Numerous drug substances have been reported to exist in more than one crystal form (polymorph). These polymorphs can be metastable or stable at a certain temperature. Polymorphs can either be monotropic or enantiotropic. If the polymorphs are enantiotropic they can inter-convert in the solid tumor. Therefore, drug manufacturers usually formulate drugs as the stable polymorphic modification. However, metastable forms may have certain desired characteristics such as better dissolution properties and hence better bioavailability than the stable form. This of significance when the drug is poorly water-soluble. Formulation of such poorly water- soluble drugs in the metastable form for oral administration will enhance drug absorption and therapeutic effectiveness. However, if a drug is formulated as the metastable form and the polymorphs are enantiotropic, the metastable form may convert to the stable form during processing or storage. Therefore, it is important to develop drug formulations that lead to the stabilization or metastable polymorphs of drug substances. In this project, it is hypothesized that metastable polymorphs of drug substances can be stabilized by formulation of the drug in polymeric systems. To this end, carbamazepine has been chosen as the model drug and polyethylene glycol (PEG) and povidone (PVP) have been chosen as the polymers. Carbamazepine is an anti-epileptic agent that is practically insoluble in water. Several polymorphs of carbamazepine have been identified and fully characterized. Forms I and III are of special interest because they are enantiotropic polymorphs and inter-convert in the solid state. The transition temperature for the conversion is 71 degrees Centigrade. The two polymers, PEG and PVP, are commonly used in pharmaceutical formulation and have been reported as safe for non-parenteral administration. Two approaches will be taken for formulation of the drug with the polymers: 1) a solid dispersion of drug and polymer will be formed by melting or co-precipitation, and 2) the drug will be incorporated in the polymer to form microcapsules. The polymorphs of the drug in each formulation will be identified and characterized by several techniques, namely, hot stage microscopy, differential scanning calorimetry, thermogravimetric analysis, X-ray powder diffraction analysis and infrared spectroscopy. The stability of the polymorphs will be determined by heating isothermally over various periods of time and at different temperatures in the DSC apparatus. The amount converted from one form to the other will be determined by measuring the enthalpy of melting of the polymorph under study. The relative stability of the polymorph in the polymer formulation to that of the pure drug will be determined by the comparison of the conversion rates.
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