Hydrochloric Acid That Split Type Polycrystalline Preparation And Characterization Of Research

In recent years, the impact of drug polymorphism on the physical and chemical properties, bioavailability and preparations quality of drugs attracted more and more attention of pharmacy workers. Thus the study on drug polymorphism has become an important part of the research, development and quality control process of drugs.Benazepril hydrochloride, which is an important anti-hypertensive drugs, exists some polymorphs. There are two known polymorphs as form A and form B of benazepril hydrochloride, but no findings about their crystal structures. In this paper, we select benazepril hydrochloride as the object, prepare and characterize two polymorphs--form A and form B, screen new and stable polymorphs of benazepril hydrochloride, and study the preparation process of the crystalline forms, crystal structures, and stability. The main work and results are as follows:(1) Form A and form B of benazepril hydrochloride were prepared and their crystal structures were studied. The results show that form A is in the monoclinic system, space group P21, with unit cell parameters:a=7.8655(4) A, b=11.7700(6) A, c=13.5560(7)A,β=102.9470(10)0, V=1223.07(11)A3, Z=2, while form B is in the orthorhombic system, space group P212121, with unit cell parameters:a=1.9353(8)A, b=11.6654(11)A, c=26.6453(16)A, V=2466.5(4)A3, Z=4. Molecules in form A were orderly arranged, while molecules stacking in form B were relatively disorder, which shows that form A was more stable at high temperatures while form B was more stable at low temperatures.(2) Two new polymorphs of benazepril hydrochloride-form I and form II were selected. Four polymorphs were all characterized by X-ray powder diffraction (PXRD), single-crystal X-ray diffraction (SCXRD), thermo gravimetric analysis (TG), differential scanning calorimetry (DSC) and infrared spectroscopy (IR). The results indicate that form I is in the monoclinic system, space group P1211, with unit cell parameters:a=8.0410(6)A, b=11.5343(8)A, c=28.4191(13)A,β=91.736(2)0, V=2634.6(3)A3, Z=2, while form II is in the orthorhombic system, space group P21212, with unit cell parameters:a=28.7014(12)A, b=11.4349(4)A, c=8.0071(3)A, V=2627.91(17) A3, Z=2. Two new polymorphs both belong to solvates.(3) Transformation conditions and the relationship of stability between form A and form B was investigated. Studies shown that after heating at120℃for1.5h, form B would transformed into form A which indicated that form A exhibited more stable than form B at high temperatures.(4) A new preparation process of form A of benazepril hydrochloride was found out. The preparation process enjoyed the advantages such as using a single solvent(C1-C6alcohol, preferably ethanol), less solvents, easy to control, high yield(increased from60%to80%), so it is suitable for industrial production.The originality in this thesis:Two novel polymorphs of benazepril hydrochloride were selected and a new preparation process of form A was discovered.