1994_Physical Solubility of Carbon Dioxide in Aqueous Alkanolamines_Browning
Poor Aqueous Solubility - an Industry Wide Problem … Aqueous Solubility - an...Poor Aqueous...
Transcript of Poor Aqueous Solubility - an Industry Wide Problem … Aqueous Solubility - an...Poor Aqueous...
Lipinski Spotfire 2002 1
Poor Aqueous Solubility - an Industry Wide Problem in ADME Screening
Christopher A. Lipinski
Pfizer Global Research and Development
Groton Laboratories
Lipinski Spotfire 2002 2
Aqueous solubility and permeability data must be provided to chemistry as early as possible to avoid serious oral absorption problems
Lipinski Spotfire 2002 3
Leads at Pfizer and in the drug industry in general, now trend toward higher MWT and lipophilicity
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Lipinski Spotfire 2002 4
High throughput screening hits are more lipophilicthan Phase-2 or marketed drugs.
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Lipinski Spotfire 2002 5
Use the presence of an INN name or a USAN name or marketed status as a flag for a compound with “drug-like” properties
7483 Drugs with INN name, USAN name or approved for marketing
Compare to 2679 New Drugs from the Derwent World Drug Index
mechanism field - trial preparations
No CAS registry number, no INN/USAN name, abstracted in 1997, 1998, 1999
Computationally comparing libraries. Drug-like v.s. new drugs
Lipinski Spotfire 2002 6
Newer drugs are larger
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Newer drugs are more lipophilic
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Lipinski Spotfire 2002 8
Distribution Parameters for 7483 INN/USAN Drugs Define the 90% Limits Corresponding to Properties Unfavorable for Oral Drug Absorption.
Lipinski Spotfire 2002 9
The “rule of five” mnemonic
Poor absorption or permeation are more likely when there are:
More than 5 H-bond donors.
The MWT is over 500.
The CLog P is over 5 (or MLOGP is over 4.15).
The sum of N’s and O’s is over 10.
Substrates for transporters and natural products are exceptions.
Lipinski Spotfire 2002 10
Minimum Acceptable Solubility in ug/mL Bars shows the minimum solubility for low, medium and high permeability (Ka) at a clinical dose. The middle 3 bars are for a 1 mg/Kg dose. With medium permeability you need 52 ug/mL solubility.
Lipinski Spotfire 2002 11
The Logic for a turbidimetric solubility assay
Solubility in Discovery Solubility in Development
turbidimetric solubility thermodynamic solubility
non crystalline crystalline
solids not characterized polymorphs characterized
solubilized in DMSO solubility measured by solid added to stirred gavage equilibrating with aqueous
medium medium
10’s of minutes time scale 24 to 48 hours time scale
used for early in-vivo SAR used for minimum absorbable dose, dissolution, salt selection
correlation with in-vivo correlation with clinical dosage animal SAR form
better in early discovery essential in development
Lipinski Spotfire 2002 13
Used to measure solubility at 5-65 ug/mL for poorly soluble heterocyclic compounds
Turbidimetric solubility in a flow cell
Lipinski Spotfire 2002 14
Drugs, often poorly crystalline, are dissolved in DMSO and added to aqueous media.
Solubility measurement in a flow cell
Lipinski Spotfire 2002 16
A single assistant runs both the flow cell solubility assay and the plate reader solubility assay. In the flow cell assay, each of three robots can run a plate of 45 compounds per day.
Lipinski Spotfire 2002 17
Flow cell turbidimetric solubity assay errors are low at the extremes and higher in the middle ranges
Lipinski Spotfire 2002 18
Low error rate for false negatives and for correct positives. The error rate for false positives is highly correlated with high Log P
Lipinski Spotfire 2002 19
Used to measure solubility at 50-500 ug/mL for poorly permeable compounds
Turbidimetric solubility with a plate reader is used if solubility in the flow cell assay is at the upper limit of > 65 ug/mL.
Lipinski Spotfire 2002 20
The same formatting is used for both plate reader and flow cell solubility assays
Lipinski Spotfire 2002 21
Poor solubility is likely with high Log P. However 50% of poorly soluble compounds are not predicted by high Log P
Lipinski Spotfire 2002 22
Effectiveness of our intervention strategy is measured by the decrease in our “Rule of 5” alerts
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Experimental Solubility Information
Syracuse Research Corporation “property” database
http://esc.syrres.com/interkow/database.htm
Yalkowsky AQUASOL dATAbASEhttp://www.pharmacy.arizona.edu/peopleprograms/aquasol/index.html
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Computational Solubility Software
ACDLABS solubility calculationhttp://www.acdlabs.com/
Syracuse Research Corporation WsKowhttp://esc.syrres.com/interkow/estsoft.htm
Univ of GA SPARC property calculatorhttp://ibmlc2.chem.uga.edu/sparc/style/welcome.cfm
Schrodinger Qikprop softwarehttp://www.schrodinger.com/qikprop2.html
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Pfizer Turbidimetric Solubility Model
Based on 20,000 experimental turbidimetricsolubility values
binning type data, low, medium , high
<= 5 ug/ml, 10-60 ug/mL, > 65 ug/mL
80% of experimental values are in the low and high bin
test set of 10,000 experimental values
87% accuracy in solubility assignment
Lipinski Spotfire 2002 26
Permeability, solubility grid for chemical libraries
Suggests 30% of drugs are transporter substrates
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Know the permeability, solubility matrix
Internal or external solubility predictors
Internal or external permeability predictorsDon’t get hung up on individual details
Idea is to get a ballpark estimate
Know the cutoff limits
PermeabilityPSA > 150-200 Angstroms^2 is getting bad
SolubilitySolubility < 5-20 ug/mL is getting bad
Poor permeability is much worse than poor solubility - no easy formulation fix exists
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Literature Citation
Journal of Pharmacological and Toxicological Methods
44 (2000) 235-249
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Summing up. Candidate quality starts with the lead
Solubility and Permeability are hard to change by chemistry
♦ the quality of the starting lead is the best predictor for candidate quality
♦ there is no excuse for not knowing the relative solubility and permeability rankings of collections of chemistry compounds
♦ solubility and permeability calculations are accurate enough to allow ranking of real or virtual chemical libraries