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.     

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.     

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.     

Influence of pH, temperature and buffers on cefepime degradation kinetics and stability predictions in aqueous solutions

First-order rate constants (k) were determined for cefepime degradation at 45, 55, 65, and 75 degrees C, pH 0.5 to 8.6, using an HPLC assay. Each pH-rate profile exhibited an inflection between pH 1 and 2. The pH-rate expression was k(pH) = kH1 f1(aH+) + kH2 f2(aH+) + ks + kOH(aOH-), where kH1 and kH2 are the catalytic constants (M(-1) h(-1)) for hydrogen ion activity (aH+), kOH is the catalytic constant for hydroxyl ion activity (aOH-), and ks is the first-order rate constant (h(-1)) for spontaneous degradation. The protonated (f1) and unprotonated (f2) fractions were calculated from the dissociation constant, Ka = (8.32x10(-6))e(5295)/RT where T was absolute temperature (T). Accelerated loss due to formate, acetate, phosphate, and borate buffer catalysis was quantitatively described with the catalytic constant, kGA (M(-1) h(-1)) for the acidic component, [GA], and kGB (M(-1) h(-1) for the basic component, [GB], of each buffer. The temperature dependency for each rate constant was defined with experimentally determined values for A and E and the Arrhenius expression, kT = Ae-E/RT, where kT represented kH1, kH2 , kS, kOH, kGA, or kGB. Degradation rate constants were calculated for all experimental pH, temperature, and buffer conditions by combining the contributions from pH and buffer effects to yield, k = k(pH) + kGA[GA] + kGB[GB]. The calculated k values had <10% error for 103 of the 106 experimentally determined values. Maximum stability was observed in the pH-independent region, 4 to 6. Degradation rate constants were predicted and experimentally verified for cefepime solutions stored at 30 degrees C, pH 4.6 and 5.6. These solutions maintained 90% of their initial concentration (T90) for approximately 2 days.     

Kinetics and mechanism of the hydrolytic degradation of indinavir: intramolecular catalysis

The pH-rate profile of first-order rate constants for the lactonization of Indinavir in aqueous solutions with ionic strength I = 1 (KCl) at 40 degrees C is reported. The lactonization reaction is a subject of strong buffer catalysis with a nonlinear dependence of the first-order rate constants on the concentration of the buffer. The pH-rate profile is more complex than the pH-rate profiles for the hydrolysis of simple peptides and for the intramolecular OH-catalyzed hydrolysis of gamma-hydroxyamides. This complexity appears unique to Indinavir and is a result of the cis-aminoindanol leaving group. The mechanistic pathways for the lactonization are discussed. The buffer catalysis data are consistent with kinetic general acid catalysis. The second-order rate constant for the specific-acid catalyzed hydrolysis of Indinavir at 40 degrees C (k(H) = 2.2 x 10(-4) M(-1) min(-1)) is similar to that for a simple peptide indicating similar interactions in the rate limiting transition state for both reactions.     

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.     

Stability of cefazolin sodium in various artificial tear solutions and aqueous vehicles

The stability of cefazolin sodium reconstituted in four artificial tear solutions, two acetate buffer solutions, phosphate buffer solution, and 0.9% sodium chloride injection was studied. Cefazolin was reconstituted in Tearisol, Isopto Tears, Liquifilm Forte, and Liquifilm Tears; acetate buffer solution at pH 4.5 and pH 5.7; phosphate buffer solution at pH 7.5; and 0.9% sodium chloride injection. The solutions were stored at 4 degrees C, 25 degrees C, and 35 degrees C for seven days. All of the solutions were inspected for particulates, turbidity, color, and odor. Five assay determinations on each of three samples of each formulation were performed using a stability-indicating high-performance liquid chromatographic assay. Cefazolin stability was influenced primarily by pH and storage temperature. Reconstitution of cefazolin sodium in the alkaline tear solutions Isopto Tears and Tearisol and in phosphate buffer solution resulted in particulate and color formation at 25 degrees C and 35 degrees C. Turbidity was noted after cefazolin sodium was reconstituted in Isopto Tears. No color or precipitate formation was evident after seven days at 25 degrees C and 35 degrees C in the formulations of acidic pH containing Liquifilm Tears, Liquifilm Forte, 0.9% sodium chloride injection or acetate buffer solution as the vehicles. The extent of degradation of cefazolin was substantially higher in the formulations of alkaline pH than in those of acidic pH at 35 degrees C and 25 degrees C. All of the formulations retained more than 90% of their initial concentration when stored at 4 degrees C. Cefazolin sodium, when reconstituted in artificial tear solutions with an acidic pH, is stable for up to three days at room temperature.     

Kinetics of talampicillin decomposition in solutions

Talampicillin stability in aqueous solutions was studied in a broad range of pH values using as medium solutions of hydrochloric acid (pH 0.4-1.8), phosphate buffers (pH 2.05-3.13 and 6.03-8.04), acetate buffer (pH 3.87-5.28) and borate buffer (pH 8.90-9.10) as well as sodium hydroxide solution (pH 11.48). For the determination of talampicillin concentration changes in kinetic studies, two methods were used: iodometric and spectrophotometric in UV (lambda(max) = 254.5 nm). The catalytic velocity constants (k(H+), k(x), k(o)) were established, the log k-pH profile (35 degrees C) was found, thermodynamic parameters were calculated of the hydrolysis reaction of the beta-lactam bond (k(H+): E(A)= 67.9 kJ mol(-1), delta S = -92.4 J K(-1) mol(-1), delta G = 92.6 kJ mol(-1); k(x): E(A) = 31.8 kJ mol(-1), delta S = -347.1 J K(-1) mol(-1), delta G = 131.1 kJ mol(-1); k(o), pH = 5.28: E(A) = 98.0 kJ mol(-1), delta S = -50.3 J K(-1) mol(-1), delta G = 110.3 kJ mol(-1) at 20 degrees C), and the stability of the lactone bond was studied in the medium with the highest stability of beta-lactam bond of talampicillin (pH 5.28: k(o): E(A)= 32.5 kJ mol(-1), delta S = -220.5 J K(-1) mol(-1), delta G = 94.7 kJ mol(-1) in 20 degrees C), at controlled ionic strength (mu = 0.5 mol l(-1)).     

Hydrolysis of nicotinyl 6-aminonicotinate

The degradation kinetics of nicotinyl 6-aminonicotinate in aqueous buffer solutions were studied over the pH range from 4.0 to 10.0. In all cases, pseudo-first-order kinetics were observed at constant hydronium ion concentration. The pH-rate profile indicated that the hydrolysis of nicotinyl 6-aminonicotinate may be described by at least two catalytic terms. In alkaline solution the hydrolysis is catalyzed primarily by hydroxyl ions. In acidic solution the hydrolysis may be attributed to either the water-catalyzed reaction of the protonated species or the hydronium ion catalyzed reaction of the free base. The resulting catalytic profile afforded a sharp pH minimum of approximately 5.90 at 65 degrees C. An activation energy of 16 Kcal/mol was obtained in a phosphate buffer solution at a pH of approximately 5.90 +/- 0.2. The first- and second-order reaction constants for water and hydroxyl ion catalysis were determined, and the temperature dependency of the reaction was studied. The buffer effect and solvent effect on the hydronium and hydroxyl ion catalysis was also investigated.     

A mechanistic and kinetic study of the beta-lactone hydrolysis of Salinosporamide A (NPI-0052), a novel proteasome inhibitor

The aim of the present study was to investigate the mechanism of aqueous degradation of Salinosporamide A (NPI-0052; 1), a potent proteasome inhibitor that is currently in Phase I clinical trials for the treatment of cancer and is characterized by a unique beta-lactone-gamma-lactam bicyclic ring structure. The degradation of 1 was monitored by HPLC and by both low- and high-resolution mass spectral analyses. Apparent first-order rate constants for the degradation at 25 degrees C were determined in aqueous buffer solutions (ionic strength 0.15 M adjusted with NaCl) at various pH values in the range of 1 to 9. Degradation kinetics in water and in deuterium oxide were compared as a mechanistic probe. The studies were performed at pH (pD) 4.5 at 25 degrees C. To further confirm the reaction mechanism, the degradation was also performed in (18)O-enriched water and the degradation products subjected to HPLC separation prior to mass spectral analysis. Solubility and stability in (SBE)(7m)-beta-cyclodextrin (Captisol) solutions were also determined. The hydrolytic degradation of 1, followed by both HPLC and LC/MS, showed that the drug in aqueous solutions gives a species with a molecular ion consistent with the beta-lactone hydrolysis product (NPI-2054; 2). This initial degradant further rearranges to a cyclic ether (NPI-2055; 3) via an intramolecular nucleophilic displacement reaction. The kinetic results showed that the degradation of 1 was moderately buffer catalyzed (general base) and the rate constants were pH independent in the range of 1-5 and base dependent above pH 6.5. No acid catalysis was observed. The kinetic deuterium solvent isotope effect (KSIE) was 3.1 (kH/kD) and a linear proton inventory plot showed that the rate-determining step involved only a single proton transfer. This suggested that a neighboring hydroxyl group (as opposed to a second water molecule) facilitated water attack at pD 4.5. Mass spectral analysis from the (18)O-labeling studies proved that the mechanism involves acyl-oxygen bond cleavage and not a carbonium ion mechanism. 1 is unstable in water (t(90%) 相似文献   

Kinetics and mechanism of degradation of cefotaxime sodium in aqueous solution

The degradation kinetics and mechanism of a potent new cephalosporin, cefotaxime sodium, in aqueous solution were investigated at pH 0-10 at 25 degrees and an ionic strength of 0.5. The degradation rates were determined by high-pressure liquid chromatography and were observed to follow pseudo first-order kinetics with respect to cefotaxime sodium concentration. The data suggested that the rate of degradation was influenced significantly by solvolytic, hydrogen ion, and hydroxide ion catalysis. No primary salt effects were observed in the acid or neutral regions; however, a positive salt effect was observed at pH 8.94. Buffer catalysis due to the buffer species employed was not seen during the kinetic studies. The pH-rate profile at 25 degrees indicated that the maximum stability of cefotaxime sodium occurred in the pH 4.5-6.5 region. In aqueous solution, cefotaxime was shown to degrade by two parallel reactions: de-esterification at the C-3 position and beta-lactam cleavage. Good agreement between the theoretical pH-rate profile and the experimental data support the proposed degradation process.     

Stability of aqueous solutions of mibolerone.

The kinetics and mechanism of degradation of mibolerone were studied in aqueous buffered solutions in the pH range of 1-8 at 67.5 degrees. Mibolerone showed maximum stability between pH 5.5 and 6.4. At pH 1-2, the major degradative pathway was dehydration followed by migration of the 18-methyl group to form 7alpha,17,17-trimethylgona-4,13-dien-3-one. While there was only one degradation product at pH 1-2, the degradation at pH 7-8 was complex. As many as 12 degradation products were detected by GLC. Mass spectral data indicated that the majority of these products were either oxidation products or isomers. At pH 7.6, the apparent first-order rate constants exhibited marked dependency on buffer concentration. Incorporation of a sequestering agent into the solutions eliminated this dependency, suggesting that trace metal impurities from the buffer reagents were catalyzing the degradation. This was confirmed by degradation studies of solutions in water for injection containing 5 ppm of trace metal ions. Sn+2, Cu"2, and Fe+2 accelerated the degradation, with Fe+2 having the most catalytic effect. The temperature dependence of the rate of degradation was studied in 0.05 M phosphate buffer at pH 6.4. The activation energy was 19.6 +/- 1.63 kcal/mole.     

Nefopam hydrochloride degradation kinetics in solution

A stability-indicating reversed-phase high performance liquid chromatographic method was developed for the detection of nefopam hydrochloride and its degradation products under accelerated degradation conditions. The degradation kinetics of nefopam hydrochloride in aqueous solutions over a pH range of 1.18 to 9.94 at 90 +/- 0.2 degrees C was studied. The degradation of nefopam hydrochloride was found to follow apparent first-order kinetics. The pH-rate profile shows that maximum stability of nefopam hydrochloride was obtained at pH 5.2-5.4. No general acid or base catalysis from acetate, phosphate, or borate buffer species was observed. The catalytic rate constants on the protonated nefopam imposed by hydrogen ion and water was determined to be 7.16 X 10(-6) M-1 sec-1, and 4.54 X 10(-9) sec-1, respectively. The pKa of nefopam hydrochloride in aqueous solution was determined to be 8.98 +/- 0.33 (n = 3) at 25 +/- 0.2 degrees C by the spectrophotometric method. The catalytic rate constant of hydroxyl ion on the degradation of nefopam in either protonated or nonprotonated form was determined to be 6.63 X 10(-6) M-1 sec-1 and 4.06 X 10(-6) M-1 sec-1, respectively. A smaller effect of hydroxyl ion on the degradation of nonprotonated than on the degradation of protonated nefopam was observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Aporphines. 50. Kinetics of solvolysis of N-(2-chloroethyl)norapomorphine, an irreversible dopamine receptor antagonist

The rates and mechanism of solvolysis of (-)-N-(2-chloroethyl)norapomorphine (NCA, 1c) in aqueous solution have been examined by reversed-phase liquid chromatography (HPLC) to follow the levels of starting material and products. The first-order rate constants for aziridinium ion formation at 25 and 37 degrees C at pH 7.0 are 0.024 and 0.096 min-1, respectively. Determination of the first-order rate constant for the disappearance of NCA as a function of pH has allowed the calculation of an approximate pKa of 6.3 for the tertiary amine, while the influence of reaction conditions (e.g., pH, buffer salt and concentration, and added nucleophiles) on product distribution support the view that NCA solvolysis proceeds through an intermediate aziridinium ion. Application of the HPLC procedure allowed us to observe simultaneously the loss of NCA and the appearance of an intermediate and multiple products at trace levels; it also permitted the facile isolation and subsequent identification of small amounts of hydrolysis products. At pH 7, maximum aziridinium concentration is reached only after 10 min at 37 degrees C and at 25 degrees C after 1 h. Increased temperatures and pH facilitate the rate of aziridinium ion formation, as well as of non-dopamine antagonist solvolysis products. The significance of these findings, including the ease with which buffer ions add to the intermediate ion, are discussed in relation to the use of NCA and its tritiated isomer, [3H]NCA, in dopamine receptor studies.     

Mechanistic investigation of the degradation of sulfamic acid 1,7-heptanediyl ester, an experimental cytotoxic agent, in water and 18oxygen-enriched water

The hydrolytic degradation of sulfamic acid 1,7-heptanediyl ester was carried out in water and 18O-enriched water at 47 degrees C. The degradation of 1 was also studied at various pH values in the range of 2.5 to 8.0 at constant ionic strength (0.15 M) and temperature (25 degrees C). The hydrolysis was first order and independent of pH with a mean (+/- SD) observed rate constant (kobs) of 2.38 +/- 0.6 X 10(-3) h-1. No significant buffer catalysis was observed. From TLC, HPLC, and mass spectral studies, 1 initially degraded to sulfamic acid 1,7-heptanemonoyl ester and subsequently to 1,7-heptanediol. The site of bond cleavage was assessed by mass spectrometry of the 18O-enriched water reaction mixtures. Exclusive C--O bond fission was observed. Several mechanistic pathways for the degradation of 1 could be postulated. The results from 18O-labeling studies, the pH-rate profile and buffer studies, and kinetic solvent isotope effect (KSIE) studies were consistent with an SN2 mechanism with an early transition state (reactant-like transition state) where no appreciable bond had developed between the incoming nucleophile, water, and the carbon atom of 1. Although an SN1 mechanism was unlikely, based on the need to postulate the formation of a primary carbocation, this mechanism could not be totally ruled out.     

Macromolecular prodrugs: X. Kinetics of fenoprofen release from PHEA-fenoprofen conjugate

The kinetics of fenoprofen release from poly[alpha,beta-(N-2-hydroxyethyl-DL-aspartamide)]-fenoprofen conjugate (PHEA-Fen) in aqueous buffer solutions (pH 10 and 1.1), simulated gastric (SGF) and intestinal fluids (SIF) was studied. In borate buffer pH 10, the following rate constants were obtained: k=0.2659 (t=60 degrees C) and k=0.0177 h(-1) (t=37 degrees C) and in glycine buffer solution pH 1.1 k=0.0036 h(-1). In SGF and SIF fenoprofen release did not occur in significant extend within 12 h. The hydrolysis of the ester bond between the polymeric carrier and fenoprofen followed the pseudo first-order kinetics, with activation energy indicative for the breakage of a sigma bond (E(a)=100.6 kJ mol(-1)). The concentration of the released fenoprofen was determined by high performance liquid chromatography (HPLC).     

Kinetics of degradation in aqueous solution of Abbott-79175, a potent second generation 5-lipoxygenase inhibitor

The degradation kinetics of Abbott-79175 in aqueous solution have been studied as a function of pH. Concentration/time plots indicated a pseudo-first order nature of reactions throughout the pH range studied. Additionally, the effects of temperature, ionic strength, and buffer concentration have been examined. From multiple temperature experiments, Arrhenius and activation parameters were calculated. Furthermore, it was determined that upon ionization, Abbott-79175 degradation proceeded independently of ionic strength. These data in addition to the plateau-like nature of the pH-rate constant profile above pH 10 suggest a lack of participation of hydroxide ion during the reaction. This behavior in the neutral and alkaline regions was qualitatively very similar to that of zileuton, a 5-lipoxygenase inhibitor in phase III clinical trials. In addition to allowing the determination of the buffer independent rate constants, kinetic studies as a function of buffer concentration allowed in some of the systems the deduction of which buffer species were catalytic. A multi-parameter model was fitted to the pH buffer independent rate constant data using non-linear regression. This modeling yielded parameters such as the microscopic rate constants and the pK_a under the aforementioned conditions. From the pH-rate constant profile, Abbott-79175 was found to be more labile than zileuton throughout the pH range studied. This difference was greater than three orders of magnitude at pH 1. Such acid lability produced a pH profile which had a much narrower region of maximum stability.     

Solution stability of ciclosidomine

The stability of N-cyclohexanecarbonyl-3-(4-morpholino)-sydnone imine hydrochloride (ciclosidomine) in solution was studied as a function of pH, temperature, ionic strength, and buffer species. The rate of hydrolysis in the absence of light was found to be apparent first order in drug and general acid- and base-catalyzed reactions. The pH rate profile at an ionic strength of 0.1 M at 60 degrees C had a minimum value near pH 6. Change in ionic strength in the range of 0.05 to 0.2 M did not affect the rate of degradation at pH 7 (carbonate buffer) or pH 2 (phosphate buffer) at 60 degrees C. Similar degradation rates were noticed in air or nitrogen in the dark at pH 3, 5, and 6. However, degradation in light was very rapid in either case at pH 3, 5, and 6, and, therefore, the protection of solutions from light was required during all studies. The time for 10% loss of drug in solution at pH 6 in dilute phosphate or citrate buffer at an ionic strength of 0.154 M was projected to be 9 months at 20 degrees C and 2.6 months at 30 degrees C.     

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).