Original Article FORMULATION AND EVALUATION OF MOUTH-DISSOLVING ORAL FILM OF NICOTINE USING QUALITY BY DESIGN APPROACH SACHIN DATTRAM PAWAR 1,2 , NAGOJI SHINDE 2 , GUNDAWAR RAVI 1 , TUKARAM KALYANKAR 2* 1 Department of Pharmaceutical Quality Assurance, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, India. 2 Department of Quality Assurance, School of Pharmacy, Swami Ramanand Teerth Marathwada University, Vishnupuri, Nanded-431606, Maharashtra, India * Corresponding author: Tukaram Kalyankar; * Email: kalyankarr@gmail.com Received: 05 Feb 2025, Revised and Accepted: 11 Apr 2025 ABSTRACT Objective: Nicotine is a natural alkaloid found in Nicotiana tabacum and is widely used as a potent stimulant. This study aims to extract and characterize nicotine from tobacco powder and formulate a nicotine-containing Oral Fast-Dissolving Film (OFDF) for nicotine replacement therapy. Methods: Nicotine was extracted from tobacco using water and Hydrochloric Acid (HCL). Purification was performed using column chromatography. The extracted nicotine was characterized using UV-visible spectroscopy, XRD, SEM, and FTIR. The OFDF was prepared using a Quality by Design (QbD) approach; a factorial design 3x3 was employed for film optimization. The solvent casting method was used for film preparation. The optimized formulation was evaluated for folding endurance, disintegration time, and drug release. Stability studies were performed as per ICH guidelines. Results: The extraction process successfully yielded purified nicotine in crystalline form, having a crystalline index of 88.89%. The extracted nicotine shows lambda max at 260 nm; the FTIR study confirms the stretching and bending vibration frequencies for nicotine. The polymer Hydroxypropyl Methylcellulose (HPMC-E5) and plasticizer Polyethylene Glycol (PEG) concentrations (w/w) were selected as independent variables. At the same time, disintegration time, folding endurance, and dissolution time were evaluated as dependent variables for QbD. All the formulations were assessed, and FF3 is the optimized batch based on the dissolution, drug content, and folding endurance. Conclusion: Nicotine was extracted and purified. The purified nicotine was then incorporated into an OFDF, which exhibited rapid disintegration and dissolution. This formulation can aid patients experiencing nicotine withdrawal symptoms by providing a safer, immediate nicotine release. Keywords: Nicotine, Extraction, OFDF, Powder characterization, SEM, XRD © 2025 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/) DOI: https://dx.doi.org/10.22159/ijap.2025v17i4.53880 Journal homepage: https://innovareacademics.in/journals/index.php/ijap INTRODUCTION Oral Fast-Dissolving Film (OFDF) has recently gained popularity in the pharmaceutical industry because of its immediate release action. This OFDF was developed based on the transdermal patch technology OFDF [1]. OFDF disintegrates within a minute when it comes in contact with the saliva and releases the drug [2]. The OFDF system emerged as an economical way of administering unit doses of medication to normal, pediatric, and geriatric patients who have difficulty swallowing standard pills, capsules, liquid orals, or syrup [3]. The delivery method comprises a thin oral strip that quickly absorbs saliva, hydrates rapidly, and sticks to the application site [4] when placed under the patient's tongue [5]. The film then disintegrates and dissolves, releasing the drug for absorption through the mucosal route. This maintains quick-dissolving properties and allows gastric absorption when ingested [6]. Recently, research has focused more on the buccal and sublingual drug delivery systems because of their unique anatomy and physiology. Nicotine pouches recently caught researchers' attention. It is a new class of nicotine products and is non-intrusive and appealing, especially to younger demographics [7]. Some studies raise concerns about the safety of nicotine pouches used in the US for smoking cessation, prompting researchers to analyze their trends [8]. Researchers are also working on the potential of oral film alternatives to conventional tablets for erectile dysfunction treatment. A novel sildenafil citrate-loaded orally dissolving film was prepared for rapid disintegration [9]. The combination of dexamethasone oral film was provided to the breast cancer patient undergoing highly emetogenic chemotherapy as an antiemetic [10]. The Quality by Design (QbD) principle has led to significant advancements in drug delivery, especially in formulation optimization [11]. The preparation and characterization of solid lipid nanoparticles for bioavailability enhancement follow a QbD approach to ensure quality and performance [12]. The systematic use of QbD helps to improve product quality consistency, optimize formulation process parameters, regulatory compliance, faster approval, and cost-time efficiency in development [13, 14]. Nicotine is an exogenous agonist for most nicotinic acetylcholine receptors (nAChRs), except nAChRα9 and nAChR10 [15, 16]. Found in N. tabacum, D. hopwoodii, A. syriaca, and N. rustica leaves (2– 14%), its delivery remains challenging due to physicochemical properties and adverse effects. Nicotine is highly addictive [17]. Nicotine is one of the most commonly abused substances. It acts as a Central Nervous System (CNS) stimulant. An ordinary cigarette delivers 1–2 mg of nicotine, while excessive doses (30–60 mg) can be hazardous. In animals, it induces both anxiety and behavioral excitement [18]. Nicotine addiction involves drug-reinforced behavior, compulsive use, and relapse after withdrawal. It includes tolerance, sensitization, and both physical and psychological dependence. Withdrawal symptoms include distress, depressed mood, tension, anxiety, irritability, difficulty concentrating, and sleep disturbances [19]. According to the survey, nicotine is the most addictive drug. Quitting smoking is complex and may need multiple efforts; people who stop smoking frequently relapse due to withdrawal symptoms, stress, and weight gain [20, 21]. Tobacco smoke contains a lethal combination of over 7,000 compounds, of which hundreds are toxic and approximately 70 can cause cancer. Smoking raises the chance of significant health problems, a variety of diseases, and even death. People who cease smoking have a much lower risk of disease and premature mortality. However, the health benefits to people are more significant [22]. Many nicotine delivery systems are available on the market, such as nicotine gums, lozenges, nicotine pouches, and ENDS (electronic nicotine delivery systems). In the case of nicotine chewing gum, active chewing is required, and an older person cannot chew for a International Journal of Applied Pharmaceutics ISSN- 0975-7058 Vol 17, Issue 4, 2025