Abstract
Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to ?design in? acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40 of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.
| Original language | English |
|---|---|
| Pages (from-to) | 315 - 499 |
| Number of pages | 185 |
| Journal | Pharmacological Reviews |
| Volume | 65 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2013 |
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Williams, H. D., Trevaskis, N., Charman, S. A., Shanker, R., Charman, W. N., Pouton, C. W. (2013). Strategies to address low drug solubility in discovery and development. Pharmacological Reviews, 65(1), 315 - 499. https://doi.org/10.1124/pr.112.005660
Williams, Hywel David ; Trevaskis, Natalie ; Charman, Susan Ann et al. / Strategies to address low drug solubility in discovery and development. In: Pharmacological Reviews. 2013 ; Vol. 65, No. 1. pp. 315 - 499.
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title = "Strategies to address low drug solubility in discovery and development",
abstract = "Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to ?design in? acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40 of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.",
author = "Williams, {Hywel David} and Natalie Trevaskis and Charman, {Susan Ann} and Ravi Shanker and Charman, {William Neil} and Pouton, {Colin William} and Porter, {Christopher John}",
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Williams, HD, Trevaskis, N, Charman, SA, Shanker, R, Charman, WN, Pouton, CW 2013, 'Strategies to address low drug solubility in discovery and development', Pharmacological Reviews, vol. 65, no. 1, pp. 315 - 499. https://doi.org/10.1124/pr.112.005660
Strategies to address low drug solubility in discovery and development. / Williams, Hywel David; Trevaskis, Natalie; Charman, Susan Ann et al.
In: Pharmacological Reviews, Vol. 65, No. 1, 2013, p. 315 - 499.
Research output: Contribution to journal › Article › Research › peer-review
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AU - Williams, Hywel David
AU - Trevaskis, Natalie
AU - Charman, Susan Ann
AU - Shanker, Ravi
AU - Charman, William Neil
AU - Pouton, Colin William
AU - Porter, Christopher John
PY - 2013
Y1 - 2013
N2 - Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to ?design in? acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40 of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.
AB - Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to ?design in? acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40 of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required.
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JF - Pharmacological Reviews
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Williams HD, Trevaskis N, Charman SA, Shanker R, Charman WN, Pouton CW et al. Strategies to address low drug solubility in discovery and development. Pharmacological Reviews. 2013;65(1):315 - 499. doi: 10.1124/pr.112.005660
