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.