The Screen Of Dipfluzine-Salicylic Acid Complexes

Dipfluzine is piperazines calcium channel blockers,developed by Hebei Medical University,reduce the myocardial intracellular calcium,and thus can be used for calcium overload induced cardiac arrhythmiasPharmaceutical co-crystal was the complex of the active pharmaceutical ingredients(API)and co-crystal forms(CCF),which was formed through hydrogen bonds and other non-covalent bonding.Pharmaceutical co-crystal is a new form of drug,which has the advantages that the traditional solid state does not have.The research on drug co-crystal has become an important aspect in the development of new drugs.Co-amorphous,a new method and idea for improving the physical and chemical properties of the API,is an binary amorphous system with a single glass transition temperature,which composed by API and other small molecular solid substances(co-amorphous former,CAF).Objective:To screen the complexes(co-crystal and co-amorphous)based on dipfluzine and salicylic acid,adopting PXRD?IR and DSC-TG technologies to characterize the formation of the complexes.To explore the resulting complexes changes under different grinding time and solvent.The solubility of co-amorphous of dipfluzine-salicylic acid and transformation thermodynamics between co-amorphous and crystalline were also been studied,in order to explore the possibility and potential of improving physicochemical properties using co-amorphous dipfluzinein.Methods:The co-crystals and co-amorphous of dipfluzine and salicylic acid were synthesized by neat grinding and solvent-assisted grinding,respectively.The formation of the complexes were confirmed by PXRD,DSC-TG,FT-IR methods.Using solvent-ultrasonic method to prepare dipfluzine-salicylic acid co-amorphous.The concentration of dipfluzine was determined by RP-HPLC method.The thermodynamic parameters of co-amorphous to crystal transformation were determined by solubility method,in which the solubilities of dipfluzine and salicylic acid at different temperature were determined.The equilibrium solubilities of dipfluzine and co-amorphous at different medias were determined by saturated solubility method.Result:PXRD,DSC and FT-IR spectra analysis showed that dipfluzine and salicylic acid in a 1:1 molar ratio with different grinding conditions can form both co-crystals and co-amorphous.The PXRD of co-crystal shows significantly new peaks that different from the raw materials and the new endothermic peak of melting point on DSC curve suggested that the formation of new phase.IR analysis showed that the-OH of salicylic acid joined the formation of hydrogen bonds.The typical single peak diffraction on the PXRD spectra shows that the co-amorphous is formed.The transformation temperature of co-amorphous to crystal Tt is 370 K.The solubility of dipfluzine has improved after the formation of co-amorphous,and in 20% ethanol solution and pure water mediums solubility is also greatly improved,but in dilute HCl medium of 0.1mol/L,due to the bigger solubility of monomer,the co-amorphous on the amount of solubility increased with a lesser extent.Conclusion:Different grinding methods of dipfluzine and salicylic acid leading to the formation of co-crystal and co-amorphous;the final phase states were determined by adding solution or not and the kind of solutions.Solvent assisted grinding with methanol or ethanol as solvent obtained the same crystalline products,which conformed by IR and PXRD patterns.During the experimental process,with the uncertain grinding strength,temperature and time,the different batches of experiments,result in co-crystal or coamorphous was no fixed.The co-amorphous samples of dipfluzine and salicylic acid could be unique synthesized by solvent-ultrasonic method in the molar ratio of 1:1.IR spectra showed that salicylic acid may be involved in hydrogen bonding with-OH group.The solubility of co-amorphous has greatly improved compared with the intact dipfluzine.