Transcript The conversion of IUPAC's compilations of pKas of organic

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Uses and Abuses of
Experimental pKa Data
Tony Slater
pKaData Limited
CUP XII Santa Fe March 2011
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Sources of experimental pKa data
pharmaceutical and agrochemical company in-house data
not available externally
literature compilations
for a critical list, see Profiles of Drug Substances, Excipients and Related
Methodology Volume 33, 2007, by Richard J. Prankerd, ed Harry G.
Brittain
pKa 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
nb. to be of most use, these compilations need to be in computer-readable form
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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. Perrin
Dissociation Constants of Organic Bases in Aqueous Solution, Supplement 1972, by
D. D. Perrin
Dissociation Constants of Organic Acids in Aqueous Solution, by G. Kortum, W.
Vogel, and K. Andrussow
Ionisation 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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What’s special about the IUPAC set?
pKa measurements for almost 12000 compounds in aqueous solution
number of measurements considerably higher (eg. some compounds have had their
pKa(s) measured at different temperatures/ionic strengths and by different authors)
fully referenced
measurement method recorded
temperature recorded
remarks field provides more details such as ionic strength, buffer composition etc
assessment of data quality is made
"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
In addition, we have added more value:ionisation assignments added
tautomers predicted
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Range of Chemistry and Applicability
Range of organic chemistry includes :BASES
aliphatic
alicyclic
aromatic
heterocyclic
natural products
dyes and indicators
ACIDS
aliphatic carboxylic acids
alicyclic carboxylic acids
aromatic carboxylic acids
phenolic acids
other acids
dyes and indicators
unclassified organic acids
with applicability to :Pharmaceutical industry
Agrochemical industry
Specialty Chemicals industry
pKa prediction software companies
Nb. quality assessment of particular relevance here
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Types of Search
Substructure
Search for basic pKa with 6.5 < pKa < 7.5
Search for only highest quality data
Search for data where 35°C ≤ temperature ≤ 40°C
Any combination of the above
Etc.................
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?
continued
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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Data Variation
how much variation is there?
which pKa values should I use?
glycine
8.98 – 10.36
(38 measurements)
2.24 – 2.47
(49 measurements)
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What causes the variation?
temperature variations
frequently measured at room temperature, but in pharmaceutical
context, normally interested in 37°C
pKa
78% of the variation
temperature (°C)
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What causes the variation?
continued
pKa
62% of the variation
temperature (°C)
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What causes the variation?
ionic strength variations
pKa
log10(ionic strength) physiological range
(plasma, cytoplasm...)
continued
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What causes the variation?
errors / data quality
which values to have more confidence in?
IUPAC assessment of data quality
estimated
uncertainty in
the value of K
reliable
approximate
uncertain
very uncertain
estimated
uncertainty in
the value of ΔpK
≤ 1%
≤ ±0.005
> 1%, ≤ 10%
> ±0.005, ≤ ±0.04
> 10%
> ±0.04
“cannot be estimated but is likely to be very great”
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.
continued
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Other considerations
pH of effect compartment (when known)
eg. from stomach (very acid) to plasma (approx. neutral)
acidic or basic ionisation
frequently obvious, but not always, eg. Tyramine
2 pKas in the ranges
9.22 – 9.77 and
10.78 – 10.9
but which is which?
Initial literature suggested lower pKa due to OH,
but subsequent literature disagrees
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Other considerations
continued
hydration
3 pKas given:6.52 “anhydrous" species
9.00 equilibrium pK, partial covalent hydration
9.72 covalently hydrated species
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Other considerations
stability
neutral molecule
slowly ring-closes
to give
4-methylpteridine
pKa = 5.49
continued
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Summary of IUPAC Databases
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
Contacts
Email : [email protected]
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