Solid-state characterization of beclomethasone dipropionate solvates and polymorphs
Abstract
This research examines the transformation kinetics of beclomethasone dipropionate (BCP) propellant 11 solvate, monohydrate and the anhydrous form. Both the propellant 11 solvate and the monohydrate are currently used in aerosol formulations and are subjected to stability problems, especially the propellant 11 solvate. When the solvates were exposed to a wide range of temperatures and relative humidities, four crystalline phases and one amorphous phase were found. Two anhydrous polymorphs and two solvates (propellant 11 solvate and the monohydrate) comprised the crystalline phases. The transformation of the propellant 11 solvate to the anhydrous form from 40°C to 70°C was determined by quantitative powder x-ray diffraction analysis and was analyzed as a first-order consecutive reaction. The propellant 11 solvate transformed to a metastable amorphous form where the conversion rate constant, k 1, ranged from 5.6 × 10-3 to 15.9 × 10 -2 hr-1 with an activation energy of 93.1 KJ/mole. The rate constant, k2, for the conversion of the amorphous form to the anhydrous form ranged from 1.1 × 10-3 to 4.5 × 10-2 hr-1 with an activation energy of 91.6 KJ/mole. The maximum amount of amorphous material formed was approximately 80% of the total sample. The transformation of the monohydrate form was also analyzed as a first-order consecutive reaction. The rate constants k 1 and k2 ranged from 1.3 × 10-3 to 50 × 10-2 hr-1 and 1.2 × 10 -3 to 5.0 × 10-2 hr-1, respectively. The monohydrate form changes to polymorph II when dehydrated (Ea = 221.7 KJ/mole) and subsequently converts to polymorph I (Ea = 118.3 KJ/mole). Upon desolvation and transformation of the monohydrate to polymorph I, the average particle size was reduced from ∼31μm to ∼8μm. A three dimensional crystal arrangement model was generated with the aid of the CERIUS2 software and the monohydrate crystallographic data obtained from the literature to specifically show the localization of water molecules in the lattice structure.
Degree
Ph.D.
Advisors
Kildsig, Purdue University.
Subject Area
Pharmaceuticals|Chemistry
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