Ceutics Exam 2: Buffer Solution

A critical physicochemical property of a drug is

ionization

ionization

is a process by which a neutral molecule gains or loses a proton and thereby acquires a positive or negative electrical charge.

charged species formed thru ionization are called

ions

can conduct an electrical current, and so substances that form ions in solution are called electrolytes.

ions

a compound that does not ionize when dissolved in water, and exists solely as the neutral, uncharged species.

nonelectrolyte

Many drug compounds do not ____ under physiological conditions and are considered to be _______.

ionize, nonelectrolytes

Compounds with the following functional groups do not generally ionize in aqueous solution:

Alcohols and sugars

Ethers

Esters

Ketones

Aldehydes

The majority of amides

Structures of some common nonelectrolyte functional groups.

alcohols, estes, ethers, aldehydes, ketones, amides

a strong electrolyte ionizes _____ when dissolved in water

completely

a strong electrolyte exists ____ in the form of positive and negative ions in solution

soley

what is an example of a strong electrolyte

sodium chloride (NaCl)

sodium chloride ionizes to form

Na+ and Cl- in aqueous solution

weak electrolyte

is ionizable, but ionizes partially; a fraction of dissolved molecules remain un-ionized, while others acquire a positive or negative charge.

examples of weak electrolytes

acetic acid and ammonia

importance of ionization of weak electrolytes

The properties of ionized (charged) and un-ionized (uncharged) forms of a drug or biologically active compound are dramatically different from each other, even though the only change in structure is the gain or loss of a proton, and the presence or absence of a charge.

charged and uncharged forms will be

Absorbed and distributed differently.

Will bind to receptors differently…

And may be metabolized and eliminated differently.

for a drug that can ionize, the proportion of ionized and un-ionized forms in the body is critical in determining

behavior.

why is the ionization of drugs in the drug product is also important,

influencing route of administration and shelf life of the drug product.

what is a drug that is a good example of the importance of ionization in drug design

indomethacin

what type of drug is Indomethacin

oral anti-inflammatory

- weak electrolyte

the ionized form of a drug dissolves more _____ and to a _____ extent than the un-ionized form

rapidly, greater

to enter the blood stream, the drug need to cross

lipophilic cell barriers

to be able to cross lipophilic cell barriers what is required

at least some molecules to be in the un-ionized form in the intestines

once indomethacin has reached its site of action, only the _____ form binds to the receptor

ionized

both _____ and _____ forms are important for different aspects of ADME and pharmacodynamics of indomethacin

ionized and un-ionized

According to the Bronsted–Lowry theory of acids and bases, an acid is

a compound that can donate a proton

According to the Bronsted–Lowry theory of acids and bases, a base is

a compound that can accept a proton

based on bronsted-lowry there has to be ____ compound present to _____ the proton from the acid, or to ____ the proton to the base

another compound, receive, provide

in almost all situations the other compound involved in the bronsted-lowry concept is

water

why is water a remarkable solvent

it can behave as both an acid and a base

ampholytes

compounds with the dual property of being able to act as both an acid and a base

The water molecule possesses a ____ giving it the ability to accept or donate a positively charged proton

dipole

dipole

two electric charges of equal magnitude but opposite sign, separated by a small distance

hydronium ion

hydrogen ion combines with a water molecule to form a hydronium ion, H3O(+)

the pH od body fluids ranges between

1 and 8

the ____ is the most acidic region of the body

acidic

stomach pH

1 - 3

the normal pH of intestinal fluids is

6-7

the pH of blood is ____ which corresponds to a [H+] of ____

7.4, 40 nM

the value of [H+] can only vary from ______ to ______ with out serious metabolic consequences

37 to 43

Local pH in various tissues depends on _______ and _______ of each tissue, and rarely exceeds ____

composition and function

8

a drug can be expected to encounter physiological environments that vary between pH 1_____and ____ which makes ionization in this pH range of the _____ interest

1 and 8, greatest

if a drug does not have a function group that ionizes in the pH region of 1-8 then it behaves as a _________. what does this mean?

nonelectrolyte, remains un-ionized over the entire physiological pH range

why from a formulation perspective is it important to control pH of a product

1)To minimize drug degradation

2)To improve patient comfort and compliance

3) …or to improve delivery.

what type of dosage form can have a pH outside of the 1-8 range

liquids ( solutions, suspensions, and emulsions)

why are higher pH values of pharmaceutical liquids often required

to make the drug more soluble, or to maintain good stability and an adequate shelf life

when a strong acid is added to water hydrogen ion concentration in solutions ______ and pH _____

increases, decreases

what happens because a strong acid dissociates completely

The molar concentration of H+ is equal to the molar concentration of acid added for a monoprotic acid (HCl), and twice the molar acid concentration for a diprotic acid (H2SO4

example of a strong base

hydroxide ion OH-

what happens when a strong base reacts with H+ in water

the concentration of H+ will decrease and the solution of pH will increase

The molar decrease in H+ concentration will be equal to the molar concentration of _____ added

NaOH

Although strong acids and bases are often used in pharmaceutical products to adjust the pH of liquids, there are _____ strong acid or strong base drug.

no

main difference between strong acid and bases compared to weak acid and bases

weak acids and bases are only partially dissociated in water because of their diminished ability to donate or accept protons

what are the 2 forms that weak acids exist in

uncharged, un-ionized species and negatively charged ions

when a weak base is dissolved in water

only a fraction of molecules accept protons

what are the 2 forms that weak bases exist in

uncharged, un-ionized species and positively charged ions

Typical weak acids have the following functionalities:

Carboxylic acids

Sulfonic acids

Phenols

Thiols

Imides

conjugate acid-base pair

An acid and base that can be represented by an equilibrium in which the two species differ only by a proton

Ka

acid dissociation constant
- A- is the conjugate base of the acid HA

what is the conjugate base of base B in Ka equation

BH+

how do we understand or predict the behavior of ions

Because ions behave differently from uncharged molecules, we are interested in what proportion of a weak acid or weak base is un-ionized or ionized in a given situation

law of mass

describes the dissociation of a weak acid and of the conjugate acid of a weak base.

It states that at equilibrium the product of the concentrations on one side of an equation, when divided by the product of concentrations on the other side of the equation, is a constant regardless of the individual concentrations

the larger the Ka the ______ the acid HA and the _____ its conjugate base A-

stronger, weaker

Ka is a property of the conjugate acid-base pair and gives is information about the

strengths of both forms

define Ka for the conjugate acid of a weak base

the larger of the value of Ka the ______ BH+ dissociates to ____ protons

more, donate

the larger Ka the _____ the conjugate acid BH+ and the _____ the base B

stronger, weaker

weak acids or conjugate acids of weak bases with a large Ka have a _____ pKa

small

weak acids with a small Ka have a _____ pKa

large

does the pKa value itself tell us whether a drug is a weak acid or base

no

a weak acid with a pKa of 3 is a ________ acid than a weak acid with a pKa of 4

stronger

the higher the pKa of a compound the ________ is the basic form of the conjugate acid-base pair

stronger

a weak base of pKa 8 is a _________ base than a weak base of pKa 7

stronger

weak acid and base drugs are frequently available as their

salts

weak acid naproxen is also available as its sodium form

sodium, naproxen

the weak base clonidine is available in its salt form

clonidine hydrochloride

how is the salt of a weak acid usually obtained

reacting it with a strong base such as NaOH

reacting the salt of a weak acid with a strong base results in

sodium salt

reacting the salt of a weak base with a strong acid such as HCL results in

hydrochloride salt

why are salts themselves strong electrolytes

dissociate completely into their constituent ions in water

ions generated do not remain _________________ if one of the components of the salt is a weak acid or base

completely ionized

pharmaceutical companies often develop the salt form of a __________ rather than the original weak acid or base form for several reasons- why

drug
salts can be more readily crystallized into stable, easy to manufacture crystals

salt form of a drug dissolve ______ in aqueous solution

faster

salt form of a drug are more ____ on storage, and are ______ to handle during processing

stable, easier

salts of ______ drugs are preferred over the weak base form

amine

amines are

volatile and unstable

amines have a short shelf life as

solids

stability and shelf life improve dramatically if an amine is converted to the

hydrochloride salt

The relative concentrations of the ionized and un-ionized forms depend not only on the _____ of the weak acid or base, but also on the _____ of the aqueous solution in which it is dissolved.

pKa, pH

buffered solution

one that resists changes in its pH when small amounts of acid or base are added, or when the solution is diluted

buffer solutions contain an acid to react with added

OH-

buffer solutions contain a base to react with added

H+

buffered solutions can be any weak acid-weak base pair, but are usually

conjugate acid-conjugate base pair

the pH of the buffer depends on the

pKa of the buffering substance and on the relative concentrations of conjugate acid and base

pH value of acidic buffer solutions

7

acidic buffer solutions are commonly made from a

weak acid and one of its salts- often a sodium salt

pKa of buffer solution of acetic acid

4.75

an example of a buffered solution of

acetic acid and sodium acetate

If additional hydrogen ions are added to this solution, they are consumed in the reaction with CH3COO−, and the equilibrium shifts to the

left
- [H+] and pH of the solution remain constant

what is the pH of an alkaline buffer solution

7