Research On Polymorphism Of Lovir Antiviral Medicine

The research on drugs polymorphism has become an important part of the study of drugs due to the impact of drug polymorphism on the product and quality of API and formulation.Both of acyclovir and valacyclovir hydrochloride are important antiviral drugs,however,there exist significant polymorphism during their production.It is reported that there are six and seven known polymorphs of acyclovir and valacyclovir hydrochloride,respectively.Some problems from drug polymorphism have gathered increasing attention in clinical application,such as unstable phenomenon of quality and curative effect.So the comprehensive research of acyclovir and valacyclovir hydrochloride is necessary and conductive to improve the quality of drugs.In this thesis,better polymorphic manufacturing technologies of acyclovir and valacyclovir hydrochloride were presented basing on a systematic study of crystallization processes.The main work and results are as follows:(1)First,the purification process of 3:2 acyclovir/H2 O hydrate was optimized by increasing the solubility of acyclovir in the water.XRD,TGA and DSC were employed to characterize the crystal form,and the results demonstrated that the optimized process do improve the purity and productivity of 3:2 acyclovir/H2 O hydrate.The stability of the crystal form made in this study was also tested under the condition of strong light,high temperature and humidity.Moreover,the particle size of the crystal form made by the new process was bigger than that obtained by traditional process,and it was more convenient for manufacture and formulation basing on its better processing fluency.(2)Four crystal forms of valacyclovir hydrochloride,known as Form I,II,V and VII,were prepared by adjusting experimental conditions such as solvent system,water content,charging method,cool rate and drying time.Afterwards,the affiliation of crystal form was verified by XRD and thermal analysis,the difference of crystal structure was then discussed and the identification method of each crystal form was established.(3)The screenning of crystal form was carried out by regulating recrystallization process,and a new crystal form(Form IX)of valacyclovir hydrochloride was finally prepared with ethylene glycol as the solvent,and the mixture solvent including isopropanol and trichloromethane as the anti-solvent.Form IX showed characteristic diffraction peaks at 2? 3.5 °,6.9 °,7.9 °,8.5 °,9.3 °,13.0 °,14.4 °,16.3 °,20.0 °,23.5 °,24.5 °,27.2 ° from the XRD pattern,and a melting point of 197 oC with a water weight loss of 2.42 % from the thermal analysis.The stability of the new crystal form was also measured,and the results suggest that it is a stable crystal form and remain the same for several months under high temperature and humidity.In addition,apparent solubility experiment indicated that the aqueous solubility of anhydrous forms were superior to the hydrate forms.And the new form was the most stable one at experiment condition for it expressed the minimum apparent solubility.