Acidity and basicity of Drugs Pharmaceutical Medicinal Chemistry-I Dr. Bilal Al-Jaidi Assistant Professor in Medicinal Chemistry and Drug Design Faculty of Pharmacy, Philadelphia University-Jordan Email: [email protected] Learning Outcomes At the end of this lesson, students will be able to: Define what do we mean by acidic and basic drugs. Demonstrate how to calculate the % ionization of drugs. Outline the importance of drug dissociation in different body compartments. Explain the effect of drug chemical structure on ionization. Describe how to study the strength of acidity and basicity
Ionisation and dissociation ACIDS ARE PROTON DONORS acid is a substance that can dissociate to give H+ and a negative ion (anion) which is called a conjugate base: HA Ka H + A Kb ACID CONJUGATE BASE
UNIONISED I ONISED UNDISSOCIATED DISSOCIATED Ionisation and dissociation BASES ARE PROTON ACCEPTORS Bases can accept a proton to form the positively charged cation ( conjugate acid of the base): Ka BH B
Kb CONJUGATE ACID BASE IONISED UNIONISED UNDISSOCIATED DISSOCIATED + H pH in different body compartments
Plasma 7.35 7.45 Buccal cavity 6.2 7.2 Stomach 1.0 3.0 Duodenum 4.8 8.2 Jejunum & ileum 7.5 8.0 Colon 7.0 7.5 O O Ka H3C
H3C H OH O [CH 3COO ][ H ] Ka [CH 3COOH ] Ka for CH3CO2H is approximately 10-5 1 Ka 5 10
i.e. only 1 molecule in 100,000 is DISSOCIATED (ionised). -log10Ka = pKa So pKa for acetic acid is 5 O HO S O Ka OH HO O S
O O [ HSO4 ][ H ] Ka [ H 2 SO4 ] Ka for H2SO4 is approximately 105 105 Ka 1 i.e. 100,000 molecules are DISSOCIATED (ionised) for every one undissociated. The pKa of H2SO4 is therefore -5
H NH3 NH2 H [ PhCH 2 NH 2 ][ H ] Ka [ PhCH 2 NH 3 ] Ka for PhCH2NH3+ is approximately 10-9 (pKa = 9) 1 Ka 9 10 i.e. only 1 molecule in 1,000,000,000 is DISSOCIATED (UNIONISED). A weak conjugate acid does not easily donate its proton
(1 molecule in 1,000,000,000 donates a proton) Therefore a strong base willingly accepts a proton (1,000,000,000 molecules accept a proton for every one) Ionization and dissociation of drugs-2 pKa is a different term than pH pH is simply a measure of the [H+] concentration in a given solution pH = 1 ...........the environment is acidic pKa = 1 DOES NOT mean an acidic molecule pH = 14 ............the environment is basic pKa = 1 DOES NOT mean a basic molecule You cant tell from the pKa value whether the species in question is acidic or basic Weak acid
Strong base H+ OH O O Phenoxide anion is stable by resonance this means that phenol can give stable anion upon donating its proton "act as an acid" O OH Factors affecting the strength of acid
The more stable conjugate base (anion) formed, the stronger the acid will be. So any factor will stabilize the anion will increase the acidity of the group, such as resonance and induction stabilization. Stable negative charge results from lowering the electron density on the atom Cl Cl Cl C Cl OH COOH
Cl C COO H pKa = 0.9 Cl O H Which one is the stronger acid? pKa = 10.0
Considering Ka values relates ratio of products to reactants Cl Cl C Cl OH pKa = 0.9 Cl COOH Cl C COO
H Ka = 10-0.9 [Cl3COO ][ H ] Ka [Cl3COOH ] 1 K a 0.9 10 Cl O pKa = 10.0 H
[ PhO ][ H ] Ka [ PhOH ] Ka = 10-10 1 K a 10 10 Phenols are weaker acids than acetates Ionization and dissociation of drugs-3 NH2 Basicity means availability of electrons If the atom has an available lone pair of electrons, it
can act as a base The availability of these electrons will determine the strength of the base As a result of that, aromatic amino group is much weaker base than aliphatic one NH2 Aliphatic amine..............strong base..... Pka of 10.6 N O Diphenhydramine Antihistaminic agent H2N
O O S N H N O Sulfamethoxazole Antibacterial agent Aromatic amine............. weaker base....... Pka of 4.6 O H2N O O S N
H N tertiary amine: methyl groups compared to phenyl group are better donating groups by induction (more available lone pair of electrons) N O HN the lone pair of electrons are not available....delocalized through the phenyl group (stable by resonance) O O S N H
N O NH2 NH3 NH H NH2 pKa = 0.5 pKa = 9.0 H Which one is the stronger base?
pKa = 0.5 Ka = 10-0.5 NH2 NH3 NH [ Ph2 NH ][ H ] Ka [ Ph2 NH 2 ] 1 K a 0.5 10 H NH2
pKa = 9.0 H Ka = 10-9 [ PhCH 2 NH 2 ][ H ] Ka [ PhCH 2 NH 3 ] 1 Ka 9 10 Aromatic amines are weaker bases than aliphatic amines We can quantify how pH changes the ratio of dissociated to undissociated species as follows: pH pK a log10
10 pH pKa Dissociated Undissociated Dissociated Undissociated anti log pH pK a Dissociated Undissociated Dissociated Undissociated For acidic drugs, this ratio describes the % ionization. For basic drugs, this ratio describes the % unionized form to the ionized form.
* Effect of ionization on pharmacokinetic and pharmacodynamic profile What is the importance of studying the pKa values for Acidic and basic drugs? only the unionised form of a drug can partition across biological membranes (providing the unionized form is lipophilic) the ionised form tends to be more water soluble [required for drug administration and distribution in plasma] PARTITIONING OF ACIDS AND BASE For acidic drugs, with a pKa of 4.0, the ionization state will be as follows
Biological Membrane Gut Contents IN stomach RCOOH RCOOH IN intestine H + RCOO X
No Drug Absorption Drug Absorption PARTITIONING OF ACIDS AND BASE If the pH shifts the balance towards the unionized form, the drug would be absorbed. If the pH shifts the balance towards the ionized form, the drug would not be absorbed. Assume the pH of the stomach is 2.0 and the pH of the small intestine is 8.0. Where would you expect absorption to take place from? PARTITIONING OF ACIDS AND BASE For basic drugs, the ionization will be as follows Biological Membrane
Gut Contents IN intestine RNH2 RNH2 IN stomach H + RNH3 X No Drug Absorption Drug Absorption
Gentamicin So we should expect that this compound will not be readily absorbed though the lipophilic membranes although it is in the unionized form Practice question Loratadine is an orally available drug, it has a pKa of 5, answer the followings according to its structure: N Is it basic, acidic or neutral compound? Calculate the % ionization: N O
O In stomach (pH = 2): In intestine (pH = 8): Based on your calculation, from where do you think loratadine will be absorbed? Cl Cl N Weak base N O pH pK a log10
= 103 % ionization = 0.1% So loratadine will be mainly in unionized form It will be better absorbed from intestinal membrane not from stomach * Effect of ionization on drug lipophilicity Ionization and lipophilicity When the drug become ionized, this will increase its water solubility because there will be a better solvation by ionic-dipole interaction between ionized drug and water molecule. So, once the drug get ionized it will have lower
logP than the unionized from (more polar). Ionization and lipophilicity Because most drugs are ionizable at different body pH ranges, the % ionization must be taken into consideration when we are about to synthesize or develop certain drug. Lipophilicity will determine from where the drug will be absorbed and what target tissue will reach. Partition coefficient P P = [Co ]/[Cw] LogP = Log[Co ]/[Cw]. This equation does not determine the effect of ionization on the lipophilicity of drugs Partitioning of acids and base
Papp can be used to predict the behaviour of a compound at all pH values, as long as we know P. For acids, at pH values below the pKa, Papp = P At pH values above the pKa the value of Papp decreases because the species is ionizing and moving into the aqueous layer. Papp P pH pKa
1 10 Partitioning of acids and base For bases, the equation becomes: Papp P pKa pH 1 10 PARTITIONING OF ACIDS AND BASE Consider drugs that are acids, for example RCOOH, which has a pKa of 4.0, and a Partition coefficient of 200. Biological Membrane Gut Contents
RCOOH H + RCOO RCOOH X No Drug Absorption Drug Absorption Papp
P 1 10 pH pKa Papp becomes 198 in the stomach suggesting that absorption will take place pH 8.0 in the small intestine, the calculated Papp suggests no absorption. This equation allows to predict that an acidic drug whose unionized form has a very low partition coefficient would not be absorbed. Oral administration and absorption
If a drug is to be absorbed through the mucosal membranes that line the gut, then it must be in its lipophilic unionised form to partition out of the aqueous medium. The partition co-efficient of the unionised form will also determine how much is absorbed. The absorption phase of the dose-response curve is therefore heavily influenced by the pKa and log P of a drug. Oral administration and absorption Orally administered drugs must have: logP < 5. No more than 10 hydrogen bond acceptors.
No more than 5 hydrogen bond donors. A molecular weight less than 500 Dalton. These points are called Lipinskis rule of five Not more than 7 rotatable bonds. Applications of drug ionization Remember the followings For acids: 1. a high pka means the species is predominantly unionised, is a bad proton donor, and a weak acid 2. a low pka means the species is predominantly ionised, is a good proton donor, and a strong acid pH < pKa by 2 units, 99% unionised pH > pKa by 2 units, 99% ionised For bases:
1. a high pka means the species is predominantly ionised, is a good proton acceptor, and a strong base 2. a low pka means the species is predominantly is a bad proton acceptor, and a weak base pH < pKa by 2 units, 99% ionised pH > pKa by 2 units, 99% unionised unionised, Common acidic functional groups in pharmaceutical chemistry and their pKa values O R O 4-5 OH
R OH S S O NH O 10 O R
O R NH O 9.9 R R 8-10 OH <2
Examples of acidic drugs O O O S N N H H Tolbutamide hypoglycemic agent O OH OH 4-hexylresorcinol topical anesthetic
O OH O O Aspirin NSAID H NH S N NH2 O O
HO Cephalexin Antibacterial agent Common basic functional groups in pharmaceutical chemistry and their pKa values R NH2 10.0 NH2 4.6 R NH
R 10.6-11.0 HN N 6.5 R N R R 9.8-10.8 N
5.2 Examples of basic drugs N N OH O HO O O OH Atropine Anticholinergic agent
Morphine opioid analgesic O N Diphenhydramine Antihistaminic agent Ketoconazole Antifungal agent Common neutral functional groups in pharmaceutical chemistry R R O
NH2 R R O O R O NH O R
O R HN N R R R OH N H R Molecular properties and routes of administration
Oral rectal vaginal topical parenteral Respiratory The molecular properties of the drug must be determined before any route can be considered, but other factors are important
Factors to consider when choosing a route of administration molecular properties of the drug physiological nature of the route patient compliance onset of action the condition being treated systemic or local effect (side effects) metabolism
1. An introduction to Medicinal Chemistry by Graham L. Patrick. 4th edition, Oxford, 2009 2. Wilson and Gisvolds text book of organic medicinal and pharmaceutical chemistry by John H. Black and John M. Beale, jr. 12th edition, Lippincott Williams and Wilkings 2011. 3. Foyes principle of medicinal chemistry by David H. Williams, Thomas L. Leuke, Williams O. Foye. Lippincott William and Wilkins. 7th edition, 2013. The End
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