Crystal And Crystal Morphology Of Metformin Hydrochloride

Metformin hydrochloride（MET·HCl）is one of the most widely used oral hypoglycemic agents in the world.MET·HCl produced in industry are mostly needle-like crystals resulting in subsequent filtration and drying difficulties and poor preparation performance.The key scientific problem lies in the unclear crystal growth mechanism.To deal with the above problems,the crystallization thermodynamics and crystal growth process of MET·HCl were studied in this thesis.The crystal morphology and size control method were also explored.To solve the problem of insufficient study on crystallization thermodynamics of MET·HCl,the solubility of MET·HCl at the temperature of 283.15 K-323.15 K in three pure solvents and seven mixed solvents was determined by gravimetric method under atmospheric pressure.The modified Apelblat equation,CNIBS/R-K equation and Apelblat-Jouyban-Acree equation were used to fit the experimental data.The solubility of MET·HCl increased with increasing temperature and water content in the mixed solvent.Hansen parameters（HSP）and apparent thermodynamic parameters were used to analyze the thermodynamic behavior of solute.The thermodynamic parameters showed that the dissolution process of MET·HCl was endothermic and spontaneous.In view of the unknown growth mechanism of MET·HCl crystal and poor crystal morphology which is difficult to control,the effects of crystallization method,solvent and additive on crystallization process were studied.Firstly,the effects of additives on crystal morphology were screened and investigated.It was found that sodium dodecylbenzenesulfonic acid（SDBS）could adjust MET·HCl from needle-like crystal to short rod-like crystal.The effect of SDBS on the growth of MET·HCl crystal was further studied by single crystal growth experiment and nucleation induction time measurement combined with molecular simulation technology.It was found that the SO₃^-group on SDBS could form hydrogen bonds with the amine groups on the（100）and（020）faces of MET·HCl crystal.As a result,SDBS molecules competed with solute molecules and were adsorb on the crystal plane of MET·HCl,occupying the growth sites on the crystal surface and inhibiting the crystal growth.Secondly,the effects of crystallization method and solvent on crystal habit and particle size were investigated.It was found that the morphology of crystal was not improved by antisolvent crystallization and the crystal was still needle-like.The reverse antisolvent crystallization changed the crystal shape from needle-like to lamellar and short rod.The crystal size was significantly decreased.The impacts of temperature,solvent system and additives on crystal morphology were studied.It was found that the crystal morphology of MET·HCl changed from needle-like to lamellar in water+acetone+PVP K_16-18system and methanol+acetone system at low temperature.The microparticles MET·HCl are difficult to be produced by conventional crystallization method.Ultrasonic field was introduced during the process of reverse antisolvent crystallization.The influences of solvent system,ultrasonic time,dripping mode,ultrasonic power and additive concentration on crystal morphology and crystal size distribution were investigated.Under the dual action of supersaturation and cavitation effect,the average size of crystal decreased to about 10μm.In addition,the aspect ratio of the crystal was significantly reduced.The morphology and particle size of the micronized MET·HCl crystals were successfully controlled by multi-objective crystallization.