Study On Improving Bioavailability Of Ibuprofen By Synthesis Of Cocrystals

The physicochemical properties and bioavailability of active pharmaceutical ingredient?API?are the key factors that determine whether it can be successfully used in clinical practice.One of the most important parts of the drug development is to optimize the performance of pharmaceutical products through appropriate solid modification methods.The core content is the selection of crystalline solids.Pharmaceutical cocrystals,as a new research area,have become a focus of attention in crystal engineering research and the pharmaceutical industry.Compared with other solid modification methods,such as polymorphs,solvates,salts and so on,pharmaceutical cocrystals have many unique advantages.It can improve the physicochemical properties of the API,such as solubility,dissolution rate,stability,etc.,without changing the structure of itself,and finally achieve an increase in the bioavailability.In this paper,ibuprofen,a poorly soluble drug,is selected as the research object for the development of cocrystal with the aim of improve the solubility of ibuprofen in aqueous and thereby increasing its bioavailability.The ibuprofen molecule contains a carboxyl functional group.According to the supramolecular synthesis rules,its hydrogen bonding mode may be O-H?O and O-H?N.Twenty-three cocrystal formers?CCF?containing pyridine,carboxyl,and amide groups were selected.The solution crystallization method combined with ultrasonic technology was used to screen ibuprofen cocrystals.The formation,structure and composition of the cocrystals were studied by single crystal X-ray diffraction?SCXRD?,powder X-ray diffraction?PXRD?,differential scanning calorimetry?DSC?,thermogravimetric analysis?TGA?,infrared spectroscopy?IR?,nuclear magnetic resonance?NMR?and elemental analysis?EA?.The solubility of cocrystals in water and the stability in artificial gastric fluid were investigated.Bovine serum albumin?BSA?was used instead of human serum albumin?HSA?to investigate the interaction between cocrystals and albumin.And the binding mode,binding constant and the type of force were analyzed to infer the process of the transport and distribution with blood in vivo.The ultimate goal of improving solubility of API is to increase its bioavailability.Therefore,the bioavailability of ibuprofen cocrystals in rats was investigated.The rats were given ibuprofen and cocrystals by a single oral administration.The pharmacokinetic parameters were calculated based on the blood concentration within24 hours.The relative bioavailability was calculated based on the AUC of cocrystals and ibuprofen to verify whether the bioavailability of ibuprofen can be improved after the synthesis of the cocrystal.The ibuprofen-isonicotinamide cocrystal and ibuprofen-2-picolinamide cocrystal were successfully prepared by solution crystallization method combined with ultrasonic technology.DSC and PXRD results showed that a new crystalline phase was formed.TGA results showed that the product did not contain water and organic solvents.SCXRD results showed that hydrogen bonds?O-H?N?were formed between the carboxyl group of ibuprofen and the pyridine nitrogen of isonicotinamide.IR,NMR and EA results showed that the hydrogen bond between ibuprofen and2-picolinamide may be formed between the carboxyl group and the amide group or pyridine nitrogen and the stoichiometric ratio is ibuprofen:2-pocolinamide=1:2.The results of solubility experiments showed that both cocrystals improved the solubility of ibuprofen without affecting its stability in artificial gastric fluid.The results of interaction with BSA showed that the cocrystals can still form complexes with plasma proteins and undergo static quenching.The types of forces between the two are mainly hydrogen bonds and van der Waals forces.The results of pharmacokinetic experiments of cocrystals in rats showed that the area under the drug-time curve(AUC(_0-t)?AUC(_0-?))and peak concentration(C_max)of the cocrystals have a significant increase compared with the control group.The relative bioavailability of the two cocrystal groups and the ibuprofen group were 248.12%and 183.69%,respectively,which significantly increased the bioavailability of ibuprofen in rats.This paper systematically studied the methods of design,screening,synthesis,characterization and properties of cocrystals and successfully obtained two ibuprofen cocrystals.It is found that the two ibuprofen cocrystals synthesized in this paper can effectively improve the solubility and bioavailability of the drug substance,and cocrystallization is a solid modification method with good development prospects.In this paper,the study of the interaction between cocrystals and biological macromolecules and the pharmacokinetics of cocrystals in vivo provides research ideas and theoretical bases for the research field of cocrystals.