(M1130-06-38) Real-Time PAT Monitoring of Coating Process in the Design and Optimization of a Dose-Flexible Tolfenamic Acid Dosage Form for Cancer Indication

Purpose: This research aims to develop a novel, dose-flexible, enteric-coated formulation of tolfenamic acid to address its current clinical limitations and enhance its potential use in cancer therapy. Tolfenamic acid, commonly known as a non-steroidal anti-inflammatory drug (NSAID), has demonstrated significant anti-cancer effects by influencing key molecular pathways, especially by lowering the levels of specific proteins (Sp1, Sp3, and Sp4) and cyclooxygenase-2 (COX-2) in pancreatic cancer. Despite these promising effects, its poor aqueous solubility and the risk of gastric irritation at therapeutic doses have hindered its clinical application. By developing an enteric-coated, dose-flexible formulation, the goal is to protect tolfenamic acid from acidic degradation in the stomach, enhance its absorption in the intestine, and better provide flexibility in dosing to meet individual patient needs. Integrating Process Analytical Technology (PAT) tools aims to ensure precise manufacturing control. Ultimately, this research seeks to establish a safe, personalized treatment option that could improve therapeutic outcomes when tolfenamic acid is used alongside standard chemotherapy regimens.

Methods: The research employed a structured, multi-phase approach, starting with the development and validation of analytical methods such as high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS/MS) for accurate quantification of Tolfenamic acid and its impurities. Solubility studies were conducted across different pH ranges to mimic gastrointestinal conditions and identify the need for solubilizers or excipients that could enhance dissolution. Pre-formulation studies evaluated the physicochemical properties of the active pharmaceutical ingredient (API), including particle size, flowability, hygroscopicity, and compatibility with selected excipients. Based on this data, three different formulations were developed: a simple matrix tablet, an enteric-coated tablet, and a multiparticulate system designed for different release profiles. Process Analytical Technology (PAT), specifically Near-Infrared (NIR) spectroscopy, was integrated to monitor coating thickness and uniformity in real time during manufacturing. Animal pharmacokinetic studies were carried out to compare the absorption characteristics of enteric-coated versus non-enteric-coated formulations. Bioanalytical methods were validated for plasma concentration analysis. Statistical methods are used to interpret pharmacokinetic results. We also collaborated to plan potential pharmacokinetic evaluations in human volunteers.

Results: Initial investigations revealed that the validated analytical methods displayed outstanding performance, characterized by high accuracy (R² = 0.999), sensitivity, and reproducibility in detecting Tolfenamic acid and its associated impurities. These results guaranteed consistency during formulation development and analytical testing. The incorporation of 0.1% sodium lauryl sulfate (SLS) successfully enhanced solubility by 97.4%. Following meticulous adjustments to the ingredients and processing protocols, the final enteric-coated formulation released 87% of the drug within two hours when evaluated in a pH 8.2 buffer, surpassing the requisite Q specification threshold of 75% in two hours. Moreover, the assessment of the divided tablet revealed a 49% drug release after two hours, thereby validating that the enteric-coated and multiparticulate systems successfully postponed drug release in gastric conditions and enabled targeted intestinal delivery.The incorporation of near-infrared (NIR) spectroscopy as a process analytical technology (PAT) tool facilitated real-time monitoring and accurate regulation of the coating process. Through the monitoring of the polymer's spectral peaks, it exhibited characteristics that enabled the system to precisely monitor thickness increment over time during the coating phase. Chemometric modeling of the spectral data demonstrated exceptional predictive accuracy, with the actual coating thickness measured at 15.2%, in contrast to a predicted value of 14.25%, thereby affirming the model's robustness for endpoint determination. Statistical analyses corroborated these findings, demonstrating statistically significant differences between the coated and non-coated formulations. Furthermore, the dose-flexible characteristics of the formulated products enabled personalized patient dosing without compromising the mechanical integrity or pharmacokinetic efficacy of the dosage form.

Conclusion: This research successfully developed a dose-flexible, enteric-coated formulation of tolfenamic acid capable of overcoming its primary limitations of poor bioavailability and gastric irritation. The integration of real-time process analytical technology significantly enhanced manufacturing precision and consistency, demonstrating a clear advantage in quality control over traditional methods. The flexibility of the new dosage forms supports personalized medicine approaches by allowing dose adjustments based on individual patient needs and responses, which is particularly valuable in cancer treatment, where balancing efficacy and toxicity is critical. These advancements lay the groundwork for future clinical evaluations of tolfenamic acid as a safe and effective adjunct to standard anti-cancer therapies. If successful in human trials, this innovative formulation could significantly improve patient outcomes, reduce side effects, and provide a more adaptable treatment regimen for patients with advanced or metastatic cancers.

References: 1. Arora, S., Bhardwaj, A., Srivastava, S. K., Singh, S., McClellan, S., & Singh, A. P. (2013). Tolfenamic acid: A novel approach for pancreatic cancer therapeutics. Frontiers in Physiology, 4, 1-9.
2. Wang, J., Wen, Y., Hu, Y., Zhang, Y., & Lu, J. (2010). Pharmaceutical strategies to improve oral bioavailability of poorly water-soluble drugs. Drug Development and Industrial Pharmacy, 36(9), 1015–1028.
3. Food and Drug Administration (FDA). (2004). Guidance for Industry: PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance.
4. Basit, A. W., & Newton, J. M. (2005). Strategies for oral delivery of poorly soluble drugs using enteric coatings. Pharmaceutical Research, 22(5), 701–708.


Real-time monitoring of the coating process using NIR data of the coating polymer.


Using deviation analysis, compare the actual and expected percentages of weight gain over time.


Dissolution Profiles of Full and Split Tablets show Dose Flexibility.