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Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings 1PII of original article: S0169-409X(96)00423-1. The article was originally published in Advanced Drug Delivery Reviews 23 (1997) 3–25. 1
Abstract
Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described. In the discovery setting 'the rule of 5' predicts that poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the molecular weight (MWT) is greater than 500 and the calculated Log P (CLogP) is greater than 5 (or MlogP > 4.15). Computational methodology for the rule-based Moriguchi Log P (MLogP) calculation is described. Turbidimetric solubility measurement is described and applied to known drugs. High throughput screening (HTS) leads tend to have higher MWT and Log P and lower turbidimetric solubility than leads in the pre-HTS era. In the development setting, solubility calculations focus on exact value prediction and are difficult because of polymorphism. Recent work on linear free energy relationships and Log P approaches are critically reviewed. Useful predictions are possible in closely related analog series when coupled with experimental thermodynamic solubility measurements.
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“which typically results in low aqueous solubility and high metabolic clearance (Lipinski et al., 2001).”
From A Fungal-Selective Cytochrome bc1 Inhibitor Impairs Virulence and Prevents the Evolution of Drug Resistance (2016) · cites this paper as Lipinski et al., 2001
In the citing paper
“Considering the restrictive Lipinski’s rules for BBB penetration (MW ≤ 450, clogP ≤5, hydrogen bond donors ≤ 5, hydrogen bond acceptors ≤ 10, polar surface area ≤ 90 Å2) and the calculated logBB values (Table S2), both L1 and L2 satisfy these requirements, suggesting that these compounds should be capable of crossing the BBB.”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ42Peptide (2012) · cites this paper as [75]
In the citing paper
“In general, PROTAC physicochemical property space falls beyond the ‘rule of 5’ (refs59,60) owing to the bifunctional nature of the molecules.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [59]
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Metadata
- Authors
- Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J.
- Affiliations
- Pfizer (United States) (US)
- Corresponding author
- Lipinski, Christopher A
- Venue
- Advanced Drug Delivery Reviews
- Publisher
- Elsevier BV
- Published
- 2001-03
- Volume
- 46
- Issue
- 1-3
- Pages
- 3-26
- ISSN
- 0169-409X (ISSN-L)
- OpenAlex
- W2135732933
- Cited by
- 18,139
- References
- 51
- Citations by year
- 2026: 869 · 2025: 962 · 2024: 1264 · 2023: 1296 · 2022: 1248 · 2021: 1459 · 2020: 1317 · 2019: 945 · 2018: 876 · 2017: 791 · 2016: 790 · 2015: 724 · 2014: 752 · 2013: 741 · 2012: 708
- FWCI
- 19.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Advanced Drug Delivery Reviews (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Physical Sciences › Materials Science › Materials Chemistry › Crystallization and Solubility Studies
- Keywords
- drug solubility, intestinal permeability, Rule of 5, molecular weight, lipophilicity, polymorphism, linear free energy relationships, thermodynamic solubility, solubility prediction, drug absorption
- MeSH terms
- Adsorption, Chemistry, Physical, Computers, Pharmaceutical Preparations, Permeability, Pharmacology, Solubility, Thermodynamics, Chemical Phenomena
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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