Lecture Notes Pharmaceutics 2005

Pharmaceutics (Part I) – Spring 2005 Page 1
Prof. C. Thompson (SB 383; 243-4643; charles.thompson@umontana.edu
Pharmaceutics Class
This document contains lecture notes for Part I of the class (about 4 weeks). These lecture notes are
intended as an aid for your note taking and are not comprehensive. Additional/clarifying information, select
resources, and practice problems will also be provided in the classroom. Although the notes have been
scanned and checked for errors, mistakes are possible so feel free to drop me a line with any corrections.
Helpful Hints (really).
• Relocate your general chemistry book. Briefly review sections on equilibrium, acids & bases. Answer a
few calculations of pH problems. It helps to get the feel for the numbers.
• Relocate your organic and biochemistry chemistry books. Familiarize yourself with organic functional
groups, particularly carboxylic acids and amines. Amines (organic bases) are synonymous with
pharmaceuticals and a brief review of their structure and properties will be helpful in this class and
beyond. Carboxylic acids will be the subject of a majority of calculations in this class and worth a quick
review. Your biochemistry book will have examples and problems in the area of pKa, Henderson-
Hasselbalch, buffers, and ionization. Please review these sections.
• Do not ignore the first two helpful hints. Right about now you’re thinking, “Where are those chem.
books? Oh yeah, I sold them for a case of Lunch Noodles, I don’t really need them.”
• Check those seldom used calculator keys! You will need to calculate log and antilog so find those fun
keys on your calculator and reacquaint yourself with them (it may have been a while). Remember that:
log (100) = 2, and log (10) = 1. So, when you solve for x in the equation “log(x) = 1.7” does it makes
sense that x = 50? Just for fun, push the antilog key about 50 times and let it know who is boss.
• Web Assistance: The internet can be an excellent source of information, but beware. In the area of pH,
pKa, buffers, etc., about half of them very useful, one-fourth OK and one-fourth had many incorrect
statements. I am not responsible for the content in these web sites, or the vast resource of the internet
but do encourage you to find instructional materials on the web that complement our topics. One
example is an interactive website that allows you to visualize how the Henderson-Hasselbalch equation
is graphed. You simply put in the pKa and pH boundaries, and voila, a nice S-shaped titration. Check
out the following website and follow the link to Henderson-Hasselbalch weak acid or weak base.
http://www.cpb.uokhsc.edu/cc/
• Stay Current. Try to keep up with the assigned problems. This section is short and once you fall
behind, it is difficult to catch up. I encourage workgroups but I wish to emphasize the importance of
being confident in your own calculations and understanding.
At the end of this document is a copy of last year’s exam. Answers will be provided in a few weeks.
C Thompson
Acids, bases, pH/pKa calculations and the Henderson Hasselbalch equation
Introductory questions:
1. What is the difference between an organic compound that is described as an acid (proton donor) and a
compound described as capable of hydrogen bonding?
2. The alkaloid natural product, cocaine is a “nitrogenous base” typically isolated as the hydrochloride salt.
a. What is a nitrogenous base?
b. What is a hydrochloride salt?
c. What benefits if any would result from forming an alternate salt (e.g., HBr, HI, benzoate,
maleate, and succinate) with cocaine?
3. Three common classifications of organic compounds are polar non-protic, polar protic and non polar.
a. Which class is more likely to penetrate skin? Why?
b. Which class is more likely to dissolve in saliva? Why?
c. What is DMSO and which class does it belong?
d. One compound class that is not included is non-polar protic. Can a molecule with these
properties exist?
e. How do these “chemical” properties relate to lipophilic/hydrophobic or lipophobic/hydrophilic?
4. Almost all modern drugs are “organic,” that is, they contain one or more carbon atoms. Name some
inorganic drugs that pharmacists MUST be knowledgeable of.
5. What percentage of drugs currently prescribed is likely to be in use in 5 yrs, 10 yrs, and 25 yrs from
now? How will an understanding of basic molecular properties enable you to withstand this change?
Acids & bases

Keywords:
acid base buffer pH pKa ionization equilibria

Henderson-Hasselbalch equation ‘salt’
Objective(s):
• Restore understanding of fundamental acid-base ionization equilibria.

• Relate acidity and basicity of organic compounds to that of water.
• Conduct and gain confidence in ionization calculations.
• Gain a basic understanding of the physiologic importance/implication of drug ionization – specifically in
relation to absorption, transport, and excretion.
Definitions and descriptions:
Hydrogen ions (H+): Hydrogen ions (H+), or protons, do not have electrons, but can bond to nitrogen or
oxygen containing molecules because nitrogen and oxygen have “non-bonding” pairs of electrons.
Hydrogen ions cannot bond to carbon since carbon does not have “non-bonding” electrons.
Acids: According to the Bronsted-Lowry theory of acids and bases, an acid is a substance capable of
donating a proton, or hydrogen ion (H+) to a base.
Bases: A base is a substance that is capable of accepting a proton from an acid.
pH: A method of expressing the hydrogen ion concentration [H+], or more correctly, hydronium ion
[H3O+] concentration in solution. pH is equal to the negative log of the molar hydrogen ion concentration.
pH = -log[H+]
pOH: A method of expressing hydroxyl ion (OH-) concentration in solution. pOH is equal to the negative
log of the molar hydroxyl ion concentration.
pOH = -log[OH-]
IONIZATION OF WATER
Kw and pKw: Water ionizes (dissociates) slightly to yield hydronium and hydroxyl ions:
H2O + H2O H3O+ + OH-
The dissociation constant for water is Kw:

Kw = [H3O+] x [OH-] . 1.0 x 10-14
pKw is equal to the negative log of the dissociation constant of water:
pKw = -logKw = pH + pOH = 14
So, how do pH and pOH correlate? Some pH examples:
[H+] pH [OH-] pOH Kw pKw

10-1 1 10-13 13 10-14 14
10-5 5 10-9 9 10-14 14
10-7 7 10-7 7 10-14 14
10-10 10 10-4 4 10-14 14
10-14 14 1 0 10-14 14
1 0 10-14 14 10-14 14
Note: At [H+] = 10-7, [OH-] = 10-7 and therefore [H+] = [OH-] and pH = pOH. This is neutral pH
(pH = 7).
Questions:
1. For a 0.000001 M solution of hydroiodic acid (HI) what are:

a. the H+ concentration
b. the pH
c. the OH- concentration
d. pOH
2. As a successful pharmacist, you chlorinate your hottub on a regular basis and find the pH = 5. What is
the concentration of H+ and molarity of HCl?
ACID-BASE EQUILIBRIA AND IONIZATION OF ELECTROLYTES
Acid-Base Reactions: Acid-base reactions are equilibrium reactions. That means that there is a forward
reaction and a reverse reaction. At equilibrium, the forward and reverse reaction rates are the same, and the
relative concentrations of reactants and products and remain constant.
Strong and weak acids:
Strong acid - HCl is considered a strong acid because it has a strong tendency to ionize resulting in a
large [H3O+] and the reverse reaction occurs only to a small amount. This further indicates that Cl- is very
weak as a conjugate base and not likely to accept a proton. What this means is that Cl- is ‘stable’ just the
way it is. This is an attribute of many strong acids – the conjugate base is stable while bearing a negative
charge. This means the conjugate base happily accepts the extra electron. Strong acids are completely
ionized at all pH values (pH independent ionization).
HCl + H2O H3O+ + Cl-

Weak Acid – Phenol is a good example of a weak acid. In comparison to HCl, phenol has a weaker
tendency to ionize and the conjugate base, phenoxide ion, is moderately strong. As a result, the equilibrium
shifts further to the left and the acid (protonated) form of phenol predominates.
OH O-
+ H2O H3O+ +
Question: When substituents are added to the aromatic ring (e.g., methyl, nitro, etc.), what effect on the
ionization might they have?
One example of how the phenol structure has been altered to achieve the desired pharmacologic property is
the anti-bacterials:
Fun fact: Phenol
causes some of the
most serious and
damaging chemical
burns to the skin. In
the laboratory phenol
is used to lyse cells!
Anti-bacterial activity was increased by increasing the waxy chain to enhance membrane
infiltration. Hexylresorcinol and hexachlorophene are used in hospital sterilization methods.
In general, for a weak acid:
kf
HA + H2O H3O+ + A-
kr (conj base)
Note that the product (A-) is designated as the conjugate base. The conjugate base is also known as the salt
of the acid when combined with a counterion such as Na+ to give Na+A-.
An equilibrium constant (K) can be defined that is equal to the forward rate constant (kf) divided by the
reverse rate constant (kr). It is also equal to the product concentrations divided by the reactant
concentrations:
K = kf = [A-][H3O+]
kr [HA][H2O]
since water is constant @ 55 M
Ka = 55M = [A-][H3O+]
[HA]
Ka is a measure of (weak) acid strength as expressed by the concentration of ionized molecules divided by
the concentration of unionized molecules.
Question: Alcohol are organic ‘analogs of water meaning they share the identical functional group
(OH) but vary in one component, the “switch” of an H for a Me, Et, etc. Explain the increasing trend in
pKa values (table at right) for the alcohols and the “unusual” drop in pKa for phenol relative to the other
alcohols.
R-OH pKa
H-OH (water) 15.8
MeOH (methanol) 16.4
Et-OH (ethanol) 16.8
iPr-OH (isopropanol) 17.2
t-Bu-OH (tert-butanol) 18
Ph-OH 10
Trends to consider based on the Ka equation:
As acid strength increases (8):

Ka increases
[A-] increases
[H3O+] increases
[HA] decreases
A helpful utility is pKa, which relates the strength of weak acids on logarithmic scale. It provides a means
to compare the acidity of a class of compounds or across classes of compounds in whole numbers. Because
the scale is log-based, comparisons are typically based on ten-fold increments, which is fine for most
comparisons.
pKa = -log(Ka)
As the acid strength increases, so does the Ka. However, the pKa decreases as the acid strength
increases.
For weak acids, the ionization in water is: HA H+ + A-

(conj base)
Ka = [A-][H+]
Which can be expressed as: [HA]
Ka = [H+][H+] = [H+]2 and [H+]2 = Ka[HA]

With no other ions in solution, the concentration of
[HA] [HA]
H+ and A- should be equal and, therefore:
[H+] = Ka[HA]
Rearrange and substitute to:
[H+] = KaC
if you take the -log of each side:

This equation in bold is useful for calculating the pH of a weak
acid in water when you know the molar concentration and the pKa -log[H+] = 1/2 (-log Ka - log C) or
of the weak acid or drug (usually found in tables).
pH = 1/2 (-logKa - log C)
pH = 1/2(pKa) - 1/2(logC)
Question: Calculate the pH of a 0.1 M solution of a drug at 25 oC. The pKa of the acid is 4.76 at 25 oC.
Weak Bases. Weak bases react with water to take up hydrogen atoms to form a conjugate acid resulting in
hydroxyl ions that turn the solution alkaline (basic).
B: + H2O BH+ + OH-

(conj acid)
Note that the product (BH+) is designated as the conjugate acid. The conjugate acid is also known
as the salt of the base when combined with a counterion such as Cl- to give BH+Cl-.
One example of a weak base is ammonia (NH3), which reacts with water to form ammonium hydroxide
(NH4OH or NH4 + / OH-). Ammonia has a weak tendency to ionize and the conjugate acid is strong: the
equilibrium favors the left side of the equation.
The basicity constant is defined as Kb (expressed similarly to the Ka) and is a measure of base strength.
When base strength is increased the equilibrium is moved to the right. Kb is mostly unused and has been
replaced by Ka.
Ka and pKa are generally used for both acids and bases because pKa uses the same scale and goes in the
same direction as pH. For bases, Ka and pKa indicate the strength of the conjugate acid, BH+.
Ka and Kb are related: Ka x Kb = Kw = 1.0 x 10-14
pKa and pKb are also related: pKa + pKb = pKw = 14
So, if the Ka and pKa terms are used, as base strength increases:
Ka decreases
pKa increases
Examples of pKa
Acids and bases:
Acetic acid: Ka = 1.75 x 10-5; Ka = 4.76
O O
H3C C H3C C
OH + H O O- + H O+
2 3
Salicylic acid: Ka = 1.06 x 10-3; Ka = 2.97
CO2H CO2
+ H2O + H3O+
OH OH
salicyclic acid
Phenobarbital: Ka = 3.9 x 10-8, pKa = 7.41
O O
H H
Et N Et N
O O
Ph N Ph N-
H
O + H2O O + H3O+
Pyridine: Ka = 7.1 x 10-6, pKa = 5.15 (the pyridinium or protonated form is the acid).
N NH+
+ H2O + OH-
Question: Amines rarely give up a proton and behave like an acid. Why does the proton on
phenobarbital (above) act like an acid?
Some pKa’s of interest..…please note the range in pKa, correlation with water
Compound pKa Compound pKa
sulfuric acid -9 RNH3+ (protonated primary amines) 10 to 11

hydrochloric acid -7 HCO3- 10.3
nitric acid -1.4 RSH (sulfides) 10 to 11
RCOOH (carboxylic acids) 4 to 5 water 15.7
H2CO3 6.3 ROH (alcohols) 15 to 18
NH4+ 9.2 RC(O)NH2 (amides) 17 to 18
phenol 8.5 to 11 alkanes 48-50
Weak acids and bases are weak electrolytes meaning that they are only ionized to a small extent (less than
1%) in solution. Weak acids have Ka values which are << 1 and positive pKa values. Acetic acid,
phenobarbital, and pyridine are examples of weak acids and bases. Most drugs are weak acids or bases.
Henderson-Hasselbalch Equation - Utility
The Henderson-Hasselbalch equation can be used to determine pH, pKa and/or the relative amounts of acid
and base in a solution. It can be used for both weak acids and weak bases and primarily for the following:
calculating the ratio of base to acid when the pKa and pH of the solution are known. [This
information can be used to prepare buffer solutions].
calculating the pH of a solution if the ratio of base to acid and the pKa are known.
calculating the pKa if the ratio of base to acid and pH of the solution are known.
One of the more important features of the HH equation in Pharmacy is the ability to predict the
proportions of ionized and unionized forms of a drug at a given pH. Since pH varies in vivo
depending on the system/location and a one (1) pKa unit difference results in a ten-fold change in
the ionization (log scale), small changes in the local environment can have a dramatic effect on
uptake, distribution, net effect, metabolism, and excretion. Also important to consider is that the
ionized form of a drug, for example, may not bind the receptor or target whereas the neutral form
of the drug does. Careful use of the HH equation, therefore, may permit better prediction of the
physiologic effect.
From the equilibrium and Ka equation:

Ka = [A-][H3O+]
HA + H2O H3O+ + A-
(conj base) [HA]
the following equation can be derived:
Ka = [A-]
[H3O+] [HA]
which in log form is converted to:
log Ka = log [A-]

[H3O+] [HA]
or
logKa - log[H3O+] = log [A-]

[HA]
log[H3O+] = - logKa + log [A-]

or [HA]
pH = pKa + log [A-]
[HA]
finally, in descriptive terms,
pH = pKa + log [conj base]

[acid]
Key points:
One important thing to keep in mind is that the weak acid is the proton donor. That means the
“form” or “structure” of the acid may vary as a carboxylic acid, alcohol, sulfide or even amine
hydrochloride, for example.
You can rearrange the equation to solve a number of calculations, but the real issue is to keep
“trends” and ratios at the forefront. For example, rearrange the equation to get an understanding of the acid
to base ratio as follows:
pH - pKa = log [conj base]

[acid]
In this instance, the difference between the pH and the pKa (typically defined for the drug in question) can
tell you how much of one form the drug is in (ionized or unionized). Important: this difference is
logarithmic!
[base] % conj.
pH - pKa [acid] % acid base % unionized % ionized
4 10,000/1 0.01 99.99 0.01 99.99

3 1000/1 0.1 99.9 0.1 99.9
2 100/1 1 99 1 99
1 10/1 9 91 9 91
0 1/1 50 50 50 50
-1 1/10 91 9 91 9
-2 1/100 99 1 99 1
-3 1/1000 99.9 0.1 99.9 0.1
-4 1/10,000 99.99 0.01 99.99 0.01
Note that when the pKa = pH, there will be an equal amount of ionized and ionized (because the log of zero
= 1).
Using the table above, one could get a “sense” for the amount of acid and base forms. So, if a drug
contained a carboxylic acid group that had a pKa of 4.2, one could determine that the drug was deprotonated
at physiologic pH (approx. 6.8-7.5). That is, the carboxylic acid group lost its proton to form the ionized
carboxylate. However, in the stomach, at pH 1, the drug would remain in the protonated, acid form.
Question: Which form of a carboxylic acid (carboxylic acid or carboxylate anion) is more likely to
traverse cell membranes?
Salts of Weak Acids
In chemistry classes we learn that metals like sodium, potassium and calcium are common counterions for
salts of drugs that are weak acids. Salts of weak acids have the general form R-M+ where R is a carboxylic
acid, phenol, imide or other ionizable group.
O O O
R OH
OH R N R
H
Question: Why is lithium not used as a countercation for drugs that are weak acids in salt formation?
Example of drug salt formation:

O O
Et NH Et NH
NaOH
O O
Ph NH Ph N
O O Na
Phenobarbital Phenobarbital
sodium
CO2H CO2 Na radiologic

I I I I contrast
NaOH agent
H3C(OC)HN C(O)NHCH3 H3C(OC)HN C(O)NHCH3
I I
Iothalamate Iothalamate
sodium
In the case of the radiologic (x-ray) contrast agent, iothalamate, the formation of the sodium salt adds
significant water solubility, which allows the contrast agent to distribute evenly throughout extracellular
space. There is no significant penetration into intracellular matrices and moreover, the contrast agent is
cleared rapidly from the body (t ½ = 2 h).
Fun fact: There are five radiologic x-ray densities: air, fat, fluid, bone and metallic, all of which show up
differently on “film.” And, as many know, many organs and tissues do not show up well on traditional
x-ray, e.g., liver, spleen, kidneys, intestines, bladder, and abdominal muscles (all have similar density
and ‘shadow’ each other). Certain compounds increase the radiographic contrast b/c they have x-ray
absorption characteristics that afford a ‘bone-like’ or metal-like’ density. Compounds that fall into this
class are iodinated aromatic compounds (bone-like density) and barium salts (metal like density). Talk
about high doses! Contrast agents are administered as 100 mL of a 60% solution. Osmotoxicity!
Examples of other drugs that are salts of weak acids and their counterions:
1. Warfarin sodium Na+ 3. Fenoprofen calcium Ca+2
2. Penicillin G potassium K+
Salts of Weak Bases
Most of the weak bases of interest to pharmacists are the amines and anilines. Both classes are capable of
being protonated by an acid to form an amine or aniline salt. The acid used to do the protonation contains a
conjugate anion that forms the anion after the amine has been protonated.
primary secondary tertiary aniline
amine amine amine
R1 R2 R1 R
R1 N N 2
NH2
H R3
NH2
HA HA HA HA
R1 R1 R2 R1 R2
NH3 A N N
H H A H A
R3
NH3 A
where R1, R2 and R3 are various alkyl/aryl groups
and A is the conjugate base, e.g., Cl, Br, etc.
Amines have a pKa ranging from 9-11 and anilines have a pKa 4 to 5.
Question: Why are the pKa values so different for amines and anilines?
Another example of a base is the aromatic heterocycle pyridine. Its structure appears in many drugs and it
readily forms salts with mineral and weak acids.
HCl
N N H Cl
pyridine pyridine
hydrochloride
Examples of drugs that are salts of weak bases and their counterions:
Meperidine hydrochloride Cl-

Dextromethorphan hydrobromide Br-
Atropine sulfate SO4-2
Codeine phosphate PO4-3
Biperiden lactate CH3CHOHCOO-
Ergotamine tartrate -OOCCHOHCHOHCOO-
Chlorpheniramine maleate -OOCCH=CHCOO-
Benztropine mesylate CH3SO3-
Lets examine the “organic” salts a little closer.
OH OH
HO2C
H3C CO2H CO2H HO2C CO2H
OH
lactic acid tartaric acid maleic acid
from $10-100/kg
These carboxylic acids serve as proton donors to weakly basic amines. Amines comprise one of the largest
classes of organic molecules used as pharmaceutically important drugs. The amine and one of these acids
(for example) combine to form an amine salt, which improves its water solubility. Some other important
considerations in the use of these acids include: (a) low cost, (b) high chemical purity, (c) high
stereochemical purity, and (d) potential to serve as ‘dual’ or as a twofold proton donor (e.g., tartaric acid and
maleic acid).
Maleic acid is the cis isomer – the trans isomer is called succinic acid (succinate). You are likely to see all
of these acids in advertisements for pharmaceuticals.
BUFFERS
Keywords/Concepts:
buffer buffer equation buffer capacity
Objective(s):
• Restore understanding of buffer systems and establish importance for use.

• Develop the physicochemical relationship between weak acids and bases and buffer systems.
• Gain confidence in selecting pharmaceutical buffers.
• Define preliminary physiologic buffer systems.
Definitions and descriptions:
Buffer – A buffer is a solution that resists pH changes when acids or bases are added to the solution.
Most buffer solutions consist of a weak acid and its conjugate base (salt of the weak acid).
Common Examples of Weak Acid Buffer Systems.
Acetic acid Sodium acetate
Boric acid Sodium borate
Citric acid Sodium citrate
Phosphoric acid Potassium phosphate
Examples of Weak Acid Buffer System.
tris(hydroxymethyl)aminomethane tris(hydroxymethyl)aminomethane hydrochloride

"Tris" "Tris HCl"
OH OH
HO NH2 HO NH3 Cl
OH OH
The pH of some ‘well known’ liquids containing buffer systems:
Product pH (room temp)
Apple juice 3.7

Club Soda (Schwepps) 5.1
Coffee (instant) 4.7
Diphenhydramine 5.0
Distilled Vinegar 2.6
Gatorade 3.0
Ipecac 1.7
Listerine 3.9
Pepsi 2.6
Robitussin DM 2.5
Saline USP 6.8
Visine 6.3
Buffer Properties and Function:
When acids or bases are added to pure water, they immediately produce H3O+ or OH- ions that decrease or
increase the pH, respectively. Buffer systems resist large pH changes because added acids or bases are
neutralized by the existing HA/A- system (equilibrium).
Added acids are neutralized by the conjugate base (A-) which is converted to the acid (HA). Added bases
are neutralized by the acid (HA), which is converted to the conjugate base (A-). Addition of acids or bases
therefore change the HA/A- ratio. However……
- we know that from the Henderson-Hasselbalch (buffer) equation, changes in the HA/A- ratio will
also change the pH. However, the pH change is related to the log of the change in the HA/A-
ratio. Therefore, the pH change is relatively small.
Also, the assumption here is that the concentration of buffer salts exceeds that of the acid being introduced
to the solution and therefore, there is a large number of “solvation ions” (halleluiah) to handle.
The Buffer Equation(s): The buffer equation is the Henderson-Hasselbalch equation adapted to consider
acids and their conjugate bases leading to solutions that are resistant to pH change. The buffer equation can
be used to calculate:
• the pH of a buffer solution when the HA/A- ratio is known.
• the HA/A- ratio required to give a buffer of a given pH.
• the pH change which results from the addition of an acid or base to a buffer solution
In most cases, you will need to know the pKa of the weak acid to conduct these calculations.
The following forms of the buffer equation are useful for buffer calculations:
pH = pKa + log B/A (useful to calculate the pH of the buffer solution)
pH - pKa = log B/A (useful to calculate the ratio of base to acid )
pKa = pH + log A/B (useful to calculate the pKa of a buffer at a known pH)
pKa - pH = log A/B (useful to calculate the ratio of acid to base)
Question: Calculate the pH of a buffer solution prepared by dissolving 242 mg of Tris in 10 mL of 0.170
M HCl and diluting to 100 mL with water. [Tris: mw 121 g/mol and pKa = 8.08 for the conjugate acid]
Buffer Capacity: The ability of a buffer system to resist pH changes is its buffer capacity and indicated by
the buffer index (β):
β = ∆B/∆pH
where: B = strong base (in molarity) ∆ = change (delta)
Buffer capacity is defined as the number of equivalents of strong base (∆B) required to cause a one-unit
change in pH (∆pH ) in 1 L of solution. The greater the buffer capacity, the smaller the change in pH from
the addition of a given amount of strong acid or base. Buffer capacity is dependent on the total
concentration of the buffer system and on the HA/A- ratio. The buffer index number is generally
experimentally derived in a manner like a titration (see Table below). For example, when 0.03 moles of
NaOH was added to an acetate buffer system prepared at 0.1 M, the pH expectedly increased from 4.76 to
5.03; a change of 0.27 pH units. Therefore, the equation β = δB/∆pH = 0.03/0.27 = 1/9 = 0.11
Note that the buffer capacity is highest when the smallest number of moles of NaOH are added. Also, the
buffer equation can be adapted for the addition of acids, except the pH would decrease in these experiments.
Buffer capacity is increased by the following factors:
- increasing the concentration of the buffer system components (e.g. doubling the total molar
concentration of the buffer system will double the buffer capacity at a given pH).
- using equimolar concentrations of the acid (HA) and its conjugate base (A-). Buffer capacity is
maximal when pH = pKa ([HA]=[A-]).
Why use buffers in pharmacy?
Solubility - The ionized form of a drug is more water soluble than the unionized form. Buffers can be used
to maintain a drug in its ionized (salt) form for aqueous solutions.
Absorption - The unionized form of a drug is more lipid soluble than the ionized form. The unionized form
therefore penetrates biological membranes much more efficiently than the ionized form. buffers can also be
used to maintain the drug in its unionized form.
Stability - pH can affect the stability of a drug in an aqueous solution. For example, ester drugs are very
susceptible to hydrolytic reactions. Buffering formulations at low pH (pH 3-5) can reduce the rate of
hydrolysis.
Tissue irritation - High or low pH can cause tissue irritation. Buffering a formulation to near neutral pH can
reduce tissue irritation. Ophthalmic products are least irritating at pH 7-9.
Buffers and the Body:
Body fluids contain buffering agents and buffer systems that maintain pH at or near pH=7.4.
Important endogenous (natural) buffer systems include carbonic acid/sodium bicarbonate and sodium
phosphate in the plasma and hemoglobin, and potassium phosphate in the cells. An in vivo value of pH < 6.9
or pH > 7.8 can be life threatening.
Pharmaceutical solutions generally have a low buffer capacity in order to prevent overwhelming the
bodies own buffer systems and significantly changing the pH of the body fluids. Buffer concentrations of
between 0.05 and 0.5 M and buffer capacities between 0.01 to 0.1 are usually sufficient for pharmaceutical
solutions.
Choosing the Right Pharmaceutical Buffer :
• Choose a weak acid with pH » pKa.
• Use buffer equation to calculate ratio of acid/base needed to give required pH.
• Choose concentration needed to give suitable buffer capacity.
• Choose available ingredients considering sterility, stability, cost, toxicity.
• Use pH meter or, at least, pH indicator paper.

PHARMACEUTICAL BUFFER EXAMPLES
The following are some buffer systems that are used in the formulation of pharmaceuticals. Most
pharmaceutical buffers are composed of ingredients that are found in the body (e.g. acetate, phosphate,
citrate):
Buffer System pKa buffer pH range
Acetic acid/sodium acetate 4.76 3.8 to 5.6
Phosphoric acid/sodium phosphate

H3PO4/NaH2PO4 2.1(pK1)
NaH2PO4/Na2HPO4 7.2(pK2) 5 to 8
Na2HPO4/Na3PO4 12.3(pK3)
Citric acid/sodium citrate

3.1(pK1)
4.8(pK2) 1.2 to 6.6
9.2(pK3)
Boric acid/sodium borate
9.2 7.8-10.6
BONDING
Bonding and molecular interactions: Understanding the basic forces that hold molecules together is
important for understanding how molecules interact with each other. These interactions affect solubility,
stability and other properties of drugs.
BOND TYPES
Covalent Bonds - the strongest bond (arrows), worth

anywhere from -40 to -110 kcal/mol in stability. Bonds in the
molecule at right are all covalent even though some are single,
double or triple bonds. Not shown are the carbon-hydrogen
bonds that are also covalent. Although most drug interactions
are non-covalent, alkylation of DNA for example in cancer
chemotherapy is an example of covalent bond formation by
drugs.
Ionic Bonds – a.k.a. Electrostatic interactions can be attractive or

repulsive, depending on the relative charges. Like charges repel each
other and opposite charges attract. For ionic bonds, opposite charges
hold ions together. Electrons are not shared, but are transferred. As
an example, at physiologic pH basic side chains of certain amino
acids like arginine, lysine, and, in part, histidine are protonated and
therefore provided a cationic environment. Acidic groups like
aspartic and glutamic acid are deprotonated to give negatively
charged groups. Therefore, drugs and their target receptors can be
mutually attracted by opposite charges on their surfaces, e.g., cationic drug with anionic receptor site. A
simple ionic attraction can provide as much as -5.0 kcal/mol and declines as the square of the distance
between the charged sites. If an ionic attraction is reinforced by other interactions (H-bonding, etc) is can
provide up to -10.0 kcal/mol.
Ion-dipole and dipole-dipole Interactions - by virtue of varied electronegativity values when compared to
carbon certain groups have an asymmetric distribution of electrons that produce dipoles. Dipolar
interactions refer to unequal distribution of charge within a bond or a molecule. Dipoles exist where one
atom (X) is more electronegative than another (H). The dipoles in a drug molecule, therefore, can find
complementary dipole interactions in the receptor. However, since the net charge on a dipole is less than on
a full ion, the interaction is generally weaker (G ranges from -1 to -7 but is usually -1 to -2).
δ- -
δδ+ δF
O +
δ δ+
+ O- H
δδδ+ δ δ
Hydrogen Bonds - simply a variation of a dipole-dipole interaction

formed between the proton of one group and an electronegative atom of
O
another group. In molecules of biological interest the hydrogen bonds
most widely experienced are when X = O, N, S. Hydrogen bonds are
N NH
usually denoted by a dashed or dotted line as in the case of the DNA H
bases at right sharing two hydrogen bonds:
O O
What makes hydrogen bonds so unique is that hydrogen is the only atom H
N
that can carry a positive charge at physiologic pH while remaining N
covalently attached to a molecule. Further, hydrogen is small enough to

permit close approach by another electronegative atom or molecule to N
H
N NH2
accept the hydrogen bond.
There are two forms of hydrogen bonds - intramolecular (within a single molecule) and intermolecular
(between two molecules). Hydrogen bonds for example, are important in maintaining the structural integrity
of peptides and proteins - -helical structure and -sheets derive their structure from hydrogen bonds. The G
for hydrogen bonding ranges from -1 to -7 kcal/mol but in biosystems is usually between -3 and -5 kcal/mol.
Charge Transfer Complexes - this attraction comes about when molecules containing a good electron
donor group (on an aromatic ring) interact with a molecule that contains an electron-withdrawing (acceptor)
group. The interaction involves transfer of charge from donor to
acceptor.
Electron donor groups or molecules usually contain a -bond (alkene,
alkyne, aromatic moiety) that bears a good electron donating group
(alkyl, methoxy, OR, SR, etc.). Acceptor groups or molecules usually
contain a π-bond with electron withdrawing groups attached (e.g.,
cyano, carbonyl, halogen, etc.). The interaction is rare and most likely
found with the tyrosine residue on certain receptors (as the donor). The
G for charge-transfer complexes range from -1 to -7 kcal/mol.
Hydrophobic Interactions - involve a non-polar/non-polar interaction between receptor and drug. Usually
alkyl chains are found to stack as in the lipid bilayer except this is for a single interaction. It is important to
consider in this interaction that each receptor and drug molecule aliphatic chain is surrounded by water
molecules, and as the chains approach each the water molecules are squeezed out to permit the non-polar
chains to align with each other in a "side by side" position. This orienting results in a drop in the free energy
of about 0.1 to -2.0 kcal/mol.
Van der Waals or London Forces - Some atoms on mostly non

drug molecule R1 R2
polar molecules experience or exert a temporary non-symmetric +
δ
distribution of electrons to cause a dipole. As these atoms approach
each other in different molecules, the opposite dipoles attract
δ− O δ−
forming an interaction. The G varies greatly and values from -0.1 O
to -2.0 are reasonable.
R4HN δ+
NHR
receptor target
R3
SOLUBILITY
Solubility is the maximum concentration that can be attained by a solute in a specific solvent.
A saturated solution is one in which the solvent has dissolved all of the solute that it can, and addition of
further solute will not increase the concentration of the solute in the solvent. When excess solute is added to
a saturated solution, an equilibrium will exist between the solid solute and the solute in solution.
Solutions are the result of intermolecular attractive forces between solutes and solvents.
Electrostatic, dipole-dipole (van der Waals) and hydrogen-bonding forces may be involved in solute-
solvent interactions. In order for a solute to dissolve in a solvent, the intermolecular attractive forces
between solute molecules and between solvent molecules must be overcome and replaced with solute-
solvent attractive forces.
Solubility can be affected by temperature, pH, and the physical form of the solute.
• temperature: Increasing temperature generally increases solubility. Most solutes absorb heat upon
dissolution and have a positive heat of solutions. In comparison, a few solutes have a negative heat of
solution which means that they give off heat during dissolution and solubility decreases with increasing
temperature.
• pH: Weak acids and bases are more soluble in their ionized (conjugate base or conjugate acid) forms than
their unionized forms, so pH is very important for the solubility of weak electrolytes.
• physical form: Non-crystalline (amorphous) solids are generally more soluble than crystalline solids.
Also, different polymorphic forms, solvates and hydrates will have different solubilities. These terms will be
discussed later.
Water as solvent. Why is water important toward an

understanding of drug action? It is the universal solvent, delivery
agent, dispersing agent, nucleophile, and primary source of H+ and
OH- in vivo. Therefore, water is not inert. It also is responsible for
certain aspects of protein structure (conformation), the formation and
structure of the lipid bilayer and other important intra- and
extracellular domains, and other phenomena where H-bonding plays
a role. In the figure below, some basic properties of water are
illustrated: bond angles, charge distribution and H-bonding. The water molecule is not linear. Aggregates of
water form easily based upon hydrogen bonding. Ice takes on a tetrahedral geometry and although the
structure of ice does not play a significant role in vivo, the structure of water does vary depending on its
environment and local temperature. Packets of water exist in flux, a vibrating, rotating, rapidly reorganizing
environment.
Solubility (water as a solvent): In part, the flux adds to the "solvent" properties of water. Due to a high
dipole, water has a very high dielectric constant (Debeye = D = 80) as compared to the organic solvents
acetone (D = 21) or hexane (D = 1 to 2). [Note: highly polarized solvents favor "polarized" transition states.]
With a high dielectric constant, water is capable of breaking the electrostatic attraction of ions (crystal
lattices) to favor hydration. When the heat of solvation is favored over the energy stored in the stability of
the crystal lattice, the compound dissolves (e.g., NaCl). Recall that certain organic compounds forms "ions,"
for example, carboxylic acids (oxyanions) and amines (nitrogen cations). Charged species are generally
more soluble in water and neutral compounds.
For some neutral organic molecules a different physicochemical process is involved. As a result of
solvation, the structure of the water cluster also is altered to form an envelope or "breaker" in the structure.
Think of a microscopic droplet of oil surrounded by water (as represented by an organic compound). The
water exerts a solvation effect on the compound and the compound exerts a "disturbance" on the H-bonded
water environment. Such complexes between a solvated species and the water are called "clathrates."
Compare this phenomena to a truly ionic compound in solution that is fully ionized, H-bonded and
intermingled. Within this description, some organic molecules have an ionic character and fall somewhere
in between an "inclusion" complex and solvation. To effect a spectrum of solubility characteristics, we ask
the following question:
To what extent are organic molecules soluble in water? Consider the body as a huge separatory funnel, filled
with water (aqueous layer; e.g., serum) and fat (organic layer). Where will the drug go? Why is this
important? This question is important because all biochemistry processes are based upon small amounts of
organic molecules dispersed in the aqueous or lipid (organic) phase or both. Circulating fluids (blood) have
aqueous characteristics, but tissues (e.g., tissue membranes) and the cavities of certain proteins have an
organic environment.
Some trends for organic molecule solubility in water:

a. up to five carbons with one functional group are usually soluble,
b. molecule with branched chains are more soluble than linear chain
c. water solubility deceases with increase in molecular weight
Some nomenclature used to describe solubility that you should be familiar with:
o Hydrophobic (a.k.a lipophilic); fat phase loving, aqueous phase hating

o Hydrophilic; aqueous phase loving, fat phase hating
o Amphiphilic; has atomic characteristics to permit solubility in both phases
Solvent-solute interactions:
As a general rule: like dissolves like so polar solvents dissolve polar solutes and non-polar solvents dissolve
non-polar solutes.
Polar solvents
• Polar solvents (e.g. water, methanol) readily dissolve polar solutes such as salts (ionic compounds), sugars
and other polyhydroxy compounds. Water can also dissolve (to some extent) other O- and N-containing
compounds including alcohols, amines, ketones, aldehydes, phenols. These compounds contain polar groups
which can hydrogen bond with water. Water can also dissolve the salt (ionic) forms of weak acids and weak
bases (the conjugate base and conjugate acid forms of weak acids and weak bases). Water is miscible with
other liquids such as ethanol and methanol meaning that they can be mixed in any (unlimited) proportion to
form a homogeneous liquid.
Non-polar solvents:
• Ionic and polar solutes are poorly or not soluble in non-polar solvents because the solvent cannot reduce
the attractive forces between the solute molecules (ionic or dipolar or hydrogen bonding).
• Non-polar solvents can dissolve non-polar solutes through induced dipolar interactions (non-polar solutes
are held together weakly unlike polar solutes)
acetone = ketone solvent.
Solubility Terms:
THINGS TO NOTE IN TABLE 6.2.
• “Alcohol” is synonymous
with ethanol.
• The salt of a drug is more

soluble in water than in
ethanol
• The “neutral” form of a

drug is usually more
soluble in ethanol than in
water.
Lipid vs. aqueous solubility: Drug substances must exhibit some degree of both lipid and aqueous
solubility. Lipid solubility for crossing biological membranes and aqueous solubility for distribution into
the systemic circulation and other biological fluids. Substances that are relatively insoluble in water may
exhibit poor
absorption
characteristics such as
erratic or incomplete
absorption. The
graph below shows
the correlation
between lipid/aqueous
solubility (log P, we’ll
get to this later) and
drug effect.
Modification of aqueous solubility:
• salt formation or structural modification

• adjust pH if a liquid formulation
• use co-solvent
• complexation
Rate of solution: While solubility is constant at a given temperature and pressure, rate of solution can vary
depending on the particle size of the solute and the agitation rate of the solution.
pH, pKa and solubility: Solubility is influenced by the degree of ionization of the substance. Total aqueous
solubility of an ionizable substance can be expressed as:
ST = [HA] + [A-] for a weak acid

S = [B] + [BH+]
T for a weak base
or ST = SHA + [A-] for a weak acid
S = S + [BH+]
T T for a weak base
where ST is the total solubility and SHA and SB are the solubilities of the unionized weak acid or
weak base.
For a non-ionizable substance, a non-electrolyte:
ST = SNE
For a weak acid, the following equation can be derived:
ST = SHA + KaSHA
[H3O+]
which indicates that solubility of a weak acid increases with increasing pH (decreasing H3O+ concentration):
so as ↑ pH then ↓HA, ↑A-, and ↑ST
Correlation with Henderson Hasselbalch: Maximum aqueous solubility for weak acids is attained at pH-pKa
» 2, where 99% is in the ionized (A-) form. Minimum solubility is at pH-pKa » -2 where 99% is in the
unionized (HA) form.
The logarithmic form can be used to predict the pH (pHp) below which the unionized weak acid would
precipitate from solution:
pHp = pKa + log ST-SHA

SHA
For a weak base, the following equation can be derived:
ST = SB + [H3O+]SB
Ka
which indicates that solubility of a weak base increases with decreasing pH (increasing H3O+
concentration):
as the ↓ pH then the ↓B, ↑BH+, and ↑ST
Maximum aqueous solubility for weak bases is attained at pH-pKa » -2, where 99% is in the ionized (BH+)
form. Minimum solubility is at pH- pKa » 2 where 99% is in the unionized (B) form.
The logarithmic form can be used to predict the pH (pHp)above which the weak base would precipitate
from solution:
pHp = pKa + log SB

ST-SB
Solubility of weak acids and weak bases in buffers vs. water:
• The solubilities of a weak acid and its conjugate base are identical in a buffer solution. The pH of the
buffer solution determines the B/A ratio and the solubility will be the same for either form (weak acid
or conjugate base). The same is true for a weak base and its conjugate acid.
• The solubilities of a weak acid and its conjugate base are different in water. Addition of the weak acid
makes the water acidic so there is more of the unionized weak acid form present and solubility is low.
Addition of the conjugate base makes the water basic so there is more of the ionized form present and
solubility is high.
• The solubilities of a weak base and its conjugate acid are also different in water for a similar reason.
Addition of the weak base makes the water basic so there is more of the unionized weak base form
present and solubility is low. Addition of the conjugate acid makes the water acidic so there is more of
the ionized form present and solubility is high.
PARTITION COEFFICIENTS
Distribution/partition coefficients: In order to produce a biological response, a drug molecule must cross a
mostly lipid biological membrane. Its ability to do this depends on its lipophilicity/hydrophilicity balance
and, if ionizable, its degree of ionization.
Distribution coefficients: The partition coefficient (P, K) is also known as the distribution coefficient or
distribution ratio. Higher P or K values indicate higher lipid solubility relative to aqueous solubility. The
true distribution coefficient (K) is the concentration of a substance in an oil phase ([HA]O), such as octanol,
divided by the concentration of unionized substance (e.g. weak acid or weak base) in the aqueous phase
([HA]W):
K = [HA]O
[HA]W
Since substances do not ionize significantly in the oil phase:
[HA]O = CO (where CO is the total concentration in the oil phase). The expression can then be written:
K = CO
[HA]W
The apparent distribution coefficient (K’) is the experimentally observed ratio, and it includes the
ionized fraction of the substance in the water phase.
K’ = [CO]
-
[HA]W + [ A ]W
The total concentration in the aqueous phase (CW) is:
CW = [HA]W + [A-]W
so the apparent distribution coefficient can be expressed:
K’ = CO/CW
Degree of ionization: The degree of ionization is the fraction ionized (α) in solution and is equal to:
α = [A-]W
[HA]W + [A-]W
The degree of ionization depends on the pH of the aqueous phase and the pKa of the substance. The
fraction unionized (1-α) is equal to:
1- α = [HA]W
[HA]W+[A-]W
The true distribution coefficient for non-ionizable substances may be expressed:
K = Co/CW (since K and K’ are the same for non-ionizable substances)

DISSOLUTION
The dissolution rate is the time required for a drug substance to dissolve in the fluids at the absorption site.
Dissolution rate is often the rate-limiting step in the absorption process and can control the overall
bioavailability of the drug from the dosage form. Dissolution is important for the bioavailability of solid
dosage forms including oral capsules, tablets and suspensions and intramuscular suspensions.
Methods for increasing dissolution rates:
• Decrease particle size. This increases the available surface area to the dissolving fluid. [Note: In rare
cases, agglomeration of the particles may occur leading to decreased dissolution rates.]
• Increase solubility in the diffusion layer. The ionized form of the drug (salt of the weak acid or salt of the
weak base) will have greater solubility in the diffusion layer than the unionized weak acid or weak base.
(e.g. penicillin V potassium will dissolve faster than penicillin V itself).
• Alter pH of dissolution medium (e.g. buffered aspirin).
• Increase agitation of dissolution medium (e.g. effervescent, buffered aspirin).
Noyes-Whitney equation: The Noyes-Whitney equation shows how factors such as solubility and surface
area can affect dissolution rate:
dM = DS(CS-C)
dt h
where:
dM/dt = the dissolution rate
D = the diffusion coefficient of the solute in the solution
S = the surface area of the exposed solid
h = the thickness of the diffusion layer
CS = the concentration of the drug in the diffusion layer (solubility of the drug since diffusion layer is
assumed to be saturated)
C = the drug concentration in the bulk solution at time t.
Dissolution is therefore driven by surface area (S) and the concentration gradient (CS-C).
Dissolution Equations, Calculations and Relationships - A Brief Survey.
In 1897, Noyes and Whitney described the quantitative analysis that correlated the amount of time it took to
dissolve a drug from solid particles. The current version of the equation is slightly modified from the
original but remains based on a diffusion layer model of dissolution (Scheme 1) of drug from a particle into
a large excess bulk medium.
Noyes-Whitney Equation:
The rate of dissolution (dM/dt)….
dM = DS(CS-Cb)
dt h
where:
M = amount of drug (material) dissolved (usually mg or mmol)

t = time (seconds)
D = diffusion coefficient of the drug (cm2/s)
S = surface area (cm2)
H = thickness of the liquid film
Cs & Cb = concentrations of the drug at the surface of the particle (surface = Cs) and the bulk
medium (bulk medium = Cb)
Drug
Diffusion Layer Bulk Solution
Particle
Cs
Cb
Scheme 1. Dissolution of drug particles according to diffusion layer model.

Problem 1: Calculate the dissolution rate of a hydrophobic drug having the following physicochemical
characteristics:
surface area = 2.5 x 103 cm2
saturated solubility = 0.35 mg/mL (at room temperature)
diffusion coefficient = 1.75 x 10-7 cm2/s
thickness of diffusion layer = 1.25 µm
[Note: need to convert to cm, so 1 µm = 1 x 10-4 cm and 1.25 x 10-4 cm]
conc of drug in bulk = 2.1 x 10-4 mg/mL
dM = DS(CS-Cb)
dt h
dM = (1.75 x 10-7)(2.5 x 103)( 0.35 mg/mL - 2.1 x 10-4 mg/mL)

dt 1.25 x 10-4
dM = (1.75 x 10-7)(2.5 x 103)( 0.349 mg/mL)

dt 1.25 x 10-4
dM = (1.75 x 10-7)(2.5 x 103)( 0.35 mg/mL - 2.1 x 10-4 mg/mL)

dt 1.25 x 10-4
dM = 1.53 x 10-4 = 1.22 mg/sec

-4
dt 1.25 x 10
NOTE!!!! The concentration in bulk solution is generally much lower than the saturated solubility. See for
example above, (0.35mg/mL – 0.00021 mg/mL), and the Cb term can sometimes be ignored.
Problem 2: What would the rate of dissolution be in Problem 1 if the surface area was increased to 4.3 x 104
cm2?
Answer: 4.3 x 104 cm2 is a 17.2-fold increase over the prior surface area (2.5 x 103 cm2). Therefore,
multiply the rate 1.22 mg/sec x 17.2 = 21 mg/sec (approx). Or you can recalculate the rate by substituting
all the values into the equation.
Diffusion - Through a Membrane:

A membrane is defined as a physical barrier that separates two or more regions. For our purposes, we
consider a cell membrane that is composed of phospholipids and proteins. Absorption of drugs across the
stomach lining/mucosa and the blood/brain barrier are two representative examples and important for
understanding drug transport into the circulation and CNS, respectively. Skin is another great example of a
membrane for the entry of drugs. The transport of drug molecules through a non-porous membrane occurs
by diffusion. Transport through porous membranes occurs by diffusion and convection (not covered here).
Similar to dissolution, the diffusion equation is…
dM = DAK(C1-C2)
dt h
M = amount of drug (material) dissolved (usually mg or mmol)

t = time (seconds)
D = diffusion coefficient of the drug (cm2/s)
A = surface area of membrane (cm2)
K = oil/water partition coefficient
h = thickness of the liquid film
C1 - C2 = concentration gradient where C1 is the concentration of drug at donor side of membrane
and C2 is the concentration of drug in the membrane at receptor side.
Cd
C1
donor compartment receptor compartment

(high drug conc) (low drug conc)
Cr
C2
Scheme 2. Diffusion model for Fick’s Law.

However, C1 and C2 are not measured since these are values within the membrane. Typically, the gradient is measured as Cd - Cr,
representing the partition at each phase, namely Ko/w = C1/Cd and Ko/w = C2/Cr. The Integrated Studies uses C1 and C2 where Cd
and Cr should be used, but it doesn’t really matter for the calculation so long as you know what the gradient is.
Notes: The rate of drug transport into diffusional system is predominantly dependent upon the magnitude of the
concentration gradient – the other parameters are constant.
Pharmaceutics 331 Exam 1 (February 2004)
Read each question carefully and for choice questions, circle only one answer. Relevant equations are
provided on page 4. Double check your calculations and write out all formulae used to answer a question.
Point value in parentheses. Good luck.
1. Alcohols are organic ‘analogs’ of water meaning they share the R-OH pKa
identical functional group (OH) but vary in one component, the
H-OH (water) 15.8
“switch” of an H for a Me, Et, etc. Explain in one or two statements, the
increasing trend in pKa values (table at right) for the alcohols (5). MeOH (methanol) 16.4
Et-OH (ethanol) 16.8
iPr-OH (isopropanol) 17.2
t-Bu-OH (tert-butanol) 18
Ph-OH 10
2. Phenols are aromatic analogs of alcohols, and their pKa values are dramatically lower than alcohols
(table above). If strong electron withdrawing substituents (e.g., nitro) were added to the phenyl ring of
phenol, the pKa value of the substituted phenol would:
INCREASE (LESS ACIDIC) / DECREASE (MORE ACIDIC). Choose one of the underlined words (4).
3. As the strength of a weak acid increases the (4):

(a) Ka increases
(b) [A-] increases
(c) [HA] increases
(d) answers (a) and (b)
(e) answers (b) and (c)
4. For a thiol-containing drug (weak acid donor), when the pH of the solution is adjusted to equal the pKa,
there will be (4):
(a) precipitation of the drug
(b) a greater amount of the ionized form of the drug
(c) an equal amount of ionized and ionized
(d) a greater amount of the unionized form of the drug
5. Tartaric acid is frequently used to react with an amine to form a “tartrate salt.” List three possible
advantages to using tartaric acid rather than a mineral acid (e.g., HCl, H2SO4, etc.) form amine salts. The
structure of tartaric acid is (6):
OH
HO2C
CO2H
OH
tartaric acid
6. Plausible reasons that buffers resist change in pH upon addition of acids or bases are (4):
(a) added acids and bases are too dilute to effect change
(a) the buffer anions (conjugate bases) are typically bigger and neutralize acids quickly
(b) added acid/base change the pH but the change is logarithmically related
(c) answers (a) and (b)
(d) answers (b) and (c)
7. Calculate the buffer capacity for a 0.3 M phosphoric acid/sodium phosphate buffer that has an initial pH
2.1 and changes to pH 2.2 upon the addition of 50 mmoles of NaOH (5).
8. Why is the molarity of the buffer system not found in the calculation of buffer capacity? Is it
unimportant (5)?
9. Three classifications of organic compounds are polar non-protic, polar protic and non polar (6).
(a) Which class is most likely to cross membranes? _____________________
(b) Which class is most likely to dissolve in saliva and serum? ___________________
(c) Do these “classifications” directly correlate with lipophilic/hydrophobic properties? Briefly
explain.
10. Deleted
11. An example of a chemical bond that uses the principle of dipole-dipole interaction is (4):
(a) covalent bonding
(b) hydrogen-bonding
(c) van der Waals bonding
(d) answers a and b
(e) answers b and c
12. The solubility of amine salts in aqueous systems is effected by the (4):
(a) temperature
(b) buffer/pH
(c) structure of the anion (e.g., Cl-, sulfate, maleate, etc.)
(d) all of the above
13. The unionized form of a drug (4):

(a) is less water soluble
(b) is less able to traverse membranes
(c) has a Ko/w > 1.
(d) answers (a) and (b)
(e) answers (a) and (c)
14. If sulfadiazine is sparingly soluble in water, sulfadiazine sodium is likely to be ____________ in water
(4):
(a) insoluble
(b) slightly soluble
(c) freely soluble
(d) sparingly soluble
15. The maximum aqueous solubility for weak acids is attained when (4):
(a) the pH value exceeds the pKa value by more than 2
(b) the pH = pKa
(c) the pH value is less than the pKa by more than 2
16. When 1.0 g of loratidine was added to a separatory funnel containing 50 mL of water and 50 mL of
octanol, it completely dissolved in the mixture. Analysis of the octanol solution showed a concentration of
loratidine = 16 mg/mL. Calculate the partition coefficient (K) for loratidine (5):
17. Calculate the dissolution rate of cimetidine having the physicochemical characteristics (6):
surface area = 2.5 x 104 cm2 saturated solubility = 0.60 mg/mL (at room temperature)
diffusion coefficient = 2.5 x 10-7 cm2/s thickness of diffusion layer = 1.25 µm (1.25 x 10-4 cm)
conc of drug in bulk = 2.1 x 10-4 mg/mL
18. If the drug is a weak acid and the pKa is more than the pH, the ionized species is more / less than 50%
(4).
19. Calculate the theoretical solubility S of morphine (S0 = 0.0005 M) at pH 3. (morphine pKa = 7.87;
Ka 1.35 x 10-8) (6):

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Pharmaceutics (Part I) – Spring 2005 Page 1

Prof. C. Thompson (SB 383; 243-4643; charles.thompson@umontana.edu

Helpful Hints (really).

Acids, bases, pH/pKa calculations and the Henderson Hasselbalch equation

Acids & bases

acid base buffer pH pKa ionization equilibria

• Restore understanding of fundamental acid-base ionization equilibria.

Definitions and descriptions:

Bases: A base is a substance that is capable of accepting a proton from an acid.

H2O + H2O H3O+ + OH-

The dissociation constant for water is Kw:

pKw is equal to the negative log of the dissociation constant of water:

pKw = -logKw = pH + pOH = 14

So, how do pH and pOH correlate? Some pH examples:

[H+] pH [OH-] pOH Kw pKw

1. For a 0.000001 M solution of hydroiodic acid (HI) what are:

ACID-BASE EQUILIBRIA AND IONIZATION OF ELECTROLYTES

Strong and weak acids:

HCl + H2O H3O+ + Cl-

In general, for a weak acid:

since water is constant @ 55 M

Trends to consider based on the Ka equation:

As acid strength increases (8):

For weak acids, the ionization in water is: HA H+ + A-

Ka = [H+][H+] = [H+]2 and [H+]2 = Ka[HA]

if you take the -log of each side:

B: + H2O BH+ + OH-

Ka and Kb are related: Ka x Kb = Kw = 1.0 x 10-14

pKa and pKb are also related: pKa + pKb = pKw = 14

Acetic acid: Ka = 1.75 x 10-5; Ka = 4.76

Salicylic acid: Ka = 1.06 x 10-3; Ka = 2.97

Phenobarbital: Ka = 3.9 x 10-8, pKa = 7.41

Compound pKa Compound pKa

sulfuric acid -9 RNH3+ (protonated primary amines) 10 to 11

Henderson-Hasselbalch Equation - Utility

From the equilibrium and Ka equation:

the following equation can be derived:

log Ka = log [A-]

logKa - log[H3O+] = log [A-]

log[H3O+] = - logKa + log [A-]

finally, in descriptive terms,

pH = pKa + log [conj base]

pH - pKa = log [conj base]

4 10,000/1 0.01 99.99 0.01 99.99

Salts of Weak Acids

Example of drug salt formation:

CO2H CO2 Na radiologic

Salts of Weak Bases

Meperidine hydrochloride Cl-

Lets examine the “organic” salts a little closer.

buffer buffer equation buffer capacity

• Restore understanding of buffer systems and establish importance for use.

Definitions and descriptions:

Common Examples of Weak Acid Buffer Systems.

Acetic acid Sodium acetate

Boric acid Sodium borate

Citric acid Sodium citrate

Phosphoric acid Potassium phosphate

Examples of Weak Acid Buffer System.

tris(hydroxymethyl)aminomethane tris(hydroxymethyl)aminomethane hydrochloride

The pH of some ‘well known’ liquids containing buffer systems:

Product pH (room temp)

Apple juice 3.7