Application of the quality by design (QbD) approach for the development of composition of extended-release tablets based on sodium 4,4’-(propanediamido)dibenzoate

Introduction. Pharmaceutical development is a complex work, the main goal of which is to achieve the quality target product profile (QTPP). QTPP is formulated on the basis of a whole set of requirements for the drug, including pharmacopoeial, consumer, pharmacological, etc. The traditional empirical approach to the development of the composition and technology of the dosage form in this case seems to be labor and resource-intensive, while it does not fully achieve an understanding of all processes both from the point of view of technology and from the point of view of further stages of the life cycle of the drug. The Quality by Design (QbD) approach allows you to assess the impact of factors on processes, which, in turn, contributes to proactive risk management and the creation of robust technologies.

Aim. Demonstrate the comprehensive use of QbD tools, including expert systems (Sediment Delivery Model, SeDeM), experimental planning (Design of Experiment, DoE) and risk analysis, using the example of the development of prolonged-release tablets based on sodium 4,4’-(propanediamido)dibenzoate.

Materials and methods. The paper uses the original active pharmaceutical ingredient (API) – sodium 4,4’-(propanediamido) dibenzoate, modern excipients and polymers that provide prolonged release (ethylcellulose, hydroxypropyl methylcellulose, etc.). At the first stage, the SeDeM method was used to design the compositions. In the second step, screening DoE was used to optimize the release profile

Results and discussion. The SeDeM method made it possible to quantify and neutralize the risks associated with the unsatisfactory technological properties of the API. Compositions with satisfactory technological properties were designed and experimentally confirmed. As a result of DoE, it was found that HPMC provides the most complete and uniform release (more than 80% in 12 hours), close to zero-order release kinetics.

Conclusion. The comprehensive use of QbD tools made it possible to effectively and reasonably develop a robust composition of prolonged-release tablets based on sodium 4,4’-(propanediamido) dibenzoate, providing both the required technological properties and the required release profile.

1. Lurian S., Turdean L., Tomuta I. Risk assessment and experimental design in the development of a prolonged release drug delivery system with paliperidone. Drug Design, Development and Therapy. 2017;11:733–746. DOI: 10.2147/DDDT.S125323.

2. Castillo Henríquez L., Vargas Zúñiga R., Carazo Berrocal G., Madrigal Redondo G., Calvo Guzmán B., Baltodano Viales E. Development of immediate release Rupatidine fumarate 10 mg tablets: A Quality by Design (QbD) approach. Drug Development and Industrial Pharmacy. 2019;45(10):1674–1681. DOI: 10.1080/03639045.2019.1652637.

3. Singh L., Sharma V. Implementation of Quality by Design Principles for the Evolution of optimized Sustained Release Drug Delivery System. Drug Delivery Letters. 2021;11:233–247. DOI: 10.2174/2210303111666210421121812.

4. Sousa A. S., Serra J., Estevens C., Costa R., Ribeiro A. J. A quality by design approach in oral extended release drug delivery systems: where we are and where we are going? Journalof Pharmaceutical Investigation. 2023;53:269–306. DOI: 10.1007/s40005-022-00603-w.

5. Son A.-W., Kim H. C., Kim D.-H., Ahn J.-Y., Park Y.-J., Kim J.-E. Quality-by-design applied development of tianeptine sodium sustained-release once-a-day dosing tablet. Journal of Pharmceutical Investigation. 2025;55:497–519. DOI: 10.1007/s40005-024-00707-5.

6. Chauhan B., Lata K., Agnihotri J., Kumar D. Formulation of Nanocrystal Loaded Racecadotril Immediate Release Tablets Using Quality by Design – QbD Approach. Journal of Neonatal Surgery. 2025;14(16S):668–679.

7. Smekhova I. E., Shigarova L. V., Andreeva P. I., Flisyuk E. V., Dzyuba A. S. Application of Quality-by-Design approach to justify the composition and technology of two-component suppositories. Drug development & registration. 2022;11(4):142–149. (In Russ.) DOI: 10.33380/2305-2066-2022-11-4-142-149.

8. Shmarova A. A., Pivovarova N. S., Abrosimova O. N. Risk-based approach in obtaining and analysing the characteristics of baikal skullcap suspension cultures. Drug development & registration. 2022;11(3):47–56. (In Russ.) DOI:10.33380/2305-2066-2022-11-3-47-56.

9. Kotsur J. M., Ladytko J. M., Narkevich I. A., Flisyuk E. V. Prediction of the composition of prolonged release tablets based on 4,4’-(propandiamido) sodium dibenzoate using the SeDeM method. Drug development & registration. 2021;10(4):54–62. (In Russ.) DOI: 10.33380/2305-2066-2021-10-4(1)-54-62.

10. Kotsur Yu. M., Flisyuk E. V., Sidorov K. O., Titovich I. A., Narkevich I. A. Study of the Effect of Matrix-forming Polymers on the Release Rate of Sodium 4,4’-(propanediamido)dibenzoate from Tablets. Drug development & registration. 2023;12(4):91–95. (In Russ.) DOI: 10.33380/2305-2066-2023-12-4-1579.

11. Flisyuk E. V., Kotsur J. M., Narkevich I. A., Smekhova I. E., Ivkin D. Yu. Development of the "Dissolution" test method for tablets of sodium 4,4’-(propanediamido)dibenzoate with sustained release. Drug development & registration. 2021;10(4):146–154. (In Russ.) DOI: 10.33380/2305-2066-2021-10-4(1)-146-154.

12. Golubev A. N., Nguyen T. S., Basevich A. V., Sorokin V. V., Kaukhova I. E., Marchenko A. L., Smirnova E. M. Approaches to the Development of Drugs with the Use of Modern Statistical Software Concepts and Quality-by-Design. Drug development & registration. 2019;8(3):45–48. (In Russ.) DOI: 10.33380/2305-2066-2019-8-3-45-48.

13. Terenteva O. A., Flisyuk E. V., Ivkin D. Yu., Narkevich I. A. Development of the Composition and Technology of New Neuroprotective Drug Tablets Using Fractional Factorial Design. Drug development & registration. 2020;9(1):18–22. (In Russ.) DOI: 10.33380/2305-2066-2020-9-1-18-22.