Cefpiramide Cocrystals

Pharmaceutical cocrystal is a new pharmaceutical solid form. It can modify physicochemical properties, stability and bioavailability of the drugs without damaging their covalent structure. Currently, the research of pharmaceutical cocrystals is a focus in the world. Cefpiramide belongs to the third generation, semi-synthetic cephalosporin. It exhibits antibacterial activity against Gram-positive and Gram-negative bacteria, especially Pseudomonas aeruginosa. Unstability and poor solubility are the main shortages of cefpiramide. Therefore, improving the stability, solubility and bioavailability of cefpiramide is improtant. In this paper, formation of pharmaceutical cocrystals is suggested to modify the physicochemical properties of cefpiramide. The main results are as follows.The solubility of cefpiramide in five pure solvents (ethanol,1-propanol, 2-propanol,1-butanol, water) and two binary solvents (ethanol-water, 2-propanol-water) at different temperatures were determined by the static method. The solubility data were correlated by the Apelblat equation. The correlation coefficients are all greater than 0.9989, and the mean relative deviations are all less than 1.2%. The calculated solubility values agree very well with the experimental data. These results show that the Apelblat equation could provide an accurate representation of the experimental data. The dissolution enthalpy, entropy and Gibbs free energy of cefpiramide were obtained using van’t Hoff equation according to the solublility data in five pure solvents. The solubility data of cefpiramide in binary 2-propanol-water solvent mixtures were also correlated by the Jouyban-Acree model, combined with the Apelblat equation. The correlation coefficient is 0.9935, and the mean relative deviation is 6.4%. The calculated solubility values in this binary system agree well with the experimental data. These results can provide a good theoretical foundation for choosing suitable solvents in the following screening and preparation of cefpiramide cocrystals.Neat grinding, liquid-assisted grinding, evaporation crystallisation and suspention crystallization were used for the screening and preparation of cefpiramide cocrystals.35 cocrystal formers (CCF) were used. These potential cocrystals were then characterized by X-ray diffraction (XRD), differential scanning calorimeter (DSC) and Fourier transform infrared spectroscopy (FT-IR). The experimental results show that cefpiramide-malonic acid cocrystal was successfully prepared by evaporation crystallisation, while cefpiramide-nicotinic acid cocrystal and cefpiramide-DL-tartaric acid cocrystal were successfully prepared by suspention crystallisation. The XRD patterns and melting points of cefpiramide cocrystals are different from their raw materials. Comparison of the FT-IR spectra of cefpiramide cocrystals with their raw materials show that obvious peak shifts occur in the spectra of cefpiramide cocrystals. The scanning electron microscopy analysis of the cocrystals show that their morphology is related with their preparation methods. The mole ratio between cefpiramide and the CCF (malonic acid, nicotinic acid and DL-tartaric acid) in their cocrystals was determined to be 1.97:1,1:1.90,1:1.93, respectively. The dissolution test shows that the cefpiramide cocrystals have higher dissolution rate than cefpiramide. The stability test shows that the cefpiramide cocrystals are much more stable than cefpiramide.