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Papers by John Comer

Summary A method for fast measurements of pK a values has recently been developed. The method is ... more Summary A method for fast measurements of pK a values has recently been developed. The method is based on the well established Dip Probe Absorption Spectroscopy (D-PAS), a hybrid method combining the traditional pH-metric method with spectroscopic detection. By conducting the titrations in a linear buffer solution with low UV absorbance whose pH was pre-adjusted to an initial pH of

AAPS PharmSciTech, Jan 25, 2015

The purpose of this study was to better understand the dissolution properties and precipitation b... more The purpose of this study was to better understand the dissolution properties and precipitation behavior of pharmaceutical cocrystals of poorly soluble drugs for the potential for oral administration based on a small-scale dissolution assay. Carbamazepine and indomethacin cocrystals with saccharin and nicotinamide as coformers were prepared with the sonic slurry method. Dissolution of the poorly soluble drugs indomethacin and carbamazepine and their cocrystals was studied with a small-scale dissolution assay installed on a SiriusT3 instrument. Two methodologies were used: (i) surface dissolution of pressed tablet (3 mm) in 20 mL running for fixed times at four pH stages (pH 1.8, pH 3.9, pH 5.4, pH 7.3) and (ii) powder dissolution (2.6 mg) in 2 mL at a constant pH (pH 2). Improved dissolution and useful insights into precipitation kinetics of poorly soluble compounds from the cocrystal form can be revealed by the small-scale dissolution assay. A clear difference in dissolution/precip...

Pharmaceutical Research, 1998

To investigate a novel approach for the determination of liposomal membrane-water partition coeff... more To investigate a novel approach for the determination of liposomal membrane-water partition coefficients and lipophilicity profiles of ionizable drugs. The measurements were performed by using a pH-metric technique in a system consisting of dioleylphosphatidylcholine (DOPC) unilamellar vesicles in 0.15 M KCl at 25 degrees C. The DOPC unilamellar vesicle suspension was prepared via an extrusion process. The liposomal membrane-water partition coefficients of eight ionizable drugs: ibuprofen, diclofenac, 5-phenylvaleric acid, warfarin, propranolol, lidocaine, tetracaine and procaine were determined and the values for neutral and ionized species were found to be in the ranges of approximately 4.5 to 2.4 and 2.6 to 0.8 logarithmic units, respectively. It has been shown that the liposomal membrane-water partition coefficients as derived from the pH-metric technique are consistent with those obtained from alternative methods such as ultrafiltration and dialysis. It was found that in liposome system, partitioning of the ionized species is significant and is influenced by electrostatic interaction with the membranes. We have demonstrated that the pH-metric technique is an efficient and accurate way to determine the liposomal membrane-water partition coefficients of ionizable substances.

Journal of Pharmaceutical Sciences, 1994

The pKa and log P of 20 compounds, including six substituted phenols, two substituted quinolines,... more The pKa and log P of 20 compounds, including six substituted phenols, two substituted quinolines, N-methylaniline, five barbiturate derivatives, two phenothiazines, and several other molecules of pharmaceutical interest, were determined by the potentiometric technique at 25 degrees C and ionic strength 0.1 M (KNO3). The log P values were determined also by partition HPLC. Three of the substances were of very low aqueous solubility, and for these the aqueous pKas were determined by extrapolation from methanol-water solutions using the Yasuda-Shedlovsky technique. Values of log P obtained both by potentiometry and by partition HPLC, which ranged from 0.3 to 5.4, were in very good acordance with literature values. The general applicability of the potentiometric technique to ionizable compounds of diversely varied structures was demonstrated by the study.

Journal of Pharmaceutical Sciences, 2006

A novel potentiometric procedure has recently been described for rapid measurement of equilibrium... more A novel potentiometric procedure has recently been described for rapid measurement of equilibrium aqueous solubility values of organic acids, bases, and ampholytes that form supersaturated solutions. In this procedure, the equilibrium solubility is actively sought by changing the concentration of the neutral form by adding HCl or KOH titrants and monitoring the rate of change of pH due to precipitation or dissolution in a process called Chasing Equilibrium. In this article, we seek to validate the procedure against a shake-flask protocol for solubility determination. A set of 16 small organic compounds, covering a wide range of solubilities was chosen for the study. Interestingly, while 10 compounds in the study were found to chase equilibrium, the others did not. Kinetic solubility data was also collected. It was noted that kinetic solubility was consistently higher than equilibrium solubility for chasers, but correlated well with equilibrium solubility for nonchasers. The ratio of kinetic to equilibrium solubility indicated a compound's ability to form supersaturated solutions. ß All pK a s were measured at 258C and 0.15 M ionic strength.

Journal of Pharmaceutical and Biomedical Analysis, 1998

A multiwavelength spectrophotometric approach has been developed to determine acid dissociation c... more A multiwavelength spectrophotometric approach has been developed to determine acid dissociation constants (pKa values) of sparingly soluble drug compounds. UV absorption spectra of the drug solution are acquired using a versatile device based on a fiber optics dip probe, a light source and a photodiode array (PDA) detector while the pH and the ionic strength of the chemical system is

Journal of Medicinal Chemistry, 2006

A multivariate analysis of drugs on the Swedish market was the basis for the selection of a small... more A multivariate analysis of drugs on the Swedish market was the basis for the selection of a small, physicochemically diverse set of 24 drug compounds. Factors such as structural diversity, commercial availability, price, and a suitable analytical technique for quantification were considered in the selection. Lipophilicity, pKa, solubility, and permeability across human Caco-2 cell monolayers were measured for the compiled data set. The results show that, by use of a physicochemically diverse data set, experimental responses over a wide range were obtained. The paper also shows how experimental difficulties due to the diversity of the data set can be overcome. We anticipate that this data set can serve as a benchmark set for validation of new experimental techniques or in silico models. It can also be used as a diverse starting data set for the development of new computational models.

European Journal of Pharmaceutical Sciences, 2004

The permeabilities of 43 ionisable compounds through membranes consisting of 2% dioleylphosphatid... more The permeabilities of 43 ionisable compounds through membranes consisting of 2% dioleylphosphatidylcholine (DOPC) in dodecane at pH values between 3 and 10 have been measured. The observed values are corrected for the effects of ionisation and diffusion through the unstirred water layer in order to obtain estimates of intrinsic permeability. The intrinsic permeabilities are modelled using Abraham's linear free energy relation method. This not only provides a predictive model of membrane permeability, but also reveals the factors determining passive permeation through membranes made from 2% DOPC in dodecane. Hydrogen bonding dominates, acting to strongly inhibit permeation, polarity/polarisability effects are less important, and size acts to enhance permeation.

Drug Discovery Today, 2002

A drug can be characterized by &a... more A drug can be characterized by "descriptors" that include size (volume) and H-bond acidity and H-bond basicity. These descriptors can be rapidly estimated from structure by a fragment scheme and used to predict physicochemical and transport properties of drug candidates (e.g. logP, solubility, gastrointestinal absorption, permeability and blood-brain distribution). The solvation equations can be interpreted to provide a qualitative chemical insight into biological partition and transport mechanisms. Applications to blood-brain partition and human intestinal absorption (HIA) are discussed.

Current Drug Metabolism, 2008

Ionization, lipophilicity and solubility have a profound influence on the transport properties of... more Ionization, lipophilicity and solubility have a profound influence on the transport properties of drug molecules. We will present an overview of why physicochemical properties are important, before discussing how the properties are related to each other. Findings are based on research in our own laboratories using our commercial instruments and software to measure the pKa, lipophilicity (LogP) and intrinsic solubility (LogS0) of 84 marketed ionizable drugs. In general, the most lipophilic molecules were the least soluble in water. Plots of LogP vs. LogS0 show results for these drugs clustered according to other properties, including melting point, number of H-bond donors and acceptors, ability to supersaturate, and BCS class. Molecules with high melting point tended to have a larger number of H-bond donors and acceptors, and to be less soluble than predicted from their LogP. Molecules with low melting point tended to have little H-bond donor capacity, and tended to be more soluble than predicted from their LogP. Molecules that could form supersaturated solutions tended to have higher melting points, and to be less soluble than predicted from their LogP. Molecules in BCS Classes I-III tended to cluster in different parts of the plot. It is proposed that comparing measured LogP and LogS0 of new molecules with these plots will facilitate a quick assessment of their likely BCS Class.

Analytical Chemistry, 1993

Page 1. 42 Anal. Chem. 1003, 65, 42-49 pH-Metric log P. 3. Glass Electrode Calibration in Methano... more Page 1. 42 Anal. Chem. 1003, 65, 42-49 pH-Metric log P. 3. Glass Electrode Calibration in Methanol-Water, Applied to pKa Determination of Water-Insoluble Substancest Alex Avdeef,' John EA Comer, and Simon J. Thomson ...

Analytical Chemistry, 2003

A procedure is described for measuring pKa values in a short time, e.g., 4 min/assay. Samples, as... more A procedure is described for measuring pKa values in a short time, e.g., 4 min/assay. Samples, as 10 mM solutions, are prepared in DMSO in 96-well plates. A flowing pH gradient is produced by mixing two buffer solutions containing mixtures of weak acids and bases that do not absorb significantly in the UV above 250 nm. The sample solution is diluted with water and then injected directly into the flowing gradient, which then passes through a diode array spectrophotometer measuring in the UV wavelength range. The buffer has been formulated so that its acid-base titration curve is linear over a wide pH range, such that the pH of the gradient is a linear function of time. The solution pH in the measurement flow cell is therefore proportional to the time elapsed since the start of gradient generation. The sample's pKa values are calculated from the change in UV absorbance at multiple wavelengths as a function of pH. The pKa values of 71 drugs have been measured, and results compare well with values measured by pH-metric or traditional UV methods. Rules are suggested for the rapid inspection of data and the choice of method for the calculation of pKa from the data.

Analytica Chimica Acta, 2007

In this paper the validation of pK a determination in MDM-water mixtures is presented. The MDM-wa... more In this paper the validation of pK a determination in MDM-water mixtures is presented. The MDM-water mixture is a new multicomponent cosolvent mixture (consisting of equal volumes of methanol, dioxane and acetonitrile, as organic solvents) that dissolves a wide range of poorly watersoluble compounds. The cosolvent dissociation constants (p s K a ) of 50 chemically diverse compounds (acids, bases and ampholytes) were measured in 15-56 wt% MDM-water mixtures by potentiometric or spectrophotometric titration and the aqueous pK a values obtained by extrapolation. Three different extrapolation procedures were compared in order to choose the best extrapolation in MDM-water mixture using a sub-set of 30 watersoluble compounds. The extrapolated results are in good agreement with pK a values measured in aqueous medium. No significant difference was found among these extrapolation procedures thus the widely used Yasuda-Shedlovsky plot was proposed for MDM cosolvent also. Further we also present that the single point estimation based on measurement in 20%/v MDM-mixture using a general calibration equation may be suitable for rapid pK a determination in the early phase of drug research.

Analytica Chimica Acta, 2010

In this paper the pH-equilibrium solubility profiles of six organic drugs are presented. The equi... more In this paper the pH-equilibrium solubility profiles of six organic drugs are presented. The equilibrium solubility values were determined using the saturation shake-flask and the Chasing Equilibrium Solubility (CheqSol) methods. Results obtained by the two methods are in good agreement. The aim of the present work was to study the validity of the Henderson-Hasselbalch (HH) relationship in the case of structurally diverse weak bases. The significance of pH control and the effect of the salt form (e.g., fumarate) was also investigated. In the case of monoprotic bases, namely papaverine, promethazine, propafenone and ticlopidine the experimental solubility data precisely follow the HH equation until the limit of salt solubility. The common ion effect on salt solubility was found to be significant at low pHs. Deviation from the HH equation in the case of dibasic quetiapine hydrogen fumarate and the ampholyte desvenlafaxine hydrogen fumarate can be easily interpreted with the formation of different salt compositions. It was concluded that precise pH control is essential in shake-flask solubility measurements. It is also critical that the pK a value and the intrinsic solubility are accurately determined when the HH relationship is used to predict the pH-dependent aqueous solubility of drugs.

Helvetica chimica …, 1999

The objectives of this study were to validate new experimental techniques used to measure the log... more The objectives of this study were to validate new experimental techniques used to measure the log P of protonated drugs, and to investigate the inter-and intramolecular forces influencing the partitioning behavior of b-blockers in isotropic biphasic solvent systems. The lipophilicity parameters of a number of b-blockers were measured by two-phase titration, centrifugal partition chromatography (CPC), and cyclic voltammetry (CV) in one or more of the following solvent systems: octanol/water, 1,2-dichloroethane/water, and dibutyl ether/water. CV proved to be a promising technique for measuring the lipophilicity of protonated b-blockers. Derived parameters such as Dlog P (difference between log P in two different solvent systems, a parameter valid for a given solute in a given electrical form) and diff (difference between log P of two different electrical forms of a given solute, in the same system) yielded insights into inter-and intramolecular interactions characteristic of bblockers. The relevance of these parameters in structure-permeation relationships is explored.

Summary A method for fast measurements of pK a values has recently been developed. The method is ... more Summary A method for fast measurements of pK a values has recently been developed. The method is based on the well established Dip Probe Absorption Spectroscopy (D-PAS), a hybrid method combining the traditional pH-metric method with spectroscopic detection. By conducting the titrations in a linear buffer solution with low UV absorbance whose pH was pre-adjusted to an initial pH of

AAPS PharmSciTech, Jan 25, 2015

The purpose of this study was to better understand the dissolution properties and precipitation b... more The purpose of this study was to better understand the dissolution properties and precipitation behavior of pharmaceutical cocrystals of poorly soluble drugs for the potential for oral administration based on a small-scale dissolution assay. Carbamazepine and indomethacin cocrystals with saccharin and nicotinamide as coformers were prepared with the sonic slurry method. Dissolution of the poorly soluble drugs indomethacin and carbamazepine and their cocrystals was studied with a small-scale dissolution assay installed on a SiriusT3 instrument. Two methodologies were used: (i) surface dissolution of pressed tablet (3 mm) in 20 mL running for fixed times at four pH stages (pH 1.8, pH 3.9, pH 5.4, pH 7.3) and (ii) powder dissolution (2.6 mg) in 2 mL at a constant pH (pH 2). Improved dissolution and useful insights into precipitation kinetics of poorly soluble compounds from the cocrystal form can be revealed by the small-scale dissolution assay. A clear difference in dissolution/precip...

Pharmaceutical Research, 1998

To investigate a novel approach for the determination of liposomal membrane-water partition coeff... more To investigate a novel approach for the determination of liposomal membrane-water partition coefficients and lipophilicity profiles of ionizable drugs. The measurements were performed by using a pH-metric technique in a system consisting of dioleylphosphatidylcholine (DOPC) unilamellar vesicles in 0.15 M KCl at 25 degrees C. The DOPC unilamellar vesicle suspension was prepared via an extrusion process. The liposomal membrane-water partition coefficients of eight ionizable drugs: ibuprofen, diclofenac, 5-phenylvaleric acid, warfarin, propranolol, lidocaine, tetracaine and procaine were determined and the values for neutral and ionized species were found to be in the ranges of approximately 4.5 to 2.4 and 2.6 to 0.8 logarithmic units, respectively. It has been shown that the liposomal membrane-water partition coefficients as derived from the pH-metric technique are consistent with those obtained from alternative methods such as ultrafiltration and dialysis. It was found that in liposome system, partitioning of the ionized species is significant and is influenced by electrostatic interaction with the membranes. We have demonstrated that the pH-metric technique is an efficient and accurate way to determine the liposomal membrane-water partition coefficients of ionizable substances.

Journal of Pharmaceutical Sciences, 1994

The pKa and log P of 20 compounds, including six substituted phenols, two substituted quinolines,... more The pKa and log P of 20 compounds, including six substituted phenols, two substituted quinolines, N-methylaniline, five barbiturate derivatives, two phenothiazines, and several other molecules of pharmaceutical interest, were determined by the potentiometric technique at 25 degrees C and ionic strength 0.1 M (KNO3). The log P values were determined also by partition HPLC. Three of the substances were of very low aqueous solubility, and for these the aqueous pKas were determined by extrapolation from methanol-water solutions using the Yasuda-Shedlovsky technique. Values of log P obtained both by potentiometry and by partition HPLC, which ranged from 0.3 to 5.4, were in very good acordance with literature values. The general applicability of the potentiometric technique to ionizable compounds of diversely varied structures was demonstrated by the study.

Journal of Pharmaceutical Sciences, 2006

A novel potentiometric procedure has recently been described for rapid measurement of equilibrium... more A novel potentiometric procedure has recently been described for rapid measurement of equilibrium aqueous solubility values of organic acids, bases, and ampholytes that form supersaturated solutions. In this procedure, the equilibrium solubility is actively sought by changing the concentration of the neutral form by adding HCl or KOH titrants and monitoring the rate of change of pH due to precipitation or dissolution in a process called Chasing Equilibrium. In this article, we seek to validate the procedure against a shake-flask protocol for solubility determination. A set of 16 small organic compounds, covering a wide range of solubilities was chosen for the study. Interestingly, while 10 compounds in the study were found to chase equilibrium, the others did not. Kinetic solubility data was also collected. It was noted that kinetic solubility was consistently higher than equilibrium solubility for chasers, but correlated well with equilibrium solubility for nonchasers. The ratio of kinetic to equilibrium solubility indicated a compound's ability to form supersaturated solutions. ß All pK a s were measured at 258C and 0.15 M ionic strength.

Journal of Pharmaceutical and Biomedical Analysis, 1998

A multiwavelength spectrophotometric approach has been developed to determine acid dissociation c... more A multiwavelength spectrophotometric approach has been developed to determine acid dissociation constants (pKa values) of sparingly soluble drug compounds. UV absorption spectra of the drug solution are acquired using a versatile device based on a fiber optics dip probe, a light source and a photodiode array (PDA) detector while the pH and the ionic strength of the chemical system is

Journal of Medicinal Chemistry, 2006

A multivariate analysis of drugs on the Swedish market was the basis for the selection of a small... more A multivariate analysis of drugs on the Swedish market was the basis for the selection of a small, physicochemically diverse set of 24 drug compounds. Factors such as structural diversity, commercial availability, price, and a suitable analytical technique for quantification were considered in the selection. Lipophilicity, pKa, solubility, and permeability across human Caco-2 cell monolayers were measured for the compiled data set. The results show that, by use of a physicochemically diverse data set, experimental responses over a wide range were obtained. The paper also shows how experimental difficulties due to the diversity of the data set can be overcome. We anticipate that this data set can serve as a benchmark set for validation of new experimental techniques or in silico models. It can also be used as a diverse starting data set for the development of new computational models.

European Journal of Pharmaceutical Sciences, 2004

The permeabilities of 43 ionisable compounds through membranes consisting of 2% dioleylphosphatid... more The permeabilities of 43 ionisable compounds through membranes consisting of 2% dioleylphosphatidylcholine (DOPC) in dodecane at pH values between 3 and 10 have been measured. The observed values are corrected for the effects of ionisation and diffusion through the unstirred water layer in order to obtain estimates of intrinsic permeability. The intrinsic permeabilities are modelled using Abraham's linear free energy relation method. This not only provides a predictive model of membrane permeability, but also reveals the factors determining passive permeation through membranes made from 2% DOPC in dodecane. Hydrogen bonding dominates, acting to strongly inhibit permeation, polarity/polarisability effects are less important, and size acts to enhance permeation.

Drug Discovery Today, 2002

A drug can be characterized by &a... more A drug can be characterized by "descriptors" that include size (volume) and H-bond acidity and H-bond basicity. These descriptors can be rapidly estimated from structure by a fragment scheme and used to predict physicochemical and transport properties of drug candidates (e.g. logP, solubility, gastrointestinal absorption, permeability and blood-brain distribution). The solvation equations can be interpreted to provide a qualitative chemical insight into biological partition and transport mechanisms. Applications to blood-brain partition and human intestinal absorption (HIA) are discussed.

Current Drug Metabolism, 2008

Ionization, lipophilicity and solubility have a profound influence on the transport properties of... more Ionization, lipophilicity and solubility have a profound influence on the transport properties of drug molecules. We will present an overview of why physicochemical properties are important, before discussing how the properties are related to each other. Findings are based on research in our own laboratories using our commercial instruments and software to measure the pKa, lipophilicity (LogP) and intrinsic solubility (LogS0) of 84 marketed ionizable drugs. In general, the most lipophilic molecules were the least soluble in water. Plots of LogP vs. LogS0 show results for these drugs clustered according to other properties, including melting point, number of H-bond donors and acceptors, ability to supersaturate, and BCS class. Molecules with high melting point tended to have a larger number of H-bond donors and acceptors, and to be less soluble than predicted from their LogP. Molecules with low melting point tended to have little H-bond donor capacity, and tended to be more soluble than predicted from their LogP. Molecules that could form supersaturated solutions tended to have higher melting points, and to be less soluble than predicted from their LogP. Molecules in BCS Classes I-III tended to cluster in different parts of the plot. It is proposed that comparing measured LogP and LogS0 of new molecules with these plots will facilitate a quick assessment of their likely BCS Class.

Analytical Chemistry, 1993

Page 1. 42 Anal. Chem. 1003, 65, 42-49 pH-Metric log P. 3. Glass Electrode Calibration in Methano... more Page 1. 42 Anal. Chem. 1003, 65, 42-49 pH-Metric log P. 3. Glass Electrode Calibration in Methanol-Water, Applied to pKa Determination of Water-Insoluble Substancest Alex Avdeef,' John EA Comer, and Simon J. Thomson ...

Analytical Chemistry, 2003

A procedure is described for measuring pKa values in a short time, e.g., 4 min/assay. Samples, as... more A procedure is described for measuring pKa values in a short time, e.g., 4 min/assay. Samples, as 10 mM solutions, are prepared in DMSO in 96-well plates. A flowing pH gradient is produced by mixing two buffer solutions containing mixtures of weak acids and bases that do not absorb significantly in the UV above 250 nm. The sample solution is diluted with water and then injected directly into the flowing gradient, which then passes through a diode array spectrophotometer measuring in the UV wavelength range. The buffer has been formulated so that its acid-base titration curve is linear over a wide pH range, such that the pH of the gradient is a linear function of time. The solution pH in the measurement flow cell is therefore proportional to the time elapsed since the start of gradient generation. The sample's pKa values are calculated from the change in UV absorbance at multiple wavelengths as a function of pH. The pKa values of 71 drugs have been measured, and results compare well with values measured by pH-metric or traditional UV methods. Rules are suggested for the rapid inspection of data and the choice of method for the calculation of pKa from the data.

Analytica Chimica Acta, 2007

In this paper the validation of pK a determination in MDM-water mixtures is presented. The MDM-wa... more In this paper the validation of pK a determination in MDM-water mixtures is presented. The MDM-water mixture is a new multicomponent cosolvent mixture (consisting of equal volumes of methanol, dioxane and acetonitrile, as organic solvents) that dissolves a wide range of poorly watersoluble compounds. The cosolvent dissociation constants (p s K a ) of 50 chemically diverse compounds (acids, bases and ampholytes) were measured in 15-56 wt% MDM-water mixtures by potentiometric or spectrophotometric titration and the aqueous pK a values obtained by extrapolation. Three different extrapolation procedures were compared in order to choose the best extrapolation in MDM-water mixture using a sub-set of 30 watersoluble compounds. The extrapolated results are in good agreement with pK a values measured in aqueous medium. No significant difference was found among these extrapolation procedures thus the widely used Yasuda-Shedlovsky plot was proposed for MDM cosolvent also. Further we also present that the single point estimation based on measurement in 20%/v MDM-mixture using a general calibration equation may be suitable for rapid pK a determination in the early phase of drug research.

Analytica Chimica Acta, 2010

In this paper the pH-equilibrium solubility profiles of six organic drugs are presented. The equi... more In this paper the pH-equilibrium solubility profiles of six organic drugs are presented. The equilibrium solubility values were determined using the saturation shake-flask and the Chasing Equilibrium Solubility (CheqSol) methods. Results obtained by the two methods are in good agreement. The aim of the present work was to study the validity of the Henderson-Hasselbalch (HH) relationship in the case of structurally diverse weak bases. The significance of pH control and the effect of the salt form (e.g., fumarate) was also investigated. In the case of monoprotic bases, namely papaverine, promethazine, propafenone and ticlopidine the experimental solubility data precisely follow the HH equation until the limit of salt solubility. The common ion effect on salt solubility was found to be significant at low pHs. Deviation from the HH equation in the case of dibasic quetiapine hydrogen fumarate and the ampholyte desvenlafaxine hydrogen fumarate can be easily interpreted with the formation of different salt compositions. It was concluded that precise pH control is essential in shake-flask solubility measurements. It is also critical that the pK a value and the intrinsic solubility are accurately determined when the HH relationship is used to predict the pH-dependent aqueous solubility of drugs.

Helvetica chimica …, 1999

The objectives of this study were to validate new experimental techniques used to measure the log... more The objectives of this study were to validate new experimental techniques used to measure the log P of protonated drugs, and to investigate the inter-and intramolecular forces influencing the partitioning behavior of b-blockers in isotropic biphasic solvent systems. The lipophilicity parameters of a number of b-blockers were measured by two-phase titration, centrifugal partition chromatography (CPC), and cyclic voltammetry (CV) in one or more of the following solvent systems: octanol/water, 1,2-dichloroethane/water, and dibutyl ether/water. CV proved to be a promising technique for measuring the lipophilicity of protonated b-blockers. Derived parameters such as Dlog P (difference between log P in two different solvent systems, a parameter valid for a given solute in a given electrical form) and diff (difference between log P of two different electrical forms of a given solute, in the same system) yielded insights into inter-and intramolecular interactions characteristic of bblockers. The relevance of these parameters in structure-permeation relationships is explored.