ABSTRACT
The stress and accelerated tests as well as photostability analysis in solutions and the solid phase of three selected derivatives of pyrrolo[3,4-c]pyridine-1,3-dione were carried out according the International Conference on Harmonization guidelines. For observation of the degradation of tested compounds, the RP-HPLC method was used. The study included the effect of temperature, relative humidity, water, H+ and OH- ions, hydrogen peroxide, and light (6.0×10(6), 1.2×10(6) lux·h) on the stability of pyrrolo[3,4-c]pyridine-1,3-dione derivatives. Studies have shown that these derivatives are photolabile, extremely unstable in an alkaline medium, labile in an acidic medium, and stable in a neutral medium. Their sensitivity to oxidizing agents depends on the chemical structure. The shortening of the aliphatic chain leads to an increase in the sensitivity to hydrolytic and oxidizing factors. The presence of the 1,3,4-tetraisoquinoline group promotes an increase in the susceptibility to photodegradation. The introduction of a carbonyl group to the aliphatic chain and the tetrafluoromethyl group to the phenyl ring stabilizes the molecule in the case of hydrolysis and oxidation and also increases sensitivity to light. The analysis of observed photodegradation products using the HPLC-diode array detector, HPLC/MS, and UV and IR spectrometry techniques showed degradation targeted at the breaking of the pyrrolo[3,4-c]pyridine-1,3-dione, piperazine, and/or tetrahydroisoquinoline rings.
Subject(s)
Analgesics/analysis , Pyridines/analysis , Pyrroles/analysis , Chromatography, High Pressure Liquid , Drug Stability , Guidelines as Topic , Hot Temperature , Humans , Hydrogen Peroxide/chemistry , Hydrogen-Ion Concentration , Hydrolysis , Mass Spectrometry , Oxidation-Reduction , Photolysis , Spectrophotometry, Infrared , Spectrophotometry, Ultraviolet , Structure-Activity Relationship , Water/chemistryABSTRACT
The degradation behavior of a tricyclic analog of acyclovir [6-(4-MeOPh)-TACV] was determined in accordance with International Conference on Harmonization guidelines for good clinical practice under different stress conditions (neutral hydrolysis, strong acid/base degradation, oxidative decomposition, photodegradation, and thermal degradation). Accelerated [40±2°C/75%±5% relative humidity (RH)] and intermediate (30±2°C/65%±5% RH) stability tests were also performed. For observation of the degradation of the tested compound the RP-HPLC was used, whereas for the analysis of its degradation products HPLC/MS/MS was used. Degradation of the tested substance allowed its classification as unstable in neutral environment, acidic/alkaline medium, and in the presence of oxidizing agent. The tested compound was also light sensitive and was classified as photolabile both in solution and in the solid phase. However, the observed photodegradation in the solid phase was at a much lower level than in the case of photodegradation in solution. The study showed that both air temperature and RH had no significant effect on the stability of the tested substance during storage for 1 month at 100°C (dry heat) as well as during accelerated and intermediate tests. Based on the HPLC/MS/MS analysis, it can be concluded that acyclovir was formed as a degradation product of 6-(4-MeOPh)-TACV.
Subject(s)
Acyclovir/analysis , Antiviral Agents/analysis , Acyclovir/analogs & derivatives , Chromatography, High Pressure Liquid/methods , Drug Stability , Guidelines as Topic , Hot Temperature , Humans , Hydrogen Peroxide/chemistry , Hydrogen-Ion Concentration , Hydrolysis , Oxidation-Reduction , Photolysis , Tandem Mass SpectrometryABSTRACT
Acyclovir (ACV) belongs to a class of drugs with low bioavailability. Selected ACV esters including acetyl (Ac-), isobutyryl (iBut-), pivaloyl (Piv-), ethoxycarbonyl (Etc-) and nicotinoyl (Nic-) were synthesized, and their lipophilicity was determined by the high-performance liquid chromatography (HPLC) RP method. Statistical analyses of the comparative values of log P and clog P were carried out using computational methods. It was proved that the AC log P algorithm can be useful for the analysis of these compounds and has a statistically justified application in the assessment of the quantitative structure-activity relationship. Moreover, the lipophilicity determined by the HPLC method appears as follows: ACV < Ac- < Nic- < Etc- < iBut- < Piv-.
Subject(s)
Acyclovir/analogs & derivatives , Antiviral Agents/chemistry , Models, Molecular , Acyclovir/analysis , Acyclovir/chemistry , Acyclovir/pharmacology , Algorithms , Antiviral Agents/analysis , Antiviral Agents/pharmacology , Chromatography, High Pressure Liquid , Chromatography, Reverse-Phase , Computational Biology , Hydrophobic and Hydrophilic Interactions , Molecular Structure , Quantitative Structure-Activity Relationship , Reference Standards , Solubility , Transition TemperatureABSTRACT
Knowledge of the lipophilicity of candidate compounds for prodrugs may predict their predetermined course/effect in the body. Acyclovir (ACV) belongs to a class of drugs with low bioavailability. Its tricyclic analogues, the derivatives of 3,9-dihydro-3-[(2-hydroxyethoxy)methyl]-9-oxo-5H-imidazo[1,2-a]purine (TACV) exhibit similar antiviral activities and are more lipophilic as compared with acyclovir itself. In the search for new antiviral prodrugs 6-(4- methoxyphenyl) tricyclic compound (6-(4-MeOPh)-TACV) was modified by esterification of a hydroxyl group in the aliphatic chain. Selected esters (acetyl, isobutyryl, pivaloyl, ethoxycarbonyl and nicotinoyl) were synthesized and their lipophilicity was determined by the HPLC-RP method. The study compared the log kw calculated from the linear and quadratic equations and proved the correctness of the application of the linear relationship log k as a function of the concentration of ACN in the mobile phase (30-60%). Statistical analyses of the comparative values of log kw and clogP were carried out using computational methods. It was proved that the AC logP algorithm can be useful for the analysis of these compounds, which can have a statistically justified application in the assessment of the quantitative structure- activity relationship (QSAR). The lipophilicity determined by the HPLC method appears as follows: 6-(4-MeOPh)-TACV < Ac- < Nic- < Etc- < iBut- < Piv- (log kw = 0.65-2.26). Finally, the HPLC-RP method was developed and validated for simultaneous determination of synthesized esters.