{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T08:15:36Z","timestamp":1778314536088,"version":"3.51.4"},"reference-count":42,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2024,4,26]],"date-time":"2024-04-26T00:00:00Z","timestamp":1714089600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The bitter drug, warfarin, has a narrow therapeutic index (NTI) and is used in paediatrics and geriatrics. The aim of this feasibility study was to formulate the taste-masked warfarin-containing pellets to be applicable for dose personalisation and to improve patient compliance, as well as to investigate the effect of the core type (PharSQ\u00ae Spheres M, CELPHERE\u2122 CP-507, and NaCl) on the warfarin release from the Kollicoat\u00ae Smartseal taste-masking-coated pellets. The cores were successfully drug-loaded and coated in a fluid-bed coater with a Wurster insert. An increase in particle size and particle size distribution was observed by optical microscopy. In saliva-simulated pH, at the Kollicoat\u00ae Smartseal level of 2 mg\/cm2, none of the pellets demonstrated drug release, confirming their efficient taste-masking. However, in a stomach-simulated pH, a faster drug release was observed from PharSQ\u00ae Spheres M- and CELPHERE\u2122 CP-507-coated pellets in comparison with NaCl cores. Additional experiments allowed us to explain the slower drug release from NaCl-containing pellets because of the salting-out effect. Despite the successful taste masking, the drug release from pellets was relatively slow (not more than 91% per 60 min), allowing for further formulation improvements.<\/jats:p>","DOI":"10.3390\/pharmaceutics16050586","type":"journal-article","created":{"date-parts":[[2024,4,26]],"date-time":"2024-04-26T09:26:02Z","timestamp":1714123562000},"page":"586","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Taste-Masked Pellets of Warfarin Sodium: Formulation towards the Dose Personalisation"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2690-5937","authenticated-orcid":false,"given":"Lakija","family":"Kovalenko","sequence":"first","affiliation":[{"name":"Laboratory of Finished Dosage Forms, Faculty of Pharmacy, Riga Stradi\u0146\u0161 University, LV-1007 Riga, Latvia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6895-5606","authenticated-orcid":false,"given":"Kirils","family":"Kukuls","sequence":"additional","affiliation":[{"name":"Laboratory of Finished Dosage Forms, Faculty of Pharmacy, Riga Stradi\u0146\u0161 University, LV-1007 Riga, Latvia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2699-5196","authenticated-orcid":false,"given":"Marta","family":"Berga","sequence":"additional","affiliation":[{"name":"Laboratory of Finished Dosage Forms, Faculty of Pharmacy, Riga Stradi\u0146\u0161 University, LV-1007 Riga, Latvia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8771-3470","authenticated-orcid":false,"given":"Valentyn","family":"Mohylyuk","sequence":"additional","affiliation":[{"name":"Laboratory of Finished Dosage Forms, Faculty of Pharmacy, Riga Stradi\u0146\u0161 University, LV-1007 Riga, Latvia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Lamprou, D. (2023). 3D & 4D Printing Methods for Pharmaceutical Manufacturing and Personalised Drug Delivery: Opportunities and Challenges, Springer.","DOI":"10.1007\/978-3-031-34119-9"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Taylor, Z.L., Green, F.G., Hossain, N., Burckart, G.J., Pacanowski, M., and Schuck, R.N. (Clin. Pharmacol. Ther., 2024). Assessment of Dosing Strategies for Pediatric Drug Products, Clin. Pharmacol. Ther., Early View.","DOI":"10.1002\/cpt.3250"},{"key":"ref_3","unstructured":"Patel, K., and Feng, L. (2023). Pharmaceutical Formulations for Older Patients, Springer."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1517\/17425247.4.1.37","article-title":"Paediatric and geriatric drug delivery","volume":"4","author":"Breitkreutz","year":"2007","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2643","DOI":"10.1111\/jgs.16137","article-title":"Swallowing Disorders in the Older Population","volume":"67","author":"Christmas","year":"2019","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"101712","DOI":"10.1016\/j.jddst.2020.101712","article-title":"Review on: Alternatives to large dosage forms for ease of swallowing","volume":"57","author":"Shailesh","year":"2020","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_7","unstructured":"Sim\u0161i\u010d, T., Planin\u0161ek, O., and Baumgartner, A. (2024). Taste-masking methods in multiparticulate dosage forms with a focus on poorly soluble drugs. Acta Pharm., 74, Available online: https:\/\/acta.pharmaceutica.farmaceut.org\/press\/."},{"key":"ref_8","unstructured":"Mohylyuka, V., Patela, K., Murnanea, D., Richardsonb, C., and Liua, F. (2018). A Patient-Centric Approach: Formulation of Prolonged Release Microparticles to Be Used in Oral Suspensions for Older Patients with Dysphagia, AAPS PharmSci 360."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2474","DOI":"10.1016\/j.xphs.2020.04.018","article-title":"Easy to Swallow \u201cInstant\u201d Jelly Formulations for Sustained Release Gliclazide Delivery","volume":"109","author":"Patel","year":"2020","journal-title":"J. Pharm. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e98","DOI":"10.1136\/ejhpharm-2017-001281","article-title":"Stability of warfarin sodium flavoured preservative-free oral liquid formulations","volume":"25","author":"Schlatter","year":"2018","journal-title":"Eur. J. Hosp. Pharm."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ejpb.2023.08.004","article-title":"Predicting Bioequivalence and Developing Dissolution Bioequivalence Safe Space in vitro for Warfarin using a Physiologically-Based Pharmacokinetic Absorption Model","volume":"191","author":"Cheng","year":"2023","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_12","unstructured":"Jantoven, C. (2024, February 13). Warfarin (Drug Monograph). Available online: https:\/\/www.elsevier.com\/clinical-solutions\/druginformation\/editorial-policy."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.ejpb.2019.01.011","article-title":"Formulation development of a continuously manufactured orodispersible film containing warfarin sodium for individualized dosing","volume":"136","author":"Niese","year":"2019","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1081\/DDC-120037477","article-title":"Taste masking technologies in oral pharmaceuticals: Recent developments and approaches","volume":"30","author":"Sohi","year":"2004","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2921","DOI":"10.1007\/s11095-014-1480-6","article-title":"Physical approaches to masking bitter taste: Lessons from food and pharmaceuticals","volume":"31","author":"Coupland","year":"2014","journal-title":"Pharm. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1080\/03639045.2017.1323910","article-title":"Micropellets coated with Kollicoat Smartseal 30D for taste masking in liquid oral dosage forms","volume":"43","author":"Dashevskiy","year":"2017","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_17","unstructured":"Mohylyuk, V., Jones, D.S., and Andrews, G.P. (2021, January 25\u201329). \u201cSpheronized\u201d taste-masked microparticles obtained by hot-melt extrusion and further thermal treatment. Proceedings of the CRS 2021 Virtual Annual Meeting 2021, The Controlled Release Society, Virtually."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Ghosh, T.K., and Pfister, W.R. (2005). Drug Delivery to the oral Cavity: Molecules to Market, CRC Press, Taylor & Francis Group.","DOI":"10.1201\/9780849398513"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.ijpharm.2004.10.024","article-title":"Physicochemical and release properties of pellets coated with Kollicoat SR 30 D, a new aqueous polyvinyl acetate dispersion for extended release","volume":"290","author":"Dashevsky","year":"2005","journal-title":"Int. J. Pharm."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1081\/PDT-100002614","article-title":"Influence of plasticization time, curing conditions, storage time, and core properties on the drug release from Aquacoat-coated pellets","volume":"6","author":"Wesseling","year":"2001","journal-title":"Pharm. Dev. Technol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"417","DOI":"10.3109\/10837450.2013.879883","article-title":"Comparison of film-coated retarded release pellets manufactured by layering technique or by bed rotor pelletization","volume":"20","author":"Priese","year":"2015","journal-title":"Pharm. Dev. Technol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0939-6411(96)00028-8","article-title":"Tableting of coated pellets","volume":"43","author":"Bodmeier","year":"1997","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"101320","DOI":"10.1016\/j.jddst.2019.101320","article-title":"Assessment of the effect of Cellets\u2019 particle size on the flow in a Wurster fluid-bed coater via powder rheology","volume":"54","author":"Mohylyuk","year":"2019","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.ejpb.2017.02.012","article-title":"Curing mechanism of flexible aqueous polymeric coatings","volume":"115","author":"Irfan","year":"2017","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1016\/j.xphs.2021.12.005","article-title":"Studies on the pH-Dependent Solubility of Various Grades of Calcium Phosphate-based Pharmaceutical Excipients","volume":"111","author":"Wagner","year":"2022","journal-title":"J. Pharm. Sci."},{"key":"ref_26","unstructured":"Zakowiecki, D., Lachmann, M., Huhn, A., Papaioannou, M., Hess, T., Centkowska, K., Mikolaszek, B., and Cal, K. (2019). Characterization of Physical Properties of Novel Calcium-Phosphate-Based Starter Pellets (PharSQ\u00ae Spheres CM), AAPS."},{"key":"ref_27","unstructured":"(2024, April 01). Kollicoat\u00aeSmartseal 30 D Technical Information; BASF\u2013Nutrition & Health. Available online: https:\/\/pharma.basf.com\/technicalinformation\/30492630\/kollicoat-smartseal-30-d."},{"key":"ref_28","unstructured":"Bang, F., Cech, T., Guth, F., and Assis, J. (2023). Formulation Development with Kollicoat\u00aeSmartseal: Impact of Plasticizers, BASF SE."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1208\/s12249-021-02038-2","article-title":"Effect of Elevated pH on the Commercial Enteric-Coated Omeprazole Pellets Resistance: Patent Review and Multisource Generics Comparison","volume":"22","author":"Mohylyuk","year":"2021","journal-title":"AAPS PharmSciTech"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Dimitrokalli, E., Fertaki, S., Lykouras, M., Kokkinos, P., Orkoula, M., and Kontoyannis, C. (2021). Warfarin Sodium Stability in Oral Formulations. Molecules, 26.","DOI":"10.3390\/molecules26216631"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1081\/PDT-120030246","article-title":"Influences of layering on theophylline pellet characteristics","volume":"9","author":"Sinchaipanid","year":"2004","journal-title":"Pharm. Dev. Technol."},{"key":"ref_32","unstructured":"(2024, April 01). Warfarin sodium clathrate, in European Pharmacopoeia. 2014, Commission and European Directorate for the Quality of Medicines & Healthcare: Council of Europe. Ph. Eur. 8.1, 0699 (04\/2014). Available online: https:\/\/faq.edqm.eu\/pages\/viewpage.action?pageId=1377105#:~:text=A%20good%20example%20of%20a,1742%20(01%2F2008."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.ijpharm.2015.08.065","article-title":"Understanding effect of formulation and manufacturing variables on the critical quality attributes of warfarin sodium product","volume":"495","author":"Rahman","year":"2015","journal-title":"Int. J. Pharm."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2669","DOI":"10.1002\/jps.20164","article-title":"Solid-state properties of warfarin sodium 2-propanol solvate","volume":"93","author":"Sheth","year":"2004","journal-title":"J. Pharm. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"m197","DOI":"10.1107\/S1600536802005809","article-title":"Warfarin sodium 2-propanol solvate","volume":"58","author":"Sheth","year":"2002","journal-title":"Acta Crystallogr. Sect. E Struct. Rep. Online"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1002\/jps.2600540916","article-title":"Clathrates of sodium warfarin","volume":"54","author":"Hiskey","year":"1965","journal-title":"J. Pharm. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1093\/ajh\/hpu028","article-title":"Compared with usual sodium intake, low- and excessive-sodium diets are associated with increased mortality: A meta-analysis","volume":"27","author":"Graudal","year":"2014","journal-title":"Am. J. Hypertens."},{"key":"ref_38","unstructured":"World Health Organization (2012). Guideline: Sodium Intake for Adults and Children, World Health Organization."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Musel\u00edk, J., Urbanova, M., Barton\u00ed\u010dkov\u00e1, E., Palov\u010d\u00edk, J., Vetch\u00fd, D., Czernek, J., Janisova, L., Velychkivska, N., Franc, A., and Brus, J. (2021). Structural Changes of Sodium Warfarin in Tablets Affecting the Dissolution Profiles and Potential Safety of Generic Substitution. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13091364"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.ijpharm.2009.04.003","article-title":"Effects of physicochemical properties of salting-out layer components on drug release","volume":"376","author":"Tasaki","year":"2009","journal-title":"Int. J. Pharm."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/0378-5173(90)90404-R","article-title":"The influence of additives on the cloud point, disintegration and dissolution of hydroxypropylmethylcellulose gels and matrix tablets","volume":"66","author":"Mitchell","year":"1990","journal-title":"Int. J. Pharm."},{"key":"ref_42","unstructured":"Lamprecht, A., and Bodmeier, R. (2010). Ullmann\u2019s Encyclopedia of Industrial Chemistry, Wiley-VCH Verlag GmbH & Co., KGaA."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/5\/586\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:33:48Z","timestamp":1760106828000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/16\/5\/586"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,26]]},"references-count":42,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,5]]}},"alternative-id":["pharmaceutics16050586"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics16050586","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,26]]}}}