Dissolution and antiviral activity of a novel nevirapine formulation
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Date
2014
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
University of the Western Cape
Abstract
The author’s objective was to follow the product life-cycle process of a novel antiretroviral, nevirapine formulation in South Africa, to generate and compile data to pursue market registration. Five supramolecular co-crystals, viz. nevirapine-saccharin (NVSC), nevirapine-DL-tartaric acid (NVTTA), nevirapine-maleic acid (NVMLE), nevirapine-glutaric acid (NVGLT) and nevirapine-salicylic acid (NVSLI) were reproduced and confirmed by powder X-ray diffraction (PXRD). A pre-formulation study ensued to identify the most appropriate co-former candidate to formulate a tablet dosage form comparative to the proprietor brand, Viramune®. The co-crystals were synthesized by the co-precipitation and solvent-drop grinding techniques and identified by hot stage microscopy (HSM), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), fourier transform infra-red spectrophotometry (FTIR), PXRD and single X-ray diffraction (SXRD). The solubility, dissolution and antiviral activity profiles of these co-crystals were assessed and compared to pure NV and NV:co-former mixtures in a 1:1 ratio. The preliminary dissolution analysis applied the BP 2005 rotating-basket method with water as dissolution medium. Initially, the dissolution samples were assayed with UV/VIS spectrophotometry which led to a more convincing quantitative approach where dissolution samples were assayed by HPLC. Solubility data revealed a fivefold increase in solubility of NV co-crystallized with maleic acid. Dissolution data, however revealed NVGLT as the best performing co-crystal with a 59 % NV drug release in water (dissolution media) with the remaining 4 co-crystals all indicating an enhanced aqueous solubility of NV. The antiviral activity of all 5 co-crystals performed by the National Institute of Communicable Diseases of South Africa determined whether the co-crystals had an improved antiviral activity against HIV-1 compared to pure NV. The results indicated that NVSC and NVSLI had the greatest antiviral activity compared to pure NV and the remaining co-crystals. The pre-formulation results formed the basis for the selection of the best co-former candidate for a NV co-crystal tablet formulation by direct compression. All solid dosage form quality control tests according to the USP 364 was performed on the prototype co-crystal tablet and the Viramune® tablet. Comparative dissolution analysis to evaluate bioequivalence was conducted and assayed by HPLC. The dissolution analysis utilized 3 media, viz. HCl buffer (pH 1.2),
acetate buffer (pH 4.5) and a phosphate buffer (pH 6.8) which displayed no similarity in the dissolution profile of the prototype and the proprietor brand. Solution stability of NV in these buffered media was assessed after 4 weeks exposure of the dissolution samples to cold chain (2 - 8 °C, 0 % RH) and accelerated environmental conditions (40 °C, 75 % RH). The results indicated no significant degradation of NV in the prototype co-crystal tablet and the proprietor brand during the accelerated stability tests. Cytotoxicity against a host cell 293T and antiviral activity against the pseudo-HIV-1 virus of the prototype and proprietor brand was further determined. The antiviral activity results were favourable for both the prototype co-crystal and the proprietor brand tablet.
Description
Magister Pharmaceuticae - MPharm
Keywords
Solid state chemistry, Supramolecular chemistry, High performance liquid chromatography, Nevirapine, Pharmaceutical co-crystals