Predicting Solubility of New Drugs

1 Introduction

1.1 'Not too little - not too much',

1.2 Why a Database of Aqueous Intrinsic Solubility?

1.3 Database

1.4 Measurements Can Be Improved

1.5 Solubility-pH Profiles, Intrinsic Solubility, and Profile Distortions

2 Physicochemical Properties of Wiki-pS0 Database Molecules

2.1 Most Molecules in Database are Drug-Like or Drug-Relevant

2.2 Distribution of Intrinsic Solubility

2.3 Interlaboratory Variance

2.4 Quality and Chemical Space of Experimental Data

2.5 PROTACs: Lipinski's 'Rule Of 5' Characteristics

2.6 Newly-Approved Drugs: Lipinski's 'Rule Of 5' Characteristics

2.7 Kier Flexibility Index, ?, and Abraham H-Bond Acceptor Potential, B

2.8 Principal Component Analysis

2.9 Quantitative Estimate of Drug-Likeness

3 Solubility Prediction Methods

3.1 Overview of Solubility Prediction Models

3.2 Gap between Prediction and Measurement

3.3 Yalkowsky General Solubility Equation (GSE)

3.4 'Flexible-Acceptor' General Solubility Equation, GSE(?,B)

3.5 Abraham Solvation Equation (ABSOLV)

3.6 Breiman Random Forest Regression

4 Predicting of Solubility of PROTACs

4.1 Determination of the Three GSE(?,B) Coefficients from Training Set Iso-(?+B) Bins

4.2 'Flexible-Acceptor' Lipophilicity

4.3 ABSOLV Trained to Predict the Intrinsic Solubility of PROTACs

4.4 RFR Training

4.5 Training Set Performances

4.6 Effect of Small Amounts of DMSO (? 5 vol%)

4.7 Predicting Solubility of PROTACs

5 Predicting of Solubility of New Drugs

5.1 Trends in Physicochemical Properties of Emerging Drugs

5.2 Characteristics of Emerging Drugs (2016-2022)

5.3 Re-training of the Training Sets

5.4 Predicting Solubility of Newly-Approved Drugs

5.5 Striving for Similarity Between Training Set and Test Set

6 Instruments with 'Intelligence'

6.1 Bjerrum Difference Plots for Saturated Solutions - Normalized Titration Curves

6.2 'Intelligent' Assay: Noyes-Whitney 'Dissolution Titration Template' (DTT) Method

6.3 High-Throughput Solubility Instrument with DMSO Bias Correction

6.4 Where to Aim Next

Appendix - Data Sources, Solubility Definitions, Unit Conversions

A1 Data Sources in Wiki-pS0 Database

A1.1 'Kinetic Solubility' Measurements

A1.2 Data for FDA Newly-Approved Drugs (2016-2022)

A1.3 Data from Secondary Sources

A.1.4 Single-Source Measurements

A1.5 Data from Miscellaneous Primary Sources

A1.6 Sources of pKa Data

A2 Definitions, Supersaturation, Cosolvents

A2.1 Consensus Recommendations

A2.2 pH Measurement

A3 Solubility Units - Conversions to Molarity

A4 Different Types of Aqueous Solubility of Ionizable Molecules

A4.1 Single-Point Water Solubility of Free Acid/Base (S? /S? for Free Acid/Base, or Simply Sw)

A4.2 Single-Point Solubility at a Particular Buffered pH (SpH)

A4.3 Single-Point Intrinsic Solubility (S0)

A4.4 Single-Point Water Solubility of Non-Disproportionating ?-Type Salt (Ssalt or S?)

A4.5 Single-Point Water Solubility of Disproportionating ?-Type Salt (S? )

General References

Tabulation Organization and Notes

TABULATION 1 - Wiki-pS0

TABULATION 2 - DMSO Bias-Corrected Solubility

Tabulation References

Index of Topics

Index of Molecule Names

Index of Registry Numbers (RN)

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Aqueous solubility of drugs;Wiki-pS0 database;Pharmacokinetic risks;Data-driven design of solubility assays;Intrinsic solubility values;Machine-learning prediction of solubility