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Mechanistic analysis and experimental verification of bicarbonate-controlled enteric coat dissolution: Potential in vivo implications.
Eur J Pharm Biopharm. 2019 Jun; 139:47-58.EJ

Abstract

Enteric coatings have shown in vivo dissolution rates that are poorly predicted by traditional in vitro tests, with the in vivo dissolution being considerably slower than in vitro. To provide a more mechanistic understanding of this, the dependence of the release properties of various enteric-coated (EC) products on bulk pH and bicarbonate molarity was investigated. It was found that, at presumably in vivo-relevant values, the bicarbonate molarity is a more significant determinant of the dissolution profile than the bulk pH. The findings also indicate that this steep relationship between the dissolution of enteric coatings and bicarbonate molarity limits those coatings' performance in vivo. This is attributed to the relatively low bicarbonate molarities in human intestinal fluids. Further, the hydration and dehydrations kinetics of carbonic acid and carbon dioxide are not sufficiently rapid to reach equilibrium in the diffusion layer surrounding a dissolving ionizable solid. This results in the effective pKa of bicarbonate in the diffusion layer being lower than that determined potentiometrically at equilibrium in the bulk surrounding fluid. These results demonstrate the importance of thoroughly investigating the intestinal bicarbonate concentrations and using bicarbonate buffers or properly designed surrogates (if possible) when evaluating enteric drug products during product development and quality control.

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Authors+Show Affiliations

Al-Gousous J
College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109, USA. Electronic address: jalgouso@umich.edu.
Ruan H
College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109, USA; Department of Chemical Drug, Zhejiang Institute for Food and Drug Control, Hangzhou, Zhejiang 310052, China.
Blechar JA
Institute of Pharmacy and Biochemistry, Johannes Gutenberg Universität Mainz, Staudingerweg 5, 55128 Mainz, Germany.
Sun KX
College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109, USA.
Salehi N
Department of Chemical Engineering, University of Michigan, 300 Hayward St, Ann Arbor, MI 48109, USA.
Langguth P
Institute of Pharmacy and Biochemistry, Johannes Gutenberg Universität Mainz, Staudingerweg 5, 55128 Mainz, Germany.
Job NM
College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109, USA.
Lipka E
TSRL Inc., 540 Avis Drive, Ann Arbor, MI 48108, USA.
Loebenberg R
Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Bermejo M
Department of Engineering, Pharmacy Section, Miguel Hernandez University , San Juan de Alicante, 03550 Alicante, Spain.
Amidon GE
College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109, USA.
Amidon GL
College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, MI 48109, USA.

MeSH

AcetaminophenBicarbonatesBuffersCapsulesChemistry, PharmaceuticalDrug LiberationExcipientsHumansHydrogen-Ion ConcentrationHypromellose DerivativesIntestinal MucosaIntestine, SmallMesalamineModels, ChemicalSolubility

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30872012

Citation

Al-Gousous, J, et al. "Mechanistic Analysis and Experimental Verification of Bicarbonate-controlled Enteric Coat Dissolution: Potential in Vivo Implications." European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik E.V, vol. 139, 2019, pp. 47-58.
Al-Gousous J, Ruan H, Blechar JA, et al. Mechanistic analysis and experimental verification of bicarbonate-controlled enteric coat dissolution: Potential in vivo implications. Eur J Pharm Biopharm. 2019;139:47-58.
Al-Gousous, J., Ruan, H., Blechar, J. A., Sun, K. X., Salehi, N., Langguth, P., Job, N. M., Lipka, E., Loebenberg, R., Bermejo, M., Amidon, G. E., & Amidon, G. L. (2019). Mechanistic analysis and experimental verification of bicarbonate-controlled enteric coat dissolution: Potential in vivo implications. European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Fur Pharmazeutische Verfahrenstechnik E.V, 139, 47-58. https://doi.org/10.1016/j.ejpb.2019.03.012
Al-Gousous J, et al. Mechanistic Analysis and Experimental Verification of Bicarbonate-controlled Enteric Coat Dissolution: Potential in Vivo Implications. Eur J Pharm Biopharm. 2019;139:47-58. PubMed PMID: 30872012.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanistic analysis and experimental verification of bicarbonate-controlled enteric coat dissolution: Potential in vivo implications. AU - Al-Gousous,J, AU - Ruan,H, AU - Blechar,J A, AU - Sun,K X, AU - Salehi,N, AU - Langguth,P, AU - Job,N M, AU - Lipka,E, AU - Loebenberg,R, AU - Bermejo,M, AU - Amidon,G E, AU - Amidon,G L, Y1 - 2019/03/11/ PY - 2018/09/21/received PY - 2019/01/18/revised PY - 2019/03/10/accepted PY - 2019/3/16/pubmed PY - 2019/8/30/medline PY - 2019/3/16/entrez KW - Bicarbonate KW - Buffer KW - Dissolution KW - Enteric coating KW - pH SP - 47 EP - 58 JF - European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V JO - Eur J Pharm Biopharm VL - 139 N2 - Enteric coatings have shown in vivo dissolution rates that are poorly predicted by traditional in vitro tests, with the in vivo dissolution being considerably slower than in vitro. To provide a more mechanistic understanding of this, the dependence of the release properties of various enteric-coated (EC) products on bulk pH and bicarbonate molarity was investigated. It was found that, at presumably in vivo-relevant values, the bicarbonate molarity is a more significant determinant of the dissolution profile than the bulk pH. The findings also indicate that this steep relationship between the dissolution of enteric coatings and bicarbonate molarity limits those coatings' performance in vivo. This is attributed to the relatively low bicarbonate molarities in human intestinal fluids. Further, the hydration and dehydrations kinetics of carbonic acid and carbon dioxide are not sufficiently rapid to reach equilibrium in the diffusion layer surrounding a dissolving ionizable solid. This results in the effective pKa of bicarbonate in the diffusion layer being lower than that determined potentiometrically at equilibrium in the bulk surrounding fluid. These results demonstrate the importance of thoroughly investigating the intestinal bicarbonate concentrations and using bicarbonate buffers or properly designed surrogates (if possible) when evaluating enteric drug products during product development and quality control. SN - 1873-3441 UR - https://www.unboundmedicine.com/medline/citation/30872012/Mechanistic_analysis_and_experimental_verification_of_bicarbonate_controlled_enteric_coat_dissolution:_Potential_in_vivo_implications_ DB - PRIME DP - Unbound Medicine ER -