New Insights into the Solubilization of Multicomponent Crystals: A Case Study of Pipemidic Acid

Abstract

Pipemidic acid (PPA), one of the most prominent medications of the second generation of quinolones, has broadspectrum antibacterial activity. Due to its low solubility and short half-life, it has led to a poor efficacy and numerous side effects. Multicomponent crystals have been proven to be an effective strategy for tuning the dissolution property of pharmaceuticals. Herein, multicomponent crystals of PPA with salicylic acid (SAA), gentian acid (GA), protocatechuic acid (PCA), caffeic acid (CAA), and saccharin (SAC) were synthesized. All the multicomponent crystals were characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), and thermal analysis including differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Hirshfeld Surface (HS) analysis showed that compared with PPA trihydrate, the contribution of the strong interaction in the multicomponent crystal structure to maintain the crystal structure tended to be weakened, indicating that the multicomponent crystal may increase the apparent solubility of PPA. Moreover, all the multicomponent crystals exhibit increased solubility and decelerated intrinsic dissolution rate (IDR). Specifically, the PPA-SAA and PPA-GA salts demonstrate the most significant solubility improvement in the pH 6.8 buffer by 640.98% and 213.11% when compared to the pure PPA trihydrate, respectively. For the other hydrates of the three salts (PPA-PCA salt hydrate, PPA-CAA salt hydrate, and PPA-SAC salt hydrate), the solubility increased by 45.90%, 13.11%, and 165.57%, respectively. Further, in vitro dissolution experiment results revealed that the IDR values of the multicomponent crystals (PPA-SAA salt, PPA-GA salt, PPA-PCA salt hydrate, PPA-CAA salt hydrate, and PPA-SAC salt hydrate) were 2.40, 2.14, 1.57, 1.53, and 2.80 mg/cm 2 /min, respectively, which were all less than that of the PPA trihydrate (5.24 mg/cm 2 /min). This causes the multicomponent crystals to release at a slower rate, thus improving bioavailability. Molecular dynamics simulation results indicate that the solubilizing effect is caused by the lower lattice energy and full exposure of hydrophilic groups caused by molecular assembly. Different from the cyclic supramolecular synthons in other multicomponent crystals from structure point, the ones in PPA-SAA salts are chain-like synthons, which may be one of the main reasons for the most significant increase in its apparent solubility. Stability tests showed that all multicomponent crystals exhibited excellent stability over 8 weeks at accelerated storage conditions (40 °C and 75% RH). This work demonstrates that multicomponent crystals can offer a promising potential to slow the release rate and enhance the solubility for these defective pharmaceuticals.