Co-Amorphous Formation of High-Dose Zwitterionic Compounds with Amino Acids To Improve Solubility and Enable Parenteral Delivery

• Published in: Molecular pharmaceutics 2018-01, Vol.15 (1), p.97-107
• Main Authors: Zhu, Saijie, Gao, Huisheng, Babu, Sreehari, Garad, Sudhakar
• Format: Article
• Language: English
• Subjects: Amino Acid Transport Systems, Neutral - chemistry; Amino Acids - chemistry; Freeze Drying; Hydrogen Bonding; Ofloxacin - chemistry; Solubility; Spectroscopy, Fourier Transform Infrared; Tryptophan - chemistry
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.7b00738

Solubilization of parenteral drugs is a high unmet need in both preclinical and clinical drug development. Recently, co-amorphous drug formulation has emerged as a new strategy to solubilize orally dosed drugs. The aim of the present study is to explore the feasibility of using the co-amorphous strategy to enable the dosing of parenteral zwitterionic drugs at a high concentration. A new screening procedure was established with solubility as the indicator for co-amorphous co-former selection, and lyophilization was established as the method for co-amorphous formulation preparation. Various amino acids were screened, and tryptophan was found to be the most powerful in improving the solubility of ofloxacin when lyophilized with ofloxacin at a 1:1 weight ratio, with more than 10 times solubility increase. X-ray powder diffraction showed complete amorphization of both components, and an elevated T g compared with the theoretical value was observed in differential scanning calorimetry. Fourier transform infrared spectroscopy revealed that hydrogen bonding and π–π stacking were possibly involved in the formation of a co-amorphous system in the solid state. Further solution-state characterization revealed the involvement of ionic interactions and π–π stacking in maintaining a high concentration of ofloxacin in solution. Furthermore, co-amorphous ofloxacin/tryptophan at 1:1 weight ratio was both physically and chemically stable for at least 2 months at 40 °C/75% RH. Lastly, the same screening procedure was validated with two more zwitterionic compounds, showing its promise as a routine screening methodology to solubilize and enable the parenteral delivery of zwitterionic compounds.