Stability experiments in human urine with EO9 (apaziquone): a novel anticancer agent for the intravesical treatment of bladder cancer

EO9 (apaziquone) is a novel, promising anticancer agent, which is currently being investigated for the intravesical treatment of bladder cancer. EO9 contains a highly reactive aziridine ring in its structure that limits its chemical stability in acidic aqueous solutions. The stability of the pharmaceutically formulated EO9 in human urine, including the effects of several parameters such as temperature, buffer strength and pH have been investigated. Urine extracts were analyzed by high-performance liquid chromatography coupled to electrospray tandem mass spectrometry (HPLC-MS/MS) using a TurboIonspray interface and positive-ion multiple reaction monitoring. EO9 was unstable in urine at 43 degrees C during the instillation for longer than 1 h. However, the drug was stable in human urine for 3 h at 37 degrees C. EO9 is stable in urine stabilized with TRIS buffer (pH 9.0; 5 mM) for up to three freeze/thaw cycles at -20 and -70 degrees C and 3 months of storage at -70 degrees C. The results also illustrated that with the lower pH in urine, EO9 became more unstable. Furthermore, a new degradation product of EO9 was discovered and successfully identified as EO9-Cl. The outcomes of these stability experiments will be implemented to insure proper sample handling at the clinical sites, transport, storage, and sample handling during analysis in the forthcoming preclinical studies of EO9 in superficial bladder cancer, supported by bioanalysis and pharmacokinetic monitoring.     

A systematic study on the chemical stability of ifosfamide

The degradation kinetics of ifosfamide in aqueous solution have been investigated over the pH region 1-13 at 70 degrees C. A stability indicating high-performance liquid chromatographic assay with UV detection was used to separate degradation products from the parent compound. The degradation kinetics were studied as related to pH, buffer composition, ionic strength, temperature and drug concentration. A pH-rate profile at 70 degrees C, obtained from (pseudo) first-order kinetic plots, was constructed after corrections for buffer effects were made. The degradation reactions of ifosfamide were found to be largely independent of pH, although proton or hydroxyl catalysis occurs at extreme pH values. Ifosfamide shows maximum stability in the pH region 4-9, corresponding to a half-life of 20 h.     

A comparison of the chemical stability and the enzymatic hydrolysis of a series of aliphatic and aromatic ester derivatives of metronidazole

The hydrolytic degradation rates of various aliphatic and aromatic esters of metronidazole in aqueous buffer solution and in human plasma were investigated at 37°C. Complete reversion to metronidazole was observed as determined by HPLC and in all cases the hydrolysis followed strict first-order kinetics. The susceptibility of the various ester derivatives to undergo enzyme-catalyzed hydrolysis was strongly influenced by the structure of the acyl moiety, but no unambiguous relationship between the degradation rate in aqueous buffer solution and in human plasma has been found. In aqueous solution the degradation of the aromatic esters was facilitated by low electron density at the reaction site as described by the Hammett equation. Concerning the decomposition of the aromatic esters in 2.5% human plasma a negative deviation from the Hammett plot was observed for the nitrobenzoic acid ester derivatives. A change in rate-determining step together with the polar nature of the nitro group is suggested to contribute to this deviation. It has been found that the length of the linear carbon chain in the aliphatic esters influences the enzyme catalyzed degradation rate. The ratio between the degradation rates in 2.5% human plasma and in aqueous buffer solution, pH 7.4, was greatest for the valerate ester, the value being 3800.     

Stability of batanopride hydrochloride in aqueous solutions.

The degradation of batanopride hydrochloride, an investigational antiemetic drug, was studied in aqueous buffer solutions (pH 2-10; ionic strength, 0.5; 56 degrees C) in an attempt to improve drug stability for parenteral administration. Degradation occurs by two different mechanisms depending on the pH of the solution. In acidic media (pH 2-6), the predominant reaction was intramolecular cyclization followed by dehydration to form a 2,3-dimethylbenzofuran. There was no kinetic or analytical (high-performance liquid chromatography) evidence for the formation of an intermediate; therefore, the rate of dehydration must have been very rapid compared with the rate of cyclization. In alkaline media (pH 8-10), the primary route of degradation was cleavage of the C-O alkyl ether bond. In the intermediate pH range (pH 6-8), both reactions contributed to the overall degradation. Both degradation reactions followed apparent first-order kinetics. The pH-rate profile suggests that batanopride hydrochloride attains its optimal stability at pH 4.5-5.5. Citrate buffer was catalytic at pH 3 and 5, and phosphate buffer was catalytic at pH 8. No catalytic effect was observed for the borate buffer at pH 9-10.     

奥硝唑在水溶液中的降解动力学研究

目的：研究奥硝唑在水溶液中的降解动力学,为其制剂开发提供参考,方法：通过经典恒温试验,应用HPLC法测定奥硝唑在不同pH值、不同温度、不同浓度、不同缓冲液条件下的降解动力学参数？结果与结论：奥硝唑在水溶液中的降解呈现一级动力学特征,其降解速率与溶液pH值、温度、缓冲盐种类及浓度有关。最稳pH值为3．6。随着温度、缓冲盐溶液浓度的增加,奥硝唑的降解增快。缓冲盐溶液浓度较低时。奥硝唑在枸橼酸盐缓冲液中较磷酸盐缓冲液、醋酸盐缓冲液中稳定：缓冲盐溶液浓度较高时,奥硝唑在醋酸盐缓;中液中较磷酸盐缓冲液、枸橼酸盐缓冲液中稳定。     

人工合成胸腺五肽在水溶液中的稳定性-pH及缓冲溶液对降解的影响

目的利用高效液相色谱法研究不同的pH值和各种缓冲盐(醋酸盐、硼酸盐、柠檬酸盐及磷酸盐)的水溶液(50℃时)对胸腺五肽的影响。方法高效液相色谱柱采用u-Bondapak C18柱(0μm,250×3.9mm),流动相:0.02M磷酸二氢钾溶液(pH3.0)-甲醇(90∶10),流速:1.0ml.min-1,检测波长:210nm。结果及结论胸腺五肽溶液浓度在50~200μg.ml-1时有良好的线性关系,相关系数大于0.999。胸腺五肽的降解速率符合表观一级动力学方程。水溶液中最佳的pH值很难确定。缩氨酸在pH大约5.5~8.0时相对较稳定。这些稳定状态在其他的缓冲体系都可以观察到;不同的缓冲体系产生不同影响,醋酸盐可以起到很好的稳定作用而磷酸盐则会产生很强的降解。     

Preformulation study of methazolamide for topical ophthalmic delivery: Physicochemical properties and degradation kinetics in aqueous solutions

Methazolamide (MTZ) is an anti-glaucoma drug. The present paper aims to characterize the physicochemical properties and degradation kinetics of MTZ to provide a basis for topical ophthalmic delivery. With the increase in pH (pH 5.5–8.0) of aqueous solution, the solubility of the compound increased while the partition coefficient (Ko/w) which was estimated in the system n-octanol/aqueous solution decreased. The degradation of MTZ in aqueous solution followed pseudo-first-order kinetic. The degradation rate k_pH is the rate in the absence of buffer catalysis. Plotting the natural logarithm of k_pH versus the corresponding pH value gave a V-shaped pH-rate profile with a maximum stability at pH 5.0. The degradation rate constants as a function of the temperature obeyed the Arrhenius equation (R² = 0.9995 at pH 7.0 and R² = 0.9955 at pH 9.0, respectively). A decrease in ionic strength and buffer concentration displayed a stabilizing effect on MTZ. Buffer species also influenced the MTZ hydrolysis. Phosphate buffer system was more catalytic than tris and borate buffer systems. In brief, it is important to consider the physicochemical properties and the stability of MTZ during formulation.     

A kinetic study of the chemical stability of the antimetastatic ruthenium complex NAMI-A

NAMI-A is a novel ruthenium complex with selective activity against cancer metastases currently in Phase I clinical trials in The Netherlands. The chemical stability of this new agent was investigated utilizing a stability-indicating reversed-phase high performance liquid chromatographic assay with ultraviolet detection and ultraviolet/visible light spectrophotometry. The degradation kinetics of NAMI-A were studied as a function of pH, buffer composition, and temperature. Degradation of NAMI-A follows first-order kinetics at pH<6 and zero-order kinetics at pH > or =6. A pH-rate profile, employing rate constants extrapolated to zero buffer concentration, was constructed, demonstrating that NAMI-A is most stable in pH region 3-4. The degradation rate is not significantly affected by specific buffer components. Storage temperature strongly influences the degradation rate.     

Kinetic studies on the decomposition of erythromycin A in aqueous acidic and neutral buffers

The results of a study are presented on the effect of pH, buffer concentration and temperature on the decomposition of erythromycin A in aqueous solution. The decomposition proceeds via the known intermediate erythromycin A-6,9-hemiketal and observed rate coefficients (k_obs) for both erythromycin A and hemiketal degradation are reported. Both reactions are subject to specific acid catalysis and catalysis by buffer species. Buffer independent rate coefficients have been obtained and these show a linear increase with decreasing pH. The mechanistic implications of these observations are discussed.     

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.     

Mechanism and kinetics of secretion degradation in aqueous solutions

In order to clarify the mechanism of secretin degradation in aqueous solutions, the formation of degradation products from secretin, aspartoyl3 secretin and beta-aspartyl3 secretin was investigated; the stabilities of these three peptides were investigated as well. Aspartoyl3 secretion and beta-aspartyl3 secretin, degradation peptides produced during the storage of secretin in aqueous solutions, were isolated by preparative reversed-phase HPLC (RP-HPLC). The amounts of secretin and its two degradation peptides resulting from storage of secretin in various buffer solutions (pH 2.3 to 10.0, mu = 0.5 M, 60 degrees C) were determined by analytical RP-HPLC. Secretin and the isolated degradation peptides were stored separately in various aqueous buffer solutions resulting in the degradation of each peptide. A mixture of secretin and its degradation or cleavage peptides was formed in each solution. The observed degradation rates for each peptide approximately followed first-order kinetics. The pH-rate profiles for conversion of secretin and beta-aspartyl3 secretin were similar, while that for aspartoyl3 secretin was different from these two. Aspartoyl3 secretin was more stable than the others at pH 2.3 to 4.0, but it was easily degraded between pH 5.0 and 10.0. Investigation of aspartoyl3 secretin degradation showed that its degradation was related to the pH value of the solution, and that hydroxide ion catalyzes the ring opening of the aspartoyl peptide. Secretin was most stable in pH 7.0 buffer solution and more stable in acidic solutions than in alkaline solutions. Secretion was mainly degraded through the following pathways: cleavage peptides reversible secretin in equilibrium aspartoyl peptide in equilibrium beta-aspartyl peptide vector cleavage peptides.     

Stability Studies of Gabapentin in Aqueous Solutions

Gabapentin is a -aminobutyric acid analogue, which has been shown to be an effective antiepileptic. The solution stability of gabapentin in buffered systems was studied in order to facilitate the formulation of a liquid product. The degradation of the drug was followed as a function of pH, buffer concentration, ionic strength, and temperature. The results indicated that the rate of degradation was proportional to the buffer concentration and temperature. The pH–rate profile of gabapentin degradation showed that the rate of degradation was minimum at an approximate pH of 6.0. Further, the data suggested a slower solvent-catalyzed degradation rate for the zwitterionic species compared to the cationic or anionic species in the pH range of 4.5 to 7.0. There was no influence of ionic strength on the rate of degradation. Arrhenius plots of the data indicated that a shelf life of 2 years or more at room temperature may be obtained in an aqueous solution at a pH value of 6.0.     

Degradation kinetics in aqueous solution of cefotaxime sodium, a third-generation cephalosporin

The degradation kinetics of a 3- acetoxymethylcephalosporin , cefotaxime sodium salt, in aqueous solution investigated by HPLC under different conditions (pH, ionic strength, temperature) and using different buffers. The scheme of degradation involves a cleavage of the beta-lactam nucleus and the deacetylation of the side chain. In highly acidic medium, the deacetylated derivative is easily converted to the lactone. The degradation rate constants were calculated at three pH values (1.9, 4.0, and 9.0) by measuring the residual cephalosporin and the main decomposition products. The degradation pathway is both supported by the results of a primary salt effect and by the agreement between the theoretical pH-rate profile and the experimental values. In the pH range from 3.0 to 7.0, the main process is a slow water-catalyzed or spontaneous cleavage of the beta-lactam nucleus with intramolecular participation of the side chain amido fraction in the 7-position. In alkaline or strongly acidic medium, the hydrolysis is a base- or acid-catalyzed reaction. Of the buffer systems investigated, carbonate buffer (pH 8.5) and borate buffers (pH 9.5 and 10.0) are found to increase the degradation rates, while acetate buffer decreases the degradation rates. The apparent activation energies determined at different pH values are compatible with a solvolysis mechanism and similar to those previously given in the literature for other cephalosporins. Cefotaxime in aqueous solution is slightly less stable than the main cephalosporin derivatives, despite its high resistance to the beta-lactamases and its remarkable biological activity.     

HPLC法测定阿奇霉素在水溶液中的降解动力学

目的研究阿奇霉素在水溶液中的降解动力学,为阿奇霉素液体制剂的开发提供参考。方法通过经典恒温试验,应用HPLC法测定阿奇霉素在不同pH值、不同温度、不同离子强度、不同缓冲液条件下的降解动力学参数。结果阿奇霉素在水溶液中的降解呈现一级动力学特征,其最稳定pH值(pHm)为6.41;随着离子强度和温度的增加,阿奇霉素的降解加快;阿奇霉素在磷酸盐缓冲液中比在醋酸盐、枸橼酸盐缓冲液中相对稳定。结论阿奇霉素降解速率与溶液pH值、缓冲液种类、离子强度以及温度有关;溶液pH值与温度对阿奇霉素降解作用的影响较为明显。     

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.     

Stability of Gonadorelin and Triptorelin in Aqueous Solution

The influence of pH, temperature, various buffer species at different concentrations, and ionic strength on the stability of gonadorelin and triptorelin in aqueous solution has been studied using stability-indicating high-performance liquid chromatographic methods. The degradation behavior of both peptides is similar. The maximum stability of both peptides was shown to be at an approximate pH of 5.0. Acetate has the most favorable effect on stability, while phosphate causes higher degradation. Varying the concentration of acetate buffer does not affect the degradation behavior of the peptides. A higher phosphate concentration in buffer solutions causes higher degradation, however. The ionic strength of buffer solutions has no significant influence on stability. Solutions of gonadorelin and triptorelin, respectively, buffered with acetate (0.1 M, pH 5.0) with 3% (w/v) mannitol as an additive show a predicted t _90% of 9.0 years and 7.7 years at 20°C, respectively.     

Chemical reactivity of Ro-26-9228, 1alpha-fluoro-25-hydroxy-16,23E-diene-26,27-bishomo-20-epi-cholecalciferol in aqueous solution

The degradation of Ro-26-9228, 1alpha-fluoro-25-hydroxy-16,23E-diene-26,27-bishomo-20-epi-cholecalciferol, 2, was studied in aqueous solution in the pH range of 1.17-10.56 and in alcohol solutions, at 25, 40, and 50 degrees C. The degradation of Ro-26-9228 was found to be acid catalyzed and to be independent of potassium acetate buffer concentration. Above pH 4, the reaction rate is independent of pH, with a T90 of 14.3 h at 25 degrees C in pH 7.75 buffer. 19F nuclear magnetic resonance was used to study the ratio of the vitamin (6-s-trans) to previtamin form in acetonitrile at 40 degrees C. The equilibrium percentage of previtamin and the rate of approach to equilibrium were 13.8% and 0.2 h(-1), respectively. Nuclear magnetic resonance was used to elucidate the structure of the degradation products. Novel products were formed from the elimination of the fluorine and addition of solvent to C9, with formation occurring through the previtamin form. Additional degradation products result from reaction of the side chain 25-hydroxyl and addition of solvent to C1.     

Solution Stability of Poloxamer 188 Under Stress Conditions

Poloxamer 188 (P188) is a triblock copolymer of the form polyethylene oxide–polypropylene oxide–polyethylene oxide (PEO–PPO–PEO). The center PPO block is hydrophobic, and the side PEO blocks are hydrophilic, resulting in surface-active properties. P188 has been used in the pharmaceutical industry as an excipient in various formulations and drug delivery systems. Although the chemical stability of P188 in the solid state has been reported, there are very few reports detailing the solution state stability. In this study, we report the solution state stability of P188 conducted to evaluate the effects of P188 concentration, temperature, pH and buffer type, and trace metals on chemical stability. The degradation chemistry of P188 and identification of degradation products was studied using various analytical techniques (ultraviolet, gas chromatography–mass spectrometry, and liquid chromatography-mass spectrometry). The degradation of P188 in solution was found to be strongly dependent on temperature, P188 concentration, and buffer type. For the first time, we report that in histidine buffer, oxidation of both P188 and histidine may occur at pharmaceutically relevant conditions. We observed degradation of both histidine and P188 as well as species formed from the mutual interactions of the degradation products from the 2 types of molecules.     

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).     

Solubility and stability of curcumin in solutions containing alginate and other viscosity modifying macromolecules. Studies of curcumin and curcuminoids. XXX

The solubility, chemical- and photochemical stability of curcumin in aqueous solutions containing alginate, gelatin or other viscosity modifying macromolecules have been investigated in order to obtain an alternative to the use of surfactants or cyclodextrins. The solubility of curcumin in aqueous solution at pH 5 increased by a factor > or = 10(4) in the presence of 0.5% (w/v) alginate (various qualities) or gelatin compared to plain buffer, while propylene glycol alginate ester, cesapectin and sodium carboxymethyl cellulose did not have a similar solubilizing effect. The solubilization was slightly influenced by pH, ionic strength and type and concentration of buffer salts. The macromolecules do, however, not stabilize towards hydrolytic- or photolytic degradation of curcumin.