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

Abstract

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 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.

Advances in coamorphous drug delivery systems

“…Lyophilization, also known as freeze drying, can be also used to prepare coamorphous solids with low-density and porous nature. Zhu et al 42 successfully prepared high-dose zwitterionic compound ofloxacin-amino acid coamorphous solids through lyophilization. In particular, due to the strong drug—excipient ionic interactions and π–π stacking, ofloxacin lyophilizated with tryptophan at a 1:1 molar ratio in coamorphous form exhibited over 10-times solubility increase compared to its crystalline counterpart 42 .…”

“…Zhu et al 42 successfully prepared high-dose zwitterionic compound ofloxacin-amino acid coamorphous solids through lyophilization. In particular, due to the strong drug—excipient ionic interactions and π–π stacking, ofloxacin lyophilizated with tryptophan at a 1:1 molar ratio in coamorphous form exhibited over 10-times solubility increase compared to its crystalline counterpart 42 . The ofloxacin-tryptophan coamorphous solids were physically and chemically stable for more than 2 months at 40 °C/75% RH 42 .…”

Co-Amorphous Solid Dispersions for Solubility and Absorption Improvement of Drugs: Composition, Preparation, Characterization and Formulations for Oral Delivery

“…Impregnation with small molecules, e.g., amino acids, are considered critical for preventing recrystallization. In the majority of the studies the physical stability of such systems is attributed to intermolecular interactions such as hydrogen bonds, π−π, or even ionic interactions [ 22 ].…”

“…Zhu et al [ 22 ] studied Tryptophan—ofloxacin at a 1:1 weight ratio. XRPD showed complete co-amorphization and DSC showed an elevated Tg compared with the theoretical value.…”

Preparation of Amorphous Composite Particles of Drugs with Ursodeoxycholic Acid as Preclinical Formulations

“…20,21) To disseminate a formulation that uses the API-excipient system, further study of product development with respect to the manufacturing process and regulatory requirements is necessary. 18) For instance, most of the many reported API-excipient systems that use amino acids 22,23) have been prepared via ball milling. Ball milling is an excellent method for preparing a small amount of sample, but not so for obtaining homogeneous samples in large-scale production.…”