Partition Coefficients of Pharmaceuticals as Functions of Temperature and pH

Abstract

Liquid–liquid extraction is a potential separation process for the purification of active pharmaceutical ingredients (APIs). The design of an extraction step requires knowledge of the API partition coefficient, which strongly depends on the solvent system and process conditions. Usually, cost-intensive experiments have to be performed to select the most suitable solvent system and the best process conditions. The number of experiments can be reduced by predicting the partition coefficient using perturbed chain statistical associating theory (PC-SAFT). In this work, modeling results and experimental data were compared for the partition coefficients of the APIs nicotinamide and salicylamide in different solvent systems at temperatures from 293.15 to 328.15 K and at pH values varying between 5.2 and 10.3. The results show that PC-SAFT is able to predict the API partition coefficients for different solvent systems as functions of temperature and pH.

Partitioning of water‐soluble vitamins in biodegradable aqueous two‐phase systems: Electrolyte perturbed‐chain statistical associating fluid theory predictions and experimental validation

“…The ePC-SAFT pure-component parameters and binary interaction parameters for different species have been reported in the previous works. 29,35,38 The experimentally measured partition coefficient of a vitamin between the PEG phase and the salt phase is the total partition coefficient summed over all the vitamin species present in ATPS (K pred,∞ vit,total ). This value differs from the ePC-SAFT predicted K pred,∞ vit,j if pH I 6 ¼ pH II , where I and II are the Phases I and II.…”

“…The pure-component parameters of vitamins were already published elsewhere. 29,35,38 The k ij between water and negatively charged vitamins VB2 − , VB9 2− , and VB9 3− were fitted to pH-dependent solubility data in previous work. 38 The k ij water-VB3 acid− was estimated in this study using pH-dependent solubilities reported in previous work and according to the approach from the literature (SI, Figure S1).…”

“…Perturbed-Chain SAFT (PC-SAFT) has been already proposed for modeling of vitamin partitioning just in conventional systems containing organic solvents and water. 29 To predict the partitioning of ionizable molecules in PEG-organic salt ATPS, it is of importance to consider the interactions of different ionic species in an electrolyte solution. This was done in the present work using electrolyte PC-SAFT (ePC-SAFT) model with an implemented Debye-Hückel term.…”

“…However, predictions of the partitioning of organic solutes in PEG–organic salt ATPS using any predictive model have not been yet reported in literature. Perturbed‐Chain SAFT (PC‐SAFT) has been already proposed for modeling of vitamin partitioning just in conventional systems containing organic solvents and water 29 . To predict the partitioning of ionizable molecules in PEG–organic salt ATPS, it is of importance to consider the interactions of different ionic species in an electrolyte solution.…”

Drug development and bioanalytical method validation for a novel anticancer molecule, 4‐(dimethylamino)‐2‐(p‐tolylamino) thiazole‐5‐carbonitrile

“…The ionic state of any molecule depends on its pKa, which affects the pharmacodynamics and pharmacokinetic properties (Lee, Yu, & Crippen, 2008). Partition coefficient (LogP) is a good arbiter to predict bioavailability, which significantly contributes toward the toxicological and pharmacokinetic behavior of a molecule (Chiang & Hu, 2009;Di & Kerns, 2003;Laube, Klein, & Sadowski, 2015;Mandi, 2012). Experimental determination of distribution coefficient (LogD) can be considered as an essential part of the drug development process.…”