Alex Avdeef

in-ADME Research · R&D

Yalkowsky’s General Solubility Equation (GSE), with its three fixed constants, is popular and easy to apply, but is not very accurate for polar, zwitterionic, or flexible molecules. This review examines the findings of a series of studies, where we have sought to come up with a better prediction model, by comparing the performances of the GSE to Ab...

Background and Purpose The widely-used and practically insoluble diprotic acidic dye, bromothymol blue (BTB), is a neutral molecule in strongly acidic aqueous solutions. The Schill (1964) extensive solubility-pH measurement of bromothymol blue in 0.1 and 1.0 M NaCl solutions, with pH adjusted with HCl from 0.0 to 5.4, featured several unusual findi...

The weakly basic antibiotic and anti-inflammatory drug, clofazimine (CFZ), was first described in 1957. It has been used therapeutically, most notably in the treatment of leprosy. However, the compound is extremely insoluble in aqueous media, and, indeed, there is poor consensus about what its intrinsic solubility is since the reported values range...

In memory of Konstantin Tsinman - Chief Scientific Officer at Pion Inc.

The stirring frequency exponent of -1/2 in the theoretical Levich expression appears to apply to PAMPA and Caco-2 assays, where efficient individual-well magnetic stirring ( > 20 RPM) is used. If a single molecule is used as a stirring calibrant, then scaling suggested by Eq. (5) with microtitre plate data may be used. The error in calculating hABL...

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 solu...

This study applies the ‘Flexible-Acceptor’ variant of the General Solubility Equation, GSE(Φ,B), to the prediction of the aqueous intrinsic solubility, log10S0, of FDA recently-approved (2016–2020) ‘small-molecule’ new molecular entities (NMEs). The novel equation had been shown to predict the solubility of drugs beyond Lipinski’s ‘Rule of 5’ chemi...

Creating supersaturating drug delivery systems to overcome the poor aqueous solubility of active ingredients became a frequent choice for formulation scientists. Supersaturation as a solution phenomenon is, however, still challenging to understand, and therefore many recent publications focus on this topic. This work aimed to investigate and better...

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 solu...

The main aim of this work is the biopharmaceutical characterization of a new hybrid benzodiazepine-dihydropyridine derivative, JM-20, derived with potent anti-ischemic and neuroprotective effects. In this study, the pKa and the pH-solubility profile were experimentally determined. Additionally, effective intestinal permeability was measured using t...

These are the two appendices that will appear in Supplemental Material in the Avdeef-Sugano J. Pharm. Sci. 2021 publication.

A multiphasic mass action equilibrium model was used to study the phase properties near the critical pH (‘pHmax’) in an acid-base transformation of a solid drug salt into its corresponding solid free base form in pure water slurries. The goal of this study was to better define the characteristics of disproportionation of pharmaceutical salts, objec...

The purpose of the present study was to investigate the suitability of equilibrium slurry pH (pHeq) as a surrogate of solid surface pH during drug dissolution (pH0). A comprehensive calculation scheme for pHeq and pH0 was formalized based on the principle of charge neutrality (equilibrium charge neutrality for pHeq and charge flux neutrality for pH...

Chinese translation

Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug‐drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug proper...

The prediction of solubility of drugs usually calls on the use of several open-source/commercially-available computer programs in the various calculation steps. Popular statistics to indicate the strength of the prediction model include the coefficient of determination (r2), Pearson’s linear correlation coefficient (rPearson), and the root-mean-squ...

Ten years ago, we issued an open prediction challenge to the cheminformatics community: would participants be able to predict the equilibrium intrinsic solubilities of 32 druglike molecules using only a high-precision (CheqSol instrument, performed in one laboratory) set of 100 compounds as a training set? The “Solubility Challenge” was a widely-re...

This study describes a novel nonlinear variant of the well-known Yalkowsky General Solubility Equation (GSE). The modified equation can be trained with small molecules, mostly from the Lipinski ‘Rule of 5’ (Ro5) chemical space, to predict the intrinsic aqueous solubility, S0, of large molecules (MW > 800 Da) from ‘beyond the Rule of 5’ (bRo5) space...

The aim of the study was to explore to what extent small molecules (mostly from the Rule of 5 chemical space) can be used to predict the intrinsic aqueous solubility, S0, of big molecules from beyond the Rule of 5 (bRo5) space. It was demonstrated that the General Solubility Equation (GSE) and the Abraham Solvation Equation (ABSOLV) underpredict so...

p class="ADMETkeywordsheading">The accurate prediction of solubility of drugs is still problematic. It was thought for a long time that shortfalls had been due the lack of high-quality solubility data from the chemical space of drugs. This study considers the quality of solubility data, particularly of ionizable drugs. A database is described, comp...

The solubility of three drugs (glimepiride, pioglitazone, sibutramine) with different acid/base properties and expected supersaturation behavior was examined in detail using the shake-flask (SF) and potentiometric (CheqSol) methods. Both uncharged (free) species and hydrochloride salts were used as starting materials. On the one hand, the SF method...

This commentary compares 233 CheqSol intrinsic solubility values (log S 0) reported in the Wiki-pS 0 database for 145 different druglike molecules to the 838 log S 0 values determined mostly by the saturation shake-flask (SSF) method for 124 of the molecules from the CheqSol set. The range of log S 0 spans from-1.0 to-10.6 (log molar units), averag...

Ten years ago we issued, in conjunction with the Journal of Chemical Information and Modeling, an open prediction challenge to the cheminformatics community. Would they be able to predict the intrinsic solubilities of 32 druglike compounds using only a high-precision set of 100 compounds as a training set? The “Solubility Challenge” was a widely-re...

Several key topics in solubility measurement and interpretation are briefly summarized and illustrated with case studies drawing on published solubility determinations as a function of pH. Featured are examples of ionizable molecules that exhibit solubility-pH curve distortion from that predicted by the traditionally used Henderson-Hasselbalch equa...

Although solubility-pH data for desipramine hydrochloride (DsHCl) have been reported previously, the aim of the present study was to critically examine the aqueous solubility-pH behavior of DsHCl in buffer-free and buffered solutions, in the presence of physiologically-relevant chloride concentration, using experimental practices recommended in the...

Solubility-pH profiles of drugs in phosphate buffer.

Anomalous behavior of saturated solutions of weak acids.

Prediction of Kp,uu.

Blood-brain barrier - extent of penetration.

Drug dissolution studies in simulated intestinal fluids.

p>This review discusses the disposition of the anionic surfactant, sodium dodecyl sulfate (SDS; i.e., sodium lauryl sulfate), to solubilize sparingly-soluble drugs above the surfactant critical micelle concentration (CMC), as quantitated by the solubilization capacity (k). A compilation of 101 published SDS k values of mostly poorly-soluble drug mo...

Purpose: To predict the aqueous solubility product (K sp ) and the solubility enhancement of cocrystals (CCs), using an approach based on measured drug and coformer intrinsic solubility (S 0API , S 0cof ), combined with in silico H-bond descriptors. Method: A regression model was constructed, assuming that the concentration of the uncharged drug...

PurposeThe effective rat intestinal permeability (Peff) was deconvolved using a biophysical model based on parameterized paracellular, aqueous boundary layer, transcellular permeabilities, and the villus-fold surface area expansion factor. Methods Four types of rat intestinal perfusion data were considered: single-pass intestinal perfusion (SPIP) i...

Most studies of blood-brain barrier (BBB) permeability and transport are conducted at a single pH, but more detailed information can be revealed by using multiple pH values. A pH-dependent biophysical model was applied to the mechanistic analysis of published pH-dependent BBB luminal uptake data from three opioid derivatives in rat: pentazocine (Su...

Incubation time plays a critical role in the accurate measurement of equilibrium solubility of compounds. Substances which dissolve very slowly generally need long incubation times (days or weeks) to reach equilibrium. However, long times may pose several problems, such as decomposition of solute, molding of buffer, and drifting of pH. Higuchi in 1...

A novel general computational approach is described to address many aspects of cocrystal (CC) solubility product (Ksp) determination of drug substances. The CC analysis program, pDISOL-X, was developed and validated with published model systems of various acid-base combinations of active pharmaceutical ingredients (APIs) and coformers: (i) carbamaz...

The ionization constants (pKa) and the pH-dependent solubility (log S-pH) of six phenothiazine derivatives (promazine hydrochloride, chlorpromazine hydrochloride, triflupromazine hydrochloride, fluphenazine dihydrochloride, perphenazine free base, and trifluoperazine dihydrochloride) were determined at 25 and 37 °C.The pKa values of these low-solub...

This commentary addresses data quality in equilibrium solubility measurement in aqueous solution. Broadly discussed is the “gold standard” shake-flask (SF) method used to measure equilibrium solubility of ionizable drug-like molecules as a function of pH. Many factors affecting the quality of the measurement are recognized. Case studies illustratin...

The objective of the study was to find a computational procedure to normalize solubility data determined at various temperatures (e.g., 10 – 50 o C) to values at a “reference” temperature (e.g., 25 °C). A simple procedure was devised to predict enthalpies of solution, ΔH sol , from which the temperature dependence of intrinsic (uncharged form) solu...

The accurate prediction of solubility of drug-like molecules is difficult, and perhaps a satisfactory general model is not yet available. The most cited challenge to good prediction has been the lack of enough high-quality and drug-relevant solubility data that adequately cover the chemical space of drugs. This review addresses data quality in solu...

Two weak bases, PG-300995 (anti-HIV agent) and NSC-639829 (anti-tumor agent), whose log S – pH profiles had been previously published, but whose pK a values had not been reported, were analyzed using a method which can determine pK a values from log S – pH data. This " S pH-pK a " technique, although often practiced, can result in inaccurate pK a v...

This chapter aims at giving an overview about current and future in vitro methods to assess blood-brain barrier (BBB) permeability, focusing on artificial membrane and cell culture models. Potential and possible artificial membrane and cell culture models to meet the requirements of drug discovery issues are discussed. Artificial membranes could be...

The invention provides a permeation device (2) comprising a receiving vessel (6) having an aperture adapted for receiving an insert well (4). Both the vessel (6) and well (4) are used as either donor or acceptor compartments for permeability assays. The vessel (6) or well (4) comprises a porous suppor (8)t, which may comprise biological or biomimet...

The invention provides a permeation device (2) comprising a receiving vessel (6) having an aperture adapted for receiving an insert well (4). Both the vessel (6) and well (4) are used as either donor or acceptor compartments for permeability assays. The vessel (6) or well (4) comprises a porous suppor (8)t, which may comprise biological or biomimet...

The purpose of this study is to predict human jejunal permeability (Peff) and fraction absorbed in human (%Fa) for a group of antibacterial fluoroquinolones (FQs), by using a biophysical model based on measured Caco-2 permeability. The predicted Peff (in 10-4cm·s-1 units) ranged from 0.7 (norfloxacin) to 4.5 (pefloxacin). The calculated %Fa for nor...

In vitro blood-brain barrier (BBB) models from primary brain endothelial cells can closely resemble the in vivo BBB, offering valuable models to assay BBB functions and to screen potential central nervous system drugs. We have recently developed an in vitro BBB model using primary porcine brain endothelial cells. The model shows expression of tight...

Recently, it has been proposed that drug permeation is essentially carrier-mediated only and that passive lipoidal diffusion is negligible. This opposes the prevailing hypothesis of drug permeation through biological membranes, which integrates the contribution of multiple permeation mechanisms, including both carrier-mediated and passive lipoidal...

admet.2.1.30 33 ADMET & DMPK 2(1) (2014) 33-42; doi: 10.5599/admet.2.1.30 Open Access : ISSN : 1848-7718 http://www.pub.iapchem.org/ojs/index.php/admet/index Abstract The "anomalous solubility behavior at higher pH values" of several acidic drugs originally studied by Higuchi et al. in 1953 [1], but hitherto not fully rationalized, has been re-anal...

admet.2.1.31 43 ADMET & DMPK 2(1) (2014) 43-55; doi: 10.5599/admet.2.1.31 Open Access : ISSN : 1848-7718 http://www.pub.iapchem.org/ojs/index.php/admet/index Abstract The purpose of the study was to assess the stoichiometries of phosphate precipitates and determine the intrinsic solubilities, S 0 , of 25 basic drugs from their published solubility-...

admet.1.4.24 48 ADMET & DMPK 1(4) (2013) 48-62; doi: 10.5599/admet.1.4.24 Open Access : ISSN : 1848-7718 http://www.pub.iapchem.org/ojs/index.php/admet/index Abstract A novel general approach was described to address many of the challenges of salt solubility determination of drug substances, with data processing and refinement of equilibrium consta...

In order to reach the bloodstream and thus the target receptor, an orally-administered drug must first cross the intestinal barrier, which can occur via a paracellular, passive transcellular, or carrier-mediated uptake and/or efflux process (active or concentration gradient-driven). Our work aimed to explore the transport mechanism of the antiretro...

The purposes of this study are to evaluate if the PAMPA (Parallel Artificial Membrane Permeability Assay) permeability and the true partition coefficient could be useful for predicting AUC and MIC data of a group of antibacterial fluoroquinolones (FQs). The protonation macro- and microconstants, the n-octanol/water partition coefficients at isoelec...

The invention deals with a method for the assessment of the effect of excipients, pH and combinations thereof on the predicted absorption properties of low solubility compounds, comprising the step of assessing a change in a flux function for a combination of a low solubility compound and an excipient at at least one predefined pH value. The method...

Half Title Title Copyright Dedication Contents Preface Preface to the First Edition List of Abbreviations Nomenclature Commercial Trademarks

The goal of this study was to develop a quick, reliable, and cost-effective permeability model for predicting transdermal penetration of compounds. The Parallel Artificial Membrane Permeability Assay (PAMPA) was chosen for this purpose, as it already has been successfully used for estimating passive gastrointestinal absorption and blood-brain barri...

Evidence supporting the action of passive diffusion and carrier-mediated (CM) transport in drug bioavailability and disposition is discussed to refute the recently proposed theory that drug transport is CM-only and that new transporters will be discovered that possess transport characteristics ascribed to passive diffusion. Misconceptions and fault...

An apparatus for evaluating physicochemical properties of sample materials contained in an array of vessels includes: a light detector; a light source for transmitting a light beam through the sample material in a vessel to the light detector; an analyzer for processing data from the light detector to determine concentration-related properties of t...

The search for new drugs is a long process. Attrition is high and the costs keep escalating (now more than $1 billion per marketed drug). The traditional discovery-development models are undergoing change, as many pharmaceutical companies reign in the R&D costs, by consolidating research sites, downsizing research staff, and by outsourcing.

This chapter defines the relationship between ionization constants, solubility, and permeability as a function of pH, using the framework of Fick’s laws of diffusion. In simplest terms, the flux across a membrane barrier is a product function of solubility and permeability in saturated solutions. The contrast between the flux profile and the pH par...

This chapter presents the state-of-the-art coverage of practical and theoretical aspects of the determination of ionization constants, pKa, by the potentiometric technique, with particular emphasis on drug-like molecules, which often are very poorly soluble in water. The impact of ionic strength and the effect of temperature are considered in detai...

This chapter considers lipophilicity. The ‘lipid-attraction’ molecular property is traditionally defined by the octanol-water partition coefficients, log POCT. The use of log POCT as a component in property or biological activity prediction models is widespread in pharmaceutical, agrochemical, environmental, and other fields. For ionizable molecule...

The experimental and mathematical basis of the pH dependent measurement of solubility of sparingly-soluble ionizable drugs is discussed in this chapter. Recently described compound-sparing (but still accurate) approaches, suitable for application in preclinical development, and appropriate for the analysis of solubility of ‘problematic’ molecules,...

The present chapter broadly lays out the practical and theoretical groundwork for permeability measurement and its application to predicting human jejunal permeability (HJP) and human intestinal absorption (HIA). Fundamental concepts are illustrated with the PAMPA (Parallel Artificial Membrane Permeability Assay) model, including • gradient-pH, is...

This chapter continues the second part of the permeability coverage, focusing on the analysis of permeability data from the cell-based assays using Caco-2 and MDCK (Madin-Darby Canine Kidney) epithelial cell lines. The foundations laid in Chapter 7 are built upon here. The aim is to provide ideas for improved protocols and advanced data analysis fo...

This chapter concludes the three-part permeability series, focusing on the analysis of permeability data from the cell-based assays using endothelial cell models of the blood-brain barrier (BBB) – mainly primary cell cultures but also some cell lines. The foundations laid in Chapters 7 and 8 are applied here. The aim is to provide ideas for improve...

This chapter considers ‘biomimetic’ lipophilicity, where partition coefficients of drugs are determined in the liposomes-water system. Unilamellar vesicles formed with phosphatidylcholine provide a lipophilicity scale, expressed as log PMEM, which is different from that of octanol. The log PMEM can be used as a component in property or biological a...

Many relationships between the measured physicochemical properties (as a function of pH) underlying absorption of ionizable drugs (ionization constants, octanol-water partition coefficients, liposome-water partition coefficients, solubility, permeability of artificial membranes, of in vitro epithelial and endothelial cellular monolayers, and of in...

The object of the study was to improve the blood-brain barrier (BBB) permeability in vitro-invivo correlations (IVIVC) between in vitro brain microcapillary endothelial cell (BMEC) models and the well-tested rodent in situ brain perfusion technique. Porcine, bovine, rat, mouse, and human in vitro BMEC apparent permeability values, P(e), (14 studies...

Values of the ionization constants at 37 °C, which are scarcely reported, are more meaningful for interpreting mechanisms of cellular transport by ionizable molecules and in mechanistic dissolution studies, which are often performed at the biorelevant temperature. An equation was developed where the pK(a) values of drug-like molecules determined at...

If measurements of solubility were not so laborious, slow, and consuming of sample, solubility-pH profiles would be used more often at the initial stages of drug discovery to screen out molecules with problematic pharmacokinetic profiles.An automated potentiometric titration method for solubility measurements, which addresses some of the shortcomin...

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To determine the flow-corrected luminal permeability, P(c), of lipophilic drugs measured by the in situ brain perfusion method under circumstances where the traditional Crone-Renkin equation (CRE) method, using diazepam as a flow marker, often fails. The pH-dependent rate of brain penetration of five lipophilic drugs (amitriptyline, atomoxetine, im...

To mimic the physicochemical selectivity of the blood-brain barrier (BBB) and to predict its passive permeability using a PAMPA model based on porcine brain lipid extract (PBLE 10%w/v in alkane). Three PAMPA (BD pre-coated and PBLE with 2 different lipid volumes) models were tested with 108 drugs. Abraham solvation descriptors were used to interpre...

The permeability of biological membranes is one of the most important determinants of the pharmacokinetic processes of a drug. Although it is often accepted that many drug substances are transported across biological membranes by passive transcellular diffusion, a recent hypothesis speculated that carrier-mediated mechanisms might account for the m...

The study aimed to predict effective human jejunal permeability (P(eff)) using a biophysical model based on parametrized paracellular, aqueous boundary layer, and transcellular permeabilities, and the villus-fold surface area expansion factor (k(VF)). Published human jejunal data (119 P(eff), 53 compounds) were analyzed by a regression procedure in...

To determine and compare the paracellular characteristics of permeability (Papp) of Caco (-2), MDCK, and 2/4/A1 cell lines. The Papp data from 14 studies were analyzed by weighted nonlinear regression in terms of the paracellular parameters: porosity-pathlength (epsilon/delta), pore radius (R), and electrostatic potential drop (deltaphi). Aqueous d...

The objective was to investigate the applicability and limitations of an approach for estimating particle size from powder dissolution measurement using as little as 50 microg of sample in 1 ml of buffer solutions. The powder dissolution profiles of five sparingly-soluble drugs (hydrochlorothiazide, phenazopyridine hydrochloride, 2-naphthoic acid,...

There is a major need in drug discovery for quick, precise, and cost-effective high-throughput screening (HTS) systems in the early stages of drug research. The Parallel Artificial Membrane Permeability Assay (PAMPA) aims at predicting the passive membrane properties of drugs. Since 1998, model membranes have been developed to predict gastro-intest...

The permeability characteristics of 33 amphoteric drugs (about 64% zwitterions at physiological pH) were studied using the parallel artificial membrane permeability assay (PAMPA) at pH 6.5. The PAMPA data were modified to include the paracellular permeability component found in cellular monolayers based on a newly generalized version of a popular m...

The purpose of the study was to assess the permeability of mouse blood-brain barrier (BBB) to a diverse set of compounds in the absence of P-glycoprotein (Pgp) mediated efflux, to predict it using an in combo PAMPA model, and to explore its role in brain penetration classification (BPC). The initial brain uptake (K(in)) of 19 compounds in both wild...

The objective was to investigate the applicability and limitations of a novel approach for measuring intrinsic dissolution rates (IDR) of very small quantities of compounds introduced as powders to buffered solutions and comparing these results to disk IDR obtained using the traditional Wood's apparatus. The powder dissolution profiles of 13 model...

The objective was to investigate the feasibility of using a miniaturized disk intrinsic dissolution rate (IDR) apparatus to determine the Biopharmaceutics Classification System (BCS) solubility class, and to develop an approach where IDR measurements performed in media of different buffer capacity could be compared. The disk IDR values of 14 model...