Application of Quality by Design methodology for justification of the composition and technology of generic rivaroxaban film-coated tablets at the preformulation stage
Year: 2026
Type: article
Abstract: Introduction. One of the most widely used drugs by the domestic health care is the first direct and highly specific inhibitor of activated blood coagulation factor X, Xarelto (INN: rivaroxaban) in tablet form of four strengths of 5 mg, 10 mg, 15 mg and 20 mg. The drug is used to prevent and treat thrombosis in various patients for a wide range of indications, both arterial and venous. Xarelto has been studied in detail in international randomized clinical trials, where its high efficacy in different patient categories has been demonstrated. The market launch of a domestic generic drug, which is no less effective therapeutically than the original drug, is still relevant and in demand. Aim. The aim of the study is to justify the criteria for the drug substance selection, excipients and drug technology using cause and effect analysis with the Ishikawa diagram at the preformulation stage, taking into account the requirements of the modern international paradigm of pharmaceutical development – QbD. Materials and methods. Objects of study: rivaroxaban substances of Zhejiang Liaoyuan Pharmaceutical Co., Ltd. (China), Virdev Intermediates Pvt. Ltd. (India) and Dr. Reddy's Laboratories Ltd. (India), excipients: microcrystalline cellulose, hypromellose, lactose monohydrate, sodium lauryl sulfate, croscarmellose sodium, magnesium stearate. Research methods: content analysis, comparative information and analytical methods, cause and effect risk analysis based on the Ishikawa diagram. Results and discussion. In order to develop a generic drug in the context of international pharmaceutical development practicе at the preformulation stage, a risk analysis of the use of rivaroxaban substance (API) from 3 manufacturers was carried out with the establishment of critical quality attributes (CQAs) that directly affect the rivaroxaban tablets quality, and the manufacturer was selected. Critical material attributes (CMAs) were reviewed taking into account their biopharmaceutical classification, their impact on the dosage form quality and, mainly, on the bioavailability of rivaroxaban was assessed. Given the large number of types and brands of excipients used in rivaroxaban tablets, their multifunctionality and variability of properties, the rational composition and technology of tablet cores using fluid-bed granulation with an aqueous suspension of the substance as a wetting agent are theoretically justified. The planned target product profile (QTPP) is based on the quality parameters of the innovative medicinal product – "Xarelto® 2.5 mg, 10 mg, 15 mg, 20 mg film-coated tablets", marketing authorization holder (MA) – Bayer Pharma AG, Germany. Conclusion. Based on the analytical studies performed using a risk-based approach, the choice of rivaroxaban substance and excipients was made taking into account their critical quality attributes. Wet granulation technology is proposed, potential critical parameters of the technology affecting the tablet quality are identified. The results obtained make it possible to proceed to the experimental development of the rivaroxaban tablets quantitative composition using the technology of fluid bed granulation with the critical process parameters determination and design space.
Source: Drug development & registration
Authors: S. V. Emshanova, D. V. Brik, A. A. Raspopina
Institution: National Research Nuclear University MEPhI
Language: English
Subfield: Analytical Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: diamond
OpenAlex ID: W7225426051