Preparation,characterization And Evaluation Of Antipsychotic Drugs’ Crystalline Solids

The solid-state physicochemical properties of APIs are important characteristics for drugs,especially for oral drugs,which have important impact on the dissolution,absorption and biological effects of pharmaceutical formulations,and which are important factors of the drugability to drugs.The polymorphism of drugs and their influence on drug formulation and biological efficacy make the solid-state study one of the difficulties in drug pharmacy development.Design and evaluation of crystalline pharmaceutical solids are essential for improving the API’s physicochemical properties and drug efficiency,and extending life cycle.In this study,theoretical calculations combined with supramolecular chemistry and crystal engineering are used to systematically study the crystalline solids of five antipsychotic drugs,and cocrystals for controlling drug release,preparing long-acting drugs and improving stability.Which provide theoretical and practical basis for the improvement of old drugs and the development of new drugs.（1）In view of the long-term use of psychiatric drugs,controlling the stable release and developing long-acting preparations are the current research hotspots of psychiatric drugs.In order to study the stable release oral formulations and long-acting formulations of two excellent antipsychotic drugs,aripiprazole（ARI）and olanzapine（OLZ）,they were respectively cocrystallized with resveratrol（RSV）and kaempferol（KAE）.Five cocrystals of aripiprazole were prepared with RSV and KAE,and cocrystals of OLZ and KAE was also prepared.X-ray diffraction and other analytical methods were used to characterize them,and the cocrystal formation conditions and physicochemical properties of the cocrystals were summarized.The cocrystal OLZ-KAE·0.75EA·0.25H₂O reduced the dissolution rate of OLZ,and have a continuous and stable near-linear powder dissolution profile.Pharmacokinetic experiments showed that the drug cocrystal prepared by selecting CCF with lower solubility,could provide a more moderate release profile.Long-acting intramuscular injection of ARI-RSV co-crystal was explored and prepared,and pharmacokinetic experiments showed that ARI-RSV cocrystal long-acting intramuscular injection can stable release ARI within 1～45 days,which has the potential to be clinically developed as a long-acting antischizophrenic drug.（2）Taking advantage of the variable stoichiometric ratio of individual components of solid solution,Small organic molecule solid solution was applied to compound drugs by drug cocrystallization.Non-stoichiometric ratio（88:12）1-stearoyl-2-valproyl-sn-glycerol-3-phosphatidylcholine(DP-VPA-C₁₈)and 1-palmitoyl-2-valproyl-sn-glycerol-3-phosphatidylcholine(DP-VPA-C₁₆)were cocrystallized to prepare solid solution DP-VPA.Dynamic vapour sorption（DVS）test shows that DP-VPA solid solution improves the humidity stability of the individual component DP-VPA-C₁₆,reducing caking,improving manufacturability,furthermore improving quality controllability.（3）7-（4-（4-（6-fluorobenzo[d]-isoxazol-3-yl）piperidin-1-yl）butoxy）-4-methyl-8-chloro-2H-chromen-2-one is a new preclinical antipsychotics small molecule entity discovered by our research group,and its medicinal salt is mesylate（CY611）.Molecular docking and quantum chemical calculation are applied to the predict the drug polymorphism;and the binding mode of small molecules is simulated and calculated.Five polymorphs of CY611（Forms I～V）were prepared and evaluated;and their intrinsic dissolution rates（IDR）were in the following order:FormⅡ>FormⅢ>FormⅠ>FormⅣ.Pharmacokinetic experiments showed that the bioavailability was in the following order:FormⅢ>FormⅡ>FormⅠ.Polymorph studies provide a solid foundation for quality control and pre-formulation studies.At the same time,the theoretical calculation method based on molecular docking and DFT binding energy calculation provides another tool for the future research and prediction of drug polymorphs.（4）7-（4-（4-（6-fluorobenzo[d]isoxazol-3-yl）piperidin-1-yl）butoxy）-2-methyl-3,4-dihydroisoquinolin-1（2H）-one（CY112）is a new drug candidate discovered by our group,which had been in first phase clinical research.The evaluation of drug salt forms is one of the most important procedures for pre-formulation and solid-state studies of drugs.For exploring the pharmaceutical salts of CY112,six salt forms of the antipsychotic drug candidate have been prepared.And their structures,stability,solubility and pharmacokinetics were systematically studied.PK experiment showed that the CY112 had higher bioavailability than the CY112 hydrochloride.Therefore,for ordinary oral solid preparations,CY112 may be the dominant API.All above,aiming at the needs of drugs and pharmaceutical formulations,this thesis systematically studied the cocrystals,solid solutions,polymorphs and salt forms of several drugs by using the relevant computational prediction system and solid-state research methods.It lays firm basis for the design and development of new drug crystalline solids and new formulations.