**4. Conclusions**

Palatable orodispersible film formulations are ideal for patients with swallowing di fficulties such as pediatrics because they are stable and dissolve rapidly within the oral cavity in the presence of saliva, without the need to chew or drink water. This current investigation details the successful preparation, optimization and evaluation of an edible, co-polymeric orodispersible pharmaceutical formulation containing pyrazinamide, a model first line antitubercular agen<sup>t</sup> suitable for use in actively infected children. The orodispersible formulation was manufactured by blending polymeric and non-polymeric excipients with drug molecules in an aqueous milieu coupled with the solvent casting approach. The production and optimization processes were facilitated by a one-variable-at-a-time and high performance Box Behnken experimental sesign approaches. The optimized orodispersible formulation was hollow-shaped, uniformly whitish in color, mechanically robust and bendable enough to withstand safe handling. It disintegrated rapidly (34.98 ± 3.00 s) under biorelevant conditions, maintained a close to neutral surrounding pH of 6.90 ± 0.25 and total matrix dissolution and drug release, an indication of complete drug absorption, occurred at approximately 60 min. Drug release from the optimized formulation followed the Korsmeyer–Peppas mathematical model, showing that drug liberation was controlled by anomalous di ffusion coupled with matrix disintegration and erosion mechanisms. Pyrazinamide molecules were well incorporated into the formulation matrix and displayed a high loading capacity (25.02 ± 0.71 mg ≡ 101.13 ± 2.03 %*<sup>w</sup>*/*w*). According to the WHO, a pediatric patient requires an average dose of 35 mg/kg, meaning that multiple films (relative to body weight) may be needed per child; an approach not unusual in TB managemen<sup>t</sup> with oral or water dispersible tablets. This may therefore be more usable in under 5-year-old children and, should not pose any choking hazards considering the rapidly disintegrating characteristic of the fabricated pyrazinamide films which does not necessitate the use of water for swallowing. Captured SEM micrographs and digital photographs showed that the drug formulation matrix was micro-structured and also confirmed its quick disintegration sequence. The orodispersible drug preparation was thermodynamically and environmentally stable under specific storage conditions based on findings from physicochemical characterization (TGA, DSC, FTIR, XRD, BET analyses) and stability testing processes. Preliminary organoleptic and cell toxicity enquiries presented the drug formulation as palatable, easy-to-handle and biocompatible under applied test conditions. In conclusion, the orodispersible pharmaceutical formulation developed herein can potentially ease some of the current global challenges associated with the safe administration of TB antibiotics in pediatric patients to aid desirable pharmacotherapeutic outcome. Besides, the carrier matrix designed in this study may be used as is or even modified to accommodate and safely improve the release/absorption of other antitubercular agents for use in children.

**Author Contributions:** Conceptualization, O.A.A.; Methodology, O.A.A., N.M., J.W.-S.; Software, O.A.A.; Formal Analysis, N.M., O.A.A., J.W.-S.; Investigation, N.M., O.A.A., J.W.-S.; Resources, O.A.A., J.W.-S.; Data Curation, O.A.A., N.M.; Writing—Original Draft Preparation N.M.; Writing—Review & Editing O.A.A., N.M., J.W.-S.; Visualization, O.A.A., N.M.; Validation, O.A.A., N.M., J.W.-S.; Supervision, O.A.A., J.W.-S.; Project Administration, O.A.A.; Funding Acquisition, O.A.A. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was funded by the South African National Research Foundation (Grant Number: 113143) and Sefako Makgatho Health Sciences University-DHET Research Development Grant (Grant Number: D112-RDG).

**Acknowledgments:** The authors thank the National Centre for Nano-structured Materials, Council for Scientific and Industrial Research, Pretoria, South Africa and the Preclinical Drug Development Platform, North-West University, Potchefstroom, South Africa for sample characterization and cytotoxicity testing respectively. We are grateful to Chantelle Baker from the SMU Electron Microscopy Unit, Pretoria, South Africa for her valuable advice and discussions.

**Conflicts of Interest:** The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
