Study On Polymorphism And Crystal Habit Of DL-methionine And Regulation Using Additives

DL-methionine is one of the essential amino acids for the growth of human and animals.It is widely used as medicine nutrition,food excipient,feed excipient,etc.However,there are still many unsolved problems in the industrial production of DLmethionine.First of all,solid-state polymorph transformation between different crystal form is prone to occur during production and storage of DL-methionine,which will destroy the stability of the product.Secondly,the products obtained by recrystallization of DL-methionine are mostly flaky or powdery with low bulk density and flowability,which seriously affects the processes of filtration,washing and drying.Additionally,the two crystal forms,? and ?,of DL-methionine often concomitantly nucleate,leading to the production of mixture of the two forms and influencing the solubility and dissolution kinetics of the product.Therefore,this article systematically studied the polymorphism and crystal habit regulation of DL-methionine,in particular solid-state polymorph transformation,thermodynamics and the control of polymorphs and crystal habits using additives.Firstly,the solid-state phase transformation between ? and ? polymorphs of DLmethionine was investigated by differential scanning calorimeter(DSC),hot stagepolarized microscopy,temperature-varying powder X-Ray diffraction(PXRD)and in situ Raman microscopy.It was found that the two forms are reversibly enantiotropic systems,and the temperature of the transition was determined to be 305-316 K.At the same time,the solubility in water-methanol solvent mixtures was measured at different temperatures by static method.On the basis of solubility data and derived thermodynamic equations,the transition temperature is determined to be about 319.60 ± 1.71 K,independent of solvent system.On this basis,through thermal analysis and spectral analysis,it was revealed that the change of molecular conformation and the slip of the characteristic crystal plane caused by temperature change played a central role in the solid state transition of DL-methionine.The above results provide a theoretical basis for controlling the polymorph transformation rate and the crystallization of polymorph of DL-methionine solid products.Then,the roles of structurally similar additives,namely,glycine,DL-alanine,DL-2-aminobutyric acid,DL-valine and DL-leucine on the crystallization of DLmethionine polymorphs were systematically studied.The results showed that the additives can promote the crystallization of metastable ? form and the higher the concentration,the more significant the effect.Among these additives,DL-leucine showed the most significant effect.The induction time of DL-methionine in the presence of DL-valine and DL-leucine were determined by dynamic method.And the solvent-mediated polymorphic transformation of the enantiotropic polymorphs was also investigated under the action of additives.Both amino acids were found inhibiting the nucleation kinetics and polymorphic transformation from ? to ? form of DLmethionine.As the concentration increases the inhibitory effect becomes more significant.The comprehensive analysis of the above results suggests that the selective crystallization of ? polymorph by these additives is manly due to the inhibition of the nucleation and growth of the stable ? form.Finally,the effect of amino acid additives on crystal habit of DL-methionie was further studied.It was found that the crystal habit changes significantly in the addition of DL-leucine from a long fusiform shape to a hexagonally thick platelet,and the bulk density and flowability of crystals can be dramatically improved.Then,the effect mechanism of additives on crystal habits was discussed based on the interaction analyses of among water molecules,leucine molecules and the main crystal surfaces of DL-methionine.It was found that additive molecules mainly through the selective adsorption on the characteristic crystal surface and inhibit their growth to achieve the control of the product crystal habit.