FLUX

Title

in vitro dissolution-absorption evaluation of an electrospun cyclodextrin-based formulation of aripiprazole using µFLUX

 

Authors

Enikő Borbása, Attila Balogha, Katalin Bocza, Judit Müllera, Éva Kiserdeia, Tamás Vigha, Bálint Sinkób, Attila Marosic, Attila Halászd, Zoltán Dohányosd, Lajos Szentee, György T. Baloghf, Zsombor K. Nagya

Current Pion intern, Enikő Borbás, now published in the International Journal of Pharmaceutics for her work done using the Pion µFLUX system for her formulation development work. Her article is now available online at: https://lnkd.in/edUDQHe

 

Abstract

Since it is a well-known fact that among the newly discovered active pharmaceutical ingredients the number of poorly water soluble candidates is continually increasing, dissolution enhancement of poorly water soluble drugs has become one of the central challenges of pharmaceutical studies. So far the preclinical studies have been mainly focused on formulation methods to enhance the dissolution of active compounds, in many cases disregarding the fact that the formulation matrix not only affects dissolution but also has an effect on the transport through biological membranes, changing permeation of the drug molecules. The aim of this study was to test an electrospun cyclodextrin-based formulation of aripiprazole with the novel μFlux apparatus, which monitors permeation together with dissolution, and by this means better in vitro–in vivo correlation is achieved. It was evinced that a cyclodextrin-based electrospun formulation of aripiprazole has the potential to ensure fast drug delivery through the oral mucosa owing to the ultrafast dissolution of the drug from the formulation and the enhanced flux across membranes as shown by the result of the novel in vitro dissolution and permeation test.

 

Publication

International Journal of Pharmaceutics

 

Bibliography

Borbás, E.; Balogh, A.; Bocz, K.; Müller, J.; Kiserdei, É.; Vigh, T.; Sinkó, B.; Marosi, A.; Halász, A.; Dohányos, Z.; Szente, L.; Balogh, GT.; Nagy, ZK. In vitro dissolution-permeation evaluation of an electrospun cyclodextrin-based formulation of aripiprazole using μFlux™. Int J Pharm. 2015 Aug 1;491(1-2):180-9.

 

Link

https://www.ncbi.nlm.nih.gov/pubmed/26117189

 

 

 

 

Ionization

 

Title

Spectrophotometric pKa determination of ionizable pharmaceuticals: Resolution of molecules with weak pH-dependent spectral shift

 

Authors

Deren Dohoda, Konstantin Tsinman, Oksana Tsinman, Haotian Wang, Kin Y. Tam

 

Abstract

The extent of ionization of a drug molecule at different pH values can be characterized by its pKa (acid dissociation constants). It is an important parameter in pharmaceutical development to rationalize the physiochemical and biopharmaceutical properties of the drug molecule. UV titration for pKa determination is one of the popular methods. The success of this method requires the molecule exhibiting strong pH-dependent spectral shift related to the ionization process. Depending on the proximity between the ionizable group and the chromophore, the spectral shift may not be strong enough to warrant a successful determination. In a previous study, it has been reported that a distance of three σ bonds between the chromophore and the ionizable group was the limit for a precise pKa determination. In this work, a UV titration method for pKa determination, with a particular emphasis on molecules with weak pH-dependent spectral shift is investigated. It has been shown that the pKa values determined from this study are in good agreement with those determined using potentiometric method and literature data (R2 = 0.998). Our methodology revealed that successful pKa determination is feasible even with a separation distance of five σ bonds between the chromophore and the ionizable group.

 

Publication

Journal of Pharmaceutical and Biomedical Analysis

 

Bibliography

Dohoda, D.; Tsinman, K.; Tsinman, O.; Wang, O.; Tam, KY. Spectrophotometric pKa determination of ionizable pharmaceuticals: Resolution of molecules with weak pH-dependent spectral shift. J Pharm Biomed Anal. 2015 Oct 10;114:88-96.

 

Link

https://www.ncbi.nlm.nih.gov/pubmed/26026267

 

 

 

 

Title

Drug ionization and physicochemical profiling

 

Authors

A Avdeef

 

Publication

Molecular Drug Properties - Measurement and Prediction

 

Bibliography

Avdeef, A. Drug ionization and physicochemical profiling. In: Mannhold, R. (Ed.), Drug Properties: Measurement and Computation, Wiley-VCH, 2007, pp. 55-83. (Part 1 in pKa series)

 

Link

http://onlinelibrary.wiley.com/doi/10.1002/9783527621286.ch3/references

 

 

 

 

Title

pH-metric solubility. 3. Dissolution titration template method for solubility determination

 

Authors

A Avdeef; C.M. Berger

 

Abstract

The main objective of this study was to develop an effective potentiometric saturation titration protocol for determining the aqueous intrinsic solubility and the solubility-pH profile of ionizable molecules, with the specific aim of overcoming incomplete dissolution conditions, while attempting to shorten the data collection time. A modern theory of dissolution kinetics (an extension of the Noyes-Whitney approach) was applied to acid-base titration experiments. A thermodynamic method was developed, based on a three-component model, to calculate interfacial, diffusion-layer, and bulk-water reactant concentrations in saturated solutions of ionizable compounds perturbed by additions of acid/base titrant, leading to partial dissolution of the solid material. Ten commercial drugs (cimetidine, diltiazem hydrochloride, enalapril maleate, metoprolol tartrate, nadolol, propoxyphene hydrochloride, quinine hydrochloride, terfenadine, trovafloxacin mesylate, and benzoic acid) were chosen to illustrate the new titration methodology. It was shown that the new method is about 10 times faster in determining equilibrium solubility constants, compared to the traditional saturation shake-flask methods.

 

Publication

European Journal of Pharmaceutical Sciences

 

Bibliography

Avdeef, A.; Berger, C.M. pH-Metric Solubility. 3. Dissolution Titration Template Method for Solubility Determination. Eur. J. Pharm. Sci. 2001, 14, 271-280. (Part 3 in pSOL series)

 

Link

https://www.ncbi.nlm.nih.gov/pubmed/11684402

 

 

 

 

Title

pH-Metric Solubility. 2. Correlation Between the Acid-Base Titration and the Saturation Shake-Flask Solubility-pH Methods

 

Authors

A Avdeef, CM Berger, C Brownell

 

Abstract

PURPOSE: The objective of this study was to compare the results of a normal saturation shake-flask method to a new potentiometric acid-base titration method for determining the intrinsic solubility and the solubility-pH profiles of ionizable molecules, and to report the solubility constants determined by the latter technique.

 

METHODS: The solubility-pH profiles of twelve generic drugs (atenolol, diclofenac.Na, famotidine, flurbiprofen, furosemide, hydrochlorothiazide, ibuprofen, ketoprofen, labetolol.HCl, naproxen, phenytoin, and propranolol.HCl), with solubilities spanning over six orders of magnitude, were determined both by the new pH-metric method and by a traditional approach (24 hr shaking of saturated solutions, followed by filtration, then HPLC assaying with UV detection).

 

RESULTS: The 212 separate saturation shake-flask solubility measurements and those derived from 65 potentiometric titrations agreed well. The analysis produced the correlation equation: log(1/S)titration = -0.063(+/- 0.032) + 1.025(+/- 0.011) log(1/S)shake-flask, s = 0.20, r2 = 0.978. The potentiometrically-derived intrinsic solubilities of the drugs were: atenolol 13.5 mg/mL, diclofenac.Na 0.82 microg/mL, famotidine 1.1 mg/ mL, flurbiprofen 10.6 microg/mL, furosemide 5.9 microg/mL, hydrochlorothiazide 0.70 mg/mL, ibuprofen 49 microg/mL, ketoprofen 118 microg/mL, labetolol.HCl 128 microg/mL, naproxen 14 microg/mL, phenytoin 19 microg/mL, and propranolol.HCl 70 microg/mL.

 

CONCLUSIONS: The new potentiometric method was shown to be reliable for determining the solubility-pH profiles of uncharged ionizable drug substances. Its speed compared to conventional equilibrium measurements, its sound theoretical basis, its ability to generate the full solubility-pH profile from a single titration, and its dynamic range (currently estimated to be seven orders of magnitude) make the new pH-metric method an attractive addition to traditional approaches used by preformulation and development scientists. It may be useful even to discovery scientists in critical decision situations (such as calibrating computational prediction methods).

 

Publication

European Journal of Pharmaceutical Sciences

 

Bibliography

Avdeef, A.; Berger, C.M.; Brownell, C. pH-Metric Solubility. 2. Correlation Between the Acid-Base Titration and the Saturation Shake-Flask Solubility-pH Methods. Pharm. Res. 2000, 17, 85-89. (Part 2 in pSOL series)

 

Link

https://www.ncbi.nlm.nih.gov/pubmed/10714613

 

 

 

 

Title

pH-metric logP. 11. pKa determination of water-insoluble drugs in organic solvent-water mixtures

 

Authors

A Avdeef, KJ Box, JEA Comer, M Gilges, M Hadley, C Hibbert, W Patterson, KY Tam

 

Abstract

The apparent acid dissociation constants (p(s)Ka) of two water-insoluble drugs, ibuprofen and quinine, were determined pH-metrically in acetonitrile water, dimethylformamide water, dimethylsulfoxide water, 1,4-dioxane-water, ethanol water, ethylene glycol-water, methanol water and tetrahydrofuran water mixtures. A glass electrode calibration procedure based on a four-parameter equation (pH = alpha + SpcH + jH[H+]+jOH[OH-]) was used to obtain pH readings based on the concentration scale (pcH). We have called this four-parameter method the Four-Plus technique. The Yasuda Shedlovsky extrapolation (p(s)Ka + log [H2O] = A/epsilon + B) was used to derive acid dissociation constants in aqueous solution (pKa). It has been demonstrated that the pKa values extrapolated from such solvent water mixtures are consistent with each other and with previously reported measurements. The suggested method has also been applied with success to determine the pKa values of two pyridine derivatives of pharmaceutical interest.

 

Publication

Journal of Pharmaceutical and Biomedical Analysis

 

Bibliography

Avdeef, A.; Box, K.J.; Comer, J.E.A.; Gilges, M.; Hadley, M.; Hibbert, C.; Patterson, W.;Tam, K.Y. pH-metric logP. 11. pKa determination of water-insoluble drugs in organic solvent-water mixtures. J. Pharm. Biomed. Anal., 1999, 20, 631-641.

 

Link

https://www.ncbi.nlm.nih.gov/pubmed/10704132

 

 

 

 

Title

Structure-lipophilicity relationships of neutral and protonated b-blockers, part I: intra and intermolecular effects in isotropic solvent systems

 

Authors

G Caron, G Steyaert, A Pagliara, F Reymond, P Crivori, P Gaillard, P-A Carrupt, A Avdeef, J Comer, KJ Box, HH Girault, B Testa

 

Abstract

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 β-blockers in isotropic biphasic solvent systems. The lipophilicity parameters of a number of β-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 β-blockers. Derived parameters such as Δlog 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 β-blockers. The relevance of these parameters in structure-permeation relationships is explored.

 

Publication

Helvetica Chimica Acta

 

Bibliography

Caron, G.; Steyaert, G.; Pagliara, A.; Reymond, F.; Crivori, P.; Gaillard, P.; Carrupt, P.-A.; .Avdeef, A.; Comer, J.; Box, K.J.; Girault, H.H.; Testa, B. Structure-lipophilicity relationships of neutral and protonated b-blockers, part I: intra and intermolecular effects in isotropic solvent systems. Helv. Chim. Acta, 1999, 82, 1211-1222.

 

Link

http://onlinelibrary.wiley.com/doi/10.1002/(SICI)1522-2675(19990804)82:8%3C1211::AID-HLCA1211%3E3.0.CO;2-K/abstract

 

 

 

 

Title

pH-Metric Solubility. 1. Solubility-pH Profiles from Bjerrum Plots. Gibbs Buffer and pKa in the Solid State

 

Author

A Avdeef

 

Abstract

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 shortcomings of the traditional methods, is described. A simple graphical procedure for estimating solubility constants, based on Bjerrum difference plots, is developed, and the relationships between titration data and solubility-pH profiles for mono- and diprotic ionizable substances are explored, drawing on generalized mass-balance based simulation methods. One useful derived equation (valid in a solution where part of the sample precipitates early in the titration) is:

log So = log (C/2) - |ΔpKa|

where C is the sample concentration, So is the intrinsic solubility of the unchanged substance, and ΔpKa = pKappa - pKa, the difference between the apparent pKa determined under conditions of precipitation and the true pKa, measured in the absence of the solid phase. The relationship holds in both aqueous and cosolvent solutions (e.g. dimethylsulphoxide-water). The properties of the state where an unchanged substance (e.g. HX) coprecipitates with its ionized form (e.g. X salt) were explored. A super buffer, termed the Gibbs buffer, was formed and characterized by an ionization constant, pK(s)a, of the substance in the solid state. It was shown that pK(s)a - pKa = log SHX - log SX, where SHX and SX refer to the solubility constants of HX and X species. Flurbiprofen (acid), benzydamine (base), and buprenorphine (ampholye) were used to illustrate the experimental procedure.

Our initial studies indicate that these new methods will meet many of the needs of not only discovery-stage researchers but also of preformulation and development scientists, traditionally concerned with solubility measurements.

 

Publication

Pharmacy and Pharmacological Communications

 

Bibliography

Avdeef, A. pH-Metric Solubility. 1. Solubility-pH Profiles from Bjerrum Plots. Gibbs Buffer and pKa in the Solid State. Pharm. Pharmacol. Commun. 1998. 4, 165-178. (Part 1 in pSOL series)

 

Link

http://onlinelibrary.wiley.com/doi/10.1111/j.2042-7158.1998.tb00328.x/abstract

 

 

 

 

Title

Potentiometric pKa Determination of Water-Insoluble Compounds. Validation Study in Methanol/Water Mixtures

 

Author

K Takács-Novák, KJ Box, A Avdeef

 

Abstract

The apparent ionization constants (psKa) of 25 molecules, based on 431 separate potentiometric titrations, were determined in methanol/water mixtures of 15–65 wt% methanol content. The Yasuda-Shedlovsky extrapolation (psKa+log[H2O]=a/ϵ+b) was used to obtain the pKa values in zero methanol%. In the case of water-soluble drugs the extrapolated data were in very good agreement with pKa values measured in aqueous solutions under the same experimental conditions (average deviation=0.05). The water-insoluble molecules showed acceptable accordance with spectroscopically measured or with literature pKa values. Concentration dependence between 1–5 mM was not observed while the range of extrapolation (water-rich: R=15–35 wt%, or methanol-rich: R=40–65 wt%) significantly influenced the accuracy of pKa values. Remarkable changes in the solvation structure of weak acids in methanol-rich mixtures (>35 wt%) were suggested from analyzing the slopes of Yasuda-Shedlovsky equations. Recommendations for the proper application of a mixed-solvent procedure in order to gain the most reliable aqueous pKa values are suggested.

 

Publication

International Journal of Pharmaceutics

 

Bibliography

Takács-Novák, K.; Box, K.J.; Avdeef, A. Potentiometric pKa Determination of Water-Insoluble Compounds. Validation Study in Methanol/Water Mixtures. Int. J. Pharm. 1997, 151, 235-248.

 

Link

http://www.sciencedirect.com/science/article/pii/S0378517397049077

 

 

 

 

Title

pH-metric logP. 10. Determination of liposomal membrane-water partition coefficients of ionizable drugs

 

Authors

A Avdeef, KJ Box, JEA Comer, C Hibbert, KY Tam

 

Abstract

Purpose. To investigate a novel approach for the determination of liposomal membrane-water partition coefficients and lipophilicity profiles of ionizable drugs.

Methods. The measurements were performed by using a pH-metric technique in a system consisting of dioleylphosphatidylcholine (DOPC) unilamellar vesicles in 0.15 M KC1 at 25°C. The DOPC unilamellar vesicle suspension was prepared via an extrusion process.

Results. 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.

Conclusions. 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.

 

Publication

Pharmaceutical Research

 

Bibliography

Avdeef, A.; Box, K.J.; Comer, J.E.A.; Hibbert, C.; Tam, K.Y. pH-metric logP. 10. Determination of liposomal membrane-water partition coefficients of ionizable drugs. Pharm. Res. 1998, 15, 208-214.

 

Link

https://www.ncbi.nlm.nih.gov/pubmed/9523305

 

 

 

 

Title

Octanol-, Chloroform-, and PGDP-Water Partitioning of Morphine-6-Glucuronide and Other Related Opiates

 

Authors

A. Avdeef, D.A. Barrett, P.N. Shaw, R.D. Knaggs, S.S. Davis

 

Abstract

The pKa and log P values of morphine-6-β-d-glucuronide (M6G) and morphine-3-β-d-glucuronide (M3G) and a range of structurally-related opiates (morphine, normorphine, codeine, norcodeine, 6-acetylmorphine, diacetylmorphine, and buprenorphine) were accurately measured using a potentiometric approach. The measured lipophilicity profiles (pH 2−11, 0.15 M KCl matrix) of M3G and M6G were compared using a proton donor solvent (chloroform) and a proton acceptor solvent (propylene glycol dipelargonate, PGDP), in addition to octanol. The log P values and lipophilicity profiles of M6G and M3G determined in octanol−water have confirmed the unexpectedly high lipophilicity of the two glucuronides. These results show the importance of measuring the effect of pH on lipophilicity, since log D (pH 7.4) values gave a notably different order of lipophilicity for the opiates compared with log P. M6G, but not M3G, showed significant differences in log P between different types of partitioning solvents. The observed order of lipophilicities (log D, pH 7.4) was buprenorphine (3.93), diacetylmorphine (0.85), 6-acetylmorphine (0.61), codeine (0.22), morphine (−0.07), M6G (−0.79), M3G (−1.12), norcodeine (−1.26), and normorphine (−1.56).

 

Publication

Journal of Medicinal Chemistry

 

Bibliography

Avdeef, A.; Barrett, D.A.; Shaw, P.N.; Knaggs, R.D.; Davis, S.S. Octanol-, Chloroform-, and PGDP-Water Partitioning of Morphine-6-Glucuronide and Other Related Opiates. J. Med. Chem. 1996, 39, 4377-4381. (pH-Metric logP, part 7)

 

Link

http://pubs.acs.org/doi/abs/10.1021/jm960073m

 

 

 

 

Title

Interlaboratory study of logP determination by shake-flask and potentiometric methods

 

Authors

K Takács-Novák, A Avdeef

 

Abstract

The pKa and log P values of 23 structurally diverse compounds, including well known drugs and two pharmacons under development, were determined by potentiometry. Also, the log P data were measured by the shake-flask method. Many of the samples were investigated at both of the participating laboratories in order to evaluate the reproducibility of the pH-metric log P technique. The interlaboratory evaluation of pKa and log P data obtained by potentiometry showed excellent agreement (average ΔpKa = ± 0.02 and Δ log P = ± 0.07). The log P values obtained by the two different methods, ranging from −1.84 to 5.80 (nearly eight orders of magnitude), were in very good concordance, as shown by the linear regression analysis: log PpH-metric = 0.9794 log Pshake-flask −0.0397 (r = 0.9987, s = ± 0.091, F = 8153). The advantages of potentiometric log P determination are discussed.

 

Publication

Journal of Pharmaceutical and Biomedical Analysis

 

Bibliography

Takács-Novák, K.; Avdeef, A. Interlaboratory study of logP determination by shake-flask and potentiometric methods. J. Pharm. Biomed. Anal. 1996, 14, 1405-1413. (pH-Metric logP, part 9)

 

Link

https://www.ncbi.nlm.nih.gov/pubmed/8877846

 

 

 

 

Title

Limits for successful measurement of pKa and logP by pH-metric titration

 

Author

Comer, J.E.A.; Avdeef, A.; Box, K.J

 

Publication

American Laboratory

 

Bibliography

Comer, J.E.A.; Avdeef, A.; Box, K.J. Limits for successful measurement of pKa and logP by pH-metric titration. Amer. Lab. 1995, 4, 36c-36i.

 

 

 

 

Title

pH-Metric logP. 4. Comparison of Partition Coefficients Determined by HPLC and Potentiometric Methods to Literature Values

 

Authors

B. Slater, A. McCormack, A. Avdeef, J.E.A. Comer

 

Abstract

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 °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.

 

Publication

Journal of Pharmaceutical Sciences

 

Bibliography

Slater, B.; McCormack, A.; Avdeef, A.; Comer, J.E.A. pH-Metric logP. 4. Comparison of Partition Coefficients Determined by HPLC and Potentiometric Methods to Literature Values. J. Pharm. Sci. 1994, 83, 1280-1283.

 

Link

https://www.ncbi.nlm.nih.gov/pubmed/7830244

 

 

 

 

Title

Determination of Protonation Macro- and Microconstants and Octanol/Water Partition Coefficient of Antiinflammatory Niflumic Acid

 

Authors

K. Takács-Novák, A. Avdeef, B. Podányi, G. Szász

 

Abstract

The drug niflumic acid is an amphoteric substance with overlapping pKa values. The acid-base chemistry of the molecule has been characterized in terms of protonation macroconstants (with reference to stoichiometric ionizations) and microconstants (with reference to ionizations of individual species). The proton-binding sites were assigned using 1H and 13C NMR spectroscopy. Due to the very poor water solubility of niflumic acid, the aqueous pKa values were determined from the apparent ionization constants in methanol—water solutions of various proportions by extrapolation to zero co-solvent using the Yasuda—Shedlovsky procedure. The kz tautomerization microconstant of the equilibrium unionized form zwitterionic form was determined from mixtures of organic solvent (dioxane or methanol) with aqueous buffer (at the pH of isoelectric point) by UV spectroscopy, and used for calculation of the other protonation microconstants. The zwitterionic form of the molecule predominates over the uncharged form, the concentration being maximal at the isoelectric pH. The apparent partition coefficients (Papp) of niflumic acid were measured in octanol/water solution by the shake-flask method over a wide pH range. The lipophilicity profile (logPapp vs pH) shows a parabolic shape near its maximum at the isoelectric point. A relationship derived between Papp, pXH0(micropartition coefficient of the uncharged microspecies) and PX−(partition coefficient of the anion) is valid for amphoteric drugs, in cases where the partition of the unionized form and the ion-pair partition of anion can be confirmed. The logP values of microspecies indicate the high lipophilicity of niflumic acid, which is consistent with its good skin penetration and absorption.

 

Publication

Journal of Pharmaceutical and Biomedical Analysis

 

Bibliography

Takács-Novák, K.; Avdeef, A.; Podányi, B.; Szász, G. Determination of Protonation Macro- and Microconstants and Octanol/Water Partition Coefficient of Antiinflammatory Niflumic Acid. J Pharm Biomed Anal. 1994 Nov;12(11):1369-77. (pH-Metric logP, part 5)

 

Link

https://www.ncbi.nlm.nih.gov/pubmed/7849133

 

 

 

 

Title

pH-Metric logP. 2. Refinement of Partition Coefficients and Ionization Constants of Multiprotic Substances

 

Author

A Avdeef

 

Abstract

A generalized, weighted, nonlinear least squares procedure is developed, based on pH titration data, for the refinement of octanol-water partition coefficients (log P) and ionization constants (pKa) of multiprotic substances. Ion-pair partition reactions, self-association reactions forming oligomers, and formations of mixed-substance complexes can be treated with this procedure. The procedure allows for CO2 corrections in instances where the base titrant may have CO2 as an impurity. Optionally, the substance purity and the titrant strength may be treated as adjustable parameters. The partial differentiation in the Gauss-Newton refinement procedure is based on newly derived analytical expressions. The new procedure was experimentally demonstrated with benzoic acid, 1-benzylimidazole, (+/-)-propranolol, and mellitic acid (benzenehexacarboxylic acid, AH6). Ionic strength (l) was adjusted with KNO3. Benzoic acid (20 degrees C; l 0.1 M): pKa = 3.99 +/- 0.02, log P = 1.96 +/- 0.02, log P (anion) = -1.2; 1-benzylimidazole (25 degrees C; l 0.1 M): pKa = 6.70 +/- 0.03, log P = 1.60 +/- 0.04; propranolol (25 degrees C; l 0.1 M): pKa = 9.53 +/- 0.06, log P = 3.35 +/- 0.03, log P (cation) = 0.62 +/- 0.08; mellitic acid (26 degrees C; l 0.2 M): pKas 1.10 +/- 0.46, 1.69 +/- 0.03, 2.75 +/- 0.02, 4.00 +/- 0.02, 5.05 +/- 0.01, and 6.04 +/- 0.02; in the presence of 0.01 M n-Bu4NBr, log P (AH6) = 1.5, log P (AH5-) = 1.1, log P (AH4(2-)) = 0.8, log P (AH3(3-)) = 0.3, log P (AH2(4-)) = -0.1, and log P (AH5-) = -0.5 (all +/- 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)

 

Publication

Journal of Pharmaceutical Sciences

 

Bibliography

Avdeef, A. pH-Metric logP. 2. Refinement of Partition Coefficients and Ionization Constants of Multiprotic Substances. J. Pharm. Sci. 1993, 82, 183-190.

 

Link

https://www.ncbi.nlm.nih.gov/pubmed/8445533

 

 

 

 

Title

pH-Metric logP. 3. Glass Electrode Calibration in Methanol-Water, Applied to pKa Determination of Water-Insoluble Substances

 

Author

A. Avdeef, J.E.A. Comer

 

Abstract

A series of semiaqueous HCI solutions of known concentration, containing 0.1 M KNO3 (as ionic strength adjuster) and 0-70 wt % methanol, was titrated at 21, 25, and 37-degrees-C with standardized KOH, pH 2-12. The pH measuring circuit (Ross-type electrode) was calibrated with an aqueous pH buffer (Nernst slope assumed). The operational pH readings were related to p(c)H (=- log [H+]) by the four-parameter equation: pH = alpha + Sp(c)H + j(H)+] + J(OH)[OH-]. The parameters were determined by a weighted nonlinear least squares procedure, which allows for CO2 Corrections. This calibration procedure was applied at 25-degrees-C in titrations to determine the pK(a) values of acetic acid, benzoic acid, 4-n-butoxyphenol, 4-ethoxyphenol, 1-benzylimidazole, (+/-)-propranolol, and N-methyl-D-glucamine and of two water-insoluble highly lipophilic benzoic acid derivatives of pharmaceutical interest, with the aim of determining their octanol-water partition coefficients. Yasuda-Shediovsky plots were used to extrapolate semiaqueous apparent pK(a)'s to zero methanol.

 

Publication

Analytical Chemistry

 

Bibliography

Avdeef, A.; Comer, J.E.A.; Thomson, S.J. pH-Metric logP. 3. Glass Electrode Calibration in Methanol-Water, Applied to pKa Determination of Water-Insoluble Substances. Anal. Chem. 1993, 65, 42-49.

 

Link

http://pubs.acs.org/doi/abs/10.1021/ac00049a010

 

 

 

 

Title

pH-Metric logP. 1. Difference Plots for Determining Ion-Pair Octanol-Water Partition Coefficients of Multiprotic Substances

 

Author

A. Avdeef

 

Abstract

New potentiometrically-based octanol-water partition coefficient (log P) equations for di-, tri- and tetraprotic weak acids are derived. These equations are valid when one or more species partition into the octanol phase as neutral or ion-paired substances. Citric and phthalic acids were selected to demonstrate the log Pderivation procedure experimentally. Citric acid appears to participate in weak ion-pair partitioning. Addition of tetra-n-butylammonium bromide to the solutions containing the weak acids, induces the hydrogen phthalate anion, the dihydrogen citrate anion and the hydrogen citrate dianinn to partition into octanol, presumably as ion-pairs with the lipophilic cation. Extensive use is made of difference titration curves. The graphically derived models were refined by a general weighted nonlinear least squares procedure.

 

Publication

Molecular Informatics

 

Bibliography

Avdeef, A. pH-Metric logP. 1. Difference Plots for Determining Ion-Pair Octanol-Water Partition Coefficients of Multiprotic Substances. Quant. Struct.- Act. Relat. 1992, 11, 510-517.

 

Link

http://onlinelibrary.wiley.com/doi/10.1002/qsar.2660110408/abstract

 

 

 

 

Title

A Versatile Potentiometric Analyzer, Part One: Hardware, the User Interface, and Titration Techniques

 

Authors

A. Avdeef, J. Comer

 

Publication

American Laboratory

 

Bibliography

A. Avdeef, J. Comer. A Versatile Potentiometric Analyzer, Part One: Hardware, the User Interface, and Titration Techniques. Amer. Lab. 1987, 19(2), 116-125.

 

 

 

 

Title

A Versatile Potentiometric Analyzer, Part Two: Multiple Known Addition and Gran Titration Techniques

 

Author

A. Avdeef, J. Comer

 

Publication

American Laboratory

 

Bibliography

A. Avdeef, J. Comer. A Versatile Potentiometric Analyzer, Part Two: Multiple Known Addition and Gran Titration Techniques. Amer. Lab. 1987, 19(4), 116-124.

 

 

 

 

Title

Weighting Scheme for Regression Analysis Using pH Data from Acid-Base Titrations

 

Authors

A. Avdeef

 

Abstract

A general weighting scheme is proposed for use in least-squares fits of pH data. The scheme assigns lower weight to pH measurements in end-point regions and regions of ph < 3 and pH > 11 than for buffer and intermediate regions. The weighting scheme is evaluated with nearly 1200 pH measurements (pH 1.6–12.4), in 16 separate acid—base titrations of ethylenediamine done with a computerized titrator. The weighting scheme yields near-random distributions of residuals, and the slope (0.96) and intercept (−0.05) of an Abrahams—Keve normal probability plot approach the expected values of 1.0 and 0.00.

 

Publication

Analytica Chimica Acta

 

Bibliography

Avdeef, A. Weighting Scheme for Regression Analysis Using pH Data from Acid-Base Titrations. Anal. Chim. Acta 1983, 148, 237-244.

 

Link

http://www.sciencedirect.com/science/article/pii/S0003267000851685

 

 

 

 

Title

Bjerrum Plots for the Determination of Systematic Concentration Errors in Titration Data

 

Authors

A. Avdeef, D.L. Kearney, J.A. Brown, A.R. Chemotti, Jr.

 

Abstract

It is demonstrated how Bjerrum formation plotes, which normally are useful in estimating equilibrium constants, can also be used to determine systematic concentration errors and detect nonideal electrode responses in pH-metric titration data….Examples are presented where a nonlinear regression procedure treating total concentration as adjustable parameters (along with pKas). Converges to a false minimum. The application of the Bjerrum diagnosis averts the problem.

 

Publication

Analytical Chemistry

 

Bibliography

Avdeef, A.; Kearney, D.L.; Brown, J.A.; Chemotti Jr., A.R. Bjerrum Plots for the Determination of Systematic Concentration Errors in Titration Data. Anal. Chem. 1982, 54, 2322-2326

 

Link

http://pubs.acs.org/doi/abs/10.1021/ac00250a041

 

 

 

 

Title

Accurate Measurements of the Concentration of Hydrogen Ions with a Glass Electrode: Calibrations Using the Prideaux and Other Universal Buffer Solutions and a Computer-Controlled Automatic Titrator

 

Author

A. Avdeef, J.J. Bucher

 

Abstract

Several universal buffer solutions, variably composed of 3 to 5 mM potassium acetate, potassium dihydrogen phosphate, ethylenediammonium dichloride, and Borax, were examined as a convenient and reliable method for calibrating a glass electrode to read true hydrogen ion concentration. From the results of 19 titrations, 25/sup 0/C, pH 2 to 12, I, 0.05 to 0.20 M (KCl), pH meter (adjusted with NBS pH/sub s/ 4.008 and 6.865 buffers) readings, pH/sub m/, using a Beckman 39501 combination electrode, can be converted to -log (H/sup +/), p(H), by pH/sub m/ = ..delta..' + S'p(H) where ..delta..' = 0.2269 - 1.949 I + 7.756 I/sup 2/, sigma(..delta..') = 0.019 pH and S' = 0.9657 + 0.4752 I - 1.532 I/sup 2/, sigma(S') = 0.0022. At I 0.1 M pH/sub m/ = 0.110 + 0.998 p(H). A FORTRAN computer program was coded to calculate ..delta..' and S' for any titration in the range 0 to 40/sup 0/C and 0 to 0.3 M (KCl), and for any combination of the four buffer components. A microcomputer-controlled automatic titrator, programmed in BASIC, was used to collect the potentiometric data. 6 figures, 2 tables.

 

Publication

Analytical Chemistry

 

Bibliography

Avdeef, A.; Bucher, J.J. Accurate Measurements of the Concentration of Hydrogen Ions with a Glass Electrode: Calibrations Using the Prideaux and Other Universal Buffer Solutions and a Computer-Controlled Automatic Titrator. Anal. Chem. 1978, 50, 2137-2142.

 

Link

http://pubs.acs.org/doi/abs/10.1021/ac50036a045