Use of DSC to Study the Degradation Behavior of PLA and PLGA Microparticles

Abstract

Poly (D, L-lactide) (PLA) and poly (D, L-lactide-co-glycolide) (PLGA) microparticles were evaluated for their in vitro degradation behavior in 0.1 M phosphate buffer pH 7.4 at 37°C. The influence of polymer characteristics, particle size, and preparation technique was investigated. Differential scanning calorimetry (DSC) was used to follow the time-dependent physical and morphological changes within the hydrated and dried microparticles, to determine the physical state of the absorbed water, and to detect penetration of buffer ions into the particle bulk. Results were compared with degradation kinetics obtained by gel permeation chromatography (GPC) and gravimetry. The latter revealed triphasic degradation profiles for R 202 and RG 755 microparticles with a mean particle size of 55 μm and 60 μm, respectively. An induction period was followed by a period of accelerated ester cleavage pre-onset of erosion and a final period of slow ester cleavage post-onset of erosion. According to DSC data the induction period is characterized by a glassy hydrated polymer matrix with a T_gH > 37°C. The induction period (t_i) correlated well with the lag-time of T_gH to reach 37°C (t_{lag 37°C}), thus confirming the importance of chain mobility for the degradation kinetic. The final decrease in the rate of ester chain cleavage post-onset of erosion turned out to be the result of an increase in matrix permeability for buffer ions inducing sodium salt formation and phase separation of the water-soluble degradation products within the particle bulk. Particle size effects depended on the preparation technique. A decrease in the degradation rate with a decrease in mean particle size was only observed when the molecular weight distribution of the polymer was not affected by the prepa ration procedure used to reduce the particle size. According to DSC data, the effect is due to a faster and more continuous release of the water-soluble degradation products from the smaller particles, thus reducing their plasticizing and autocata-lytic effects within the particle bulk.     

Degradation of tobramycin in aqueous solution

Abstract

The kinetics of degradation of tobramycin (Ne-De-Ka) in aqueous solution was studied as a function of pH. Tobramycin hydrolyzes in acidic solution to yield kanosamine (Ka-OH) and nebramine (Ne-De-OH) with a pseudo first-order rate constant of 2.7 × 10^?6 s^?1 in 1 N HCl at 80°C. The activation energy for the acid catalyzed hydrolysis is 32 kcal mol^?1. In basic solution, the hydrolysis products are deoxystreptamine (De-OH), nebramine (Ne-De-OH) and deoxystreptamine-kanosaminide (HO-De-Ka). The pseudo first-order rate constant for the hydrolysis in 1 N KOH is 1 × 10^?8 s^?1 at 80°C. The activation energy for the base catalyzed hydrolysis is 15 kcal mol^?1. Tobramycin is very stable towards hydrolysis at neutral pH; however, it rapidly oxidizes giving several products including De-OH, Ne-De-OH, and HO-De-Ka. In pH 7 phosphate buffer (0.01 M), the t₉₀ value is 70 hr at 80°C.     

Effect of water activity and temperature on the stability of creatine during storage

Creatine degradation to creatinine, which has no biological activity, in combinations of glycerol and pH 4.0 buffer solutions followed first-order kinetics up to a point where degradation started to level off, generally beyond the first half-life. Practical data are reported for a wide range of water activity (a_w) values (0.31–0.983) at 4°C, 23°C, and 35°C. Creatine degradation did not exhibit a dilution effect, that is a decrease in rate about an a_w of 0.7, as is found for both microbiological growth and chemical reactions in semisolid food matrix systems. The temperature dependence obeyed the Arrhenius relationship with an energy of activation of about 20 kcal/mol at a_w ≥ 0.68 increasing to 23 kcal/mole below that a_w. In addition, a semilog plot of half-life as a function of a_w at each temperature follows a predicted straight line. The pH and assumed liquid viscosity increase through increased glycerol concentration were not able to completely explain the decrease in rate of degradation as a function of a_w. Furthermore, we confirmed that creatine stability in the crystal form is very high as long as it does not reach the deliquescence state.     

Reactivity of Valganciclovir in Aqueous Solution

The rates of hydrolysis of valganciclovir to ganciclovir and L-valine and isomerization of the R and S diastereomers of valganciclovir in aqueous buffer solution from pH 3.8 to 11.5 were determined at 37°C. The kinetics of hydrolysis were first order for at least two half-lives in neutral and basic solutions. In acidic solutions where less than 10% degradation occurred, the rate of hydrolysis was determined assuming a first-order loss in drug. At 37°C and pH 7.08, the half life is 11 h. The maximum stability at the pH values studied occurred at pH 3.81 with a half life of 220 days. The kinetics of the approach to equilibrium for the isomerization were first order and the ratio of the R:S isomer at equilibrium was 52:48. Isomerization was approximately 10 fold faster than hydrolysis over the pH range studied with a half-life at pH 7.01 of 1 h. The maximum stability toward isomerization (t_1/2 > 533 h) occurs at a pH below 3.8. The pH-rate profile for the hydrolysis and the isomerization reaction are best described by hydroxide ion catalyzed mechanisms. In acidic and neutral solutions, the hydroxide reacts with the protonated form of the drug, while in basic solutions, the hydroxide reacts with the neutral form of the drug.     

Preparation of tetragonal zirconia powders by a solid state reaction: Kinetics, phases and morphology

Powders of tetragonal (t)ZrO₂ have been prepared by a solid state reaction between sodium metazirconate and sodium metaphosphate. The reaction temperatures and times have been varied between 450 and 550°C and 5 and 75 h, respectively. Zirconia powder, mostly in thet andt′ phases, is obtained. The yield of ZrO₂ powder increases monotonically with time at all reaction temperatures according to a phase boundary controlled kinetics. The fraction oft phase also increases with time at 450°C and 500°C but goes through a maximum at 550°C, the highest temperature employed. A maximum of 55% of the precursor monoclinic zirconia (used to prepare sodium meta zirconate) is converted tot phase at 500°C/75 h. The ZrO₂ powder consists of crystallites of size 9–25 nm agglomerated into particles having average size between 2 and 4μm. The agglomerates have a breaking strength of 100 MPa. A hydrothermal treatment is found to break the agglomerates into smaller sizes. Grinding the powder in a mortar and pestle converts only 12% of thet phase into monoclinic, indicating that substantial fraction of the tetragonal phase is the non transformable varietyt′. Heating experiments also confirm this.     

Study on the rate of decomposition of amoxicillin in solid state using high-performance liquid chromatography

Abstract

Amoxicillin sodium salt degradation in solid state relies on a sequential reaction consisting of two pseudo-first-order processes. Amoxicillin trihydrate, now used in pharmaceutical formulations, is significantly more stable than sodium amoxicillin. It degrades according to Prout-Tompkins model. We studied the stability of amoxicillin at temperatures of 37°, 50°, 80°, 90°, 100° y 110° C. HPLC was chosen as the analytical method. Amoxicillin and its decomposition products are separated by reversed-phase (C18) HPLC with gradient elution.     

Effect of Various Salts on the Stability of Lansoprazole,Omeprazole, and Pantoprazole as Determined by High-Performance Liquid Chromatography

A fast and reproducible reverse-phase high-performance liquid chromatography (HPLC) assay method has been developed for the simultaneous quantitation of omeprazole, lansoprazole, and pantoprazole. The three compounds were monitored at 280 nm using Zorbax Eclipse XDB C₈ (5 μm, 150 cm × 4.6 mm i.d.) and a mobile phase consisting of 700:300 phosphate buffer:acetonitrile with the pH adjusted to 7.0 with phosphoric acid. The method was used to study the effect of pH and various salts on the stability of the three compounds. The pH rate profile curve showed that pantoprazole was the most stable compound and lansoprazole the least stable. The stabilities of the compounds in salt solutions were found to be in the following order: phosphate buffer < trisodium citrate < citrate buffer ≤ acetate buffer < citric acid ≤ monosodium citrate ≤ calcium carbonate < sodium bicarbonate < sodium chloride < water. The rate of degradation had a direct relationship with the H⁺ and salt concentration.     

Characterisation of CorGlaes<Superscript>®</Superscript> Pure 107 fibres for biomedical applications

A degradable ultraphosphate (55?mol?% P₂O₅) quinternary phosphate glass composition has been characterised in terms of its chemical, mechanical and degradation properties both as a bulk material and after drawing into fibres. This glass formulation displayed a large processing window simplifying fibre drawing. The fibres displayed stiffness and strength of 65.5?±?20.8?GPa and 426±143 MPa. While amorphous discs of the glass displayed a linear dissolution rate of 0.004?mg cm^?2?h^?1 at 37?°C, in a static solution with a reduction in media pH. Once drawn into fibres, the dissolution process dropped the pH to <2 in distilled water, phosphate buffer saline and corrected-simulated body fluid, displaying an autocatalytic effect with >90?% mass loss in 4 days, about seven times faster than anticipated for this solution rate. Only cell culture media was able to buffer the pH taking over a week for full fibre dissolution, however, still four times faster dissolution rate than as a bulk material. However, at early times the development of a HCA layer was seen indicating potential bioactivity. Thus, although initial analysis indicated potential orthopaedic implant applications, autocatalysis leads to accelerating degradation in vitro.     

Stability of 4-DMAP in Solution

A stability-indicating reversed-phase performance liquid chromatographic method was developed for the detection of 4-(N, N-dimethylamino)phenol (4-DMAP) and its degradation products under accelerated degradation conditions. The degradation kinetics of 4-DMAP in aqueous solution over a pH range of 1.12–6.05 and its stability in solutions based on propylene glycol or polyethylene glycol 400 were investigated. The observed rate constants were shown to follow apparent first-order kinetics in all cases. The pH rate profile shows that maximum stability of 4-DMAP was observed in the pH range 2.0 to 3.0. Acid/base catalysis of 4-DMAP was not affected by systems of various ionic strengths. Incorporation of nonaqueous propylene glycol or polyethylene glycol 400 in the pH 3.05 solution of 4-DMAP showed an increase in the stability at 55°C ± 0.5°C,     

Antimicrobial activity of chitosan attached to ethylene copolymer films

Ethylene copolymer film was coated with chitosan by attachment of the polymer to the corona‐treated surface of the film, and the composite film was analysed for antimicrobial activity. The film was active against bacteria in 0.625 mM phosphate buffer; it reduced colony counts of Escherichia coli 25922 and of Listeria monocytogenes Scott A by 5 and 2–3 log₁₀, respectively after 24 h exposure. The activity of the chitosan‐coated film against bacteria in buffer was increased when silver ions were incorporated into the films as demonstrated by complete killing of Escherichia coli O157:H7 DD3795 and the chicken exudate isolate Stenotrophomonas maltophilia within 2 h in buffer. The film was active against L. monocytogenes Scott A in 0.5% buffered peptone water up to a pH of about 7.0. Tests on beef and chicken meat exudates revealed antimicrobial activity of the film against Escherichia coli O157:H7 and L. monocytogenes Scott A of about 2 and 1–2 log₁₀ reductions in colony‐forming units, respectively. The antimicrobial activity of the film against L. monocytogenes Scott A was also tested on turkey breast, and a log₁₀ reduction of about 1.7 log₁₀ units after 10 days and 1.2 log₁₀ after 15 days at 4°C was achieved. Exposure to chitosan‐coated film and 350 MPa of pressure, 55°C or 1% sodium diacetate resulted in a synergistic effect. Copyright © 2008 John Wiley & Sons, Ltd     

Application of Flow-Through Dissolution Method for the Evaluation of Oral Formulations of Nifedipine

Abstract

The drug release characteristics of three oral formulations (one conventional and 2 extended-release) of nifedipine were evaluated using a flow-through apparatus. The experiments were conducted for 4 to 24 hours using water or phosphate buffer (0.05 or 0.1 M; pH 7.4) with or without solubilizing agent, Tween, as a dissolution medium at a flow rate of 12.5 mL/min. The drug concentrations were determined using an HPLC method based on ratios of peak heights corresponding to UV absorbances at 254 nm for nifedipine and nitrendipine (internal standard). Dissolution characteristics in various media correspond to the nifedipine solubility in the medium. Peak nifedipine concentrations with 0.05 M phosphate buffer containing 0.5% Tween were significantly higher than those in the medium without Tween (21.5±1.0 vs 8.3±0.2 μg/mL, p c 0.001). Using a 0.05 M phosphate buffer with no Tween, the products tested showed distinct dissolution profiles representative of the respective formulation type. The conventional release product (10 mg) showed a higher mean peak nifedipine concentration (C_max,d) of 49.5±2.4 pg/mL (p < 0.001) attained at (t_max,d) 0.46±0.05 h as compared to those of modified-release products. The corresponding mean values for the modified-release tablets were 8.3±0.2 and 2.6±.3 μg/mL for C_max,d, and 0.28±0.03 and 12.0±3.8 h for t_max,d for the 20 and 30 mg tablets, respectively. Area under the concentration-time curves (AUC_o-t,d) for the 10, 20 and 30 mg formulations were 12.3±0.4,20.5±2.6 and 32.6±3.7 μg.h/mL, respectively (p < 0.001). As the dissolution profiles are similar to those of plasmakerum drug concentrations-time profiles obtained from clinical studies, application of this dissolution method, along with the derived in vitro drug-release kinetics parameters for potential correlation with in vivo parameters are discussed. The results of this study show that, compared to the USP dissolution method using apparatus 1 or 2, the flow-through dissolution system offers a potentially better alternative to assess drug release characteristics for different types of formulations, especially for drugs of low aqueous solubility such as nifedipine.     

Degradation Kinetics of Fluorouracil-Acetic-Acid-Dextran Conjugate in Aqueous Solution

ABSTRACT

The degradation kinetics of fluorouracil-acetic-acid-dextran conjugate (FUAC-dextran) was investigated in various buffer solutions with different pH value and physiological saline solution at 60°C and 37°C, respectively. The hydrolytic reaction displayed pseudo-first-order degradation kinetics. Hydrolytic rate constant obtained was the function of pH value and independent of species of buffering agents. The smallest rate constant was observed at pH round 3.00. The activation energy of the hydrolytic reaction was estimated from Arrhenius equation as 88.73 ± 6.00 kJ·mol^?1. The special base catalytic degradation of the conjugate was observed from acidic to slight alkaline condition and the special base catalytic rate constants were calculated. The conjugate was more stable in physiological saline than that in buffer solution at pH 7.00 or 9.00 at 37°C. The results revealed that the conjugate was stable in acidic condition and will degrade in alkaline condition.     

Stability of Mixtoxantrone Hydrochloride in Solution

Abstract

A stability-indicating reversed-phase high performance liquid chromatographic method was developed for the detection of mitoxantrone HC1 and its degradation products under accelerated degradation conditions. The degradation kinetics of mitoxantrone HC1 in aqueous solution over a pH range of 1.18 to 7.20 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 pH-rate profile shows that maximum stability of mitoxantrone HC1 was obtained at pH 4.01. No general acid or base catalysis from acetate or phosphate buffer species was observed. The catalysis rate constants on the protonated mitoxantrone imposed by hydrogen ion water and hydroxy ion were determined to be 3.72 × 10 min^?1 5.64 × 10-min^?1 and 1.108 × 10^?2min^?1, respectively. The degradation rate constants of mitoxantrone affected by different ionic strength systems. Irradiation with 254 nm UV light at 25±0.5°C was found when canpared with the light-protected controls. Incorporation of nonaqueous propylene glycol or polyethylene glycol in the pH 4.01 mitoxantrone solution shows an increase in its stability at 502±0.5°C.     

Thermal degradation behavior and kinetic analysis of poly(L-lactide) in nitrogen and air atmosphere

The non-isothermal and isothermal degradation behaviors and kinetics of poly(L-lactide) (PLLA) were studied by using thermogravimetry analysis (TGA) in nitrogen and air atmosphere, respectively. At lower heating rate ((5–10)°C/min), PLLA starts to decompose in air at lower temperature than those in nitrogen atmosphere; however, at higher heating rate ((20–40)°C/min), the starting decomposition temperature in air are similar to those in nitrogen atmosphere, not only showing that PLLA has better thermal stability in nitrogen than in air atmosphere, but also suggesting that the faster heating rate will decrease the decomposition of PLLA in thermal processing. Whether in air or in nitrogen atmosphere, the decomposition of PLLA has only one-stage degradation with a first-order decomposed reaction, suggesting that the molecular chains of PLLA have the similar decomposed kinetics. The average apparent activation energy of nonisothermal thermal degradation (Ē _non) calculated by Ozawa theory are 231.7 kJ·mol⁻¹ in air and 181.6 kJ·mol⁻¹ in nitrogen; while the average apparent activation energy of isothermal degradation (Ē _iso) calculated by Flynn method are 144.0 kJ·mol⁻¹ in air and 129.2 kJ·mol⁻¹ in nitrogen, also suggesting that PLLA is easier to decompose in air than in nitrogen. Moreover, the decomposed products of PLLA are also investigated by using thermogravimetry-differential scanning calorimetry-mass spectrometry (TGDSC-MS). In air atmosphere the volatilization products are more complex than those in nitrogen because the oxidation reaction occurring produces some oxides groups.     

Factors Affecting Stability of Z-Ligustilide in the Volatile Oil of Radix Angelicae Sinensis and Ligusticum Chuanxiong and Its Stability Prediction

ABSTRACT

The purpose of this investigation is to obtain a suitable vehicle for Z-ligustilide in the volatile oil of Radix Angelicae Sinensis and Ligusticum Chuanxiong in which it is stable enough for the application in pharmaceutics, to investigate its degradation laws, and to predict its shelf-life at 25°C. Factors including temperature, light, pH value, co-solvents and antioxidants can all influence the stability of Z-ligustilide, thereinto antioxidants could markedly improve its stability in aqueous solution by almost 35%. The suitable vehicle for Z-ligustilide contains 1.5% tween-80, 0.3% Vitamin C, and 20% propylene glycol (PG).

Furthermore, the degradation rates of Z-ligustilide were found to conform to a rate equation following Weibull probability distribution within a range of degradation ratio, and the equation could be expressed as follow:

ln ln (1/1?α) = ln k + m ln t

Where α is degradation ratio; t is time; m and k are constants relating to the degradation rate. The degradation rate will get greater as the increasing of parameter k. According to the degradation law obtained from the equation, the drug shelf-life (10% of active ingredient degraded, T₉₀) in this vehicle was predicted to be more than 1.77 years at 25°C through Arrehenius equation and accelerating experiments.

The present investigation was undertaken to propose a kinetic treatment that may be applicable to any type of degradation of the active ingredient of pharmaceutical formulation, and also could provide a good foundation for the new drug development of Z-ligustilide, especially for injection formulation.     

Synthesis of Piperazinylalkyl Ester Prodrugs of Ketorolac and their In Vitro Evaluation for Transdermal Delivery

Ketorolac, an NSAID, has low intrinsic permeation capacity through the skin. In this work, seven piperazinylalkyl ester prodrugs of ketorolac were synthesized to enhance its skin permeation. The chemical hydrolysis and the stability in human serum at 37°C were investigated in buffer solutions (pH 5.0 and 7.4) and in 80% human serum (pH 7.4), respectively. The prodrugs were chemically more stable at pH 5.0 than at pH 7.4 with prodrug 8 being the most stable (t_1/2 = 119.75 h and 11.97 h at pH 5 and 7.4, respectively). The prodrugs' t_1/2 in human serum ranged from 0.79 to 3.92 min. The prodrugs' aqueous solubility was measured in buffer solution at pH 5.0 and 7.4 and Log P_app was measured by partitioning between buffer solution (pH 5.0 and 7.4) and n-octanol. The prodrugs were more lipophilic than ketorolac at pH 7.4. Skin permeation of ketorolac and prodrug 8, the most stable chemically, through rat skin was studied at pH 5.0 and 7.4. Prodrug 8 enhanced permeation by 1.56- and 11.39-fold at pH 5 and 7.4, respectively. This is attributed to higher lipophilicity at pH 7.4 and higher aqueous solubility at pH 5 compared to ketorolac.     

Effects of Cellulose Derivatives and Additives in the Spray-Drying Preparation of Acetaminophen Delivery Systems

Microcrystalline cellulose (MCC), sodium carboxymethylcellulose (NaCMC), hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), hydroxypro pylcellulose (HPC), and ethylcellulose (EC) were used for the production of time-controlled acetaminophen delivery systems using a spray-drying technique. The influence of factors such as polymer concentration, inlet temperature, and drug/polymer ratio were investigated. The product yields were a function of the type and concentration of the polymer, with the highest values being reached from feeds containing 1% MCC and EC. Parameters of 1% polymer concentration and an inlet temperature of 140°C gave rise to optimal processing conditions. Using these parameters, the influence of some adjuncts, such as polyethylene glycol 6000 (PEG 6000), dibutyl sebacate (DBS), polyvinylpyrrolidone (PVP), and carboxylic acids such as citric acid (CA), phthalic acid (PA), succinic acid (SA), tartaric acid (TA), and oxalic acid (OA), on the spray-drying process was evaluated. Of the additives tested, PVP (with MCC), DBS (with EC), and PEG 6000 (with NaCMC) induced yield decreases from 70% to 49%, 66% to 39%, and 37% to 17%, respectively. As for carboxylic acids (with NaCMC), similar or better performances of 43%, 45%, 47%, and 49% were obtained with SA, OA, PA, and TA, respectively. Dissolution studies in pH 1 dilute HCl and pH 6.8 phosphate buffer dissolution media showed that formulations consisting of 1% polymer with a drug/polymer ratio of 1/1 exhibited the slowest drug release, with the spheroids coated with NaCMC and HEC showing the longest T_50% values (with 45 and 53 min at pH 1 and 49 and 55 min at pH 6.8, respectively). Slightly better sustained drug release in pH 6.8 dissolution medium was reached, showing the following trend: HEC > NaCMC > MCC > EC > HPMC. Concerning the additives, the trends in dissolution T_50% of drug revealed TA > SA > CA > OA > PVP > PA > DBS in acidic pH 1 dissolution medium and PVP > OA > TA > SA > PA > CA > DBS in phosphate buffer at pH 6.8.     

Decomposition of Anthralin in Alkaline Solutions

Abstract

Using conventional absorbance spectra and a first-derivative transformation technique anthralin was shown to undergo apparent first-order decomposition. The pH-log rate profile for the rate of disappearance of anthralin from aqueous solutions was determined at 25°C in the pH range of 7.74 to 10.02 at an ionic strength of 0.5 M. The profile indicated a maximum near the pK_a of anthralin. Measured values of the half life of anthralin decreased from 43.9 min at pH 7.74 to 14.8 min at pH 9.44 and then increased to 18.4 min at pH 10.02. No primary kinetic salt effect was observed. Since it was thought likely that trace amounts of metal ions could catalyze the degradation of anthralin, the effect of disodium ethylenediamine-tetraacetic acid addition was also investigated; this chelating agent did not influence the rate. Thermodynamic parameters were calculated from the temperature dependency of the decomposition.     

Physicochemical Properties of CWJ-a-5, a New Antitumor 3-Arylisoquinoline Derivative

ABSTRACT

The compound CWJ-a-5 [1-(4-methylpiperazinyl)-3-phenylisoquinoline hydrochloride] is a novel 3-arylisoquinoline derivative which has exhibited potent antitumor activity. As part of an effort to develop a useful formulation for clinical evaluation of this compound, the aqueous stability of CWJ-a-5 as a function of pH, ionic strength, and temperature, as well as its various physicochemical properties, have been examined. The pK_a value obtained by potentiometric titration in methanol–water mixtures was 3.61, at 25°C. The aqueous solubility and the apparent partition coefficient of CWJ-a-5 over the pH range 2.08–9.88 were consistent with those expected of a weak acid of similar pK_a value. The degradation of CWJ-a-5 was found to follow apparent first-order kinetics. The pH–rate profiles generated at 80°C were accounted for by acid-catalyzed degradation at low pH and base-catalyzed degradation at high pH. The activation energy was determined as 22.12 kcal/mol for the degradation of CWJ-a-5 in a pH 2.92 solution with a constant ionic strength of 0.2. Increasing the ionic strength up to 0.9 led to a higher degradation rate constant at pH 2.92. However, CWJ-a-5 was very stable even in a pH 2.92 solution, and its shelf-life was calculated to be 2.03 years at 25°C from the Arrhenius plot.     

Degradation Rates of Captopril in Aqueous Medium Through Buffer-Catalysis Oxidation

Initial degradation rates of captopril (0.1 mg/mL) in acetate, citric, and phosphate buffer solutions with different buffer concentrations at 80° (µ=0.5) were studied at pH 6.0. All degradation reactions of captopril solutions fitted an apparent first-order plot. The degradation rates of captopril rose with increasing buffer concentrations. A mechanism involving the buffer-catalysis oxidation reaction of captopril was proposed in this study. The low apparent first-order degradation rates of captopril in citric buffer solutions might have been due to the chelating effect of the citric buffer, which reduced the metal-catalysis oxidation reaction of captopril. Therefore, using low concentrations of citric buffer to improve solution stability seems to be an appropriate approach in a liquid formulation development of captopril. To select citric buffer at a low concentration for the dissolution medium might be the right choice for a sustained-release formulation dissolution study of captopril.