Design, Preparation, Characterization And Properties Of Mycophenolic Acid Eutectic And Salt

Mycophenolic acid,(namely 4-methyl-5-methoxy-7-hydroxy-6-(5-carboxy-3-methylpent-2-en-1-yl)-phthalide,abbreviated as MPA).Is a potent non-competitive hypoxanthine nucleotide dehydrogenase(IMPDH)inhibitor.It not only can selectively inhibit lymphocyte proliferation,but also inhibit T and B lymphocytes were stimulated by mitogens and allogeneic Antigen resulting from proliferation.At the same time,it also inhibits the B lymphocytes produce antibodies.Furthermore,MPA also through inhibition of adhesion to the endothelial cells of lymphocyte and monocyte adhesion molecules on the cell surface glycosylation,can blocking the migration of lymphocyte and monocyte part to rejection and infection.Therefore,the MPA has good antiviral,antifungal,antibacterial,antineoplastic and immunosuppressive activity.It often used in heart and kidney transplant rejection and autoimmune diseases such as Vasculitis and lupus nephritis therapy.Mycophenolic acid is poorly soluble(13μg/mL),thus,MPA usually in the form of mycophenolate mofetil(MMF)or Mycophenolate Sodium(MPS)enter the body,then thought metabolism in the body after the release the active pharmaceutical ingredients(API),so as to improve the solubility and bioavailability of mycophenolic acid.But the two forms are in the form of esters and salts,both change the molecular structure of Mycophenolate acid.Poor stability of mycophenolate Sodium that easily absorb moisture metamorphism.Mycophenolate mofetil hydrolysis in gastric acid stimulate the gastrointestinal tract,moreover,it is very low solubility in water and intestinal.This paper is purpose to select appropriate crystal coformer(CCF)to form cocrystal or organic salt with Mycophenolic acid.In order to without changing the original structure of Mycophenolic acid to improve the solubility and stability of API.This article includes the following content:(1)According to acidic characteristics of Mycophenolate acid,and contact with the rules of ΔpKa.Major tries to select weak base or weak acid to prepared cocrystal or organic salt.Select types of CCF are amide,thioamides,five or six-membered heterocyclic compounds,Carboxylic acids,purine compound and benzene derivatives.Adopt solvent-assisted grinding and solution reaction crystallization to prepare cocrystal or organic salt.This paper was prepare three cocrystals and three organic salts,and developed their crystals.Determined by SXRD to confirm mycophenolic acid’s H Proton of three cocrystals no transfer to receptor molecules on the object,it description of mycophenolic acid and guest molecular react to cocrystal.Mycophenolic acid’s H Proton of three salts transfer to receptor molecules on the object.(2)Make use of PXRD,IR,TG-DSC and other characterization methods to analysis mycophenolic acid cocrystal and salt.Proof that the spectrum characteristic diffraction peaks of cocrystal and salt are consistent to the following spectrum characteristic diffraction of crystal Analysis simulation.Identified that the samples of prepare are what we want.It can be seen from the IR that the carboxylic acid groups C=O,O-H on the cocrystal change NH-stretching region in certain degree,it confirmed the effects of hydrogen bonding.The carboxylic acid groups C=O,O-H on the salt change from double peak to single peak that confirmed the influence of proton transfer.According to TG-DSC of three cocrystals and three organic salts analysis results indicate that the CCF weight loss first,then MPA weight loss.The piperazine salt loss one molecule of water first that lead to structural collaspse,then CCF weight loss.The ratio of sequence weight loss is consistent correspondence to the ratio of crystal structure,it confirm the accuracy of its crystal structure.Moreover,we comparative analysis the phase change and weight loss of the raw materials,cocrystal and salt.(3)Through designing screened amide,thioamides and replacing the amide group with contraposition the N on the pyridine ring: Acetamide,Nicotinamide,Isonicotinamide,Benzamide,Pyrazinamide,Isoniazid,Thioisonicotinamide,Thiobenzamide,4-Dimethylaminopyridine and Benzoic acid.Only successful connect with nicotinamide form to cocrystal.Indicate that amides and contraposition N of pyridine ring are indispensable factor for forming cocrystal.Screening for five or sixmembered heterocyclic compounds: The results show that HMPA-MI,HMPA-2MI and HMPA-PIP-H2 O were form to salts,MPA-MIN and MPA-DPA were form to cocrystals.Imidazole and 2-methylimidazole just differ one methyl,but can lead to their salts structure varies considerably.(4)Cocrystal solubility test results show that formation of cocrystal form not only can increase the active substances solubility,but also can reduces the active substances solubility.MPA-ISO’s solubility increases.MPA-MIN and MPA-DPA’s solubility reduces.Organic salts solubility test results show that formation of organic salt form can greatly improves the active substances solubility.(5)Use accelerated stability test methods which experimental of high temperature and high humidity test to comparative analysis the stability of active ingredient,three cocrystals,three salts and two listed drugs.High humidity test results display that HMPA-PIP-H2 O and MPS possess hygroscopicity.Seven other test articles for humidity below 1% belong to slightly hygroscopicity.High temperature test results show that MPA-DPA and HMPA-PIP-H2 O color changes to yellow.Mycophenolate Sodium become fluffier.Other cocrystals and salts are quite good stability,with no apparent color change.