Fast dissolving eutectic compositions of two anti-tubercular drugs

Abstract

Co-crystallization of anti-tubercular drugs pyrazinamide (PZA) and isoniazid (INH) with each other and with dicarboxylic acid coformers was studied. Grinding of the two drugs to make a co-crystal resulted instead in a 1:1 binary eutectic, PZA-INH, and addition of succinic acid (SA) and fumaric acid (FA) to the binary drugs gave a 1:1:1 ternary eutectic composition, PZA-SA-INH and PZA-FA-INH, respectively. The 1:0.5 binary drug-diacid adducts, PZA-SA, PZA-FA, INH-SA and INH-FA, are co-crystal structures by single crystal X-ray diffraction. The ternary eutectics PZA-diacid-INH were identified as composed of the co-crystals PZA-(diacid) 0.5 and INH-diacid (0.5) rather than the pure components. All new crystalline multi-component phases were characterized by powder X-ray diffraction, differential scanning calorimetry, infrared, and solid-state NMR. Solubility and dissolution experiments on the novel phases showed that their intrinsic dissolution rates are in the order, PZA-SA-INH > INH > PZA-INH > PZA-FA-INH > PZA. Thus pyrazinamide-isoniazid two-drug combination becomes a fast dissolving ternary eutectic phase with succinic acid. © The Royal Society of Chemistry 2012.