Research On The Thermodynamics Of Carbamazepine-Malonic Acid Cocrystal

In pharmaceutical engineering,low solubility is still one of the main challenges facing the majority of active pharmaceutical ingredients(APIs).As a new solid form,co-crystals could improve the physical and chemical properties of the main drug without changing its chemical composition.It has shown great potential value for research and therefore attracted much attention.In the biopharmaceutics classification system(BCS),carbamazepine(CBZ)is classified as class ? drugs with poor water solubility,and malonic acid(MA)can be used as a pharmaceutical adjuvant.In the current study,CBZ-MA co-crystallization was selected as the research topic.Preparation,characterization,ternary phase diagram and thermodynamic of the co-crystal were systematically investigated in this workFour methods were adopted to prepare CBZ-MA co-crystals:dry grinding that didn't produce co-crystal product,and solvent-drop grinding prepared form A of CBZ-MA 2:1 co-crystal,and evaporation and cooling methods both obtained form B of CBZ-MA 2:1 co-crystal.The result indicated that solvent played an important role in promoting the formation of the co-crystals.The co-crystal products obtained were characterized by X-ray powder diffraction,differential scanning calorimetry,Fourier infrared spectroscopy and microscope.The characterization result showed that the melting temperature of the co-crystal is lower than both components,and the size and morphology of the co-crystal is also different from the API.A new HPLC method for quantitative analysis of CBZ and MA at the same time was presented.Gravimetric method was used to measure the solubility curves of CBZ and MA in different solvents,and the temperature range is from 293.15K to 323.15K.Based on the difference between the solubility of co-crystal components,293.15K and 313.15K were selected as temperature conditions,and acetonitrile and methanol were selected as solvent conditions for measuring the ternary phase diagrams of CBZ-MA co-crystal.The results showed that pure co-crystal can be prepared based on solution method at 313.15K and mixture will be obtained at 293.15KThe solubility behavior of CBZ-MA co-crystals in different conditions was measured by static method and three mathematical models for describing solution complex were established.The models combined with experimental data to perform nonlinear fitting to determine the solution complex type in each condition by Matlab.The effect of temperature and solvent on the solution complex was analyzed,and the results displayed that with the increase of temperature,the system had a tendency to transform from 2:1 complex to 1:1 complex.It's also known that the solubility behavior of co-crystals in methanol is better and the solution complex effect in acetonitrile is stronger.