Study On The Polymorphism Of Cobamamide

The polymorphism of solid chemicals affects the stability,bioavailability and physicochemical properties of the material.The change of these properties will affect the function and application of the product to a certain extent.Polymorphic research has become an important part of the drug development process.The solution crystallization method is the main method for the purification of the drug substance,and is also an important method for preparing the drug polymorph.Cobamamide is initially used to treat pernicious anemia.In recent years,the clinical application range of cobamamide has been expanded to include radiculitis,peripheral neuritis,ophthalmoplegia,liver disease,cancer,chronic atrophic gastritis,treatment of reproductive system diseases,etc.in clinical application.It exhibits remarkable therapeutic effects and is a promising treatment for many diseases.It is an active coenzyme form of vitamin B12 in the body.It is a substance necessary for cell growth and reproduction and maintenance of the myelin sheath of the nervous system.It has higher biological activity and bioavailability than cyanocobalamin and can be directly absorbed by the body.During the preparation and storage process,cobamamide is prone to produce impurities such as cyanocobalamin and hydroxocobalamin.These impurities are similar to the structure of cobamamide and belong to the cobalamin compound.Cobalamin-like compounds tend to form a homogeneous crystal,that is,impurities are easily crystallized together with cobamamide and are difficult to remove.The requirement for cobamamide bulk drug listed in the 2015 edition of the Chinese Pharmacopoeia is that the impurity content should not exceed 1%.The impurity is obviously high when used in the preparation of injections.In China,the drug quality evaluation system is continuously improved and the evaluation standard is continuously improved.In the context of the search,it is important to find a purification method that is easy to operate and that is easy to operate and that meets the green chemistry concept.When the solution crystallization method was used for the refining of cobamamide,it was found that the color and other traits of cobamamide changed significantly before recrystallization,suggesting that it has a polymorphic phenomenon.Further research confirmed the formation of new crystal form.The stability of the new crystal form and the change of the impurity content of the raw materials were systematically studied.The main contents of the research work include:?1?Preparation of new crystal formUsing a latent solution of cobamamide in a mixed solvent,a new form of cobamamide was prepared by a latent solvent-antisolvent recrystallization method at room temperature,and was defined as a C crystal form.In the study,it was found that when the new crystalline form of cobamamide was prepared,its color changed,that is,the dark red solid particles before preparation were converted into bright red flocculent powder after preparation,that is,the new crystal form was colored polycrystalline type.The preparation process adopts low toxicity solvent,is environmentally friendly,has mild reaction conditions,does not require cooling and low temperature operation,has low requirements on equipment,and can realize large-scale preparation.?2?Identification of new crystal formsThe prepared new crystal form was confirmed by thermogravimetry-differential scanning calorimetry,X-ray single crystal diffraction,X-ray powder diffraction and infrared spectroscopy.The new crystal form is significantly different from the crystal form of the commercial raw material and is a new crystal form.Compared with the new crystal form,the commercial raw material crystal is an orthorhombic system,the space group P2₁2₁2₁.A single crystal of cobamamide C crystal form is cultured.The cobamamide C crystal form belongs to the monoclinic system,the space group P2₁.?3?New crystal form stability studyThe stability of the crystal form before and after preparation was studied by high temperature,high humidity and light experiments.It was found that the crystal form after preparation was more stable.Under the conditions of high temperature,high humidity and strong light irradiation,the prepared cobamamide C crystal form is superior to the cobamamide A crystal form before preparation.?4?New crystal content researchThe content of the new crystal form was tested by HPLC analysis.The content of the new crystal form was increased by the external standard method,and the total impurity content was reduced to less than 0.5%,far exceeding the requirements of the2015 edition of the Chinese Pharmacopoeia.The new crystal form preparation process has obvious effect of reducing impurities.