Research On Pharmaceutical Cocrystal Formation And Dissolution Property

Pharmaceutical cocrystal can effectively improve the physicochemical properties of active pharmaceutical ingredients(API)without compromising their structural integrity and overcome the disadvantages of other solid forms.Especially,it has great advantages in improving the solubility of insoluble drugs.It is of great importance in the research and development of new drugs.The synthesis process and dissolution property affect the manufacturing and bioavailability of cocrystal.Therefore,the investigation of the preparation and dissolution process of cocrystal can improve the clinical efficacy of insoluble drugs,and provide theoretic basis and data support for the mechanism research and clinical applications of pharmaceutical cocrystal.In this paper,theophylline-benzoic acid cocrystal was chosen as model system to study the influence of operating conditions on synthesis process in mechanochemistry and solution preparation of cocrystal.Then,indomethacin-saccharin cocrystal was chosen as model system to study the dissolution property of pharmaceutical cocrystal.The interplay between thermodynamic properties and kinetic processes of indomethacin-saccharin cocrystal was studied under different cocrystal solubility advantage.(1)The influence of grinding time,nature and amount of solvent on theophyllinebenzoic acid cocrystal formation in mechanochemistry was investigated.The cocrystal formation rate in liquid-assistant grinding is higher than neat grinding,indicating that solvent acts as a role of “catalysis” and lubrication to promote molecular mobility.The mechanism of theophylline-benzoic acid cocrystal formation in mechanochemistry was determined by considering the cocrystal structure and comparing the final cocrystal products obtained from neat and liquid-assistant grinding.(2)The suitable solvent system to prepare theophylline-benzoic acid cocrystal was screened based on the effect of solvent nature on cocrystal formation via grinding and the solubility of API and coformer.Pure theophylline-benzoic acid cocrystal was firstly prepared by solution synthesis.By employing solvent mixture,the solubility difference between theophylline and benzoic acid was decreased and the molar ratio of raw materials was modified to the stoichiometric ratio of cocrystal.The slurry and cooling cocrystallization process of theophylline-benzoic acid cocrystal in solution was monitored via on-line Raman Spectroscopy.The results obtained from on-line Raman monitoring can exhibit that suspension density of raw materials and temperature both have an impact on theophylline-benzoic acid cocrystal formation rate.Meanwhile,various information of cocrystallization process in cooling crystallization can be gained from results of on-line Raman monitoring to optimize cooling crystallization process and improve process efficiency.(3)Surfactant would decrease the solubility advantage of indomethacin-saccharin cocrystal and weaken the driving force of the conversion from cocrystal to drug,which can increase the concentration and supersaturation of parent drug during cocrystal dissolution process.This work demonstrates a quantitative method for additive selection to control cocrystal disproportionation based on cocrystal solubility advantage(SA)and drug-solubilizing power of surfactants to control cocrystal dissolution and impede drug precipitation.The thermodynamic properties(solubility and SA)and kinetic processes(cocrystal dissolution-drug supersaturation-drug precipitation)of indomethacin-saccharin cocrystal was studied by measuring the dissolution profiles of cocrystal in different media.