2/24/15 1 HendersonHasselbalch • The difference between the pH of the solu<on and the pKa of the drug is the common logarithm of the ra<o of ionized to unionized forms of the drug. • For acid drugs Log(Ionized/Unionized) = pH pKa, or [I]/[U] = 10 (pHpKa) Deriva’on: Ka = [H+][A]/[HA] log Ka = log([H+][A]/[HA]) log Ka = log[H+] log ([A]/[HA]) pKa = pH log ([A]/[HA]) log ([A]/[HA]) = pH pKa H.H.: a quan<ta<ve picture • Most drugs are weak acids or weak bases • It is not all or nothing, there are always several species at different concentra<ons pKa pH BH B pKa pH HA A − = + − = − ] [ ] [ log ] [ ] [ log Frac<on Ionized as a func<on of pKa and pH + 0 0 Weak acid is mostly neutral in stomach A drug is a weak acid, has a pKa of 5.5. Taken orally, it is in a stomach solu<on of pH 3.5. pH – pKa = 3.5 – 5.5 = 2 For an acid, we use: ionized/unionized = 10 2 /1= 1/100 For every 1 molecule of the drug that is ionized, 100 are unionized. This drug in the stomach is highly fat soluble. Basic Drugs For basic drugs, everything is the same except that the ra#o reverses: Log(Unionized/Ionized) = pH – pKa Examples: Chlorpheniramine, chlorpromazine, ephedrine and phenylephrine, amphetamine, methamphetamine, and methcathinone, amitriptyline, imipramine, lofepramine and clomipramine, nortriptyline, desipramine, and amoxapine. pKa pH BH B pKa pH HA A − = + − = − ] [ ] [ log ] [ ] [ log NH2+ [Cl] Amphoteric drugs • Ordinary ampholytes, e.g. maminophenol • pKa acidic > pKa basic . pKa A =9.8, pKa B =4.4 • Increasing pH: 1. NH3+ 2. Neutral 3. O
Transcript
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Henderson-‐Hasselbalch • The difference between the pH of the solu<on and the pKa of the drug is the common logarithm of the ra<o of ionized to unionized forms of the drug.
• For acid drugs Log(Ionized/Unionized) = pH -‐ pKa, or [I]/[U] = 10(pH-‐pKa) Deriva'on:
Ka = [H+][A-‐]/[HA] -‐log Ka = -‐log([H+][A-‐]/[HA]) -‐log Ka = -‐log[H+] -‐ log ([A-‐]/[HA]) pKa = pH -‐ log ([A-‐]/[HA]) log ([A-‐]/[HA]) = pH -‐pKa
H.H.: a quan<ta<ve picture
• Most drugs are weak acids or weak bases
• It is not all or nothing, there are always several species at different concentra<ons pKapH
BHB
pKapHHAA
−=⎟⎟⎠
⎞⎜⎜⎝
⎛
+
−=⎟⎟⎠
⎞⎜⎜⎝
⎛ −
][][log
][][log
Frac<on Ionized as a func<on of pKa and pH
+ -‐
0 0
Weak acid is mostly neutral in stomach
A drug is a weak acid, has a pKa of 5.5. Taken orally, it is in a stomach solu<on of pH 3.5.
pH – pKa = 3.5 – 5.5 = -‐2 For an acid, we use: ionized/unionized = 10-‐2/1= 1/100
For every 1 molecule of the drug that is ionized, 100 are unionized. This drug in the stomach is highly fat soluble.
Basic Drugs For basic drugs, everything is the
same except that the ra#o reverses:
Log(Unionized/Ionized) = pH – pKa
Examples: Chlorpheniramine, chlorpromazine, ephedrine and phenylephrine, amphetamine, methamphetamine, and methcathinone, amitriptyline, imipramine, lofepramine and clomipramine, nortriptyline, desipramine, and amoxapine.
Distribu<on of ionic species for the zwicerionic ampholyte labetalol. from A. Pagliara, P.-‐A. Carrupt, G. Caron, P. Gaillard and B. Testa, Chem. Rev., 97, 3385 (1997).
Isoelectric Point • pI = pH = ½ ( pKaacidic + pKa basic ) • It can be both uncharged and zwicerionic or mul<ply charged
• For absorp<on every charge counts (not the total charge)
• pI is used for isoelectric focusing (Agarose gel electrophoresis)
Zwicerion drugs: Examples Calcula<on of the pH of drug solu<ons
• The drug solu<on itself can develop its own pH
• The pH can be derived from its pKa and concentra<on, C
A weakly acidic drug: HA + H2O=[A-‐] + [H30+] (1-‐a)c ac ac a – degree of dissocia<on
a<<1 ac=[H+] at c >≈ 10-‐7M
Note: this approxima#on
breaks at infinitesimal concentra#ons.
cpKpH a log21
21 −=
Ka =a2c2
(1− a)c≈ a2c
a2 = Ka / ca2c2 = Kac
[H+]= (Kac)12
− log([H+]) = − log((Kac)12 )
− log([H+]) = − log(Ka )− log(c)12
Deriva'on:
For the solu'on of a weakly acidic drug:
Weakly basic drugs • Similarly it can be shown that
• Example: codeine monohydrate (317.4), pKa=8.2
C=0.026 M pH=7+4.1-‐0.79
cpKpHcpKpKpH
a
aw
log7log
21
21
21
21
21
++=
++=
Basic Amine is charged at neutral pH
Ion Trapping of an acidic drug
The same highly fat soluble drug readily crosses the stomach membranes and enters blood plasma, which has a pH of 7.5
pH – pKa = 7.5 – 5.5 = 2 [I]/[U] = 102/1= 100/1 For every 100 molecules of the drug that are ionized, only 1 is unionized. The drug in the blood is not very fat soluble.
This phenomenon is called ion trapping.
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Absorp<on is quan<ta<ve too
• Permea<on rate, RP= P Area ΔC • Amount absorbed = RP• Time
– P is membrane par<<on coefficient (related to LogP)
– Area is effec<ve surface area of membrane
– ΔC is concentra<on difference for the neutral form of the drug
• Astomach/Aileum differ 1000 <mes. That means that even if the frac<on of neutral species in stomach is 100 <mes greater, s<ll 10 <mes more compound will be absorbed in the gut. The effect of <me comes on top.
Cout
Cin
A=120m2
A=0.1m2
Drug Salts: Bases
Note: Hydrochloride in Drug.HCl may be misleading, it should be just chloride (Drug+.[Cl-‐]), same with H2SO4
Two opposite requirements: • Solubility is good for charged compounds with mul<ple polar groups (e.g. pep<des)
• Permeability is good for hydrophobic and apolar compounds
Two solu<ons: • Be exactly in the middle with the same chemical structure (minority)
• Be able to change via enzyma<c ac<va<on (prodrug) or adopt alterna<ve charged forms
Solubility, LogP, and LogD
• Not all uncharged compounds are insoluble
• Not all polar or charged compounds can not permeate a membrane
• It is a quan#ta#ve macer • Three measurable quan<<es are used to characterize a drug substance: LogSw, LogP and LogD
water
membrane
Drug Solubility: defini<on • Water (aqueous) solubility (SW) is the maximum amount of a substance that can dissolve in water. SW depends on P,T.
• Sw is in moles/L (M). Watch for mg/L or mg/dL !
• LogSw (or LogS ) = Log(Sw)
Sucrose
Succinylcholine >10M! But not fat soluble Mitotane: 0.1 mg/L
Solubility and Gibbs energy
• Solubility is defined by a difference between the free energy in the crystal form (primarily enthalpy) and the dissolved form (solva<on, different entropy terms)
• The entropy-‐of-‐mixing contribu<on to dissolu<on (and rigid body rota<on/transla<on) does not depend on chemical type and interac<ons. The main difference: – the number of freed rotatable bonds, hydrophobic surface, (ΔS);
– intermolecular interac<ons in the crystal vs water, ΔH
water
µ 0aq + RT lnSW = µ 0crystal
Polymorphism • Compounds can crystallize as different polymorphs (different molecular conforma<on and packing, cell)
• Polymorphs can have drama<cally different solubility, mel<ng point, <me of dissolu<on, habits
A
AA
AA
AAA
A
AA
A
A
A
AA
AA
AAA
A
AA
A
A
A
A
A
A
A
AA
A A
AA A
A AA
AAA A
AA A AA
A
A
A
A
A
AA
A A
AA A
A AA
AAA A
AA A AA
G
AA
AAA
AAA
G
G
G
GGG
A
A
A
GG
AG
G
AA
AAA
AAA
G
G
G
GGG
A
A
A
GG
AG
C-A+
C- C-C-
C- C-C-C-
A+
A+
A+A+
A+
A+A+
A+C-
A+C- C-C-
C- C-C-C-
A+
A+
A+A+
A+
A+A+
A+
Salts
Co-‐crystals??
Polymorphs Same API Same Ac've Moiety
Different API
Where Do Co-‐Crystals Fit?
Is a New Regulatory Class of Solids Needed?
Adopted from the presenta<on of FDA-‐Div-‐Director Dr. Andre S. Raw
API: Ac<ve Pharmaceu<cal Ingridients
Crystal habits of drugs • The same symmetry group may lead to
different size and shape of a crystal • Crystal habits (and size) may influence
– injec<on (plates: easy, needles: difficult), – tablexng (easy for compression) – rate of dissolu<on
Our body is watching the lipophilicity of xenobio<cs
Kidneys take care of the polar Liver takes care of the hydrophobs
• Polar and charged molecules – renal clearance (fast). *Probenecid (OAT inh.) increases excre<on of uric acid but blocks renal excre<on of and other drugs.
• BBB blocks the polar and charged compounds
• Hydrophobic compounds are made into polar ones by metabolism. Cyp450s modify hydrophobic compounds,
Lipophilicity – a determinant of pharmacokine<cs
• LogD, pH=7.4 (from Shalaeva, ““New Technologies to Increase Drug Candidate Survivability”, Philadelphia, 2002)
• < 0 Too polar. Intes<nal and CNS permeability problems. Suscep<ble to renal clearence
• 0 to 1 A good balance between permeability and solubility. At low values, (more polar), CNS permeability may suffer
• 1 to 3 Op'mum range for CNS and non-‐CNS orally bioavailable drugs. Low metabolic liabili'es, generally good CNS penetra'on
• 3 to 5 Solubility tends to become lower. Metabolic liabili<es.
• Above 5 Low solubility and poor oral bioavailability. Erra<c absorp<on. High metabolic liability, although potency may s<ll be high.
0
1
2
3
4
5
LogD
Cytochrome P450 • R-‐H + O2 + 2e => R-‐OH + H2O (uses NADPH) • Adding One Oxygen: monooxygenase • R-‐OH is further modified by solubilizing sulfate or sugars • bergamoxn, dihydroxybergamoxn, and paradicin-‐A in
grape fruit juice (and other juices) have been found to inhibit CYP3A4 , -‐ overdose
• Saint-‐John's wort induces CYP3A4, but also inhibits CYP1A1, CYP1B1, and CYP2D6, -‐ no ac<on
• Tobacco smoking induces CYP1A2, ..
4-‐hydroxy-‐tamoxifen in the estrogen receptor pocket
Cytochrome P450 2B4 with paroxe<ne
Problema<c permeability
• Natural products (big and polar) – permeability a major problem
• Pep<domime<cs (long and polar) – permeability a major problem
• RNAi • CNS targets (<ght barrier) – Blood-‐brain permeability a major problem
Solubility/Permeability gate • Permeability – PSA > 140-‐200 Å2 is problema<c for systemic distr. – PSA > 75 Å2 is problema<c for CNS delivery
• Solubility – Solubility < 5-‐20 µg/mL is problema<c
• Poor permeability is worse than poor solubility -‐ no easy formula#on fix exists
• Intra-‐molecular H-‐bonds improve permeability with minimal affect on solubility.
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