Understanding and measuring pk a. John Comer CSO Sirius Analytical Ltd.
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1 Understanding and measuring pk a John Comer CS Sirius Analytical Ltd.
2 How did the concept of pk a first arise? Identifying drugs that have pk a s Why are pk a s useful? How to measure pk a Comer, J. Ionization Constants and Ionization Profiles. In Comprehensive Medicinal Chemistry II, ed. Triggle, D. Vol. 5, pp Elsevier, /45
3 The term pk a comes from solution chemistry pk a means -log 10 K a pk a values provide a way to express the strength of acids and bases as numbers The concept of pk a is derived from solution chemistry and the behaviour of water 3 /45
4 Kohlrausch conductivity of water Kohlrausch measured the electrical conductivity of water He first distilled it 50 times under vacuum in apparatus made from platinum Friedrich Kohlrausch /45
5 Harned ionic strength rule Herbert Harned Harned measured ph using a platinum-hydrogen electrode ph means -log 10 of the activity of hydrogen ions If all measurements are made at constant ionic strength, H is proportional to [H + ] 5 /45
6 Beckman invented ph electrode An inventor and entrepreneur Invented the ph meter in 1934 This allowed high impedance glass electrodes to be used for ph measurement Father of Silicon Valley Arnold Beckman /45
7 Hydrogen ions are protons Electron, charge = -1 Hydrogen atom, H Proton, charge = +1 Hydrogen ion, H + 7 /45
8 Acids and bases Acetic acid dissolved in water (a Brønsted-Lowry base) 1 General equation for monoprotic acids 2 Johannes Brønsted K a is the acid dissociation constant 4 Thomas Lowry /45 General equation for monoprotic bases Because the concept also works for bases, it s better to call K a the ionisation constant 5 6
9 General equation for monoprotic acids ph and pk a Taking logarithms, Lawrence Henderson Karl Hasselbalch Henderson-Hasselbalch equation 9 /45 Henderson, L J. Am. J. Physiol. 1908, 21, Hasselbalch, K. A. Biochemische Zeitschrift 1917, 78,
10 pk a of monoprotic acids and bases Percent species H 100 HA A - - HA A - F F N N 50 ph = pk a CH 3 CH 3 Flumequine (an acid). pk a = ph (Concentration scale) 10 /45
11 pk a of monoprotic acids and bases Percent species Percent species H 100 HA A - - HA A - F F N N 50 ph = pk a CH 3 CH 3 Flumequine (an acid). pk a = ph (Concentration scale) H 3 C H 3 C H 3 C BH + NH 2 + H H 3 C B NH H 100 BH + B 50 ph = pk a 11 /45 Propranolol (a base). pk a = ph (Concentration scale)
12 Monoprotic acids Diclofenac, 4.0 Flumequine, 6.3 Zidovudine, 9.6 Stronger acids, e.g. HCl Glipizide, 5.1 Hexobarbital, Stronger bases, e.g. KH Diazepam, 3.3 Verapamil, 8.8 Clopidogrel, /45 Aripiprazole, 7.5 Fluoxetine, 10.0 Monoprotic bases
13 Percent species Percent species Molecules with two pk a s C H 3 C H 3 S XH 2 + XH ± C H 3 C H 3 C H C S - C H 3 C H 3 S X - C XH 2 + XH ± X - H H N H N H H N H N H H N H N 50 N H 3 + N H 3 + N H 2 Ampicillin (a zwitterion). pk a s = 7.14, ph (Concentration scale) 100 XH 2 + X - H XH 2 + H XH 0 - X XH 0 H H N H N 50 H 13 /45 N H + C H 3 C H 3 C H 3 H H 0 Morphine (an ampholyte). pk a s = 9.26, ph (Concentration scale)
14 Why are pk a s useful? pk a has many impacts in pharmaceutical science, such as It shows the ph range where a drug is neutral (i.e. better absorbed) It can affect binding with receptors, membranes and proteins Elimination of toxic overdoses via ph control Interpretation of analytical data from HPLC and other techniques Useful in manufacturing and process control Need to know pk a for salt selection pk a affects other physicochemical properties Lipophilicity (logp) Solubility 14 /45 Dissolution
15 logd pk a and lipophilicity Ibuprofen 2 4 Ibuprofen pk a = 4.35 Log P = 3.97 logd = logp Carvedilol pk a = 7.97 LogP = 4.14 Carvedilol Labetalol pk a s = 9.36, 7.42 LogP = 1.48 PhysiologicalpH range ph 15 /45 Labetalol
16 pk a and solubility Propafenone, (base, pk a = 9.5) Papaverine, (base, pk a = 7.0) g/100ml g/100ml H 3 C H 3 C 4 CH 3 logs 3 H logs 3 H 3 C N 2 NH CH ph ph Dashed lines calculated using measured pk a and S 0 values 16 /45 Völgyi, G. Baka, E. Box, K.J. Comer, J.E. Takács-Novák, K. Anal Chim Acta 2010, 673 (1),
17 Concentration, um pk a and dissolution pH pH pH Time (min) 3-pH 5.3 Na + - Diclofenac, sodium salt. pk a = 4.0 HN Cl Cl 17 /45
18 How to measure pk a Adrien Albert Australian scientist This book is still the one of the best guides to pk a! Sadly, it s out of print. 18 /45 Albert, A. Serjeant, E P. The Determination of Ionization constants. 3rd Ed, 1984, Chapman & Hall, London
19 /45 Manual methods for measuring pk a Albert and Serjeant described an accurate phmetric method for measuring pk a values, using a ph meter and manual micro-burette They also described a manual single-wavelength UV method, as well as methods using Raman spectroscopy NMR Conductivity thermometry 19 Then came Sirius
20 Three generations of pk a measurement 20 /45 PCA101 Launched 1991 ph-metric pk a GLpKa with D-PAS Launched 1997 D-PAS 1999 UV-metric method ph-metric pk a SiriusT3 Launched 2009 Fast UV method UV-metric method ph-metric pk a
21 Measurement cell inert gas UV dip probe (optional) Electronic temperature sensor Ceramic containing quartz capillaries (up to 6), for adding acid, base, water solvents and buffers argon cap stirrer Glass ph electrode 3mm diameter glass vial solution of sample Reference electrode built into glass electrode; liquid must be below solution surface 21 /45 Turbidity sensor (photodiode) Typical solution volume 1.5 ml. Temperature maintained by Peltier system Red LED
22 Fast UV Fast method for pk a /s between 2 and 12 Titrations done in Neutral Linear Buffer Saved reference spectrum used for multiple assays pk a methods on SiriusT3 UV-metric Measures pk a /s over the full range, to below 1 and above 13 Titrations done in unbuffered media Each experiment requires reference spectrum measured in separate vial ph-metric Measures all pk a s between 2 and to 1 mg required, maybe more for extreme values No UV absorbance required 22 /45
23 ph ph-uv pk a example: labetalol (base) UV methods NH 2 H Dissolve, adjust ph Titrate with HCl or KH Results from ph/uv data H NH CH 3 Very low conc. required ph-metric titration Dissolve, adjust ph 11 9 pk a is here H 3 C CH 3 NH H Titrate with HCl or KH Calculate pk a from ml/ph data / ml of titrant KH ph-metric pk a example: propranolol (base)
24 pk a measurement protocol Start Fast UV pk a aqueous 6 minute assay using 5µL DMS stock Measurement successful? No Is sample UV active? No Yes, but it precipitated Fast UV pk a Cosolvent 24 minute assay using 5µL DMS stock Measurement successful? Yes pk a measured in 6 minutes using 5µL of 10mM DMS stock No ph-metric pk a aqueous 25 minute assay using weighed sample*. Measurement successful? Did sample precipitate? Yes ph-metric pk a Cosolvent 75 minute assay using weighed sample*. Measurement successful? Yes pk a measured in 30 minutes using a total of 10µL of 10mM DMS stock Yes Yes 24 /45 pk a measured in 32 minutes pk a measured in 81 minutes we often do triple titration lasting 16 minutes *Instead of using weighed sample, it s possible to use an additional 50µL of DMS stock but see comments later
25 UV methods require very little sample Features of pk a by UV Typically, 5µL of 10mM stock solution in solvent Equivalent to 0.002mg of sample with MW 400 Equally sensitive over entire ph range Sample must have a ph-active chromophore Changes in ionisation state of the sample must cause observable changes in UV absorbance at wavelengths of 230 nm and above 25 /45
26 Before measuring pk a Look at the structure Identify the ionisable groups Are they acidic or basic? Predict the pk a values Design the experiment AssayExpert uses ACD software to make predictions 26 /45
27 Is UV suitable for your sample? N YES Glyphosate Quinine No chromophore that absorbs UV above 230 nm. Need to use ph-metric method This group is remote from the chromophore, but can approach it because the molecule is flexible. Remote, flexibly-attached groups often have a weak but observable effect on UV absorbance. 27 /45 This ionisable group is part of the chromophore (a structural feature usually with two or more conjugated double bonds). The UV absorbance of this chromophore changes strongly when the nitrogen is ionised.
28 Diode array spectrometer with deuterium lamp Wavelength range nm (UV + visible) strongest output in UV ( nm) Solarisation-resistant quartz fibres* Deuterium lamp powered continuously during UV assays Shutter opens for collecting spectra during titration UV light passes through probe for approx. 1 second per ph point (depends on integration time and spectra averaging) 28 /45 * Solarisation = damage caused to quartz fibres by UV at low wavelength
29 pk a from UV spectra: absorbance vs. ph Cl S NH 2 HN N H S 29 /45
30 Poorly soluble samples Titrate for pk a in presence of water-miscible cosolvent Result in presence of cosolvent is called p s K a Measure p s K a s at three or more different ratios of water to cosolvent Use Yasuda-Shedlovsky (graphical method) to extrapolate to aqueous pk a 30 /45
31 Absorbance pska + log[h2] Absorbance ph Absorbance Percent species Percent species Percent species Bendroflumethiazide in MeH/H % MeH ph Versus Time Dilute to 40% Dilute to 30% ph (Concentration scale) :00 10:00 15:00 20:00 25: Time (min, sec) Yasuda-Shedlovsky extrapolation Subtract from intercepts to get aqueous pk a s F F S NH 2 F S N H NH ph (Concentration scale) / dielectric constant / ph (Concentration scale)
32 Fast UV result y = x R² = Validation of Fast UV method Amiloride 8.67 Bendroflumethiazide 8.29, 9.81 Benzocaine 2.55 Chlorzoxazone 8.04 Diazepam 3.44 Flumequin 6.22 Fluoxetine Furosemide 3.56, Hydrochlorothiazide 8.75, Ketoprofen 3.99 Labetalol 7.42, 9.29 Naproxen 4.10 Nortryptiline Papaverine 6.54 Phenazopyridine 5.10 Promethazine 9.04 Quinine 4.39, 8.59 Terbutaline 8.71, Tolmetin 3.48 Warfarin 4.94 Literature result (measured at 25 C and an ionic strength of 0.15 M) 32 /45 Box, K. J.; Comer, J. E., Curr Drug Metab 2008, 9 (9), Tam, K. Y.; Takács-Novák, K., Anal. Chim. Acta 2001, 434, Sköld, C. et al. J Med Chem 2006, 49 (23), Sammes, P. G.; et al. Comprehensive Medicinal Chemistry: Volume 6, Pergamon Press: xford, 1989; Vol. 6. Sirius Technical Applications Notes. STAN 1994, 1, Avdeef, A., Topics in Medicinal Chemistry 2001, 1, Di, L; Kerns, E. H. Drug-like Properties, Academic Press, 2008, pp. 54
33 ph-metric pk a A weighed sample of the drug is dissolved in aqueous solution Acid or base is added to reach a starting ph at which the sample is ionised Small volumes of titrant (e.g. 0.5M HCl or KH) are then added, and the ph is measured after each addition The next slides will explain how pk a values are calculated from the experimental data 33 /45
34 ph ph-metric pk a plotting the experimental data Propranolol is a base with one pk a This example shows 0.52 mg of propranolol dissolved in 1.5 ml of 0.15M KCl acidified with 0.5M HCl and then titrated with 0.5M KH 11 pk a is here / ml of titrant KH
35 ph Getting a result from the experimental data We fit a calculated titration curve to the experimental data points Each calculated point represents the ph at a given volume of KH Each ph is calculated using an equation derived from mass balance and charge balance 11 pk a is here / ml of titrant KH
36 Data required to calculate ph Volumes of solutions, concentration of titrants Ionic strength of background electrolyte solutions Concentration of samples Temperature Ionisation model Calculating ph Identity of samples (e.g. acid with one pk a, base with two pk a s, etc.) pk a s of samples 36 /45
37 Example of calculation Sample = weak acid, AH with one pk a 3 2 H H K c c H K c c c K K K K 0 a KH HCl a KH Where: c KH = total amount of base added c HCl = total amount of acid added c AH = total amount of AH added K a = ionisation constant of AH K W = ionic product of water The ph value for each point is calculated from [H] HCl AH a W W a 37 /45
38 Refinement Refinement is the name of the process for Fitting the data When the best fit has been achieved, the pk a value(s) required to achieve that fit are taken to be the correct results The Refinement calculation also determines other parameters, e.g. Acidity error: the amount of excess strong acid or base in the solution that is not accounted for by the stated sample formula Concentration factor: the ratio between the amount of sample stated to be present, and the amount that has been titrated 38 /45
39 ph Before starting Refinement This slide shows the data before Refinement Acidity error is set to 0 mm Concentration factor is set to 1.0 The proposed pk a value is set to 7 The calculated curve (green) does not fit the experimental data RMSD for fit = / ml of titrant KH
40 ph Part-way through refinement Partially refined data The acidity error has been refined The concentration factor is still set to 1.0 The pk a has been refined to 9.06 The calculated curve now fits the experimental data better RMSD for fit = / ml of titrant KH
41 ph Fully refined data This is the same data, after auto-refinement. Some points have been clipped All parameters have been refined The pk a has been determined: 9.53 RMSD for fit = / ml of titrant KH
42 Finally, click icon to refine data with errors displayed. Results and errors shown here 42 /45
43 Absorbance Absorbance Turbidity detection during pk a measurement Detection by UV Absorbance at single wavelength in visible range is monitored during assay Default is 500 nm, but higher wavelength better for coloured samples If sample is clear, absorbance is close to zero Threshold = 0.1 Absorbance Units If precipitate appears, absorbance increases sharply, due to light scattering /45 Wavelength (nm) Flupenthixol, low to high ph in 30% methanol, at ph 6.77, no precipitate Wavelength (nm) Flupenthixol, low to high ph in 30% methanol, at ph 7.89 precipitate is present
44 Make sure baseline correction is switched off 44 /45
45 45 /45 Do you need measured pk a values? If you need to do serious work with a compound, it s too risky to use a predicted pk a ; you must use a measured value Some customers purchase instruments for pk a measurement Typical applications High throughput measurements during drug discovery Careful studies during pre-formulation ther customers send samples to Sirius for measurement If the sample has a pk a, we will find it!
46 46 /45
47 Adrien Albert Adrien Albert Australian scientist His opinion about drug discovery: the relationship between physico-chemical properties and biological activities in molecules is more important to the ultimate development of medicinal chemistry than is any direct search for new or improved drugs. People used to measure pk a by the half-neutralization method. Albert didn t like it. Here s why 47 /45
48 pk a from half-neutralisation point Traditional pk a measurement uses titration, ph and maths. pk a = 7 Are there short cuts? ne idea - determine the half-neutralisation point of an acid-base titration curve. Sample with pk a = M solution, titrated with 0.1M KH; ph measured by glass electrode and ph meter 48 /45 When half the sample has been titrated, ph = pk a
49 Half-neutralisation point pk a = 8 This method works K for samples with mid-range pk a s 49 /45 When half the sample has been titrated, ph = pk a
50 Half-neutralisation point pk a = 9 The further away from 7, the harder it is to distinguish the half-neutralization point 50 /45
51 Half-neutralisation point pk a = 10 Eventually, it becomes impossible to use this method. We need maths! 51 /45
52 Albert and Serjeant s ph-metric method for Boric acid Titrate sample using this apparatus, adding equal volumes of 0.1N KH Measure ph using ph meter (picture shows typical meter from 1980) btain a curve like this Do some maths (next slide) 52 /45
53 Albert and Serjeant s ph-metric calculation The basic calculation can be refined to allow for volume changes and ph scale changes at high ph. 53 /45 It really easy - but sample must be 0.001M or above.
54 pk a for users with UV an efficient protocol It s hard to find a single method to measure any and all pk a s in one attempt. An efficient approach is first to measure pk a s in aqueous solution by Fast UV. If it works, excellent! Failed experiments are easily analysed to enable an alternative, successful method to be chosen and run. A suggested work-scheme is shown in the next slide. Note: in a typical laboratory measuring pk a values, >70% of samples are successful by a UV method. 54 /45
55 pk a for users without UV Start If sample is soluble, Start ph-metric pk a aqueous 25 minute assay using weighed sample. Measurement successful? Yes ph-metric pk a Cosolvent 75 minute assay using weighed sample. Measurement successful? Yes 55 /45 pk a measured in 25 minutes pk a measured in 75 minutes
56 Which UV method to use? Fast UV We always try this method first Uses saved reference spectrum Measurement in presence of linear buffer solution, so ph electrode equilibrates fast Titration from ph 2 to ph 12 takes 6 minutes Some poorly soluble samples don t have time to precipitate Possible drawbacks Can t use outside ph range 2-12 UV absorbance of buffer limits signal at low wavelength 56 /45 UV-metric Formerly our standard method Validation study suggests Fast UV is as good for most samples However, UV-metric is more flexible than Fast UV Better signal at low wavelength Good for extreme pk a s (<2, >12) Possible drawbacks Slower than Fast UV Less throughput, because it requires two vials per assay (one for reference, one for sample) A dirty reference vial would cause problems
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