Isoniazid, pyrazinamide and rifampicin content variation in split fixed-dose combination tablets

Area of Science:

• Pharmaceutical Sciences
• Paediatric Medicine
• Drug Quality Control

Background:

• Paediatric tuberculosis treatment in developing nations often relies on splitting fixed-dose combination (FDC) tablets.
• This practice raises concerns about accurate drug delivery and patient exposure to Isoniazid, Pyrazinamide, and Rifampicin.
• Limited data exists on the content uniformity of first-line anti-tuberculosis drugs in split FDC tablets.

Purpose of the Study:

• To assess the content uniformity of Isoniazid, Pyrazinamide, and Rifampicin in split FDC tablets.
• To evaluate the quality of split FDC tablets against established pharmacopoeial standards.
• To determine the suitability of split FDC tablets for accurate paediatric tuberculosis treatment.

Main Methods:

• Analysis of drug content in 15 whole, 30 half, and 36 third tablets using high-performance liquid chromatography (HPLC).
• Assessment of content uniformity by comparing measured drug amounts in split portions against expected values.
• Evaluation of split portion quality based on qualitative specifications for whole tablets.

Main Results:

• All whole tablets met United States Pharmacopeia (USP) proxy standards for the three drugs.
• A significant proportion of half and third tablet portions fell outside the acceptable variation range.
• The split FDC tablet formulation failed to meet content uniformity requirements, even with weight-adjustment strategies.

Conclusions:

• Split FDC tablets exhibit non-uniform drug content for Isoniazid, Pyrazinamide, and Rifampicin, exceeding USP recommendations.
• The current practice of splitting tablets compromises therapeutic efficacy and safety in paediatric tuberculosis treatment.
• Development and availability of child-friendly, fixed-dose formulations are essential for effective childhood tuberculosis management.