Optimal Selection of Incoming Materials from the Inventory for Achieving the Target Drug Release Profile of High Drug Load Sustained-Release Matrix Tablet
- 40 Downloads
In the pharmaceutical process, raw material (including APIs and excipients) variability can be delivered to the final product, and lead to batch-to-batch and lot-to-lot variances in its quality, finally impacting the efficacy of the drug. In this paper, the Panax notoginseng saponins (PNS) sustained-release matrix tablet was taken as the model formulation. Hydroxypropyl methylcellulose with the viscosity of 4000 mPa·s (HPMCK4M) from different vendors and batches were collected and their physical properties were characterized by the SeDeM methodology. The in-vitro dissolution profiles of active pharmaceutical ingredients (APIs) from matrix tablets made up of different batches HPMC K4M displayed significant variations. Multi-block partial least squares (MB-PLS) modeling results further demonstrated that physical properties of excipients played dominant roles in the drug release. In order to achieve the target drug release profile with respect to those far from the criteria, the optimal selection method of incoming materials from the available was established and validated. This study provided novel insights into the control of the input variability of the process and amplified the application of the SeDeM expert system, emphasizing the importance of the physical information of the raw materials in the drug manufacturing process.
KEY WORDSexcipient variability SeDeM latent variable modeling sustained-release matrix tablet formulation optimization
Project of National Standardization of Traditional Chinese Medicine (No. ZYBZH-C-QIN-45) and National Natural Science Foundation of China (No. 81403112) provided generous financial supports.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that there is no conflict of interests.
- 1.Moreton C. Functionality and performance of excipients in a quality-bydesign world, part 4: obtaining information on excipient variability for formulation design space. Am Pharm Rev. 2009;12:28–33.Google Scholar
- 3.International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Quality guideline Q8 pharmaceutical development Q8. Center for Drug Evaluation and Research; 2006.Google Scholar
- 4.U.S. Food Drug Administration. Pharmaceutical cGMPs for the 21st century. Rockville; 2004.Google Scholar
- 13.Willecke N, Szepes A, Wunderlich M, Remon JP, Vervaet C, De Beer T. A novel approach to support formulation design on twin screw wet granulation technology: understanding the impact of overarching excipient properties on drug product quality attributes. Int J Pharm. 2018;545:128–43.CrossRefGoogle Scholar
- 22.Negre JMS, Montoya EG, Díaz JEA, Díaz JEA, Carreras MR, García RF, et al. SeDeM diagram: a new expert system for the formulation of drugs in solid form. In: Balik M, editor. Expert systems for human, materials and automation: InTech INTECH open access Publisher; 2011. p. 17–34.Google Scholar
- 24.Font Quer P. Medicamenta: guía teórico práctica para farmacéuticos y médicos. Labor Ed.; 1962. p. 340–341.Google Scholar
- 25.Council of Europe. Section 2.9.34. Bulk density and tapped density of powders. European Pharmacopeia 9.0; 2018.Google Scholar
- 29.The United States Pharmacopeial Convention. United States Pharmacopeia 35 - National Formulary 29 (USP 35- NF 30). United states pharmacopeia; 2012.Google Scholar
- 30.Bonferoni MC, Rossi S, Ferrari F, Bertoni M, Sinistri R, Caramella C. Characterization of three hydroxypropylmethylcellulose substitution types: rheological properties and dissolution behaviour. Eur J Pharm Biopharm. 1995;41:242–6.Google Scholar