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The Thermodynamics And The Solution Complexation Mechanism Of Theophylline-nicotinamide Cocrystal

Posted on:2014-12-02Degree:MasterType:Thesis
Country:ChinaCandidate:J J GuoFull Text:PDF
GTID:2181330422968325Subject:Chemical Engineering
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Theophylline (TP) is a commonly used drug which has low solubility in water. Ingeneral, the low dissolution rate of the drug will affect its bioavailability. Thepharmaceutical cocrystal is prepared to improve its chemical and physical properties,such as melting point, solubility and so on, while maintaining the structural integrityof the API. Nicotinamide (NCT) is a water-soluble vitamin drug, which can formhydrogen bonds with theophylline, so it can form the theophylline–nicotinamidecocrystal with theophylline. In this thesis, the theophylline-nicotinamide cocrystalwas prepared and characterized by different ways, and the thermodynamic propertiesof the prepared cocrystal were also studied.By the methods of drying gringding, liquid-assisted grinding, slow evaporationcrystallization and crystallization, the theophylline–nicotinamide cocrystal wasprepared. The effect of grinding time on the cocrytstal preparation was studied bychanging the grinding time. The results showed that, with the increase of grindingtime, the characteristic peaks of the cocrystal constantly enhanced, along with thediminishing of characteristic peaks of the active pharmaceutical ingredient and theconformer. The products were analysised by using differential scanningcalorimetry(DSC), X-ray powder diffraction(XRD)and high performance liquidchromatography (HPLC).The solubilities of TP, NCT and TP-NCT cocrystal in six solvents weredetermined by using the static method. The experimental results were correlated bydifferent empirical equations, such as the modified Apelblat equation and the λhequation. The enthalpy and entropy of dissolution of the theophylline nicotinamideand theophylline-nicotinamide cocrystal were also calculated by using theexperimental data.The complexation form, the solubility product and the complex constant oftheophylline-nicotinamide cocrystal in different solvent were studied by using thesolubility product theory. The influence of different temperature and different solventson the solubility product and the complexation constant were investigated bychanging the temperature and the solvents. The results showed that1:1TP-NCT cocrystal in ethanol leads to no complex formation, and leads to1:1complexformation in isopropanol. With the increase of the temperature, the solubility productincreases, while solution complexation constant decreases. In ethanol the solubilityproduct is lower than that in isopropanol, and the complexation constant calculated ishigher than in isopropanolThe ternary phase diagrams of the theophylline-nicotinamide-ethanol ortheophylline-nicotinamide-isopropanol at25°C and35°C were constructed by thecombination of XRD and HPLC analysis. Based on the diagrams, the effects ofdifferent temperature and solvents on the phase change trend were disscused. Theternary phase diagram can be used to predicted the solid forms obtained from thesolution crystallization, and as well as for the theoretical study ontheophylline-nicotinamide cocrystal.
Keywords/Search Tags:theophylline, nicotinamide, cocrystal, solvent complexation, ternary phase diagram
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