The Effect of Compaction Force on the Transition to Hydrate of Anhydrous Aripiprazole

Abstract

Aripiprazole (APZ) is used to treat schizophrenia and is administered as a tablet containing the anhydrous form of APZ. In this study, the effect of compaction force on the crystal form transition was investigated. The crystalline state was observed by X-ray diffraction (XRD). APZ Anhydrous Form II was compacted into tablets. The XRD intensity of anhydrous APZ became lower with higher compressive force. The degree of crystallinity decreased with the compaction force. The powder and the compacted tablets of anhydrous APZ were stored for one week under 60°C and 75% relative humidity. The powder showed no crystal form transition after storage. For the tablets, however, XRD peaks of APZ hydrate were observed after storage. The tablets compacted with higher force showed the higher XRD diffraction intensity of hydrate form. We concluded that the crystallinity reduction of APZ Anhydrous Form II by compaction caused and accelerated the transition to hydrate under high temperature and humidity conditions. In order to manufacture crystallographically stable tablets containing anhydrous APZ, it is important to prevent this crystallinity reduction during compaction.Key words aripiprazole; crystal transition; hydration; compaction; tablet Many active pharmaceutical ingredient (API) bulk powders have various solid states, such as polymorphic forms, solvates, and amorphous forms. 1)The physicochemical properties, chemical stability and dissolution behaviors of the meta-stable crystalline forms and amorphous forms of poorly water-soluble APIs in pharmaceutical preparations are significantly affected by storage conditions including temperature and humidity. Therefore, changes in the crystalline and amorphous forms during the manufacturing process may affect the bioavailability of the pharmaceutical products as a result of changes to their physical properties (melting point, solubility, etc.), chemical stability and absorbability in the gastrointestinal tract.2,3) The crystallization process of metastable bulk drug powder is important for the quality assurance of drugs, depending on the bioavailability of the pharmaceutical formulation. [4][5][6][7][8][9][10] As examples, the meta-stable crystalline form of carbamazepine is transformed into a stable form during granulation and drying, 11) and anhydrous caffeine and chlorproamide are transformed during grinding and compressing.12,13) The crystallinity of SX3288 decreases by grinding and compressing, leading to reduced chemical stability.14)The amorphous state is a state lacking regularity with a wide range of orders and orientations of the molecule. Since an amorphous solid with high chemical potential is more easily soluble in water than the crystalline solid, some poorly water-soluble pharmaceuticals have been used in an amorphous state, with the expectation of improving the dissolution rate in water. 15,16) However, the amorphous state has the potential to change to a more stable crystalline state by adsorbing various solvent vapors during the storage of pharmaceuticals. 17)Ari...