Influence of Drug–Polymer Interactions on Dissolution of Thermodynamically Highly Unstable Cocrystal

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.

Dissolution Advantage of Nitazoxanide Cocrystals in the Presence of Cellulosic Polymers

“…Indeed, rapid conversion of the cocrystals into pure drug was demonstrated by PXRD analysis of the solids recovered after the dissolution tests in short time periods (~1-5 min, Figure 3). A similar behavior has been documented for other cocrystal phases in the literature [24,25,30,36,37,[55][56][57]. For example, exemestane-maleic-acid cocrystals did not increase solubilization of the drug due to rapid phase transformation [55].…”

“…For example, exemestane-maleic-acid cocrystals did not increase solubilization of the drug due to rapid phase transformation [55]. In a recent publication this cocrystal was reinvestigated observing that transformation into the parent drug occurred in less than 1 min in fasted state simulated intestinal fluid (FaSSIF) [37]. The critical role of the coformer physicochemical properties on the solubility and dissolution advantages of cocrystals it is now accepted, even though the exact mechanism by which this enhancement occurs is not fully understood.…”

“…Cellulosic polymers are the most common hydrophilic polymers used for the development of formulations with cocrystals [24,26,28,29,33,36,37]. They can inhibit or at least delay phase transformations of cocrystals [29,30], by establishing drug-polymer interactions [37] and maintaining the solubilization state of APIs.…”

“…Cellulosic polymers are the most common hydrophilic polymers used for the development of formulations with cocrystals [24,26,28,29,33,36,37]. They can inhibit or at least delay phase transformations of cocrystals [29,30], by establishing drug-polymer interactions [37] and maintaining the solubilization state of APIs. Therefore, the improvement of the NTZ dissolution profiles in the presence of pre-dissolved polymer could be explained by the following mechanism: after the rapid NTZ release into solution starting from the cocrystal, the cellulosic polymer interacts with NTZ molecules delaying its nucleation and eventually NTZ crystallized also interact with polymer interfering the crystal growth and agglomeration process.…”

“…In this line, there are several recent reports on the effect of polymers and surfactants in increasing solubility and dissolution rates of poorly soluble drugs, starting from a cocrystalline solid phase. Some representative APIs and nutraceutical compounds studied under this approach are celecoxib [23], danazol [24], indomethacin [25], carbamazepine [26][27][28][29][30][31], flufenamic acid [32], cilostazol [33], resveratrol [34], dihydromyricetin [35], tadalafil [36], exemestane [37] and posaconazole [38].…”