Enhancement of Topical Delivery of Aceclofenac Using Limonene: A Quality by Design Approach
Abstract
Aceclofenac is a non-steroidal anti-inflammatory drug used to treat pain and inflammation caused by musculoskeletal disorders. Oral administration of Aceclofenac is associated with various gastrointestinal side effects like dyspepsia, abdominal pain, or discomfort. To reduce systemic side effects and to improve patient compliance, a topical gel was formulated using the Quality by Design approach. The Aceclofenac gel was prepared by using Carbopol 974P as a polymer and optimized by custom design. The design suggested 8 runs for 3 factors (Carbopol 974P, limonene and PEG 400) and 2 responses (viscosity, in vitro drug release). The 8 different formulations were prepared and evaluated. The optimized topical gel was characterized for homogeneity, pH, spreadability, viscosity, drug content, in vitro drug release, ex vivo permeation, and stability studies. The optimized Aceclofenac gel formulation predicted global desirability was 0.9980; in-vitro and ex vivo studies were found to be 84.64% and 77.42%. The drug release kinetics were analyzed using zero-order drug kinetics, the highest correlation of 0.999. A stability study was performed, and the shelf life was predicted to be 23.8 months using JMP statistical software. The optimized Aceclofenac gel avoids the first pass metabolism, and it showed a significantly enhanced permeability through the porcine skin and good stability.
Keywords:
Aceclofenac, Custom Design, Limonene, Quality by Design, Shelf Life
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References
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Sanap, S. N., Bisen, A. C., Mishra, A., Biswas, A., Agrawal, S., Yadav, K. S., ... & Bhatta, R. S. (2022). QbD based antifungal drug-loaded ophthalmic liposomal formulation for the management of fungal keratitis: in vitro, ex vivo and in vivo pharmacokinetic studies. Journal of Drug Delivery Science and Technology, 74, 103517. https://doi.org/10.1016/j.jddst.2022.103517
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Ali, S. S., De, P. K., & Maji, H. (2025). Development and assessment of aceclofenac gel-based topical formula. International Journal of Scientific Research and Technology, 2(2), 115 – 124. https://doi.org/10.5281/zenodo.14873940
Anaya-Mancipe, J. M., Carlos, A. L. M., Bastos, J. V. D. D. A., Tovar Ambel, E. M., Velasco-Díez, G., Fialho, R. L., &Thiré, R. M. D. S. M. (2025). Solution blow spun mats with beaded-fiber morphologies as a drug delivery system with potential use for skin wound dressing. ACS Applied Materials & Interfaces, 17(16), 23466-23483. https://doi.org/10.1021/acsami.4c16675
Bayan, M. F., Chandrasekaran, B., & Alyami, M. H. (2023). Development and characterization of econazole topical gel. Gels, 9(12), 929. https://doi.org/10.3390/gels9120929
Benetti, C., & Benetti, A. A. (2024). Quality by Design in Formulation Development. In: Jain, N.K., Bajwa, N. (eds) Introduction to Quality by Design (QbD). Springer, Singapore. https://doi.org/10.1007/978-981-99-8034-5_6
Chaturvedi, S., Ayaz, S., & Shah, K. (2021). Validated UV Spectrophotometric Method for in-vitro Dissolution Studies in Phosphate Buffer pH 7.4. International Journal of Pharmaceutical Sciences and Research, 12(4), 2417-2421. https://doi.org/10.13040/IJPSR.0975-8232.12(4).2417-21
Conforti, A., Di Cola, I., Pavlych, V., Ruscitti, P., Berardicurti, O., Ursini, F., ... & Cipriani, P. (2021). Beyond the joints, the extra-articular manifestations in rheumatoid arthritis. Autoimmunity Reviews, 20(2), 102735. https://doi.org/10.1016/j.autrev.2020.102735
Deshmukh, P. P., Changediya, V., & Rajurkar, V. (2022). Formulation and development of transdermal patches of ibuprofen with novel penetration enhancers. World Journal of Pharmaceutical Research, 11(2), 561-577. https://doi.org/10.20959/wjpr202212-25317
Devi, K., Joshi, V. G., Kabra, P., Malviya, N., Bukka, R., Nargund, R., ... & Nargund, S. L. (2025). Transfersomes: A Review for Transdermal Drug Delivery. World Journal of Research and Review (WJRR), 20(5), 32-38. https://doi.org/10.31871/WJRR.20.5.25.
Elgaddal, N., Kramarow, E. A., Weeks, J. D., & Reuben, C. (2024). Arthritis in adults age 18 and older: united states, 2022. US Department of Health and Human Services, Centers for Disease Control and Prevention. National Center for Health Statistics. https://dx.doi.org/10.15620/cdc:145594
Fytory, M., Alabrahim, O. A. A., Abouzid, A. E., Lababidi, J. M., …………&Azzazy, H. M. E. (2026). β-Cyclodextrin Inclusion Complex of d-Limonene: A Promising Biocompatible Formula for Enhanced Wound Healing—In Vitro and In Vivo Studies. Journal of Biomedical Materials Research Part A, 114, e70016. https://doi.org/10.1002/jbma.70016
Gavinet, B., Sigurani, S., Garcia, C., & Roso, A. (2024). Alternatives to Conventional Topical Dosage Forms for Targeted Skin Penetration of Diclofenac Sodium. International Journal of Molecular Sciences, 25(13), 7432. https://doi.org/10.3390/ijms25137432
Hanif, A. M., Bushra, R., Shafiq, Y., Aslam, N., Mughal, M. A., Huma, A., ... & Khan, M. A. (2023). Influence of different gelling polymers on dexibuprofen gel formulation: In-vitro characterization and stability profile. Pakistan Journal of Pharmaceutical Sciences, 36(1 special), 287-293. https://doi.org/10.36721/PJPS.2023.36.1.SP.287293.1
Karamkar, P. G., Agrawal, A., &Chatap, V. K. (2023). A review article: Formulation of topical gel by QbD approach. Advances in Pharmacology and Pharmacy, 11(2), 90-101. https://doi.org/10.13189/app.2023.110202
Korzeniowska, K., &Malesza, K. (2023). Aceclofenac-induced gastrointestinal adverse reactions-a case report and literature review. Anaesthesiology& Rescue Medicine / Anestezjologia i Ratownictwo, 17(1), 19 pages. https://doi.org/10.53139/AIR.20231703
Kovács, A., Falusi, F., Gácsi, A., Budai-Szűcs, M., Csányi, E., Veréb, Z., ... & Berkó, S. (2024). Formulation and investigation of hydrogels containing an increased level of diclofenac sodium using risk assessment tools. European Journal of Pharmaceutical Sciences, 193, 106666. https://doi.org/10.1016/j.ejps.2023.106666
Kumar, A., & Kumar, M. (2025). Design, characterization, and evaluation of an aceclofenac cocrystal for improved solubility and stability. Journal of Applied Pharmaceutical Research, 13(6), 132-145. https://doi.org/10.69857/joapr.v13i6.1699
Mahanty, J., Rasheed, S. H., Kumar, S., Singh, H., & Sharma, A. (2023). Potential of essential oils as alternative permeation enhancers for transdermal delivery. World Journal of Traditional Chinese Medicine, 9(3), 258-269. https://doi.org/10.4103/2311-8571.351508
Moretti, A., Snichelotto, F., Liguori, S., Paoletta, M., Toro, G., Gimigliano, F., &Iolascon, G. (2024). The challenge of pharmacotherapy for musculoskeletal pain: an overview of unmet needs. Therapeutic Advances in Musculoskeletal Disease, 16, 1759720X241253656. https://doi.org/10.1177/1759720X241253656
Opatha, S. A. T., Titapiwatanakun, V., Boonpisutiinant, K., &Chutoprapat, R. (2022). Preparation, characterization and permeation study of topical gel loaded with transfersomes containing asiatic acid. https://doi.org/10.3390/molecules27154865
Rani, K. R. V., Rajan, S., Bhupathyraaj, M., Priya, R. K., Halligudi, N., Al-Ghazali, M. A., ... &Pol, P. D. (2022). The Effect of Polymers on Drug Release Kinetics in NanoemulsionIn Situ Gel Formulation. Polymers 2022, 14(3), 427.https://doi.org/10.3390/polym14030427
Salloum, R., Baddour, F., & Abbood, A. (2024). A Questionnaire to Evaluate Undergraduate Students’ Consumption and Awareness of Non-Steroidal Anti-Inflammatory Drugs in Syria. International Journal of Advanced Pharmaceutical Sciences and Research (IJAPSR), 4(4), 1-6. http://doi.org/10.54105/ijapsr.C4041.04040624
Sanap, S. N., Bisen, A. C., Mishra, A., Biswas, A., Agrawal, S., Yadav, K. S., ... & Bhatta, R. S. (2022). QbD based antifungal drug-loaded ophthalmic liposomal formulation for the management of fungal keratitis: in vitro, ex vivo and in vivo pharmacokinetic studies. Journal of Drug Delivery Science and Technology, 74, 103517. https://doi.org/10.1016/j.jddst.2022.103517
Schlich, M., Lai, F., Maria Fadda, A., Sinico, C., & Pini, E. (2021). Drug-excipients compatibility studies in proniosomal formulation: A case study with resveratrol. Journal of Nanoscience and Nanotechnology, 21(5), 2917-2921. https://doi.org/10.1166/jnn.2021.19056
Shah, R. S. (2021). Formulation and evaluation of Turmeric emulgel. Asian Journal of Pharmacy and Technology, 11(3), 213-2199. http://dx.doi.org/10.52711/2231-5713.2021.00035
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Govindarajan, S., Narayanappa, S., Samy, M., Patil, S. and Reddy, T. (2026) “Enhancement of Topical Delivery of Aceclofenac Using Limonene: A Quality by Design Approach”, International Journal of Advancement in Life Sciences Research, 9(3), pp. 25-42. doi: https://doi.org/10.31632/ijalsr.2026.v09i03.003.
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