Recrystallization of Nifedipine and Felodipine from Amorphous Molecular Level Solid Dispersions Containing Poly(vinylpyrrolidone) and Sorbed Water

Although there was a great interest in solid dispersion systems during the past four decades to increase dissolution rate and bioavailability of poorly water-soluble drugs, their commercial use has been very limited, primarily because of manufacturing difficulties and stability problems. Solid dispersions of drugs were generally produced by melt or solvent evaporation methods. The materials, which were usually semisolid and waxy in nature, were hardened by cooling to very low temperatures. They were then pulverized, sieved, mixed with relatively large amounts of excipients, and encapsulated into hard gelatin capsules or compressed into tablets. These operations were difficult to scale up for the manufacture of dosage forms. The situation has, however, been changing in recent years because of the availability of surface-active and self-emulsifying carriers and the development of technologies to encapsulate solid dispersions directly into hard gelatin capsules as melts. Solid plugs are formed inside the capsules when the melts are cooled to room temperature. Because of surface activity of carriers used, complete dissolution of drug from such solid dispersions can be obtained without the need for pulverization, sieving, mixing with excipients, etc. Equipment is available for large-scale manufacturing of such capsules. Some practical limitations of dosage form development might be the inadequate solubility of drugs in carriers and the instability of drugs and carriers at elevated temperatures necessary to manufacture capsules.

Crystallization of drugs formulated in the amorphous form may lead to reduced apparent solubility, decreased rate of dissolution and bioavailability and compromise the physical integrity of the solid dosage form. The purpose of this work was to develop thermodynamic approaches, both practical and theoretical, that will yield a better understanding of which factors are most important for determining the ability of polymers to stabilize amorphous active pharmaceutical ingredients (API). Lattice based solution models were used to examine miscibility criteria in API-polymer blends. Different methods were used to estimate the Flory-Huggins interaction parameter for model API-polymer systems consisting of felodipine or nifedipine with poly(vinylpyrrolidone) (PVP). These were melting point depression and determination of solubility parameters using group contribution theory. The temperature and enthalpy of fusion of crystalline API alone and the fusion temperature of the API in the presence of the polymer were measured by differential scanning calorimetry. The resultant thermal data were used to estimate the reduced driving force for crystallization and the solubility of the API in the polymer. Flory-Huggins theory predicts that, for typical API-polymer systems, the entropy of mixing is always favorable and should be relatively constant. Due to the favorable entropy of mixing, miscibility can still be achieved in systems with a certain extent of unfavorable enthalpic interactions. For the model systems, interaction parameters derived from melting point depression were negative indicating that mixing was exothermic. Using these interaction parameters and Flory-Huggins theory, miscibility was predicted for all compositions, in agreement with experimental data. A model was developed to estimate the solubility of the API in the polymer. The estimated solubility of the model APIs in PVP is low suggesting that kinetic rather than thermodynamic stabilization plays a significant role in inhibiting crystallization. The thermodynamics of API-polymer systems can be modeled using solution based theories. Such models can contribute towards providing an understanding of the compatibility between API and polymer and the mechanisms of physical stabilization in such systems.