Study On Thermodynamics And Crystal Transformation Process Of Lenalidomide Polymorph

The pharmaceutical industry is an important industry related to national economy and people's livelihood.It is an important area to cultivate strategic emerging industries.The low clinical efficacy of drugs is one of the key issues restricting the development of China's pharmaceutical industry at this stage.The fundamental way to solve this problem is the development of new drug solid forms and the regulation of their morphology and structure.Lenalidomide is an anti-tumor drug developed by the United States Celgene Biopharmaceutical Company,which is a typical polymorphic drug.The study found that the phenomenon of crystal transformation is common in the crystallization process.In addition,there are significant differences in bioavailability and medicinal effects between different crystalline forms.In this paper,three crystal forms,B,E and J,were selected as research objects,and their thermodynamics and crystal transformation process were systematically studied.(1)Three crystal forms of lenalidomide B,E and J were prepared,and their structures were characterized by TG,DSC,XRD,FTIR and polarized light microscope.The crystal form and purity of the product were verified.(2)The solubility of lenalidomide form B in a methanol aqueous solution(methanol:water volume ratio:1:0.1,1:0.2,1:0.5,1:1 and 1:2)was determined by a dynamic method.The static method was used to determine the three crystal forms of lenalidomide B,E and J in phosphoric acid aqueous solution(phosphoric acid volume fractions:0.10%,0.20%,0.50%,0.75%,1.00%,5%,10%and 20%).The improved Apelblat empirical equation and van't Hoff model were used to correlate the solubility data.The dissolution enthalpy and dissolution entropy of each system in different solvents were estimated.This provided basic data for subsequent research on process optimization.(3)The methods of the three crystal forms of B,E and J being transformed into each other were explored separately.In-depth experiments were conducted on the process of the transformation of form B to E and form E to J.The effects of operating conditions such as temperature(30?,40?,50?,60? and 70?),phosphoric acid concentration(phosphoric acid volume fraction:0.1%,1%,5%,10%and 20%),and stirring time on the crystal form of lenalidomide were investigated by means of stirring and cooling crystallization.The preparation process was further effectively controlled,and provided a basis for determining the stable relationship between different crystal forms of lenalidomide.(4)The metastable area and induction period of lenalidomide form J under different solution compositions(phosphoric acid volume fraction:1%,5%and 10%)and cooling rates(0.5 K/min,1 K/min,1.5 K/min,2 K/min and 2.5 K/min)were measured.The self-consistent Nyvlt-like model and the classic 3D nucleation model were used to study its nucleation kinetics and mechanism.