Methods of preparing aripiprazole crystalline forms

This application is a divisional of U.S. application Ser. No. 11/015,068, filed Dec. 16, 2004, which claims the benefit of U.S. provisional Application No. 60/530,297, filed Dec. 16, 2003; U.S. provisional Application No. 60/533,831, filed Dec. 30, 2003; U.S. provisional Application No. 60/618,404, filed Oct. 13, 2004; and U.S. provisional Application No. 60/618,960, filed Oct. 14, 2004.

The invention encompasses crystalline forms of aripiprazole forms and methods of preparing them.

Schizophrenia is the most common type of psychosis caused by excessive neurotransmission activity of the dopaminergic nervous system in the central nervous system. A number of drugs which block the neurotransmission of dopaminergic receptor in the central nervous system have been developed for use in treating schizophrenia. Among the drugs developed are phenothiazine-type compounds such as chlorpromazine, butyrophenone-type compounds such as haloperidol, and benzamide-type compounds such as sulpiride. These drugs improve so-called positive symptoms in the acute period of schizophrenia such as hallucinations, delusions, and excitations. Many drugs for treating schizophrenia, however, are not effective for improving the so-called negative symptoms which are observed in the chronic period of schizophrenia such as apathy, emotional depression, and hypopsychosis. The drugs currently used produce undesirable side effects such as akathisia, dystonia, Parkinsonism dyskinesia, and late dyskinesia, by blocking the neurotransmission of dopaminergic receptor in the striate body. Drugs that improve both the negative and positive symptoms of schizophrenia but diminish the undesirable side effect of schizophrenia are particularly desirable.

Aripiprazole is a pyschotropic drug that exhibits high affinity for dopamine D₂ and D₃, serotonin 5-HT_1A and 5-HT_2A receptors; moderate affinity for dopamine D₄, serotonin 5-HT_2C and 5-HT₇, α₁-adrenergic and histamine H₁ receptors; and moderate affinity for the serotonin reuptake site. Aripiprazole has no appreciable affinity for cholinergic muscarinic receptors. The mechanism of action of aripiprazole, as with other drugs having efficacy in schizophrenia, is unknown. It has been proposed, however, that the efficacy of aripiprazole is mediated through a combination of partial agonist activity at D₂ and 5-HT_1A receptors and antagonist activity at 5-HT_2A receptors.

Japanese Patent Kokai No. 02-191256 discloses that anhydride crystals of aripiprazole are typically manufactured by recrystallization of anhydride aripiprazole from ethanol or by heating aripiprazole hydrate at a temperature of 80° C. According to WO 03/26659, anhydride aripiprazole prepared by these methods is significantly hygroscopic.

The Proceedings of the 4^th Japanese-Korean Symposium on Separation Technology (Oct. 6-8, 1996) disclosed that aripiprazole anhydride crystals may exist as Type-I and Type-II crystals. Type-I aripiprazole crystals can be prepared by recrystallizing aripiprazole from an ethanol solution or by heating aripiprazole hydrate at 80° C. Type-II aripiprazole crystals can be prepared by heating the Type-I crystals at 130° C. to 140° C. for 15 hours. This process is not easily applied to an industrial scale preparation of anhydride aripiprazole.

PCT publication WO 03/26659 discloses the preparation of anhydrous aripiprazole Type I and crystalline forms Form A, B, C, and D. Typically, the process for preparing the crystalline forms comprises heating crystalline anhydrous aripiprazole. The process, however, is cumbersome because it requires crystalline anhydrous aripiprazole as the starting material. The process in the PCT publication can only be carried out after the preparation, isolation, and purification of aripiprazole. Thus, only after performing the additional steps may one heat the crystalline anhydrous aripiprazole to obtain the desired crystalline forms of aripiprazole. Additionally, drying or heating may affect the distribution of crystalline forms and/or crystalline purity, if drying causes crystalline transformation from one crystalline form to another.

Alternate crystalline structures possessing the stability and manufacturing advantages of anhydrous aripiprazole are highly desired. Likewise, methods for making aripiprazole without additional steps and cost also are necessary.

The invention encompasses anhydrous aripiprazole crystalline forms which are non-hygroscopic and which maintain compound stability during storage, and methods for preparing the non-hygroscopic aripiprazole crystalline forms.

One embodiment of the invention encompasses a crystalline anhydrous aripiprazole Form I characterized by X-ray powder diffraction peaks at 16.8, 19.6, 20.6, 22.3, and 25.1 degrees two-theta, ±0.2 degrees two-theta.

Another embodiment of the invention encompasses aripiprazole Form II characterized by X-ray powder diffraction peaks at 16.5, 18.7, 21.9, 22.4, and 23.5 degrees two-theta, +0.2 degrees two-theta.

Another embodiment of the invention encompasses substantially pure crystalline aripiprazole Form II. For example, substantially pure Form II may encompass Form II having less than 40% by weight of other crystalline aripiprazole forms and preferably no more than 10% by weight of other crystalline aripiprazole forms.

Particular embodiments of the invention encompass Form II having no more than 40% by weight of crystalline compound 1, crystalline compound 2, Form C, or Form D. In another embodiment, Form II has no more than 30% by weight of crystalline compound 1, crystalline compound 2, Form C, or Form D, preferably no more than 20%, more preferably no more than 10%, and most preferably no more than 5% by weight.

Another embodiment of the invention encompasses crystalline aripiprazole Form VI characterized by X-ray powder diffraction peaks at 17.6, 17.8, 20.6, and 24.9 degrees two-theta, ±0.2 degrees two-theta.

Yet another embodiment of the invention encompasses aripiprazole crystalline Form VIII characterized by X-ray powder diffraction peaks at 4.4, 8.7, 20.8, 21.6, and 26.0 degrees two-theta, ±0.2 degrees two-theta. Another embodiment of the invention encompasses crystalline aripiprazole Form X characterized by X-ray powder diffraction peaks at 18.2, 22.4, 22.8, and 24.3 degrees two-theta, +0.2 degrees two-theta.

Yet another embodiment of the invention encompasses aripiprazole crystalline Form XI characterized by X-ray powder diffraction peaks at 5.9, 18.0, 20.5, 24.5, and 25.1 degrees two-theta, ±0.2 degrees two-theta.

Another embodiment of the invention encompasses crystalline aripiprazole Form XIV characterized by X-ray powder diffraction peaks at 11.0, 23.6, 24.7, 25.2, and 29.0 degrees two-theta, ±0.2 degrees two-theta.