36 | Pharmaceutics

stream, rather than propellant to draw the drug and powder carrier out of the
inhaler and into the patient’s respiratory tract.
For drug particles to penetrate to the lower respiratory tract, they must be
5 μm in diameter or smaller. Their large surface and small size generally gives
them poor flow properties.
Powder flow can be improved by creating uniform particles with a
spherical shape, granulation, mixing with excipients with good flow
properties, and use of flow enhancers (lubricants, glidants and antiadherents)
in the commercial production of tablets.

Definition
Granulation is a process used in the manufacture of tablets and
capsules in which drug and other excipient powders are prepared in
larger, spherical granules to improve their flow and the metering of the
solids into a tablet die. The optimal size of granules for this purpose is
between 500 and 800 μm.

Solubility and dissolution

Key Points

Water solubility of a drug is dependent on the intermolecular attractive interactions
between drug–drug, water–water and drug–water.

Water has strong attractive forces for other water molecules.

Drug molecules that have a formal electric charge or polarized covalent bonds can
form hydrogen bonds with water.

Dissolution rate is increased by higher surface area exposed to the solvent and
greater solubility of the drug.

Definitions

A molecular solution is a homogeneous mixture of the molecules of
one substance with another. This implies that the molecules of the
solute (dissolved substance) are interacting with the molecules of
the solvent and not with one another as might occur in crystals.

Dissolution is the process of solute molecules mixing with solvent
molecules and can be studied mathematically as a rate.

Solubility is the extent to which a drug dissolves in a given solvent
at a given temperature. Close attention to the factors that influence
drug solubility allows the pharmacist to prepare and maintain drug
solutions required for patient care.
 Intermolecular forces and the physical and pharmaceutical properties of drugs | 37

Melting point, solubility and dissolution rate

What is it that determines that one drug will form a molecular solution
and another a coarse dispersion?

Thermodynamics tell us that there are two major driving forces for any
reaction:
 disorder (entropy) S
 enthalpy (heat energy) H

Drug solutions are created by a combination of disorder and attractive
forces that occur when a solute mixes with a solvent.
When a drug moves from orderly interactions of molecules in a crystalline
solid to less orderly interactions with liquid solvent, the entropy term favors
formation of a solution. However, it is the enthalpy term, the favorable
energetics that some drugs derive from interacting with water molecules, that
makes them water soluble while others have no attraction for water
molecules and remain in the solid state.

DD C WW/ 2 DW

A solution begins with a drug solid, DD, in which the molecules of drug
are interacting with other drug molecules in the solid, and a solvent, in
this case water, in which molecules of water are interacting with other
molecules of water, WW.

To form a solution from these two separate entities, all molecules of drug
will need to move out of the solid and interact with molecules of solvent,
DW.

For a drug to be water soluble, it must replace the attractive interactions
with other drug molecules in its solid form with attractive interactions
with water molecules.

If DD and WW attractive forces predominate, the drug will form a coarse
dispersion.

Desirable DW interactions occur when water molecules can replace the
hydrogen bonding with other water molecules with hydrogen bonding
with polar groups on the drug molecule.

To provide the reader with perspective on the impact of attractive forces
on solubility of dissimilar drugs, Yalkowsky estimates that each 100˚C
increase in melting point above 25˚C (room temp) corresponds to at least
a 10-fold decrease in solubility (Table 2.6).
38 | Pharmaceutics

Table 2.6 Effect of melting point on drug solubility

Melting point Impact on drug solubility

>300°C Major factor

>200°C Probable factor

100–200°C Equivocal

<100°C Not a factor

Information from SH Yalkowsky (ed), Techniques of Solubilization of Drugs, New York:

Marcel Dekker, 1981.

Predicting water solubility from desirable drug–water interactions

Drug solutes that are able to form favorable interactions with water
molecules include polar solutes such as:

Nonelectrolytes with bonds in which the electrons are not equally shared
(OH, NH, SH)

Strong electrolytes (inorganic and drug salts) that carry a formal charge:
 The sodium and potassium salts of inorganic anions are all quite
water soluble as are the chloride and acetate salts of inorganic cations.
 Not all inorganic salts are water soluble. Magnesium, calcium and
aluminum carbonates, phosphates and hydroxides form suspensions
in water.
 The pharmacist must be alert to the fact that a combination of two
water soluble salts, calcium chloride and sodium carbonate, may
precipitate insoluble calcium carbonate.
 Preparation of a salt form of a drug (a strong electrolyte) creates a
species that dissociates readily from its counter ion to form attractive
interactions with water.

Weak electrolytes that ionize (become charged) incompletely:
 Drugs that are weak organic acids and bases donate or accept protons
incompletely in water.
 Ionization produces a formal charge on the molecule.
 Ionization is a reversible process that, if the pH or counter ion
concentration of the solution is altered, can result in formation of the
uncharged form of the drug and precipitation from solution.
 If we increase the extent of ionization using strong acid or base, the
water solubility of the drug molecule is enhanced considerably. (See
strong electrolytes above.)
 Not all salts of drug acids and bases are water soluble. Drug salts
formed by the reaction of a drug with another weak acid or base do
not dissociate appreciably and will have lower water solubility than
drugs salts formed with strong acid or base.
 Intermolecular forces and the physical and pharmaceutical properties of drugs | 39

Common ion effect on solubility

Hydrochloride and sodium salts of weak drug bases and acids may be
considered preferable to other ions because they are physiologically
abundant and would not be expected to cause adverse effects. However,
the abundance of these ions in the blood or gastrointestinal tract may
suppress the solubility of the drug they are intended to enhance through the
common ion effect. The common ion effect is the displacement of an ionic
equilibrium by the addition of more of one of the ions involved. Dissolution
of an ionic compound can be depicted as follows:

CAðsÞ % CC −
ðaqÞ CAðaqÞ

where C is the cation and A is the anion.

And the equilibrium expression for the dissolution would be:

½CC −
ðaqÞ ½AðaqÞ 
Keq ¼
CAðsÞ

If we were to add more of the anion, A−, the law of mass action tells us
that the equilibrium will be driven to the left or back towards the solid form.
For example, addition of chloride ion to an aqueous solution of terfenadine
hydrochloride will suppress its solubility by driving the solubility equilibrium
back towards terfenadine hydrochloride solid.

← Cl−ðaqÞ
−
R3 NHClðsÞ % R3 NHC
ðaqÞ C ClðaqÞ

Partitioning behavior of drug molecules: Log P

Definition
Log partition coefficient or log P is a parameter that estimates whether
a drug will prefer to interact with water or prefer to escape water and
interact with an immiscible organic solvent such as octanol. It is the
log of the drug concentration in the solvent divided by the drug
concentration in water.

Partition coefficient can be measured experimentally by dissolving a known

amount of drug in water, mixing the solution well with octanol and allowing
enough time for the mixture to reach equilibrium in partitioning between
the two layers. The drug concentration in the aqueous layer is quantified
40 | Pharmaceutics

and used to calculate the concentration in the octanol phase. The two
concentrations are expressed as a ratio:

½Drugo ½Drugo
P¼ and log P ¼ log
½Drugw ½Drugw

Pharmaceutical example
A log P of 2 indicates that there are 100 molecules of drug in octanol for every
1 molecule of drug in the water phase.

Key Points

Log partition coefficient is the log of the drug concentration in octanol divided by the
drug concentration in water.

Log P provides the pharmacist an appreciation of the drug's partitioning preference.
– A positive log P tells us that more drug has moved into octanol
– A negative log P tells us that the drug has partitioned more into water.

The log P of an ionizable drug is understood to be for the unionized form.

Log D is the partition coefficient for the combination of ionized and unionized forms
of a drug at a specified pH.

Using the United States Pharmacopoeia definition of water solubility (greater than
3.3% in water), compounds with a log P less than 0.5 are considered water soluble.

Compounds with a log P of 0.5 or greater are considered water insoluble. Although
log P is used in some instances to predict water solubility, its significance lies in its
ability to predict partitioning into biological membranes.

Measurement of solubility
The accurate prediction of water solubility from drug structure is the
pharmaceutical ‘holy grail’. While the practicing pharmacist has access to
water solubility data, it is at times unsatisfactory, using descriptive terms
rather than precise values and is not specific about the form of the drug to
which the solubility applies. However, equations that estimate water
solubility from a molecule’s structure are insufficiently accurate to replace
measurement techniques. Solubility is measured in the lab using excess solid
drug and a known volume of solvent at a specified temperature. The solvent
is allowed to interact with the drug solid until the number of molecules going
into solution is equal to the number returning to the solid state.
Sources of information on drug solubility are:

The Merck Index

The United States Pharmacopoeia
 Intermolecular forces and the physical and pharmaceutical properties of drugs | 41

Table 2.7 Solubility definitions

Descriptive terms Parts of solvent for 1 part of solute

Very soluble Less than 1

Freely soluble From 1 to 10

Soluble From 10 to 30

Sparingly soluble From 30 to 100

Slightly soluble From 100 to 1000

Very slightly soluble From 1000 to 10 000

Practically insoluble, or insoluble More than 10 000

From L Felton (ed.) Remington: Essentials of Pharmaceutics. Pharmaceutical Press, London, 2012, reproduced
with permission.

Martindale’s Extra Pharmacopoeia

AHFS Drug Information

DrugBank (http://www.drugbank.ca/), a database provided by David
Wishart at the University of Alberta

ChemIDplus (http://chem.sis.nlm.nih.gov/chemidplus/) from the United
States National Library of Medicine

PubChem Compound (http://pubchem.ncbi.nlm.nih.gov/) from the
United States National Library of Medicine.

Methods of expressing solubility

When searching for solubility information on older drug compounds, the
pharmacist will encounter descriptive terms. The meaning of the descriptive
terms used for the expression of solubility is presented in Table 2.7.

Key Point

Although the concentrations of most drugs are expressed using weight in specified
milliliters of solution, the solubility of most drugs is expressed using weight in
specified milliliters of solvent.

Dissolution of solids
Dosage forms that present the drug in solid form such as tablets and capsules,
or incompletely dissolved form such as suspensions must dissolve to release
drug for absorption. An important parameter for understanding how quickly
a drug will be available for absorption is the intrinsic dissolution rate,
the amount of a drug that dissolves per unit time and unit surface area.
42 | Pharmaceutics

Stagnant film h
with concentration = Cs

Crystal

Bulk solution with

concentration = Ct

Figure 2.6 Dissolving particle

Measurement of intrinsic dissolution rate requires the use of a nondisinte-

grating disc that exposes a known surface of drug to the dissolution medium.
Drugs with water solubility less than 0.01 mg/mL typically will demonstrate
dissolution rate limited absorption. Rapid dissolution for a dosage form is
defined as ≥85% of the amount of drug in the dosage form dissolved within
30 minutes in a volume of ≤900 mL dissolution medium at 37˚C.
To understand the relationship of dissolution and drug solubility, consider
the following mathematical description of dissolution rate. If we have a
spherical particle dissolving in a bulk medium, the rate of transfer of mass
from the particle to the dissolution medium can be described by the Noyes
Whitney equation (Figure 2.6):
dm DAðCs − Ct Þ
Dissolution rate ¼ ¼
dt h
where D is the diffusion coefficient of drug in dissolution medium; A is the
area exposed to solvent; Cs − Ct is the saturation solubility of the drug minus
the concentration in the bulk medium – in other words, the concentration
gradient; and h is the the width of the boundary layer around the dissolving
particle.
In the body, the drug is rapidly carried away from the dissolving particle,
making the concentration of drug in the bulk body fluids close to zero. The
Noyes Whitney equation is often simplified to:
dm DACs
¼
dt h
If these different variables affect how fast a drug gets into the blood stream
(dissolution rate limited absorption) then we are interested as pharmacists in
how we might affect these parameters.
Intermolecular forces and the physical and pharmaceutical properties of drugs | 43

Questions and cases

1. Ionic compounds would be expected to have:
(a) High melting points due to strong attractive forces between ions
(b) Low melting points due to strong attractive forces between ions
(c) High melting points due to weak attractive forces between ions
(d) Low melting points due to weak attractive forces between ions
2. A polymorph describes:
(a) A solid with solvent molecules incorporated in its crystalline structure
(b) A solid that takes up water from the environment
(c) A solid that forms distinct orderly arrangements between molecules
(d) A solid that sorbs water vapor from the environment and gradually forms a
solution
3. A hygroscopic solid refers to:
(a) A solid with solvent molecules incorporated in its crystalline structure
(b) A solid that takes up water from the environment
(c) A solid that forms distinct orderly arrangements between molecules
(d) A solid that sorbs water vapor from the environment and gradually forms a
solution
4. The melting points (mp) of three beta agonist homologues are given below:
OH
H
HO N
C(CH3)3

OH
Terbutaline mp 119-122°C
OH
H
HO N CH3

CH3

OH
Metaproterenol mp 100°C
44 | Pharmaceutics

OH
H
HO N CH3

CH3
HO

Isoproterenol mp 155.5°C

What is their expected order of solubility in water, from highest to lowest?

(a) terbutaline > metaproterenol > isoproterenol
(b) metaproterenol > terbutaline > isoproterenol
(c) isoproterenol > metaproterenol > terbutaline
(d) isoproterenol> terbutaline > metaproterenol
5. Reduction of the particle size of a drug enhances:
(a) Drug stability
(b) Drug dissolution rate
(c) Powder flow
(d) Particle segregation
6. A pharmacist purchased a bottle of procaine hydrochloride crystal. Which of the
following describe this solid?
(a) Poor solubility due to disorderly arrangement of molecules within the solid
(b) Good solubility due to disorderly arrangement of molecules within the solid
(c) Slow dissolution due to orderly arrangement of molecules within the solid
(d) Rapid dissolution due to orderly arrangement of molecules within the solid
7. The pharmacist prepares a capsule dosage form with the procaine hydrochloride
crystal. Which of the following may enhance the absorption rate from this dosage
form?
(a) Milling
(b) Use of diffusive mixing
(c) Granulation
(d) Use of shear mixing
8. The pharmacist would like to enhance flow of a drug powder. Which of the
following particles would demonstrate the best flow?
(a) A large spherical shaped solid
(b) A small rod-shaped solid
(c) A large needle shaped solid
(d) A small cylindrical shaped solid
9. A hydrophobic drug with some attraction for alcohol molecules would
demonstrate which of the following?
(a) A contact angle greater than 90°
(b) Complete wetting
(c) A contact angle of 0°
(d) Partial spreading on the solid surface
Intermolecular forces and the physical and pharmaceutical properties of drugs | 45

10. Drug derivatives are:

(a) Different arrangements of drug molecules within a crystal
(b) A drug molecule that has been chemically altered to change its physical
properties
(c) A drug molecule that interacts with water molecules in its crystal
(d) A drug molecule that hydrogen bonds with a conformer within a crystal
11. You are looking in a catalog to buy sodium phosphate monobasic for
compounding. It is available as a powder and a granular form. Which of the
following characteristics describes the granular form?
(a) Greater surface area, poor wettability, better flow
(b) Greater surface area, smaller surface energy, poorer flow
(c) Greater surface area, faster dissolution, tendency to aggregate
(d) Smaller surface area, faster dissolution, better flow
(e) Smaller surface area, slower dissolution, better flow
12. You have a patient who has a painful, sprained ankle. Which of the following advice
will hasten the dissolution of the ibuprofen in the tablet he has purchased?
CH3

CH3 COOH

H3C
Ibuprofen
(a) Take the tablet without water to increase its concentration at the
gastrointestinal membrane surface
(b) Take the tablet with food so it remains in the acidic environment of the
stomach longer
(c) Crush the tablet first and take with lots of water
(d) Take the tablet with acidic fluids so it is ionized as it dissolves
13. Warfarin is an anticoagulant drug used to treat deep venous thrombosis and other
cardiovascular thrombotic disorders. It has a narrow therapeutic index and must be
carefully dosed and monitored to prevent bleeding. The first available warfarin
product was Coumadin, the crystalline sodium salt of warfarin. In 1980, a generic
version of the drug was introduced that was amorphous warfarin sodium. How
might these two forms of warfarin be different? Would you observe a difference in
the extent of warfarin solubility, the rate of warfarin dissolution or both? What
effect might these differences have on patients who were switched from Coumadin
to generic warfarin?
14. Search through catalogs and the web to find compounds that can serve as
desiccants for your hygroscopic or deliquescent drug powders. List the names of
these compounds. What do they have in common? Make a plan for how you will
know that it is time to replace your desiccant in your desiccant containers used to
protect drug powders.
46 | Pharmaceutics

Selected reading
1. SR Vippagunta, HG Brittain, DJW Grant (2001). Crystalline solids. Adv Drug Del Rev 48:
3–26.
2. NR Goud, S Gangavaram, K Suresh, et al. Novel furosemide cocrystals and selection of high
solubility drug forms. J Pharm Sci 2012; 101: 664–680.
3. H Nakamura, Y Yanagihara, H Sekiguchi, et al. Effect of mixing method on the mixing
degree during the preparation of triturations. J Pharm Soc Japan. 2004; 124: 127–134.
4. H Nakamura, Y Yanagihara, H Sekiguchi, et al. Effect of particle size on mixing degree in
dispensation. J Pharm Soc Japan 2004; 124: 135–139.
5. AW Newman, SM Reutzel-Edens, G Zografi. Characterization of the “hygroscopic”
properties of active pharmaceutical ingredients, J Pharm Sci 2007, 97: 1047–1059.
6. Chapter <786> Particle size distribution estimation by analytical sieving, United States
Pharmacopeia, 34. USP Convention, Rockville, MD, 2011.
7. RD Odegard, Minimizing the probability of out-of-specification preparations: results that
make you say … hmmm! Int J Pharm Compounding 2008; 12: 130–135.