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Preparation And Analysis Of Novel Pharmaceutical Solid-state Forms

Posted on:2016-10-10Degree:MasterType:Thesis
Country:ChinaCandidate:L WangFull Text:PDF
GTID:2191330464951291Subject:Chemistry
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To study and improve physicochemical properties of pharmaceutical materials, we prepared novel solid forms(polymorphism, cocrystal or salt) of three raw medicines. The products were analyzed by XRD, DSC, ss NMR et al. The novel solid forms show different physicochemical properties.(1) Felodipine form IV was obtained by using solvent evaporation method and characterized by single crystal X-ray diffraction. Comparing with form I, the crystal form used in the marketed products, form IV has higher melting temperature but lower melting enthalpy. Hence, according to the heat of fusion rule, polymorphs I and IV should be in an enantiotropic relationship. Form I is thermodynamically more stable than form IV at room temperature. Their theoretical polymorphic transformation temperature was estimated at 87.6 oC, which was also con?rmed by the solvent mediated polymorphic transformation experiments.(2) Two novel crystalline salts of 5-Fluorocytosine(FC) were obtained with an artificial sweetener, Acesulfame(AH), in molar ratios of 2:1(FCAH21) and 1:1(FCAH11), respectively. The result products were characterized by a variety of analytical methods, including single crystal and powder X-ray diffractions(XRD), differential scanning calorimetry(DSC), nuclear magnetic resonance(NMR), as well as dynamic vapor sorption(DVS). 13 C and 15 N solid state NMR spectra provide solid evidences on the salt formation. The new salts are nonhygroscopic/slightly hygroscopic, and resistant to FC hydrate formation at high RH condition(> 80%). FCAH21 has higher FC content and presents more favorable thermal stability than those of FCAH11, which make it more attractive for further pharmaceutical application.(3) Two cocrystal of Theophylline(THP) were prepared with Acesulfame(AH), in molar ratios of 1:2(THPAH12) and 1:1(THPAH11), respectively. 13 C and 15 N solid state NMR spectra provide solid evidences on the cocrystal formation. Both of the cocrystal show improved solubility as well as enhanced hydration stability. The ternary phase diagram for the two components was constructed in toluene.
Keywords/Search Tags:crystal engineering, polymorphism, cocrystal, salt, solid-state NMR
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