Cocrystal Approach to Reduce the Aqueous Solubility and Dissolution Rate for Improved Residence Time of an Anti-Tubercular Drug in the Lungs
Basanth Babu Eedara, Ian G. Tucker & Shyamal C. Das
School of Pharmacy, University of Otago, Adams Building, 18 Frederick Street, P.O. Box 56, Dunedin 9054, New Zealand.
Pharmaceutical cocrystals show promise for the controlled modification of key pharmaceutical properties such as solubility, stability and dissolution rate. In this study, we developed new crystalline forms of moxifloxacin, a broad-spectrum fluoroquinolone antibiotic recommended for the treatment of tuberculosis, by cocrystallization using trans-cinnamic acid as a coformer to prolong its residence time in the lungs by reducing the solubility and dissolution rate. Cocrystals of moxifloxacin with cinnamic acid (MCA2:1, MCA1:1 and MCA1:2, where the subscripts indicate molar ratios) were prepared by the solvent evaporation crystallization method. The formation of new crystalline phases were identified by X-ray diffraction analysis and further confirmed by differential scanning calorimetry, hot stage microscopy and attenuated total reflectance Fourier transform infrared spectroscopy. The aqueous solubilities of moxifloxacin and cinnamic acid were 13.9 ± 0.2 mg/mL and 0.48 ± 0.01 mg/mL, respectively. The solubility of the cocrystals decreased with an increase in cinnamic acid concentration: MCA2:1 (67.6 ± 2.2 mg/mL) > MCA1:1 (12.0 ± 0.4 mg/mL) > MCA1:2 (4.7 ± 0.2 mg/mL) such that MCA1:2 was three times less soluble than moxifloxacin. The intrinsic dissolution rates (IDR, mg cm−2 min−1) of cocrystals MCA1:1 (IDR- 0.322) and MCA1:2 (IDR- 0.278) were significantly lower, whereas MCA2:1 (IDR- 0.469) was higher compared to that of moxifloxacin (IDR- 0.411). This study concluded that MCA1:2 had a lower solubility and dissolution rate than moxifloxacin and could be formulated into an inhalable dry powder formulation for improved local therapeutic action in the lungs.