Development Of A Quality By Design Framework For Oral Solid Dosage Forms (Atorvastatin Calcium Ir) Using In-Silico Risk Assessment And Design Space Prediction.
Keywords:
Quality by Design,Atorvastatin Calcium,FMEA, DoE,Design Space,PBPK Modeling,BCS Class II,DDDPlus, GastroPlus.Abstract
A comprehensive Quality by Design (QbD) framework was developed for Atorvastatin Calcium immediate-release (IR) tablets, integrating systematic in-silico risk assessment and design space prediction. Atorvastatin calcium, classified as a BCS Class II HMG-CoA reductase inhibitor, presents significant formulation challenges owing to its low aqueous solubility and dissolution-limited absorption. The Quality Target Product Profile (QTPP) and Critical Quality Attributes (CQAs) were defined in line with ICH Q8(R2), followed by identification of Critical Material Attributes (CMAs) and Critical Process Parameters (CPPs) through Failure Mode and Effects Analysis (FMEA) risk scoring. A 2 Fractional Factorial screening design (16 runs) and Central Composite Design (CCD) implemented in Design Expert® established empirical factor–response relationships. Mechanistic dissolution modeling using DDDPlus™ and physiologically based pharmacokinetic / biopharmaceutics modeling (PBPK/PBBM) using GastroPlus® enabled virtual bioequivalence assessment. A robust design space was established: disintegrant level 3–5 % w/w, compression force 1800–2300 lbf, and API particle size 20–40 µm. Virtual bioequivalence trials confirmed Cmax ratio
98.9 % (90 % CI: 91–105 %) and AUC0–t ratio 99.1 % (90 % CI: 93–107 %), both within the 80–125 % acceptance limits. The integrated QbD–in-silico approach provides a science-based, clinically relevant design space and control strategy for Atorvastatin calcium IR tablets consistent with ICH Q8(R2), Q9, and Q10 guidelines..
Downloads
References
[1] Roth GA, Mensah GA, Johnson CO, et al. Global Burden of Cardiovascular Diseases and Risk Factors, 1990–2019. J Am Coll Cardiol. 2020;76(25):2982–3021.
[2] DrugBank. Atorvastatin Monograph. Available at: https://go.drugbank.com/drugs/DB01076
[3] Wu CY, Benet LZ. Predicting drug disposition via application of BCS. Pharm Res. 2005;22(1):11–23.
[4] International Council for Harmonisation (ICH). ICH Q8(R2): Pharmaceutical Development. 2009.
[5] International Council for Harmonisation (ICH). ICH Q9: Quality Risk Management. 2005.
[6] International Council for Harmonisation (ICH). ICH Q10: Pharmaceutical Quality System. 2008.
[7] Jones HM, Mayawala K, Poulin P. Dose selection based on physiologically based pharmacokinetic (PBPK) approaches. AAPS J. 2013;15(2):377–387.
[8] Prince Patel, Piyush Jain, Hetvarth Patel, Aman Tiwari, Sanjesh Rathi and Shubham Singh (2025) Formulation, optimization and evaluation of mucoadhesive buccal tablets of ondansetron for enhanced bioavailability and sustained drug release. Biochem. Cell. Arch. 25, 1063-1069. DOI: https://doi.org/10.51470/bca.2025.25.1.1063
[9] Kushwaha et al. Enhancement of solubility of Atorvastatin using solid dispersion technique. Asian J Pharm Sci. 2021.
[10] Various Authors. QbD-based formulation development for oral solid dosage forms. J Pharm Sci.
[11] 2022;111(5):1200–1215.
[12] Ameer et al. Comparative dissolution profiling of Atorvastatin tablet formulations. Dissolution Technol. 2023;30(2):24–31.
[13] Multiple Researchers. Application of DoE and QbD in IR tablet development: Recent advances. Int J Pharm. 2024;645:123456.
[14] Bhagvansinh Chauhan, Vraj Patel, Aakash Solanki, Aman Tiwari, Shubham Singh, Sanjesh Rathi. Pathophysiology Reimagined: Integrating Systems Biology and AI for Disease Understanding. Research and Reviews: A Journal of Pharmaceutical Science. 2025; 16(02). Available from: https://journals.stmjournals.com/rrjops/article=2025/view=0
[15] Saeed et al. Self-nanoemulsifying drug delivery system (SNEDDS) for enhanced bioavailability of Atorvastatin. Eur J Pharm Biopharm. 2025;196:110567.
[16] Hidayat et al. QbD-driven optimization of oral lipidbased delivery systems. Int J Pharm. 2025;660:123456.
[17] Nanosuspension Studies. Particle size reduction for BCS Class II drugs. Drug Dev Ind Pharm. 2025;51(3):234–248.
[18] Yu LX. Pharmaceutical quality by design: product and process development, understanding, and control. Pharm Res. 2008;25(4):781–791.
[19] Lawrence XY et al. Understanding pharmaceutical quality by design. AAPS J. 2014;16(4):771–783.
[20] Beg S et al. QbD-based development of nanostructured lipid carriers. Expert Opin Drug Deliv.
[21] 2016;13(9):1303–1318.
[22] Montgomery DC. Design and Analysis of Experiments.
[23] 8th ed. Wiley; 2013.
[24] Noyes AA, Whitney WR. The rate of solution of solid substances in their own solutions. J Am Chem Soc. 1897;19(12):930–934.
[25] Dressman JB, Amidon GL, Reppas C, Shah VP. Dissolution testing as a prognostic tool for oral drug absorption. Pharm Res. 1998;15(1):11–22.
[26] US FDA. Guidance for Industry: Dissolution Testing of Immediate Release Solid Oral Dosage Forms. 1997.
[27] EMA. Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev.1). 2010.
[28] Aulton ME, Taylor KMG. Aulton’s Pharmaceutics: The Design and Manufacture of Medicines. 5th ed. Elsevier; 2018.
Downloads
Published
How to Cite
Issue
Section
License
This work is licensed under a Creative Commons Attribution 4.0 International License.
You are free to:
- Share — copy and redistribute the material in any medium or format
- Adapt — remix, transform, and build upon the material for any purpose, even commercially.
Terms:
- Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.
- No additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.
