Nitrous Acid Solution Research Articles

Trace Aldehydes in Solid Oral Dosage Forms as Catalysts for Nitrosating Secondary Amines

Nitrosamine impurities may form during drug substance manufacturing processes. Here, we focus on nitrosamine impurity level growth in oral drug products during long term stability studies. Nitrosamine growth mechanisms in oral dosage forms are typically framed as due to nitrosating agents that can be formed in solutions of nitrous acid with a required pH value of around pH 5 or below. We strive in this work to bring awareness to pharmaceutical scientists that formaldehyde, common in oral dosage form excipients, has previously been shown in solution to catalyze the reaction between secondary amines and nitrite ion to give nitrosamine products. This mechanism operates at pH ∼6 and higher. We attempt to re-frame the solution work as relevant to pharmaceutical solid dosage forms. Recent examples of solid dosage form product recalls are used to demonstrate the formaldehyde catalyzed nitrosation pathway operating in the solid state.

Kinetics of the homogenous diazotization of p-nitroaniline with nitrous acid solution using stopped-flow technique

Diazotization is common in the fine chemical industry however its kinetics study is rare. In this work, the stopped-flow technique was adopted to study the kinetic parameters of the diazotization reaction between p-nitroaniline and nitrous acid. The results revealed that the p-nitroaniline diazotization is a second-order reaction with excessive hydrochloric acid, and the reaction rate equation with a pre-exponential factor and activation energy of 6.95 × 108 L·mol−1·s−1 and 37.79 kJ·mol−1 respectively was obtained according to Arrhenius equation. In addition, the kinetic model was established, the correlated values of k1 matched well with the experimental values with an AAD of 7.1%. This work provides theoretical data and guidance for its process optimization.

Dilute nitric or nitrous acid solution containing halide ions as effective media for pure gold dissolution.

The greatly enhanced oxidation ability of dilute aqueous nitric acid (0.10-2.0 mol L(-1)) containing bromide and iodide salts as well as chloride salts has been examined based on the dissolution kinetics of pure gold at 30-60 °C. It has been found that bromide salts are more effective than chloride salts in gaining the ability of dissolving gold in dilute aqueous nitric acid solution. At 60 °C, a piece of gold-wire (ca. 20 mg) is dissolved in 20 mL of as low as 0.10 mol L(-1) HNO3 solution containing 1.0-5.0 mol L(-1) NaBr and the dissolution rate constant, log(k/s(-1)), increases linearly (from -5.78 to -4.52) with the increasing NaBr concentration. The addition of organic solvents, such as acetonitrile and acetic acid, causes acceleration of gold dissolution in LiBr and NaBr solutions. With increasing MeCN contents, for instance, the log(k/s(-1)) value of 0.10 mol L(-1) HNO3 solution containing 2.0 mol L(-1) NaBr increases linearly from -5.30 to -4.61 at 30% (v/v) MeCN. The bromide salts affect the gold dissolution rate constant in the order of KBr < NaBr < LiBr < CaBr2. With increasing NaI concentration (0.20-3.0 mol L(-1)), some acceleration in log(k/s(-1)) of 0.50 or 1.0 mol L(-1) HNO3 solution has been observed; however, the slope of acceleration as the function of NaI concentration is much smaller than that of NaCl or NaBr. The gold dissolution ability has been examined also for nitrous acid containing chloride and bromide ions at 35 °C. The NaNO2 solution containing twice or more amounts of HX (X = Cl, Br) gives the maximum efficiency for gold dissolution, according to the log(k/s(-1)) values of the mixed solutions of NaNO2 (0.10-2.0 mol L(-1)) and HX of various concentrations. The influence of oxidation by dilute nitric and nitrous acids on the gold dissolution is discussed from the standpoint of the redox potentials in "modified" aqueous solutions and not of the changes in the activity coefficients of ions.

Nitrogenous chemicals generated from acidification of saliva influence transient lower oesophageal sphincter relaxations

Objective. Saliva contains high concentrations of nitrite derived from the enterosalivary recirculation of dietary nitrate and its reduction by buccal bacteria. Acidic gastric juice converts the swallowed nitrite to varying proportions of nitrous acid and nitric oxide (NO) depending upon ascorbic acid availability. Neuronally generated NO is the key in the pathway of transient lower oesophageal sphincter relaxations in vivo. Furthermore, in vitro NO and nitrous acid relax the smooth muscle of the stomach, lower oesophageal sphincter (LOS) and oesophageal body. The objective of this article was to determine whether luminal administration of NO or nitrous acid affects the generation of transient LOS relaxations following a meal. Material and methods. Fifteen healthy subjects were studied on three separate days. A manometry catheter was used to record oesophageal, LOS and gastric pressures, and two oesophageal pH probes were used to record reflux. One of three solutions was infused each day into the cardia after a standardized meal: 1) control solution of hydrochloric acid pH 1.0, 2) nitrous acid and 3) nitrous acid plus ascorbic acid to generate NO. The solutions were randomized and double-blinded. Results. The frequency of transient LOS relaxations was increased by the NO-generating solution at 5.2/h compared with both the control (3.5, p<0.01) and nitrous acid solution (3.1, p<0.0001). The NO-generating solution also increased oesophageal acid exposure to 62.2%, compared with both the control (37.5%, p<0.03) and nitrous acid solution (36.6%, p<0.002). Conclusions. Luminal NO at the gastro-oesophageal junction increases the generation of transient LOS relaxations following a meal. Chemicals generated by the acidification of salivary nitrite may contribute to gastro-oesophageal motility disorders.

‘In situ’ preparation of nitrous acid solutions by photoreduction in a flow assembly for analysis of pharmaceuticals

The solutions of nitrite ion, or nitrous acid, are frequently used as reagent in different analytical procedures and in pharmaceutical analysis. The low stability of the aqueous solutions of this reagent implies the tedious work of freshly prepared solutions every day and being kept in the refrigerator. In this paper, a photoreactor formed by a low pressure mercury lamp and nesting in a continuous-flow manifold is studied, tested, and proposed for the in situ reduction of nitrate solution into nitrite. The conversion into nitrite is reproducible and it has been successfully applied to determination of different drugs, mostly from the sulphonamide family, in an FIA assembly.

Oxidation of Pearlitic Steels in Nitrite Solutions

The effect of treatment parameters on the protective properties of oxide coatings, which are obtained on pearlitic steels in solutions of nitrous acid and nitrites is studied. The optimal parameters of pearlitic steel oxidation are determined. It is shown that, when NH4NO2 is used as the passivating agent, the passivation technology can be waste-free.

Spectroscopic Study of the Nitric Oxide Adlayers Formed from Nitrous Acid Solutions on Palladium-Covered Platinum Single-Crystal Electrodes

Palladium multilayers deposited on Pt(111), Pt(100), and Pt(110) single-crystal electrodes have been characterized by using adsorbed nitric oxide as a probe molecule. Nitric oxide adlayers can be e...

Nitrous acid pretreatment of tendon xenografts cross-linked with glutaraldehyde and sterilized with gamma irradiation

Collagenous xenografts made from kangaroo tail tendon cross-linked with glutaraldehyde have a potential application in the reconstruction of massive digital tendon deficits. However, a limitation to the clinical use of these xenografts has been the optimization of collagen cross-linking, and subsequent bio-incorporation and retention of mechanical properties following implantation. The purpose of this study was to evaluate the effect of nitrous acid on modulating the biologic and mechanical properties of tendon xenografts cross-linked with glutaraldehyde. Tendon xenografts were pretreated with 0.1 or 0.01 m nitrous acid solution, prior to cross-linking in 2% glutaraldehyde and sterilization by gamma irradiation. Xenografts were implanted intramuscularly in rabbits to examine biocompatability, and also used to repair ovine digital extensor tendon deficits to evaluate functional incorporation. Histologically, intramuscularly implanted nitrous acid pretreated xenografts in rabbits had a greater degree of diffuse cellular infiltration into interstitial splits in the graft than controls after 12 weeks. Xenografts implanted in an ovine extensor tendon deficit were evaluated after 26 and 52 weeks. Rate of failure of tenorrhaphies between host tendon and xenografts overall (15/21) was significantly greater ( P<0.05) than for autografts (1/21), suggesting that the holding power of sutures in xenografts was inferior to that obtained in autografts. Tensile failure stress of midsections of both nitrous acid pretreated and control xenografts was about 100 MPa prior to implantation (time zero). After 26 and 52 weeks, failure stress of both types of xenografts was significantly less than at time zero ( P<0.05). At 52 weeks, failure stress of nitrous acid pretreated xenografts (47.4±3.1 MPa) was significantly less than control xenografts (63.7±5.4 MPa); ( P<0.05). However, nitrous acid pretreated xenografts were similar to control xenografts in failure load (357±29 and 354±26 N, respectively), but they tended to have larger cross-sectional areas (7.6±0.5 versus 5.7±0.6 mm 2, respectively) which were responsible for the lower calculated value for failure stress. Histologically, autografts maintained their normal tissue architecture and evoked a more limited cellular response in surrounding tissues than xenografts ( P<0.05). Both types of xenograft were surrounded by a thicker cuff of cellular response than autografts. However, compared to control xenografts, nitrous acid pretreated xenografts had more extensive fragmentation and splitting of collagen bundles, and more diffuse cellular and vascular infiltration into these interstitial splits, and these alterations were apparently contributing to the greater ‘swelling’ of these xenografts. It was concluded that pretreatment of tendon xenografts with nitrous acid modulated their biologic and material properties. Further studies are needed to elucidate the mechanism of these effects, and to determine if the protocol for tendon xenograft preparation could be optimized for improved clinical performance.

Leaching of Manganese Dioxide in Nitrous Acid

The reductive dissolution of γ-MnO2 has been studied in nitrous acid solutions at atmospheric pressure. The effects of undissociated HNO2, NO2− ion, aqueous NO and H+ ion concentrations on the rate of reaction are investigated over wide concentration ranges at 25° and 0°C. Reaction mechanisms are proposed and rate equations are derived which satisfy both the mass transport limited regime at 25°C and the chemically-controlled regime at 0°C. The dissolution process is described as occurring via three independent reaction paths involving HNO2, NO2− and NO(aq). With respect to the total nitrous acid concentration, a reaction order of one-half is found below pH 2 at 0°C agreeing with the predictions of the electrochemical reaction theory. The overall activation energy of 8.0 kcal mol−1 supports the concept that the dissolution process is not solely limited by mass transport throughout the total temperature range investigated. Below pH 1 the dissolution rates were found to be independent of the H+ ion concentration, and comparatively high overall rates were measured.

Hydrolysis equilibrium of dinitrogen trioxide in dilute acid solution

Solutions of nitrous acid in dilute (0.1 M HC1) or more concentrated (approx. 5 M HC1O/sub 4/) acid exhibit a contribution to the ultraviolet absorbance that is quadratic in (HNO/sub 2/). In dilute acid this excess absorbance is attributed to N/sub 2/O/sub 3/ formed through equilibrium 1,2HNO/sub 2/ = N/sub 2/0/sub 3/ + H/sub 2/O. From the measured spectrum of epsilon/sub N/sub 2/O/sub 3//K/sub 1/ vs. wavelength (245-260 nm) and by comparison with epsilon/sub N/sub 2/O/sub 3// obtained in pulse radiolysis by Graetzel et al., K/sub 1/ is determined as (3.03 +- 0.23) x 10/sup -3/M/sup -1/ in agreement with the value calculated thermochemically. The coefficient of physical solubility of N/sub 2/O/sub 3/ in water is computed as 0.70 +- 0.05 M atm/sup -1/. The extinction quadratic in (HNO/sub 2/) is independent of acid concentration of dilute acid but increases strongly in more concentrated acid, suggesting a possible second absorbing species of stoichiometry HN/sub 2/O/sub 3//sup +/.

Reaction and transport of nitrogen oxides in nitrous acid solutions.

Depletion of nitrous acid from its aqueous solution is studied over a wide range of experimental conditions. The rate and stoichiometry of this process are determined as a function of mass transfer characteristics of gas-liquid contacting devices. It is found that the depletion of nitrous acid is brought about by three different mechanisms: 1) simultaneous hydration of N2O4 and evolution of NO, both existing in equilibrium with HNO2, 2) desorption of nitrous acid molecules and 3) decomposition of HNO2 into NO and NO2 occurring in the vicinity of the liquid surface. A quantitative analysis is made using the various rate and equilibrium constants with the oxides of nitrogen. The relative importance of the three mechanisms and, hence, the rate and stoichiometry of the whole process vary with the mass transfer characteristics of the gas-liquid contactors. The rate constants of the hydration of N2O4 and of the decomposition of nitrous acid (2HNO2→NO+NO2+H2O) as well as the solubility of N2O4 were established.

Formation of anhydrosugars in the chemical depolymerization of heparin.

In the reactions used to break heparin down to mono- and oligosaccharides, androsugars are formed at two stages. The first of these is the well-known cleavage of heparin with nitrous acid to convert the N-sulfated D-glucosamines to anhydro-D-mannose residues; this reaction has been studied in detail. It is demonstrated here that only low pH (less than 2.5) reaction conditions favor the deamination of N-sulfated D-glucosamine residues; the reaction proceeds very slowly at pH 3.5 or above. On the other hand, N-unsubstituted amino sugars are deaminated at a maximum rate at pH 4 with markedly reduced rates at pH2 or pH6. At room temperature solutions of nitrous acid lose one-fourth to one-third of their capacity to deaminate amino sugars in 1 h at all pHs. A low pH nitrous acid reagent which will convert heparin quantitatively to its deamination products in 10 min at room temperature is described, and a comparison of the effectiveness of this reagent with other commonly used nitrous acid reagents is presented. It is also shown that conditions used for acid hydrolysis of heparin convert approximately one-fourth of the L-iduronosyluronic acid 2-sulfate residues to a 2,5-anhydrouronic acid. This product is an artifact of the reaction conditions, and its formation represents one of several pathways followed in the acid-catalyzed cleavage of the glycosidic bond of the sulfated L-idosyluronic acid residues.

Aminoacridine dyes and the secondary structure of DNA in situ.

A new method is proposed to study the secondary structure of deoxyribonucleic acid (DNA) in situ in fixed chromatin. It is based on acriflavine staining and on differentiation with a nitrous acid solution of the fixed cytologic preparation. The presence of green fluorescence after this treatment is regarded as indicative of double stranded DNA. Experiments are described with DNA-acriflavine mixtures in solution, DNA-agar models and cytologic preparations submitted to different pretreatments. The feasibility and limitations of the method are discussed in the light of the results reported upon.

The Chemistry of Esters of Leuco Vat Dyes IV—Oxidation with Solutions of Nitrous Acid

When the sulphuric esters of leuco vat dyes are developed with acidic nitrous acid solutions in the complete absence of oxygen, the sulphate groups am removed only by hydrolysis; the resulting leuco dye is then oxidised by nitrous acid. When oxygen is present development is far more rapid, the majority of sulphate groups being removed by direct oxidation with hydroxyl radicals via a chain mechanism. The chain reaction is initiated by hydrogen peroxide (or HO2 radical) and propagated by the homolytic fission of pernitrous acid and its re‐formation from nitrogen dioxide and nitrous acid. This mechanism is thought to operate in normal development. A modification of the technical development process is suggested.

Reaction of Nitrous Acid. III. Reaction of Copper with Nitrous Acid Solution Acidified by Nitric Acid.

Reaction of Nitrous Acid. III. Reaction of Copper with Nitrous Acid Solution Acidified by Nitric Acid.

A New Cleavage Product of Guanine

BY heating guanine in an autoclave with acid, about 20 per cent of the purine is converted to a base of the composition C4H7N5, from analysis of the two salts C4H7N5.H2SO4 and C4H7N5.2HCl. By oxidation with bromine, guanidine picrate has been obtained from the base, and by oxidation with potassium permanganate a yield of approximately 47 per cent of guanidine has been obtained by colorimetric estimation. After boiling with barium hydroxide, the resulting acidified solution yielded a blue colour when made alkaline, or when treated with a small amount of potassium permanganate; it gave a deep red nitroprusside test in alkaline solution; after treatment with nitrous acid solution gave a deep brown colour when mixed with a solution of -naphthol in sodium hydroxide: all of which tests are probably given by 4- (or 5-) aminoglyoxaline1. This acidified solution when allowed to stand in contact with air also yields a marked ninhydrin test, which is highly probably traceable to glycine, since this amino acid was found amongst the autoclaved guanine products.