Polymorphism of Dehydro-Aripiprazole, the Active Metabolite of the Antipsychotic Drug Aripiprazole (Abilify)

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• 作者：Tarek A. Zeidan ; Jacob T. Trotta ; Renato A. Chiarella ; Mark A. Oliveira ; Magali B. Hickey ; 脰rn Almarsson ; Julius F. Remenar
• 刊名：Crystal Growth & Design
• 出版年：2013
• 出版时间：May 1, 2013
• 年：2013
• 卷：13
• 期：5
• 页码：2036-2046
• 全文大小：606K
• 年卷期：v.13,no.5(May 1, 2013)
• ISSN：1528-7505

文摘

Crystal form exploration of dehydro-aripiprazole (dAPZ), the active metabolite of the antipsychotic drug aripiprazole (APZ), elucidated five polymorphs (I, II, III, IV, and V), two methanol solvates, and a monohydrate. The forms were characterized by thermal microscopy, differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), single and powder X-ray diffraction (SCXRD and PXRD), and infrared spectroscopy. DSC analysis showed monotropic relationships among polymorphs I, II, III, and IV and enantiotropic relationships for the two form pairs I 鈫?V and II 鈫?V. Solvent-mediated conversion experiments indicated that Form V is the thermodynamically stable form in the temperature range 5鈥?0 掳C and Form I is the stable form at 鈮?0 掳C, where a transition temperature lies between 60 and 70 掳C. Two polymorphs of the methanol solvate (S_MeOH1 and S_MeOH2) were crystallized from methanol solutions in 1:1 dAPZ/methanol molar ratio. S_MeOH2 is the thermodynamically stable form of the two methanol solvates at ambient temperature. The monohydrate (S_H2O) was obtained by solvent-mediated conversion experiments of any of the methanol solvates in water. Single-crystal structure analysis of polymorphs I, II, V and the two methanol solvates showed the formation of dimeric structures with N鈥揌路路路O鈺怌 (amide鈥揳mide) hydrogen-bonded homodimer synthons. In the case of S_H2O, two water molecules are present between the units of the dimer, and each water molecule exhibits hydrogen-bonding with one of the piperazine nitrogen atoms of a third dAPZ molecule. Analysis of the crystal structures and PXRD patterns for both the APZ and dAPZ nonsolvated polymorphs reveals that all the forms are distinct from one another. When solvates and hydrates were added to the comparison (a total of 18 crystalline forms of APZ and dAPZ), only S_MeOH2 of dAPZ was found to have an identical packing arrangement to the APZ methanol solvate. This study illustrates that despite the chemical structure similarity between dAPZ and APZ鈥攖he differences being one C鈺怌 double-bond vs a C鈥揅 single-bond and a molecular weight change of 2 Da out of 448鈥攖he observed crystal packing arrangement in the polymorphs of the active metabolite differs significantly from those observed for the parent drug.