| In recent years,pharmaceutical crystals have played a vital role in the field of medicine as a kind of research material.The research mainly includes polymorphs,cocrystals,salts,hydrations and solvates.In particular,pharmaceutical cocrystals and pharmaceutical salts are more valuable because of their well performance in pharmaceutical,physical and chemical properties,such as improving drug solubility,improving drug stability and improving bioavailability,without destroying the composition of the active ingredient?API?.Therefore,pharmaceutical crystal materials,which are the interdisciplinary products of pharmacochemistry,crystallography,materials science and organic synthesis,have attracted wide attention of scientists.Based on supramolecular chemistry and crystal engineering,different kinds of pharmaceutical salts were designed and synthesized by mechanochemistry and traditional solution methods with urotropin,nicotinic acid,indomethacin and naproxen as API;secondly,a series of 1,2,3,4-tetrahydroquinoxaline derivatives were synthesized with baicalein,and their potential applications in the field of pharmaceuticals were carefully studied and discussed.The main research contents are as follows:?1?Four salts?SSA?1?HMTA?1?H2O?1,?SSA?1?HMTA?1,?SSA?1?HMTA?2?H2O?1and?SSA?1?HMTA?2 were formed by using urotropin?HMTA?as API and sulfosalicylic acid dihydrate?SSA·2H2O?,and their structures were characterized.Urotropine in the four salts is monotonized.Since the degree of proton transfer of the carboxyl group and the sulfonic acid group of SSA is different,HMTA salts having a molar ratio of 1:1 and1:2 can be formed.In addition,water molecules also affect the structure of pharmaceutical salts.Controlled synthesis,conversion and reversible conditions of four salts with different ratios of water/anhydrous salts were studied by mechanical grinding,differential thermal analysis and crystal dynamic vapor adsorption.This work shows that mechanochemistry has obvious advantages both in the synthesis technology of salts and in the controllable transformation of crystal forms.This work provides a good model for the insight on the structural transformation of materials in the solid state.?2?Three pharmaceutical salts?DPEN?1?NA?2,?DPEN?1?NA?2?EA?1 and?DPEN?1?NA?2?ACN?1?EA:ethyl acetate;ACN:acetonitrile?were designed and synthesizedbyusingnicotinicacid?NA?asAPIand?1R,2R?-1,2-diphenylethylenediamine?DPEN?as salt-forming reagent,and isonicotinic acid?INA?as contrast was introduced to form salt?DPEN?1?INA?2 with DPEN.The crystal structure analysis showed that NA salts contained two new stable synthons,namely,the COO-group of NA and the NH3+group of DPEN(COO-?NA?···NH+3?amino?)and the NH3+group of DPEN and pyridine N of NA(NH+3?amino?···N?NA?),and that was confirmed the existence of stable synthons in INA salt.The hydrogen bonding properties of new synthetic salts of pharmaceutical salts were further revealed by Hirshfeld surface energy analysis.The thermal stability of NA salts was tested,and the results showed that the NA salts containing different solvents had different thermal properties,indicating that the thermal properties of NA salts were related to the solvent contained.Solubility experiments show that the solubility of?DPEN?1?NA?2 and?DPEN?1?NA?2?EA?1 at different pH values is 3-7 times higher than that of the raw material NA.The calculation of thermodynamic parameters in the dissolution process shows that the higher the molar Gibbs free energy,the lower the solubility,and the dissolution process of salts in the buffer solution is endothermic.The work identified novel synthons of NA and provided a new approach to improve drug solubility and bioavailability.?3?Twopharmaceuticalsalts?DPEN?2·?Indo?2·?H2O?2and?DPEN?1·?Nap?1·?H2O?0.5 were designed and synthesized using BCS-II indomethacin?Indo?and naproxen?Nap?as APIs and DPEN as a salt-forming reagent.The structures are characterized,with proton transfer present in both salts,DPEN is monoprotonated.?DPEN?2·?Indo?2·?H2O?2 forms a chain structure through three different motifs,and?DPEN?1·?Nap?1·?H2O?0.5 forms a DNA-like double helix chain structure The thermal stability,hygroscopic stability and solvent stability of the two pharmaceutical salts were tested.Solubility tests of the two pharmaceutical salts in pH=1.2,4.5 and 6.8 buffers showed that the equilibrium solubility was significantly increased compared to the raw materials Indo and Nap,and was related to the buffer medium;the solubility of the two salts was used to dissolve the process.The thermodynamic parameters were calculated.The results show that the higher the molar Gibbs free energy,the lower the solubility,and the dissolution process of salts in the buffer solution is endothermic.This work shows that the DPEN salts formation method can overcome the shortcomings of indomethacin and naproxen,which have low solubility and poor bioavailability,and provide good expectations for improving bioavailability.?4?A series of 1,2,3,4-tetrahydroquinoxaline derivatives?3A-3F?were synthesized by condensation reaction of baicalein with 6 kinds of 1,2-diamine compounds,and the reaction process was non-catalytic.All the target compounds were characterized by1H-NMR,13C-NMR,FTIR and MS.Among them?1R,2R?-1,2-diphenylethylenediamine and baicalein were directly crystallized in ethanol to obtain 3A·EtOH.The crystal structure was characterized by single crystal diffraction.The crystal structure was characterized by SCXRD.Fluorescence detection of nitrobenzene?NB?,2-nitrotoluene?2-NT?and 3-nitrotoluene?3-NT?in acetonitrile suspension showed that fluorescence quenching occurred in all three nitrobenzene compounds.The quenching constants were1.391×104 M-1,1.501×104 M-1 and 1.040×104 M-1,and the detection limits were 1.1×10-6M,0.98×10-6 M and1.41×10-6 M,respectively.The linear relationship between F0/F and quencher concentration indicates that the process is static quenching.This work developed a one-step condensation reaction of phenolic hydroxyl groups with amine groups without catalyst,and expanded the application of 1,2,3,4-tetrahydroquinoxaline derivatives in the detection of fluorescent nitrobenzene.In this thesis,the pharmaceutical salts of urotropine,nicotinic acid,indomethacin and naproxen were designed and synthesized.The structures,properties,solid-state transformation of different stoichiometric ratios and different solvation pharmaceutical salts were studied,and the existence of a novel supramolecular synthon was discovered.The improvement and influence of salt formation on solubility were discussed.,and the application of drug molecules in fluorescence detection was extended.This work provides data for further enriching the basic research of pharmaceutical cocrystal or salts,and provides a reference for the future synthesis and application of pharmaceutical salt. |
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