Thermodynamic Study to Form More Stable and Soluble Drug-Polymer Mixtures Using SoluplusRTM and Its Component Homopolymers.

摘要

Solid dispersions of crystalline drugs in polymer matrices are promising as an approach to improve bioavailability. However, the high energy of amorphous drug in a solid dispersion leads to crystallization. In this work, the Flory-Huggins Theory predicts the solubility of crystalline drugs in the triblock graft copolymer SoluplusRTM and its homopolymers components, namely polyvinyl caprolactam (PCL), polyvinyl acetate (PVAc), and polyethylene glycol (PEG). Evaluation of the physicochemical and in vitro characteristics of solid dispersions of each drug with SoluplusRTM and its component homopolymers was conducted.;Nifedipine (NIF) and sulfamethoxazole (SMX) of 99.3 and 99.5% purity, respectively, were selected as BCS II crystalline model drugs. The melting point depression of each drug measured at various polymer levels using differential scanning calorimetry (DSC) allowed calculation of chi, the interaction parameter. chi provides a measure of drugpolymer interaction strength and allows the estimation of the free energy of mixing of the drug with the polymer and, ultimately, its solubility in that polymer. Solubility is calculated by solving solubility equations and by construction of a phase diagram. A low molecular weight PEG was used as a solvent to experimentally measure model drug solubility. Solid dispersions were prepared by lyophilization and by spray drying. Drug crystallinity in the dispersions was evaluated by DSC. Dissolution studies were conducted in simulated gastric and intestinal fluids without enzymes at 37 °C.;The Flory-Huggins Theory indicates that SoluplusRTM interacts effectively with each drug. The predicted solubility in Soluplus RTM compared favorably across the two methods and with literature values. PVAc demonstrated weak interactions with each drug and it is unlikely to participate in drug solubilization. PCL was not a suitable candidate for the selected method due to its elevated Tg. SoluplusRTM and PEG 6000, however, interacted well with each drug, would solubilize them, and would enhance the dissolution rate in an aqueous medium; the dissolution rate for NIF improved to a greater extent than for SMX. Faster dissolution rates for PEG 6000 in comparison to SoluplusRTM dispersions were due to the more hydrophilic nature of PEG. DSC analysis revealed no crystalline material in the dispersions.