Development of the formulation and manufacturing process of lozenges with Ajania fruticulosa (Ledeb.) Poljak dry extract using the Quality by Design concept

Introduction. This article presents the development of a technology for obtaining lozenges containing Ajania fruticulosa dry extract using the direct compression method. The Quality by Design (QbD) concept reflects a modern approach to pharmaceutical development based on the identification and control of Critical Quality Attributes (CQA) and Critical Process Parameters (CPP) that determine their variability. The application of Design of Experiments (DoE) allows for the quantitative assessment of the influence of technological variables and their interactions, optimization of production conditions, reduction of experimental series volume, and ensuring the control of the technological process.

Aim. To develop the composition and technology of lozenges with Ajania fruticulosa dry extract using the direct compression method and applying the principles of the QbD concept.

Materials and methods. A standardized Ajania fruticulosa dry extract, obtained by maceration with ultrasonic intensification in accordance with the EAEU Pharmacopoeia, was used as the Active Pharmaceutical Ingredient (API). The lozenges were obtained by the direct compression method with varying concentrations of talc (0.1–3.0 %), copovidone (2.0–5.0 %), and compression pressure (15–30 kN). Disintegration time and friability were chosen as the CQAs. Experimental design and statistical analysis were performed using Minitab Statistical Software 22.3.0 (LLC "Minitab", USA) with the DoE module. Disintegration time and friability were determined in accordance with the requirements of the EAEU Pharmacopoeia using ZT 320 and TAR 220 apparatuses (ERWEKA GmbH, Germany).

Results and discussion. The optimal API concentration was 1.5 %. According to the DoE results, the copovidone content and compression pressure had a statistically significant effect on the disintegration time, while the contribution of talc was insignificant. The optimal parameters were: copovidone – 5 %, talc – 2 %, compression force – 22 kN. Under these conditions, the disintegration time was 12.9 min, friability was 0.50 %, and the overall desirability index D = 0.8168.

Conclusion. The implementation of the QbD concept in combination with DoE provided a scientifically grounded approach to the development of lozenges with Ajania fruticulosa dry extract. The developed lozenges meet the requirements of the EAEU Pharmacopoeia and are recommended for scale-up and industrial production.

1. Pharmacopoeia of the Eurasian Economic Union. Volume 1, part 2. Moscow: The Eurasian Economic Commission; 2023. 430 p. (In Russ.)

2. Ghourichay M. P., Kiaie S. H., Nokhodchi A., Javadzadeh Y. Formulation and Quality Control of Orally Disintegrating Tablets (ODTs): Recent Advances and Perspectives. BioMed Research International. 2021;2021:6618934. DOI: 10.1155/2021/6618934.

3. Baitenov M. S. Flora of Kazakhstan. In 2 volumes. Vol. 2. Generic complex of flora. Almaty: Gylym; 2001. 280 p. (In Russ.)

4. Liang J.-Y., Lu P.-Y., Ning A.-Q., Yang Y.-Y., Shao Y.-Z., Xu J. Chemical constituents from the aerial parts of Ajania fruticulosa. Biochemical Systematics and Ecology. 2020;92:104124. DOI: 10.1016/j.bse.2020.104124.

5. Min X., Chen J., Mu W., Huang J., Huang G., Cao J. A new dimeric sesquiterpenoid from Ajania fruticulosa. Phytochemistry Letters. 2025;66:60–65. DOI: 10.1016/J.PHYTOL.2025.02.001.

6. Sampietro D. A., Gomez A. de los A. Gomez A., Jimenez C. M., Lizarraga E. F., Ibatayev Z. A., Suleimen Y. M., Catalán C.A. Chemical composition and antifungal activity of essential oils from medicinal plants of Kazakhstan. Natural Product Research. 2017;31:1464–1467. DOI: 10.1080/14786419.2016.1258560.

7. Jakiyanov A. M., Sakipova Z. B., Zhumashova G. T., Karіm O. A. Method of obtaining an extract from plant raw materials. Utility model patent of the Republic of Kazakhstan No. 7449. 16.09.2022. Available at: https://gosreestr.kazpatent.kz/Utilitymodel/Details?docNumber=354942. Accessed: 14.01.2026. (In Russ.)

8. Gurski C. S., Edison Luna Lazo R., Aparecida Gelinsk M., Antunes Alves L., Schastai Sovinsk M., Henrique Marcondes Sari M., Hiemisch Lobo Borba H., Stumpf Tonin F., Pontarolo R., Mota Ferreira L. Quality by Design applied to pediatric-friendly formulations: a scoping review-based manufacturing process mapping for solid dosage forms. Journal of Drug Delivery Science and Technology. 2025;108:106915. DOI: 10.1016/j.jddst.2025.106915.

9. Shahab M., Bachawala S., Gonzalez M., Nagy Z., Reklaitis G. A hybrid system for design space estimation in a rotary tablet press. International Journal of Pharmaceutics. 2025;678:125663. DOI: 10.1016/j.ijpharm.2025.125663.

10. Geremia M., Bezzo F., Ierapetritou M. G. Design space determination of pharmaceutical processes: Effects of control strategies and uncertainty. European Journal of Pharmaceutics and Biopharmaceutics. 2023;194:159–169. DOI: 10.1016/j.ejpb.2023.12.008.

11. Jakiyanov A. M., Sakipova Z. B., Ibragimova L. N., Ibraeva M. B., Kaldybaeva A. M., Ensebaeva G. B. Pharmaceutical composition from plant substance with antibacterial and antifungal action and method of its preparation. Utility model patent of the Republic of Kazakhstan No. 11229. 03.10.2026. Available at: https://gosreestr.kazpatent.kz/Utilitymodel/Details?docNumber=429851. Accessed: 14.01.26. (In Russ.)

12. Pham E. C., Van V. V. L., Nguyen C. V., Nguyen Duong N. T., Le Thi T. V. Formulation development, optimization, in vivo antidiabetic effect and acute toxicity of directly compressible herbal tablets containing Merremia tridentata (L.) extract. Journal of Drug Delivery Science and Technology. 2023;84:104445. DOI: 10.1016/j.jddst.2023.104445.

13. Nait Bachir Y., Said R. M., Terki N. Z., Antar R., Slamani M., Gharbi D., Foligni R. Biopharmaceutical and Pharmacotechnical Characterization of Plant Powder Tablets Obtained by Direct Compression Process: The Case of Atriplex halimus. Applied Sciences. 2025;15:8623. DOI: 10.3390/app15158623.

14. Bolhuis G. K., Rexwinkel E. G., Zuurman K. Polyols as filler-binders for disintegrating tablets prepared by direct compaction. Drug Development and Industrial Pharmacy. 2009;35:671–677. DOI: 10.1080/03639040802587799.

15. Chaudhary R. S., Patel C., Sevak V., Chan M. Effect of Kollidon VA®64 particle size and morphology as directly compressible excipient on tablet compression properties. Drug Development and Industrial Pharmacy. 2017;44:19–29. DOI: 10.1080/03639045.2017.1371735.

16. Ribet J., Poret K., Arseguel D., Chulia D., Rodriguez F. Talc functionality as lubricant: texture, mean diameter, and specific surface area influence. Drug Development and Industrial Pharmacy. 2003;29:1127–1135. DOI: 10.1081/DDC-120025870.

17. Lakio S., Vajna B., Farkas I., Salokangas H., Marosi G., Yliruusi J. Challenges in Detecting Magnesium Stearate Distribution in Tablets. AAPS PharmSciTech. 2013;14:435–444. DOI: 10.1208/s12249-013-9927-3.

18. Tafere C., Yilma Z., Abrha S., Yehualaw A. Formulation, in vitro characterization and optimization of tastemasked orally disintegrating co-trimoxazole tablet by direct compression. PLOS ONE. 2021;16:e0246648. DOI: 10.1371/journal.pone.0246648.

19. Naman S., Madhavi N., Singh B., Madan J., Baldi A. Implementing risk-based quality by design for development and optimization of flavored oral disintegrating mini tablets. Journal of Drug Delivery Science and Technology. 2021;66:102799. DOI: 10.1016/j.jddst.2021.102799.