There has been growing interest in investigating the role of solvents played in nucleation pathways; nevertheless, the nucleation mechanism is still poorly understood. In this work, flufenamic acid (FFA) was selected as model compound to investigate the relationship between solvent and nucleation kinetics. Over 1000 induction time experiments were conducted. Solution IR spectroscopy and molecular dynamic simulations were used to explore the solvent–solute interaction and conformation distribution in solutions. Given the same driving force, the order of nucleation rate of FFA was found following acetonitrile > methanol > toluene, in which dimers are significantly distributed in toluene solutions. The observation cannot support the previously proposed hypothesis that the breakage of solvent–solute hydrogen bonds and dimerization determine the nucleation rate. Through crystal growth experiment and detailed discussions, we have reached an interesting conclusion that the weak C–H···π interactions play a vital role in the nucleation pathway via probably regulating the growth of the nucleating clusters.
Enoxacin (ENX), a third-generation fluoroquinolone, demonstrates broad-spectrum antibacterial activities and is widely applied for the treatment of various bacterial infections. However, it is challenging to improve its antibacterial activity and drug resistance effects based on solubility changes owing to ENX being categorized as a class II drug in the Biopharmaceutics Classification System (BCS). In this experiment, three novel salts formed between ENX and non-steroidal anti-inflammatory drugs (NSAIDs) involving diclofenac (ENX-DFA), flufenamic acid (ENX-FFA) and niflumic acid (ENX-NFA) were firstly synthesized and then characterized. X-ray diffraction, thermodynamic analysis and infrared spectroscopy confirmed the salt formation. Interestingly, all the new salts demonstrated superior antibacterial activities against Escherichia coli ( E. coli ), Shigella flexneri ( Sh. flexneri ), Staphylococcus aureus ( S. aureus ) and Staphylococcus albicans ( S. albus ) compared with ENX. Further investigation of the pharmaceutical properties of the three salts revealed that they possessed lower aqueous solubility and intrinsic dissolution compared with ENX but exhibited better solubility than the three NSAIDs. Moreover, our results demonstrated that fluctuations in the solubility of ENX salts were pH-dependent. Thus, the solubility changes of ENX salts were assessed using pH-window diagrams. The order of lipid-water partition coefficient ( P ) was consistent with antibacterial performance (ENX-FFA > ENX-DFA > ENX-NFA > ENX) and was 2.04, 1.95, and 1.69 times greater than that of ENX, indicating that the higher Log P values of salts with strong cell membrane penetration ability improved the efficacy of the drug to inhibit bacterial growth. In summary, this study provides new insights to elucidate antibacterial effects from solubility and Log P values.
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