Uses and Abuses of Experimental pKa Data

Tony SlaterpKaData Limited

CUP XII Santa Fe March 2011

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Sources of experimental pKa data

pharmaceutical and agrochemical company in-house datanot available externally

literature compilationsfor a critical list, see Profiles of Drug Substances, Excipients and Related Methodology Volume 33, 2007, by Richard J. Prankerd, ed Harry G. BrittainpKa data sets used in comparing pKa prediction programs, eg.

Manchester, J.; Walkup, G.; Rivin, O.; You, Z. Evaluation of pKa estimation methods on 211 druglike compounds. J. Chem. Inf. Model. 2010, 50, 565–571.Liao, C.; Nicklaus, M. Comparison of Nine Programs Predicting pKa Values of Pharmaceutical Substances. J. Chem. Inf. Model. 2009, 49, 2801–2812.

the IUPAC pKa compilations

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nb. to be of most use, these compilations need to be in computer-readable form

The IUPAC compilations

Four books containing pKa data for organic acids and bases in aqueous solution :-

Dissociation Constants of Organic Bases in Aqueous Solution, by D. D. PerrinDissociation Constants of Organic Bases in Aqueous Solution, Supplement 1972, by D. D. PerrinDissociation Constants of Organic Acids in Aqueous Solution, by G. Kortum, W. Vogel, and K. AndrussowIonisation Constants of Organic Acids in Aqueous Solution, by E. P. Serjeant and Boyd Dempsey

One book containing pKa data for organic acids and bases in non-aqueous solution :-

Acid-Base Dissociation Constants in Dipolar Aprotic Solvents (1990); K. Izutsu

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pKa measurements for almost 12000 compounds in aqueous solutionnumber of measurements considerably higher (eg. some compounds have had their pKa(s) measured at different temperatures/ionic strengths and by different authors)fully referencedmeasurement method recordedtemperature recordedremarks field provides more details such as ionic strength, buffer composition etcassessment of data quality is made

What’s special about the IUPAC set?

"The critical assessment of data quality is one of the major features of this seminal group of pKa compilations for weak organic acids and bases sponsored by the International Union of Pure and Applied Chemistry (IUPAC)“

from Profiles of Drug Substances, Excipients and Related Methodology Volume 33, 2007, by Richard J. Prankerd, ed Harry G. Brittain

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In addition, we have added more value:- ionisation assignments added tautomers predicted

Range of organic chemistry includes :-

BASESaliphaticalicyclicaromaticheterocyclicnatural productsdyes and indicators

ACIDS aliphatic carboxylic acids alicyclic carboxylic acids aromatic carboxylic acids phenolic acids other acids dyes and indicators unclassified organic acids

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Range of Chemistry and Applicability

with applicability to :-

Pharmaceutical industryAgrochemical industrySpecialty Chemicals industrypKa prediction software companies

Nb. quality assessment of particular relevance here

Types of Search

SubstructureSearch for basic pKa with 6.5 < pKa < 7.5Search for only highest quality dataSearch for data where 35°C ≤ temperature ≤ 40°CAny combination of the aboveEtc.................

We only supply the data, in suitable format, not the search software, so the types of search possible will depend on your in-house software.However, OpenEye are writing software around these data................

IUPAC pKa data can be merged with your existing in-house data, with the IUPAC-sourced data clearly identified.

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In what areas are pKas used?

strength of interaction with receptor, eg.will required charges and proton donor/acceptor pattern be presented to the receptor?

protein binding, eg.correlation between pKa and human serum albumin binding constant for a set of anthranilic acid analogs (Stiff, C.; Zhong, M. et. al. Correlation of carboxylic acid pKa to protein binding and antibacterial activity of a novel class of bacterial translation inhibitors. Bioorg. Med. Chem. Lett. 2007, 17, 5479-82).

absorption, eg.will the drug be orally absorbed?use of prodrugs or heterocyclic guanidines to remove positive charge or reduce basicity of oral inhibitors of the blood coagulation cascade

distribution, eg.knowing type of ionisation, pKa, and logP, can calculate logD for a given pH

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In what areas are pKas used?

metabolism, eg.affect strength of interaction with metabolising enzymes

elimination, eg. elimination increases with increasing amounts of ionised form

solubility, eg.weak acids and bases are more soluble in their ionised forms

dissolution rate, eg.the ionised form of the drug will have greater solubility in the diffusion layer than the unionised weak acid or weak base (e.g. penicillin V potassium dissolves faster than penicillin V itself)

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continued

Data Variation

how much variation is there? which pKa values should I use?

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glycine

2.24 – 2.47(49 measurements)

8.98 – 10.36(38 measurements)

What causes the variation?

temperature variations frequently measured at room temperature, but in pharmaceutical

context, normally interested in 37°C

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pKa

temperature (°C)

78% of the variation

What causes the variation?www.pkadata.com

pKa

temperature (°C)

62% of the variation

continued

What causes the variation?

ionic strength variations

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continued

pKa

log10(ionic strength) physiological range(plasma, cytoplasm...)

What causes the variation?

errors / data qualitywhich values to have more confidence in?IUPAC assessment of data quality

reliable ≤ 1% ≤ ±0.005approximate > 1%, ≤ 10% > ±0.005, ≤ ±0.04uncertain > 10% > ±0.04very uncertain “cannot be estimated but is likely to be very great”

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continued

estimated uncertainty in the value of K

estimated uncertainty in

the value of ΔpK

Considering only reliable data and ones measured between 20 - 25°C, the variation for glycine reduces from 2.24 – 2.47 (0.23) to 2.35 – 2.37 (0.02) for the acid, and from 8.98 – 10.36 (1.38) to 9.78 – 9.91 (0.13) for the base.

Other considerations

pH of effect compartment (when known)eg. from stomach (very acid) to plasma (approx. neutral)

acidic or basic ionisationfrequently obvious, but not always, eg. Tyramine

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2 pKas in the ranges 9.22 – 9.77 and

10.78 – 10.9but which is which?

Initial literature suggested lower pKa due to OH, but subsequent literature disagrees

Other considerations

hydration

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continued

3 pKas given:-

6.529.009.72

“anhydrous" speciesequilibrium pK, partial covalent hydrationcovalently hydrated species

Other considerations

stability

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continued

pKa = 5.49

neutral molecule slowly ring-closes

to give 4-methylpteridine

Summary of IUPAC Databaseswww.pkadata.com

ContactsEmail : tony@pkadata.comWebsite : www.pkadata.com

IUPAC pKa compilations as computer-readable data pKa data for ~12000 organic acids and bases in aqueous solution Good range of organic chemistry with applicability to pharmaceutical,

agrochemical and specialty chemicals research IUPAC assignment of data quality Very useful data set for pKa prediction software Fully referenced with method, temperature, ionic strength etc recorded Ionisation assignment for logD calculations and greater search capability Ability to merge with existing in-house data, with IUPAC-sourced data

clearly identified All data given in this presentation were taken from the IUPAC databases