One Step In Situ Co-Crystallization of Dapsone and Polyethylene Glycols during Fluidized Bed Granulation.

Several studies have demonstrated the feasibility of in situ co-crystallization in different pharmaceutical processes such as spray drying, hot melt extrusion, and fluidized bed granulation (FBG) to produce co-crystal-in-excipient formulations. However, no previous studies have examined such a one step in situ co-crystallization process for co-crystal formulations where the coformer is a polymer. In the current study, we explored the use of FBG to produce co-crystal granules of dapsone (DAP) and different molecular weight polyethylene glycols (PEGs). Solvent evaporation (SE) was proven to generate DAP-PEGs co-crystals at a particular weight ratio of 55:45 w/w between DAP and PEG, which was subsequently used in FBG, using microcrystalline cellulose and hydroxypropyl methyl cellulose as filler excipient and binder, respectively. FBG could generate co-crystals with higher purity than SE. Granules containing DAP-PEG 400 co-crystal could be prepared without any additional binder. DAP-PEG co-crystal granules produced by FBG demonstrated superior pharmaceutical properties, including flow properties and tableting properties, compared to DAP and DAP-PEG co-crystals prepared by SE. Overall, in situ co-crystallization via FBG can effectively produce API-polymer co-crystals and enhance the pharmaceutical properties.

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 different polymers affect the dissociation of cocrystals prepared by co-spray-drying active pharmaceutical ingredient (API), coformer, and polymer. Diclofenac acid-l-proline cocrystal (DPCC) was selected in this study as a model cocrystal due to its previously reported poor physical stability in a high-humidity environment. Polymers investigated include polyvinylpyrrolidone (PVP), poly(1-vinylpyrrolidone-co-vinyl acetate) (PVPVA), hydroxypropyl methyl cellulose, hydroxypropylmethylcellulose acetate succinate, ethyl cellulose, and Eudragit L-100. Terahertz Raman spectroscopy (THz Raman) and powder X-ray diffraction (PXRD) were used to monitor the cocrystal dissociation rate in a high-humidity environment. A Raman probe was used in situ to monitor the extent of the dissociation of DPCC and DPCC in crystalline solid dispersions (CSDs) with polymer when exposed to pH 6.8 phosphate buffer and water. The solubility of DPCC and solid dispersions of DPCC in pH 6.8 phosphate buffer and water was also measured. The dissociation of DPCC was water-mediated, and more than 60% of DPCC dissociated in 18 h at 40 °C and 95% RH. Interestingly, the physical stability of the cocrystal was effectively improved by producing CSDs with polymers. The inclusion of just 1 wt % polymer in a CSD with DPCC protected the cocrystal from dissociation over 18 h under the same conditions. Furthermore, the CSD with PVPVA was still partially stable, and the CSD with PVP was stable (undissociated) after 7 days. The superior stability of DPCC in CSDs with PVP and PVPVA was also demonstrated when systems were exposed to water or pH 6.8 phosphate buffer and resulted in higher dynamic solubility of the CSDs compared to DPCC alone. The improvement in physical stability of the cocrystal in CSDs was thought to be due to an efficient mixing between polymer and cocrystal at the molecular level provided by spray drying and in situ gelling of polymer. It is hypothesized that polymer chains could undergo gelling in situ and form a physical barrier, preventing cocrystal interaction with water, which contributes to slowing down the water-mediated dissociation.