Systematic strategies for degradation kinetic study of pharmaceuticals: an issue of utmost importance concerning current stability analysis practices

Bhangare, Dhiraj; Rajput, Niraj; Jadav, Tarang; Sahu, Amit Kumar; Tekade, Rakesh K.; Sengupta, Pinaki

doi:10.1186/s40543-022-00317-6

Cited by 34 publications

(19 citation statements)

References 45 publications

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“…Meeting the official requirements made it possible to obtain reliable data for degradation kinetics of DIPH, AZE and BEPO. This, in turn, is extremely important in terms of predicting the shelf life of the drugs and their safety for patients [ 40 ].…”

Section: Resultsmentioning

confidence: 99%

Chemical Stability Study of H1 Antihistaminic Drugs from the First and the Second Generations, Diphenhydramine, Azelastine and Bepotastine, in Pure APIs and in the Presence of Two Excipients, Citric Acid and Polyvinyl Alcohol

2022

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The chemical stability of diphenhydramine (DIPH), azelastine (AZE) and bepotastine (BEPO) was examined in solutions and solids. The drugs were subjected to high temperature (70 °C for 35 h) or UV/VIS light (18.902–94.510 kJ/m2) at pH 1–13, to examine their percentage degradation and kinetics of degradation. Further, the stability of solid DIPH, AZE and BEPO was examined in the presence of excipients of different reactivity, i.e., citric acid (CA) and polyvinyl alcohol (PVA) under high temperature/high humidity (70 °C/80% RH) or UV/VIS light (94.510 kJ/m2). Under high temperature, DIPH degraded visibly (>19%) at pH 1 and 4, AZE was shown stable, while the degradation of BEPO was rather high (>17%) in all pH conditions. Under UV/VIS irradiation all the drugs were shown labile with degradation in the range 5.5–96.3%. As far as the solid mixtures were concerned, all drugs interacted with excipients, especially under high temperature/high humidity or UV/VIS light. As a result, DIPH, AZE and BEPO were compared in terms of their stability, with regard to their different structures and acid/base properties. All these results may be helpful for manufacturing, storing and applying these drugs in their topical (skin, nasal and ocular), oral and injectable formulations.

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Section: Resultsmentioning

confidence: 99%

Chemical Stability Study of H1 Antihistaminic Drugs from the First and the Second Generations, Diphenhydramine, Azelastine and Bepotastine, in Pure APIs and in the Presence of Two Excipients, Citric Acid and Polyvinyl Alcohol

2022

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“…The term degradation kinetics refers to the study of the rate of drug degradation. Most pharmaceutical products are degraded through rst-order reactions 34 . A series of experiments were performed according to the procedure described in Section 2.2.1. for the determination of stability, the rate of disappearance, and to evaluate the metabolic e ciency of nitisinone and its metabolites.…”

Section: Degradation Of Ntbc and Its Metabolitesmentioning

confidence: 99%

Metabolic profiles and fingerprints for the investigation of the influence of nitisinone on the metabolism of the yeast Saccharomyces cerevisiae

Kostina-Bednarz

Płonka

Nowak

et al. 2022

Preprint

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Nitisinone (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione, NTBC) is considered a potentially effective drug for the treatment of various metabolic diseases associated with disorders of L-tyrosine metabolism however, side-effects impede its widespread use. This work aimed to broaden the knowledge of the influence of NTBC and its metabolites 2-amino-4-(trifluoromethyl)benzoic acid (ATFA), 2-nitro-4-(trifluoromethyl)benzoic acid (NTFA), and cyclohexane-1,3-dione (CHD) on the catabolism of L-tyrosine and other endogenous compounds in Saccharomyces cerevisiae. Based on a targeted analysis performed by LC-ESI-MS/MS, based on multiple reaction monitoring, it was found that the dissipation kinetics of the parent compound and its metabolites are compatible with a first-order reaction mechanism. The same mode of analysis was used to reveal that NTBC metabolites formed in the model organism cause a 15–59% decrease in L-tyrosine, L-tryptophan, and L-phenylalanine compared to the untreated model organism. The overall changes in the metabolism of yeast exposed to NTBC or its derivatives were evaluated by non-targeted analysis via LC-ESI-MS/MS in the ion trap scanning mode. Based on principal components analysis, a statistically significant similarity between metabolic responses of yeast treated with ATFA or NTFA was observed. These findings facilitate further studies investigating the influence of NTBC on the human body and the mechanism of its action.

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“…The rate of drug hydrolysis depends not only on the composition of the formulation but also on storage temperature [ 29 ]. The quantitative relationship between the rate of a chemical reaction and the temperature can be modelled by the Arrhenius equation.…”

Section: Introductionmentioning

confidence: 99%

Degradation kinetics of artesunate for the development of an ex-tempore intravenous injection

Gashe

Wynendaele

Spiegeleer

et al. 2022

Malar J

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Background Artesunate is recommended by the World Health Organization (WHO) for parenteral treatment of severe Plasmodium falciparum malaria. However, artesunate is inherently unstable in an aqueous solution and hydrolyses rapidly after its preparation for injection. Therefore, the aim of the study was to evaluate the stabilizing effects of phosphate buffer and mannitol against short-term (ex-tempore) artesunate hydrolysis. Methods A HPLC–UV isocratic method was developed using a reversed-phase fused core column (HALO RP-C18) and a mobile phase consisting of a mixture of 45% ammonium formate 10 mM in water (pH 4.5) and 55% methanol. Artesunate was formulated as aqueous solutions using a design of experiment (DOE) to investigate the artesunate stabilizing effects of pH (8–10), phosphate buffer strength (0.3–0.5 M), and mannitol (0–0.22 mmol/mL). The solutions were incubated at predefined temperatures (5, 25, and 40 °C) with subsequent analysis. Arrhenius equation was applied to model and evaluate the stability results. Results The developed HPLC-based method using fused-core stationary phase allowed to selectively quantify artesunate in the presence of its main hydrolysis degradants; namely β-dihydroartemisinin (β-DHA) and α-dihydroartemisinin (α-DHA) within 10 min. By applying the Arrhenius equation, the rate of hydrolysis of the drug increased approximately by 3.4 as the temperature raised by 10 °C. Buffer strength was found to be the main factor affecting the hydrolysis rate constants at 5 and 25 °C (p < 0.05), the activation energy (p = 0.009), and the frequency factor (p = 0.045). However, the effect of the buffer was predominant on the activation energy and hydrolysis rate constants, revealing its stabilizing effect on the drug at lower buffer strength (0.3 M). Within the investigated range (pH = 8–10), pH was found to influence the activation energy, with a positive stabilizing effect in the pH range of 8–9. The addition of mannitol as stabilizing agent into artesunate aqueous formulation did not show an improved response. Conclusion Phosphate buffer was the main stability determining factor of artesunate in the aqueous intravenous (i.v.) formulation and was found to be more effective in stabilizing artesunate at a buffer strength of 0.3 M in pH 8–9, while mannitol lacked stabilizing effect.

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Systematic strategies for degradation kinetic study of pharmaceuticals: an issue of utmost importance concerning current stability analysis practices

Cited by 34 publications

References 45 publications

Chemical Stability Study of H1 Antihistaminic Drugs from the First and the Second Generations, Diphenhydramine, Azelastine and Bepotastine, in Pure APIs and in the Presence of Two Excipients, Citric Acid and Polyvinyl Alcohol

Chemical Stability Study of H1 Antihistaminic Drugs from the First and the Second Generations, Diphenhydramine, Azelastine and Bepotastine, in Pure APIs and in the Presence of Two Excipients, Citric Acid and Polyvinyl Alcohol

Metabolic profiles and fingerprints for the investigation of the influence of nitisinone on the metabolism of the yeast Saccharomyces cerevisiae

Degradation kinetics of artesunate for the development of an ex-tempore intravenous injection

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