Poor Aqueous Solubility - an Industry Wide

Problem in ADME Screening

Christopher A. Lipinski
Pfizer Global Research and Development
Groton Laboratories
christopher_a_lipinski@groton.pfizer.com

Lipinski Spotfire 2002 1

Aqueous solubility and permeability data must be provided to chemistry
as early as possible to avoid serious oral absorption problems

Lipinski Spotfire 2002 2

Leads at Pfizer and in the drug industry in general,
now trend toward higher MWT and lipophilicity

Percent MWT > 500 35

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1985 1986 1987 1988 1989 1990 1991 1992 1993 1994

%Syn_MWT %Comm_MWT

Lipinski Spotfire 2002 3

High throughput screening hits are more lipophilic
than Phase-2 or marketed drugs.

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Lipinski Spotfire 2002 4

 Computationally comparing libraries. Drug-like v.s.
new drugs

X Use the presence of an INN name or a USAN name or

marketed status as a flag for a compound with “drug-like”
properties

X 7483 Drugs with INN name, USAN name or approved for

marketing

X Compare to 2679 New Drugs from the Derwent World Drug

Index
O mechanism field - trial preparations

O No CAS registry number, no INN/USAN name, abstracted

in 1997, 1998, 1999

Lipinski Spotfire 2002 5

 Newer drugs are larger

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B WDI-Drugs J INN/USAN-Drugs H New-Drugs F NCE-Drugs

Lipinski Spotfire 2002 6

Newer drugs are more lipophilic

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B WDI-Drugs J INN/USAN-Drugs H New-Drugs F NCE-Drugs

Lipinski Spotfire 2002 7

Distribution Parameters for 7483 INN/USAN Drugs Define the
90% Limits Corresponding to Properties Unfavorable for Oral
Drug Absorption.

Lipinski Spotfire 2002 8

The “rule of five” mnemonic

Poor absorption or permeation are more likely when there are:

X More than 5 H-bond donors.

X The MWT is over 500.
X The CLog P is over 5 (or MLOGP is over 4.15).
X The sum of N’s and O’s is over 10.

X Substrates for transporters and natural products are

exceptions.

Lipinski Spotfire 2002 9

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 10

The Logic for a turbidimetric solubility assay

Solubility in Discovery Solubility in Development

X turbidimetric solubility thermodynamic solubility

X non crystalline
X solids not characterized
X solubilized in DMSO
X added to stirred gavage
medium
X 10’s of minutes time scale
X used for early in-vivo SAR
X correlation with in-vivo
animal SAR
X better in early discovery
crystalline
polymorphs characterized
solubility measured by solid
equilibrating with aqueous
medium
24 to 48 hours time scale
used for minimum absorbable
dose, dissolution, salt selection
correlation with clinical dosage
form
essential in development

Lipinski Spotfire 2002 11

Schematic for flow cell solubility assay

Lipinski Spotfire 2002 12

 Turbidimetric solubility in a flow cell

X Used to measure solubility at 5-65 ug/mL for poorly soluble

heterocyclic compounds

Lipinski Spotfire 2002 13

 Solubility measurement in a flow cell

X Drugs, often poorly crystalline, are dissolved in DMSO and

added to aqueous media.

Lipinski Spotfire 2002 14

Detailed view of the flow cell assay mixing chamber

Lipinski Spotfire 2002 15

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.

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Flow cell turbidimetric solubity assay errors are low at
the extremes and higher in the middle ranges

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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 18

Turbidimetric solubility with a plate reader is used if solubility
in the flow cell assay is at the upper limit of > 65 ug/mL.

X Used to measure solubility at 50-500 ug/mL for poorly

permeable compounds

Lipinski Spotfire 2002 19

The same formatting is used for both plate reader and flow
cell solubility assays

Lipinski Spotfire 2002 20

Poor solubility is likely with high Log P. However 50% of
poorly soluble compounds are not predicted by high Log P

Lipinski Spotfire 2002 21

Effectiveness of our intervention strategy is
measured by the decrease in our “Rule of 5” alerts

Lipinski Spotfire 2002 22

Experimental Solubility Information

X Syracuse Research Corporation “property”

database
O http://esc.syrres.com/interkow/database.htm

X Yalkowsky AQUASOL dATAbASE

O http://www.pharmacy.arizona.edu/peopleprogra
ms/aquasol/index.html

Lipinski Spotfire 2002 23

Computational Solubility Software

X ACDLABS solubility calculation

O http://www.acdlabs.com/
X Syracuse Research Corporation WsKow
O http://esc.syrres.com/interkow/estsoft.htm
X Univ of GA SPARC property calculator
O http://ibmlc2.chem.uga.edu/sparc/style/welcom
e.cfm
X Schrodinger Qikprop software
O http://www.schrodinger.com/qikprop2.html

Lipinski Spotfire 2002 24

Pfizer Turbidimetric Solubility Model

X Based on 20,000 experimental turbidimetric

solubility values
X binning type data, low, medium , high
X <= 5 ug/ml, 10-60 ug/mL, > 65 ug/mL
X 80% of experimental values are in the low and
high bin
X test set of 10,000 experimental values
X 87% accuracy in solubility assignment

Lipinski Spotfire 2002 25

Permeability, solubility grid for chemical libraries

Suggests 30% of
drugs are transporter
substrates

Lipinski Spotfire 2002 26

Know the permeability, solubility matrix

X Internal or external solubility predictors

X Internal or external permeability predictors
O Don’t get hung up on individual details
O Idea is to get a ballpark estimate
X Know the cutoff limits
X Permeability
O PSA > 150-200 Angstroms^2 is getting bad
X Solubility
O Solubility < 5-20 ug/mL is getting bad
X Poor permeability is much worse than poor
solubility - no easy formulation fix exists

Lipinski Spotfire 2002 27

Solubility impact on permeability screens

Lipinski Spotfire 2002 28

 Literature Citation

Journal of Pharmacological and Toxicological Methods

44 (2000) 235-249

Lipinski Spotfire 2002 29

Summing up. Candidate quality starts with the lead

O 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

Lipinski Spotfire 2002 30