rt, 0°C), methanol:diisopropyl ether (1 :10 v/v, rt, -78°C), acetone:diisopropyl ether (1 :5 v/v, rt), acetone: n-heptane (1 :10 v/v, rt and fast addition or at reflux), ethanol:n-heptane (1 :5 v/v, reflux), ethyl acetate:MTBE (12:25 v/v, during cooling after reflux), 2-propanol/n-heptane (1 : 10 v/v, 76°C), 1-propanol/n-heptane (1 :40 v/v, rt) and nitromethane:diethyl
  • mixtures of asenapine maleate forms H and L are obtained by recrystallization from ethyl acetate and toluene, by recrystallization with evaporation at air from acetonitrile, methanol and acetone, and with the following solvent / anti-solvent mixtures: acetone: n-heptane (1 :10 v/v, rt and slow addition), 1 ,4-dioxane/diisopropyl ether (1 :2 v/v, rt) and 1-butanol:n-heptane (1 :40 v/v, rt). It also states that typically asenapine maleate form H is obtained by recrystallization from alcoholic solvents.
  • IP.com 208816D published on July 19 th , 2011 discloses form A of asenapine maleate, which is obtained by crystallization from acetone/diethyl ether or from acetone/methyl te/f-butyl ether (MTBE) at -5 to -10 °C.
  • This form A apparently matches with the asenapine maleate form M reported herein.
  • It also discloses form B of asenapine maleate, which is obtained by crystallization from acetone/diethyl ether at -20 to -30 °C.
  • form C of asenapine maleate which is obtained by crystallization from acetone/diethyl ether, acetone/MTBE and isopropanol at temperatures above 20 °C.
  • IP.com 210074D published on August 25 th , 2011 discloses form S of asenapine maleate, which is substantially equivalent to form C as disclosed in IP.com 208816D, and which is obtained by treating a solution of asenapine base in isopropanol with maleic acid at 50 °C and cooling to room temperature.
  • IP.com 214225D published on January 18 th 2012 discloses forms I, II, III and IV of asenapine maleate.
  • Form IV is substantially equivalent to form A as disclosed in IP.com 208816D and consequently matches with the asenapine maleate form M reported herein.
  • Forms I, II and IV are obtained by mixing an ethanolic solution of asenapine maleate with MTBE using different procedures for the mixing step, solvent ratios, temperatures and stirring times.
  • Form III was obtained by crystallization from an ethanol/water mixture.
  • a well known problem associated with the micronization of crystalline products having more than one polymorphic form is that the high energy input associated with the micronization process for the reduction of particle size can promote the polymorphic transition from a less stable form to a more stable one. Generally, the most stable polymorph is known to have the lowest solubility value.
  • the orthorhombic form of asenapine maleate (form L) shows reduced water solubility when compared to the monoclinic form (form H), which is detrimental for its use in pharmaceutical formulations that are required to have high water solubility such as tablets for sublingual administration. Therefore, there is a need for new polymorphic forms of asenapine maleate that do not transform to the less soluble orthorhombic form (form L) during the micronization process, and that show an improved water solubility when compared to other asenapine maleate crystalline forms described in the prior art, such as the orthorhombic form (form L) and the monoclinic form (form H).
  • the present invention provides crystalline polymorphic forms of asenapine maleate, which are designated herein as "form M” and "form T".
  • Applicants have now identified new crystalline polymorphic forms of asenapine maleate (form M and form T), which can be micronized to a suitable particle size without a substantial conversion into the orthorhombic form (form L) and which show an improved water solubility when compared to the other polymorphic forms described in the prior art, for example the orthorhombic form (form L) and the monoclinic form (form H).
  • crystalline asenapine maleate form M and form T show excellent properties in term of stability, bioavailability, solubility and flowability, which contributes to a successful drug development.
  • these crystalline polymorphic forms M and form T are suitable to be formulated, for example in the form of tablets for sublingual or buccal administration.
  • the inventors of the present invention have found that these crystalline polymorphic form M and/or form T are surprisingly stable, for example in terms of chemical stability as well as in terms of polymorphic stability both as isolated products and when incorporated into compositions, for example in the form of tablets for sublingual or buccal administration, and additionally show a suitable dispersion and dissolution profile.
  • the first aspect of the invention provides crystalline asenapine maleate form M.
  • Crystalline asenapine maleate form M as herein disclosed may be characterized using XRD techniques.
  • the XRPD pattern of the crystalline asenapine maleate form M as herein disclosed comprises at least the following peaks (2-theta, 2 ⁇ ) at 5.5, 12.6 and 19.9° ( ⁇ 0.2 degrees), more preferably at 5.5, 12.6, 19.1 , 19.9 and 25.2° ( ⁇ 0.2 degrees), and even more preferably at 5.5, 9.9, 1 1.0, 12.6, 13.7, 14.6, 16.7, 17.3, 18.5, 19.1 , 19.9, 20.8, 21.6, 22.0, 23.4, 24.2, 25.2, 25.9, 26.7, 27.7, 28.7, 29.3, 29.8, 30.6, 33.4, 34.4, 34.9, 38.8, 39.2 and 40.2° ( ⁇ 0.2 degrees).
  • Figure 1 shows a X-Ray Powder Diffraction pattern of crystalline asenapine maleate form M as herein disclosed.
  • asenapine maleate form M which contains 20% (w/w) or less of another crystalline form, preferably 10% (w/w) or less of another crystalline form, more preferably 5% (w/w) or less of another crystalline form, and even more preferably 1 % (w/w) or less of another crystalline form.
  • the present invention provides asenapine maleate wherein at least 80% (w/w) of the asenapine maleate is crystalline asenapine maleate form M, preferably at least 90% (w/w) of the asenapine maleate is crystalline asenapine maleate form M, more preferably at least 95% (w/w) of the asenapine maleate is crystalline asenapine maleate form M.
  • the asenapine maleate as herein disclosed consists essentially of crystalline asenapine maleate form M, namely, the asenapine maleate contains more than 99% (w/w) of the crystalline asenapine maleate form M, preferably the asenapine maleate contains more than 99.5% (w/w) of the crystalline asenapine maleate form M, more preferably the asenapine maleate contains more than 99.9% (w/w) of the crystalline asenapine maleate form M.
  • the present invention provides asenapine maleate form M wherein less than 20% (w/w) of the asenapine maleate is asenapine maleate amorphous form, preferably less than 10% (w/w) of the asenapine maleate is asenapine maleate amorphous form, more preferably less than 5% (w/w) of the asenapine maleate is asenapine maleate amorphous form, and even more preferably less than 1 % (w/w) of the asenapine maleate is asenapine maleate amorphous form.
  • the present invention further provides asenapine maleate form M that is microcrystalline.
  • asenapine maleate form M is considered to be microcrystalline when it has a particle size distribution characterized by a d 90 of 100 ⁇ or less, preferably a d 90 of 50 ⁇ or less, even more preferably a d 90 of 30 ⁇ or less.
  • the notation d x [also written as d(v, 0.X)] means that X% of the particles have a diameter less than a specified diameter d.
  • a d 90 [or D(v, 0.9)] of 100 ⁇ means that 90% of the particles have a diameter less than 100 ⁇ .
  • Yet another aspect of the present invention relates to a process for the preparation of crystalline asenapine maleate form M as herein disclosed.
  • the process comprises crystallization of asenapine maleate from a solvent or mixture of solvents and seeding with crystalline asenapine maleate form M.
  • seeding with crystalline asenapine maleate form M refers to the addition of crystalline asenapine maleate form M to facilitate obtaining crystalline asenapine maleate form M.
  • Another embodiment of the present invention relates to a process for preparing crystalline asenapine maleate form M comprising at least the following steps: i) dissolving asenapine maleate in a solvent or a mixture of solvents at a temperature between 5°C and 80°C, more preferably between 30°C and 60°C, even more preferably between 40°C and 56°C;
  • step (iii) combining the solution prepared in step (i) or in step (ii) with an antisolvent while maintaining the temperature between 40°C and 100°C;
  • step (iii) cooling the mixture prepared in step (iii) to a temperature between -20°C and 39°C, preferably between -10°C and 25°C, wherein the solvent or the mixture of solvents comprises a ketone, preferably acetone, methyl ethyl ketone or methyl isobutyl ketone, and the antisolvent comprises an alkane or a mixture of alkanes such as pentane, hexane, cyclohexane, methylcyclohexane, heptane or mixtures thereof.
  • the solvent or the mixture of solvents comprises a ketone, preferably acetone, methyl ethyl ketone or methyl isobutyl ketone
  • the antisolvent comprises an alkane or a mixture of alkanes such as pentane, hexane, cyclohexane, methylcyclohexane, heptane or mixtures thereof.
  • the temperatures within the above ranges need to be selected taking into consideration the specific and/or antisolvents employed so that it is avoided to work at temperatures above the boiling points of these solvents and/or antisolvents.
  • the solvent or the mixture of solvents is selected from the group consisting of ketones, preferably acetone, methyl ethyl ketone or methyl isobutyl ketone and mixtures thereof
  • the antisolvent is selected from the group consisting of alkanes such as pentane, hexane, cyclohexane, methylcyclohexane, heptane and mixtures thereof.
  • the above mentioned process is conducted either without any seeding step or seeding at any time after step (ii) with crystalline asenapine maleate form M.
  • the term "combining the solution prepared in step (i) or in step (ii) with an antisolvent” as used herein comprises the addition of the solution prepared in step (i) or in step (ii) over the antisolvent, or the addition of the antisolvent over the solution prepared in step (i) or in step (ii), or the simultaneous addition of the solution prepared in step (i) or in step (ii) and the antisolvent into a receiving vessel.
  • the mixtures of solvent or mixture of solvents and antisolvent have a solvent or mixture of solvents/antisolvent volume/volume ratio from 3: 1 to 1 :5, more preferably from 2: 1 to 1 :2, even more preferably from 1.2:1 to 1 : 1.2.
  • Crystalline asenapine maleate form M as herein disclosed is preferably obtained by a process which comprises at least the following steps: i) dissolving asenapine maleate in acetone at a temperature between 30°C and 56°C; ii) optionally filtering the solution prepared in step (i);
  • step (iii) combining the solution prepared in step (i) or in step (ii) with hexane, heptane or mixtures thereof, while maintaining the temperature between 40°C and 98°C;
  • step (iii) cooling the mixture prepared in step (iii) to a temperature between -20°C and 39°C, preferably between -10°C and 25°C.
  • the above mentioned process is conducted either without any seeding step or seeding at any time after step (ii) with crystalline asenapine maleate form M.
  • asenapine maleate form M is obtained by a process which comprises at least the following steps: i) dissolving asenapine maleate in acetone at a temperature between 30°C and 56°C; ii) optionally filtering the solution prepared in step (i);
  • step (iii) combining the solution prepared in step (i) or in step (ii) with hexane while maintaining the mixture between 40°C and 60°C;
  • step (iii) cooling the mixture prepared in step (iii) to a temperature between -20°C and 39°C, preferably between -10°C and 25°C.
  • the above mentioned process is conducted either without any seeding step or seeding at any time after step (ii) with crystalline asenapine maleate form M.
  • the mixtures of acetone and hexane used for the preparation of asenapine maleate form M as herein disclosed have an acetone/hexane volume/volume ratio from 3:1 to 1 :5, more preferably from 2: 1 to 1 :2, even more preferably from 1.2: 1 to 1 : 1.2.
  • hexane is added over the solution of asenapine maleate in acetone at a temperature between 40°C and 60°C.
  • asenapine maleate form M is obtained by a process which comprises at least the following steps: i) dissolving asenapine maleate in acetone at a temperature between 30°C and 56°C; ii) optionally filtering the solution prepared in step (i);
  • step (iii) combining the solution prepared in step (i) or in step (ii) with heptane while maintaining the temperature between 40°C and 98°C;
  • step (iii) cooling the mixture prepared in step (iii) to a temperature between -20°C and 39°C, preferably between -10°C and 25°C.
  • the above mentioned process is conducted either without any seeding step or seeding at any time after step (ii) with crystalline asenapine maleate form M.
  • the mixtures of acetone and heptane used for the preparation of asenapine maleate form M as herein disclosed have an acetone/heptane volume/volume ratio from 3:1 to 1 :5, more preferably from 2: 1 to 1 :2, even more preferably from 1.2: 1 to 1 :1.2.
  • heptane is added over the solution of asenapine maleate in acetone at a temperature between 40°C and 98°C.
  • crystalline asenapine maleate form M is obtained by a process which comprises suspending asenapine maleate in a solvent or mixture of solvents wherein asenapine maleate remains at least partially undissolved and seeding with crystalline asenapine maleate form M.
  • the solvent or mixture of solvents in which asenapine maleate is suspended comprises C1-C4 alkyl alcohols such as methanol, ethanol, propanol and butanol, more preferably isopropanol and still more preferably the solvent is isopropanol alone.
  • the crystalline asenapine maleate form M obtained according to the precesses disclosed herein is preferably isolated by filtration.
  • the asenapine maleate form M that is microcrystalline as herein disclosed can be obtained by any conventional mechanical process of reducing the size of particles of asenapine maleate form M.
  • Non-limiting examples of mechanical processes of reducing the size of particles of asenapine maleate form M are cutting, chipping, micronizing, milling, crushing, grinding and triturating.
  • milling typically by carrying out milling comprises air-jet milling or pin milling.
  • Micronizing and/or air-jet milling can be preferably carried out in any commercially available micronizer and/or mill working at a gas pressure from 1 bar to 15 bar.
  • gas pressure comprises air pressure or nitrogen pressure.
  • Pin milling can be preferably carried out in any commercially available pin mill working from 3000 rpm to 14000 rpm.
  • the asenapine maleate form M that is microcrystalline as herein disclosed can also be directly obtained by means of the crystallization and/or slurrying processes as herein disclosed without the need of including an additional step of reducing the particle size of the asenapine maleate form M.
  • Particle size of the microcrystalline asenapine maleate form M as herein disclosed is determined by laser diffraction using a Malvern Mastersizer instrument as explained in the experimental section.
  • a further aspect of the present invention provides pharmaceutical compositions comprising the crystalline asenapine maleate form M, alone or in combination with at least one additional polymorphic and/or amorphous form of asenapine maleate, and at least one pharmaceutically acceptable carrier.
  • compositions as herein disclosed may contain from 0.005 mg to 500 mg of crystalline asenapine maleate form M, preferably from 1 mg to 250 mg of crystalline asenapine maleate form M, more preferably the pharmaceutical compositions as herein disclosed contain from 3 mg to 150 mg of crystalline asenapine maleate form M.
  • the invention further relates to the use of crystalline asenapine maleate form M for the manufacture of a sublingual or buccal pharmaceutical composition for treating mental disorders such as psychosis, schizophrenia and bipolar disorders.
  • a further aspect of the invention provides new crystalline asenapine maleate form T.
  • Crystalline asenapine maleate form T as herein disclosed may be characterized using X-Ray diffraction (XRD) techniques.
  • XRD X-Ray diffraction
  • the XRPD pattern of the crystalline asenapine maleate form T as herein disclosed comprises at least the following peaks (2-theta, 2 ⁇ ) at 7.6, 10.4 and 19.1° ( ⁇ 0.2 degrees), more preferably at 7.6, 9.5, 10.4, 19.1 , 19.5 and 20.0° ( ⁇ 0.2 degrees), and even more preferably at 7.6, 8.3, 9.5, 10.4, 1 1.2, 12.6, 13.3, 13.9, 15.7, 16.3, 16.7, 17.1 , 17.4, 17.8, 18.6, 19.1 , 19.5, 20.0, 20.9, 21.7, 22.5, 22.9, 23.5, 24.4, 24.9, 25.3, 26.7, 28.0, 28.3, 29.1 , 29.6 and 31.9° ( ⁇ 0.2 degrees).
  • Figure 2 shows a X-Ray Powder Diffraction pattern of crystalline asen
  • asenapine maleate form T which contains 20% (w/w) or less of another crystalline form, preferably 10% (w/w) or less of another crystalline form, more preferably 5% (w/w) or less of another crystalline form, and even more preferably 1 % (w/w) or less of another crystalline form.
  • the present invention provides asenapine maleate wherein at least 80% (w/w) of the asenapine maleate is crystalline asenapine maleate form T, preferably at least 90% (w/w) of the asenapine maleate is crystalline asenapine maleate form T, more preferably at least 95% (w/w) of the asenapine maleate is crystalline asenapine maleate form T.
  • the asenapine maleate as herein disclosed consists essentially of crystalline asenapine maleate form T, namely, the asenapine maleate contains more than 99% (w/w) of the crystalline asenapine maleate form T, preferably the asenapine maleate contains more than 99.5% (w/w) of the crystalline asenapine maleate form T, more preferably the asenapine maleate contains more than 99.9% (w/w) of the crystalline asenapine maleate form T.
  • the present invention provides asenapine maleate form T wherein less than 20% (w/w) of the asenapine maleate is asenapine maleate amorphous form, preferably less than 10% (w/w) of the asenapine maleate is asenapine maleate amorphous form, more preferably less than 5% (w/w) of the asenapine maleate is asenapine maleate amorphous form, and even more preferably less than 1 % (w/w) of the asenapine maleate is asenapine maleate amorphous form.
  • the present invention further provides asenapine maleate form T that is microcrystalline.
  • the asenapine maleate form T is considered to be microcrystalline when it has a particle size distribution characterized by a d 90 of 100 ⁇ or less, preferably a d 90 of 50 ⁇ or less, even more preferably a d 90 of 30 ⁇ or less.
  • the notation d x [also written as d(v, 0.X)] means that X% of the particles have a diameter less than a specified diameter d.
  • a d 90 [or D(v, 0.9)] of 100 ⁇ means that 90% of the particles have a diameter less than 100 ⁇ .
  • Yet another aspect of the present invention relates to a process for the preparation of crystalline asenapine maleate form T as herein disclosed.
  • the process comprises crystallization of asenapine maleate from a solvent or mixture of solvents and seeding with crystalline asenapine maleate form T.
  • seeding with crystalline asenapine maleate form T refers to the addition of crystalline asenapine maleate form T to facilitate obtaining crystalline asenapine maleate form T.
  • Another embodiment of the present invention relates to a process for preparing crystalline asenapine maleate form T comprising at least the following steps: i) dissolving asenapine maleate in a solvent or a mixture of solvents at a temperature between 5°C and 80°C, more preferably between 15°C and 40°C, even more preferably between 20°C and 25°C;
  • iii) combining the solution prepared in step (i) or in step (ii) with an antisolvent while maintaining the mixture at a temperature between -20°C and 35°C, more preferably between -10°C and 25°C, wherein the solvent or the mixture of solvents comprises a ketone, preferably acetone, methyl ethyl ketone or methyl isobutyl ketone, and the antisolvent comprises an alkane or a mixture of alkanes such as pentane, hexane, cyclohexane, methylcyclohexane, heptane or mixtures thereof.
  • the temperatures within the above ranges need to be selected takinh into consideration the specific and/or antisolvents employed so that it is avoided to work at temperatures above the boiling points of these solvents and/or antisolvents.
  • the solvent or the mixture of solvents is selected from the group consisting of ketones, preferably acetone, methyl ethyl ketone or methyl isobutyl ketone and mixtures thereof
  • the antisolvent is selected from the group consisting of alkanes such as pentane, hexane, cyclohexane, methylcyclohexane, heptane and mixtures thereof.
  • step ii) the above mentioned process is conducted either without any seeding step or seeding at any point in time after step ii) with crystalline asenapine maleate form T.
  • combining the solution prepared in step (i) or in step (ii) with an antisolvent comprises the addition of the solution prepared in step (i) or in step (ii) over the antisolvent, or the addition of the antisolvent over the solution prepared in step (i) or in step (ii), or the simultaneous addition of the solution prepared in step (i) or in step (ii) and the antisolvent into a receiving vessel.
  • the solvent or mixture of solvents and the antisolvent have a solvent or mixture of solvents/antisolvent volume/volume ratio from 3:1 to 1 : 10, more preferably from 2:1 to 1 :6, even more preferably from 1 : 1 to 1 :5.
  • the process for preparing crystalline asenapine maleate form T comprises at least the following steps: i) dissolving asenapine maleate in a solvent or a mixture of solvents at a temperature between 5°C and 80°C, more preferably between 15°C and 40°C, even more preferably between 20°C and 25°C;
  • step (iii) combining the solution prepared in step (i) or in step (ii) with an antisolvent while maintaining the mixture at a temperature between 20°C and 25°C, wherein the solvent or the mixture of solvents comprises a ketone, preferably acetone, methyl ethyl ketone or methyl isobutyl ketone, and the antisolvent comprises an alkane or a mixture of alkanes such as pentane, hexane, cyclohexane, methylcyclohexane, heptane or mixtures thereof.
  • the solvent or the mixture of solvents comprises a ketone, preferably acetone, methyl ethyl ketone or methyl isobutyl ketone
  • the antisolvent comprises an alkane or a mixture of alkanes such as pentane, hexane, cyclohexane, methylcyclohexane, heptane or mixtures thereof.
  • asenapine maleate form T is obtained by a process which comprises at least the following steps: i) dissolving asenapine maleate in methyl ethyl ketone at a temperature between 20°C and 25°C;
  • step (iii) combining the solution prepared in step (i) or in step (ii) with cyclohexane while maintaining the mixture at a temperature between 20°C and 25°C.
  • the above mentioned process is conducted either without any seeding step or seeding at any point in time after step ii) with crystalline asenapine maleate form T.
  • the mixtures of methyl ethyl ketone and cyclohexane used for the preparation of asenapine maleate form T as herein disclosed have a methyl ethyl ketone/cyclohexane volume/volume ratio from 3: 1 to 1 :10, more preferably from 1 :2 to 1 :6, even more preferably from 1.2:1 to 1 :2.5.
  • the solution of asenapine maleate in methyl ethyl ketone is added over the cyclohexane while maintaining the mixture at a temperature between 20°C and 25°C, or the cyclohexane is added over the solution of asenapine maleate in methyl ethyl ketone while maintaining the mixture at a temperature between 20°C and 25°C.
  • asenapine maleate form T is obtained by a process which comprises at least the following steps: i) dissolving asenapine maleate in acetone at a temperature between 20°C and 25°C; ii) optionally filtering the solution prepared in step (i);
  • step (iii) combining the solution prepared in step (i) or in step (ii) with cyclohexane while maintaining the mixture at a temperature between 20°C and 25°C.
  • the above mentioned process is conducted either without any seeding step or seeding at any point in time after step ii) with crystalline asenapine maleate form T.
  • the mixtures of acetone and cyclohexane used for the preparation of asenapine maleate form T as herein disclosed have an acetone/cyclohexane volume/volume ratio from 3:1 to 1 : 10, more preferably from 1 :2 to 1 :6, even more preferably from 1 :3.1 to 1 :3.5.
  • the solution of asenapine maleate in acetone is added over the cyclohexane while maintaining the mixture at a temperature between 20°C and 25°C.
  • the process for preparing crystalline asenapine maleate form T comprises at least the following steps: i) dissolving asenapine maleate in a solvent or a mixture of solvents at a temperature between 5°C and 80°C, more preferably between 15°C and 40°C, even more preferably between 20°C and 25°C;
  • step (iii) combining the solution prepared in step (i) or in step (ii) with an antisolvent while maintaining the mixture at a temperature between 0°C and 10°C, preferably 5°C, wherein the solvent or the mixture of solvents comprises a ketone, preferably acetone, methyl ethyl ketone or methyl isobutyl ketone, and the antisolvent comprises an alkane or a mixture of alkanes such as pentane, hexane, cyclohexane, methylcyclohexane, heptane or mixtures thereof.
  • the solvent or the mixture of solvents comprises a ketone, preferably acetone, methyl ethyl ketone or methyl isobutyl ketone
  • the antisolvent comprises an alkane or a mixture of alkanes such as pentane, hexane, cyclohexane, methylcyclohexane, heptan
  • step ii) the above mentioned process is conducted either without any seeding step or seeding at any point in time after step ii) with crystalline asenapine maleate form T.
  • asenapine maleate form T is obtained by a process which comprises at least the following steps: i) dissolving asenapine maleate in methyl ethyl ketone at a temperature between 20°C and 25°C;
  • step (iii) combining the solution prepared in step (i) or in step (ii) with heptane while maintaining the mixture at a temperature between 0°C and 10°C, preferably 5°C.
  • the above mentioned process is conducted either without any seeding step or seeding at any point in time after step ii) with crystalline asenapine maleate form T.
  • the mixtures of methyl ethyl ketone and heptane used for the preparation of asenapine maleate form T as herein disclosed have a methyl ethyl ketone/heptane volume/volume ratio from 3:1 to 1 :10, more preferably from 1 : 1 to 1 :6, even more preferably from 1 :2.1 to 1 :2.5.
  • the heptane is added over the solution of asenapine maleate in methyl ethyl ketone while maintaining the mixture at a temperature between 0°C and 10°C, preferably 5°C.
  • the process for preparing crystalline asenapine maleate form T comprises at least the following steps: i) dissolving asenapine maleate in a solvent or a mixture of solvents at a temperature between 5°C and 80°C, more preferably between 15°C and 40°C, even more preferably between 20°C and 25°C;
  • step (iii) combining the solution prepared in step (i) or in step (ii) with an antisolvent while maintaining the mixture at a temperature between -10°C and -5°C
  • the solvent or the mixture of solvents comprises a ketone, preferably acetone, methyl ethyl ketone or methyl isobutyl ketone
  • the antisolvent comprises an alkane or a mixture of alkanes such as pentane, hexane, cyclohexane, methylcyclohexane, heptane or mixtures thereof.
  • the above mentioned process is conducted either without any seeding step or seeding at any point in time after step ii) with crystalline asenapine maleate form T.
  • asenapine maleate form T is obtained by a process which comprises at least the following steps: i) dissolving asenapine maleate in acetone at a temperature between 20°C and 25°C; ii) optionally filtering the solution prepared in step (i);
  • step (iii) combining the solution prepared in step (i) or in step (ii) with hexane while maintaining the mixture at a temperature between -10°C and -5°C.
  • step ii) the above mentioned process is conducted either without any seeding step or seeding at any point in time after step ii) with crystalline asenapine maleate form T.
  • the mixtures of acetone and hexane used for the preparation of asenapine maleate form T as herein disclosed have an acetone/hexane volume/volume ratio from 3:1 to 1 : 10, more preferably from 1 :2 to 1 :6, even more preferably from 1 :3.1 to 1 :3.5.
  • the solution of asenapine maleate in acetone is added over the hexane while maintaining the mixture at a temperature between -10°C and -5°C.
  • asenapine maleate form T is obtained by a process which comprises at least the following steps: i) dissolving asenapine maleate in acetone at a temperature between 20°C and 25°C; ii) optionally filtering the solution prepared in step (i);
  • step (iii) combining the solution prepared in step (i) or in step (ii) with heptane while maintaining the mixture at a temperature between -10°C and -5°C.
  • the above mentioned process is conducted either without any seeding step or seeding at any point in time after step ii) with crystalline asenapine maleate form T.
  • the mixtures of acetone and heptane used for the preparation of asenapine maleate form T as herein disclosed have an acetone/heptane volume/volume ratio from 3:1 to 1 : 10, more preferably from 1 :2 to 1 :6, even more preferably from 1 :3.1 to 1 :3.5.
  • the solution of asenapine maleate in acetone is added over the heptane while maintaining the mixture at a temperature between -10°C and -5°C.
  • asenapine maleate form T is obtained by a process which comprises at least the following steps: i) dissolving asenapine maleate in acetone at a temperature between 20°C and 25°C; ii) optionally filtering the solution prepared in step (i);
  • step (iii) combining the solution prepared in step (i) or in step (ii) with methylcyclohexane while maintaining the mixture at a temperature between -10°C and -5°C.
  • the above mentioned process is conducted either without any seeding step or seeding at any point in time after step ii) with crystalline asenapine maleate form T.
  • the mixtures of acetone and methylcyclohexane used for the preparation of asenapine maleate form T as herein disclosed have an acetone/methylcyclohexane volume/volume ratio from 3:1 to 1 : 10, more preferably from 1 :2 to 1 :6, even more preferably from 1 :3.1 to 1 :3.5.
  • the solution of asenapine maleate in acetone is added over the methylcyclohexane while maintaining the mixture at a temperature between -10°C and -5°C.
  • asenapine maleate form T is obtained by a process which comprises at least the following steps: i) dissolving asenapine maleate in methyl ethyl ketone at a temperature between 20°C and 25°C;
  • step (iii) combining the solution prepared in step (i) or in step (ii) with hexane while maintaining the mixture at a temperature between -10°C and -5°C.
  • the above mentioned process is conducted either without any seeding step or seeding at any point in time after step ii) with crystalline asenapine maleate form T.
  • the mixtures of methyl ethyl ketone and hexane used for the preparation of asenapine maleate form T as herein disclosed have an methyl ethyl ketone /hexane volume/volume ratio from 3:1 to 1 : 10, more preferably from 1 :2 to 1 :6, even more preferably from 1 :2.1 to 1 :2.5.
  • the solution of asenapine maleate in methyl ethyl ketone is added over the hexane while maintaining the mixture at a temperature between -10°C and -5°C.
  • asenapine maleate form T is obtained by a process which comprises at least the following steps: i) dissolving asenapine maleate in methyl ethyl ketone at a temperature between 20°C and 25°C;
  • step (iii) combining the solution prepared in step (i) or in step (ii) with heptane while maintaining the mixture at a temperature between -10°C and -5°C.
  • step ii) the above mentioned process is conducted either without any seeding step or seeding at any point in time after step ii) with crystalline asenapine maleate form T.
  • the mixtures of methyl ethyl ketone and heptane used for the preparation of asenapine maleate form T as herein disclosed have an methyl ethyl ketone/heptane volume/volume ratio from 3:1 to 1 : 10, more preferably from 1 :2 to 1 :6, even more preferably from 1 :2.1 to 1 :2.5.
  • the solution of asenapine maleate in methyl ethyl ketone is added over the heptane while maintaining the mixture at a temperature between -10°C and -5°C.
  • asenapine maleate form T is obtained by a process which comprises at least the following steps: i) dissolving asenapine maleate in methyl ethyl ketone at a temperature between 20°C and 25°C;
  • step (iii) combining the solution prepared in step (i) or in step (ii) with methylcyclohexane while maintaining the mixture at a temperature between -10°C and -5°C.
  • the above mentioned process is conducted either without any seeding step or seeding at any point in time after step ii) with crystalline asenapine maleate form T.
  • the mixtures of methyl ethyl ketone and methylcyclohexane used for the preparation of asenapine maleate form T as herein disclosed have an methyl ethyl ketone /methylcyclohexane volume/volume ratio from 3: 1 to 1 : 10, more preferably from 1 :2 to 1 :6, even more preferably from 1 :2.1 to 1 :2.5.
  • the solution of asenapine maleate in methyl ethyl ketone is added over the methylcyclohexane while maintaining the mixture at a temperature between -10°C and -5°C.
  • the process for preparing crystalline asenapine maleate form T comprises at least the following steps: i) dissolving asenapine maleate in methyl ethyl ketone at a temperature between 5°C and 80°C, more preferably between 15°C and 40°C, even more preferably between 20°C and 25°C;
  • step (iii) combining the solution prepared in step (i) or in step (ii) with an antisolvent comprising an ether such as diethyl ether, diisopropyl ether, methyl te/f-butyl ether, cyclopentyl methyl ether or mixtures thereof, while maintaining the mixture at a temperature between -10°C and -5°C.
  • an antisolvent comprising an ether such as diethyl ether, diisopropyl ether, methyl te/f-butyl ether, cyclopentyl methyl ether or mixtures thereof, while maintaining the mixture at a temperature between -10°C and -5°C.
  • the antisolvent is selected from the group consisting of ethers, preferably diethyl ether, diisopropyl ether, methyl te/f-butyl ether, cyclopentyl methyl ether or mixtures thereof.
  • the above mentioned process is conducted either without any seeding step or seeding at any point in time after step ii) with crystalline asenapine maleate form T.
  • the mixtures of methyl ethyl ketone and ether used for the preparation of asenapine maleate form T as herein disclosed have an methyl ethyl ketone/ether volume/volume ratio from 3:1 to 1 : 10, more preferably from 1 :2 to 1 :6, even more preferably from 1 :2.1 to 1 :2.5.
  • asenapine maleate form T is obtained by a process which comprises at least the following steps: i) dissolving asenapine maleate in methyl ethyl ketone at a temperature between 20°C and 25°C;
  • step (iii) combining the solution prepared in step (i) or in step (ii) with methyl te/f-butyl ether while maintaining the mixture at a temperature between -10°C and -5°C.
  • the above mentioned process is conducted either without any seeding step or seeding at any point in time after step ii) with crystalline asenapine maleate form T.
  • the mixtures of methyl ethyl ketone and methyl te/f-butyl ether used for the preparation of asenapine maleate form T as herein disclosed have an methyl ethyl ketone / methyl te/f-butyl ether volume/volume ratio from 3:1 to 1 :10, more preferably from 1 :2 to 1 :6, even more preferably from 1 :2.1 to 1 :2.5.
  • the solution of asenapine maleate in methyl ethyl ketone is added over the methyl te/f-butyl ether while maintaining the mixture at a temperature between -10°C and -5°C.
  • asenapine maleate form T is obtained by a process which comprises at least the following steps: i) dissolving asenapine maleate in methyl ethyl ketone at a temperature between 20°C and 25°C;
  • step (iii) combining the solution prepared in step (i) or in step (ii) with cyclopentyl methyl ether while maintaining the mixture at a temperature between -10°C and -5°C.
  • the above mentioned process is conducted either without any seeding step or seeding at any point in time after step ii) with crystalline asenapine maleate form T.
  • the mixtures of methyl ethyl ketone and cyclopentyl methyl ether used for the preparation of asenapine maleate form T as herein disclosed have an methyl ethyl ketone / cyclopentyl methyl ether volume/volume ratio from 3: 1 to 1 : 10, more preferably from 1 :2 to 1 :6, even more preferably from 1 :2.1 to 1 :2.5.
  • the solution of asenapine maleate in methyl ethyl ketone is added over the cyclopentyl methyl ether while maintaining the mixture at a temperature between -10°C and -5°C.
  • the process for preparing crystalline asenapine maleate form T comprises at least the following steps: i) dissolving asenapine maleate in acetone at a temperature between 20°C and 25°C; ii) optionally filtering the solution prepared in step (i);
  • step (iii) combining the solution prepared in step (i) or in step (ii) with cyclopentyl methyl ether while maintaining the mixture at a temperature between -10°C and -5°C.
  • step ii) the above mentioned process is conducted either without any seeding step or seeding at any point in time after step ii) with crystalline asenapine maleate form T.
  • the mixtures of acetone and cyclopentyl methyl ether used for the preparation of asenapine maleate form T as herein disclosed have an acetone / cyclopentyl methyl ether volume/volume ratio from 3: 1 to 1 :10, more preferably from 1 :2 to 1 :6, even more preferably from 1 :3.1 to 1 :3.5.
  • the solution of asenapine maleate in acetone is added over the cyclopentyl methyl ether while maintaining the mixture at a temperature between -10°C and -5°C.
  • the crystalline asenapine maleate form T obtained according to the processes disclosed herein is preferably isolated by filtration at a temperature between -20°C and 35°C, preferably between -10°C and 25°C.
  • crystalline asenapine maleate form T is obtained by a process which comprises suspending asenapine maleate in a solvent or mixture of solvents wherein asenapine maleate remains at least partially undissolved and seeding with crystalline asenapine maleate form T.
  • the asenapine maleate form T that is microcrystalline as herein disclosed can be obtained by any conventional mechanical process of reducing the size of particles of asenapine maleate form T.
  • Non-limiting examples of mechanical processes of reducing the size of particles of asenapine maleate form T are cutting, chipping, micronizing, milling, crushing, grinding and triturating.
  • milling typically by carrying out milling comprises air-jet milling or pin milling.
  • Micronizing and/or air-jet milling can be preferably carried out in any commercially available micronizer and/or mill working at a gas pressure from 1 bar to 15 bar.
  • gas pressure comprises air pressure or nitrogen pressure.
  • Pin milling can be preferably carried out in any commercially available pin mill working from 3000 rpm to 14000 rpm.
  • the asenapine maleate form T that is microcrystalline as herein disclosed can also be directly obtained by means of the crystallization and/or slurrying processes as herein disclosed without the need of including an additional step of reducing the particle size of the asenapine maleate form T.
  • Particle size of the microcrystalline asenapine maleate form T as herein disclosed is determined by laser diffraction using a Malvern Mastersizer instrument as explained in the experimental section.
  • a further aspect of the present invention provides pharmaceutical compositions comprising the crystalline asenapine maleate form T, alone or in combination with at least one additional polymorphic and/or amorphous form of asenapine maleate, and at least one pharmaceutically acceptable carrier.
  • compositions as herein disclosed may contain from 0.005 mg to 500 mg of crystalline asenapine maleate form T, preferably from 1 mg to 250 mg of crystalline asenapine maleate form T, more preferably the pharmaceutical compositions as herein disclosed contain from 3 mg to 150 mg of crystalline asenapine maleate form T.
  • the invention further relates to the use of crystalline asenapine maleate form T for the manufacture of a sublingual or buccal pharmaceutical composition for treating mental disorders such as psychosis, schizophrenia and bipolar disorders.
  • pharmaceutically acceptable carrier refers to a excipient, diluent, adjuvant, or carrier with which a compound of the invention is administered.
  • alkane is used to designate fully saturated, linear or branched hydrocarbon compounds which may be monocyclic or non-cyclic.
  • Non-cyclic alkanes have empiric formula C n H 2 n+2 wherein n is an integer. Examples of non-cyclic alkanes are pentane, hexane and heptane.
  • Non-cyclic alkanes may be branched or non-branched.
  • hexane encompasses any isomer of formula C 6 H 14 such as hexane, 2-methylpentane, 3-methylpentane, 2,3-dimethylbutane, 2,2- dimethylbutane and mixtures thereof.
  • heptanes encompasses any isomer of formula C 7 H 16 such as n-heptane, 2-methylhexane, 3-methylhexane, 2,2- dimethylpentane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3- ethylpentane, 2,2,3-trimethylbutane and mixtures thereof.
  • Monocyclic alkanes have empiric formula C n H 2n wherein n is an integer. Cyclic alkanes may be branched or non- branched. Thus, for example, both cyclohexane and methylcyclohexane will be considered cycloalkanes.
  • excipient refers to any pharmaceutically acceptable ingredient that is commonly used in the pharmaceutical technology for preparing granulate and/or solid oral dosage formulations.
  • categories of excipients include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers and diluents.
  • One of ordinary skill in the art may select one or more of the aforementioned excipients with respect to the particular desired properties of the granulate and/or solid oral dosage form by routine experimentation and without any undue burden.
  • the amount of each excipient used may vary within ranges conventional in the art.
  • the following references, which are all hereby incorporated by reference discloses techniques and excipients used to formulate oral dosage forms.
  • diluent refers to an excipient which fills out the size of a tablet or capsule, making it practical to produce and convenient for the consumer to use. Suitable diluents include e.g.
  • inert fillers such as microcrystalline cellulose, lactose, dibasic calcium phosphate sugar, sugar alcohols, corn starch, sucrose, silicic anhydride, polysaccharides, N-methyl pyrrolidone (Pharmasolve (ISP)) and mixtures thereof.
  • sugar and sugar alcohols comprises mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and mixtures thereof.
  • adjuvant refers to any component which improves the body's response to a pharmaceutical composition.
  • carrier refers to a compound that facilitates the incorporation of an active ingredient into the body.
  • pharmaceutical compositions as herein disclosed are sublingual or buccal tablets.
  • compositions as herein disclosed can be preferably prepared as disclosed in US patent No 5,763,476 and as described in example 16 of European Patent application EP 1 ,710,245 A1.
  • asenapine maleate used herein as starting material to obtain asenapine maleate form M or form T as disclosed herein can be obtained by any of the processes described in the prior art.
  • Powdered samples were pressed between two glass plates, forming a film.
  • DIFFRAC Plus measurement software with EVA evaluation software (Bruker) was used to record the data and for a primary analysis of the diffraction patterns.
  • the equipment was periodically calibrated using quartz and silicon.
  • the chromatographic separation was carried out in a Phenomenex Prodigy ODS-3, 5 ⁇ , 4.6 x 250 mm column at 30 °C.
  • the mobile phase A was prepared by adjusting the pH of a water / acetonitrile / methanol / methanesulfonic acid (60 : 18 : 22 : 0.1) v/v/v/v to 2.5 with diethylamine.
  • the mobile phase B was acetonitrile.
  • the chromatograph was programmed as follows: initial 0-4 min 0 % mobile phase B, 4- 18 min linear gradient to 15 % mobile phase B, 18-60 min isocratic 15% mobile phase B, 60-65 min linear gradient to 0 % mobile phase B and 65-70 min equilibration with 0 % mobile phase B.
  • the chromatograph was equipped with a 210 nm detector and the flow rate was 1.5 mL per minute. 10 ⁇ _ of the test samples were injected. The samples were prepared by dissolving the appropriate amount of sample in mobile phase A, to obtain a concentration of 1.5 mg per mL. The chromatogram was run for at least 50 min. The approximate retention time for asenapine was found to be 18 min.
  • HPLC method 2 The chromatographic separation was carried out in a Kromasil 100 C18, 5 ⁇ , 4.6 x 250 mm column at 30 °C.
  • the mobile phase A was prepared by adjusting the pH of a 0.1 % methanesulfonic acid solution in water to 2.5 with diethylamine.
  • the mobile phase B was acetonitrile.
  • the chromatograph was programmed as follows: initial 0-3 min 25 % mobile phase B, 3-50 min linear gradient to 65 % mobile phase B, 50-55 min isocratic 65 % mobile phase B, 55-70 min linear gradient to 90 % mobile phase B, 70-100 min isocratic 90 % mobile phase B, 100-105 min linear gradient to 25 % mobile phase B and 105-1 10 min equilibration with 25 % mobile phase B.
  • the chromatograph was equipped with a 210 nm detector and the flow rate was 1.0 mL per minute. 10 ⁇ _ of the test samples were injected. The samples were prepared by dissolving the appropriate amount of sample in methanol, to obtain a concentration of 0.5 mg per mL. The chromatogram was run for at least 100 min. The approximate retention time for asenapine was found to be 17.4 min.
  • the particle size parameters measured in the present invention have been obtained by means of laser light diffraction technique, and specifically by means of a Malvern Mastersizer 1000 equipped with a 2 milliwatt Helium/Neon laser (633 nm wavelength) and a Fourier Transform lens system.
  • the sample unit was a MS1 Small Volume Sample Dispersion Unit stirred cell.
  • the dispersant was Isopar G.
  • the sample particle size distribution was assumed to follow a normal distribution.
  • Sample dispersant (5% solution of soybean lecithin in Isopar G) was prepared by adding 2.5 g of soybean lecithin to 50 mL of Isopar G, and mixing gently until lecithin dissolved. Samples for analysis were prepared by wetting a weighed amount of asenapine maleate (approximately 60 mg) with 20 mL of sample dispersant (5% solution of soybean lecithin in Isopar G). The samples were sonicated for 2 minutes, and were delivered dropwise to the previously background and corrected measuring cell filled with dispersant until the obscuration reached the desired level (approximately 15-17%).
  • volume distributions were obtained for al least six measures. For characterization, the values of D 10 , D 50 and D 90 (by volume), D[4,3] (mean diameter by volume) and D[3,2] (mean diameter by surface area to volume, or Sauter diameter) were specifically listed, each one being the mean of the six values available for each characterization parameter.
  • Solubility method 1 g of asenapine maleate was suspended in 40 mL of deionized water at 25 °C. The resulting suspension was stirred at 300 rpm. 0.50 mL aliquots were taken and filtered through a 0.20 ⁇ filter after stirring times from 1 to 180 minutes. The filtered aliquots were diluted to 20 mL with methanol and analyzed by HPLC (method 2). The amount of dissolved asenapine maleate in the aliquots was determined by comparing the area % of the asenapine peak as measured by HPLC with a calibration curve obtained from 7 samples of asenapine maleate having known concentrations between 0 mg/mL and 0.5 mg/mL.
  • This Comparative Example is a partial reproduction of Example 3 (step D+E), process 1 of International patent application number WO2008/003460 A1 , which discloses the crystallization of asenapine maleate from isopropanol in a first step.
  • 512 mg of asenapine (free base, 1.79 mmol) were dissolved in 2 mL of isopropanol.
  • the resulting solution was vacuum distilled to remove the solvent and to leave asenapine as a yellowish oil.
  • Maleic acid (229.4 mg, 1.98 mmol) was dissolved in isopropanol (3.6 mL) at 45-50 °C. This solution was added to the yellow oil at 45-50 °C.
  • This Comparative Example is a partial reproduction of Example 1 (step D+E), process 3 of International patent application number WO2008/003460 A1 , which discloses the crystallization of asenapine maleate from isopropanol / water.
  • 675.6 mg of asenapine (free base, 2.36 mmol) were dissolved in 0.9 mL of isopropanol, whereupon a solution of maleic acid (314.1 mg; 2.71 mmol) in isopropanol (6.1 mL) and water (0.16 mL) was added under stirring at room temperature. After stirring for 19 hours at room temperature the crystals of asenapine maleate were collected and dried under vacuum at 40 °C for 2 hours to afford a white solid.
  • XRPD step time: 0.5 seconds: Form H with traces of form L (see Figure 4).
  • Asenapine maleate form H as obtained in Reference Example 1 was micronized in a Rina-jet turbomicronizer from Riera Nadeu S.A. using compressed air at 20-25 °C. Conditions: venturi at 3 bar, grinding chamber at 2 bar.
  • XRPD step time: 1 second
  • Form L Form L (see Figure 6).
  • Particle Size Distribution D 10 1.5 ⁇ , D 50 5.2 ⁇ , D 90 10.0 ⁇ .
  • Example 2 Synthesis of asenapine maleate form M 7.12 g (53.4 mmol) of aluminum trichloride and 3.55 g (93.5 mmol) of lithium aluminum hydride were suspended in 200 mL of anhydrous tetrahydrofuran below 10 °C. The resulting suspension was stirred at 0°C for 15 minutes. A solution of 10.0 g (33.4 mmol) of frans-11-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 /-/-dibenz[2,3:6,7]oxepino[4,5-c] pyrrol-1-one in 100 mL of anhydrous tetrahydrofuran was added dropwise while keeping the temperature below 15 °C.
  • the resulting mixture was stirred at 10 °C for 1 hour, and the consumption of trans- 1-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 /-/- dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one was checked by TLC.
  • 1 10 mL of a 0.6M aqueous solution of sodium hydroxide was added dropwise while keeping the temperature below 10 °C.
  • the resulting mixture was stirred at 20 °C for 20 minutes. 150 mL of toluene and 100 mL of water were added, and the resulting mixture was stirred for 20 minutes. Phases were separated and the aqueous phase was washed with 2 x 100 mL of toluene.
  • the combined solids (20.5 g of asenapine maleate) were dissolved in 120 mL of acetone at 34 °C. After heating to reflux temperature, 40 mL of hexane (mixture of isomers) were added dropwise. Further, additional 100 mL of hexane (mixture of isomers) were added dropwise over 1 hour. Optionally, the resulting mixture can be seeded at this point with asenapine maleate form M. The resulting mixture was cooled and a white solid precipitated off at 35 °C.
  • the resulting mixture was stirred at 10 °C for 1 hour, and the consumption of trans- 1-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 /-/- dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one was checked by TLC. 275 mL of a 0.6M aqueous solution of sodium hydroxide was added dropwise while keeping the temperature below 10 °C. The resulting mixture was stirred at 20 °C for 20 minutes. 450 mL of toluene and 300 mL of water were added, and the resulting mixture was stirred for 20 minutes.
  • Phases were separated and the aqueous phase was washed with 2 x 200 mL of toluene. The combined organic phases were washed with 2 x 300 mL of brine, and dried with anhydrous sodium sulfate. Asenapine base was isolated after removing the solvent under reduced pressure. Then, asenapine base was dissolved in 175 mL of isopropanol. The resulting solution was filtered and heated to 30 °C. At this temperature, 9.0 g (77.5 mmol) of maleic acid were added. The resulting mixture was heated to 46 °C and stirred at 45-50 °C for 1 hour. Then, the mixture was cooled to 0 °C and stirred at this temperature for 3 hours. The resulting suspension was filtered and the cake was washed with 50 mL of cooled isopropanol.
  • the resulting mixture was stirred at 10 °C for 1 hour, and the consumption of trans- 1-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 /-/- dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one was checked by TLC.
  • 1 10 mL of a 0.6M aqueous solution of sodium hydroxide was added dropwise while keeping the temperature below 10 °C.
  • the resulting mixture was stirred at 20 °C for 20 minutes. 150 mL of toluene and 100 mL of water were added, and the resulting mixture was stirred for 20 minutes. Phases were separated and the aqueous phase was washed with 2 x 100 mL of toluene.
  • the resulting mixture was stirred at 10 °C for 1 hour, and the consumption of trans- 1-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 /-/- dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one was checked by TLC.
  • 1 10 mL of a 0.6M aqueous solution of sodium hydroxide was added dropwise while keeping the temperature below 10 °C.
  • the resulting mixture was stirred at 20 °C for 20 minutes. 150 mL of toluene and 100 mL of water were added, and the resulting mixture was stirred for 20 minutes. Phases were separated and the aqueous phase was washed with 2 x 100 mL of toluene.
  • the resulting mixture was stirred at 45 °C for 30 minutes and then cooled to -5 °C.
  • the resulting solution was seeded with asenapine maleate. 60 mL of isopropanol were added, and the resulting suspension was stirred overnight at -5 °C.
  • the solid was filtered. The filtered solid was suspended in 45 mL of acetone and heated to 50 °C. 45 mL of hexane (mixture of isomers) were added dropwise. The resulting solution was cooled to -5 °C and stirred at this temperature for 30 minutes.
  • Example 8 Synthesis of asenapine maleate form M 0.75 g (2.6 mmol) of asenapine base in form of a yellow oil were dissolved in 5 mL of isopropanol. A solution of 0.42 g (3.6 mmol) of maleic acid in 5 mL of isopropanol was added dropwise. The resulting mixture was heated to 45-50 °C and stirred at this temperature for 5 minutes. After cooling to room temperature, the resulting suspension was filtered and the obtained solid was suspended in 4 mL of isopropanol. The suspension was seeded with asenapine maleate form M and was stirred for 1 hour.
  • Example 10 Synthesis of asenapine maleate form T 282.2 mg of asenapine maleate were dissolved in 2.1 mL of methyl ethyl ketone at a temperature between 20 to 25 °C. The resulting solution was filtered. 5 mL of cyclohexane were added dropwise over the filtered solution, and the resulting mixture was stirred at 20-25 °C for 2 hours. A white suspension was obtained. The solid was filtered under vacuum. XRPD (step time: 0.5 seconds): Form T (see Figure 2).
  • Example 22 Synthesis of asenapine maleate form T 267.5 mg of asenapine maleate were dissolved in 2.2 mL of methyl ethyl ketone at a temperature between 20 to 25 °C. The resulting solution was filtered, and the filtrate was added dropwise over 5 mL of methylcyclohexane, which had been previously cooled to a temperature between -10 to -5 °C. The resulting mixture was stirred at -10 to -5 °C for 2.5 hours. A white suspension was obtained. The solid was filtered under vacuum.
  • XRPD step time: 0.5 seconds: Form T (substantially equivalent to Figure 2).
  • XRPD step time: 1 second: Form M (substantially equivalent to Figure 1).
  • Particle Size Distribution D 10 1.3 ⁇ , D 50 4.3 ⁇ , ⁇ 90 28.9 ⁇ .
  • Example 29 Part of the homogeneous solid mixture of asenapine maleate form M obtained in Example 29 was micronized in a Rina-jet turbomicronizer from Riera Nadeu S.A. using compressed air at 20-25 °C. Conditions: venturi at 5 bar, grinding chamber at 3 bar. The obtained material was micronized for three additional times under the same conditions.
  • XRPD step time: 1 second: Form M (see Figure 7).
  • Particle Size Distribution D 10 1.0 ⁇ , D 50 2.2 ⁇ , D 90 4.3 ⁇ .
  • Asenapine maleate form T as obtained in Example 21 was micronized in a Rina-jet turbomicronizer from Riera Nadeu S.A. using nitrogen at 20-25 °C. Conditions: venturi at 3 bar, grinding chamber at 2 bar.
  • XRPD step time: 0.5 seconds: Form T (see Figure 8).
  • Particle Size Distribution D 10 1.0 ⁇ , D 50 1.9 ⁇ , D 90 3.5 ⁇ .
  • Example 33 Use of asenapine maleate form M in the preparation of a pharmaceutical composition
  • Example 34 Use of asenapine maleate form T in the preparation of a pharmaceutical composition
  • thermodynamic water solubility of asenapine maleate form M was determined by applying the solubility method herein described to micronized asenapine maleate form M as obtained in Example 31. A solubility plateau was reached after stirring for 90 minutes. The water solubility obtained from aliquots taken between 90 and 180 minutes of stirring (7 samples taken at time intervals of 15 minutes) was 8.7 ⁇ 0.4 mg/mL.
  • thermodynamic water solubility of asenapine maleate form T was determined by applying the solubility method herein described to micronized asenapine maleate form T as obtained in Example 32. A solubility plateau was observed after stirring for 10 minutes.
  • the water solubility obtained from aliquots taken between 10 and 105 minutes of stirring (5 samples taken at time intervals of 5 minutes between 10 and 30 minutes of stirring, and 5 samples taken at time intervals of 15 minutes between 30 and 105 minutes of stirring) was 10.2 ⁇ 1.7 mg/mL.
  • Example 37 Water solubility of asenapine maleate form H
  • the thermodynamic water solubility of asenapine maleate form H was determined by applying the solubility method herein described to asenapine maleate form H as obtained in Reference Example 2. A solubility plateau was reached after stirring for 10 minutes.
  • the water solubility obtained from aliquots taken between 10 and 180 minutes of stirring (5 samples taken at time intervals of 5 minutes between 10 and 30 minutes of stirring, and 10 samples taken at time intervals of 15 minutes between 30 and 180 minutes of stirring) was 6.9 ⁇ 1.0 mg/mL.
  • thermodynamic water solubility of asenapine maleate form L was determined by applying the solubility method herein described to micronized asenapine maleate form L as obtained in Reference Example 3. A solubility plateau was reached after stirring for 105 minutes. The water solubility obtained from aliquots taken between 105 and 180 minutes of stirring (6 samples taken at time intervals of 15 minutes) was 3.9 ⁇ 0.2 mg/mL.

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Abstract

La présente invention concerne deux nouvelles formes cristallines du sel de trans-5-chloro-2- méthyl-2,3,3a,12b-tétrahydro-1H-dibenzo[2,3:6,7]oxépino[4,5-c]pyrrole avec l'acide maléique, des procédés pour la préparation de celles-ci et des compositions comprenant celles-ci. Ces nouvelles formes cristallines du sel de trans-5-chloro-2-méthyl-2,3,3a,12b-tétrahydro-1H- dibenzo[2,3:6,7]oxépino[4,5-c]pyrrole avec l'acide maléique sont stables sous micronisation et présentent une hydrosolubilité améliorée par rapport à d'autres formes cristallines de maléate d'asénapine décrites dans l'art antérieur, telles que la forme orthorhombique (forme L) et la forme monoclinique (forme H).
PCT/EP2012/053988 2011-03-11 2012-03-08 Nouvelles formes cristallines du sel de trans-5-chloro-2-méthyl-2,3,3a,12b-tétrahydro-1h-dibenzo[2,3:6,7] oxépino[4,5-c]pyrrole avec l'acide maléique Ceased WO2012123325A1 (fr)

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WO2013041604A1 (fr) * 2011-09-21 2013-03-28 Sandoz Ag Forme cristalline de maléate d'asénapine
ITMI20121810A1 (it) * 2012-10-24 2014-04-25 Chemo Iberica Sa Poliformi di maleato di asenapina e processo per la loro preparazione
CN103772402A (zh) * 2014-01-07 2014-05-07 万特制药(海南)有限公司 一种新的阿塞那平马来酸盐粗品精制方法
CN103864802A (zh) * 2014-03-31 2014-06-18 四川科伦药业股份有限公司 高纯度马来酸阿塞那平的制备方法
CN104447771A (zh) * 2013-09-12 2015-03-25 天津市汉康医药生物技术有限公司 一种稳定的马来酸阿塞那平化合物
WO2014207664A3 (fr) * 2013-06-28 2015-04-02 Alembic Pharmaceuticals Limited Composition pharmaceutique stable d'asénapine
WO2015125152A3 (fr) * 2014-02-18 2015-12-10 Hetero Research Foundation Compositions pharmaceutiques d'asénapine
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US12329862B2 (en) 2018-06-20 2025-06-17 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US12485099B2 (en) 2016-12-20 2025-12-02 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013041604A1 (fr) * 2011-09-21 2013-03-28 Sandoz Ag Forme cristalline de maléate d'asénapine
ITMI20121810A1 (it) * 2012-10-24 2014-04-25 Chemo Iberica Sa Poliformi di maleato di asenapina e processo per la loro preparazione
WO2014207664A3 (fr) * 2013-06-28 2015-04-02 Alembic Pharmaceuticals Limited Composition pharmaceutique stable d'asénapine
CN104447771A (zh) * 2013-09-12 2015-03-25 天津市汉康医药生物技术有限公司 一种稳定的马来酸阿塞那平化合物
CN103772402A (zh) * 2014-01-07 2014-05-07 万特制药(海南)有限公司 一种新的阿塞那平马来酸盐粗品精制方法
WO2015125152A3 (fr) * 2014-02-18 2015-12-10 Hetero Research Foundation Compositions pharmaceutiques d'asénapine
CN103864802A (zh) * 2014-03-31 2014-06-18 四川科伦药业股份有限公司 高纯度马来酸阿塞那平的制备方法
CN103864802B (zh) * 2014-03-31 2016-08-17 四川科伦药业股份有限公司 马来酸阿塞那平的制备方法
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US10980753B2 (en) 2016-12-20 2021-04-20 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US12138353B2 (en) 2016-12-20 2024-11-12 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US12485099B2 (en) 2016-12-20 2025-12-02 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US12329862B2 (en) 2018-06-20 2025-06-17 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine

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