A Study On The Polymorphism And Solution-mediated Phase Transformation Of Donepezil Hydrochloride

Donepezil hydrochloride (DHCl) is an important acetylcholinesterase inhibitor in order to treat Alzheimer’s Disease (AD).It has been reported that donepezil hydrochloride has6different polymorphs, including2hydrates (Form I, Form IV,) and4anhydrates (Form II, Form III, Form V and Form VI). Different polymorphs of donepezil hydrochloride exhibit different chemical and physical properties including stability, solubility, melting point, density, hardness, bioavailability, etc. Currently, Donepezil hydrochloride (DHCl) exists many polymorph problems such as poor crystal stability,poor purity, crystal fragmentation and other issues, resulted in pharmacodynamics decline. In our study, by polymorphs screening, we performed systematic study on donepezil hydrochloride polymorphs and solution-mediated phase transformation.We discovered a new polymorph by polymorph screening and used a systematic method combing DSC, TG, PXRD, FT-IR and moisture analyser to characterize and study the stability of the polymorphsIn the present work, the solubility of the new polymorph and Form II of Donepezil Hydrochloride in n-butanol/isopropyl ether mixtures of different compositions was determined at temperatures ranging from283.15K to323.15K using a laser monitoring observation technique. The experimental data were correlated with modified Apelblat equation.According to the standards of the particle size and crystal polymorphs in the solution, the effects of temperature, dilution rate and stirring rate were experimentally studied in detail. The final process parameters of dilution crystallization of the new polymorph were determined.In the n-butanol (solvent)-isopropyl ether (antisolvent) mixture, the experimental solution-mediated transformation process was studied and characterized by online and offline measurement system such as focused beam reflectance measurement (FBRM), powder x-ray diffraction (XPRD) and the polarizing microscope. The transformation involves nucleation of the metastable solid (the new polymorph), dissolution of the metastable solid, self-recognition of the molecular units to nucleate a more stable solid phase (Form II), and growth of the stable phase.