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WO2004060347A2 - Compositions pharmaceutiques de solvates de propylene glycol - Google Patents

Compositions pharmaceutiques de solvates de propylene glycol Download PDF

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Publication number
WO2004060347A2
WO2004060347A2 PCT/US2003/041642 US0341642W WO2004060347A2 WO 2004060347 A2 WO2004060347 A2 WO 2004060347A2 US 0341642 W US0341642 W US 0341642W WO 2004060347 A2 WO2004060347 A2 WO 2004060347A2
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WO
WIPO (PCT)
Prior art keywords
solvate
propylene glycol
degrees
api
pxrd pattern
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PCT/US2003/041642
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WO2004060347A3 (fr
Inventor
Mark Tawa
Örn ALMARSSON
Julius Remenar
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Transform Pharmaceuticals Inc
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Transform Pharmaceuticals Inc
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Filing date
Publication date
Priority claimed from US10/232,589 external-priority patent/US6559293B1/en
Priority claimed from PCT/US2003/019574 external-priority patent/WO2004000284A1/fr
Priority claimed from PCT/US2003/028982 external-priority patent/WO2004026235A2/fr
Priority claimed from PCT/US2003/041273 external-priority patent/WO2004061433A1/fr
Application filed by Transform Pharmaceuticals Inc filed Critical Transform Pharmaceuticals Inc
Priority to AU2003300452A priority Critical patent/AU2003300452A1/en
Priority to US10/551,014 priority patent/US20060223794A1/en
Priority to PCT/US2004/009947 priority patent/WO2004089313A2/fr
Publication of WO2004060347A2 publication Critical patent/WO2004060347A2/fr
Publication of WO2004060347A3 publication Critical patent/WO2004060347A3/fr
Anticipated expiration legal-status Critical
Ceased 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen
    • C07H5/06—Aminosugars

Definitions

  • the present invention relates to drug-containing compositions, pharmaceutical compositions comprising such drugs, and methods for preparing same.
  • Drugs in pharmaceutical compositions can be prepared in a variety of different forms. Such drugs can be prepared so as to have a variety of different chemical forms including chemical derivatives or salts. Such drugs can also be prepared to have different physical forms. For example, the drugs may be amorphous or may have different crystalline polymorphs, perhaps existing in different solvation or hydration states. By varying the form of a drug, it is possible to vary the physical properties thereof. For example, crystalline polymorphs typically have different solubilities from one another, such that a more thermodynamically stable polymorph is less soluble than a less thermodynamically stable polymorph. Pharmaceutical polymorphs can also differ in properties such as shelf-life, bioavailability, morphology, vapor pressure, density, color, and compressibility. Accordingly, variation of the solvation state of a drug is one of many ways in which to modulate the physical properties thereof.
  • a solvate may be defined as a compound formed by solvation, for example as a combination of solvent molecules with molecules or ions of a solute.
  • Well known solvent molecules include water, alcohols and other polar organic solvents. Alcohols include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and t- butanol. Alcohols also include polymerized alcohols such as polyalkylene glycols (e.g., polyethylene glycol, polypropylene glycol).
  • the best-known and preferred solvent is typically water, and solvate compounds formed by solvation with water are termed hydrates.
  • Propylene glycol (1,2-propanediol) is a known substance which is a liquid at ambient temperature. As far as the applicants are aware, propylene glycol is not generally well-known for use in the formation of solvates.
  • US Pat. No. 3,970,651 does disclose the use of propylene glycol in the formation of a crystalline cephalosporin derivative. According to this disclosure a propylene glycolate derivative of a specific cephalosporin zwitterion may be formed in the presence of propylene glycol at acidic pH. This disclosure indicates that the propylene glycol derivative is more stable in solid form than the corresponding ethanolate, especially having excellent colour stability and thermal stability. No other solvates are disclosed in this US patent other than the specific solvate of cephalosporin.
  • Solvates are rarely used in pharmaceuticals because the solvents are usually volatile thus making it difficult to maintain the solvent in the crystal. If one were to desolvate a pharmaceutical solvate or if it desolvated due to storage conditions or otherwise, it could lead to the formation of multiple polymorphs or complete collapse of the crystal structure, forming an amorphous compound with different physical properties. Obviously, this batch-to-batch variability and questionable shelf life is undesired.
  • Propylene glycol is similar in structure to propanol, but is not thought of as a solvent.
  • Propylene glycol solvates of the present invention desolvate only at considerably higher temperatures and harsher conditions than traditional solvates. Propylene glycol solvates are also pharmaceutically acceptable in much larger amounts thanone would expose people to with a traditional solvate.
  • the propylene glycol solvates of the present invention have characteristics that are vastly superior to traditional solvates.
  • amorphous, crystalline, hygroscopic, or poorly soluble drugs can be made more soluble, more stable, and less hygroscopic and can be prepared simply, reliably and inexpensively.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a propylene glycol solvate of a drug which is hygroscopic or has low aqueous solubility.
  • the invention further relates to methods of making a pharmaceutical solvate more stable at high temperatures by making a PG solvate of the drug.
  • propylene glycol solvates are generally more pharmaceutically acceptable than other common solvates, including those formed from alcohols other than ethanol. It has further been found that the PG solvates of the present invention have fewer solvation states than hydration states. This is beneficial because production and quality of a drug can be more predictable and consistent.
  • an aspect of the present invention relates to methods of reducing the number of hydration states by making a PG solvate of a drug.
  • PG solvates are also beneficial in addressing the problem of polymorphism.
  • an aspect of the present invention relates to methods of reducing the rate and extent a drug changes form and methods of reducing the chance of making an unwanted form because the PG solvates drive production of a single form.
  • Another aspect of the present invention relates to changing the crystal habit of the drug crystal and preventing a drug crystalline habit from changing to a different habit.
  • the invention relates to making a pharmaceutical that can be made as a hydrate, more soluble or stable by forming a PG solvate of the drug.
  • the invention further relates to making a pharmaceutical more stable in a humid environment by making a PG solvate of the drug.
  • the invention further relates to making a crystalline compound from a pharmaceutical that does not readily crystallize by making a crystalline PG solvate of the drug.
  • the invention further relates to increasing the solubility of a crystalline pharmaceutical by making a PG solvate of the drug.
  • the invention further relates to methods of lowering the amount of drug solvation during wet granulation by making a PG solvate of the drug.
  • a particularly important aspect of the present invention is the realization that formation of propylene glycol solvates is applicable in a general way to drugs whereby the above advantages may be conferred.
  • the invention further relates to reducing the level of hygroscopicity of a pharmaceutical metal salt (crystalline, amorphous, solvate (e.g., hydrate)) by forming a PG solvate of the salt.
  • a pharmaceutical metal salt crystalline, amorphous, solvate (e.g., hydrate)
  • a PG solvate of the salt e.g., hydrate
  • the invention is particularly applicable to those drags that are in the form of metal salts, such as alkali metal or alkaline earth metal salts. This is especially the case where the metal is selected from sodium, potassium, lithium, calcium and magnesium.
  • Such salts can be hygroscopic and it has hitherto been difficult to find a suitable general means of formulation for these drugs.
  • the molar ratio of propylene glycol to drag in the solvate is in the range 0.5 to 2, (e.g., 0.5, 1.0, 1.5, 2.0). Depending on the nature of the drag, the ratio of propylene glycol to drug in the solvate may be approximately 0.25, 0.33, 0.5, 0.67, 0.75, 1.0, 1.5, 2.0 or 3.0.
  • composition may further comprise a pharmaceutically-acceptable diluent, excipient or carrier and details of pharmaceutical compositions are also set out in further detail below.
  • the solvate of the pharmaceutical composition according to the present invention is preferably in a crystalline form.
  • the powder X-ray diffraction spectram of the composition according to the invention differs from the corresponding powder X-ray diffraction spectram of unsolvated drag by at least one property selected from:
  • the solvate is stable to temperatures of up to 50 degrees C under a stream of nitrogen gas in a thermogravimetric analysis apparatus.
  • the PXRD could be the same if their were a host-guest relationship and the PG was not completely frozen out. This would be an inclusion compound rather than a true solvate, but it may still be less hygroscopic than a hydrate, less prone to solvent loss than an inclusion with ethanol, less prone to being filled by some toxic co-solvent if PG fits well, and less prone to polymorphism to a less soluble form due to instability caused by a vacated void in the structure.
  • the DSC transitions are likely to occur at different temperatures and have different intensities than for the parent molecule and it's other hydrates/solvates.
  • the drug is a hygroscopic drug, including hygroscopic metal salts.
  • a non-exhaustive list of hygroscopic drags is set out in Table 1, along with their suppliers and routes of administration.
  • the formulation comprises celecoxib.
  • celecoxib provides a suitable example of the efficacy of the invention. Further details of celecoxib are set out below.
  • the drug comprises naproxen, further details of which are also set out below.
  • the drag has low aqueous solubility.
  • low aqueous solubility in the present application refers to a compound having a solubility in water which is less than or equal to lOmgml, when measured at 37 degrees C, and preferably less than or equal to 5mg/ml or lmg/ml.
  • Low aqueous solubility can further be defined as less than or equal to 900, 800, 700, 600, 500, 400, 300, 200 150 100, 90, 80, 70, 60, 50, 40, 30, 20 micrograms/ml, or further 10, 5 or 1 micrograms/ml, or further 900, 800, 700, 600, 500, 400, 300, 200 150, 100 90, 80, 70, 60, 50, 40, 30, 20, or 10 ng/ml, or less than 10 ng/ml when measured at 37 degrees C.
  • Aqueous solubility can also be specified as less than 500, 400, 300, 200, 150, 100, 75, 50 or 25 mg/ml.
  • SGF simulated gastric fluid
  • Steroids are an important class of drugs which have low aqueous solubility.
  • Particularly important steroids include acetoxypregnenolone, alclometasone dipropionate, aldosterone, anagestone , norethynodrel., androsterone, betamethasone, budesonide, chlormadinone , chloroprednisone , corticosterone, cortisone, cyclosporine, desogestrel , desoximethasone, desoxycorticosterone, dexamethasone, dichlorisone , dimethisterone, equilenin, equilin, estradiol, estriol, estrogens, estrone, ethisterone, ethynodiol di, ethynyl estradiol, fludrocortisone, fludrocortisone , flunsolide, flu
  • Embodiments of the present invention are methods of increasing the solubility of steroids by making a PG solvate. Solubility can be specified as discussed above. It is difficult to make crystals of steroids because of their planar stracture. Crystallization can be facilitated by making PG solvates. Thus, crystalline PG solvates of steroids and methods of making the same are included in embodiments of the present invention. Steroids generally tend to form non-stoichiometric channel hydrates in which water molecules are trapped in channels between planar steroid regions. Thus, embodiments of the present invention include inhibiting channel formation in steroids by making a PG solvate.
  • steroid PG solvates are in accordance with one aspect of the present invention.
  • Steroid drugs whether hygroscopic or not, su ⁇ risingly and advantageously form stoichiometric solvates with propylene glycol. Further, the dissolution rate and solubility can be increased with propylene glycol solvates.
  • the steroid solvates have su ⁇ risingly new properties that make them more favourable for pharmaceutical use and are easier to handle than other forms such as hydrates.
  • the present invention provides a method for preparing a propylene glycol solvate of a drug, which method comprises:
  • the drag may be, for example, a hygroscopic drug or a drag of low aqueous solubility).
  • the present invention provides a method for decreasing the hygroscopicity of a drag, which method comprises
  • the present invention provides a method for increasing the aqueous solubility of a drag, which method comprises
  • conditions for making a solvate are the same as for preparing the corresponding non-solvated form of the drag: the solvate of neutral compound would not be pH controlled; the solvate of an acid addition salt would be prepared by including PG with the drug and the acid; and the solvate of a base addition salt would involve adding the drug, the desired base, and the PG.
  • Different co-solvent systems, anti-solvents, or temperature conditions may be used to encourage PG solvate formation. Seed crystals may be added if they have previously been prepared and isolated.
  • the step of isolating the solvate may include separating the solution phase from the solvate. Any common method of separation may be employed, including filtration and decanting.
  • the crystalline solvate may be rinsed one or more times with an appropriate solvent following filtration or decanting.
  • the crystalline solvate is preferably dried to remove excess solution phase. Drying may be carried out by thermal processing, vacuum, blowing a stream of gas such as air, nitrogen, argon or another inert gas, or a combination of any or all of these methods.
  • the intention of the rinsing and drying steps is to remove impurities including residual co-solvents and excess PG, acid, or base if used.
  • Fig. 1 shows a thermogravimetric analysis of a propylene glycol solvate of a celecoxib sodium salt.
  • Fig. 2A-D shows the PXRD pattern of a propylene glycol solvate of a celecoxib sodium salt.
  • Fig. 3 shows a thermogravimetric analysis of a propylene glycol solvate of a celecoxib potassium salt.
  • Fig. 4 shows the PXRD pattern of a propylene glycol solvate of a celecoxib potassium salt.
  • Fig. 5 shows a thermogravimetric analysis of a propylene glycol solvate of a celecoxib lithium salt.
  • Fig. 6 shows the PXRD pattern of a propylene glycol solvate of a celecoxib lithium salt.
  • Fig. 7 shows the thermogravimetric analysis of a propylene glycol solvate of naproxen sodium salt.
  • Fig. 8 shows a PXRD pattern of a propylene glycol solvate of naproxen sodium salt.
  • Fig. 9 shows the thermogravimetric analysis of a propylene glycol solvate of olanzapine form I.
  • Fig. 10 shows the differential scanning " calorimetry thermogram of a propylene glycol solvate of olanzapine form I.
  • Fig. 11A-B shows PXRD patterns of a propylene glycol solvate of olanzapine form I.
  • Fig. 12 shows a packing diagram of olanzapine form I PG solvate.
  • Fig. 13 shows the thermogravimetric analysis of a propylene glycol solvate of cortisone acetate.
  • Fig. 14 shows the differential scanning calorimetry thermogram of a propylene glycol solvate of cortisone acetate.
  • Fig. 15A-B shows PXRD patterns of a propylene glycol solvate of cortisone acetate.
  • Fig. 16 shows a PXRD pattern of cortisone acetate.
  • Fig. 17 shows a packing diagram of cortisone acetate PG solvate.
  • Fig. 18 shows the thermogravimetric analysis of a trihydrate of celecoxib sodium PG solvate.
  • Fig. 19 shows the PXRD pattern of a trihydrate of celecoxib sodium PG solvate.
  • Fig. 20 shows the thermogravimetric analysis of a trihydrate of celecoxib sodium PG solvate.
  • Fig. 21 shows the PXRD pattern of a trihydrate of celecoxib sodium PG solvate.
  • Fig. 22 shows the PXRD pattern of celecoxib sodium salt.
  • Fig. 23 shows the PXRD pattern of celecoxib lithium salt.
  • Fig. 24 shows the PXRD pattern of celecoxib potassium salt.
  • the present invention relates to propylene glycol solvate forms, preferably stoichiometric, of certain drags, including those which are hygroscopic or have low aqueous solubility. Whilst the invention is applicable to any such drags in general, metal salts of the non-steroidal anti-inflammatory drug celecoxib serve to illustrate the present invention by way of example. Unlike traditional non-steroidal anti- inflammatory drags (NSAIDs), celecoxib is a selective inhibitor of cyclooxygenase II (COX-2) which causes fewer side effects when administered to a subject. The present applicants have identified new forms of celecoxib that have improved properties, particularly as oral formulations.
  • Salts of celecoxib are formed by reaction of celecoxib with an acceptable base.
  • Acceptable bases include, but are not limited to, metal hydroxides and alkoxides with sufficiently high pK a 's (e.g., pK a 's greater than about 11 to about 12).
  • Naproxen is a further API which may be used to illustrate the present invention.
  • Naproxen is a member of the ibufenac group of NSAIDs. This API is practically insoluble in water.
  • Other examples of illustrations of the present invention include olanzapine and cortisone acetate.
  • An aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a propylene glycol solvate of a drag that is less hygroscopic than the amo ⁇ horous, neutral crystalline, or salt crystalline form, and/or has greater aqueous solubility.
  • Hygroscopicity should be assessed by dynamic vapor so ⁇ tion analysis, in which 5-50 mg of the compound is suspended from a Cahn microbalance.
  • the compound being analyzed should be placed in a non-hygroscopic pan and its weight should be measured relative to an empty pan composed of identical material and having nearly identical size, shape, and weight. Ideally, platinum pans should be used.
  • the pans should be suspended in a chamber through which a gas, such as air or nitrogen, having a controlled and known percent relative humidity (%RH) is flowed until eqilibrium criteria are met.
  • a gas such as air or nitrogen
  • Typical equilibrium criteria include weight changes of less than 0.01 % change over 3 minutes at constant humidity and temperature.
  • the relative humidity should be measured for samples dried under dry nitrogen to constant weight ( ⁇ 0.01 % change in 3 minutes) at 40 degrees C unless doing so would de- solvate or otherwise convert the material to an amo ⁇ hous compound.
  • the hygroscopicity of a dried compound can be assessed by increasing the RH from 5 to 95 % in increments of 5 % RH and then decreasing the RH from 95 to 5 % in 5 % increments to generate a moisture so ⁇ tion isotherm.
  • the sample weight should be allowed to equilibrate between each change in % RH. If the compound deliquesces or becomes amo ⁇ hous between above 75 % RH, but below 95 % RH, the experiment should be repeated with a fresh sample and the relative humidity range for the cycling should be narrowed to 5-75 % RH or 10-75 % RH instead of 5-95 %RH.
  • the sample cannot be dried prior to testing due to lack of form stability, than the sample should be studied using two complete humidity cycles of either 10-75 % RH or 5-95 % RH, and the results of the second cycle should be used if there is significant weight loss at the end of the first cycle.
  • Hygroscopicity can be defined using various parameters.
  • a non-hygroscopic molecule should not gain or lose more than 1.0%, or more preferably, 0.5 % weight at 25 degrees C when cycled between 10 and 75 % RH (relative humidity at 25 degrees C).
  • the non-hygroscopic molecule more preferably should not gain or lose more than 1.0%, or more preferably, 0.5 % weight when cycled between 5 and 95 %RH at 25 degrees C, or more than 0.25 % of its weight between 10 and 75 % RH.
  • a non-hygroscopic molecule will not gain or lose more than 0.25 % of its weight when cycled between 5 and 95 % RH.
  • hygroscopicity can be defined using the parameters of Callaghan et al., Equilibrium moisture content of pharmaceutical excipients, in Drag Dev. Ind. Pharm., Vol. 8, pp. 335-369 (1982). Callaghan et al. classified the degree of hygroscopicity into four classes.
  • Class 1 Non-hygroscopic Essentially no moisture increases occur at relative humidities below 90%.
  • Class 2 Slightly hygroscopic Essentially no moisture increases occur at relative humidities below 80%.
  • Class 3 Moderately hygroscopic Moisture content does not increase more than 5% after storage for 1 week at relative humidities below 60%.
  • Class 4 Very hygroscopic Moisture content increase may occur at relative humidities as low as 40 to 50%.
  • hygroscopicity can be defined using the parameters of the European Pharmacopoeia Technical Guide (1999, p. 86) which has defined hygrospocity, based on the static method, after storage at 25 degrees C for 24 h at 80 % RH:
  • Hygroscopic Increase in mass is less than 15 percent m/m and equal to or greater than 0.2 percent m m.
  • Deliquescent Sufficient water is absorbed to form a liquid.
  • PG solvates of the present invention can be set forth as being in Class 1, Class 2, or Class 3, or as being Slightly hygroscopic, Hygroscopic, or Very hygroscopic. PG solvates of the present invention can also be set forth based on their ability to reduce hygroscopicity. Thus, preferred PG solvates of the present invention are less hygroscopic than the non-PG solvated reference compound, e.g., the reference compound of a celecoxib sodium salt PG solvate is celecoxib sodium salt.
  • PG solvates that do not gain or lose more than 1.0% weight at 25 degrees C when cycled between 10 and 75 % RH, wherein the reference compound gains or loses more than 1.0% weight under the same conditions. Further included in the present invention are PG solvates that do not gain or lose more than 0.5%) weight at 25 degrees C when cycled between 10 and 75 % RH, wherein the reference compound gains or loses more than 0.5% or more than 1.0% weight under the same conditions. Further included in the present invention are PG solvates that do not gain or lose more than 1.0% weight at 25 degrees C when cycled between 5 and 95 % RH, wherein the reference compound gains or loses more than 1.0% weight under the same conditions.
  • PG solvates that do not gain or lose more than 0.5% weight at 25 degrees C when cycled between 5 and 95 % RH, wherein the reference compound gains or loses more than 0.5% or more than 1.0% weight under the same conditions.
  • PG solvates that do not gain or lose more than 0.25% weight at 25 degrees C when cycled between 5 and 95 % RH, wherein the reference compound gains or loses more than 0.5% or more than 1.0% weight under the same conditions.
  • PG solvates that have a hygroscopicity (according to Callaghan et al.) that is at least one class lower than the reference compound or at least two classes lower than the reference compound.
  • Non-limiting examples include; a Class 1 PG solvate of a Class 2 reference compound, a Class 2 PG solvate of a Class 3 reference compound, a Class 3 PG solvate of a Class 4 reference compound, a Class 1 PG solvate of a Class 3 reference compound, a Class 1 PG solvate of a Class 4 reference compound, or a Class 2 PG solvate of a Class 4 reference compound.
  • PG solvates that have a hygroscopicity (according to the European Pharmacopoeia Technical Guide) that is at least one class lower than the reference compound or at least two classes lower than the reference compound.
  • Non-limiting examples include; a Slightly hygroscopic PG solvate of a Hygroscopic reference compound, a Hygroscopic PG solvate of a Very Hygroscopic reference compound, a Very Hygroscopic PG solvate of a Deliquescent reference compound, a Slightly hygroscopic PG solvate of a Very Hygroscopic reference compound, a Slightly hygroscopic PG solvate of a Deliquescent reference compound, a Hygroscopic PG solvate of a Deliquescent reference compound.
  • the dissolution profile of the API (active pharmaceutical ingredient) (e.g. celecoxib) is modulated whereby the aqueous dissolution rate or the dissolution rate in simulated gastric fluid (SGF) or in simulated intestinal fluid (SIF), or in a solvent or plurality of solvents is increased.
  • Dissolution rate is the rate at which API solids dissolve in a dissolution medium.
  • the rate-limiting step in the abso ⁇ tion process is often the dissolution rate. Because of a limited residence time at the abso ⁇ tion site, APIs that are not dissolved before they are removed from the intestinal abso ⁇ tion site are considered useless. Therefore, the rate of dissolution has a major impact on the performance of APIs that are poorly soluble. Because of this factor, the dissolution rate of APIs in solid dosage forms is an important, routine, quality control parameter used in the API manufacturing process.
  • Dissolution rate K S (C 3 -C) (1)
  • K dissolution rate constant
  • S is the surface area
  • C s is the apparent solubility
  • C is the concentration of API in the dissolution media.
  • C 3 -C is approximately equal to C s .
  • the dissolution rate of APIs may be measured by conventional means known in the art.
  • the increase in the dissolution rate of a composition of the present invention may be specified, such as by 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 %, or by 2, 3, 4, 5 ,6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 500, 1000, 10,000, or 100,000 fold greater than the unsolvated form in the same solution. Conditions under which the dissolution rate is measured are discussed above.
  • the increase in dissolution may be further specified by the time the composition remains supersaturated.
  • compositions with a dissolution rate, at 37 degrees C and a pH of 7.0, that is increased at least 5 fold over the unsolvated form compositions with a dissolution rate in SGF that is increased at least 5 fold over the unsolvated form
  • compositions with a dissolution rate in SIF that is increased at least 5 fold over the unsolvated form.
  • the present invention demonstrates that the length of time in which celecoxib or other APIs remains in solution can be increased to a su ⁇ rising high degree by using a PG solvate form as discussed herein.
  • the presence of propylene glycol allows the formation of a supersaturated solution of the API and a high concentration of API will remain in solution for an extended period of time.
  • Celecoxib for example, has a solubility in water of less than 1 microgram mL and cannot be maintained as a supersaturated solution for any appreciable time.
  • compositions that can be maintained for a period of time (e.g., 15, 30, 45, 60, minutes and longer) as supersaturated solutions at concentrations 2, 3, 5, 7, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100%, or by 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 500, 1000, 10,000, or 100,000 fold greater than the solubility of the unsolvated form in the same solution (e.g., water or SGF).
  • a period of time e.g., 15, 30, 45, 60, minutes and longer
  • concentrations 2, 3, 5, 7, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% or by 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 500, 1000, 10,000, or 100,000 fold greater than the solubility of the unsolvated form in the same solution (e.g., water or S
  • the methods of the present invention can be used to make a pharmaceutical API formulation with greater solubility, dissolution, bioavailability, AUC, reduced time to T max. the average time from administration to reach peak blood serum levels, higher C m x ,, the average maximum blood serum concentration of API following administration, and longer T 2 , the average terminal half-life of API blood serum concentration following T max , when compared to the unsolvated form.
  • AUC is the area under the plot of plasma concentration of API (not logarithm of the concentration) against time after API administration.
  • the area is conveniently determined by the "trapezoidal rule": the data points are connected by straight line segments, pe ⁇ endiculars are erected from the abscissa to each data point, and the sum of the areas of the triangles and trapezoids so constructed is computed.
  • the AUC is of particular use in estimating bioavailability of drags, and in estimating total clearance of drags (Or).
  • F the bioavailability of the drag.
  • the present invention provides a process for modulating the bioavailability of an API when administered in its normal and effective dose range, whereby the AUC is increased, the time to T raax is reduced, or C max is increased, which process comprises the preparation of a PG solvate.
  • compositions with a time to T max that is reduced by at least 10% as compared to the neutral free form compositions with a time to T max that is reduced by at least 20% over the free form, compositions with a time to T max that is reduced by at least 40% over the free form, compositions with a time to T max that is reduced by at least 50% over the free form, compositions with a T max that is reduced by at least 60% over the free form, compositions with a T max that is reduced by at least 70% over the free form, compositions with a T max that is reduced by at least 80% over the free form, compositions with a C max that is increased by at least 20% over the free form, compositions with a C max that is increased by at least 30% over the free form, compositions with a C ma ⁇ that is increased by at least 40% over the free form, compositions with a Cmax that is increased by at least 50% over the free form, compositions with a C max that is increased by at least 60% over the free form, compositions with a
  • compositions with a more rapid onset to therapeutic effect typically reach a higher maximum blood serum concentration (C max ) a shorter time after oral administration (T max ).
  • C max maximum blood serum concentration
  • T max time after oral administration
  • compositions of the present invention have a higher Cma and/or a shorter T max than in the unsolvated form.
  • the T max for the compositions of the present invention occurs within about 60 minutes, 55 minutes, 50 minutes, 45 minutes, 40 minutes, 35 minutes, 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, or within about 5 minutes of administration (e.g., oral administration).
  • compositions of the present invention begin to occur within about 60 minutes, 55 minutes, 50 minutes, 45 minutes, 40 minutes, 35 minutes, 30 minutes, within about 25 minutes, within about 20 minutes, within about 15 minutes, within about 10 minutes, or within about 5 minutes of administration (e.g., oral administration).
  • compositions of the present invention have a bioavailability greater than their respective unsolvated forms.
  • the compositions of the present invention have a bioavailability of at least 50%, 60%, 65%, 70%, 75%, 80%, 85%, 87%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%.
  • administering may result in effective pain relief.
  • Pain relief can be attained by mter alia reaching an appropriate blood serum concentration of a suitable analgesic.
  • celecoxib about 250 ng/mL is an appropriate concentration for the relief of pain of various causes.
  • Any standard pharmacokinetic protocol can be used to determine blood seram concentration profile in humans following oral administration of a celecoxib formulation, and thereby establish whether that formulation meets the pharmacokinetic criteria set out herein.
  • the prior art includes many examples of pharmacokinetic studies and as such US Pat. No. 6,579,895 and WO 01/91750 are hereby included as references in their entirety.
  • the present invention provides a process for improving the dose response of an API by making a composition of the present invention.
  • Dose response is the quantitative relationship between the magnitude of response and the dose inducing the response and may be measured by conventional means known in the art.
  • the curve relating therapeutic effect (as the dependent variable) to dose (as the independent variable) for an API-cell system is the "dose-response curve".
  • the dose-response curve is the measured response to an API plotted against the dose of the API (mg/kg) given.
  • the dose response curve can also be a curve of AUC against the dose of the API given.
  • the dose-response curve for many APIs is nonlinear.
  • the dose-response curves for the PG solvate compositions of the present invention are linear or contain a larger linear region than presently-marketed celecoxib.
  • a preferred embodiment of the present invention may inco ⁇ orate a dose-response curve with a linear slope that is steeper than that of celecoxib. This would allow a faster-onset of therapeutic relief from a smaller dosage of API.
  • An initially steep dose-response curve which gradually levels out could be employed to generate a controlled-release formulation.
  • the abso ⁇ tion or uptake of many APIs e.g.
  • celecoxib depends in part on food effects, such that uptake of the API increases when taken with food, especially fatty food.
  • uptake of the PG solvates of the present invention exhibit a decreased dependence on food, such that the difference in uptake of the PG solvates when taken with food and when not taken with food is less than the difference in uptake of the unsolvated form.
  • compositions of the present invention including the active pharmaceutical ingredient (API) and formulations comprising the API, are suitably stable for pharmaceutical use.
  • the API or formulations thereof of the present invention are stable such that when stored at 30 degrees C for 2 years, less than 0.2% of any one degradant is formed.
  • degradant refers herein to product(s) of a single type of chemical reaction. For example, if a hydrolysis event occurs that cleaves a molecule into two products, for the pu ⁇ ose of the present invention, it would be considered a single degradant. More preferably, when stored at 40 degrees C for 2 years, less than 0.2% of any one degradant is formed.
  • the relative humidity (RH) may be specified as ambient (RH), 75% (RH), or as any single integer between 1 to 99%.
  • APIs prepared in the form of propylene glycol solvates have several important advantages over other solvates and their free form counte ⁇ arts.
  • solvates are more commonly formed with water, methanol, ethanol, or other alcohols than with propylene glycol. These more common solvates are more easily removed from the crystal matrix by elevated temperatures than propylene glycol.
  • PG solvates have an increased thermal stability over those of more traditional solvates.
  • PG solvates are generally more pharmaceutically acceptable than other common solvates, including those formed from alcohols other than ethanol. Investigations of the PG solvates of the present invention have shown fewer solvation states than hydration states.
  • Reference compounds for PG solvates can be unsolvated free acid, unsolvated free base, zwitter ions, hydrates, or other solvates (e.g. methanol, ethanol, etc.). This decrease in form diversity associated with PG solvates can lead to more predictability and more consistent results during production and quality control. Stabilization of a desired solvate or polymo ⁇ h can be achieved by causing the less desirable forms (e.g. solvates, polymo ⁇ hs, hydrates) to be energetically less favorable than the desired form. In this way, PG solvates can aid in the production of pharmaceutical formulations with increased form stability.
  • the present invention further relates to methods of making a pharmaceutical solvate more stable at elevated temperatures (e.g.
  • the present invention further relates to methods of making a more pharmaceutically acceptable solvate of many APIs by employing propylene glycol rather than more biologically harmful solvents (e.g. methanol).
  • the present invention further relates to methods of reducing the number of forms (e.g. hydration states, solvation states, polymo ⁇ hs, etc.) possible for a pharmaceutical solvate.
  • Pharmaceutically acceptable PG solvates can be admimstered by controlled- or delayed-release means.
  • Controlled-release pharmaceutical products have a common goal of improving drug therapy over that achieved by their non-controlled release counte ⁇ arts.
  • the use of an optimally designed controlled-release preparation in medical treatment is characterized by a minimum of drag substance being employed to cure or control the condition in a minimum amount of time.
  • Controlled-release formulations include: 1) extended activity of the drag; 2) reduced dosage frequency; 3) increased patient compliance; 4) usage of less total drag; 5) reduction in local or systemic side effects; 6) minimization of drug accumulation; 7) reduction in blood level fluctuations; 8) improvement in efficacy of treatment; 9) reduction of potentiation or loss of drag activity; and 10) improvement in speed of control of diseases or conditions.
  • Conventional dosage forms generally provide rapid or immediate drug release from the formulation. Depending on the pharmacology and pharmacokinetics of the drag, use of conventional dosage forms can lead to wide fluctuations in the concentrations of the drug in a patient's blood and other tissues. These fluctuations can impact a number of parameters, such as dose frequency, onset of action, duration of efficacy, maintenance of therapeutic blood levels, toxicity, side effects, and the like.
  • controlled-release formulations can be used to control a drug's onset of action, duration of action, plasma levels within the therapeutic window, and peak blood levels.
  • controlled- or extended-release dosage forms or formulations can be used to ensure that the maximum effectiveness of a drag is achieved while minimizing potential adverse effects and safety concerns, which can occur both from under dosing a drag (i.e., going below the minimum therapeutic levels) as well as exceeding the toxicity level for the drag.
  • Controlled-release formulations are designed to initially release an amount of drag (active ingredient) that promptly produces the desired therapeutic effect, and gradually and continually release other amounts of drag to maintain this level of therapeutic or prophylactic effect over an extended period of time. In order to maintain this constant level of drug in the body, the drag must be released from the dosage form at a rate that will replace the amount of drag being metabolized and excreted from the body.
  • Controlled-release of an active ingredient can be stimulated by various conditions including, but not limited to, pH, ionic strength, osmotic pressure, temperature, enzymes, water, and other physiological conditions or compounds.
  • a variety of known controlled- or extended-release dosage forms, formulations, and devices can be adapted for use with the PG solvates of the present invention. Examples include, but are not limited to, those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,733,566; and 6,365,185 Bl; each of which is inco ⁇ orated herein by reference.
  • dosage forms can be used to provide slow or controlled-release of one or more active ingredients using, for example, hydroxypropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems (such as OROS® (Alza Co ⁇ oration, Mountain View, Calif. USA)), multilayer coatings, microparticles, liposomes, or microspheres or a combination thereof to provide the desired release profile in varying proportions.
  • ion exchange materials can be used to prepare immobilized, adsorbed salt forms and thus effect controlled delivery of the drug. Examples of specific anion exchangers include, but are not limited to, Duolite® A568 and Duolite® AP143 (Rohm & Haas, Spring House, PA. USA).
  • One embodiment of the invention encompasses a unit dosage form which comprises a pharmaceutically acceptable PG solvate, or a polymo ⁇ h, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amo ⁇ hous form thereof, and one or more pharmaceutically acceptable excipients or diluents, wherein the pharmaceutical composition or dosage form is formulated for controlled-release.
  • Specific dosage forms utilize an osmotic drag delivery system.
  • OROS® Alza Co ⁇ oration, Mountain View, Calif. USA
  • This technology can readily be adapted for the delivery of compounds and compositions of the invention.
  • Various aspects of the teclmology are disclosed in U.S. Pat. Nos. 6,375,978 Bl; 6,368,626 Bl; 6,342,249 Bl; 6,333,050 B2; 6,287,295 Bl; 6,283,953 Bl; 6,270,787 Bl; 6,245,357 Bl; and 6,132,420; each of which is inco ⁇ orated herein by reference.
  • OROS® that can be used to administer compounds and compositions of the invention
  • OROS® Push-PullTM Delayed Push-PullTM, Multi-Layer Push-PullTM, and Push-StickTM Systems, all of which are well known. See, e.g., http://www.alza.com.
  • Additional OROS® systems that can be used for the controlled oral delivery of compounds and compositions of the invention include OROS@-CT and L-OROS®. Id.; see also, Delivery Times, vol. II, issue II (Alza Co ⁇ oration).
  • OROS® oral dosage forms are made by compressing a drag powder (e.g., celecoxib sodium PG solvate) into a hard tablet, coating the tablet with cellulose derivatives to form a semi-permeable membrane, and then drilling an orifice in the coating (e.g., with a laser).
  • a drag powder e.g., celecoxib sodium PG solvate
  • the advantage of such dosage forms is that the delivery rate of the drug is not influenced by physiological or experimental conditions. Even a drag with a pH-dependent solubility can be delivered at a constant rate regardless of the pH of the delivery medium.
  • a specific dosage form of the invention comprises: a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a dry or substantially dry state drag layer located within the cavity adjacent to the exit orifice and in direct or indirect contacting relationship with the expandable layer; and a flow-promoting layer inte ⁇ osed between the inner surface of the wall and at least the external surface of the drag layer located within the cavity, wherein the drug layer comprises a PG solvate, or a polymo ⁇ h, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amo ⁇ hous form thereof. See U.S. Pat. No. 6,368,626, the entirety of which is inco ⁇ orated herein by reference.
  • Another specific dosage form of the invention comprises: a wall defining a cavity, the wall having an exit orifice formed or formable therein and at least a portion of the wall being semipermeable; an expandable layer located within the cavity remote from the exit orifice and in fluid communication with the semipermeable portion of the wall; a drug layer located within the cavity adjacent the exit orifice and in direct or indirect contacting relationship with the expandable layer; the drug layer comprising a liquid, active agent formulation absorbed in porous particles, the porous particles being adapted to resist compaction forces sufficient to form a compacted drug layer without significant exudation of the liquid, active agent formulation, the dosage form optionally having a placebo layer between the exit orifice and the drag layer, wherein the active agent formulation comprises a PG solvate, or a polymo ⁇ h, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amo ⁇ hous form thereof. See U.S. Pat. No. 6,342,249, the entirety of which is
  • Excipients employed in pharmaceutical compositions of the present invention can be solids, semi-solids, liquids or combinations thereof.
  • Compositions of the invention containing excipients can be prepared by any known technique of pharmacy that comprises admixing an excipient with a drag or Jherapeutic agent.
  • a pharmaceutical composition of the invention contains a desired amount of API per dose unit and, if intended for oral administration, can be in the form, for example, of a tablet, a caplet, a pill, a hard or soft capsule, a lozenge, a cachet, a dispensable powder, granules, a suspension, an elixir, a dispersion, a liquid, or any other form reasonably adapted for such administration.
  • Presently preferred are oral dosage forms that are discrete dose units each containing a predetermined amount of the drag, such as tablets or capsules.
  • Non-limiting examples follow of excipients that can be used to prepare pharmaceutical compositions of the invention.
  • compositions of the invention optionally comprise one or more pharmaceutically acceptable carriers or diluents as excipients.
  • suitable carriers or diluents illustratively include, but are not limited to, either individually or in combination, lactose, including anhydrous lactose and lactose monohydrate; starches, including directly compressible starch and hydrolyzed starches (e.g., CelutabTM and EmdexTM); mannitol; sorbitol; xylitol; dextrose (e.g., CereloseTM 2000) and dextrose monohydrate; dibasic calcium phosphate dihydrate; sucrose-based diluents; confectioner's sugar; monobasic calcium sulfate monohydrate; calcium sulfate dihydrate; granular calcium lactate trihydrate; dextrates; inositol; hydrolyzed cereal solids; amylose; celluloses including microcrystallme cellulose, food grade sources of alpha-
  • Such carriers or diluents constitute in total about 5% to about 99%, preferably about 10% to about 85%, and more preferably about 20% to about 80%, of the total weight of the composition.
  • the carrier, carriers, diluent, or diluents selected preferably exhibit suitable flow properties and, where tablets are desired, compressibility.
  • Lactose, mannitol, dibasic sodium phosphate, and microcrystallme cellulose are preferred diluents. These diluents are chemically compatible with celecoxib.
  • the use of extragranular microcrystallme cellulose that is, microcrystallme cellulose added to a granulated composition
  • Lactose, especially lactose monohydrate is particularly preferred.
  • Lactose typically provides compositions having suitable release rates of celecoxib, stability, pre-compression flowability, and/or drying properties at a relatively low diluent cost. It provides a high density substrate that aids densification during granulation (where wet granulation is employed) and therefore improves blend flow properties and tablet properties.
  • compositions of the invention optionally comprise one or more pharmaceutically acceptable disintegrants as excipients, particularly for tablet formulations.
  • Suitable disintegrants include, but are not limited to, either individually or in combination, starches, including sodium starch glycolate (e.g., ExplotabTM of PenWest) and pregelatinized corn starches (e.g., NationalTM 1551 of National Starch and Chemical Company, NationalTM 1550, and ColorconTM 1500), clays (e.g., VeegumTM HV of R.T.
  • Vanderbilt celluloses such as purified cellulose, microcrystallme cellulose, methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose, croscarmellose sodium (e.g., Ac-Di-SolTM of FMC), alginates, crospovidone, and gums such as agar, guar, locust bean, karaya, pectin and tragacanth gums.
  • Disintegrants may be added at any suitable step during the preparation of the composition, particularly prior to granulation or during a lubrication step prior to compression. Such disintegrants, if present, constitute in total about 0.2 % to about 30 %, preferably about 0.2 % to about 10 %, and more preferably about 0.2 % to about 5 %, of the total weight of the composition.
  • Croscarmellose sodium is a preferred disintegrant for tablet or capsule disintegration, and, if present, preferably constitutes about 0.2 % to about 10 %>, more preferably about 0.2 % to about 7 %>, and still more preferably about 0.2 % to about 5 %, of the total weight of the composition. Croscarmellose sodium confers superior intragranular disintegration capabilities to granulated pharmaceutical compositions of the present invention.
  • Pharmaceutical compositions of the invention optionally comprise one or more pharmaceutically acceptable binding agents or adhesives as excipients, particularly for tablet formulations.
  • binding agents and adhesives preferably impart sufficient cohesion to the powder being tableted to allow for normal processing operations such as sizing, lubrication, compression and packaging, but still allow the tablet to disintegrate and the composition to be absorbed upon ingestion.
  • binding agents may also prevent or inhibit crystallization or recrystallization of a celecoxib salt of the present invention once the salt has been dissolved in a solution.
  • Suitable binding agents and adhesives include, but are not limited to, either individually or in combination, acacia; tragacanth; sucrose; gelatin; glucose; starches such as, but not limited to, pregelatinized starches (e.g., NationalTM 1511 and NationalTM 1500); celluloses such as, but not limited to, methylcellulose and carmellose sodium (e.g., TyloseTM); alginic acid and salts of alginic acid; magnesium aluminum silicate; PEG; guar gum; polysaccharide acids; bentonites; povidone, for example povidone K-15, K-30 and K-29/32; polymethacrylates; HPMC; hydroxypropylcellulose (e.g.,
  • binding agents and/or adhesives constitute in total about 0.5 % to about 25 %, preferably about 0.75 % to about 15 %, and more preferably about 1 % to about 10 %, of the total weight of the pharmaceutical composition.
  • binding agents are polymers comprising amide, ester, ether, alcohol or ketone groups and, as such, are preferably included in pharmaceutical compositions of the present invention.
  • Polyvinylpyrrolidones such as povidone K-30 are especially preferred.
  • Polymeric binding agents can have varying molecular weight, degrees of crosslinking, and grades of polymer.
  • Polymeric binding agents can also be copolymers, such as block co-polymers that contain mixtures of ethylene oxide and ' propylene oxide units. Variation in these units' ratios in a given polymer affects properties and performance. Examples of block co-polymers with varying compositions of block units are Poloxamer 188 and Poloxamer 237 (BASF Co ⁇ oration).
  • compositions of the invention optionally comprise one or more pharmaceutically acceptable wetting agents as excipients.
  • surfactants that can be used as wetting agents in pharmaceutical compositions of the invention include quaternary ammonium compounds, for example benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride, dioctyl sodium sulfosuccinate, polyoxyethylene alkylphenyl ethers, for example nonoxynol 9, nonoxynol 10, and octoxynol 9, poloxamers (polyoxyethylene and polyoxypropylene block copolymers), polyoxyethylene fatty acid glycerides and oils, for example polyoxyethylene (8) caprylic/capric mono- and diglycerides (e.g., LabrasolTM of Gattefosse), polyoxyethylene (35) castor oil and polyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkyl ethers, for example polyoxyethylene (20) cetostearyl ether
  • Sodium lauryl sulfate is a particularly preferred wetting agent.
  • Sodium lauryl sulfate if present, constitutes about 0.25 % to about 7 %, more preferably about 0.4 % to about 4 %, and still more preferably about 0.5 % to about 2 %, of the total weight of the pharmaceutical composition.
  • compositions of the invention optionally comprise one or more pharmaceutically acceptable lubricants (including anti-adherents and/or glidants) as excipients.
  • suitable lubricants include, but are not limited to, either individually or in combination, glyceryl behapate (e.g., CompritolTM 888 of Gattefosse); stearic acid and salts thereof, including magnesium, calcium and sodium stearates; hydrogenated vegetable oils (e.g., SterotexTM of Abitec); colloidal silica; talc; waxes; boric acid; sodium benzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine; PEG (e.g., CarbowaxTM 4000 and CarbowaxTM 6000 of the Dow Chemical Company); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate.
  • Such lubricants if present, constitute in total about 0. 1 % to about 10 %
  • Magnesium stearate is a preferred lubricant used, for example, to reduce friction between the equipment and granulated mixture during compression of tablet formulations.
  • Suitable anti-adherents include, but are not limited to, talc, cornstarch, DL-leucine, sodium lauryl sulfate and metallic stearates.
  • Talc is a preferred anti-adherent or glidant used, for example, to reduce formulation sticking to equipment surfaces and also to reduce static in the blend.
  • Talc if present, constitutes about 0.1 % to about 10 %, more preferably about 0.25 % to about 5 %, and still more preferably about 0.5 % to about 2 %, of the total weight of the pharmaceutical composition.
  • Glidants can be used to promote powder flow of a solid formulation. Suitable glidants include, but are not limited to, colloidal silicon dioxide, starch, talc, tribasic calcium phosphate, powdered cellulose and magnesium trisilicate. Colloidal silicon dioxide is particularly preferred.
  • compositions of the invention can further comprise, for example, buffering agents.
  • one or more effervescent agents can be used as disintegrants and/or to enhance organoleptic properties of pharmaceutical compositions of the invention.
  • one or more effervescent agents are preferably present in a total amount of about 30 % to about 75 %>, and preferably about 45 % to about 70 %, for example about 60 %, by weight of the pharmaceutical composition.
  • an effervescent agent present in a solid dosage form in an amount less than that effective to promote disintegration of the dosage form, provides improved dispersion of the celecoxib in an aqueous medium.
  • the effervescent agent is effective to accelerate dispersion of the drug, such as celecoxib, from the dosage form in the gastrointestinal tract, thereby further enhancing abso ⁇ tion and rapid onset of therapeutic effect.
  • an effervescent agent is preferably present in an amount of about 1 % to about 20 %, more preferably about 2.5 % to about 15 %, and still more preferably about 5 % to about 10 %, by weight of the pharmaceutical composition.
  • an “effervescent agent” herein is an agent comprising one or more compounds which, acting together or individually, evolve a gas on contact with water.
  • the gas evolved is generally oxygen or, most commonly, carbon dioxide.
  • Prefened effervescent agents comprise an acid and a base that react in the presence of water to generate carbon dioxide gas.
  • the base comprises an alkali metal or alkaline earth metal carbonate or bicarbonate and the acid comprises an aliphatic carboxylic acid.
  • Non-limiting examples of suitable bases as components of effervescent agents useful in the invention include carbonate salts (e.g., calcium carbonate), bicarbonate salts (e.g., sodium bicarbonate), sesquicarbonate salts, and mixtures thereof.
  • carbonate salts e.g., calcium carbonate
  • bicarbonate salts e.g., sodium bicarbonate
  • sesquicarbonate salts e.g., calcium carbonate
  • Calcium carbonate is a prefened base.
  • Non-limiting examples of suitable acids as components of effervescent agents and/or solid organic acids useful in the invention include citric acid, tartaric acid (as D-, L-, or D/L-tartaric acid), malic acid, maleic acid, fumaric acid, adipic acid, succinic acid, acid anhydrides of such acids, acid salts of such acids, and mixtures thereof.
  • Citric acid is a prefened acid.
  • the weight ratio of the acid to the base is about 1 : 100 to about 100: 1, more preferably about 1:50 to about 50: 1, and still more preferably about 1:10 to about 10:1.
  • the effervescent agent comprises an acid and a base
  • the ratio of the acid to the base is approximately stoichiometric.
  • Excipients which solubilize metal salts of drags like celecoxib typically have both hydrophilic and hydrophobic regions, or are preferably amphiphilic or have amphiphilic regions.
  • One type of amphiphilic or partially-amphiphilic excipient comprises an amphiphilic polymer or is an amphiphilic polymer.
  • a specific amphiphilic polymer is a polyalkylene glycol, which is commonly comprised of ethylene glycol and/or propylene glycol subunits. Such polyalkylene glycols can be esterified at their termini by a carboxylic acid, ester, acid anhyride or other suitable moiety.
  • excipients examples include poloxamers (symmetric block copolymers of ethylene glycol and propylene glycol; e.g., poloxamer 237), polyalkyene glycolated esters of tocopherol (including esters formed from a di- or multi-functional carboxylic acid; e.g., d-alpha-tocopherol polyethylene glycol-1000 succinate), and macrogolglycerides (formed by alcoholysis of an oil and esterification of a polyalkylene glycol to produce a mixture of mono-, di- and tri-glycerides and mono- and di-esters; e.g., stearoyl macrogol-32 glycerides).
  • poloxamers symmetric block copolymers of ethylene glycol and propylene glycol
  • polyalkyene glycolated esters of tocopherol including esters formed from a di- or multi-functional carboxylic acid; e.g., d-alpha-tocopherol
  • Solid dosage forms of the invention can be prepared by any suitable process, not limited to processes described herein.
  • An illustrative process comprises (a) a step of blending a celecoxib salt of the invention with one or more excipients to form a blend, and (b) a step of tableting or encapsulating the blend to form tablets or capsules, respectively.
  • solid dosage forms are prepared by a process comprising (a) a step of blending a drag salt such as a celecoxib salt of the invention with one or more excipients to form a blend, (b) a step of granulating the blend to form a granulate, and (c) a step of tableting or encapsulating the blend to form tablets or capsules respectively.
  • Step (b) can be accomplished by any dry or wet granulation technique known in the art, but is preferably a dry granulation step.
  • a salt of the present invention is advantageously granulated to form particles of about 1 micrometer to about 100 micrometer, about 5 micrometer to about 50 micrometer, or about 10 micrometer to about 25 micrometer.
  • One or more diluents, one or more disintegrants and one or more binding agents are preferably added, for example in the blending step, a wetting agent can optionally be added, for example in the granulating step, and one or more disintegrants are preferably added after granulating but before tableting or encapsulating.
  • a lubricant is preferably added before tableting. Blending and granulating can be performed independently under low or high shear.
  • a process is preferably selected that forms a granulate that is uniform in drug content, that readily disintegrates, that flows with sufficient ease so that weight variation can be reliably controlled during capsule filling or tableting, and that is dense enough in bulk so that a batch can be processed in the selected equipment and individual doses fit into the specified capsules or tablet dies.
  • solid dosage forms are prepared by a process that includes a spray drying step, wherein a celecoxib salt is suspended with one or more excipients in one or more sprayable liquids, preferably a non-protic (e.g., non-aqueous or non-alcoholic) sprayable liquid, and then is rapidly spray dried over a cunent of warm air.
  • a spray drying step wherein a celecoxib salt is suspended with one or more excipients in one or more sprayable liquids, preferably a non-protic (e.g., non-aqueous or non-alcoholic) sprayable liquid, and then is rapidly spray dried over a cunent of warm air.
  • a granulate or spray dried powder resulting from any of the above illustrative processes can be compressed or molded to prepare tablets or encapsulated to prepare capsules.
  • Conventional tableting and encapsulation techniques known in the art can be employed. Where coated tablets are desired, conventional coating techniques are suitable.
  • Excipients for tablet compositions of the invention are preferably selected to provide a disintegration time of less than about 30 minutes, preferably about 25 minutes or less, more preferably about 20 minutes or less, and still more preferably about 15 minutes or less, in a standard disintegration assay.
  • Celecoxib dosage forms of the invention preferably comprise celecoxib in a daily dosage amount of about 10 mg to about 1000 mg, more preferably about 25 mg to about 400 mg, and most preferably about 50 mg to about 200 mg.
  • the PG solvate comprises an API from Table 3.
  • the PG solvate can either be of the form listed in Table 3 or a PG solvate of the free form, or a PG solvate of another form that is not listed.
  • Table 3 includes the CAS number, chemical name or a PCT or patent reference (each inco ⁇ orated herein in their entireties).
  • any one or more of the APIs of Table 3 may be specifically excluded from the present invention. Any APIs cunently known in the art may also be specifically excluded from the present invention. For example, azithromycin and cephalosporin may be specifically excluded from the present invention.
  • the sample was either left in the glass vial in which it was processed or an aliquot of the sample was fransfened to a glass slide.
  • the glass vial or slide was positioned in the sample chamber.
  • the measurement was made using an AlmegaTM Dispersive Raman (AlmegaTM Dispersive Raman, Thermo-Nicolet, 5225 Verona Road, Madison, WI 53711-4495) system fitted with a 785 nm laser source.
  • the sample was manually brought into focus using the microscope portion of the apparatus with a lOx power objective (unless otherwise noted), thus directing the laser onto the surface of the sample.
  • the spectrum was acquired using the parameters outlined in Table 1. (Exposure times and number of exposures may vary; changes to parameters will be indicated for each acquisition.)
  • precipitate can be amo ⁇ hous or crystalline.
  • the loaded capillary was mounted in a holder that was secured into the x- y stage.
  • a diffractogram was acquired (e.g., Control software: RINT Rapid Control Software, Rigaku Rapid XRD, version 1.0.0, ⁇ 1999 Rigaku Co.) under ambient conditions at a power setting of 46 kV at 40 mA in reflection mode, while oscillating about the omega-axis from 0 - 5 degrees at 1 degree/s and spinning about the phi-axis at 2 degrees/s.
  • the exposure time was 15 minutes unless otherwise specified.
  • the diffractogram obtained was integrated over 2-theta from 2-60 degrees and chi (1 segment) from 0-360 degrees at a step size of 0.02 degrees using the cyllnt utility in the RINT Rapid display software (Analysis software: RINT Rapid display software, version 1.18, Rigaku/MSC.) provided by Rigaku with the instrument.
  • the dark counts value was set to 8 as per the system calibration (System set-up and calibration by Rigaku); normalization was set to average; the omega offset was set to 180°; and no chi or phi offsets were used for the integration.
  • the analysis software JADE XRD Pattern Processing, versions 5.0 and 6.0 (( 8 1995-2002, Materials Data, Inc. was also used.
  • the relative intensity of peaks in a diffractogram is not necessarily a limitation of the PXRD pattern because peak intensity can vary from sample to sample, e.g., due to crystalline impurities. Further, the angles of each peak can vary by about +/- 0.1 degrees, preferably +/-0.05. The entire pattern or most of the pattern peaks may also shift by about +/- 0.1 degree due to differences in calibration, settings, and other variations from instrament to instrament and from operator to operator. The above limitations result in a PXRD enor of +/- 0.1 degrees 2-theta for each diffraction peak.
  • sample pan e.g., Pan part # 900786.091; lid part # 900779.901; TA Instruments, 109 Lukens Drive, New Castle, Delaware 19720
  • the sample pan was sealed either by crimping for dry samples or press fitting for wet samples (e.g., hydrated or solvated samples).
  • the sample pan was loaded in to the apparatus (DSC: Q1000 Differential Scanning Calorimeter, TA Instruments, 109 Lukens Drive, New Castle, Delaware 19720), which is equipped with an autosampler, and a thermogram was obtained by individually heating the sample (e.g., Control software: Advantage for QW- Series, version 1.0.0.78, Thermal Advantage Release 2.0, ⁇ 2001 TA instruments - Water LLC) at a rate of 10 degrees C /min from T m ; n (typically 20 degrees C) to T max (typically 300 degrees C) (Heating rate and temperature range may vary, changes to these parameters will be indicated for each sample) using an empty aluminum pan as a reference.
  • DSC Differential Scanning Calorimeter, TA Instruments, 109 Lukens Drive, New Castle, Delaware 19720
  • Control software Advantage for QW- Series, version 1.0.0.78, Thermal Advantage Release 2.0, ⁇ 2001 TA instruments - Water LLC
  • T m typically 20 degrees C
  • T max typically 300 degrees C
  • Dry nitrogen (e.g., Compressed nitrogen, grade 4.8, BOC Gases, 575 Mountain Avenue, Munay Hill, New Jersey 07974-2082) was used as a sample purge gas and was set at a flow rate of 50 mL/min. Thermal transitions were viewed and analyzed using the analysis software (Analysis Software: Universal Analysis 2000 for Windows 95/95/2000/NT, version 3. IE; Build 3.1.0.40, ⁇ 1991 - 2001TA instraments - Water LLC) provided with the instrument.
  • Analysis Software Universal Analysis 2000 for Windows 95/95/2000/NT, version 3. IE; Build 3.1.0.40, ⁇ 1991 - 2001TA instraments - Water LLC
  • Thermograms were obtained by individually heating the sample at 10 degrees C /min from 25 degrees C to 300 degrees C (Heating rate and temperature range may vary, changes in parameters will be indicated for each sample) under flowing dry nitrogen (e.g., Compressed nitrogen, grade 4.8, BOC Gases, 575 Mountain Avenue, Munay Hill, New Jersey 07974-2082), with a sample purge flow rate of 60 mL/min and a balance purge flow rate of 40 mL/min.
  • Thermal transitions e.g. weight changes
  • a propylene glycol solvate of the sodium salt of celecoxib was prepared. To a solution of celecoxib (312 mg; 0.818 mmol) in diethyl ether (6 mL) was added propylene glycol (0.127 mL, 1.73 mmol). To the clear solution was added sodium ethoxide in ethanol (21%, 0.275 mL, 0.817 mmol). After 1 minute, crystals began to form. After 5 minutes, the solid had completely crystallized. The solid was collected by filtration and was washed with additional diethyl ether (10 mL). The off-white solid was then air-dried and collected. The crystalline salt form was identified as a 1 : 1 solvate of propylene glycol. The solid was characterized by TGA and PXRD. The results are depicted in Figs. 1 and 2 A.
  • Fig. 1 shows the results of TGA. A weight loss of about 15.6 % was observed between about 65 and 200 degrees C which represents 1 molar equivalent of propylene glycol to celecoxib Na salt.
  • Fig. 2A shows the results of PXRD. Peaks, in 2-theta angles, that can be used to characterize the solvate include any 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 of the following: 3.77, 7.57, 8.21, 11.33, 14.23, 16.13, 18.69, 20.65, 22.69 and 24.77 degrees or any one or any combination of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks of Fig. 2 A.
  • the TGA thermogram or PXRD diffractogram data may be used alone or in any combination to characterize the solvate. A 0.8 mm collimator was used during acquisition of the diffractogram.
  • Figs. 2B, 2C, and 2D are additional diffractograms of the propylene glycol solvate of celecoxib sodium salt. A comparison of these diffractograms yields a number of noticeable differences. For example, the peak at 8.21 degrees 2-theta in Fig. 2A is not present in Figs. 2B or 2C. Another peak at 8.79 degrees 2-theta, present in Figs. 2B and 2D, is not found in Figs. 2A or 2C. Other distinctions can also be found between the four diffractograms. Such distinctions in otherwise similar diffractograms suggest the existence of polymo ⁇ hism or perhaps a variable hydrate.
  • a PG solvate of an API can give rise to distinct PXRD diffractograms. This can be caused by polymo ⁇ hism, a variable hydrate, a different environmental condition, etc.
  • the propylene glycol solvate of celecoxib sodium salt can yield a PXRD pattern with the absence or presence of a peak at 8.21 degrees 2-theta.
  • the propylene glycol solvate of celecoxib sodium salt can yield a PXRD pattern with the absence or presence of a peak at 8.79 degrees 2-theta.
  • a propylene glycol solvate of the potassium salt of celecoxib was prepared. To a solution of celecoxib (253 mg, 0.664 mmol) in diethyl ether (6 mL) was added propylene glycol (0.075 mL, 1.02 mmol). To the clear solution was added potassium t-butoxide in tetrahydrofuran (THF) (1 M, 0.66 mL, 0.66 mmol). Crystals immediately began to form. After 5 minutes, the solid had completely crystallized. The solid was collected by filtration and was washed with additional diethyl ether (10 mL). The white solid was then air-dried and collected. The crystalline salt form was found to be a 1 : 1 propylene glycol solvate of celecoxib K salt. The solid was characterized by TGA and PXRD. The results are depicted in Figs. 3 and 4.
  • Fig. 3 shows the results of TGA. A weight loss of about 14.94 % was observed between about 65 and about 250 degrees C which is consistent with 1 molar equivalent of propylene glycol to celecoxib K.
  • Fig. 4 shows the results of PXRD. Peaks, in 2-theta angles, that can be used to characterize the solvate include any 1, 2, 3, 4, 5, 6, 7, 8 , 9, or 10 of the following: 3.75, 7.47, 11.33, 14.89, 15.65, 18.31, 20.49, 21.73, 22.51, and 24.97 degrees or any one or any combination of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks of Fig. 4.
  • a propylene glycol solvate of the lithium salt of celecoxib was prepared. To a solution of celecoxib (264 mg, 0.693 mmol) in diethyl ether (8 mL) was added propylene glycol (0.075 mL, 1.02 mmol). To the clear solution was added t-butyl lithium in pentane (1.7 M, 0.40 mL, 0.68 mmol). A brown solid formed immediately but dissolved within one minute which subsequently yielded a white fluffy solid. The white solid crystallized completely after 10 minutes. The solid was collected by filtration and was washed with additional diethyl ether (10 mL). The white solid was then air-dried and collected.
  • the crystalline salt form was found to be a 1 : 1 propylene glycol solvate of celecoxib Li.
  • the solid was characterized by TGA and PXRD.
  • the results of TGA are depicted in Fig. 5 and show a weight loss of about 16.3 % between 50 degrees C and 210 degrees C which is consistent with 1 molar equivalent of propylene glycol to celecoxib Li.
  • the results of PXRD are shown in Fig. 6.
  • Characteristic peaks of 2-theta angles that can be used to characterize the salt include any one, or combination of any 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 of 3.79, 7.51, 8.19, 9.83, 11.41, 15.93, 18.29, 19.19, 19.87, 20.63, 22.01, or 25.09 degrees or any one or any combination of peaks of Fig. 6.
  • Example 4
  • a propylene glycol solvate of a sodium salt of naproxen was prepared. To a solution of naproxen (348 mg, 1.51 mmol) in diethyl ether (10 mL) was added propylene glycol (0.200 ml, 2.72 mmol). To the clear solution was added sodium ethoxide in ethanol (21 %, 0.750 mL, 2.01 mmol). The solution became slightly yellow due to the sodium ethoxide. After 1 minute, crystals began to form. After 5 minutes, the solid had completely crystallized. The solid was collected by filtration and was washed with diethyl ether (10 mL). The product was then air-dried and collected. The solvate was 2:1 naproxen Na:propylene glycol. The solid was characterized by TGA and PXRD.
  • the TGA thermogram of naproxen sodium salt PG solvate is shown in Fig. 1, and indicates a 13.5 percent weight loss between about 75 and 150 degrees C. This weight loss is consistent with a 2: 1 naproxen Na:propylene glycol solvate.
  • the PXRD diffractogram of naproxen sodium salt PG solvate is shown in Fig. 8, and shows peaks at 2-theta angles, including but not limited to, 6.67, 9.65, 13.41, 15.77, 18.55, 20.83, 22.79, and 27.17 degrees. Any one, any two, any three, any four, any five, any six, any seven, or all eight of the above peaks or any one or any combination of peaks in Fig. 8 can be used to characterize naproxen sodium salt PG solvate.
  • Olanzapine PG solvate was prepared by dissolving 1.05 g of olanzapine fonn I in 8 mL of isopropylacetate and 2.0 mL of propylene glycol with heating. The hot liquid was filtered through a 0.2 micrometer nylon syringe filter. Crystallization occuned after cooling to room temperature. The addition of a small amount of seed crystals from a previous reaction followed by sonication for 10 seconds also facilitated crystallization. Olanzapine PG solvate was isolated by suction filtration, rinsed with isopropylacetate and allowed to air dry. The product was a fine yellow powder. The crystals grew in three dimensions, yielding chunks.
  • a second preparation of olanzapine form I PG solvate was completed by dissolving 16.2 mg of olanzapine form I in 0.05 ml of propylene glycol and 0.05 ml of isopropylacetate with heating.
  • the sample was cooled to room temperature and a single crystal from a previous preparation was added.
  • the sample was allowed to sit undisturbed for 2 days during which an aggregate clump of several large crystals grew.
  • the crystals were fransfened to filter paper, rinsed with a single drop of isopropylacetate, and dried by dabbing with the filter paper.
  • the rinse procedure was repeated a total of four times with fresh filter paper. Characterization of the product has been achieved via TGA, DSC, PXRD, and Raman spectroscopy.
  • Results from TGA analysis show an 18.05 % weight loss representing loss of about 1 equivalent of propylene glycol (Fig. 9).
  • Results from DSC show a peak endothermic transition at 92.63 degrees C (Fig. 10).
  • the PXRD pattern has characteristic peaks as shown for two sample preparations in Fig. 11 A and 1 IB. Peaks can be seen at 2-theta angles including but not limited to 8.33, 8.95, 11.75, 14.47, 15.61, 17.95, 19.21, 19.57, 20.65, 21.41, 22.03, and 23.29 in Fig. 11 A.
  • the crystal can be characterized by any one, any two, any three, any four, any 5, any 6, any 1, any 8, any 9, any 10, any 11, or all 12 of the peaks above or one or a combination of peaks in Fig. 11A.
  • peaks can be seen at 2-theta angles including, but not limited to, 8.39, 8.89, 13.95, 14.45, 15.55, 17.91, 19.13, 19.55, 20.61, 21.47, 22.07, and 23.31 in Fig. 1 IB.
  • the crystal can be characterized by any one, any two, any three, any four, any 5, any 6, any 7, any 8, any 9, any 10, any 11, or all 12 of the peaks above or one or a combination of peaks in Fig. 1 IB.
  • FIG. 12 shows a packing diagram of the single-crystal stracture of olanzapine form I PG solvate.
  • Cortisone acetate PG solvate was prepared by dissolving 9.7 mg cortisone acetate in 0.6 mL propylene glycol with heating. Needle-like crystals formed upon cooling, followed by the conversion to large, very thin, rectangular plates over a couple hours.
  • a second preparation of cortisone acetate PG solvate was completed by dissolving 11.9 mg cortisone acetate in 0.7 mL isopropylacetate with heating to reflux. Upon crystal formation, 0.05 mL propylene glycol was added, heated to reflux to dissolve, and crystals again formed. The resultant crystals were collected and analyzed by PXRD, TGA, and DSC.
  • a third preparation of cortisone acetate PG solvate was completed by dissolving 65.8 mg cortisone acetate in 7.0 mL isopropylacetate and 0.05 mL propylene glycol with heating. The mixture was cooled slightly and seed crystals from a previous reaction (second preparation above) were added. The resultant crystals form rods, or long rectangular plates that are birefringent when viewed by plane polarized microscopy. Crystals were harvested after 30 minutes and analyzed by single crystal x-ray. Prior to PXRD measurement, the sample was ground, fransfened to a vial, and left open to the atmosphere for 4 days.
  • Results from TGA analysis show a 15.9 %> weight loss at temperatures up to 150 degrees C (Fig. 13). 14.9 % weight loss occured between 70 and 150 degrees C while up to 1.2 % weight loss occuned at lower temperatures. This weight loss is representative of a cortisone acetate PG solvate with 1.0 equivalents of propylene glycol.
  • DSC was completed in a closed, not sealed aluminium pan from room temperature to 300 degrees C at 10 degrees/minute (Fig. 14). The compound was discovered to have two endothermic transitions, one at 148 degrees C with an intensity of 146 J/g, and the second at 237 degrees C with an intensity of 77 J/g.
  • the PXRD of cortisone acetate PG solvate crystallized from isopropylacetate/propylene glycol solution is shown in two diffractograms in Fig. 15A and Fig. 15B. Peaks can be seen at 2-theta angles including, but not limited to, 5.31 , 10.71, 14.54, 15.66, 18.49, 21.33, and 23.49 degrees.
  • the crystal can be characterized by any one, any two, any three, any four, any five, any six, or any seven, or any combination of the peaks listed above or one or a combination of peaks listed in Fig.
  • peaks can be seen at 2-theta angles including, but not limited to, 5.29, 10.73, 14.57, 15.69, 18.51, 21.39, 23.51, and 27.49 in Fig. 15B.
  • the crystal can be characterized by any one, any two, any three, any four, any 5, any 6, any 7, or all 8 of the peaks above or one or a combination of peaks in Fig. 15B.
  • Fig. 16 shows a PXRD diffractogram of material crystallized from isopropylacetate alone. This is provided only to differentiate the PG solvate from the unsolvated form of the API.
  • FIG. 17 shows a packing diagram of the single-crystal structure of cortisone acetate PG solvate.
  • Celecoxib Na propylene glycol trihydrate was formed by allowing the celecoxib sodium salt propylene glycol solvate to sit at 60 % RH and 20 degrees C for 3 days. (Note: Formation of the trihydrate at 75 % and 40 degrees C occurs as well). The trihydrate begins to form somewhere between 31 and 40 % RH at room temperature.
  • the solid was characterized by TGA and PXRD, which are shown in Fig. 18 and 19, respectively.
  • Fig. 18 shows the results of the TGA where 9.64 % weight loss was observed between room temperature and 60 degrees C and 13.6 % weight loss was observed between 60 degrees C and 175 degrees C.
  • the PXRD pattern has characteristic peaks at 2-theta angles shown in Fig. 19. Any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more peaks can be used to characterize the trihydrate, including for example, peaks at 3.47, 6.97, 10.37, 13.97, 16.41, 19.45, 21.29, 22.69, 23.87, and 25.75 degrees.
  • a 0.8 mm collimator was used during acquisition of the diffractogram.
  • the trihydrate can also be formed by crystallization of celecoxib Na propylene glycol solvate in the presence of H 2 O.
  • a solid formed within one minute and was isolated via filtration. The solid was then washed with additional diethyl ether (2.0 mL) and allowed to air dry.
  • Fig. 20 shows the results of TGA where 10.92% weight loss was observed between room temperature and 50 degrees C and 12.95% weight loss was observed between 50 degrees C and 195 degrees C.
  • the PXRD pattern has characteristic peaks at 2-theta angles shown in Fig. 21. Any 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or more peaks can be used to characterize the trihydrate, including for example, peaks at 3.43, 6.95, 10.25, 13.95, 16.39, 17.39, 17.75, 18.21, 19.43, 21.21, 22.61, and 25.71 degrees.
  • a 0.8 mm collimator was used during acquisition of the diffractogram.
  • Figs. 22-24 have been included as reference PXRD diffractograms.
  • Fig. 22 shows the PXRD diffractogram of celecoxib sodium salt.
  • Fig. 23 shows the PXRD diffractogram of celecoxib lithium salt.
  • Fig. 24 shows the PXRD diffractogram of celecoxib potassium salt.
  • Dynamic moisture so ⁇ tion studies of several embodiments of the present invention have been discussed in PCT/US03/XXXXX filed on December 24, 2003, entitled “Pharmaceutical Compositions With Improved Dissolution" (Attorney Docket No. TPI-1700CXC2 PCT) by Tawa et al, which is hereby inco ⁇ orated by reference, in its entirety.
  • Dynamic moisture so ⁇ tion studies can be used to illustrate important characteristics of the solvates of the present invention, such as decreased hygroscopicity or increased form stability.

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Abstract

L'invention concerne des compositions pharmaceutiques comprenant des solvates d'API de propylène glycol.
PCT/US2003/041642 2002-02-15 2003-12-29 Compositions pharmaceutiques de solvates de propylene glycol Ceased WO2004060347A2 (fr)

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AU2003300452A AU2003300452A1 (en) 2002-12-30 2003-12-29 Pharmaceutical propylene glycol solvate compositions
US10/551,014 US20060223794A1 (en) 2002-02-15 2004-03-31 Novel olanzapine forms and related methods of treatment
PCT/US2004/009947 WO2004089313A2 (fr) 2003-04-01 2004-03-31 Nouvelles formes de l'olanzapine et methodes de traitement associees

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US10/232,589 US6559293B1 (en) 2002-02-15 2002-09-03 Topiramate sodium trihydrate
US43751602P 2002-12-30 2002-12-30
US60/437,516 2002-12-30
US44133503P 2003-01-21 2003-01-21
US60/441,335 2003-01-21
US45602703P 2003-03-18 2003-03-18
US60/456,027 2003-03-18
US45660803P 2003-03-21 2003-03-21
US60/456,608 2003-03-21
US45950103P 2003-04-01 2003-04-01
US60/459,501 2003-04-01
USPCT/US03/19574 2003-06-20
PCT/US2003/019574 WO2004000284A1 (fr) 2002-06-21 2003-06-20 Compositions pharmaceutiques a dissolution amelioree
US10/601,092 2003-06-20
US10/601,092 US20050025791A1 (en) 2002-06-21 2003-06-20 Pharmaceutical compositions with improved dissolution
US48671303P 2003-07-11 2003-07-11
US60/486,713 2003-07-11
USPCT/US03/28982 2003-09-16
PCT/US2003/028982 WO2004026235A2 (fr) 2002-09-20 2003-09-16 Compositions pharmaceutiques presentant une dissolution amelioree
PCT/US2003/041273 WO2004061433A1 (fr) 2002-12-30 2003-12-24 Compositions pharmaceutiques a dissolution amelioree
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