2 Ionisation and dissociation ACIDS ARE PROTON DONORSacid is a substance that can dissociate to give H+ and a negative ion (anion) which is called a conjugate base:
3 Ionisation and dissociation BASES ARE PROTON ACCEPTORSBases can accept a proton to form the positively charged cation ( conjugate acid of the base):
4 pH in different body compartments Plasma – 7.45Buccal cavity 6.2 – 7.2Stomach 1.0 – 3.0Duodenum 4.8 – 8.2Jejunum & ileum 7.5 – 8.0Colon – 7.5
5 Ka for CH3CO2H is approximately 10-5 i.e. only 1 molecule in 100,000 is DISSOCIATED (ionised).-log10Ka = pKaSo pKa for acetic acid is 5
6 Ka for H2SO4 is approximately 105 The pKa of H2SO4 is therefore -5 i.e. 100,000 molecules are DISSOCIATED (ionised) for every one undissociated.The pKa of H2SO4 is therefore -5
7 Ka for PhCH2NH3+ is approximately 10-9 (pKa = 9) 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)
9 pKa is a different term than pH pH is simply a measure of the [H+] concentration in a given solutionpH = the environment is acidicpKa = 1 DOES NOT mean an acidic moleculepH = the environment is basicpKa = 1 DOES NOT mean a basic molecule
10 You can’t tell from the pKa value whether the species in question is acidic or basic Weak acidStrong base
12 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
13 pKa = 0.9pKa = 10.0Which one is the stronger acid?
14 Considering Ka values relates ratio of products to reactants pKa = 0.9Ka =pKa = 10.0Ka = 10-10Phenols are weaker acids than acetates
16 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 baseAs a result of that, aromatic amino group is much weaker base than aliphatic one
18 tertiary amine: methyl groups compared to phenyl group are better donating groups by induction (more available lone pair of electrons)the lone pair of electrons are not available....delocalized through the phenyl group(stable by resonance)
19 pKa = 0.5pKa = 9.0Which one is the stronger base?
20 pKa = 0.5Ka =pKa = 9.0Ka = 10-9Aromatic amines are weaker bases than aliphatic amines
21 We can quantify how pH changes the ratio of dissociated to undissociated species as follows:
22 For acidic drugs, this ratio describes the % ionization. For basic drugs, this ratio describes the % unionized form to the ionized form.*
23 Effect of ionization on pharmacokinetic and pharmacodynamic profile
24 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]
25 PARTITIONING OF ACIDS AND BASE For acidic drugs, with a pKa of 4.0, the ionization state will be as followsIN stomachIN intestine
26 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 Where would you expect absorption to take place from?
27 PARTITIONING OF ACIDS AND BASE For basic drugs, the ionization will be as followsIN intestineIN stomach
28 So we should expect that this compound will not be readily GentamicinSo we should expect that this compound will not be readilyabsorbed though the lipophilic membranes although it is in theunionized form
29 Practice questionLoratadine is an orally available drug, it has a pKa of 5, answer the followings according to its structure:Is it basic, acidic or neutral compound?Calculate the % ionization:In stomach (pH = 2):In intestine (pH = 8):Based on your calculation, from where do you think loratadine will be absorbed?
31 It will be better absorbed from intestinal membrane not from stomach Under intestinal pH:= 103% ionization = 0.1%So loratadine will be mainly in unionized formIt will be better absorbed from intestinal membrane not from stomach*
33 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).
34 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.
35 Partition coefficient P P = [Co ]/[Cw]LogP = Log[Co ]/[Cw].This equation does not determine the effect of ionization on the lipophilicity of drugs
36 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 = PAt pH values above the pKa the value of Papp decreases because the species is ionizing and moving into the aqueous layer.
37 Partitioning of acids and base For bases, the equation becomes:
38 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.Papp becomes 198 in the stomach suggesting that absorption will take placepH 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.
39 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.
40 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 ‘’ Lipinski’s rule of five’’Not more than 7 rotatable bonds.
42 Remember the followings For acids: 1. a high pka means the species is predominantly unionised, is a bad proton donor, and a weak acid a low pka means the species is predominantlyionised, is a good proton donor, and a strong acidpH < pKa by 2 units, 99% unionisedpH > pKa by 2 units, 99% ionised For bases: 1. a high pka means the species is predominantly ionised, is agood proton acceptor, and a strong base2. a low pka means the species is predominantly unionised, is a bad proton acceptor, and a weak basepH < pKa by 2 units, 99% ionisedpH > pKa by 2 units, 99% unionised
43 Common acidic functional groups in pharmaceutical chemistry and their pKa values 4-5109.9<28-10
47 Common neutral functional groups in pharmaceutical chemistry
48 Molecular properties and routes of administration OralrectalvaginaltopicalparenteralRespiratoryThe molecular properties of the drug must be determined before any route can be considered, but other factors are important
49 Factors to consider when choosing a route of administration molecular properties of the drugphysiological nature of the routepatient complianceonset of actionthe condition being treatedsystemic or local effect (side effects)metabolism