Trends in PhysChem Properties of Newly Approved Drugs over the Last Six Years; Predicting Solubility of Drugs Approved in 2021

Abstract

For the ‘small-molecule’ NMEs (new molecular entities) approved in 2021 by the US FDA, quantitative solubility values were found for 28 drugs, nearly all from published New Drug Applications (NDAs). Comparisons of physicochemical properties over the last six years indicate that the NMEs are slowly continuing to increase in size and decrease in solubility. Since 2016, the intrinsic solubility values (S0) have decreased on average by 0.50 log10 unit, the calculated octanol–water partition coefficients (clogP) have increased by 0.34 log10 unit, and the molecular weights (MW) have increased by 22 g·mol−1 (to 477, compared to 298 in older drugs). The average number of H-bond acceptors has remained constant, while the average number of H-bond donors and the Kier Φ molecular flexibility indices have decreased slightly. The reported solubility data for the 2021 small-molecule NMEs were processed using the program pDISOL-X to obtain S0 values, normalized to 25 °C. The S0 values ranged from 2 ng·mL−1 (avacopan) to 43 mg·mL−1 (viloxazine). In the new set, MW spanned from 233 g·mol−1 (dexmethylphenidate) to 1215 g·mol−1 (voclosporin). Values of clogP ranged from − 0.3 (serdexmethylphenidate, a quaternary ammonium molecule) to 8.1 (avacopan). Five different in-silico models were used to predict the aqueous intrinsic log10 solubility of the 28 novel NMEs: (i) Yalkowsky’s General Solubility Equation (GSE(classic)), (ii) Abraham’s Linear Solvation Equation (ABSOLV), (iii) Avdeef–Kansy ‘Flexible-Acceptor’ General Solubility Equation ((GSE(Φ,B)), (iv) Breiman’s Random Forest Regression (RFR), and (v) consensus model based on (ii) and (iii) above. The various models were retrained with an enlarged version of the Wiki-pS0 database (currently at 7655 log10 S0 entries of drug-relevant molecules). The consensus model (r2 = 0.67, RMSE = 1.08) just slightly outperformed the other four models. The relatively simple consensus prediction equation can be easily incorporated into spreadsheet calculations. As new drugs are approved, it will be important to continue monitoring the quality of measured solubility. Matching prediction to measurement is valuable when prediction methods are applied to virtual libraries, in order to seek opportunities to minimize pharmacokinetic risks of large, but otherwise promising, candidate molecules.