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.     

Degradation kinetics of phentolamine hydrochloride in solution

The degradation kinetics of phentolamine hydrochloride in aqueous solution over a pH range of 1.2 to 7.2 and its stability in propylene glycol- or polyethylene glycol 400-based solutions were investigated. The observed rate constants were shown to follow apparent first-order kinetics in all cases. The pKa determination for phentolamine hydrochloride was found to be 9.55 +/- 0.10 (n = 5) at 25 +/- 0.2 degrees C. This indicated the protonated form of phentolamine occurs in the pH range of this study. The pH-rate profile indicated a pH-independent region (pH 3.1-4.9) exists with a minimum rate around pH 2.1. The catalytic effect of acetate and phosphate buffer species is ordinary. The catalytic rate constants imposed by acetic acid, acetate ion, dihydrogen phosphate ion, and monohydrogen phosphate ion were determined to be 0.018, 0.362, 0.036, and 1.470 L mol-1 h-1, respectively. The salt effect in acetate and phosphate buffers followed the modified Debye-Huckel equation quite well. The ZAZB value obtained from the experiment closely predicts the charges of the reacting species. The apparent energy of activation was determined to be 19.72 kcal/mol for degradation of phentolamine hydrochloride in pH 3.1, 0.1 M acetate buffer solution at constant ionic strength (mu = 0.5). Irradiation with 254 nm UV light at 25 +/- 0.2 degrees C showed a ninefold increase in the degradation rate compared with the light-protected control. Propylene glycol had little or no effect on the degradation of phentolamine hydrochloride at 90 +/- 0.2 degrees C; however, polyethylene glycol 400 had a definite effect.     

Stability of the new antileukemic 4-pyranone derivative, BTMP, using HPLC and LC-MS analyses

The stability of the new antileukemic kojic acid derivative, 5-benzyloxy-2-thiocyanatomethyl-4-pyranone (BTMP) was investigated. The degradation of BTMP was studied using specific and reproducible HPLC and LC-MS methods. Accelerated stability studies of BTMP were conducted in 0.1 M hydrochloric acid solution, physiological phosphate buffer solution (pH 7.5) and basic phosphate buffer solution (pH 9.0) at 30, 40 and 60 degrees C, respectively. The degradation of BTMP was found to follow pseudo-first order kinetics. In basic solution (pH 9.0) BTMP underwent rapid hydrolysis at a degradation rate constant (0.183-0.638 h-1) and degradation half-life (3.67-1.06 h) depending on the temperature setting. On the other hand, BTMP was significantly stable in 0.1 M hydrochloric acid solution (kdeg: 0.0017-0.0052 h-1; degradation half-life t1/2: 408.6-135.7 h), whereas in physiological phosphate buffer solution (pH 7.5), BTMP was only moderately stable (kdeg: 0.006-0.231 h-1; degradation half-life: 117.7-3.0 h). Arrhenius plots were constructed to predict the degradation kinetic parameters of BTMP at 25 degrees C and 4 degrees C. LC-MS analyses confirmed the degradation of BTMP in basic solutions and indicated at least two degradation products; namely 5-benzyloxypyran-2-ol-4-one (m/z 217.8) and 2-thiocyanatomethylpyran-5-ol-4-one (m/z 181.6).     

Effects of alkali and simulated gastric and intestinal fluids on danazol stability

The degradation kinetics of methanolic solution of danazol (0.020% w/v) in aqueous buffers and sodium hydroxide was investigated using stability-indicating HPLC method. The drug degrades in alkaline medium through a base-catalysed proton abstraction rather than via an oxidative mechanism involving oxygen species. The degradation followed pseudo-first-order kinetics. The rates pH-profile exhibited specific base catalysis. The stability of the drug was found to be dependent on pH, buffer concentration, buffer species (acetate, borate, phosphate) and temperature. The ionic strength did not affect the stability of the drug. The energy of activation according to Arrhenius plot was estimated to be 22.62 kcal mol(-1) at pH 12 and temperatures between 30 and 60 degrees C. The effect of simulated gastric and intestinal fluids on the drug stability was also investigated. Two major hydrolytic degradation products were separated and identified by IR, NMR and mass spectrometry and the degradative pathway suggested.     

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 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.     

Influence of pH and temperature on kinetics of ceftiofur degradation in aqueous solutions.

The objective of this study was to evaluate the stability of ceftiofur (1 mg mL(-1)) in aqueous solutions at various pH (1, 3, 5, 7.4 and 10) and temperature (0, 8, 25, 37 and 60 degrees C) conditions. The ionic strength of all these solutions was maintained at 0.5 M. Ceftiofur solutions at pH 5 and 7.4 and in distilled water (pH = 6.8) were tested at all the above temperatures. All other solutions were tested at 60 degrees C. Over a period of 84 h, the stability was evaluated by quantifying ceftiofur and its degradation product, desfuroylceftiofur, in the incubation solutions. HPLC was used to analyse these compounds. At 60 degrees C, the rate of degradation was significantly higher at pH 7.4 compared with pH 1, 3, 5 and distilled water. At both 60 degrees C and 25 degrees C, degradation in pH 10 buffer was rapid, with no detectable ceftiofur levels present at the end of 10 min incubation. Degradation rate constants of ceftiofur were 0.79+/-0.21, 0.61+/-0.03, 0.44+/-0.05, 1.27+/-0.04 and 0.39+/-0.01 day(-1) at pH 1, 3, 5, 74 and in distilled water, respectively. Formation of desfuroylceftiofur was the highest (65%) at pH 10. The rate of degradation increased in all aqueous solutions with an increase in the incubation temperature. At pH 7.4 the degradation rate constants were 0.06+/-0.01, 0.06+/-0.01, 0.65+/-0.17, and 1.27+/-0.05 day(-1) at 0, 8, 25, 37 and 67 degrees C, respectively. The energy of activation for ceftiofur degradation was 25, 42 and 28 kcal mol(-1) at pH 5, 7.4 and in distilled water, respectively. Desfurylceftiofur formation was the greatest at alkaline pH compared with acidic pH. Ceftiofur degradation accelerated the most at pH 7.4 and was most rapid at pH 10. The results of this study are consistent with rapid clearance of ceftiofur at physiological pH.     

The effect of drug concentration on the thermal (dark) degradation of promethazin hydrochloride in aqueous solution.

The thermal (dark) degradation of promethazine hydrochloride in aqueous solution presents a complex kinetic picture. The process is oxygen dependent and is modified by EDTA. In citrate buffer, pH 4.0, ionic strength 0.5M, containing 0.1% EDTA, the thermal degradation at 90 degrees can be fitted to first order rate plots at drug concentrations up to 1.56 x 10.27 (0.5%) and to zero order rate plots at drug concentrations greater than 9.35 x 10.2M (3.0%). At intermediate concentrations no simple equation can describe the data. These effects have been correlated with the formation of drug micelles and the rate date have been interpreted on the basis of a first order monomer process and a half order micellar process occurring simultaneously.     

Study of forced degradation behavior of enalapril maleate by LC and LC-MS and development of a validated stability-indicating assay method

In the present study, comprehensive stress testing of enalapril maleate was carried out according to ICH guideline Q1A(R2). The drug was subjected to acid (0.1N HCl), neutral and alkaline (0.1N NaOH) hydrolytic conditions at 80 degrees C, as well as to oxidative decomposition at room temperature. Photolysis was carried out in 0.1N HCl, water and 0.1N NaOH at 40 degrees C. Additionally, the solid drug was subjected to 50 degrees C for 60 days in a dri-bath, and to the combined effect of temperature and humidity, with and without light, at 40 degrees C/75% RH. The products formed under different stress conditions were investigated by LC and LC-MS. The LC method that could separate all degradation products formed under various stress conditions involved a C18 column and a mobile phase comprising of ACN and phosphate buffer (pH 3). The flow rate and detection wavelength were 1 ml min(-1) and 210 nm, respectively. The developed method was found to be precise, accurate, specific and selective. It was suitably modified for LC-MS studies by replacing phosphate buffer with water, where pH was adjusted to 3.0 with formic acid. The drug showed instability in solution state (under acidic, neutral, alkaline and photolytic stress conditions), but was relatively stable in the solid-state, except formation of minor products under accelerated conditions. Primarily, maximum degradation products were formed in acid conditions, though the same were also produced variably under other stress conditions. The LC-MS m/z values and fragmentation patterns of two of the five products matched with enalaprilat and diketopiperazine derivative, previously known degradation products of enalapril. Also, m/z value of another product matched with an impurity listed in the drug monograph in European Pharmacopoeia. Rest two were hitherto unknown degradation products. The products were characterized through LC-MS fragmentation studies. Based on the results, a more complete degradation pathway for the drug could be proposed.     

Kinetics of degradation of cefazolin and cephalexin in aqueous solution.

The kinetics of degradation of cefazolin and cephalexin in aqueous solution were investigated at 60 degrees C and constant ionic strength over the entire pH range. The observed degradation rates were obtained by measuring the residual cephalosporin and were shown to follow pseudo-first-order-kinetics. They were influenced significantly by solvolytic and hydroxide ion catalysis. No primary salt effect was observed in the acid or basic pH region. Of the buffer systems employed in the kinetics studies only the phosphate buffer system showed a catalytic effect. The pH-rate profile for cefazolin showed a degradation minimum between pH 5.5 and 6.5. Cephalexin did not show a pH minimum in that region. The apparent energies of activation were determined for cefazolin and cephalexin at pH 5.5 and were calculated to be 24.3 Kcal/mole and 26.2 Kcal/mole, respectively. The agreement between the calculated theoretical pH-rate profiles and the experimental points for both compounds support the hypothesis presented concerning the reactions involved in their respective degradation pathways.     

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.     

Preformulation study of epigallocatechin gallate, a promising antioxidant for topical skin cancer prevention.

Epigallocatechin gallate (EGCG) is a potent polyphenolic antioxidant extracted from green tea. Due to its antimutagenic and antitumor activities, it is a promising candidate for use in topical formulations for skin cancer prevention. The overall goal of this study was therefore to determine the influence of several factors on the stability of EGCG in solution to obtain information that would facilitate the subsequent development of topical formulations. Our first objective was to determine the influence of pH, temperature, and ionic strength on the aqueous stability of EGCG. A second objective was to determine the stability of EGCG in various solvents in the presence and absence of different antioxidants. A simple and rapid stability indicating high-performance liquid chromatography assay for EGCG was developed. Stability studies were performed in 0.05 M aqueous buffers at pH 3, 5, 7, and 9 at 4, 25, and 50 degrees C. The effect of ionic strength on EGCG stability was evaluated in 0.05 M acetate buffer, pH 5, adjusted to the desired ionic strength with sodium chloride. An accelerated stability study of EGCG was performed at 50 degrees C in the organic solvents glycerin and Transcutol P in the presence of antioxidants. The degradation of EGCG increased rapidly as temperature and solution pH were increased. Ionic strength increases also caused an accelerated degradation. The solution stability of EGCG was prolonged in glycerin and Transcutol P compared with an aqueous environment. The addition of 0.1% concentrations of several antioxidants in combination with 0.025% EDTA caused variable effects on EGCG stability. Butylated hydroxytoluene in glycerin produced the greatest stability improvement for EGCG. The t(90) (time for 10% degradation to occur) was 76.1 days at 50 degrees C. It can be concluded that glycerin-based vehicles are suitable for stabilizing EGCG.     

Intraliposomal chemical activation patterns of liposomal cis-bis-neodecanoato-trans-R,R-1,2-diaminocyclohexane platinum (II) (L-NDDP)-a potential antitumour agent

L-NDDP is a liposome-entrapped platinum compound currently in phase 2 clinical trials that has been shown to undergo intraliposomal activation. The degradation/activation kinetics of liposome entrapped cis-bis-neodecanoato-trans-R,R-1,2-diamminocyclohexane platinum (II) [L-NDDP] at different conditions of pH, and temperature is presented. Liposomes were reconstituted in a solution of 0.9% sodium chloride (NaCl) in water (pH 5) at room temperature (formulation conditions currently used in the ongoing clinical trials). In the temperature experiments, L-NDDP 0.9% sodium chloride liposomes were incubated in a water-bath at 40, 60, and 80 degrees C. In the pH experiments, these solutions were compared to water, phosphate with and without chloride ion present, phosphate buffer without chloride ion at pH 3.1, 5.0, and 7.4, and glycine buffer with and without chloride ion. In 0.9% sodium chloride at room temperature, the chemical degradation/activation of liposome-bound NDDP was biphasic, with most of the degradation (approximately 45% conversion) occurring during the first hour after formation of the liposome suspension. NDDP degradation was pH dependent: when using pH 3 phosphate buffer as a reconstituting solution, liposome-bound NDDP degraded rapidly, whereas in pH 7.4 phosphate buffer it was stable for > 72 h. NDDP degradation was also temperature-dependent, the 50% point decreasing from 12 h at 25 degrees C to 9.5 h at 40 degrees C, 3.8 h at 60 degrees C, and 0.3 h at 80 degrees C when using 0.9% NaCl in water as a reconstituting solution. Using glycine buffer solution with and without NaCl at room temperature, no NDDP degradation over a 72 h period was observed at 25 degrees C; however, at 40 degrees C, only 68% NDDP remained intact at 72 h. Atomic absorption spectrophotometry (AAS) analysis of the eluting fractions after injection of L-NDDP samples reconstituted in chloride-containing and non chloride-containing solutions clearly indicated that the formation of DACH-Pt-Cl2 was only observed when chloride-containing solutions were used and was first detected at 3 h when using 0.9% NaCl in water as a reconstituting solution. These results indicate that pH and temperature, and not the presence of chloride ion, are the main factors leading to the activation of NDDP. Since 45% of NDDP is already degraded at 1 h in the same conditions, it is concluded that (1) the first active intermediates of L-NDDP formed within the liposomes are the DACH-Pt chloro-aquo and diaquo intermediates, and (2) the in vivo, antitumour activity of L-NDDP is most likely mediated by direct intracellular delivery of the active species.     

Kinetics and mechanisms of degradation of the antileukemic agent 5-azacytidine in aqueous solutions.

The hydrolytic degradation of 5-azacytidine was studied spectrophotometrically as a function of pH, temperature, and buffer concentration. Loss of drug followed apparent first-order kinetics in the pH region below 3. At pH less than 1,5-azacytosine and 5-azauracil were detected; at higher pH values, drug was lost to products which were essentially nonchromophoric if examined in acidic solutions. The apparent first-order rate constants associated with formation of 5-azacytosine and 5-azauracil from 5-azacytidine are reported. Above pH 2.6, first-order plots for drug degradation are biphasic. Apparent first-order rate constants and coefficients for the biexponential equation are given as a function of pH and buffer concentration. A reaction mechanism consistent with the data is discussed together with problems associated with defining the stability of the drug in aqueous solutions. At 50 degrees, the drug exhibited maximum stability at pH 6.5 in dilute phosphate buffer. Similar solutions were stored at 30 degrees to estimate their useful shelflife. Within 80 min, 6 times 10(-4) M solutions of 5-azacytidine decreased to 90% of original potency based on assumptions related to the proposed mechanisms.     

Hydrolysis of l-phenylalanine mustard (melphalan). II. Further observations on the effects of pH,chloride ions and buffers on the rate of reaction

The effects of pH (3.7—13), ionic strength, buffer composition (acetate, phosphate and borate) and buffer concentration (15–200 mM) on the rate of degradation of melphalan in the presence 0.3 M chloride at 50 ± 0.1 °C were investigated using high-performance liquid chromatography. In addition, the data published in the literature for the degradation of phosphoramide mustard have been compared with those of melphalan, placing emphasis on mechanisms of hydrolysis and the effects of pH and chloride. In the presence of chloride, the degradation rate of melphalan was influenced by pH and buffer composition but not by ionic strength. These effects were not seen in the absence of added chloride and have been explained in terms of competition between chloride and other nucleophiles such as the hydroxide ion, water and buffer components for the active intermediate of the alkylating agent. These results help to explain differences in reported values for the rates of hydrolysis of various alkylating agents in the presence of chloride.     

Stability studies of topical carbonic anhydrase inhibitor 6-hydroxyethoxy-2-benzothiazole sulfonamide.

A new carbonic anhydrase inhibitor, 6-hydroxyethoxy-2-benzothiazole sulfonamide (6-hydroxyethyoxyzolamide), was studied to determine its stability in aqueous solution from pH 2.9 to 9.2 at a constant ionic strength of 0.15 M. This newly synthesized derivative of ethoxyzolamide has demonstrated clinical efficacy for use as an ophthalmic drug to lower intraocular pressure. Drug solution in sealed ampules was placed in a constant temperature over either at two temperatures (75 and 85 +/- 0.2 degrees C) or four temperatures (75, 80, 85, and 90 +/- 0.2 degrees C). Samples were analyzed by known HPLC methods. The results indicated that 6-hydroxyethoxyzolamide is most stable at pH 4 to 5.5. The aqueous drug solutions at pH 7.0 and 8.0 were, nevertheless, sufficiently stable, based on extrapolation of kinetic data at high temperatures using the experimentally determined Arrhenius equation. The degradation compound was identified by spectral analysis to have a hydroxyl group substituting for the original -SO2NH2 group.     

氨甲喋呤(MTX)多相脂质体化学稳定性的研究

以多相脂质体为载体能增强MTX的化学稳定性。在避光条件下,MTX多相脂质体注射液,25℃时贮存期为4.2年。pH 7的磷酸盐缓冲溶液中的MTX,25℃避光条件下,是以一种新的途径降解。磷酸盐对该反应有特殊的催化作用;而在高温或多相脂质体的存在能防止该反应的发生。     

Stability of ribonuclease A in solution and the freeze-dried state

The solution stability of bovine pancreatic ribonuclease A (RNase) in phosphate buffer (pH 4.0, 6.4, and 10.0) at 45 degrees C decreased with increasing pH. Soluble aggregates were formed at each pH and corresponded qualitatively to the loss of enzymatic activity in the samples. Freeze drying of RNase resulted in no immediate loss of enzymatic activity in both the presence and absence of phosphate buffer salts. Freeze-dried RNase stored at 45 degrees C lost enzymatic activity and formed nondissociable aggregates at rates described by the following rank order of formulation contents: distilled water less than pH 6.4 phosphate buffer, less than pH 4.0 phosphate buffer less than pH 10.0 phosphate buffer. The amount of residual moisture remaining in the freeze-dried cakes was directly related to the rate of enzymatic activity loss and aggregate formation. The degradation rate was also directly related to the concentration of phosphate buffer salts added to the freeze-dried formulation.     

Preformulation study of pelrinone hydrochloride

Pelrinone HCl is essentially nonhygroscopic. The pH-solubility profile exhibits a U-shaped curve, while the octanol-water partition coefficient-pH profile shows a bell-shaped curve. Two ionizable functions, with a pKa1 value of 4.71 and a pKa2 value of 8.94, produce the cationic and anionic forms, respectively. A weak ionic strength effect on solubility of the compound is observed: at pH 3.9 (0.1 M acetate buffer), the solubility increases with increasing ionic strength, while at pH 7.5 (Tris HCl buffer), the solubility decreases with increasing ionic strength. No gross incompatibility of the compound is seen with the 13 excipients selected, except povidone. The solubility phase diagram, X-ray diffraction pattern, and IR spectroscopy demonstrate the presence of polymorphs. The compound in solution is stable at various pH conditions under 500-foot-candle (ft-c) light at room temperature and at 80 degrees C for 64 d. In the solid state, no decomposition is observed at 80 degrees C and on exposure to 500-ft-c light for at least 112 d.     

Preformulation studies of spironolactone: effect of pH, two buffer species, ionic strength, and temperature on stability

Using a stability-indicating HPLC assay method, the effect of pH, two buffer species (citrate and phosphate), ionic strength, and temperature on the stability of spironolactone in 20% solution of ethyl alcohol in water has been studied. The optimum pH of stability appears to be approximately 4.5. On increasing the buffer concentration, both species hastened the decomposition of spironolactone. The ionic strength did not affect the stability of the drug. The energy of activation has been estimated to be approximately 78.8 kJ/mol at pH 4.3. The un-ionized spironolactone is subject to general acid-base catalysis. The Kh and Koh values at 40 degrees C have been estimated to be 1.63 and 2.8 x 10(5) day-1, respectively. The HPO4(-2) ion had approximately 10 times more catalytic effect than the H2PO4(-1) ion. This data will be used to develop a stable oral liquid dosage form of the drug.