Predicting Solubility of New Drugs Handbook of Critically Curated Data for Pharmaceutical Research

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

2.1 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, Φ, and Abraham H-Bond Acceptor Potential, B

2.8 Principal Component Analysis

2.9 Quantitative Estimate of Drug-Likeness

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(Φ,B)

3.5 Abraham Solvation Equation (ABSOLV)

3.6 Breiman Random Forest Regression

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

5.1 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

6.1 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

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 pK_a 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_α /S_β for Free Acid/Base, or Simply S_w)

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

A4.3 Single-Point Intrinsic Solubility (S₀)

A4.4 Single-Point Water Solubility of Non-Disproportionating μ-Type Salt (S_salt or S_μ)

A4.5 Single-Point Water Solubility of Disproportionating δ-Type Salt (S_δ )

Biography

Alex Avdeef has been an American Association of Pharmaceutical Scientists (AAPS) Fellow since 2014, a former visiting senior research fellow at King’s College London, and is the author of Absorption and Drug Development (2nd ed., Wiley, 2012). In 2021, the book was translated into Chinese, by translators affiliated with the China Food and Drug Administration. For nearly 50 years, he has been teaching, researching, and developing methods, instruments, and analysis software for the measurement of ionization constants, solubility, dissolution, and permeability of drugs. His accomplishments in the development of instrumentation include several well-known instruments that are or recently have been manufactured by leading companies in the instrument market, including Thermo Fisher Scientific, Sirius Analytical, and Pion Inc. He has over 200 technical publications in primary scientific journals and book chapters. He has written several comprehensive technical guides and is a coinventor on six patents. He cofounded Sirius Analytical (UK) in 1989, pION Inc. (USA) in 1996, and founded in–ADME Research (New York City) in 2011. His other positions were at Orion Research, Syracuse University, UC Berkeley, and Caltech.