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Differentiating Resistance from Formulation Failure: Isoniazid Instability and Poor Dissolution in Crushed Multi-Drug
Halima Samsodien1, Jana Winkler2, Marique Aucamp1
1Pharmaceutics Discipline, School of Pharmacy, University of the Western Cape, Robert Sobukwe Road, Bellville, Cape Town 7535, South Africa.
Pharmaceutics
|March 28, 2026
Summary
Crushing and suspending anti-tuberculosis drugs like isoniazid (INH) can degrade the medication, leading to undetectable drug levels. This highlights the need for careful formulation to ensure accurate paediatric dosing and avoid misinterpreting formulation failure as drug resistance.
Area of Science:
- Pharmaceutical Sciences
- Drug Formulation
- Analytical Chemistry
Background:
- Bedside manipulation of adult anti-tuberculosis tablets for pediatric dosing is common in low-resource settings.
- This practice can compromise drug stability and accurate dosing.
- Investigating the impact of manipulation on drug integrity is crucial for pediatric tuberculosis treatment.
Purpose of the Study:
- To investigate the effects of grinding and co-suspension on isoniazid (INH) stability and dissolution.
- To assess the supramolecular organization and thermal stability of INH under simulated pediatric formulation conditions.
- To differentiate between true drug resistance and formulation failure in pediatric multi-drug resistant tuberculosis (MDR-TB) regimens.
Main Methods:
- Analysis of INH raw, branded tablets (whole and ground), and multi-drug combination mixtures (MCMs).
- Utilized hot-stage microscopy (HSM), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), Raman spectroscopy, FTIR-ATR, USP dissolution, and HPLC.
- Assessed samples in both solid states and aqueous suspensions across different pH conditions.
Main Results:
- Grinding and co-mixing altered INH's thermal properties and supramolecular structure, indicated by spectroscopic shifts.
- In multi-drug suspensions, INH levels fell below HPLC quantification limits at pH 1.2 and 6.8, suggesting complex formation.
- Dissolution testing revealed minimal INH release from suspensions compared to intact tablets/API, particularly at pH 6.8.
Conclusions:
- Co-suspension of INH with other TB drugs disrupts its supramolecular integrity, causing degradation before administration.
- The study identified a significant loss of quantifiable INH in simulated pediatric suspensions.
- Rational formulation design is essential to maintain drug stability and accurately assess treatment efficacy, distinguishing formulation issues from true drug resistance.
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