No abstract

Solubility advantage of thermodynamically highly unstable cocrystals, which undergo solution-mediated phase transformation (SMPT) in less than 1 min, does not translate to enhanced dissolution. The present study was aimed to understand the impact of polymeric additives on dissolution of thermodynamically highly unstable cocrystal with specific emphasis on influence of drug–polymer interactions. Exemestane-maleic acid was selected as a model cocrystal with SMPT time of <30 s and eutectic constant (K eu) of 75475. Hydroxypropylcellulose (HPC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and polyvinylpyrrolidone (PVP) were selected as polymers for a dissolution study based on measurement of induction time using precipitation study. In the presence of 0.2% w/v of HPC, the cocrystal showed significantly higher drug release (∼3-fold) as compared with the cocrystal in the absence of predissolved polymers. Differential dissolution profiles of the cocrystal were observed with each polymer and the order of increasing dissolution rate was found to be HPC ≈ HPMCAS > PVP. The molecular basis of the differential dissolution performance was investigated using infrared spectroscopy, solution-state nuclear magnetic resonance spectroscopy, and nuclear Overhauser effect spectroscopy (NOESY). The polymers with stronger interactions with drug in the cocrystal (HPMCAS and HPC) displayed higher dissolution rate as compared with that of no intermolecular interaction (PVP). The study also highlighted that, despite no influence of the polymers on the cocrystal SMPT, dissolution enhancement was achieved. This was attributed to small-sized drug crystals (1–3 μm) generated from the supersaturation-mediated crystallization and improved solvation due to drug–polymer interactions. These findings have implications on development of drug products using thermodynamically unstable cocrystals.

The present study aims to investigate the molecular basis of water sorption behavior of rivaroxaban-malonic acid cocrystal (RIV-MAL). It was hypothesized, that the amount of water sorbed by a crystalline solid is governed by the surface molecular environment of different crystal facets and their relative abundance to crystal surface. Water sorption behavior was measured using a dynamic vapor sorption analyzer. The surface molecular environment of different crystal facets and their relative contribution were determined using single crystal structure evaluation and face indexation analysis, respectively. The surface area-normalized water sorption for rivaroxaban (RIV), malonic acid (MAL), and RIV-MAL at 90% RH/25 °C was 0.28, 92.6, and 11.1% w/w, respectively. The crystal surface of MAL had a larger contribution (58.7%) of hydrophilic (Hphi) functional groups and showed the “highest” water sorption (92.6% w/w). On the contrary, RIV had a larger surface contribution (65.2%) of hydrophobic (Hpho) functional groups, and the smaller contribution (34.8%) of Hphi+Hpho groups exhibited the “lowest” water sorption (0.28% w/w). The “intermediate” water sorption (11.1% w/w) by RIV-MAL, as compared to RIV, was ascribed to the increased surface contribution of Hphi+Hpho groups (from 34.8 to 42.1%) and reduced hydrophobic surface contribution (from 65.2 to 57.9%). However, the significantly higher water gained (∼39-fold) by the cocrystal as compared to RIV, despite the nominal change in the surface contributions, was further attributed to the relatively stronger hydrogen bonding interactions between the surface-exposed carboxyl groups and water molecules. The study highlights that the amount of water sorbed by the cocrystal is governed by the surface molecular environment and additionally by the strength of hydrogen bonding. This investigation has implications on designing materials with a desired moisture-sorption property.

The present investigation substantiates the efficacy of adapalene loaded solid lipid nanoparticles (Ada-SLNs) in ameliorating the skin irritation potential of adapalene owing to its altered skin distribution.