Polymorphic characterization and compatibility study of clozapine: implications on its stability and some biopharmaceutics properties

Abstract

Clozapine is an antipsychotic drug used for refractory schizophrenia and severe psychiatric disorders associated with several side effects. Studies on standardi- zation of raw material and bulk products are necessary to ensure reproducibility batch to batch during all stages of the industrial pharmaceutical process. The aim of this study was to conduct studies of polymorphic characterization and compatibility study of clozapine. Different solvatomorphic forms of clozapine were obtained by recrystallization tech- nique. Polymorphic characterization was performed using optical microscopy, SEM, intrinsic dissolution, and thermal analysis. Compatibility studies of clozapine:excipients were performed by TG and DSC techniques. The polymorphic characterization obtained by analytical and thermal techniques showed the formation of a solvatomorphic form of clozapine (clozapine monohydrate) when recrystallized in aqueous solvents and in alkaline medium. The polymor- phic form (clozapine anhydrate) showed higher intrinsic dissolution rate compared to solvatomorphic form (cloza- pine monohydrate). All industrial batches of clozapine presented in anhydrate form. The DSC/TG data demon- strated similar melting peaks for 2 polymorphic forms, but desolvation peaks characteristic of monohydrate form was observed in clozapine monohydrate. Studies of binary mixtures showed no incompatibilities between clozapine and excipients, except for clozapine:lactose which can reduce the stability of bulk and tablets of clozapine. Tablets of clozapine presented the same thermal analysis profile of clozapine:lactose but did not contribute in decreasing shelf life of clozapine tablets before 24 months of storage. Dis- solution studies of the tablets did not show variability between batches of clozapine during 24 months but pre- sented decreasing on stability for 36 months of storage.