Study On The Formation And Properties Of Pharmaceutical Multi-component Crystals

Many innovative drugs have problems such as poor crystal habit,low solubility,high hygroscopicity and etc.These problems can usually be solved by forming multi-component crystal forms,such as freeze-dried mixed crystals,solvates and cocrystals(salts).However,due to the complex intermolecular interactions,there is a lack of regularity in the screening,design and preparation processes,which could not give instructions in the industrial application.In this study,four typical drugs were selected as the model compound,the effects of operating parameters,properties of solvents and chemical structure of coformers on the crystal structures and properties of multi-component crystals were investigated.Lyophilized powder is a kind of common mixed crystals,which is hard to be freeze-dryed due to its high concentration and low eutectic point of solution.The key problem is that it is difficult to control the crystallization in pre-freezing process,thus making the solution into glass state which is difficult to dry.Oxiracetam was selected as typical model.Firstly,the thermodynamics and crystal structure were determined and analyzed.Then the thermal analysis and microscopic analysis were applied to investigate the process of pre-freezing,and the reason for the formation of glass state was the high supersaturation.So we developed a process of prefreezing using different cooling rate to control the crystallization.Then the product had sublimation channels,which made the drying process much easier.Solvates are the common pharmaceutical multi-component crystals,but the rules of formation and phase transformation,as well as the application of solvates are still unclear.In this study,obeticholic acid,a chiral drug with poor solid form,was selected as the model drug.Firstly,two new solvates of obeticholic acid were obtained by controlling the solvents and the temperatures.Then the mechanism of the solvation,desolvation and the phase transformation of the two solvates in different solvents or under various temperatures were investigated.It was found that S-I contained two kinds of solvents,which had two stages of desolvation,and S-II was a kind of channel type solvate.Furthermore,the single crystal structure and absolute configuration of obeticholic acid were determined via isostructural solvents.Besides,a technique to get the block-like amorphous obeticholic acid by the desolvation was developed.Cocrystal(or salt)is an effective multi-component crystal to improve the physicochemical properties of drugs.Lamotrigine and gabapentin were selected as model drugs.Solid grinding and solution crystallization were applied to screen the multicomponent crystals,several cocrystals or salts of lamotrigine and gabapentin were developed.It is found that isomeric dipyridine coformers could form cocrystals with lamotrigine at different stoichiometric ratio,steric hindrance might affect supramolecular assembly and the properties of cocrystals.Some odd-even phenomenon of the co-crystallization of gabapentin and dicarboxylic acids was detected.This work also found that gabapentin could form diverse multi-component crystals with oxalic acid and fumaric acid,such as different stoichiometric salt,salt polymorphisms or salt hydrate.During the developing of multi-component crystals,we found that oxalic acid and fumaric acid,whose carbon atoms were in the same plane,could form different kinds of supramolecular synthons with gabapentin.Studies on the preparation and crystal structure of multi-component crystals of lamotrigine and gabapentin indicated that the stability of supramolecular synthons is the fundamental reason for the formation and phase transformation.This research provides a theoretical basis and technical support for the development and optimization of pharmaceutical multi-component crystal products.