The DOI matches its Crossref record; 49 of the 51 references it cites were found in a registry or an index.
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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Citations
Cites
Solvents and Solvent Effects in Organic Chemistry
Reichardt, C. L. (2002) · Wiley eBooks · doi:10.1002/3527601791 · Cited by 5,795
Abraham, M. H. (1993) · Chemical Society Reviews · doi:10.1039/cs9932200073 · Cited by 1,968
Are Crystal Structures Predictable?
Gavezzotti, A. (1994) · Accounts of Chemical Research · doi:10.1021/ar00046a004 · Cited by 922
The use of characteristic volumes to measure cavity terms in reversed phase liquid chromatography
Abraham, M. H., & McGowan, J. C. (1987) · Chromatographia · doi:10.1007/bf02311772 · Cited by 861
Abraham, M. H., Chadha, H. S., Whiting, G. S., & Mitchell, R. C. (1994) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600830806 · Cited by 766
Calculating log Poct from structures
Leo, A. J. (1993) · Chemical Reviews · doi:10.1021/cr00020a001 · Cited by 705
Solubility and partitioning I: Solubility of nonelectrolytes in water
Yalkowsky, S. H., & Valvani, S. C. (1980) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600690814 · Cited by 581
Functional group contributions to drug-receptor interactions
Andrews, P. R., Craik, D. J., & Martin, J. L. (1984) · Journal of Medicinal Chemistry · doi:10.1021/jm00378a021 · Cited by 538
Simple Method of Calculating Octanol/Water Partition Coefficient.
MORIGUCHI, I., Hirono, S., Qian, L. I. U., Nakagome, I., & MATSUSHITA, Y. (1992) · Chemical and Pharmaceutical Bulletin · doi:10.1248/cpb.40.127 · Cited by 536
Abraham, M. H. (1993) · Journal of Physical Organic Chemistry · doi:10.1002/poc.610061204 · Cited by 354
Hydrogen Bonding. 33. Factors That Influence the Distribution of Solutes between Blood and Brain
Abraham, M. H., Chadha, H. S., & Mitchell, R. C. (1994) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600830915 · Cited by 302
Working Group IV: lipids and the immune system. Report and recommendations.
Newberne, P. M., & Thurman, G. B. (1981) · PubMed · Cited by 291
Comparison of Reliability of log P Values for Drugs Calculated by Several Methods.
MORIGUCHI, I., Hirono, S., Nakagome, I., & Hirano, H. (1994) · Chemical and Pharmaceutical Bulletin · doi:10.1248/cpb.42.976 · Cited by 280
Transport of small molecules through the blood-brain barrier: biology and methodology
Pardridge, W. M. (1995) · Advanced Drug Delivery Reviews · doi:10.1016/0169-409x(95)00003-p · Cited by 279
Design principles for orally bioavailable drugs
Navia, M. A., & Chaturvedi, P. R. (1996) · Drug Discovery Today · doi:10.1016/1359-6446(96)10020-9 · Cited by 207
In vitro systems for studying intestinal drug absorption
Hillgren, K. M., Kato, A., & Borchardt, R. T. (1995) · Medicinal Research Reviews · doi:10.1002/med.2610150202 · Cited by 183
Lipophilicity in Molecular Modeling
Testa, B., Carrupt, P., Gaillard, P., Billois, F., & Weber, P. B. (1996) · Pharmaceutical Research · doi:10.1023/a:1016024005429 · Cited by 164
Bodor, N. S., Huang, M., & Harget, A. J. (1994) · Journal of Molecular Structure THEOCHEM · doi:10.1016/0166-1280(94)80078-2 · Cited by 163
Diffusion of Small Non-Electrolytes across Liposome Membranes
Cohen, B., & Bangham, A. (1972) · Nature · doi:10.1038/236173a0 · Cited by 136
Famini, G. R., Penski, C. A., & Wilson, L. Y. (1992) · Journal of Physical Organic Chemistry · doi:10.1002/poc.610050704 · Cited by 131
Murray, J. S., & Politzer, P. A. (1991) · The Journal of Organic Chemistry · doi:10.1021/jo00023a045 · Cited by 130
Murray, J. S., Ranganathan, S., & Politzer, P. A. (1991) · The Journal of Organic Chemistry · doi:10.1021/jo00011a060 · Cited by 118
Abraham, M. H., Chadha, H. S., & Leo, A. J. (1994) · Journal of Chromatography A · doi:10.1016/0021-9673(94)00686-5 · Cited by 114
Complete Thermodynamic Description of H‐Bonding in the Framework of Multiplicative Approach
Raevsky, O. A., Grigorev, V. Y., Kireev, D., & Zefirov, N. S. (1992) · Quantitative Structure-Activity Relationships · doi:10.1002/qsar.19920110109 · Cited by 114
A New Predictive Equation for the Solubility of Drugs Based on the Thermodynamics of Mobile Disorder
Ruelle, P., Rey‐Mermet, C., Buchmann, M., Nam‐Trân, H., Kesselring, U. W., & Huyskens, P. (1991) · Pharmaceutical Research · doi:10.1023/a:1015891126287 · Cited by 108
Neural network studies. 1. Estimation of the aqueous solubility of organic compounds
Bodor, N. S., Harget, A. J., & Huang, M. J. (1991) · Journal of the American Chemical Society · doi:10.1021/ja00025a009 · Cited by 107
Melting Point, Boiling Point, and Symmetry
Abramowitz, R., & Yalkowsky, S. H. (1990) · Pharmaceutical Research · doi:10.1023/a:1015949907825 · Cited by 103
Myrdal, P. B., Manka, A. M., & Yalkowsky, S. H. (1995) · Chemosphere · doi:10.1016/0045-6535(95)00026-5 · Cited by 100
Chapter 33. Recent Advances in the Generation of Molecular Diversity
Moos, W. H., Green, G. D., & Pavia, M. R. (1993) · Annual reports in medicinal chemistry · doi:10.1016/s0065-7743(08)60903-3 · Cited by 98
Suzuki, T. (1991) · Journal of Computer-Aided Molecular Design · doi:10.1007/bf00129753 · Cited by 89
The molecular properties governing solubilities of organic nonelectrolytes in water
Taft, R. W., Abraham, M. H., Doherty, R. M., & Kamlet, M. J. (1985) · Nature · doi:10.1038/313384a0 · Cited by 88
Prediction of Aqueous Solubility of Organic Compounds
Nelson, T. M., & Jurs, P. C. (1994) · Journal of Chemical Information and Computer Sciences · doi:10.1021/ci00019a019 · Cited by 83
A new method for the estimation of the aqueous solubility of organic compounds
Bodor, N. S., & Huang, M. (1992) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600810924 · Cited by 82
Applications of small-molecule combinatorial chemistry to drug discovery
Patel, D. V., & Gordon, E. M. (1996) · Drug Discovery Today · doi:10.1016/1359-6446(96)89062-3 · Cited by 74
Brinck, T., Murray, J. S., & Politzer, P. A. (1993) · The Journal of Organic Chemistry · doi:10.1021/jo00077a028 · Cited by 73
Prediction of carbazole solubility and its dependence upon the solvent nature
Ruelle, P., Sarraf, É., & Kesselring, U. W. (1994) · International Journal of Pharmaceutics · doi:10.1016/0378-5173(94)90187-2 · Cited by 60
A Non‐aqueous Partitioning System for Predicting the Oral Absorption Potential of Peptides
Paterson, D. A., Conradi, R. A., Hilgers, A. R., Vidmar, T. J., & Burton, P. S. (1994) · Quantitative Structure-Activity Relationships · doi:10.1002/qsar.19940130103 · Cited by 57
Estimation of the aqueous solubility of complex organic compounds
Yalkowsky, S. H. (1993) · Chemosphere · doi:10.1016/0045-6535(93)90179-9 · Cited by 48
H‐Bond Contribution to Octanol‐Water Partition Coefficients of Polar Compounds
Raevsky, O. A., Schaper, K. ‐., & Seydel, J. K. (1995) · Quantitative Structure-Activity Relationships · doi:10.1002/qsar.19950140504 · Cited by 46
Molecular Symmetry and Related Properties
Dannenfelser, R., Surendran, N., & Yalkowsky, S. H. (1993) · SAR and QSAR in environmental research · doi:10.1080/10629369308029892 · Cited by 45
Analysis of Solute/Solvent Interactions for the Acidity of Acetic Acids by Theoretical Descriptors
Headley, A. D., Starnes, S. D., Wilson, L. Y., & Famini, G. R. (1994) · The Journal of Organic Chemistry · doi:10.1021/jo00105a020 · Cited by 43
Strategies and recent technologies in drug discovery.
Kubinyi, H. (1995) · PubMed · Cited by 43
Combinatorial Approaches Provide Fresh Leads for Medicinal Chemistry
BAUM, R. M. (1994) · Chemical & Engineering News · doi:10.1021/cen-v072n006.p020 · Cited by 40
Chow, H. ‐. S., Chen, H., Ng, T., Myrdal, P. B., & Yalkowsky, S. H. (1995) · Journal of Chemical Information and Computer Sciences · doi:10.1021/ci00026a009 · Cited by 38
Estimation of aqueous solubility and melting point of PCB congeners
Abramowitz, R., & Yalkowsky, S. H. (1990) · Chemosphere · doi:10.1016/0045-6535(90)90142-g · Cited by 38
Solubility Predictions for Solid Nitriles and Tertiary Amides Based on the Mobile Order Theory
Ruelle, P., & Kesselring, U. W. (1994) · Pharmaceutical Research · doi:10.1023/a:1018990904867 · Cited by 29
Critique of Recent Comparison of log P Calculation Methods.
Leo, A. J. (1995) · Chemical and Pharmaceutical Bulletin · doi:10.1248/cpb.43.512 · Cited by 24
Kamlet, M. J. (1993) · Progress in physical organic chemistry · doi:10.1002/9780470171981.ch5 · Cited by 15
Estimation of the Aqueous Solubility of Organic Compounds
Yalkowsky, S. H. (1988) · Springer eBooks · doi:10.1007/978-3-642-74140-1_27 · Cited by 11
Research works printed but not linked: 3
- Lipinski, C.A. (1995) Computational alerts for potential absorption problems: profiles of clinically tested drugs. In: Tools for Oral Absorption. Part Two. Predicting Human Absorption. BIOTEC, PDD symposium, AAPS, Miami.
- Workshop on Oral Drug Delivery: Interface Between Discovery and Development. Report and Recommendations. National Institutes of Health, National Institute of General Medical Sciences. Herndon, Virginia, December 5–7, 1993.
- Lipinski, C.A., Davis, A.L., Aldridge, P.K. and Brown, C.W. (1994) Biologically relevant UV-based solubility assays. Pharmaceutical Analysis Session, 45th Pittsburgh Conf., Chicago, Oral Presentation 959.
Cited by
Sorted by citations
Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death
Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., Patel, D. N., Bauer, A. J., Cantley, A. M., Yang, W. S., et al. (2012) · Cell · doi:10.1016/j.cell.2012.03.042 · Cited by 18,691
Daina, A., Michielin, O., & Zoete, V. (2017) · Scientific Reports · doi:10.1038/srep42717 · Cited by 18,367
Lead- and drug-like compounds: the rule-of-five revolution
Lipinski, C. A. (2004) · Drug Discovery Today Technologies · doi:10.1016/j.ddtec.2004.11.007 · Cited by 6,455
Self-citationPires, D. E. V., Blundell, T. L., & Ascher, D. B. (2015) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b00104 · Cited by 6,126
TCMSP: a database of systems pharmacology for drug discovery from herbal medicines
Ru, J., Li, P., Wang, J., Zhou, W., Li, B., Huang, C., Li, P., Guo, Z., Tao, W., Yang, Y., et al. (2014) · Journal of Cheminformatics · doi:10.1186/1758-2946-6-13 · Cited by 5,092
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 ›
Are you an author, or do you see a problem with this page? Request a review
