Polymorphic transitions of cimetidine during manufacture of solid dosage forms

Abstract

Four modifications of cimetidine (A, B, C, D) and a monohydrate (M1) were prepared in pure form according to published protocols. Modification D, however, could only be obtained after substantial alterations of the protocol. In many cases crystal phase mixtures of the water-free forms were yielded. Melting points of the modifications being very close to each other, neither differential scanning calorimetry (DSC) nor thermomicroscopy would hint at the existence of different modifications, but light microscopy, X-ray diffraction (XRD) and IR spectroscopy do. Stabilities of polymorphs under conditions of industrial production of solid dosage forms were assessed: during dry storage all the pure modifications, even the monohydrate, were found to be stable for more than a year. In aqueous suspension, modification A changed completely into B after a short time, whereas it transformed to D in 50% ethanol. Transformation in the dry state was observed upon milling. Both B and C transformed to A, whereas A transformed into D only upon nucleation. In all cases milling caused substantial amorphisation. Upon compression no transformation was found. Tabletability of the raw materials was investigated. The results indicate that form A, which is used in the marketed tablets, shows fairly good properties only surpassed by M1.