Stability of 5-aminolevulinic acid in aqueous solution

The chemical stability of 5-aminolevulinic acid (ALA) was studied in aqueous solution as a function of concentration, pH, temperature and in the presence of ethylenediaminetetraacetic acid (EDTA). The degradation of ALA was followed by reversed-phase liquid chromatography using a pH where ALA is protonated (pK_a1=3.90; pK_a2=8.05, as determined potentiometrically). ALA was degraded by a reaction following second order kinetics. Stock solutions of 1% (60 mM) ALA were incubated at 50°C. At pH 2.35, ALA was stable during the whole incubation period (37 days). The half-lives for the second-order decomposition of 1% ALA at pH 4.81 and 7.42 were 257 and 3.0 h, respectively. The degradation rate increased about 1.5 times with each 10°C rise in temperature at pH 7.53 within the range studied (37–85°C). The energy of activation, E_a, for the second-order decomposition of ALA was 43.7 kJ mol⁻¹. EDTA did not influence the degradation of ALA when a mixture of 1% ALA and 1% EDTA was incubated at pH 7.42.     

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。     

A Systematic Degradation Kinetics Study of Dalbavancin Hydrochloride Injection Solutions

The degradation kinetics of the glycopeptide antibiotic dalbavancin in solution are systematically evaluated over the pH range 1–12 at 70°C. The decomposition rate of dalbavancin was measured as a function of pH, buffer composition, temperature, ionic strength, and drug concentration. A pH-rate profile was constructed using pseudo first-order kinetics at 70°C after correcting for buffer effects; the observed pH-rate profile could be fitted with standard pseudo first order rate laws. The degradation reactions of dalbavancin were found to be strongly dependent on pH and were catalyzed by protons or hydroxyl groups at extreme pH values. Dalbavancin shows maximum stability in the pH region 4–5. Based on the Arrhenius equation, dalbavancin solution at pH 4.5 is predicted to have a maximum stability of thirteen years under refrigerated conditions, eight months at room temperature and one month at 40°C. Mannosyl Aglycone (MAG), the major thermal and acid degradation product, and DB-R6, an additional acid degradation product, were formed in dalbavancin solutions at 70°C due to hydrolytic cleavage at the anomeric carbons of the sugars. Through deamination and hydrolytic cleavage of dalbavancin, a small amount of DB-Iso-DP2 (RRT-1.22) degradation product was also formed under thermal stress at 70°C. A greater amount of the base degradation product DB-R2 forms under basic conditions at 70°C due to epimerization of the alpha carbon of phenylglycine residue 3.     

Degradation Pathways of Ampicillin in Alkaline Solutions

Ampicillin trihydrate, sodium salt, in aqueous solution has a pH of about 8. No complete degradation pathway has been proposed to explain the degradation of ampicillin under alkaline conditions and the information available explains the formation of only certain products. The present work was carried out with the aim of providing this information. The formation of degradation products of ampicillin trihydrate, sodium salt, produced in aqueous solutions (pH 12 and 37°C) have been studied as an accelerated form of the possible degradation that may occur in aqueous solutions at pH 8. Some of the degradation products formed under these conditions were then obtained either by synthesis or by degradation of ampicillin sodium followed by isolation using semi-preparative HPLC. These compounds were characterized by ¹H NMR spectroscopy. The information obtained from the experiments by HPLC and NMR spectroscopy made it possible to propose a degradation pathway for ampicillin under the conditions described above. 5R-penicilloic acid is the first degradation product of ampicillin and subsequently undergoes epimerization at C-5 to form the 55 isomer via the imine tautomer. Mechanisms for the formation of compounds previously believed to form only under acidic conditions are proposed, i.e. ampicillin penilloic acid and 2-hydroxy-3-phenylpyrazine. The formation of ampicillin polymers was detected in dilute solutions (1% w/v) within a few hours of dissolution. The presence of ampicillin penicillenic acid and ampicillin penamaldic acid was detected by ¹H NMR and their main spectroscopic features determined.     

A differential kinetic method for the determination of mecillinam in the presence of its hydrolysis and epimerization products

A differential kinetic method is described for the selective determination of mecillinam in the presence of its degradation products including (6S)-mecillinam formed by a C₆-epimerization. The method involves spectrophotometric measurement at 330 nm of a 4-aminomethyleneimidazol-5(4H)-one derivative, formed by reaction of mecillinam with an aqueous glycine buffer at 35°C, and is based on the different rates of reaction of mecillinam and its 6-epimer with the glycine reagent. The procedure makes use of the method of proportional equations and it permits simultaneous determination of mecillinam and its 6-epimer. The accuracy and precision of the procedure were evaluated and its applicability for assessing the stability of mecillinam was demonstrated. C₆-epimerization to yield (6S)-mecillinam was shown to account for 30% of the total degradation of mecillinam in aqueous solution at pH 9.9 and 35°C.     

Aqueous stability of leuprolide acetate: effect of temperature,dissolved oxygen,pH and complexation with β-cyclodextrin

In the present research, the aqueous stability of leuprolide acetate (LA) in phosphate buffered saline (PBS) medium was studied (pH?=?2.0–7.4). For this purpose, the effect of temperature, dissolved oxygen and pH on the stability of LA during 35 days was investigated. Results showed that the aqueous stability of LA was higher at low temperatures. Degassing of the PBS medium partially increased the stability of LA at 4?°C, while did not change at 37?°C. The degradation of LA was accelerated at lower pH values. In addition, complexes of LA with different portions of β-cyclodextrin (β-CD) were prepared through freeze-drying procedure and characterized by Fourier transform infrared (FTIR) and differential scanning calorimetry (DSC) analyses. Studying their aqueous stability at various pH values (2.0–7.4) showed LA/β-CD complexes exhibited higher stability when compared with LA at all pH values. The stability of complexes was also improved by increasing the portion of LA/β-CD up to 1/10.     

The degradation of carboplatin in aqueous solutions containing chloride or other selected nucleophiles

The degradation kinetics of carboplatin in aqueous solution in the presence and absence of chloride ions were studied at elevated temperatures (43–70 °C) at pH 7.0 and at various pH values at 70 °C. Reaction rates were then extrapolated to temperatures of interest (infusion storage temperature, ‘in-use’ infusion temperature and body temperature) from Arrhenius plots. Additionally, the effects of pH and added chloride, thiosulphate, thiocyanate, azide and iodide on the rate of degradation of carboplatin were determined in an attempt to obtain a greater insight into the mechanism of nucleophilic substitution of carboplatin.     

Degradation of acetonitrile in eluent solutions for [18F]fluoride PET chemistry: impact on radiosynthesis of [18F]FACBC and [18F]FDG

In [¹⁸F]fluoride chemistry, an eluent solution containing a weak aqueous base is used to release [¹⁸F]fluoride after adsorption on an anion exchange resin. Traditionally, the eluent solution is freshly prepared, but modern PET tracer manufacturers may utilize the benefits of preparing bulk solutions or prefilled vials for storage. We discovered that typical eluent solutions containing kryptofix and K₂CO₃ in aqueous acetonitrile degraded upon storage. Acetonitrile will at alkaline pH hydrolyse to acetamide and ammonium acetate. Acetate may serve as a competing nucleophile to [¹⁸F]fluoride. Eluent solutions used in the synthesis of [¹⁸F]FACBC and [¹⁸F]FDG generated mg/ml levels of acetamide and ammonium acetate during storage at room temperature or above. The synthesis of [¹⁸F]FACBC was prone to eluent degradation, with gradual reduction of radiochemical yield (RCY) from 62.5% to 44.7% during 12 months of storage at 30 °C. The synthesis of [¹⁸F]FDG was only affected when the eluent was stored at 50 °C, reducing the RCY from 86.8% to 66.7% after 3 months of storage. For degradation effects to be avoided, an alternative eluent solution with no acetonitrile was investigated in the synthesis of [¹⁸F]FACBC. A methanol‐based eluent was successfully made, showing no degradation and unchanged RCY after 6 months of storage at 50 °C. Copyright © 2012 John Wiley & Sons, Ltd.     

The solution stability of vancomycin in the presence and absence of sodium carboxymethyl starch

The purpose of this work was to study the potential for drug-excipient interactions to alter the stability of pharmaceutical drug products. Previous studies have demonstrated the interactions between glycopeptide antibiotics (e.g. vancomycin) and sodium carboxymethyl starch (NaCMS). A key objective of this work was to determine the effect of NaCMS binding on the solution stability of the glycopeptide antibiotic, vancomycin. The solution stability of vancomycin was studied under various pH and ionic strength conditions at physiological temperature (37°C). A stability-indicating HPLC method specific for vancomycin was developed and validated for use in this research. Vancomycin stability was evaluated alone and in the presence of NaCMS in various buffers from pH 2 to 9, and in simulated gastric and intestinal fluids to determine if NaCMS influences the degradation rate of vancomycin in solution. Results indicated that the pH stability profile of vancomycin at 37°C from pH 2 to 7 was slightly stabilized in the presence of NaCMS at the pH and ionic strength conditions where binding to NaCMS was shown to occur.     

The solution,solid state stability and kinetic investigation in degradation studies of lercanidipine: study of excipients compatibility of lercanidipine

The objectives of this research were to evaluate the stability of lercanidipine in solution state and solid state and explore the compatibility of drug with oils, surfactants and cosurfactants as excipients. The effect of pH on the degradation in solution state was studied through pH-rate profile of lercanidipine in constant ionic strength buffer solutions in pH range 1–8 which gives the pH of maximum stability. Powdered lercanidipine was stored under 40°C/0%~75% relative humidities (RH) or 0% RH/5~50°C to study the influence of RH and temperature on the stability of lercanidipine in solid state. Binary mixtures of lercanidipine and different excipients were stored at 40°C/75% RH, 40°C and at room temperature for excipient compatibility evaluation. The degradation of lercanidipine at different pH appears to fit a typical first-order reaction, but in solid state, it does not fit any obvious reaction model. Moisture content and temperature both play important roles affecting the degradation rate. Lercanidipine exhibits good compatibility with surfactants, cosurfactants and oils as excipients under stressed conditions of different storage temperature in a 3-week screening study. Moreover, the proposed high-performance liquid chromatography method was utilized to investigate the kinetics of the acidic and alkaline degradation processes of lercanidipine at different temperatures.     

Effect of ultrasound on the stability of oligodeoxynucleotides in vitro

In order for oligodeoxynucleotides (ODNs) to be viable candidates for phonophoresis (i.e. ultrasound-enhanced delivery), they must remain stable on exposure to therapeutic ultrasonic waves. We have examined the stability of radiolabelled ODNs as a function of their chemistry (phosphodiester (PO) and phosphorothioate (PS)) and chain length (7-mer and 20-mer) in aqueous solutions at three different pH values (1, 2 and 7) when subjected to ultrasound at an intensity of 1.5 W cm⁻² for 30 min. Whereas all ODNs remained stable at pH 1, pH 2 or pH 7 in the absence of ultrasound, significant degradation was observed at pH 1 upon ultrasound treatment. The sensitivity of ultrasound-enhanced ODN degradation at this pH, starting with the most rapidly degradable species first, was 7-mer PO > 20-mer PO > 7-mer PS > 20-mer PS. Interestingly, ODN stability was unaffected by exposure to an equivalent heat-alone application (pH 1 at 44°C) thus indicating that the mechanical, rather than heating, effects of ultrasound are responsible for the observed ODN degradation.     

Formulation parameters of albendazole solution

The solubility of albendazole, a poorly water-soluble drug was evaluated. The effect of cosolvents and pH on the aqueous solubility of albendazole are described here. Albendazole aqueous solubility was tested over the pH range of 1.2–7.5. Albendazole solubility was lower for the highest pH values. The solubility coefficient obtained was 0.376 mg/ml in a 1.2 pH buffer solution. Transcutol was the cosolvent with which the increase of the solubility was highest. Albendazole solubility at different percentages of transcutol presented a sigmoid kinetic with an initial acceleration phase. This kinetic shows an exponential correlation for transcutol values smaller than 80%). The exponent value (n) was higher as the pH of the solution was increased. This high value of the exponent (n) is due to a stronger influence of the transcutol on the solubility of albendazole at elevated pH values. The albendazole solution containing 40% w/w of transcutol in a pH 1.2 buffer solution was selected because of its high solubility (2.226 mg/ml). Analysis of the stability data of this albendazole solution showed good correlation (r = 0.9831) when the data were fitted to a first order equation. This albendazole solution showed good stability, with less than 10%, degradation occurring after 30 days of storage at 4°C.     

The influence of carbohydrates and polyhydric alcohols on the stability of cephalosporins in aqueous solution

The kinetics of the degradation of cephaloridine, cephalothin and cefazolin in aqueous solutions containing various carbohydrates (glucose, fructose, sucrose and dextrans) or polyhydric alcohols (sorbitol, mannitol and glycerol) was studied over the pH range 5–12 at 35°C. The degradation rate increased linearly with the hydroxy compound concentration up to 15% at constant pH for pH > 6.5. The rate-accelerating effect of the compounds was directly proportional to the hydroxide ion activity up to pH about 11 above which value the rate of reactions levelled off with increasing pH as demonstrated for glucose. Maximal stability of the cephalosporins in solutions containing carbohydrates or polyhydric alcohols is attained at pH 5–6.5. It is proposed that the rate-accelerating effect of the hydroxy compounds is due to a nucleophilic reaction mechanism involving opening of the cephalosporin β-lactam moiety by an alkoxide ion derived from proton ionization of one of the hydroxyl groups in the compounds.     

Characterization and comparison of leuprolide degradation profiles in water and dimethyl sulfoxide

Abstract: The effect of solvent on the rate of leuprolide degradation and on the structure of the degradation products was explored. Leuprolide solutions (370 mg/mL) were prepared in water and dimethyl sulfoxide (DMSO) for delivery in DUROS^TM osmotic implants. Both solvent systems demonstrated better than 90% stability after 1 year at 37°C, where the DMSO formulation afforded better stability than the aqueous formulation and was used in subsequent clinical trials. The rate of leuprolide degradation in DMSO was also observed to accelerate with increasing moisture content, indicating that the aprotic solvent minimized chemical degradation. Interestingly, leuprolide degradation products varied with formulation vehicle. The proportions of leuprolide degradation products observed to form in water and DMSO at 37°C were hydrolysis > aggregation > isomerization > oxidation and aggregation > oxidation > hydrolysis > isomerization, respectively. Specifically, more N-terminal hydrolysis and acetylation were observed under aqueous conditions, and increased Trp oxidation and Ser β-elimination were seen under non-aqueous conditions. Furthermore, the major chemical degradation pathway changed with temperature in the DMSO formulation (decreasing oxidation with increasing temperature), but not in the aqueous formulation.     

Preformulation studies to aid in the development of a ready-to-use injectable solution of the antitumor agent,topotecan

Topotecan ((S)-9-dimethylaminomethyl-10-hydroxycamptothecin hydrochloride; SKF-S-104864-A) is a promising anticancer agent that is currently available as a lyophilized formulation. To evaluate the feasibility of formulating topotecan as a ready-to-use injectable solution, the pH-solubility profile was generated over a pH range of 2.5 to 4.5 at 25°C, and the pH-stability profile was generated over a pH range of 2 to 4, a temperature range of 60–80°C, and at an ionic strength of ∼ 0.15 M. The former experiments revealed that desirable solubilities (i.e. 2.5 mg/ml in free base equivalents) are achievable at pH < 4, whereas extrapolation of the degradation kinetics to 25°C indicated that desirable stabilities (i.e. ≤ 2% degradation of topotecan over 2 years) are achievable at pH < 3. The stability results are consistent with a degradation mechanism involving deamination of topotecan proceeding through a reactive quinone methide intermediate. Subsequent attack of water on this intermediate gives the dihydroxylated product, 9-hydroxymethyl-10-hydroxycamptothecin, which may then lose formaldehyde to form the monohydroxylated product, 10-hydroxycamptothecin. The overall study results suggest that a solution pH of <- 2.5 is most appropriate for the formulation of a ready-to-use solution. Prototype formulations meeting these criteria have been placed on long-term stability.     

Degradation kinetics of L-alanyl-L-glutamine and its derivatives in aqueous solution

The degradation kinetics of five glutamine dipeptides in aqueous solution, i.e. glycyl-L-glutamine (Gly-Gln), L-alanyl-L-glutamine (Ala-Gln), L-valyl-L-glutamine (Val-Gln), L-leucyl-L-glutamine (Leu-Gln) and L-isoleucyl-L-glutamine (Ile-Gln), were studied. Stability tests were performed using a stability-indicating high-performance liquid chromatographic assay. Two different Ala-Gln degradation routes, i.e. the cleavage of a peptide bond and the deamination of an amide group, were observed. The degradation was adequately described by pseudo-first-order kinetics. The maximum stability of Ala-Gln was obtained at an approximate pH of 6.0. The pH–rate profile described by specific acid–base catalysis and hydrolysis by water molecules agreed with the experimental results. The activation energy of Ala-Gln at pH 6.0 was determined to be 27.1 kcal mol⁻¹, and the shelf-life (90% remaining) at 25 and 40°C was predicted to be 5.3 years and 7.1 months, respectively. The rate constants of the glutamine dipeptides were influenced by the N-terminal amino acid residue and decreased in the order: Gly-Gln, Ala-Gln, Leu-Gln, Val-Gln and Ile-Gln.     

Stability of antineoplaston A10 in aqueous solution

The analysis method and stability test of antineoplaston A10, a new anticancer drug candidate, were established. A10 and phenylacetyl- L-glutamine, one of the degradation products, can be detected by high-performance liquid chromatography. The degradation kinetics of antineoplaston A10 in aqueous solutions from pH 1 to 10 buffers were carried out at 40, 50 and 60°C. Pseudo-first order kinetics were obtained throughout the entire pH ranges studied. The pH-rate profiles showed that antineoplaston A10 was very unstable in alkaline conditions and most stable at pH4.     

Stability of Luteinizing Hormone Releasing Hormone: Effects of pH,Temperature, Pig Skin,and Enzyme Inhibitors

The purpose of this investigation was to determine the stability of luteinizing hormone releasing hormone (LHRH) as a function of solution pH, temperature, and pig skin with and without enzyme inhibitors. LHRH, incubated with a 0.1 M phosphate buffer (pH 2.5–8.1), pig skin, and pig skin with enzyme inhibitors, was analyzed using reversed-phase high performance liquid chromatography. The solution's pH affected the rate constants of LHRH, following apparent first-order kinetics. Maximum stability was achieved at pH 6.05. Therefore, the effect of various temperatures (i.e., 65, 75, 80, and 90°C) was studied on the stability of LHRH at pH 6.05. The activation energy for the overall reaction was 23.4 kcal/mol at pH 6.05. The shelf-life of LHRH at 25°C and pH 6.05, calculated using the Arrhenius equation, was approximately 4 years. The rate constant of LHRH in the skin (area: 9 cm²; thickness: 0.5 mm) was 0.167 hr^?1. Out of three inhibitors (i.e., aprotinin, bestatin, and leupeptin), bestatin had the best stabilizing effect on the degradation of LHRH by the skin. The rate constant of LHRH in the presence of bestatin was 0.082 hr^?1. Sixty percent of LHRH was found to be degraded in the skin within 5 hr in the absence of enzyme inhibitors, whereas only 33% of LHRH was degraded in the presence of bestatin (an aminopeptidase inhibitor).     

Preparation method and stability of ellagic acid-rich pomegranate fruit peel extract

A simple one-step purification using liquid–liquid extraction for preparing pomegranate peel extract rich in ellagic acid has been demonstrated. The method involved partitioning of the 10% v/v water in methanol extract of pomegranate peel between ethyl acetate and 2% aqueous acetic acid. This method was capable of increasing the ellagic acid content of the extract from 7.06% to 13.63% w/w. Moreover, the antioxidant activity of the extract evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay was also increased (ED₅₀ from 38.21 to 14.91?μg/mL). Stability evaluations of the ellagic acid-rich pomegranate peel extract in several conditions through a period of four months found that the extracts were stable either kept under light or protected from light. The extracts were also stable under 4° ± 2°C, 30° ± 2°C and accelerated conditions at 45°C with 75% relative humidity. However, study on the effect of pH on stability of the extract in the form of solution revealed that the extract was not stable in all tested pH (5.5, 7 and 8). These results indicated that the ellagic acid-rich pomegranate peel extract was stable when it was kept as dried powder, but it was not stable in any aqueous solution.     

The Effects of pH and PEG 400–Water Cosolvents on Oxytetracycline–Magnesium Complex Formation and Stability

The effects of pH and PEG 400 on the stoichiometry, conformation, and stability of the magnesium–oxytetracycline (Mg⁺²–OTC) complex were evaluated. Circular dichroism (CD) and HPLC were used to investigate Mg⁺²–OTC complex formation and determine the stability of the complexes formed. The stoichiometry of the complex was determined to be a 1:1 molar ratio of Mg⁺² to OTC regardless of changes in pH, in the range 7–10, and regardless of the percentage of polyethylene glycol (PEG) 400 in solution. CD showed that the conformation assumed by Mg⁺²–OTC complex is sensitive to changes in pH, however, little to no effect was found when the PEG 400 concentration was varied. PEG 400 was found to effect the magnitude of complexation as evident by the dependence of CD peak intensity on the cosolvent concentration in solution. The Job's method confirmed that the formation of this complex increased with increasing PEG 400 concentration and was most favored at pH 8. HPLC analyses of OTC solutions at pH 9 revealed the formation of multiple degradation products after storage at 50°C. The incidence and magnitude of OTC degradation products were reduced in the presence of Mg⁺² and PEG 400. Despite the HPLC results of maintained OTC stability in magnesium-complexed solutions over time, visual inspection showed these solutions to have darkened, indicating that an oxidative process is responsible for initial degradation of OTC. Therefore, the need for additional measures (i.e., antioxidants) was established to ensure the long-term stability of OTC in solution.