(328x) Co-Formulation of Phenytoin and Pharmaceutical Polymers by Precipitation Using Compressed CO2 Antisolvent

The co-formulation of active pharmaceutical ingredients with polymeric excipients is a relevant way to achieve more favourable pharmacokinetics of the drug, e.g. enhancement of bioavailability, controlled release or drug targeting. Precipitation with compressed antisolvent (PCA) is a promising technique that enables the production of virtually solvent free drug-polymer co-formulations in a one step process. The PCA process is characterized by a number of advantages, namely mild operating conditions, high product purity and low solvent consumption, which satisfy precisely the demands for the manufacturing of pharmaceutically relevant drug-polymer co-formulations. Therefore PCA can be considered as a practical alternative to other processing techniques such as spray drying, lyophilization or melt extrusion.

The poorly water soluble anticonvulsant drug phenytoin and the biodegradable polymer PVP K30 have been selected as a model system to study the properties of co-precipitates formed by means of the PCA technique. The drug to polymer ratio was found to be the most influential parameter with respect to the obtained product morphology. Up to a relative drug content of 45 wt.%, fully amorphous co-precipitates are obtained, with the drug molecularly dispersed in the polymer matrix. At higher relative drug contents, products contain crystalline phenytoin besides the fully amorphous polymeric phase. The dissolution behaviour of the amorphous co-precipitates clearly outperforms the pure crystalline drug, as a determination of the intrinsic dissolution rate shows. Further, all fully amorphous co-formulations were stable and did not recrystallize during one year of storage at ambient conditions.

Co-precipitaion experiments with phenytoin have been extended to other water-soluble pharmaceutical excipients, namely hydroxypropyl methyl cellulose (HPMC), HPMC acetate succinate (HPMC-AS) and HPMC phthalate (HPMC-P). As compared to PVP, a similar behaviour has been observed for these polymers; however the maximal drug to polymer ratio up to which fully amorphous co-precipitates could be obtained was significantly lower. Currently, the four component system polymer, drug, solvent and CO2 anti-solvent, its thermodynamics and the possible mechanisms of particle formation for drug and polymer are under investigation. The long term stability of co-precipitation products indicates that the solubility of phenytoin in the polymers might play a key role for amorphous co-precipitates to be obtained. How this ?solid solubility? is related to the structure of the polymer, e.g. to its ability to preferentially bond with the drug molecules, thereby hindering their organization into a crystal lattice, and whether drug-polymer solubility can be either predicted or measured, still remains to be fully understood.