The present invention relates to pharmaceutical tablet compositions that contain crystalline aripiprazole Type II and pharmaceutically acceptable excipients.
Aripiprazole or more properly 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril, is a compound of the formula (1).
It is a commercially marketed, pharmaceutically active substance useful for treatment of schizophrenia and bipolar disorder. It is disclosed in EP 367141/U.S. Pat. No. 5,006,528. The commercially marketed product is the free base of the title compound (1).
Solid state aripiprazole was prepared in U.S. Pat. No. 5,006,528 by a two-fold recrystallization of crude aripiprazole from ethanol resulting in colorless flake crystals having a melting point of 139-139.5° C. In an article of Aoki (Study on Crystal Transformation of Aripiprazole, The Fourth Japan-Korea Symposium on Separation Technology, p.937 ff (1996)), this solid state form was designated as Type I aripiprazole and identified as an anhydrate. Aoki also teaches that the Type I aripiprazole may be converted into a Type II aripiprazole by heating at 130-140° C. for 15 hours. This product is also an anhydrate with a melting point of 150° C. When both Type I and Type II aripiprazole were recrystallized from an alcoholic solvent containing water up to 20%, the product was an aripiprazole hydrate labeled as Type III by Aoki. Type III aripiprazole can be converted into Type I by heating at 80° C.
WO 03/26659 (EP 1330249) teaches that Type I aripiprazole, the alleged original solid form of aripiprazole, is significantly hygroscopic. In an effort to find a form of aripiprazole having reduced hygroscopicity and better processing qualities, seven crystalline forms (A-G) were described.
Hydrate Form A is taught as a useful intermediate for making anhydrate forms. Hydrate Form A can be prepared by milling Aoki's hydrated Type III. Contrary to the conventional Form III hydrate, the Hydrate Form A does not exhibit sharp dehydration endothermic peak at 123.5° C. at TGA, but has a gradual endothermic peak between 60-120° C.
Anhydrous Form B, which seems to be the preferred crystalline form, is not hygroscopic; i.e., less than 0.4% water uptake in 24 hours, and is a stable crystalline form. It can be prepared by heating the Hydrated Form A, preferably at 90-125° C. for 3-50 hours or by heating the Type I/Type II aripiprazole at 90-125° C. Although the Anhydrate Form B of WO 03/26659 is not hygroscopic, it suffers from being unsuitable for milling. Specifically, if milling is attempted in order to create small particle sizes such as 50 microns or less, the milled substance tends to adhere to the milling machine making an industrial process difficult. To overcome this problem, WO 03/26659 teaches forming Hydrate Form A aripiprazole, milling the Hydrate Form A to the desired size and then heat converting to Anhydrate Form B.
The other anhydrate forms disclosed therein are briefly summarized below:
Form C: Prepared by heating an aripiprazole anhydrate to 140-150° C. Endothermic peak around 150.2° C.
Form D: Prepared by recrystallization of aripiprazole anhydrate from toluene. Endothermic peaks at 136.8 and 141.6° C.
Form E: Prepared by double heating, dissolving, and crystallizing aripiprazole in acetonitrile with crystallization at about 70° C. Endothermic peak at 146.5° C.
Form F: Prepared by heating a suspension of aripiprazole anhydrate in acetone. Endothermic peaks at 137.5 and 149.8° C.
Form G: Prepared by putting glassy state of aripiprazole anhydrate in a sealed vessel and keeping it at room temperature for at least 2 weeks. Exothermic peak at 122.7° C., endothermic peak at 141.0° C.
More recently techniques for crystallizing Type II aripiprazole directly from a solution were disclosed in U.S. Provisional application Serial Nos. 60/662,552, filed Mar. 17, 2005, and 60/692,557, filed Jun. 22, 2005; the entire contents of each being incorporated herein by reference. In general the Type II was found to be obtainable by precipitation from 2-propanol, dimethyl sulfoxide, or tetrahydrofuran, with a mixture of 2-propanol and ethyl acetate being a preferred embodiment, especially at somewhat elevated temperatures. Similarly, WO2005/058835 also purports to have directly crystallized Type II aripiprazole.
Although various polymorphs of crystalline aripiprazole are known, it is believed that the commercial aripiprazole product uses Type I aripiprazole. However, the commercial product apparently suffers from moisture sensitivity in that the U.S. product is packaged with a large amount of desiccant (3 mg instead of the usual 2 mg desiccant) and the EU product is packaged in moisture protecting aluminum-aluminum blisters.
It would be desirable to form an aripiprazole tablet composition that is less moisture sensitive than the current commercial product.