pk a, solubility and supersaturation in excipients and biorelevant media
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1 pk a, solubility and supersaturation in excipients and biorelevant media 1 /46 John Comer Technical Director Sirius Analytical Ltd., East Sussex, UK
2 Topics covered during this talk Our innovative methods & instrumentation for measuring solubility and dissolution rates with small sample weights How these methods can be used to study the effects of excipients to enhance the extent and duration of supersaturation, thus improving the chances of drugs getting absorbed in the GI tract Because it is so important in these studies, we will start by discussing pk a We will not have time to discuss logp or BCS, but please read our recent paper on these topics* 2 /46 * Box, K J. Comer, J E. Using Measured pk a, LogP and Solubility to Investigate Supersaturation and Predict BCS Class. Curr. Drug Metab. 2008, 9(9),
3 Kinetic (or Turbidimetric) Solubility We use these solubility definitions the concentration of a compound in solution when an induced precipitate first appears Equilibrium (or Thermodynamic) Solubility the concentration of compound in a saturated solution when excess solid is present, and solution and solid* are at equilibrium Result is ph-dependent for ionisable drugs Intrinsic solubility (S 0 ) is the equilibrium solubility* of the free acid or free base form of an ionisable compound at a ph where it is fully un-ionised 3 /46 * ote that the solid may have several crystalline forms (polymorphs)
4 We specialise in studying ionisable compounds Perhaps 90% of marketed drugs are ionisable compounds At least two species exist in solution, depending on the ph Example: Dicyclomine, a weak base, used to treat symptoms of irritable bowel syndrome. Dicyclomine comes as a capsule, a tablet, and a syrup to take by mouth. O H 3 C O H 3 C O H + O CH 3 CH 3 Ionised form, exists at low ph Can be called BH + Free base, exists at high ph Can be called B 4 /46
5 Relative concentration of each species Ionisable compounds have pk a s pk a is the ph where HALF the compound is ionised BH + Ç B + H + [H ][B] K a [BH ] pk a = -log 10 K a Dicyclomine Distribution of species graph 1 BH + B O H 3 C O H 3 C 0.5 O H + O CH 3 CH 3 ph = pk a 0 5 /46 ph
6 6 /46 pk a can be measured by potentiometric titration Potentiometric ( ph-metric ) titration for pk a Example: 4mg dicyclomine; add HCl to ph2.5; titrate with KOH Calculated ph values are compared with measured ph ph is calculated using equations like this*: H 3 H 2 K c c c H K c c K K K 0 a KOH HCl B a KOH HCl 29 measured ph values in 10mL of 50% methanol/ 0.15M KCl Measured pk a of 8.00 comes from the value of K a that gets the best fit between the calculated and measured ph values W W a * H represents [H + ]
7 % Species ½Á (bound H per B) Bjerrum Graphs: another way to plot titration data Bjerrum graphs are plotted using ph and pk a They are related to the Distribution of Species graph They show the number of H + ions per mole of substance For a monoprotic base, n H [H ] [H ] K a Solution Bjerrum graph 80 7 / ph ph
8 p s K a + log[h 2 O] pk a from Yasuda-Shedlovsky extrapolation 11 0% cosolvent Dicyclomine pk a 10 pk a of 8.63 obtained by subtracting log[h 2 O] from intercept /ε *10 3 Widely-used method of obtaining pk a from p s K a values measured in water-cosolvent mixtures * Also works for ph-uv results 30% 35% 40% 45% 50% methanol 55% 8 /46 * Avdeef, A. Comer, J E A. Thomson, S J. Glass Electrode Calibration in Methanol-Water, Applied to pka Determination of Water-Insoluble Substances. Anal. Chem. 1993, 65, 42-49
9 Absorbance Absorbance at 24 ph values and 108 wavelengths between 240 and 470nm pk a by ph-uv Example shows titration in 10mL of 0.25mg of Dipyridamole pk a values of 0.85 and 6.20 are derived from changes in absorbance vs. ph ph OH OH H + HO H + OH HO OH 9 /46 OH OH
10 Importance of pk a pk a has many impacts in pharmaceutics, such as Its effect on drug-receptor binding Binding with membranes, membrane analogs and proteins Its effect on absorption, via ph-partition theory Elimination of toxic overdoses via ph control Interpretation of analytical data from HPLC and other techniques pk a affects other physicochemical properties Lipophilicity (logp) Solubility 10 /46
11 pk a and solubility Compounds are more soluble at ph where they are ionised Relationship between ph, pk a and solubility is described by Henderson-Hasselbalch equation. For bases, S S 0 (Ka [H]) K a where S = solubility at a given ph and S 0 = intrinsic solubility 11 /46
12 LogS (S = [B] + [BH+]). Shake-flask vs. Henderson-Hasselbalch 7 6 Low ph outliers: Salt solubility? All compound dissolved? Curve calculated using Henderson-Hasselbalch equation and measured data 5 CH 3 H 3 C O Unionized at high ph: S = S 0 4 CH 3 H Lidocaine CH 3 pk a 7.95 Intrinsic solubility,s ph 12 /46 Shake-flask data from: Bergström, C A S. Luthman, K. Arturson, P. Accuracy of calculated ph-dependent aqueous drug solubility. Eur. J. Pharm. Sci (22) pp
13 Potentiometric titrations for solubility For ph-uv UV Dip Probe. Fibre optics inside stainless steel sheath.flow cell open to sample. Quartz mirror inside base of flow cell. temperature sensor dispenser tips inert gas argon cap Sirius GLpKa and D-PAS ew SiriusT3 does titrations in 1.0mL volumes Solubility measured with 1mg of sample stirrer ph electrode glass vial 13 /46 SiriusT3 solution of sample For ph-metric experiments
14 How we measure kinetic solubility Example: imipramine (pk a 9.54) dissolved in ionised form at low ph, then titrated with KOH. Precipitate detected by light scattering Kinetic solubility estimated from the concentration of unionised species at the ph of precipitation BH + B Precipitate detected at ph 9 Kinetic solubility = concentration of unionised species at this ph 14 /46 H 3 C CH 3
15 What happens after the sample precipitates? What happens next depends on the extent of supersaturation at the time the sample precipitated We have identified two classes of compound O-CHASERS do not appear to form supersaturated solutions under any conditions CHASERS readily form supersaturated solutions 15 /46
16 Aqueous solubility of dicyclomine, a O-CHASER Curve-fitting method Precipitation detected by light scattering Result = 4.3μg/mL Precipitation Bjerrum Graph. For a base with one pk a, n H S [X 0 [H ] ]K total a 30 minutes to get here Solution Bjerrum Graph. For a base with one pk a, n H [H ] [H ] K a 16 /46 Avdeef, A. Solubility-pH profiles from Bjerrum plots. Gibbs buffer and pk a in the solid state. Pharm. Pharmacol. Commun. 1998, 4,
17 Aqueous solubility of dipyridamole, a CHASER CheqSol method Precipitates here Result = 3.6μg/mL Chases equilibrium here Supersaturated here 17 /46 Box, K. Comer, J. Gravestock, T. Stuart, M. ew ideas about the solubility of drugs. Chemistry and Biodiversity. In Press. doi: /cbdv
18 Calculating solubility from each Crossing Point Mass Balance and Charge Balance equations 1 Hydrogen ion concentration [H + ] is determined from the ph [H ] 10 p[h] 2 Total volume v t is determined from the volumes of water, acid and base v t v w v a v b 3 Hydroxide ion concentration [OH - ] is determined from [H+] and ionic product of water K W [OH ] K [H w ] 4 Potassium ion concentration [K + ] is determined from volume and concentration of base (KOH) v c m z v b b s s [K ] t /fw 5 Chloride ion concentration [Cl - ] is determined from volume and concentration of acid (HCl) - [Cl ] v a c a msz v t s /fw 6 Anion ion concentration [A - ] is determined from charge balance equation [A-] [H ] - [OH ] [K - ] - [Cl - ] 7 Concentration of unionised sample [HA] is determined from [A-], [H+] and pk a of sample [HA] [A ][H ] pk 10 a 8 18 /46 Solubility S is equal to [HA] when solution and solid are at equilibrium S [HA]
19 Concentration (molar) Equations can be derived for other useful graphs eutral species concentration profile for Imipramine (a O-CHASER), drawn using data from earlier slide Concentration of neutral species after precipitation, i.e. intrinsic solubility Concentration of neutral species at low ph 19 / Time (s)
20 Concentration (molar) Extent of supersaturation eutral species concentration profile for Dipyridamole Dipyridamole (a CHASER), drawn using data from earlier slide These profiles are used in CheqSol excipient assays Duration of supersaturation Intrinsic solubility / Time (s)
21 Typical properties of CHASERS vs. O-CHASERS CHASERS Can be acids, bases or ampholytes Precipitate slowly; dissolve slowly Solubility usually increases with temperature O-CHASERS on-chasing mainly observed for bases Precipitate fast; dissolve slowly Solubility unchanged or decreases with temperature High melting points Low melting points. Many liquid at 25ºC Sum of H-bond donors + acceptors is 3 or above Always able to form supersaturated solutions in water Solid forms of free acid or base are probably always crystalline Using additives, we can sometimes prolong supersaturation and inhibit crystallization Little capacity for hydrogen bonding. Most have no H-bond donors Do not appear to form supersaturated solutions in water Often supplied as HCl salts, which are crystalline. However, free bases may be liquid or amorphous Do not appear to form supersaturated solutions under any conditions 21 /46
22 Slide shows how solubility of some compounds can be increased, placing them next to others in BCS Class I 22 /46 Full story in: Box, K. Comer, J. Gravestock, T. Stuart, M. ew ideas about the solubility of drugs. Chemistry and Biodiversity. In Press. doi: /cbdv
23 CheqSol excipient assays of Metoclopramide Metoclopramide is used to relieve nausea and vomiting; heartburn, stomach pain, and bloating; and a persistent feeling of fullness after meals. Metoclopramide comes as a tablet and liquid to take by mouth. It s a base (pk a 9.24), and a CHASER H 3 C H O CH 3 CH 3 O Cl H 2 23 /46
24 Extent of supersaturation These additives increase the extent of supersaturation Extent Metoclopramide Duration 24 /46 DGME is diethylene glycol monoethyl ether PEG 400 is a low molecular weight grade of Polyethylene Glycol Cremophor EL is the registered trademark of BASF Corp. for its version of polyethoxylated castor oil.
25 Extent PVP lengthens the duration of supersaturation Metoclopramide Duration Duration of supersaturation in presence of PVP 25 /46 CAVASOL W7 HP is a highly water-soluble beta-cyclodextrin derivative, from Wacker Chemie AG. Pluronics is a trade name of BASF Corp for nonionic triblock copolymers, also known as Poloxamers. PVP (polyvinyl-pyrrolidine) aids the solubility of drugs by inhibiting recrystallization. Mannitol is an alcohol derived from sugar.
26 Extent Effect of simulated intestinal fluids Metoclopramide Duration atc is sodium taurocholate. 26 /46 FaSSIF and FeSSIF were prepared from Instant SIF powder obtained from Formulae from Kostewicz, E.S., Brauns, U., Becker, R., Dressman, J.B. Pharm. Res. 2002, 19(3),
27 CheqSol excipient assays of Haloperidol Haloperidol is used to treat psychotic disorders, motor tics, verbal tics in adults and children who have Tourette's disorder, and severe behavioural problems such as explosive, aggressive behaviour or hyperactivity in children. Haloperidol comes as a tablet and concentrated liquid to take by mouth. F It s a base (pk a 8.42), and a CHASER O OH 27 /46 Cl
28 Extent Changing the extent of supersaturation Haloperidol Duration 28 /46
29 Extent atc and FaSSIF and enhance duration slightly Duration Haloperidol 29 /46
30 Extent FeSSIF causes huge increase in duration! Haloperidol Duration 30 /46
31 CheqSol excipient assays of Dipyridamole Dipyridamole is used with other drugs to reduce the risk of blood clots after heart valve replacement Dipyridamole comes as a tablet to take by mouth It s a base (pk a s 0.85, 6.20), and a CHASER OH HO OH OH 31 /46
32 Extent Cavasol increases the extent of supersaturation Dipyridamole Duration 32 /46
33 Extent The more Cavasol, the more supersaturation Dipyridamole Duration Data shown in previous slide 33 /46
34 Extent FaSSIF and FeSSIF: extent and duration slightly up Dipyridamole Duration 34 /46
35 Extent atc causes big increase in supersaturation Dipyridamole Duration 35 /46
36 Extent Lecithin: less supersaturation than FeSSIF Dipyridamole Duration 36 /46
37 Powerful new technology We believe the ability to study these supersaturation effects on small samples by ph-metric technology will be very useful in drug formulation Is it a drawback that the experiments are done over a ph range dictated by the experiment, and not by the scientist? Probably not. The following dissolution experiments show similar effects at appropriate ph ranges 37 /46
38 GI Dissolution experiment A dissolution assay can be run on SiriusT3 The assay can also be run on GLpKa/D-PAS Pure drug (approx. 5mg) is pressed into a pellet UV absorbance vs. time is measured for 30 minutes at four successive ph values (e.g. ph2.0, 3.8, 5.4, 7.3) to simulate passage of the drug through the GI tract 38 /46
39 GI Dissolution of Dipyridamole ph 2.0 ph 3.8 ph 5.4 ph /46 Triton X-100 is a non-ionic surfactant. Tween 80, a trademark of ICI Americas, Inc.), is a nonionic surfactant and emulsifier.
40 GI Dissolution of Clopidogrel Clopidogrel is used to prevent strokes and heart attacks in patients at risk for these problems. Clopidogrel comes as a tablet to take by mouth Huge dose required, maybe because most of it precipitates! It s a base, pk a 4.85, and a O-CHASER CH 3 O O Cl S 40 /46
41 GI Dissolution of Clopidogrel ph 2.0 ph 3.8 ph 5.4 ph /46
42 Gi Dissolution of Carvedilol Carvedilol is used to treat heart failure and high blood pressure. Carvedilol comes as a tablet and an extended-release (long-acting) capsule to take by mouth. It s a base, pk a 7.97, and a CHASER O H OH O H O CH 3 42 /46
43 Things don t always get better! ph 2.0 ph 3.8 ph 5.4 ph 7.3 Carvedilol 43 /46
44 Conclusions It s possible to study the extent and duration of supersaturation in real-time experiments using 1 mg of drug We have shown many examples with different excipients We are learning how to predict which excipients will be more effective for extending or prolonging supersaturation Difficult to improve solubility of non-chasers, except by using solvents or surfactants GI Dissolution results provide a complementary method We offer these assays on our automated instruments, and also through our CRO services. 44 /46
45 45 /46 Acknowledgements Thanks to colleagues in the Sirius Chemistry Team, especially: Karl Box Tom Gravestock Liz Frake and to colleagues in the Sirius Software Team: Martin Stuart Roger Allen Andy Latham as well as to the many scientists and customers that have discussed these ideas and concepts with us
46 For more information For details of our automated instrumentation for pk a, logp, logd, solubility & dissolution measurement: For details of our CRO services for physchem outsourcing: /46
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