In Situ Cocrystallization via Spray Drying with Polymer as a Strategy to Prevent Cocrystal Dissociation

The aim of the present study was to investigate how differentpolymersaffect the dissociation of cocrystals prepared by co-spray-dryingactive pharmaceutical ingredient (API), coformer, and polymer. Diclofenacacid-l-proline cocrystal (DPCC) was selected in thisstudy as a model cocrystal due to its previously reported poor physicalstability in a high-humidity environment. Polymers investigated includepolyvinylpyrrolidone (PVP), poly(1-vinylpyrrolidone-co-vinyl acetate) (PVPVA), hydroxypropyl methyl cellulose, hydroxypropylmethylcelluloseacetate succinate, ethyl cellulose, and Eudragit L-100. TerahertzRaman spectroscopy (THz Raman) and powder X-ray diffraction (PXRD)were used to monitor the cocrystal dissociation rate in a high-humidityenvironment. A Raman probe was used in situ to monitorthe extent of the dissociation of DPCC and DPCC in crystalline soliddispersions (CSDs) with polymer when exposed to pH 6.8 phosphate bufferand water. The solubility of DPCC and solid dispersions of DPCC inpH 6.8 phosphate buffer and water was also measured. The dissociationof DPCC was water-mediated, and more than 60% of DPCC dissociatedin 18 h at 40 & DEG;C and 95% RH. Interestingly, the physical stabilityof the cocrystal was effectively improved by producing CSDs with polymers.The inclusion of just 1 wt % polymer in a CSD with DPCC protectedthe cocrystal from dissociation over 18 h under the same conditions.Furthermore, the CSD with PVPVA was still partially stable, and theCSD with PVP was stable (undissociated) after 7 days. The superiorstability of DPCC in CSDs with PVP and PVPVA was also demonstratedwhen systems were exposed to water or pH 6.8 phosphate buffer andresulted in higher dynamic solubility of the CSDs compared to DPCCalone. The improvement in physical stability of the cocrystal in CSDswas thought to be due to an efficient mixing between polymer and cocrystalat the molecular level provided by spray drying and in situ gelling of polymer. It is hypothesized that polymer chains couldundergo gelling in situ and form a physical barrier,preventing cocrystal interaction with water, which contributes toslowing down the water-mediated dissociation.