Hydrolysis of Benzothiadiazines

Mollica, Joseph A.; Rehm, Carl R.; Smith, J. B.; Govan, H. K.

doi:10.1002/jps.2600600920

Journal of Pharmaceutical Sciences

1971

DOI: 10.1002/jps.2600600920

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Hydrolysis of Benzothiadiazines

Joseph A. Mollica¹,

Carl R. Rehm²,

J. B. Smith³

et al.

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Cited by 51 publications

(23 citation statements)

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“…Hydrolysis of HCTZ is complete at pH higher than 12 (14,15). at pHs below 2.5 and above pH 12 degradation is linear and shows first-order dependence of H + and OH -concentration (14,15). The degradation profile between pH 7 and 11.5 is probably the result of dissociation equilibrium.…”

mentioning

confidence: 97%

“…HCTZ is slightly soluble in water and has therefore poor gastrointestinal absorption (14,15). Its solubility is potentially improved by addition of weak organic and inorganic bases that increase pH of solution.…”

mentioning

confidence: 99%

“…Its solubility is potentially improved by addition of weak organic and inorganic bases that increase pH of solution. On the other hand, HCTZ undergoes alkaline hydrolysis in the presence of heat and moisture (14,15). Solubility of HCTZ in aqueous solutions is low, in the pH range from 1.0 to 7.4, ranging from 0.0608 to 0.103 g per 100 ml.…”

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confidence: 99%

“…The HCTZ ionization constant (pK a ) ranges from 8.60 (potentiometric titration) to 8.81 (photometric titration) (14,15). Solid HCTZ stored at room temperature for five years shows no degradation (14).…”

mentioning

confidence: 99%

“…(14)(15)(16). Hydrolysis of HCTZ is complete at pH higher than 12 (14,15). at pHs below 2.5 and above pH 12 degradation is linear and shows first-order dependence of H + and OH -concentration (14,15).…”

mentioning

confidence: 99%

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Influence of pH modifiers on the dissolution and stability of hydrochlorothiazide in the bi- and three-layer tablets

2015

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Influence of pH modifiers on the dissolution and stability of hydrochlorothiazide in the bi-and three-layer tabletsDuring the past few years, the studies of bi-and multi-layered tablets increased due to the consumption of several different drugs per day by a patient and requests for appropriate patient compliance. The demographic shift toward older population increases the use of combination therapy as polypharmacy. Hydrochlorothiazide (HCTZ), as a model drug, is most commonly used in the treatment of hypertension, congestive heart failure and as a diuretic. The aim of the present study is to investigate the effect of the local environment on dissolution and stability behaviour of HCTZ in fixed multilayered tablet combinations, which are commonly used in polypharmacy. For this purposes, three different systems were introduced: (i) two conventional tablets (HCTZ and pH modifying placebo), (ii) 2-layer tablets (HCTZ, pH modifying placebo) and (iii) 3-layer tablets (HCTZ, barrier and pH modifying placebo). Disintegration of tablets, dissolution of HCTZ from tablets and HCTZ related substances were moni tored for all systems. Results showed that there was a significant difference between dissolution profiles of the conventional two-tablet system (HCTZ tablet and pH modifying tablet) and the 2-layer and 3-layer tablets, which include the pH modifying layer. In the case of the conventional two-tablets system, 85 % of HCTZ was dissolved in less than 15 minutes. The dissolution profiles of HCTZ from 2-layered and 3-layered tablets showed a decrease in the dissolution rate. In addition, during the stability studies, it has been confirmed that the typical degradation product of HCTZ is formed, impurity B (4-amino-6-chloro-1,3-benzenedisulfonamide), which implies formation of formaldehyde as hydrolytic impurity not reported in the Ph. Eur. (16). Both impurities are particularly raised in 2-layered tablets with alkaline and neutral placebo layers. Stability of HCTZ was improved in the case of the 3-layer tablet, where the intermediate separation layer of glycerol monostearate was present. It is presumed that the HCTZ dissolution rate was decreased due to formation of non-soluble substances as a result of HCTZ degradation in the presence of alkaline layer.

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confidence: 97%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Influence of pH modifiers on the dissolution and stability of hydrochlorothiazide in the bi- and three-layer tablets

2015

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Accelerated Forced Degradation of Pharmaceuticals in Levitated Microdroplet Reactors

Liu

Gao

et al. 2018

Chemistry A European J

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Forced degradation is a method of studying the stability of pharmaceuticals in order to design stable formulations and predict drug product shelf life. Traditional methods of reaction and analysis usually take multiple days, and include LC-UV and LC-MS product analysis. In this study, the reaction/analysis sequence was accelerated to be completed within minutes using Leidenfrost droplets as reactors (acceleration factor: 23-188) and nanoelectrospray ionization MS analysis. The Leidenfrost droplets underwent the same reactions as seen in traditional bulk solution experiments for three chemical degradations studied. This combined method of accelerated reaction and analysis has the potential to be extended to forced degradation of other pharmaceuticals and to drug formulations. Control of reaction rate and yield is achieved by manipulating droplet size, levitation time and whether or not make-up solvent is added. Evidence is provided that interfacial effects contribute to rate acceleration.

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ChemInform Abstract: HYDROLYSE VON BENZOTHIADIAZINEN

Mollica¹,

Smith²,

Govan³

1972

Chemischer Informationsdienst

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Hydrolysis of Benzothiadiazines

Cited by 51 publications

References 15 publications

Influence of pH modifiers on the dissolution and stability of hydrochlorothiazide in the bi- and three-layer tablets

Influence of pH modifiers on the dissolution and stability of hydrochlorothiazide in the bi- and three-layer tablets

Accelerated Forced Degradation of Pharmaceuticals in Levitated Microdroplet Reactors

ChemInform Abstract: HYDROLYSE VON BENZOTHIADIAZINEN

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