Solid State Chemistry Research Of Calcium Pantothenate

The stability of drug refers to its ability to maintain physical,chemical,biological and microbiological properties,which directly affects the effectiveness and safety of drugs.The molecular structure and packing patterns are internal factors that affect the stability of drugs.The active pharmaceutical ingredients(API)may present as one of two different solid states: crystal or amorphousness.The crystalline state mainly includes polymorph,solvate,cocrystal and salt.Since different solid forms have different molecular packing patterns and intermolecular interactions,they exhibit different physical and chemical properties,such as melting point,solubility,hygroscopicity,and stability.Therefore,the solid-state chemistry study of APIs plays an important role in the development of new drugs.Calcium pantothenate(CP),also known as vitamin B5,which functions as the metabolic precursor of coenzyme A.CP exhibits great hygroscopicity and unfavorable chemical stability.It is sensitive to moisture,heat,acid and alkali.CP may suffer markedly loss of activity by combination with other acidic vitamins such as ascorbic acid,thiamine,and pyridoxine hydrochloride.In order to solve these problems,the solid-state chemistry study(including polymorph,cocrystal and double salts study)of CP were conducted in this research.Initially,the reported three polymorphs and a new1,4-dioxane solvate(CP-form S1)were obtained and they were fully characterized by XRPD,SCXRD,IR,TGA and DSC.In this paper,we firstly reported the single crystal structure of CP β-form and 1,4-dioxane solvate.In the polymorph screening process,we obtained a double salt of CP formed with CP and its decomposition product pantoic acid calcium(CP-PA).Inspiring by the formation of CP-PA double salt,11 kinds of calcium salts were selected as ligands to design and synthesize double salts with CP.Finally,three double salts of CP with calcium lactate,calcium isobutyrate and β-hydroxy-β-methyl butyrate were prepared successfully(CP-IBA,CP-HMB,CP-LA).The four double salts were fully characterized and their chemical stability under different conditions were also studied.The results show that,compared to the CP market amorphous form and β-form,all the four double salts present improved hygroscopicity and chemical stability.Among them,CP-PA and CP-LA exhibit significantly improved hygroscopicity and stability.In addition,the stability enhancement mechanism was also discussed.The finding in this report may promise potential applications of CP double salts in the vitamin premix,and provide valuable insight to the improvement of chemical stability and properties in organic salts by forming double salts.