An Evolving Role of Aqueous Piperazine to Improve the Solubility of Non-Steroidal Anti-Inflammatory Drugs

Piperazine (PIP) is a pharmaceutically acceptable molecule and a good co-conformer in crystallographic engineering. Most of the non-steroidal anti-inflammatory drugs (NSAIDs) have poor aqueous solubility, which hinders their clinical application. The reports show that the solubility of many insoluble drugs can be significantly improved through salt formation with the PIP. In this work, we obtained a series of NSAIDs−PIP salts, such as ibuprofen-piperazine (IBU−0.5PIP) salt, indomethacin−piperazine (IND−0.5PIP) salt, sulindac−piperazine (SUL−0.5PIP) salt, phenylbutazone−piperazine (PBZ−0.5PIP) salt, ketoprofen−piperazine (KPF-0.5PIP) salt and flurbiprofen−piperazine (FLB-0.5PIP) salt. The spatial structure, arrangement, interaction and associations were expatiated by single crystal X−ray diffraction. Powder X−ray diffraction, Fourier transform infrared, differential scanning calorimetry, and thermogravimetric analysis were used to characterize the novel salts. The six new salts had more than 10 folds of solubility and a faster dissolution rate improved corresponding to the bulk drugs in pure water, and the significant improvement of solubility is closely related to the structure of salts.