Preparation Of New Solid Forms Of Pharmaceuticals And Exploration Of Unconventional Crystallization Methods

In the pharmaceutical field,formulations are mostly developed in solid form.In fact,solid active pharmaceutical ingredients(APIs)often face some challenges such as solubility,bioavailability,and stability.These physicochemical(phychemical)properties of the APIs depend on their solid form.Improving the physical properties of APIs via developing new solid forms is the core task of pharmaceutical crystallography.In order to accurately analyze the crystal structure of the APIs,it is an indispensable part to cultivate satisfying crystal samples.Because there are many APIs that are difficult to obtain by conventional methods,it is necessary to develop some unconventional methods for crystallization research.The APIs include fluorocytosine,fisetin and ursolic acid were selected as the research compounds.These APIs have poor stability,solubility,or degree of crystallinity.Though carefully screening new solid forms,including orotic acid and isoorotic acid salts of fluorocytosine,ethanol solvate and acetic acid monohydrate of fiseten,ursolic acid form III were successfully obtained.(1)The salt forms of fluorocytosine with orotic acid and isoorotic acid were screened out by suspension and ball milling methods,and their single crystal samples were obtained by solvent evaporation.The properties of the new solid forms were characterized by solid state nuclear magnetic resonance,powder X-ray diffraction,and differential scanning calorimetry.Moisture stability experiments showed that the two salt forms were stable at 25 ?/ 90% relative humidity,moisture stability of fluorocytosine was improved.(2)The ethanol solvate and acetic acid monohydrate of the fisetin were screened by solvent suspension methods,and their structures were analyzed by single crystal X-ray diffraction.Differential scanning calorimetry indicated that the two solvates are desolvated at 104.7 ? and 147.8 ?,respectively,which means that they can be stable in normal environments.Solubility experiments showed that acetic acid monohydrate of fisetin improves API dissolution performance,and the maximum solubility was increased by 2.09 times than API.(3)It is difficult to obtain satisfactory crystals of ursolic acid.The crystallinity of ursolic acid form ? and form ? were improved by adding choline chloride.In order to obtain higher quality single crystal,the surfactant Triton was added tocultivate crystal of ursolic acid.At last,we got the higher quality single crystal,and by powder X-ray diffraction comparison,it is a new solid phase crystal form III different from the known crystal form.