Mechanistic explanation to the catalysis by pyrazinamide and ethambutol of reaction between rifampicin and isoniazid in anti-TB FDCs

Bhutani, Hemant; Singh, Saranjit; Jindal, K.C.; Chakraborti, Asit K.

doi:10.1016/j.jpba.2005.05.015

Cited by 52 publications

(30 citation statements)

References 9 publications

(9 reference statements)

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“…This behavior was a replica of the marketed formulations containing these three drugs, [11] and it confirmed the catalytic role of Z and E in the reaction between R and H. While there was no physical change in RHZ mixture, RHE combination mixture turned brownish black and sticky in appearance with time, which is attributed to the moisture gained by E in due course of time. Recently we also postulated a mechanism for catalysis of the interaction of R and H in solid state by Z and E. [17] The RZE combination showed similar physical change to RHE (Table 4), again due to the presence of E. However, in this mixture 3-formylrifamycin was found to be the main degradation product. The same was not the case with mixtures containing RHE, as it interacted with H and converted to HYD.…”

Section: Interaction Among Three Drug Combinationsmentioning

confidence: 72%

Drug-Drug Interaction Studies on First-Line Anti-tuberculosis Drugs

Bhutani

Singh

Jindal

2005

Pharmaceutical Development and Technology

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The purpose of this study was to carry out drug-drug compatibility studies on pure first line anti-tuberculosis drugs, viz., rifampicin (R), isoniazid (H), pyrazinamide (Z), and ethambutol hydrochloride (E). Various possible binary, ternary, and quaternary combinations of the four drugs were subjected to accelerated stability test conditions of 40 degrees C and 75% relative humidity (RH) for 3 months. For comparison, parallel studies were also conducted on single drugs. Changes were looked for in the samples drawn after 15, 30, 60, and 90 days of storage. Analyses for R, H, and Z were carried out using a validated HPLC method. The E was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), as it does not absorb in ultraviolet (UV). All single pure drugs were relatively stable and showed only 3%-5% degradation under accelerated conditions for 3 months. However, significant interactions were observed in case of the drug mixtures. In particular, ternary and quaternary drug combinations containing R and H along with Z and/or E were very unstable, showing 90%-95% and 70%-75% loss of R and H, respectively. In all these cases, isonicotinyl hydrazone (HYD) of 3-formylrifamycin and H was found to be the major degradation product. In case of RE and RZE mixtures, where H was absent, 3-formylrifamycin was instead the key degradation product. Another unidentified peak was observed in the mixture containing RZE. Apart from these chemical changes, considerable physical changes were also observed in pure E and the mixtures containing E, viz., RE, ZE, RHE, RZE, and RHZE. In addition, significant physical changes associated with noteworthy loss of H and E were also observed in mixtures containing HE and HZE. The present study thus amply shows that the four primary anti-tuberculosis drugs, when present together, interact with each other in a multiple and complex manner.

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Section: Interaction Among Three Drug Combinationsmentioning

confidence: 72%

Drug-Drug Interaction Studies on First-Line Anti-tuberculosis Drugs

Bhutani

Singh

Jindal

2005

Pharmaceutical Development and Technology

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“…In our laboratory, we are carrying out extensive investigations on the stability behaviour of first-line anti-tuberculosis (TB) agents (viz., rifampicin, isoniazid, pyrazinamide and ethambutol HCl), both when they are present alone or in fixeddose combinations (FDCs) [1][2][3]. As a part of the same, we * Corresponding author.…”

Section: Introductionmentioning

confidence: 99%

LC and LC-MS study of stress decomposition behaviour of isoniazid and establishment of validated stability-indicating assay method

Bhutani

Singh

Vir

et al. 2007

Journal of Pharmaceutical and Biomedical Analysis

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102

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“…This has been ascribed to hydrolysis of rifampicin to an insoluble product in the acidic environment of stomach, and this hydrolysis is accelerated in the presence of isoniazide (48). Furthermore, recent data have shown that this reaction can also be catalyzed by pyrazinamide and ethambutol, the other two drugs of choice for the treatment of tuberculosis (49). Since frequently these four drugs are combined in FDCs, it is imperative to formulate a product that ensures optimal bioavailability of all four actives.…”

Section: In Vivo Interactions Between Components Of the Fdc Prior To mentioning

confidence: 99%

Challenges and Opportunities in Achieving Bioequivalence for Fixed-Dose Combination Products

Mitra

2012

AAPS J

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Abstract. Fixed-dose combination (FDC) products are becoming a popular treatment option because of increased patient compliance and convenience, improved clinical effectiveness, and reduced cost to the patient, among several other reasons. A commonly applied approach for approval of a FDC product is demonstrating bioequivalence between the FDC and co-administration of individual mono-products, provided that there is adequate safety and efficacy data for co-administration of the individual agents. However, achieving bioequivalence between the FDC and individual mono-products can be very challenging, and sometimes not possible since combining multiple active ingredients, especially insoluble molecules, in a single drug product could complicate its biopharmaceutical and pharmacokinetic behavior. In this review, some of the major challenges often encountered while assessing bioequivalence during FDC development will be presented along with discussion of future opportunities to facilitate FDC development and approval.

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Mechanistic explanation to the catalysis by pyrazinamide and ethambutol of reaction between rifampicin and isoniazid in anti-TB FDCs

Cited by 52 publications

References 9 publications

Drug-Drug Interaction Studies on First-Line Anti-tuberculosis Drugs

Drug-Drug Interaction Studies on First-Line Anti-tuberculosis Drugs

LC and LC-MS study of stress decomposition behaviour of isoniazid and establishment of validated stability-indicating assay method

Challenges and Opportunities in Achieving Bioequivalence for Fixed-Dose Combination Products

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