Eutectic mixtures of nevirapine: Phase diagrams, solid-state characterization, and dissolution studies

Abstract

Solid-state modifications can improve drug performance. Studies have shown that multicomponent crystals, such as cocrystals and eutectic compositions, have successfully improved the performance of certain drugs, including their solubility. Nevirapine (NEV) is an antiretroviral drug with low aqueous solubility, impacting its bioavailability. This work aimed to study different nevirapine/co-former solid eutectic systems, define their phase diagrams and evaluate their dissolution properties. Caffeine (CAF), Theobromine (TEOB), and Theophylline (THEO) were chosen as co-formers due to their functional groups that can interact with NEV. Aiming to determine both temperature and eutectic composition, phase and Tamman diagrams were obtained using the differential scanning calorimetry (DSC) analysis of the mixtures indifferent NEV-co-former compositions (%w/w). Powder X-ray diffraction (PXRD) and DSC were used to characterize the eutectic materials. To assess the influence of eutectic systems on dissolution properties, we determined the powder dissolution profiles and intrinsic dissolution rates of anhydrous NEV and eutectic systems NEV-CAF and NEV-THEO using different dissolution media (pH 1.2 and pH 6.8). The eutectic compositions were calculated through the phase diagrams, interpolating the curves obtained by linear regression. Thus, the eutectic composition of the NEV-CAF system was determined to be 36.55 % NEV and eutectic temperature at 201.1 °C, while in the NEV-THEO system, the eutectic was obtained in a composition of 71.04 % NEV and eutectic temperature at 217.8 °C. Tamman diagrams were generated using the enthalpy values obtained from the DSC curves, and eutectic compositions were calculated using linear regression. The analysis revealed a eutectic composition of 36.51 % of NEV for the NEV-CAF system, and a eutectic composition of 70.94 % of NEV for the NEV-THEO system. It was not possible to determine the eutectic mass fraction of NEV-TEOB. A comparison of dissolution profiles and intrinsic dissolution rates in different dissolution media showed a significant improvement in the NEV dissolution rate in both eutectic systems. In an acidic medium, NEV dissolved 16 times faster in the NEV-CAF sample and 4 times faster in the NEV-THEO sample compared to pure anhydrous NEV. In a neutral medium, the dissolution profile of NEV was even more favorable in the same eutectic systems, showing that the increase in dissolution is relevant in a wide range of pH. In addition, the intrinsic dissolution rate in the two eutectic systems was higher than that of anhydrous NEV in all employed dissolution mediums. These eutectic systems improve the dissolution rate compared to pure NEV, offering the potential for enhancing the dissolution of poorly water-soluble drugs in the future.