Abstract
(1) Background: Pharmaceutical cocrystals have attracted remarkable interest and have been successfully used to enhance the absorption of poorly water-soluble drugs. However, supersaturable cocrystals are sometimes thermodynamically unstable, and the solubility advantages present a risk of precipitation because of the solution-mediated phase transformation (SMPT). Additives such as surfactants and polymers could sustain the supersaturation state successfully, but the effect needs insightful understanding. The aim of the present study was to investigate the roles of surfactants and polymers in the dissolution-supersaturation-precipitation (DSP) behavior of cocrystals. (2) Methods: Five surfactants (SDS, Poloxamer 188, Poloxamer 407, Cremophor RH 40, polysorbate 80) and five polymers (PVP K30, PVPVA 64, HPC, HPMC E5, CMC-Na) were selected as additives. Tecovirimat-4-hydroxybenzoic (TEC-HBA) cocrystals were chosen as a model cocrystal. The TEC-HBA cocrystals were first designed and verified by PXRD, DSC, SEM, and FTIR. The effects of surfactants and polymers on the solubility and dissolution of TEC-HBA cocrystals under sink and nonsink conditions were then investigated. (3) Results: Both the surfactants and polymers showed significant dissolution enhancement effects, and most of the polymers were more effective than the surfactants, according to the longer Tmax and higher Cmax. These results demonstrate that the dissolution behavior of cocrystals might be achieved by the maintained supersaturation effect of the additives. Interestingly, we found a linear relationship between the solubility and Cmax of the dissolution curve for surfactants, while no similar phenomena were found in solutions with polymer. (4) Conclusions: The present study provides a basis for additive selection and a framework for understanding the behavior of supersaturable cocrystals in solution.
Highlights
IntroductionThe development of poorly water-soluble drugs remains a challenge for the foreseeable future
The present study aimed to investigate the roles of surfactants and polymers on the dissolution behavior of supersaturable cocrystals
TEC/HBA PM showed all of the major peaks from TEC and HBA at various diffraction angles, which suggested that the crystallinity of the drug and HBA remained unchanged in the physical mixture
Summary
The development of poorly water-soluble drugs remains a challenge for the foreseeable future. 40% of approved drugs and nearly 70% of developmental pipeline candidates display poor aqueous solubility, which usually results in poor oral bioavailability [1]. Oral drug absorption can be increased by enhancing solubility and dissolution, especially for BCS class II drugs with low solubility and high permeability where absorption is dissolution-rate limited. Various supersaturable formulation strategies that could create a supersaturation state have been used and have shown bioavailability enhancement of a crystalline drug [2], such as cocrystals [3], salts [4], amorphous solid dispersions [5], microemulsions [6], and inclusion complexes [7].
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