Strategic Modulation of Isoniazid Solubility through Cocrystal Formation for Long-Acting Microneedle Therapy of Tuberculosis

Tuberculosis (TB), caused by <i>Mycobacterium tuberculosis</i>, remains a global health emergency, particularly in low- and middle-income countries. Despite effective pharmacotherapy, prolonged treatment, poor adherence, and drug resistance continue to hinder eradication. Isoniazid (ISZ), a first-line antitubercular drug, is effective but limited by high aqueous solubility and short half-life, necessitating daily administration and causing plasma fluctuations. Considering these limitations, strategies to modulate ISZ solubility without altering pharmacodynamics are therefore of therapeutic interest. In this study, we report the design, synthesis, and characterization of a cocrystal of ISZ with salicylic acid (SA), a GRAS-status coformer with low solubility. Cocrystallization was employed to reduce ISZ solubility, enhancing its potential for sustained release. The ISZ-SA cocrystal was confirmed as a distinct crystalline phase by FTIR, DSC, and PXRD, and subsequently incorporated into dissolving microneedle array patches (MAPs) fabricated from biocompatible polymers via aqueous casting. These MAPs dissolve after skin insertion, releasing their load into the dermal microenvironment. FTIR confirmed the cocrystal's structural integrity within the polymeric matrix, with no dissociation observed during formulation. <i>In vitro</i> release studies showed that ISZ-SA exhibited a slower, more sustained release compared to pure ISZ. <i>Ex vivo</i> dermatokinetic studies revealed significantly greater deposition of ISZ in epidermis (89%, 171.1 μg) and dermis (90%, 468.3 μg) with the cocrystal versus pure drug (36%, 210.0 μg). Enhanced dermal retention suggests localization within skin layers, acting as a depot for gradual systemic absorption. In contrast, pure ISZ permeated faster but deposited less, underscoring the cocrystal's sustained delivery advantage. This work is among the first demonstrations of pharmaceutical cocrystals integrated into dissolving MAPs for transdermal delivery. Cocrystal engineering combined with MAPs may overcome inherent limitations of hydrophilic drugs like ISZ, enabling long-acting formulations that reduce dosing frequency, improve adherence, and enhance TB treatment outcomes, with potential application to other high-solubility drugs.