ionization of drugs powerpoint

pharm sci

what is physiological pH (pH of blood)

7.4

pH range for stomach

1-3

pH range for small intestines

6-7

ionized drugs dissolve…

faster and to a greater extent than nonionized forms

to enter the blood stream the drug must cross

lipophilic barriers, which requires a nonionized state

bronsted lowry definition of acid

acid=proton (H+) donor

bronsted lowry definition of a base

base= proton (H+) acceptor

what are acidic functional groups

FGs that have the ability to donate/give up a proton under physiological conditions

list of acidic functional groups and their pKa ranges

-sulfonic acid (1)

-carboxylic acid (4-5)

-tetrazole (4-5)

-sulfonylureas (6-8)

-sulfonamides (7-9)

-imides (8-10)

-phenols (10)

what should always be done when deciding if a functional group is acidic

check to see if there is an acidic proton (H that it will give up)

what happens when a neutral form of an acidic drug is present

it completely changes the nature of the drug because the groups have different physiochemical properties

what is pKa

the pH value at which 50% of the molecule is ionized and 50% is non-ionized

pKa serves as

a measure of acidity of a functional group

nearly all of the relevant basic functional groups contain

nitrogen (responsible for accepting a proton and acting as a base)

aliphatic amines with pKa 9-10

-nitrogen surrounded by all single bonds or a double bond at least two bonds away

-alkyl substituted, pyrrolidines, piperidines, piperazines, morpholines, tetrahydroisoquinolines

aromatic amines with pKa 4-5

anilines, pyridines, quinolines, benzimidazoles, isoquinolines

imidazole

basic, pKa 6-7, nitrogens not touching/adjacent

pKa formula to determine percent ionization

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

the magnitude of dissociation will depend on

pH of the environment and the pKa of the functional groups contributing to the acid/base properties of the drug

when pH equals pKa…

percent ionization is 50/50

rule of 9s

pH-pKa=1, 91% and 9%

pH-pKa=2, 99% and 1%…

what will electron donating groups do to pKa

increase the pKa (make the group less acidic)

what will electron withdrawing groups do to pKa

decrease the pKa (make the group more acidic)

how to determine if X atom is an electron withdrawing group or an electron donating group

-if X has multiple bonds to it, it is an EWG

-if X does not have multiple bonds, it is an EDG (except halogens have single bonds and are EWG)

examples of weak bases that are considered neutral

-6 membered ring with two or more heteroatoms and 3 double bonds

-5 membered ring with one or more heteroatoms and 2 double bonds

-bisaniline (amine between two aromatics), indole, pyrazines, phenothiazine, benzthioles, oxazoles, pyrroles

what can pH help us predict

-chemical behavior of a drug in a given environment

-degree of ionization

IV drugs must be

completely soluble

most drugs are formulated as their salts because

the ease of handling (solid form) and ease of disintegration and dissolution

what drugs can be made into their salt forms

drugs that are acidic/basic → can be ionized in the body

can neutral drugs form salts

no because they remain in their neutral state in the body regardless of pH, which limits routes of administration

a drug that can form a salt MUST have

at least one acidic or basic functional group

can you form multiple salts in a drug

unless the functional group has the same pKa, no. this would form a multidrug

what can the name of a salt tell us

tells us the acid/base nature of the parent drug, as well as how many molecules are in the drug

what to do when forming a salt if multiple FGs with different pKas

-for acidic groups: use the most acidic group (lowest pKa)

-for basic groups: use the most basic group (highest pKa)

pH controls

solubility, dissolution, and absorption

quaternary salts

-permanent charge because of 4 carbon groups on a nitrogen

-do not have the capacity to accept or donate a proton, SO permanent neutral

-can have a counterion because of charge tho

why are quats always water soluble

because of the permanent charge, they can dissociate in water due to ion-dipole interactions

can quats absorb in the body

no absorption because they are 100% water soluble

what is solubility

the concentration of a saturated solution of a compound in water/aqueous environment

partition coefficient (P)

provides an indication of the inherent solubility of substances

LogP

provides a good indication of how well a drug will absorb when administered orally

LogP scale

larger #: more lipid soluble

lower #: more water soluble

what is the ideal LogP for a drug that needs to cross the blood brain barrier

1-3

if drugs are passing through epithelial cells, they must undergo

transcellular diffusion

only what form can undergo transcellular diffusion

nonionized form (lipid soluble)

what are epithelial cells

cells on the skin/parts of the body exposed to a foreign environment (mouth, GI tract, colon, skin)

dugs that pass through endothelial cells undergo

paracellular diffusion

LogP is a good determinant of

a drugs ability to penetrate membranes or be prohibited from the process

the blood brain barrier is very

lipophilic

drugs with a high LogP might

become stuck/stored in membranes or fat, which keeps them in the body and releases them as the person loses weight