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      Intrinsic Dissolution Rate Profiling of Poorly Water-Soluble Compounds in Biorelevant Dissolution Media

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          Abstract

          The intrinsic dissolution rate (IDR) of active pharmaceutical ingredients (API) is a key property that aids in early drug development, especially selecting formulation strategies to improve dissolution and thereby drug absorption in the intestine. Here, we developed a robust method for rapid, medium throughput screening of IDR and established the largest IDR dataset in open literature to date that can be used for pharmaceutical computational modeling. Eighteen compounds with diverse physicochemical properties were studied in both fasted and fed state simulated intestinal fluids. Dissolution profiles were measured in small-scale experimental assays using compound suspensions or discs. IDR measurements were not solely linked to API solubility in either dissolution media. Multivariate data analysis revealed that IDR strongly depends on compound partitioning into bile salt and phospholipid micelles in the simulated intestinal fluids, a process that in turn is governed by API lipophilicity, hydrophobicity, and ionization.

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          Most cited references60

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          Estimation of the aqueous solubility I: application to organic nonelectrolytes.

          The estimation of aqueous solubilities of organic nonelectrolytes by the General Solubility Equation (GSE) as proposed by Valvani and Yalkowsky (1980) is used in this study. The data and assumptions on which the GSE are based are reevaluated, and the equation is revised. The revised GSE is validated on a set of 580 pharmaceutically, environmentally, and industrially relevant nonelectrolytes. The revised equation has a stronger theoretical background and provides a more accurate estimation of aqueous solubility.
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            Early pharmaceutical profiling to predict oral drug absorption: current status and unmet needs.

            Preformulation measurements are used to estimate the fraction absorbed in vivo for orally administered compounds and thereby allow an early evaluation of the need for enabling formulations. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the pharmaceutical profiling methods available, with focus on in silico and in vitro models typically used to forecast active pharmaceutical ingredient's (APIs) in vivo performance after oral administration. An overview of the composition of human, animal and simulated gastrointestinal (GI) fluids is provided and state-of-the art methodologies to study API properties impacting on oral absorption are reviewed. Assays performed during early development, i.e. physicochemical characterization, dissolution profiles under physiological conditions, permeability assays and the impact of excipients on these properties are discussed in detail and future demands on pharmaceutical profiling are identified. It is expected that innovative computational and experimental methods that better describe molecular processes involved in vivo during dissolution and absorption of APIs will be developed in the OrBiTo. These methods will provide early insights into successful pathways (medicinal chemistry or formulation strategy) and are anticipated to increase the number of new APIs with good oral absorption being discovered.
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              The effect of particle size and shape on the surface specific dissolution rate of microsized practically insoluble drugs

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                Author and article information

                Journal
                Pharmaceutics
                Pharmaceutics
                pharmaceutics
                Pharmaceutics
                MDPI
                1999-4923
                28 May 2020
                June 2020
                : 12
                : 6
                : 493
                Affiliations
                [1 ]Science for Life Laboratory, Department of Pharmacy, Uppsala University, Uppsala Biomedical Center P.O. Box 580, SE-75123 Uppsala, Sweden
                [2 ]Department of Pharmacy, Uppsala University, Uppsala Biomedical Center P.O. Box 580, SE-75123 Uppsala, Sweden; olivianylander@ 123456gmail.com
                [3 ]The Swedish Drug Delivery Center, Department of Pharmacy, Uppsala University, Uppsala Biomedical Center P.O. Box 580, SE-75123 Uppsala, Sweden
                Author notes
                [* ]Correspondence: alexandra.teleki@ 123456farmaci.uu.se (A.T.); christel.bergstrom@ 123456farmaci.uu.se (C.A.S.B.); Tel.: +46-18-471-4745 (A.T.); +46-18-471-4118 (C.A.S.B.)
                Author information
                https://orcid.org/0000-0001-6514-8960
                https://orcid.org/0000-0002-8917-2612
                Article
                pharmaceutics-12-00493
                10.3390/pharmaceutics12060493
                7356998
                32481718
                c6c1e78c-8365-4cf6-8663-30c2b89160c0
                © 2020 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 ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 06 May 2020
                : 25 May 2020
                Categories
                Article

                intrinsic dissolution rate,biorelevant dissolution media,fassif,fessif,poorly water-soluble drugs,physicochemical properties,controlled suspension

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