Citation: Gausuzzaman, S.A.L.; Saha, M.; Dip, S.J.; Alam, S.; Kumar, A.; Das, H.; Sharker, S.M.; Rashid, M.A.; Kazi, M.; Reza, H.M. A QbD Approach to Design and to Optimize the Self-Emulsifying Resveratrol–Phospholipid Complex to Enhance Drug Bioavailability through Lymphatic Transport. Polymers 2022, 14, 3220. https:// doi.org/10.3390/polym14153220 Academic Editor: Adriana Kovalcik Received: 6 June 2022 Accepted: 29 July 2022 Published: 8 August 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). polymers Article A QbD Approach to Design and to Optimize the Self-Emulsifying Resveratrol–Phospholipid Complex to Enhance Drug Bioavailability through Lymphatic Transport Syed Abul Layes Gausuzzaman 1,† , Mithun Saha 1,† , Shahid Jaman Dip 1,† , Shaiful Alam 1 , Arup Kumar 2 , Harinarayan Das 2 , Shazid Md. Sharker 1 , Md Abdur Rashid 3,4 , Mohsin Kazi 5, * and Hasan Mahmud Reza 1, * 1 Department of Pharmaceutical Sciences, North South University, Dhaka 1229, Bangladesh 2 Materials Science Division, Atomic Energy Centre, 4 Kazi Nazrul Islam Avenue, Shahbagh, Dhaka 1000, Bangladesh 3 Department of Pharmaceutics, College of Pharmacy, King Khalid University, Guraiger, Abha 62529, Saudi Arabia 4 Pharmacy Discipline, Faculty of Health, School of Clinical Sciences, Queensland University of Technology, Brisbane, QLD 4000, Australia 5 Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia * Correspondence: mkazi@ksu.edu.sa (M.K.); hasan.reza@northsouth.edu (H.M.R.); Tel.: +966-114677372 (M.K.); +880-255668200 (ext. 1954) (H.M.R.); Fax: +966-114676295 (M.K.); +880-255668202 (H.M.R.) † These authors contributed equally to this work. Highlights: i. The FTIR, DSC, and the XRD characterization confirmed the successful complex formation between resveratrol and phospholipid. ii. The optimal SEDDS formulation exhibited Grade-A self-emulsion properties. iii. Implementation of a QbD approach to select appropriate excipients and their concentrations facilitated lymphatic resveratrol transport, which increased bioavailability 48-fold. iv. The chylomicron flow blocking approach revealed that 91.3% of total systemically available resveratrol was transported through the intestinal lymphatic pathway. Abstract: Objectives: Despite having profound therapeutic value, the clinical application of resveratrol is restrained due to its <1% bioavailability, arising from the extensive fast-pass effect along with entero- hepatic recirculation. This study aimed to develop a self-emulsifying formulation capable of increasing the bioavailability of resveratrol via lymphatic transport. Methods: The resveratrol–phospholipid complex (RPC) was formed by the solvent evaporation method and characterized by FTIR, DSC, and XRD analyses. The RPC-loaded self-emulsifying drug delivery system (SEDDS) was designed, developed, and optimized using the QbD approach with an emphasis on resveratrol transport through the intestinal lymphatic pathway. The in vivo pharmacokinetic study was investigated in male Wister Albino rats. Results: The FTIR, DSC, and XRD analyses confirmed the RPC formation. The obtained design space provided robustness of prediction within the 95% prediction interval to meet the CQA specifications. An optimal formulation (desirability value of 7.24) provided Grade-A self-emulsion and exhibited a 48-fold bioavailability enhancement compared to the pure resveratrol. The cycloheximide- induced chylomicron flow blocking approach demonstrated that 91.14% of the systemically available resveratrol was transported through the intestinal lymphatic route. Conclusions: This study suggests that an optimal self-emulsifying formulation can significantly increase the bioavailability of resveratrol through lymphatic transport to achieve the desired pharmacological effects. Polymers 2022, 14, 3220. https://doi.org/10.3390/polym14153220 https://www.mdpi.com/journal/polymers