Quality specifications for antituberculosis fixed dose combination products
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Objective: The World Health Organization (WHO) requested the Research Institute for Industrial Pharmacy, at the North-West University, Potchefstroom, South Africa, to develop monographs for anti-tuberculosis products for The International Pharmacopoeia (IntPh). These included monographs for rifampicin capsules; rifampicin tablets; isoniazid and ethambutol hydrochloride tablets; rifampicin and isoniazid tablets; rifampicin, isoniazid and pyrazinamide tablets; and rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride tablets. Background: Tuberculosis (TB), caused by Mycobacterium tuberculosis, is an airborne disease that mainly affects the lungs. TB is currently causing a global health emergency and is among the principal killers of HIV infected people. First line anti-tuberculosis medicines include the active pharmaceutical ingredients (APIs) rifampicin, isoniazid, pyrazinamide, ethambutol and streptomycin. The WHO recommends the use of fixed dose combination products (FDCs) for the treatment of TB and multi-drug resistant TB. In the development of monographs, it is important to consider the safety, efficacy, and in particular the quality requirements for FDC products, which comprise stability, assay and identification testing, as well as the determination of degradation products / related substances. Comprehensive guidelines on FDCs, as published by the WHO, were applied in this study. Chemical and physical compatibility of APIs in an FDC, the degradability of each API under conditions of stress when in combination with other APIs, as well as API-excipient incompatibility, are important considerations for FDCs and their specifications. The reaction between isoniazid and rifampicin to form 3-(isonicotinoylhydrazinomethyl) rifamycin (commonly known as the isonicotinyl hydrazone, or rif-iso hydrazone) is particularly important, as this could result in a loss of therapeutic activity of rifampicin, that could lead to reduced bioavailability, poor patient compliance and subsequently failure to cure TB. Experimental procedure: Methods were developed for identity, assay and related substances testing. Although not requested by the WHO, it was decided to develop a dissolution test for isoniazid and ethambutol hydrochloride tablets, for which the WHO had supplied a number of different brands of products. The aims were to compare the dissolution profiles being generated during this study with those presented in the relevant WHO draft guideline (Chapter 4), and to establish whether the recommended dissolution conditions and specifications were appropriate for control of these FDC products. General requirements set for HPLC assay methods were: one method for more than one API, easily available columns, the use of an isocratic profile, stability-indicating methods, and the possibility of determining related substances using the same assay method(s). HPLC methods from available literature were identified, screened and the best alternatives selected for further development. Method development and validation were initially performed on the 4FDC tablets, then adjusted for lower API combinations and eventually for Rifampicin tablets and capsules. The assay method for determining rifampicin was also used for testing rifampicin degradation products. An infrared spectroscopic method was developed as identity test for Rifampicin tablets and capsules. As an alternative for identifying rifampicin in Rifampicin tablets and capsules a colour -, a TLC - and an HPLC test (based on correlating retention times of Rifampicin in the sample and standard solutions from the assay test results) were developed. For the FDC products, two identity tests (HPLC and TLC) were developed. Results and discussion: 4FDC products were successfully analysed by employing two methods, i.e. one for analysing ethambutol hydrochloride, isoniazid and pyrazinamide, and a second for analysing rifampicin and its related substances. Ethambutol hydrochloride does not absorb UV light; however, it forms a complex with cupric ions, with maximum absorption at 270 nm. By including Cu(II) acetate in the mobile phase, ethambutol hydrochloride was successfully quantified by UV detection. For the assay of FDC products not containing ethambutol hydrochloride, Cu(II) acetate was omitted from the mobile phase. The validation outcomes confirmed the suitability of these methods. The mobile phase of the TLC test for the identification of APIs in FDC products, consisted of methano1:strong ammonia solution (100:1.5). The TLC plate could be inspected under W light (254 nm) after exposing it to iodine vapours. In the absence of W light (254 nm), the pyrazinamide spot was only vaguely visible when inspected in daylight after iodine exposure. The spot-intensity of isoniazid, pyrazinamide and ethambutol hydrochloride is concentration dependent and can be used for semi-quantitative determination of these APIs in anti-tuberculosis FDCs. The dissolution study was conducted according to the conditions as set out in a draft WHO guideline for products containing BCS (Biopharmaceutics Classification System) defined, highly soluble APIs. The study and acceptance criterion were accepted by the WHO and included in the monograph for isoniazid and ethambutol hydrochloride tablets. Disintegration has been included as an alternative to dissolution, with the acceptance criterion based on a correlation between the dissolution profiles and disintegration times, as had been determined for products being supplied by the WHO. Conclusion: The monographs were compiled according to the format, as required by the WHO, and submitted to the WHO. The monographs were distributed for review within the WHO advisory channels and discussed at WHO consultation and expert committee meetings. Feed-back was considered and the monographs updated accordingly. The monographs were approved for The International Pharmacopoeia during a meeting of the 4oth WHO Expert Committee on Specifications for Pharmaceutical Preparations. The monographs have been posted on the WHO website and are to be included in the fourth edition of The International Pharmacopoeia.
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