{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T21:22:41Z","timestamp":1783977761404,"version":"3.55.0"},"reference-count":39,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,7,9]],"date-time":"2021-07-09T00:00:00Z","timestamp":1625788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Higher Education, Science, Research and Innovation","award":["-"],"award-info":[{"award-number":["-"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The objective of this research was to optimize the tasted-masked microparticles for orally disintegrating tablets containing donepezil hydrochloride using quality risk assessment and design of experiment approaches. The double emulsion solvent evaporation technique using aminoalkyl methacrylate copolymer (AMC) was used to prepare taste-masked microparticles. Factors affecting the quality of the taste-masked microparticles were analyzed using an Ishikawa diagram. A risk-ranking approach was used to rank the formulation and process risks. Furthermore, the effect of AMC quantity, stirring time, and volume of outer water phase on various responses, such as particle size, the amount of drug dissolved at 5 min (Q5) in simulated saliva fluid, and mean dissolution time (MDT) in simulated gastric fluid, was investigated using the Box-Behnken design. The optimized microparticles were then used to prepare orally disintegrating tablets (ODTs) and evaluated by in vitro and in vivo testing. The results demonstrated that particle size was influenced by the AMC amount and stirring time. Q5 was significantly affected by the amount of AMC and the volume of the outer water phase. On the other hand, these two factors had a positive effect on MDT. The optimized microparticles had a particle size of 174.45 \u00b1 18.19 \u00b5m, Q5 of 5.04%, and MDT of 5.97 min. The ODTs with taste-masked microparticles showed acceptable in vitro dissolution with an MDT of 5 min. According to the results of a panel of six human volunteers, they greatly improved palatability.<\/jats:p>","DOI":"10.3390\/pharmaceutics13071046","type":"journal-article","created":{"date-parts":[[2021,7,9]],"date-time":"2021-07-09T04:14:57Z","timestamp":1625804097000},"page":"1046","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Optimized Taste-Masked Microparticles for Orally Disintegrating Tablets as a Promising Dosage Form for Alzheimer\u2019s Disease Patients"],"prefix":"10.3390","volume":"13","author":[{"given":"Lalinthip","family":"Sutthapitaksakul","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy, Silpakorn University, Nakhon Pathom 73000, Thailand"},{"name":"Pharmaceutical Biopolymer Group (PBiG), Silpakorn University, Nakhon Pathom 73000, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kasitpong","family":"Thanawuth","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Silpakorn University, Nakhon Pathom 73000, Thailand"},{"name":"Pharmaceutical Biopolymer Group (PBiG), Silpakorn University, Nakhon Pathom 73000, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crispin R.","family":"Dass","sequence":"additional","affiliation":[{"name":"Faculty of Health Sciences, Curtin Medical School, Curtin University, Perth 6845, Australia"},{"name":"Curtin Health Innovation Research Institute, Bentley 6102, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5525-1494","authenticated-orcid":false,"given":"Pornsak","family":"Sriamornsak","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Silpakorn University, Nakhon Pathom 73000, Thailand"},{"name":"Pharmaceutical Biopolymer Group (PBiG), Silpakorn University, Nakhon Pathom 73000, Thailand"},{"name":"Academy of Science, The Royal Society of Thailand, Bangkok 10300, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,9]]},"reference":[{"key":"ref_1","unstructured":"(2020, December 11). Population Division of United Nations World Population Ageing. Available online: https:\/\/www.un.org\/en\/development\/desa\/population\/publications\/pdf\/ageing\/WorldPopulationAgeing2019-Highlights.pdf."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.clinbiochem.2019.04.015","article-title":"Clinical aspects of Alzheimer\u2019s disease","volume":"72","year":"2019","journal-title":"Clin. Biochem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1254\/jjp.89.7","article-title":"Research and development of donepezil hydrochloride, a new type of acetylcholinesterase inhibitor","volume":"89","author":"Sugimoto","year":"2002","journal-title":"Jpn. J. Pharmacol."},{"key":"ref_4","unstructured":"(2020, December 10). Alzheimer\u2019s Association FDA-Approved Treatments for Alzheimer\u2019s. Available online: https:\/\/www.alz.org\/media\/documents\/fda-approved-treatments-alzheimers-ts.pdf."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2203","DOI":"10.1111\/jgs.12553","article-title":"Swallowing dysfunction and autonomic nervous system dysfunction in Alzheimer\u2019s disease: A scoping review of the evidence","volume":"61","author":"Affoo","year":"2013","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"102549","DOI":"10.1016\/j.jddst.2021.102549","article-title":"Donepezil\u2014An updated review of challenges in dosage form design","volume":"63","author":"Sutthapitaksakul","year":"2021","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_7","unstructured":"Moffat, A., Osseltion, M., and Widdop, P. (2011). Clarke\u2019s Analysis and Poisons, Pharmaceutical Press. [4th ed.]."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.ijpharm.2008.07.018","article-title":"Microencapsulation by solvent evaporation: State of the art for process engineering approaches","volume":"363","author":"Li","year":"2008","journal-title":"Int. J. Pharm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.ijpharm.2015.10.057","article-title":"Double emulsion solvent evaporation techniques used for drug encapsulation","volume":"496","author":"Iqbal","year":"2015","journal-title":"Int. J. Pharm."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/S0168-3659(03)00030-0","article-title":"Non-degradable microparticles containing a hydrophilic and\/or a lipophilic drug: Preparation, characterization and drug release modeling","volume":"88","author":"Siepmann","year":"2003","journal-title":"J. Control Release"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.jconrel.2008.09.073","article-title":"A new double emulsion solvent diffusion technique for encapsulating hydrophilic molecules in PLGA nanoparticles","volume":"133","author":"Chorny","year":"2009","journal-title":"J. Control Release"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.ijpharm.2012.08.006","article-title":"Development and evaluation of sustained-release clonidine-loaded PLGA microparticles","volume":"437","author":"Gaignaux","year":"2012","journal-title":"Int. J. Pharm."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.jconrel.2018.12.037","article-title":"Double emulsions prepared by two\u2013step emulsification: History, state-of-the-art and perspective","volume":"295","author":"Ding","year":"2019","journal-title":"J. Control Release"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1208\/s12249-018-1220-z","article-title":"Use of risk assessment and Plackett\u2013Burman design for developing resveratrol spray-dried emulsions: A quality-by-design approach","volume":"20","author":"Benjasirimongkol","year":"2019","journal-title":"AAPS PharmSciTech"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1016\/j.heliyon.2019.e01399","article-title":"Design and optimization of resveratrol-loaded porous calcium silicate powders for dissolution and photostability enhancement","volume":"5","author":"Benjasirimongkol","year":"2019","journal-title":"Heliyon"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"283","DOI":"10.4028\/www.scientific.net\/KEM.859.283","article-title":"Effect of processing parameters on release profiles of donepezil hydrochloride-loaded microparticles","volume":"859","author":"Sutthapitaksakul","year":"2020","journal-title":"Key Eng. Mater."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"252","DOI":"10.4028\/www.scientific.net\/KEM.819.252","article-title":"Influence of process parameters on the characteristics of hydrophilic drug-loaded microparticles through double emulsion solvent evaporation technique","volume":"819","author":"Sutthapitaksakul","year":"2019","journal-title":"Key Eng. Mater."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1248\/cpb.c13-00441","article-title":"Development of a novel and simple method to evaluate disintegration of rapidly disintegrating tablets","volume":"61","author":"Hoashi","year":"2013","journal-title":"Chem. Pharm. Bull."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.ajps.2018.05.001","article-title":"A donepezil\/cyclodextrin complexation orodispersible film: Effect of cyclodextrin on taste-masking based on dynamic process and in vivo drug absorption","volume":"14","author":"Liu","year":"2019","journal-title":"Asian J. Pharm. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.jcis.2008.07.013","article-title":"Surfactant dependent morphology of polymeric capsules of perfluorooctyl bromide: Influence of polymer adsorption at the dichloromethane-water interface","volume":"326","author":"Pisani","year":"2008","journal-title":"J. Colloid Interface Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1080\/02652040802141039","article-title":"Poly (\u03b5-caprolactone) microparticles containing levobunolol HCl prepared by a multiple emulsion (W\/O\/W) solvent evaporation technique: Effects of some formulation parameters on microparticle characteristics","volume":"26","author":"Sonakin","year":"2009","journal-title":"J. Microencapsul."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1211\/002235702760345383","article-title":"Preparation, characterization and taste-masking properties of polyvinylacetal diethylaminoacetate microspheres containing trimebutine","volume":"54","author":"Hashimoto","year":"2002","journal-title":"J. Pharm. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"8529","DOI":"10.1016\/j.biomaterials.2011.07.051","article-title":"PEGylated TNF-related apoptosis-inducing ligand (TRAIL) for effective tumor combination therapy","volume":"32","author":"Jiang","year":"2011","journal-title":"Biomaterials"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/2008-2231-21-68","article-title":"Preparation, characterization and optimization of sildenafil citrate loaded PLGA nanoparticles by statistical factorial design","volume":"21","author":"Ghasemian","year":"2013","journal-title":"DARU J. Pharm. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/j.jddst.2019.03.011","article-title":"Optimization of preparation method by W\/O\/W emulsion for entrapping metformin hydrochloride into poly (lactic acid) microparticles using Box-Behnken design","volume":"51","author":"Bouriche","year":"2019","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.cocis.2010.10.001","article-title":"Rheology of simple and multiple emulsions","volume":"16","author":"Pal","year":"2011","journal-title":"Curr. Opin. Colloid Interface Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"347","DOI":"10.3109\/02652049009021845","article-title":"Encapsulation of water-soluble drugs by a modified solvent evaporation method. I. effect of process and formulation variables on drug entrapment","volume":"7","author":"Alex","year":"1990","journal-title":"J. Microencapsul."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/S0169-409X(00)00099-5","article-title":"Particle control of emulsion by membrane emulsification and its applications","volume":"45","author":"Nakashima","year":"2000","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_29","first-page":"129","article-title":"FIP\/AAPS guidelines for dissolution\/in vitro release testing of novel\/special dosage forms","volume":"65","author":"Siewert","year":"2003","journal-title":"AAPS PharmSciTech"},{"key":"ref_30","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_31","doi-asserted-by":"crossref","unstructured":"Aserin, A. (2008). Multiple Emulsions: Technology and Applications, John Wiley & Sons.","DOI":"10.1002\/9780470209264"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.ijpharm.2013.02.019","article-title":"Preparation and evaluation of unpleasant taste-masked pioglitazone orally disintegrating tablets","volume":"446","author":"Nakano","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.ijpharm.2015.02.023","article-title":"Effect of granule properties on rough mouth feel and palatability of orally disintegrating tablets","volume":"484","author":"Kimura","year":"2015","journal-title":"Int. J. Pharm."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.ejpb.2012.07.010","article-title":"Novel pectin-based nanoparticles prepared from nanoemulsion templates for improving in vitro dissolution and in vivo absorption of poorly water-soluble drug","volume":"82","author":"Burapapadh","year":"2012","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_35","first-page":"15","article-title":"Impact of gastric pH and dietary fiber on calcium availability of various calcium salts","volume":"4","author":"Weerapol","year":"2010","journal-title":"Silpakorn Univ. Sci. Technol. J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1248\/bpb.33.1364","article-title":"Preparation and evaluation of taste-masked donepezil hydrochloride orally disintegrating tablets","volume":"33","author":"Yan","year":"2010","journal-title":"Biol. Pharm. Bull."},{"key":"ref_37","first-page":"107","article-title":"Taste masking of donepezil hydrochloride using different ion exchange resins\u2014A comparative study","volume":"24","author":"Zainuddin","year":"2013","journal-title":"Indones. J. Pharm."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"101298","DOI":"10.1016\/j.jddst.2019.101298","article-title":"Development and in vitro\/in vivo evaluation of tamarind seed gum-based oral disintegrating tablets after fabrication by freeze drying","volume":"54","author":"Huanbutta","year":"2019","journal-title":"J. Drug Deliv. Sci. Technol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Huanbutta, K., Sriamornsak, P., Singh, I., and Sangnim, T. (2021). Manufacture of 2D-printed precision drug-loaded orodispersible film prepared from tamarind seed gum substrate. Appl. Sci., 11.","DOI":"10.3390\/app11135852"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/7\/1046\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:28:10Z","timestamp":1760164090000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/7\/1046"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,9]]},"references-count":39,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["pharmaceutics13071046"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics13071046","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,9]]}}}