Barbituric Acid-urea Eutectic Polymorph And Its Co-crystallization Process

Cocrystallization of drug substances offers a tremendous opportunity for the development of new drug products with superior physical and pharmacological properties such as bioavailability.Pharmaceutical cocrystals have been widely used and can modify physicochemical properties without covalent modification of the drug molecule.However,cocrystals were found to be polymorphic as single component systems.These differences in physical properties among the crystal forms of a polymorphic system have become extremely interesting to pharmaceutical scientists because their manifestation can sometimes lead to observable differences that have implications for processing,formulation,and drug availability.Cocrystals can also play a role in lifecycle management,If an approved drug product contains a new patented solid form,especially where the solid form offers a commercial advantage over the original form,the solid form patent might provide meaningful intellectual property protection after the expiration of the original patent.In this study:(1)The selective cocrystallization of the desired polymorphic form of barbituric acid-urea(UBA)co-crystals(forms I and III)was demonstrated.Measurements such as XRD?DSC?FTIR and Raman spectrum were conducted to characterize the structure of cocrystal.(2)The solubility of barbituric acid(form I),urea and their cocrystal form I and form III in methanol and water were determined by the gravimetric method.Results were correlated by semi-empirical equations,which showed a good fit with the experimental data.The enthalpy and entropy of dissolution were also calculated.The ternary phase diagrams for the system of barbituric acid-urea cocrystal at different temperature were constructed.(3)Cooling crystallization of UBA form III in methanol was carried out and the metastable zone widths were determined experimentally by the polythermal method using a Turbidity Monitoring Technique.Two theoretical approaches,the self-consistent approach and classical 3D nucleation theory approach,were then employed to estimate the nucleation kinetics from the measured metastable zone width.The results suggeste that nucleation in methanol is instantaneous and follows polynuclear(PN)mechanism,fast cooling rate inhibited nucleation of cocrystal.When molar ratio of urea and barbituric acid wes less than 2:1,urea can enhance the crystallization of cocrystal;When molar ratio of urea and barbituric acid was more than 2:1,concentration of urea increase can inhibited the crystallization of cocrystal.(4)The effect of agitation rate,cooling rate,and seeds was systematically studied using the in-situ FBRM and off line optical microscope.The experimental conditions for producing pure UBA form I and form ? were optimized.