| Adefovir (PMEA), an acyclic adenine phosphonate compound, has been demonstrated a broad spectrum of antiviral in both in vitro and vivo. Activity has been demonstrated against several RNA viruses, including human immunodeficiency virus (HIV) types 1 and 2, hepatitis B virus. Adefovir, however, demonstrated poor bioavailability in vivo. But the oral bioavailability of adefovir has been substantially improved with the development of the pro-drug adefovir dipivoxil (bis-POM PMEA). Some evidence suggested that adefovir dipivoxil has enhanced activity due to the increased celluar uptake and metabolism of the lipophilic pro-drug, resulting in high intracelluar concentrations of adefovir. Today, it is mainly used to against hepatitis B virus in clinic. It is a new anti-HBV agent of nucleoside analogue after lamivudine. In order to warrant the safety, efficiency of it, we studied the all kinds of factor that influence the quality of adefovir dipivoxil, the synthesis technics, quality and quality control and degradation kinetics, pharmacokinetics. All the studies provided theory basis for adefovir dipivoxil's production, storage and usage.PART 1 Study the Synthesis technics of adefovir dipivoxil Objective: Study and modify the general process for the synthesis of adefovir dipivoxil and searching after the source of impurity to study and control the quality of it.Methods: Some key steps of the process were modified, so the synthetic method was more convenient than that in literature. NaH was replaced by sodium tert-butyl alcohol as catalyst, reacting at low temperature in the synthesis of (9-(2-phosphonyl methoxyethyl)ethyl)adenine.Adjustment of pH and re-crystallize took the place of ion-exchange chromato-graphy in the synthesis of adefovir.Results: The target compound adefovir dipivoxil (bis- (pivaloyloxymethyl)-9-(2-phosphonylmethoxyethyl)adenine) was synthesised. The melting point of it accorded with references, the chemical structure of it was confirmed by melting point, elementary analysis, UV, IR, 1H-NMR, 13C-NMR and MS.Conclusion: The process was simple, and suitable for industrialization, in this technics the use of harmful solution was reduced, the impurity was avoided and the quality of adefovir dipivoxil was improved. PART 2 The Study of adefovir dipivoxil's Quality Control Means1 Determination of adefovir dipivoxil by Non-aqueous TitrationObjective: To establish a non-aqueous potentiometry titration method for the routine analysis of adefovir dipivoxil. Method: The mixure of non-aqueous acetic acid and acetic anhydride (1:3) was used as solvent, and (0.1 mol?L-1) perchloric acid was used as standard solution. Results: The average content of adefovir dipivoxil was 99.7% with CV of 0.1%. Conclusion: It is a simple and accurate method, and is suitable for the quality control of adefovir dipivoxil raw material. 2 Determination of adefovir dipivoxil by UV- Spectrophoto- metryObjective: A UV spectrophotometry was established for the routine analysis of adefovir dipivoxil tablets. Methods: The sample was determined at 260nm with standard substance. Results: The linear range was 6.012～30.06 μg?ml-1 and the correlation coefficient was 0.9999. The average recovery of adefovir dipivoxil was 99.9% and the CV was 0.4%. Conclusions: This method is simple, rapid and accurate. It is applicable to determine the content of adefovir dipivoxil tablets.3 Determination of adefovir dipivoxil and Its Degradation Products by Reversed–phase High Performance Liquid Chromatography Objective: A rapid and simple RP-HPLC was established for the routine analysis of adefovir dipivoxil and its degradation products (adefovir and mono-POM PMEA). Methods: The separation between adefovir dipivoxil and its degradation products was performed on a CN-3 column and the quantitation was achieved with UV detection at 260 nm, Acetonitrile: 25 mmol?L-1 phosphate buffer (to makeup the pH 4.0 with phosphoric acid) (33:67, v/v) was used for mobile phase for isocratic elution with flow rate 1.0... |
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