Degradation kinetics of benzonatate in aqueous solutions

The decomposition of benzonatate in aqueous solutions followed apparent first-order kinetics. One major hydrolysis product, 4-(butylamino)benzoic acid, was efficiently and completely separated from benzonatate with a validated HPLC. The apparent activation energies obtained from an Arrhenius plot was 16.07, 20.54 and 18.23 kcal mol⁻¹ in buffer solutions with pH 3.61, 9.42 and 10.46, respectively, which indicated that hydrolysis dominated the degradation process. The buffer concentration showed significant effect on the hydrolysis of benzonatate (P<0.05). Specific acid-, specific base- and buffer catalyzed hydrolysis of benzonatate were observed in solutions with pH in the range of 0.31–12.21. The decomposition of benzonatate in basic solutions was faster than in acidic solutions by about 2000-fold. The prominent base-catalyzed breakdown of the ester bond and slower acid-catalyzed hydrolysis suggested that benzonatate should be prepared in the solutions with pH 3–7 to maximize its stability.     

Degradation kinetics of vincristine sulphate and vindesine sulphate in aqueous solutions

The degradation kinetics of the antineoplastic drugs, vincristine and vindesine, have been studied in the pH range from − 2 up to 11 at 80°C. A stability-indicating HPLC system with UV detection was utilized for the analysis of vincristine and vindesine in the reaction solutions. The influences of external factors (e.g. pH, buffer concentrations, ionic strength and temperature) on the degradation rate have been studied systematically. The relationship between pH and log k_obs was modelled by using a non-linear least-squares curve-fitting computer program. From this plot thepK_a values of vindesine have been calculated. This plot also showed that vincristine was most stable at pH 4.8 and vindesine at pH 1.9.     

Degradation of paclitaxel and related compounds in aqueous solutions I: epimerization

Paclitaxel and other taxanes have complex structures including the presence of numerous hydrolytically sensitive ester groups and a chiral center that readily undergoes epimerization thus making their kinetics complex. The present study attempts to understand the mechanism of epimerization at the 7-position of paclitaxel, 7-epi-taxol, 10-deacetyltaxol, 7-epi-10-deacetyltaxol, baccatin III and 10-deacetylbaccatin III. Kinetics were studied as function of temperature, pH and buffer concentration and analyzed using a stability indicating assay and LC/MS to identify degradation products. Epimerization was base catalyzed with no evidence of acid catalysis noted. The observed equilibrium constant for epimerization, K, indicated a thermodynamically more favorable S-epimer and a small free energy change between the two epimers. For all of the compounds in this study, removal of the C10 acetyl group increases the epimerization rate in basic aqueous solutions. The observed base-catalyzed epimerization in near neutral to higher pH range suggests a possible rapid deprotonation/protonation of the C7 -OH, followed by a structural rearrangement through a retroaldol/aldol mechanism to form the epimer. Moreover, the rate-limiting step of structure rearrangement most likely occurs with the formation of an enolate intermediate.     

Degradation peptides of secretin after storage in acid and neutral aqueous solutions

During the storage of secretin in acid and neutral aqueous solutions, five degradation peptides (A1, A2, A3, A4, A5) and one degradation peptide (N1) were produced, respectively. They were isolated in pure form by HPLC, and the intramolecular structures were studied by a combination of amino acid analysis, enzymatic digestions, HPLC, and Fab-mass spectroscopy. Although the degradation peptides are composed of the same amino acids as secretin after acid hydrolysis (except A1 and A4 which are cleavage products S16-27 and S4-27, respectively), reversed-phase HPLC analysis of their digestive fragments with trypsin and alpha-chymotrypsin are different from those of secretin. By Fab-mass spectroscopy, the m/z values for the S1-6 fragments obtained from secretin, A2, and A3 were 663, 663, and 645, respectively. When S1-6 from A2 was treated with aminopeptidase M, a fragment obtained was identical with the synthetic beta-aspartyl3 S3-6, as determined by HPLC. The A2 and N1 peptides are completely the same based on various chemical analyses. The A3 peptide can also be rapidly degraded to secretin and beta-aspartyl3 secretin. Consequently, A1 and A4 are concluded to be the cleavage peptides of secretin, S16-27 and S4-27, respectively, A2 and N1 are concluded to be beta-aspartyl3 secretin, and A3 is concluded to be aspartoyl3 secretin.     

Degradation of busulfan in aqueous solution

The influence of pH, phosphate buffer components and temperature on the degradation rate of busulfan was studied. The analysis was performed using gas chromatography with electron capture detection and reversed-phase liquid chromatography with radioactivity monitoring. The degradation rate of busulfan showed no pH dependence in the range pH 1.5-11 and increased at higher pH values. The degradation rate constant was 0.034 +/- 0.001 h(-1) (S.E.M.) for the degradation of busulfan in pure water and 0.45 +/- 0.01 h(-1)M(-1) (S.E.M.) for the reaction of busulfan with the hydroxide ion at 37 degrees C. The reactivity of HPO(4)(-2) was six times higher than the reactivity of H(2)PO(4)(-1) towards busulfan. The hydrolysis products were identified as tetrahydrofuran and methanesulphonic acid by nuclear magnetic resonance spectroscopy.     

Degradation kinetics of 4-dedimethylamino sancycline, a new anti-tumor agent, in aqueous solutions.

The kinetics of degradation of the new anti-tumor drug, 4-dedimethylamino sancycline (col-3) in aqueous solution at 25oC were investigated by high-pressure liquid chromatography (HPLC) over the pH-range of 2-10. The influences of pH, buffer concentration, light, temperature, and some additives on the degradation rate were studied. The degradation of col-3 was found to follow first order kinetics. A rate expression covering the degradation of the various ionic forms of the drug was derived and shown to account for the shape of the experimental pH-rate profile. Under basic conditions, the degradation of col-3 involves oxidation, which is catalyzed by metal ions and inhibited by EDTA and Sodium bisulfite. Copyright     

Degradation of carmustine in aqueous media.

The degradation rate of carmustine was investigated in buffered aqueous media at several pH values. The buffering agents studied were those with potential use in parenteral formulations of this drug: acetate, citrate, and phosphate. The apparent first-order degradation rate constants were calculated using a linear regression procedure. A pH range over which minimum degradation occurred was ascertained. General acid and specific base catalysis was demonstrated for the degradation of carmustine. From the data at 5, 22, and 37 degrees, the apparent activation energies for carmustine degradation in buffered aqueous media were computed and were strongly pH dependent.     

Degradation of dacarbazine in aqueous solution.

The effects of initial concentration (0.05-5.0 mg ml-1, 2.5 x 10(-4)-0.025 M) (pH 1-13), buffer concentration (0.01-0.075 M), light, antioxidants and co-solvents on the degradation of dacarbazine in aqueous solution were investigated at 37 degrees C. Liquid chromatography was used to monitor the degradation of dacarbazine as well as the appearance of degradation products. The kinetics of hydrolysis of dacarbazine in the dark were pseudo first-order and independent of the initial concentration of the drug. The degradation of dacarbazine was accelerated by light and at low concentration proceeded by pseudo zero-order kinetics. The pH-rate profiles showed that both the photolytic and the hydrolytic reactions were dependent on the ionization state of the molecule. The main degradation product of both hydrolysis and photolysis was detected by liquid chromatography and confirmed by mass spectrometry to be 2-azahypoxanthine.     

Degradation of mecillinam in aqueous solution.

The hydrolysis of mecillinam in aqueous solution (37 degrees) was studied at pH 2-10. The degradation products observed by TLC and NMR were identified and quantified. Several of these compounds were synthesized. Mecillinam and the key degradation product, (6R)-6-formamidopenicillanic acid, underwent reversible 6-epimerization in basic solution. Some of the thiazolidine derivatives formed epimerized at position 2. In contrast to penicillins, the degradation pattern of mecillinam becomes more complex with increasing pH. Rate constants for some processes are given.     

Degradation pathway of carboplatin in aqueous solution

A degradation pathway for carboplatin in aqueous solution is described. Degraded solutions of carboplatin in water and in 5% glucose solution were analysed by high performance liquid chromatography; carboplatin and its degradation products were well separated. Three degradation products of carboplatin have been determined either in pure water and 5% glucose solution and they have been identified as 1,1-cyclobutanedicarboxilate anion, its protonated forms and cis-diamminediaquoplatinum (II) complex.     

Stability of ertapenem in aqueous solutions

The kinetics of degradation of ertapenem was studied in aqueous solutions at 303, 313, 323 and 333 K and pH 0.42-12.5. Degradation was studied using two methods: HPLC (LiChrospher RP-18 column, 5 microm, 250 mm x 4 mm; mobile phase: methanol-phosphate buffer 25 mmol l(-1), pH 6.5 (15:85, v/v); flow rate--1.2 ml/min; detection UV--298 nm) and UV (294 nm). Specific acid-base catalysis involves: (a) hydrolysis of ertapenem, catalysed by hydrogen ions; (b) hydrolysis of ertapenem dianions catalysed by hydroxide ions; (c) spontaneous hydrolysis of zwitter ions and dianions of ertapenem under the influence of water. The thermodynamic parameters of these reactions--energy, enthalpy and entropy of activation were calculated. It was observed that buffer catalysis occurred in acetate, phosphate and borate buffers.     

Photo-isomerization of fluvoxamine in aqueous solutions

The hydrolysis and photolysis of fluvoxamine, a selective serotonin reuptake inhibitor, in aqueous buffer solutions (pH 5, 7, and 9), in synthetic humic water, and lake waters were investigated in the dark and in a growth chamber outfitted with fluorescent lamps simulating the UV output of sunlight at 25 degrees C. No significant hydrolytic degradation/isomerization was observed for 30 days in all aqueous solutions. However, fluvoxamine was moderately isomerized to its (Z)-isomer by simulated sunlight. The photo-isomerization occurred in two stages. The photo-isomerization occurred rapidly within the first 7 days and slowly thereafter with a rate constant of 0.12-0.19 day(-1) for the first stage and 0.04-0.05 day(-1) for the second stage. Photosensitized rate constants in synthetic humic water and in lake waters were approximately 6-7 times faster than that in pH 9 buffer with the rate constants of 1.15-1.34 day(-1) in the first stage. The (Z)-isomer of fluvoxamine was the only product detected in all aqueous solutions and was identified using LC-ESI-MS.     

Stability of galactose in aqueous solutions

The stability of 5%-30% w/v galactose in sterile water for injection and acetate and phosphate buffers was studied. The concentration of galactose was determined after each sample was diluted to a nominal concentration of 0.5% (w/v); for purposes of data analysis, the concentration as measured in the diluted sample was multiplied by a dilution factor to obtain the true concentration in the sample. The concentrations were determined from the regression line obtained by plotting the peak-height ratios (for various concentrations of galactose and the internal standard cellobiose) versus the galactose concentrations. Triplicate samples were quantitatively analyzed for galactose content by high-performance liquid chromatography. The stability of the samples was then studied in relation to buffer concentration; pH; storage at 25, 45, and 65 degrees C for six weeks, and autoclaving at 121 degrees C for 30 minutes. Galactose degradation increased in relation to its concentration, increasing temperature, and buffer concentration. Galactose solutions in water and phosphate incurred less than 5% degradation on autoclaving; however, the 30% solutions in acetate buffers lost up to 21% of initial content. Yellow discoloration of solutions was associated with autoclaving and prolonged exposure at 65 degrees C and appeared in some solutions that did not exceed the USP XXI limit of 5-hydroxymethylfurfural and related compounds in dextrose injection. The estimated room temperature shelf-life of galactose in sterile water for injection sterilized by 0.45-micron-porosity membrane filtration is four and one-half months. Solutions may also be sterilized by autoclaving at 121 degrees C for 30 minutes; galactose solutions containing pH buffers should not be sterilized by autoclaving.     

Degradation kinetics and mechanism of N6-[(dimethylamino)methylene]mitomycin C in aqueous solutions

The degradation of N6-[(dimethylamino)methylene]mitomycin C, a semisynthetic analogue of mitomycin C, was studied in aqueous solution. The compound degraded rapidly and followed pseudo-first-order kinetics in both acidic (pH less than 5) and basic pH greater than or equal to 9) media. In the near-neutral pH region, however, biphasic kinetics were observed. At the pH of maximum stability (6.5), 10% activity was lost after approximately 6 h at 22 degrees C. Citrate and phosphate species were catalytic at pH 6.5. Spectrophotometric and HPLC methods were used to elucidate the degradation mechanism at pH 7-9. Under these conditions, equilibrium addition of one water molecule into the amidine side chain occurred, followed by parallel formation of mitomycin C and N6-(formyl)mitomycin C. The latter compound subsequently hydrolyzed to mitomycin C.     

Stability of ricobendazole in aqueous solutions

The chemical stability of ricobendazole (RBZ) was investigated using a stability-indicating high performance liquid chromatographic (HPLC) assay with ultraviolet detection. The degradation kinetics of RBZ in aqueous solution was evaluated as a function of pH, buffer strength and temperature. The oxidation reaction in hydrogen peroxide solution was also studied. Degradation products were analyzed by mass spectroscopy and degradation pathways are proposed. Degradation of RBZ followed pseudo first-order kinetics and Arrhenius behavior over the temperature range 24–55 °C. A V-shaped pH-rate profile over the pH range 2–12 was observed with maximum stability at pH 4.8. The shape of the pH-rate profile was rationalized by catalytic effects of various components in the solution on each RBZ species. At pH 11 the activation energy for hydrolysis was 79.5 kJ/mol, and phosphate catalysis was not observed. Oxidation occurred in hydrogen peroxide solutions and was catalyzed by the presence of copper (Cu²⁺) ions. Ricobendazole amine and albendazole sulfone were identified by MS assay to be the degradation products of hydrolysis and oxidation respectively.     

Degradation kinetics of mometasone furoate in aqueous systems

Mometasone furoate (MF) is a synthetic glucocorticoid. There is little information available on the stability of MF and no degradation products have been unequivocally identified. Thus, the primary objective of this study was to characterize the degradation of MF, qualitatively and quantitatively. Stability of MF decreased with increasing pH (>4) and decreasing ionic strength in aqueous media. The chemical stability of MF in aqueous systems was significantly dependent on pH. MF appeared to be stable at pH < 4 but degraded to four products at higher pH. The degradation of MF in aqueous solutions follows pseudo-first-order kinetics and involved a series of parallel and consecutive reactions. The turnover of MF and its products appears to be catalyzed by the hydroxide ion. The pH dependence of these reactions should be considered, when formulating or extemporaneously compounding MF formulations. An optimal pH of stability was below pH 4. The changes in pH, however, do not appear to be the only factor of importance, since an increase in ionic strength and buffer concentration displayed a stabilizing effect on this glucocorticoid in the buffers tested. Trace metal ions are unlikely to be involved in degradation of MF in aqueous solution.     

Degradation kinetics of L-glutamine in aqueous solution.

The degradation kinetics of L-glutamine (Gln) in aqueous solution was studied as a function of buffer concentration, pH and temperature. Stability tests were performed using a stability-indicating high-performance liquid chromatographic assay. The degradation product of Gln was 5-pyrrolidone-2-carboxylic acid. The reaction order for Gln in aqueous solution followed pseudo-first-order kinetics under all experimental conditions. The maximum stability of Gln was observed in the pH range from 5.0 to 7. 5. The pH-rate profile described by specific acid-base catalysis and hydrolysis by water molecules agreed with the experimental results. Arrhenius plots showed the temperature dependence of Gln degradation, and the apparent activation energy at pH 6.41 was determined to be 9.87 x 10(4) J mol(-1).