| Anthraquinone drugs have antioxidant,antitumor,antibacterial and other pharmacological properties.They are widely used in the treatment of arthritis,cancer,Alzheimer’s disease,cardiovascular and other diseases,and have attracted the general attention of scientists all over the world.However,most anthraquinone drugs have to face the reality of poor solubility in the process of purification and clinical application.Taking diacerein as the starting point,by studying the solubility of diacerein and its cocrystal in organic solvents and the dissolution crystallization process,it has important theoretical significance and potential application value for enriching the crystallization theory and new crystallization methods of most anthraquinone drugs.As an IL-1 inhibitor initiated by zambezon Pharmaceutical Co.,Ltd.,diacerein is one of the most potential drugs to improve the condition of osteoarthritis.It can not only reduce the pain of patients with osteoarthritis and improve the working ability of joints,but also block the aggravation of the disease.Although there is no patent protection for compound preparation,there are preparation process patents and refining and purification patents,resulting in a serious shortage of supply in the domestic market.Secondly,the solubility of diacerein in different organic solvents should be involved in the process of cocrystal preparation and the purification of diacerein itself and its solvates.According to the functional requirements,the multicomponent phase equilibrium and dissolution crystallization process of diacerein were studied in this paper.The details are as follows:(1)The solubility of diacerein in polar aprotic solvents was significantly higher than that in other common organic solvents by isothermal dissolution equilibrium method.There was a cosolvency phenomenon in the mixed system of cosolvent + ethanol /isopropanol.The results of multiple linear regression analysis of solvent effect show that hydrogen bonding and the enhancement of solvent polarity contribute to the dissolution of diacerein,and the force between solvent molecules is the main factor limiting the dissolution of diacerein.The preferential solvation parameters in the mixed solvent showed that diacerein was first solvated by alcohol and water in the region rich in alcohol and water,while in the cosolvent + ethanol / isopropanol system,with the increase of cosolvent concentration,the solute was first solvated by cosolvent and then solvated by alcohol again.The results of thermodynamic model calculation show that Apelblat equation and Ma model can better correlate the solubility data of diacerein in the studied solvent.Moreover,the dissolution is an endothermic process with increased entropy.(2)The cocrystal of diacerein and nicotinamide,diacerein and isonicotinamide,diacerein and theophylline were prepared by wet grinding under heating.The ternary solid-liquid equilibrium phase diagrams of three cocrystals in DMAC at 308.15 K,318.15 K and 328.15 k were measured by static equilibrium method.When three cocrystals reach equilibrium in DMAC solvent,the nonlinear fitting results of solubility data show that it can be expressed by the solution complexation model with molar ratio of 1:1.At the same temperature,the solubility product constant showed that the force between DMAC molecule and the cocrystal of diacerein-nicotinamide was stronger than the other two groups.With the increase of temperature,the complexation constant decreases gradually,the force between DMAC molecule and cocrystal molecules increases,and the complexation between diacerein and ligand molecules decreases.Through the cocrystal phase diagram,it was found that the pure cocrystal could be obtained by properly evaporating the solvent in the DMAC solution of diacerein and theophylline with molar composition of 1:1.For the other two systems,pure cocrystal cannot be obtained by evaporating solvent.(3)Two solvates of DA-DMAC and DA-NMP were prepared by solvent evaporation method,and the corresponding single crystal structure data were obtained.NMR spectra and single crystal structure analysis showed that diacerein and solvent existed in the two groups of solvate crystals in the molar ratio of 1:1.Hirshfeld surface analysis showed that the solvate formed by diacerein with DMAC and NMP was mainly formed by hydrogen bond and π-π interaction.Density Functional Theory calculation shows that when the electrons of DA-DMAC and DA-NMP solvates are transferred from the ground state to the excited state,the electron cloud on diacerein molecules is mainly transferred to the atomic orbitals on solvent.The calculation results of electrostatic potential show that in the two groups of solvates,the hydrogen atom on the carboxyl group and the oxygen atom in the solvent correspond to the maximum and minimum regions of electrostatic potential.Due to the electrostatic mutual attraction,there is a strong complementarity between the positive and negative regions,and induced the formation of hydrogen bonds.(4)The dissolution crystallization process of diacerein in DMAC aqueous solvent was studied by focused beam reflection measurement(FBRM).The optimum technological conditions for dissolution crystallization of diacerein were obtained:in20m L solution with initial concentration of 6.67g/L,the addition amount of water was22.5m L,the drop acceleration was 1.5ml/min,the aging time was 6h,the stirring speed was 350 rpm,the crystallization temperature was 328.15 K and the addition amount of seed was 0.2%.The yield is 82.03%,and the chord length is 0-60 μm,the main chord length is 20 μm or so.This study not only provides a reference for controlling the particle distribution range of diacerein to achieve the consistency between batches and the crystallization and purification process of diacerein,but also improves the solubility of diacerein,which has important guiding significance for improving the solubility of most anthraquinone drugs. |
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