Hydroxyl Ion Catalysis Research Articles

Stability of mitoxantrone-containing liposomes

The chemical stability of mitoxantrone entrapped in liposomes was investigated. The effect of silanization on glass container, charge characteristics of the liposomes, pH of the medium, addition of ascorbic acid in the medium, and temperature for storage on the degradation of mitoxantrone followed a pseudo-first-order reaction. The loss of concentration for mitoxantrone was found at zero time of storage in the plain glass vials at pH 5.8 and 7.4. This was attributed to the adsorption of mitoxantrone on the glass vials. At pH 3.6 and 4°C, the mitoxantrone entrapped in negatively charged liposomes in Aquasil-treated glass vials resulted in an optimum half-life. The logarithm of rate constant against pH profiles for mitoxantrone in solution and in liposomes indicated that the degradation rate increased with increasing pH of the medium. This was attributed to a hydroxyl ion catalysis reaction. The results of degradation rate constant obtained from the mitoxantrone entrapped in negatively charged, positively charged and neutral liposomes showed no significant difference. This revealed that a similar stability can result from these systems. The silanization materials of Aquasil and Surfasil on the degradation of mitoxantrone in liposomes resulted in the similar rate constants and half-lives. The addition of ascorbic acid to the mitoxantrone containing liposomes exhibited no effect on the increase of stability for the entrapped mitoxantrone.

Influence of temperature and hydrophobic group-associated icebergs on the activation energy of drug decomposition and its implication in drug shelf-life prediction.

The Ea values of aspirin hydrolysis, as a result of hydronium-ion catalysis, intramolecular-nucleophilic catalysis, and hydroxyl-ion catalysis, were significantly different from each other when determined in the 30-40, 45-55, and 60-70 degrees C ranges. The different Ea values were attributed to differences in both delta H* and delta S*, which could be accounted for by the various activated complexes formed in the hydrolysis of aspirin for each mechanism and the disruptive effect of temperature on the iceberg structures of water present around the phenyl group and the methyl group of aspirin at 42 and 58 degrees C, respectively. A linear relationship observed between the calculated "differential" enthalpy and entropy values, with a slope (compensation temperature) value of about 307 degrees K, supported a role for icebergs associated with hydrophobic groups in the formation of the activated complexes. This study illustrates that the predicted shelf life of a drug at room temperature could be erroneous if estimated from a single Ea value which is calculated from the decomposition rate constants determined at widely spaced temperatures in the range of 10-70 degrees C, using the Arrhenius relationship.

ChemInform Abstract: 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 ˜5.90 at 65°C. An activation energy of 16 Kcal/mol was obtained in a phosphate buffer solution at a pH of ˜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.

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 ˜5.90 at 65°C. An activation energy of 16 Kcal/mol was obtained in a phosphate buffer solution at a pH of ˜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.

Kinetics of hydrolysis of polyoxyethylene (20) sorbitan fatty acid ester surfactants.

Abstract The kinetics of the hydrolysis of the oleate ester of polyoxyethylene (20) sorbitan (Tween 80) in aqueous buffers were studied at an initial concentration of 0ṁ020% (w/v) and over the pH range of 1ṁ10 to 10ṁ28. The hydrolysis appears to be specific acid-catalysed at pH values below 3 and specific base-catalysed at pH values greater than 7ṁ6. The pseudo first-order rate constants for hydrogen and hydroxyl ion catalysis were determined, and the temperature and ionic strength dependence of the acid-catalysed reaction was studied. Both the initial, acid- and base-catalysed hydrolysis of Tween 80 exhibited an unusual initial, micellar surfactant concentration-rate dependence, opposite to that previously reported for the hydrolysis of anionic surfactants of the n-alkyl sulphate-type. Specifically, as the initial concentration of Tween 80 was increased above its reported critical micellar concentration, there was a progressive, marked decrease in the rate of the reaction, with the rate eventually reaching a plateau value between 0ṁ100 and 1ṁ00% (w/v). It is suggested that this behaviour is due to alterations in the micellar state of the surfactant as its concentration is increased. The influence of the chemical structure of the Tween surfactant on the acid-catalysed hydrolysis reaction at 80° was also examined using the oléate (Tween 80), stéarate (Tween 60), and palmitate (Tween 40) esters of polyoxyethylene (20) sorbitan.

Prediction of Stability in Pharmaceutical Preparations XV: Kinetics of Hydrolysis of 5-Trifluoromethyl-2′-deoxyuridine

The antiviral 5-trifluoromethyl-2′-deoxyuridine, F 3 TdR, is hydrolyzed by hydrogen ions and solvent to 5-trifluoromethyluracil, F 3 T, and deoxyribose. The F 3 T is readily hydrolyzed to 5-carboxyuracil by hydroxyl ion attack on the undissociated and anionic species. At elevated temperatures, 5-carboxyuracil is decarboxylated by hydroxyl ion catalysis to uracil. The F 3 TdR is readily hydrolyzed to 5-carboxy-2′-deoxyuridine by hydroxyl ion attack on the undissociated and anion species through an observable kinetic intermediate at high alkalinity, probably 5-hydroxydifluoromethyl-2′-deoxyuridine. The optimum pH range for stabilization is 1–4 where the half-life at 30° is 280 days. The material is readily degraded at pH 7.4 where 1.5 days is the half-life at 30°.

Kinetics of Thiamine Hydrolysis

The pH-rate profile of the hydrolytic cleavage of thiamine determined from kinetics measurements has been found to be unusually complex. Under essentially buffer-free conditions, the overall behavior suggests existence of at least four separate reactions: (a) acid catalyzed mechanism leading to the formation of oxythiamine at pH below 1; (b) water cleavage of protonated thiamine yielding a pyrimidine and a thiazole fraction between pH 1–6; (c) at pH 2–6.5, hydroxyl ion catalysis of protonated thiamine producing the same products found in reaction (b); (d) above pH 6.5, water cleavage of thiol thiamine to yield a pyrimidine diamine and other undetermined products. The ionic strength and temperature dependency of the reaction has also been determined. Contrary to earlier works, the hydrolytic reaction appears not to be subject to major negative or positive catalysis by amino acid species. The rate, however, is pronouncedly influenced by what appears to be general base catalysis by several buffer species.

Stability of Pyridine-2-aldoxime Methiodide II: Kinetics of Deterioration in Dilute Aqueous Solutions

The decomposition of 2-PAM was studied at pH values 0.5 to 13 and at temperatures ranging from 37 to 87°. At constant pH and temperature, the observed rate of deterioration of 2-PAM was first order with respect to drug concentration. Below pH approximately 4, hydrogen ion catalysis of the acid form of oxime occurs; above pH 4, the reaction is either an hydroxyl ion catalysis of the acid form of oxime or is noncatalytic in which there is a direct attack on the oximate species. Two mechanisms have been postulated for the breakdown of 2-PAM. Specific velocity constants, energies of activation, and frequency factors have been determined for both mechanisms. The pH of maximum stability has been determined from initial rate constants over the entire pH range. General equations relating the half-life of 2-PAM solutions to temperature and pH have been derived.

Kinetic studies in ester hydrolysis

Acid hydrolysis of ethyl esters of fumaric and maleic acid have been studied in dioxan water mixtures as a consecutive first-order reaction. Alkaline hydrolysis is more complex and could be studied only with ammonia as the source for hydroxyl ion catalysis. There is pronounced salt effect with thecis ester for the second stage and the reaction turns out to be quite a complex one from the mechanistic and solvent influence point. Tentative conclusions on the role of the conformations could be formed.

A Kinetic Study of the Hydrolysis of Methyl DL-α-Phenyl-2-piperidylacetate

The kinetics of the hydrolysis of methyl DL-α-phenyl-2-piperidylacetate in aqueous buffers were studied over the pH range 1.1 to 6.1. The hydrolysis appears to be catalyzed specifically by hydronium and hydroxyl ions. The resulting catalytic catenary afforded a pH minimum of 2.86 at 80°. The pseudo first- and second-order velocity constants for hydronium and hydroxyl ion catalysis were determined, and the temperature dependency of the reaction was studied. The influence of ionic strength on the hydronium and hydroxyl ion catalysis was investigated. The structural characteristics of the molecule contributing to the isocatalytic point are discussed.

Allgemeine Basenkatalyse der Orientierung bei Resorcin‐Kupplungen. 14. Mitteilung zur Kenntnis der Kupplungsreaktion

Abstract Diazo coupling of 4‐phenylazo‐resorcinol takes place in 2‐ or 6‐position, depending on the acidity of the medium. It is shown that this orientation phenomenon is not caused by hydroxyl ion catalysis, but by general base catalysis. It is probable that the diazo orientation in resorcinol and in m‐phenylenediamine is to be explained on the same mechanistic basis as the orientation in α‐naphthol coupling reactions.

Inactivation of Crystalline Pepsin

CRYSTALLINE pepsin, in solutions of constant ionic strength on the alkaline side of its stability maximum, inactivates unimolecularly at a rate which is inversely proportional to the fifth power of the hydrogen ion concentration. This unusual relationship has been demonstrated over a velocity interval of 1 to 5,000 in nearly a hundred kinetic experiments at two temperatures with four different buffers. The rate varies with the buffer, but the fifth-power relation does not. As the buffer ratios change by different amounts in the same pH range, general basic catalysis is therefore excluded. It is likewise improbable that simple hydroxyl ion catalysis determines the rate.