Thermal Solvent-Free Method of Loading of Pharmaceutical Cocrystals into the Pores of Silica Particles: A Case of Naproxen/Picolinamide Cocrystal

The degradation of drugs during melting was found to be one of the obstacles which restricts the application of the thermal solvent-free (TSF) method as a simple and efficient technique for loading active pharmaceutical ingredients (APIs) into the pores of mesoporous silica particles (MSPs). The naproxen (NPX) with melting point at 158 degrees C is an example of a drug which belongs to this group. In the current report we show that this limitation can be overcome by converting NPX into new crystallographic form by synthesis of cocrystal with significantly lower melting temperature as compared to pure compounds. In the course of the study it was found that picolinamide (PA) is an appropriate coformer which fulfills the assumed thermal requirements. NPX:PA cocrystal was obtained by grinding component forms of two polymorphs (alpha and beta) which were fully characterized by solid-state NMR techniques, differential scanning calorimetry (DSC), and FTIR. The alpha polymorph of PA undergoes thermal-phase transition into form beta below the melting temperature of 95 degrees C. Two MSPs with different size of pores, MCM-41 with 37 angstrom pore diameter and SBA-15 with pore diameter 100 A, were tested as drug carriers. It has been found that during melting NPX:PA is embedded into the pores of SBA-15, while MCM-41 acts rather as a separation medium. It is concluded that effectiveness of the filling process is very likely related to complementarity between the size of the NPX:PA unit cell crystal and the dimension of MSP pores. The filling of pores was confirmed by adsorption-desorption of nitrogen measurements.