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Química Medicinal · Metabolism and drug synthesis

Propriedades dos fármacos: solubilidade, sais e estabilidade

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O que você vai aprender

  • Use the Henderson–Hasselbalch equation to find the ionised and un-ionised fractions of acidic and basic drugs at gastric, intestinal and plasma pH, and convert logP into logD.
  • Apply Lipinski and Veber rules as screening heuristics and state their limits.
  • Choose a salt counterion with the ΔpKa rule, draw the proton transfer that forms hydrochloride, mesylate and sodium salts, and explain how salts, polymorphs and hydrates change solubility and dissolution.
  • Draw the hydrolysis of ester and lactone drugs under storage conditions, recognise oxidation-sensitive groups, and estimate shelf life from first-order kinetics.
  • Explain how ester, lactone and hemisuccinate prodrugs improve absorption or solubility, and reason about single-enantiomer drugs and racemic switches.

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Ionisation and the Henderson–Hasselbalch equation

For an acidic drug HA, pH − pKa = log([A⁻]/[HA]); for a basic drug B, pH − pKa = log([B]/[BH⁺]), where pKa belongs to the conjugate acid BH⁺. So the un-ionised fraction of an acid is 1/(1 + 10^(pH − pKa)) and the neutral fraction of a base is 1/(1 + 10^(pKa − pH)). Every pH unit away from the pKa changes the ratio tenfold. Aspirin (pKa about 3.5, drawn left) is about 99% un-ionised in the stomach at pH 1.5 but almost fully ionised at pH 7.4. Propranolol (pKa about 9.5 for its ammonium ion, drawn right) is about 99% protonated at pH 7.4. Only the neutral form crosses lipid membranes quickly by passive diffusion (the pH-partition idea), but surface area matters as much: most aspirin is absorbed in the small intestine, whose huge surface outweighs its lower un-ionised fraction.

logP, logD and drug-likeness rules

logP is the octanol–water partition coefficient of the neutral molecule only. logD is the ratio of all forms, ionised and neutral, at a stated pH, so it is never larger than logP. For an acid, logD = logP − log(1 + 10^(pH − pKa)); for a base, logD = logP − log(1 + 10^(pKa − pH)). Ibuprofen (drawn, logP about 4, pKa about 4.4) has logD₇.₄ of only about 1. Lipinski's rule of five flags likely poor oral absorption when two or more of these are exceeded: molecular mass 500, logP 5, 5 hydrogen-bond donors (OH + NH), 10 acceptors (N + O). Veber added two more: at most 10 rotatable bonds and a polar surface area of at most 140 Ų. These are screening heuristics drawn from past oral drugs, not laws: Lipinski noted that substrates of transporters fall outside the rule, and many natural-product antibiotics break it and still work.

Salts: proton transfer and the ΔpKa rule

A salt forms when a basic drug takes a proton from an acid, or an acidic drug gives one to a base. The transfer is essentially complete, and the salt does not disproportionate back to free base and free acid in the solid or in suspension, when the pKa of the acid counterion is at least 2–3 units below the pKa of the protonated drug. Common choices for bases are hydrochloride, sulfate, mesylate (methanesulfonate, pKa about −1.9) and maleate; for acids, sodium and potassium. Diphenhydramine is an oily free base; its hydrochloride (drawn) is a crystalline, water-soluble solid. Salts usually dissolve faster because the dissolving salt sets the pH of the thin diffusion layer at its surface, where the drug is ionised. Hydrochlorides can dissolve less well in gastric acid because the high chloride concentration pushes the salt's solubility product back (common-ion effect). Doses are often stated as the salt, so the free-base mass is smaller by the ratio of molar masses.

Solubility and solid forms

The solubility of a weak acid rises with pH: S = S₀(1 + 10^(pH − pKa)), where S₀ is the intrinsic solubility of the neutral form, until the solubility of the salt is reached. For a base, S = S₀(1 + 10^(pKa − pH)). The same molecule can crystallise in different packings (polymorphs), with solvent or water in the lattice (solvates and hydrates), or as an amorphous solid. The most stable form under given conditions is the least soluble; a metastable form dissolves faster but can convert. In 1998 a new, much less soluble polymorph of ritonavir appeared and capsules failed their dissolution test, forcing a reformulation. In water, an anhydrous form often converts into its less soluble hydrate.

Chemical degradation in storage

Esters, amides, lactones and lactams hydrolyse in water; amides are the most resistant because nitrogen donates strongly into the C=O. Damp aspirin smells of vinegar because it hydrolyses to salicylic acid and acetic acid (drawn). Procaine solutions, pilocarpine eye drops and reconstituted amoxicillin suspensions all lose drug by hydrolysis: hydroxide opens the ester, the γ-lactone of pilocarpine or the strained β-lactam. Rates usually show specific-acid catalysis at low pH and hydroxide catalysis at high pH, so a plot of log k against pH is V- or U-shaped and the formulation is buffered near the minimum. Electron-rich groups such as catechols (adrenaline), phenols and thiols are oxidised by air, faster at higher pH and in light; antioxidants such as sodium metabisulfite, a nitrogen headspace, acidic pH and light-proof packaging slow this.

Shelf life from first-order kinetics

Most degradations in solution are first order (or pseudo-first order at fixed pH): ln([A]₀/[A]) = kt. Shelf life is usually the time to lose 10% of the drug, t₉₀ = ln(1/0.90)/k = 0.105/k, and the half-life is t½ = 0.693/k. If 5.0% is lost in 6.0 months, k = −ln(0.950)/6.0 = 0.00855 per month and t₉₀ = 12.3 months, slightly longer than the 12 months a straight-line estimate gives, because the rate falls as the drug is used up.

Prodrugs and single enantiomers

A prodrug is converted into the active drug in the body. Ester prodrugs mask polar groups to improve absorption: enalapril is the ethyl ester of enalaprilat, and valacyclovir (drawn left) is the L-valine ester of acyclovir, recognised by an intestinal peptide transporter and hydrolysed after absorption. Simvastatin is a lactone that opens to the active 3,5-dihydroxy acid. Other prodrugs add an ionisable group to raise water solubility for injection: hydrocortisone sodium succinate (a hemisuccinate ester) and fosphenytoin (a phosphate). Many drugs are chiral. A racemic switch markets one enantiomer of an established racemate: esomeprazole (drawn right) is (S)-omeprazole, whose stereocentre is the pyramidal sulfoxide sulfur, and escitalopram is (S)-citalopram. A switch only makes sense if the stereocentre does not racemise in the body.

What to carry forward

Ionisation controls almost every pharmaceutical property: compute it with Henderson–Hasselbalch (acid 1/(1 + 10^(pH − pKa)) un-ionised, base 1/(1 + 10^(pKa − pH)) neutral) and remember that logD, not logP, describes the drug at a given pH. Choose salt counterions at least 2–3 pKa units stronger than the drug, and expect the most stable polymorph or hydrate to be the least soluble. Esters, lactones and lactams hydrolyse by addition–elimination, fastest at the extremes of pH, and first-order kinetics gives t₉₀ = 0.105/k. Prodrugs and single enantiomers change how a known active molecule is delivered, not what it does at the target.

Problemas de prática (40)

Praticar é grátis com uma conta.

Desenhe o mecanismo 8

Salts, solubility and solid forms

  • Diphenhydramine hydrochloride: protonating an amine drugDraw the proton transfer from hydrogen chloride to the tertiary amine of diphenhydramine that forms its hydrochloride salt, and explain why the salt form is chosen.
  • Naproxen sodium: deprotonating a carboxylic acid drugDraw the deprotonation of naproxen by hydroxide, show the resonance that shares the charge between the carboxylate oxygens, and relate the salt to faster dissolution.
  • Rasagiline mesylate: protonation by methanesulfonic acidDraw the proton transfer from methanesulfonic acid to the secondary amine of rasagiline that forms rasagiline mesylate.

Prodrugs and chirality

  • Hydrocortisone sodium succinate: releasing the steroid from a solubilising esterDraw the hydrolysis of the 21-hemisuccinate ester of hydrocortisone, and explain why the ionisable ester makes an injectable form of a poorly water-soluble steroid.
  • Simvastatin: opening the lactone prodrug to the active hydroxy acidDraw the hydroxide-promoted ring opening of the δ-lactone of simvastatin to the 3,5-dihydroxy carboxylate that inhibits HMG-CoA reductase, and explain why the other ester survives.
  • Valacyclovir to acyclovir: hydrolysis of an amino acid ester prodrugDraw the hydrolysis of the valine ester of valacyclovir that releases the antiviral acyclovir and L-valine.

Degradation and shelf life

  • Pilocarpine eye drops: hydroxide opens the γ-lactoneDraw the hydroxide-promoted ring opening of the γ-lactone of pilocarpine to pilocarpate, and identify the second base-catalysed degradation that limits the shelf life of pilocarpine eye drops.
  • Procaine in base: hydrolysis of an ester local anaestheticDraw the hydroxide-promoted hydrolysis of the ester of procaine to 4-aminobenzoate and 2-(diethylamino)ethanol, and relate it to the buffering of procaine injections.

Preveja o produto 5

Prodrugs and chirality

  • What valacyclovir releasesPredict the antiviral released when the valine ester of valacyclovir is hydrolysed.
  • Which single enantiomer would racemise?Predict which drug stereocentre racemises under physiological conditions, making a racemic switch pointless.

Degradation and shelf life

  • Old aspirin smells of vinegarPredict the products of aspirin hydrolysis in a damp container.

Salts, solubility and solid forms

  • A solubility that falls with timePredict the solid-form change when an anhydrous drug is suspended in water.
  • Draw propranolol hydrochloridePredict the site of protonation when a basic drug is converted into its hydrochloride salt.

Classificar 5

Prodrugs and chirality

  • Where is the stereocentre in omeprazole?Classify the stereogenic centre of omeprazole as the pyramidal sulfoxide sulfur exploited in the racemic switch to esomeprazole.

Degradation and shelf life

  • Which drug turns pink in air?Classify drugs by their sensitivity to air oxidation from their functional groups.

Salts, solubility and solid forms

  • What changed in the ritonavir crisis?Classify a solid-state change as polymorphism and distinguish it from hydrate, salt and stereoisomer formation.

Ionisation, lipophilicity and drug-likeness

  • Which drug is a cation in plasma?Classify common drugs as acids, bases or neutral species and predict which one is mostly protonated at pH 7.4.
  • Which rule flags this candidate?Classify a candidate against both the Lipinski and the Veber criteria and identify the property that raises an alert.

Comparar 3

Salts, solubility and solid forms

  • Rank salt-forming acidsRank pharmaceutical counterion acids by strength from their pKa values.

Ionisation, lipophilicity and drug-likeness

  • Rank drugs by neutral fraction at pH 6Rank acidic, basic and neutral drugs by their un-ionised fraction at intestinal pH from their pKa values.

Prodrugs and chirality

  • A prodrug for an injectable solutionCompare prodrug designs and identify the one that adds an ionisable group to raise water solubility for injection.

Calcular 7

Ionisation, lipophilicity and drug-likeness

  • Aspirin in the stomachCalculate the un-ionised percentage of an acidic drug at gastric pH with the Henderson–Hasselbalch equation.
  • logD of ibuprofen at pH 7.4Convert the logP of an acidic drug into logD at plasma pH.
  • Neutral propranolol in plasmaCalculate the neutral percentage of a basic drug at plasma pH from the pKa of its conjugate acid.

Salts, solubility and solid forms

  • Free base in a hydrochloride doseCalculate the mass of free base delivered by a dose stated as the hydrochloride salt.
  • Solubility of a weak acid at pH 5.5Calculate the total solubility of an acidic drug at a given pH from its intrinsic solubility and pKa.

Degradation and shelf life

  • Extrapolate a shelf lifeEstimate t₉₀ from a single first-order stability data point and compare it with a linear estimate.
  • Shelf life from a rate constantCalculate t₉₀ from a first-order degradation rate constant.

Encontre o erro 1

  • Find the error in an ionisation estimateDiagnose the misuse of the acid form of the Henderson–Hasselbalch equation for a basic drug.

Interprete as evidências 2

Ionisation, lipophilicity and drug-likeness

  • Screen a candidate with the rule of fiveCount rule-of-five violations for a candidate and interpret the result as a screening alert.

Degradation and shelf life

  • Choose a buffer from a pH–rate profileInterpret a pH–rate profile to identify acid and base catalysis and choose the pH of maximum stability.

Planeje uma síntese 2

Degradation and shelf life

  • Protect an adrenaline injectionPlan formulation and packaging measures that slow the air oxidation of a catechol drug.

Salts, solubility and solid forms

  • Choose a counterion for a weak basePlan the counterion for a weakly basic drug using the ΔpKa rule.

Explique por quê 7

Degradation and shelf life

  • Why amoxicillin suspension expires quicklyExplain why a β-lactam antibiotic is supplied as a dry powder and has a short in-use life once mixed with water.

Ionisation, lipophilicity and drug-likeness

  • Where is aspirin absorbed?Explain why an acidic drug that is un-ionised in the stomach is still absorbed mainly in the small intestine.
  • Why logD changes with pH but logP does notExplain the difference between logP and logD for an ionisable drug.
  • Oral drugs that break the rule of fiveExplain why some orally active drugs lie outside the rule of five and what that says about the rule.

Salts, solubility and solid forms

  • A hydrochloride less soluble in acidExplain the common-ion effect on the solubility of a hydrochloride salt in gastric fluid.
  • Why naproxen sodium acts fasterExplain why the sodium salt of an acidic drug dissolves faster than the free acid, even in acidic gastric fluid.

Prodrugs and chirality

  • Why a valine ester improves acyclovirExplain how the L-valyl ester prodrug valacyclovir raises the oral bioavailability of acyclovir.

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