Preparation And Evaluation Of Famotidine Cocrystal

Pharmaceutical cocrystal is a new type of pharmaceutical solid form,which is different from traditional salts and amorphous solids.It has great potential in optimizing the physical and chemical properties of solid APIs.Drug cocrystal can fine-tune the physical and chemical properties of drugs without changing the structure of active pharmaceutical ingredient(API),so as to improve the defects of drug properties,such as improving the solubility,permeability and bioavailability of API.In this paper,famotidine was selected as the research object.According to the Biopharmaceutics classification system(BCS),famotidine is a class III drug with good solubility in gastric acid.The solubility in water is about 0.70 mg/m L,but the permeability is poor,it is difficult to enter the systemic circulation,which limits the bioavailability.Famotidine cocrystal was synthesized by cocrystal technology to improve the solubility and permeability of famotidine in water.The cocrystal coformer(CCF)of famotidine and 21 ligands in the laboratory was screened by solvent evaporation method combined with ultrasound.The obtained products were characterized by various characterization methods,including thin layer chromatography(TLC)for preliminary identification of the products.Differential scanning calorimetry(DSC),Thermogravimetric analysis(TGA),Scanning electron microscope(SEM),Powder Xray diffraction(PXRD)and other characterization methods were used to further characterize the eutectic formation.Finally,the molecular structure of the cocrystal was determined by single crystal X-ray diffraction(SXRD),and the hydrogen bonds formed between the functional groups were verified by Fourier transform infrared spectroscopy(FT-IR).The solubility and permeability of the formed cocrystal were studied by high performance liquid chromatography(HPLC).Finally,the mechanism of action between bovine serum albumin and cocrystal was studied by fluorescence quenching spectroscopy.In this paper,famotidine-p-toluenesulfonic acid,famotidine-m-nitrobenzoic acid,and famotidine-sorbic acid cocrystals formed by famotidine and ligands p-toluenesulfonic acid,m-nitrobenzoic acid,and sorbic acid were successfully obtained in acetonitrile solution by solvent evaporation combined with ultrasound.TLC results showed that the product had two points of API and CCF.The DSC spectrum shows that the product has different endothermic behavior from API and CCF,which is different from the physical mixture of the two.TGA results showed that the degradation of the product occurred after melting,indicating that the product had good thermal stability.SEM images show that the morphology of the product under SEM is different from API and CCF.The PXRD pattern indicates the formation of eutectic with high crystal phase purity.SXRD can obtain all the three-dimensional information of the tested cocrystal samples,including bond length,bond angle and molecular stacking mode,which is the most accurate and commonly used method to judge the formation of cocrystal.FT-IR spectra can verify the position of hydrogen bond functional groups in SXRD.In the three cocrystals,famotidine-ptoluenesulfonic acid and famotidine-m-nitrobenzoic acid successfully obtained single crystal structure by SXRD,famotidine-sorbic acid failed to obtain single crystal structure,and the site of hydrogen bond formation was predicted by FT-IR.The properties of two cocrystals with single crystal structure were further studied,including equilibrium solubility and permeability.The experimental results showed that the solubility and permeability of famotidine in water were successfully improved by forming cocrystals.The interaction mechanism of famotidine,famotidine-p-toluenesulfonic acid and famotidine-m-nitrobenzoic acid with BSA was studied by fluorescence quenching spectroscopy.The results showed that the formation of cocrystal did not affect the binding of famotidine to protein,which laid a foundation for the further study of in vivo bioavailability.In this paper,the design,screening,synthesis,characterization and properties of famotidine cocrystals were systematically studied.Three famotidine cocrystals were successfully obtained,and two of them obtained single crystal structures.It was found that two famotidine cocrystals with single crystal structure improved the solubility and permeability of famotidine in water.It provides a research idea for the interaction between cocrystal and biological macromolecules.