acid-base properties of drugs part 2

Henderson-Hasselbalch equation

pH=pKa + log [B]/[A]

what do B and A represent

B=conjugate base; A=conjugate acid

how to calculate base-to-acid ratio

B/A= 10^(pH-pKa)

what happens when pH is greater than pKa

deprotonated form predominates

what happens when pH is less than pKa

protonated form predominates

B/A ratio when pH = pKa +1

10:1

B/A ratio when pH = pKa + 2

100:1

B/A ratio when pH = pKa -1

1:10

why is Henderson-Hasselbalch useful in pharmacy

predicts relative amounts of protonated and deprotonated drug forms

protonated form of carboxylic acid

COOH, usually neutral

deprotonated form of carboxylic acid

COO-, negatively charged

protonated form of amine

ammonium ion, positively charged

unprotonated form of amine

neutral amine with available lone pair

carboxylic acid: which form is ionized

deprotonated COO-

amine: which form is ionized

protonated ammonium form

how to calculate % ionized for carboxylic acid

B/(A+B)*100

how to calculate % ionized for amine

A/(A+B)*100

does protonated always mean ionized

no. protonated carboxylic acids are neutral while protonated amines are charged

how to determine major ionization state of functional group

compare environmental pH with group’s pKa

how to determine net charge of drug with multiple ionizable groups

determine each group’s charge separately and add them

zwitterion

molecule with both positive and negative formal charges but overall net change of zero

which form of drug is generally more lipophilic

unionized form

which form of a drug generally crosses lipid membranes more readily

unionized form

which form of a drug is generally more hydrophilic

ionized form

why are ionized drugs often more water soluble

their charges interact strongly with polar water molecules

why do ionized drugs generally cross lipid membranes less readily

charged molecules are are energetically unfavorable in the nonpolar membrane interior

how does ionization affect urinary excretion

ionized drugs are generally less reabsorbed by passive diffusion

ion trapping

accumulation of a drug where its ionized form can’t easily cross a membrane

how does pH influence ion trapping

different pH environments change proportion of ionized drug

why does blood-brain barrier favor certain drug properties

lipophilic, unionized molecules generally cross more readily by passive diffusion

does greater unionized fraction always mean greater total trug absorption

no. surface area, dissolution, transporters, and other factors also matter

pharamaceutical salt

ionic form of drug paired with oppositely charged counterion

how can acidic drugs form salts

by reacting with suitable bases

how can basic drugs form salts

by reacting with suitable acids

what are common counterions for acidic drug salts

sodium, potassium, calcium, and magnesium

what are common counterions for basic drug salts

chloride, sulfate, phosphate, maleate, fumarate, and citrate

why are pharmaceutical salt forms used

can improve aqueous solubility and other formulation properties

general pH of strong-acid/strong-base salt solution

approximately neutral

general pH of weak-acid/strong-base salt solution

basic

general pH of strong-acid/weak-base salt solution

acidic

what can happen when acidic and basic drug salts are mixed

proton transfer may produce poorly soluble neutral forms and precipitation

why is drup precipitation a concern in iv formulations

can cause physical incompatibility and compromise safe administration

how can pH adjustments help prevent precipitation

can maintain drug in more soluble ionized form

what does titration curve show

relationship between pH and amount of acid or base added

equivalence point

point where added titrant has reacted in stoichiometric amount required

half-equivalence point

point where half of original acid has been neutralized

what is true at half-equivalence point of weak acid titration

pH=pKa, acid and conjugate base are present in equal concentrations, buffer capacity is maximal

why can molecule have multiple titration steps

contains multiple ionizable groups with different pKa values

what does a buffering region on a titration curve indicate

pH range where both conjugate acid and base are present in significant amounts

what happens to weak acid as strong base is added

becomes progressively deprotonated

what happens to protonated amine as strong base is added

loses proton and becomes neutral amine

buffer

solution that resists change in pH when small amounts of acid or base are added

typical buffer contains

weak acid and conjugate base, or a weak base and its conjugate acid

how does buffer resist added acid

conjugate base reacts with added H+

how does buffer resist added base

conjugate acid reacts with added OH-

what is approximate effective buffering range

pKa ± 1 pH unit

how does total buffer concentration affect buffer capacity

higher total concentration generally increases capacity

total buffer concentration

sum of conjugate acid and conjugate base concentrations

why are buffers important in pharmaceutical formulations

help maintain pH for stability, solubility, and drug performance

why should large-volume IV infusions generally have low buffer capacity

to avoid interfering excessively with body’s buffering systems

why are buffers used in opthalmic solutions

to help maintian appropriate pH during storage and administration

acetate buffer

buffer containing acetic acid and acetate

phosphate buffer

buffer containing conjugate phosphate species, commonly H2PO40 and HPO4 2-

tris buffer

buffer using tris(hydroxymethyl)aminomethane and its conjugate acid

how do you choose and apropriate buffer system

select one with pKa close to desired pH