Particle size reduction by desolvation technique of a model drug: Beclomethasone diproprionate

Abstract

The effect of particle size and temperature on particle size reduction by a new method, desolvation of beclomethasone dipropionate (BCP) was investigated. Solid state characterization of BCP includes kinetics of desolvation, solid phase identification and particle size analysis. Various rates of water addition during crystallization could not produce the different sizes of BCP monohydrate crystals desired. The three different sizes were produced by grinding intact crystals and as the result, crystals produced were large (intact), medium (75-150µm) and small (38-75µm). From isothermal thermogravinmetric analysis (at temperature<85.5℃), the dehydration behavior of intact (large) crystals followed the model of the Avrami-Erofeev equation (n=1/3) while the ground crystals (medium and small particles) followed the Avrami-Erofeev equation (n-1) except for the smaller crystals when exposed to temperatures higher than 85.5℃. At the temperatures above 85.5℃, the XRPD analysis after complete dehydration showed transformation of crystal from the monohydrate form to the anhydrous form. At other temperatures XRPD reveal a mix of both forms after dehydration. The activation energies obtained using Arrhenius equation in ground samples were found to be higher than intact. It is suggested that the ground crystals contained a barrier membrane of dehydrated form on surface of crystal structure, which hindered water removal from crystal nuclei (surface barrier effect). In regards to the ground samples, the water vapor pressure generated during the heating process in the larger crystals promoted higher rates of dehydration as compared to smaller crystals. After desolvation process, the results clearly showed that the desolvation of BCP monohydrate played an important role in reducing the particle size. The structure of crystal was collapsed to irregular shape. Size had no influence on the resulting size reduction after dehydration as was proven from the results of medium and small ground crystals. However, temperatures had significant influence on the final particle size after dehydration for intact crystals especially at lower temperatures. At lower temperature (56℃) the crystals appeared opaque without any collapse of the structure. But when using higher temperatures, the final size was shown to be constant at approximately 40µm. This study demonstrates the method of size reduction called “desolvation” and its kinetic behaviors, which the final size does not depend on the original size of particle, but depend on temperatures used, time at that temperature and surface irregularities induced by other process such as grinding. It can be regarded as a milestone for size reduction in other drugs.