Study On Thermodynamics And Transformation Process Of Hydrate

Hydrate is an important form of drugs; most pharmaceutical could transformatinto hydrate. Undesired hydrate form of pharmaceutical has certain negative impacton the process of manufacture, characterization, formulation and storage of drugs. Inrecently years, hydrate has been an important issue for industry of pharmaceutical andcrystallization researchers and which has become an important part of thepharmaceutical development process. Therefore, it would be meaningful to pay effortson the thermodynamic theory and application of the transformation between hydrateand anhydrate. This paper focues on the formation and theromodynamics of hydrate,with the sample research system of theophylline and carbamzepine.Theophylline, as a methyl purine drugs, has been widely used for cardiac, diuretic,expansion of coronary artery relaxation of bronchial smooth muscle and excitementhub through the system. It can be found in black and green tea. Theophylline has fouranhydrate polymorphs and a monohydrate. Carbamazepine, which is ananticonvulsant antiepileptic drugs with a good stability, has four anhydrate polymorph,a dihydrate and a acetonates. In this work, the formation mechanism andthermodynamic of theophylline was investigated as follow.Using the in-situ FBRM (Focused Beam Reflectance Measurement) and PVM(Particles Visual Measurement) and ATR-FTIR (Attenuated Total Reflection Flouriertransformed Infrared Spectroscopy), the concentration of solution and the change ofchord length in the process of transformation from theophylline form Ⅱ tomonohydrate was analyzed. The effect of temperature and fraction of water on the rateof transformation was investigated. The rate-controlling step for the trnaformationwas determined.The solubility of theophylline form Ⅱ and monohydrate was measured by thegravimetric method in the mixture of water and methanol and the mixture of waterand isopropanol. The effect of solution composition on the solubility was investigated.The data was correlated by the equation of (CNIBS)/Redlich–Kister andJouyban–Acree. The transformation water activity was determined by two methods.The enthalpy and entropy of hydration is calculated by the van’t Hoff equation. Theternary phase diagrams of water-theophylline-methanol andwater-theophylline-isopropanol were made at different temperature. The solubility ratios of theophylline form Ⅱ to monohydrate was determined byanalyzed the process of polymorph transformation. According to the solubilityproduct theory, the transition water activity was calculated by the solubility ratios.Using this equation, the solubility of meatstable form can be calculated and theactivity coefficient of solute at different water activity can also be calculated. Thetransformation water activity of carbamazepine form Ⅲ also can be determined bythis way.At last, the effect of polymorph on the transformation of hydrate was investigated.The transformation water activity of theophylline form Ⅳ was determined by thetraditional way. The solubility of theophylline form Ⅳ was measured in methanol,ethanol, acetone and acetonitrile. According to the solubility product theory, therelationship between the solubility ratio and the transformation water ratio was found.The stability and intercover of theophylline polymorph was studied.