Difenoxin hydrochloride polymorphism

Abstract

Methods for the preparation of two difenoxin hydrochloride polymorphic forms are described. X-ray diffraction patterns and IR spectra for the two forms along with a quantitative IR procedure are also presented. Solubility studies demonstrated that, of the two difenoxin hydrochloride polymorphs, form I was more soluble than form II. The apparent higher solubilities of the hydrochloride salt forms compared to the base were due to a super-saturation phenomena, as the hydrochloride salt forms converted to the base in aqueous media. The solubilities of difenoxin hydrochloride lots containing known proportions of form I to form II reflected the differences in the solubilities of the pure forms. Likewise, the dissolution of difenoxin hydrochloride from tablets was related to the ratio of form I to form II. Micronization proved to be a successful method for improving the dissolution of tablets prepared from a difenoxin hydrochloride lot with an approximately 2 : 1 form I : form II ratio. Micronization of the difenoxin hydrochloride at this form I : form II ratio made its dissolution from tablets equivalent to that of 100 mesh pure form I.