(W1230-06-39) Development of Sustained Release Isoniazid Formulation Using Twin Screw Melt Granulation

Purpose: Tuberculosis (TB) is a contagious bacterial infection caused by Mycobacterium tuberculosis. It typically affects the lungs but can extend to other organs. Isoniazid (INH), a first-line anti-TB medicine, has been used in combination therapy for many years to treat tuberculosis(1). However, it has  several meaningful considerations, such as regular daily dosing and a high risk of hepatotoxicity, which is frequently associated with increased peak plasma concentrations(2). Furthermore, differences in N-acetyltransferase 2 (NAT2) enzyme activity affect the acetylation rate of INH between individuals. Fast acetylators commonly exhibit subtherapeutic plasma concentrations, increasing the risk of treatment failure, whereas slow acetylators may encounter toxicity at standard dosages(3). A sustained-release (SR) formulation of INH could help mitigate these issues, it would reduce dosing frequency and minimize peak concentration-related toxicity. The purpose of this study was to develop a sustained-release INH formulation using Twin Screw Melt Granulation (TSMG) technology to enhance treatment efficacy.

Methods: A total of 12 formulations containing varying amounts of INH (30–50% w/w), along with different polymers and plasticizers, were prepared (Table 1) and extruded using a Thermo Fisher Process 11 mm extruder (Waltham, MA, USA). A screw configuration featuring three mixing zones was employed. Critical process parameters, particularly barrel temperature and screw speed, were optimized to prevent thermal degradation of INH. The barrel temperature was maintained at 140°C with a screw speed of 75 rpm. Temperatures above 140°C resulted in granule charring, while temperatures below 140°C were insufficient to properly melt and process the mixture. After extrusion, granules were cooled to room temperature before further evaluation. The content uniformity of the granules was assessed via HPLC analysis. The granules were filled in a size 0 capsule containing 90 mg of INH and in vitro dissolution studies were conducted in phosphate buffer (pH 7.4) using USP Apparatus II (paddle) at 100 rpm and 37 ± 0.5°C. Differential scanning calorimetry (DSC) and Fourier-transform infrared spectroscopy (FTIR) analyses were performed to verify the physical state and the molecular interaction of INH following processing.

Results: The Twin Screw Melt Granulation process successfully produced free-flowing granules. Optimizing process parameters demonstrated that controlling barrel temperature at 140°C was critical to producing granules, while the screw speed adjustments allowed for better dispersion and uniformity of granules. DSC analysis demonstrated the absence of an endothermic peak for crystalline INH in the formulations, suggesting molecular dispersion within the polymeric matrix. FTIR spectra indicated no significant chemical incompatibility between INH and excipients. All the formulations had uniform drug content (98%-100%). The in vitro dissolution studies demonstrated distinct release profiles among the different formulations. Pure INH exhibited an immediate release behavior, having 100% drug release within the first 15 minutes. In contrast, the sustained release formulations (F2, F3, F6, F11 and F12) showed a gradual drug release over the 12-hour testing period. Among the formulations, F12 exhibited the most prolonged release, achieving 100% drug release at 12 hours, this behavior may be attributed to the addition of Eudragit® RS PO to the formulation which is a highly viscous water insoluble polymer. F11 achieved 100% release at 10 hours followed by F3 at 8 hours. F6 showed a release profile, reaching 100% drug release by 6 hours. F2 demonstrated a comparatively faster release, attaining 100% drug release within 4 hours (Figure 1).

Conclusion: Twin Screw Melt Granulation is an effective, solvent-free, and continuous manufacturing technique that can be used for the development of sustained release INH formulations. By combining INH with high viscosity polymers, it was possible to produce granules that offered extended drug release. The developed sustained release INH granules could have the potential to enhance patient compliance by reducing dosing frequency and lowering hepatotoxicity risks associated with peak drug concentrations.

References: 1. Öblom H, Zhang J, Pimparade M, Speer I, Preis M, Repka M, et al. 3D-Printed Isoniazid Tablets for the Treatment and Prevention of Tuberculosis—Personalized Dosing and Drug Release. AAPS PharmSciTech. 2019 Feb;20(2):52.
2. Holkunde A, Karnik I, Uttreja P, Narala N, Wang H, Elkanayati RM, et al. Personalized Medicine Through Semisolid-Extrusion Based 3D Printing: Dual-Drug Loaded Gummies for Enhanced Patient Compliance. Pharm Res. 2025 Jan 1;42(1):185–201.
3. Population Pharmacokinetic Analysis of Isoniazid, Acetylisoniazid, and Isonicotinic Acid in Healthy Volunteers | Antimicrobial Agents and Chemotherapy [Internet]. [cited 2025 Apr 29]. Available from: https://journals.asm.org/doi/full/10.1128/aac.01244-15


Table 1. Formulation composition table.


Figure 1.Dissolution profile of pure INH, F2,F3,F6,F11,F12.