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Synthesis, Characterization And Properties Study Of Pharmaceutical Cocrystal

Posted on:2017-02-19Degree:DoctorType:Dissertation
Country:ChinaCandidate:X M ZhangFull Text:PDF
GTID:1221330482492131Subject:Inorganic Chemistry
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Pharmaceutical cocrystals have received attention in pharmaceutical industry due to their potential for their readily tuned physicochemical and biological properties of free active pharmaceutical ingredient(API). Cocrystals are usually designed and synthesized in the form of stable solid-state structures based on π···π stacking interaction or hydrogen bond interactions. The construction of a variety of organized frameworks, often with potentially demanded chemical and physical properties, is one of the aims of crystal engineering. Crystal engineering could be achieved by a flexible approach of introducing another molecular component into the crystal lattice, making it possible to establish the linkage between the compounds that mainly refers to API and cocrystal former(CCF). The CCFs were included in the pharmaceutically acceptable formers list, a classification known as Generally Recognized As Safe(GRAS). The different solid forms of the same compound have different chemical and physical properties. API are inherently predisposed for self-assembly since their utility is normally the result of the presence of one or more functional supramolecular synthons. The CCF of different structure into the crystal lattice, makes it possible to improve the physicochemical properties of API. The pharmaceutical cocrystal would be safe to use in pharmaceutical formulations and regulate and modify the solubility and bioavailability of different drugs.Based on the above reasons, this paper from the perspective of the structure of the API and CCF, focusing on the self-assembly functional groups of different API and high-throughput screening technology of CCF in supramolecular chemistry and crystal engineering as the basic principle, Based on supramolecular chemistry and crystal engineering, This article chose the four representative drug active ingredient, they each have different molecular structure, self-assembly functional groups and efficacy, The cocrystal(1-12) of APIs with the corresponding CCFs were obtained using the solution crystallization and evaporation crystallization method, the grinding method and ultrasonic method. Systematic introduction of acid groups in an aromatic periphery with a heteroatom was carried out to observe the changes in original structure. Identification of new heterosynthons changes in properties upon interacting with the ratio of the API and coformers. Their structures were characterized by single crystal X-ray diffraction, powder X-ray diffraction(PXRD) analysis, thermogravimetric analyses(TGA), differential thermal analysis(DTA),elemental analysis(EA) and infrared spectral analysis(IR). Dissolution and stability study of API and cocrystals were also measured and discussed, and their dissolution in vitro and chemical stability, moisture absorption were evaluated. Detailed the research results are as follows:1. Three novel cocrystals(1-3) were synthesized, which are composed of adefovir for hepatitis B treatment drug as the API with p-aminobenzoic acid(PABA), 3,5’-dihydroxybenzoic acid(3,5’-DHBA) and 2,6’-pyridinedicarboxylic acid(2,6’-PDA) three carboxylic acid compounds as CCFs, respectively, Pharmaceutical cocrystals(1-3) were synthesized by backflow volatile crystallization method. Among them, the cocrystal 2-3 linked were through hydrogen bonding and π···π interactions of adefovir with CCFs. The average dissolution rates of cocrystal 1, 2, 3 and original API were in following order: cocrystal 3 > cocrystal 1 > API > cocrystal 2. Overall dissolution behavior demonstrate that a complete release of cocrystal 3 from gelatincapsules in 4 h, comparing 96.8 %, 92.5 %, 94.1 % of cocrystal 1, 2 and API respectively. The initial dissolution rate in 0.5 h of cocrystal 1 is the rapidest, which reaches 77%. This profile is significant because it shows that a greater concentration of API can be achieved depending upon the cocrystal 1 and 3. The observation suggested that cocrystal 1 and 3 with an enhanced dissolution rate would potentially favorably absorption the gastrointestinal(GI) absorption and onset action of adefovir.2. Three novel cocrystals(4-6) were synthesized based on deferiprone which is the first oral medicine as iron chelator. Solitary deferiprone possesses some known problems due to its good solubility and frequent dosing side effects. For these three novel co crystals, deferiprone is the active pharmaceutical ingredient(API), p-hydroxybenzoic acid(PHBA), 2,5’-dihydroxybenzoic acid(2,5’-DHBA) and maleic acid are used as CCFs, respectively. Among them, the cocrystal 4-5 linked were through hydrogen bonding and π···π interactions of adefovir with CCFs. The average dissolution rates of cocrystal 1, 2, 3 and original API were following the order of cocrystal 5 < cocrystal 6 < cocrystal 4 < API. This profile is significant because it shows that extended release of deferiprone can be achieved via the synthesis of cocrystal(4-6). The observation suggested that the cocrystal(4-6) exhibited good extended release tendency, comparing with original deferiprone.3. The cocrystals 7 were synthesized using the reaction crystallization method and backflow volatile crystallization method, the grinding method and ultrasonic method. Cocrystals 7 are composed of Paracetamol for antipyretic analgesic as the API with 4,4’-Bipyridine. In the cocrystal 7 as a template for synthesis of the pharmaceutical cocrystal were screened, we discussed the effects of different methods of pharmaceutical cocrystals. Four methods are the same cocrystal composition cocrystal 7, The used cooling crystallization method and evaporation crystallization method synthesized more complete, can be used to determine the SXRD. The average dissolution rates of cocrystals 7 than Paracetamol has increased significantly.4. The novel cocrystals(8-12) were synthesized using the grinding method, which are composed of tavaborole for antibacterials as the API with p-aminobenzoic acid(PABA), m-aminobenzoic acid(MHBA) 2,3’-dihydroxybenzoic acid(2,3’-DHBA), salicylic acid and 2,6’-pyridinedicarboxylic acid(2,6’-PDA). The stability of API and cocrystals(8-12) were also measured and discussed, respectively. The results suggest that ermal stability and chemically stable of cocrystal(8-12) improved, no degradation occurred during the test. cocrystals(8-12) hygroscopic stability than the API improved significantly.We continue to accumulate experience for the future create more pharmaceutical cocrystals of excellent properties provide basis.
Keywords/Search Tags:Pharmaceutical cocrystals, Synthesis, Characterization, Dissolution, Stabilit
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