[Link].

A. The finished dosage form contains the active drug ingredient in association
with nondrug (usually inert) ingredients (excipients) that make up the vehicle, or
formulation matrix.

II. INTERMOLECULAR FORCES OF ATTRACTION

A. Introduction. The application of pharmaceutical principles to drug dosage
forms is illustrated when drug dosage forms are categorized according to their
Physical state,
Degree of heterogeneity,
Chemical composition.
The usual relevant states of matter are gases, liquids, and solids. Intermolecular
forces of attraction are weakest in gases and strongest in solids.
Conversions from one physical state to another can involve simply overcoming
intermolecular forces of attraction by adding energy (heat). Chemical
composition can have a dramatic effect on physicochemical properties and
behavior. For this reason, it is necessary to distinguish between polymers, or
macromolecules, and more conventional (i.e., smaller) molecules, or
micromolecules.
B. Intermolecular forces of attraction.
Because atoms vary in their electronegativity, electron sharing between different
atoms is likely to be unequal. This asymmetric electron distribution causes a
shift in the overall electron cloud in the molecule. As a result, the molecule
tends to behave as a dipole (i.e., as if it had a positive and a negative pole). The
dipole associated with each covalent bond has a corresponding dipole moment .
defined as the product of the distance of charge separation (d) and the charge
(q): q _ d
The molecular dipole moment may be viewed as the vector sum of the individual bond
moments.

1. Non polar molecules that have perfect symmetry (e.g., carbon tetrachloride)
have dipole moments of zero

2. Polar molecules are asymmetric and have non zero dipole moments.

3. When dipolar molecules approach one another close enough—“positive to

positive” or “negative to negative”—so that their electron clouds interpenetrate,
intermolecular repulsive forces arise. When these dipolar molecules approach one
another so that the positive pole of one is close to the negative pole of the other,
molecular attraction occurs (dipole–dipole interaction). When the identically
charged poles of the two molecules are closer, repulsion occurs.
 C. Types of intermolecular forces of attraction

1. Nonpolar molecules do not have permanent dipoles. However, the

instantaneous electron distribution in a molecule can be asymmetric. The resultant
transient dipole moment can induce a dipole in an adjacent molecule. This induced
dipole-induced dipole interaction (London dispersion force), with a force of 0.5
to 1 kcal/mol, is sufficient to facilitate order in a molecular array. These
relatively weak electrostatic forces are responsible for the liquefaction of non
polar gases.

2. The transient dipole induced by a permanent dipole, or dipole-induced

dipole interaction (Debye induction force), is a stronger interaction, with a force
of 1 to 3 kcal/mol.

3. Permanent dipole interactions (Keesom orientation forces), with a force of

1 to 7 kcal/mol, together with Debye and London forces, constitute van der Waals
forces. Collectively, they are responsible for the more substantive structure and
molecular ordering found in liquids.

4. Hydrogen bonds. Because they are small and have a large electrostatic
field, hydrogen atoms can approach highly electronegative atoms (e.g., fluorine,
oxygen, nitrogen, chlorine, sulfur) and interact electro statically to form a
hydrogen bond. Depending on the electronegativity of the second atom and the
molecular environment in which hydrogen bonding occurs, hydrogen bond energy
varies from approximately 1 to 8 kcal/mol.

5. Ion–ion, ion–dipole, and ion-induced dipole forces.

Positive–negative ion interactions in the solid state involve forces of 100 to 200
kcal/mol. Ionic interactions are reduced considerably in liquid systems in the presence of
other electrolytes. Ion–dipole interaction, or dipole induction by an ion, can also aff ect
molecular aggregation, or ordering, in a system.

III. STATES OF MATTER

A. Gases.
Molecules in the gaseous state can be pictured as moving along straight paths, in all
directions and at high velocities (e.g., mean velocity for H2O vapor: 587 m/sec; for
O2: 440 m/sec), until they collide with other molecules. As a result of these random
collisions, molecular velocities and paths change, and the molecules continue to collide
with other molecules and with the boundaries of the system (e.g., the walls of a
container holding the gas). This process, repeated incessantly, is responsible for the
pressure exhibited within the confines of the system.
1. The interrelation among volume (V), pressure (P), and the absolute temperature (T)
is given by the ideal gas law, which is the equation of state for an ideal gas:
PV _ nRT
PV _ (g/M)RT
where n is the number of moles of gas—equivalent to the number of grams (g) of gas
divided by he molecular weight of the gas (M)—and R is the molar gas constant
(0.08205 L atm/mole deg).

2. Pharmaceutical gases include the anesthetic gases (e.g., nitrous oxide, halothane).
Compressed gases include oxygen (for therapy), nitrogen, and carbon dioxide.
Liquefiable gases, including certain halo hydrocarbons and hydrocarbons, are used as
propellants in aerosol products (pressurized packaging), as are compressed gases, such
as nitrous oxide, nitrogen, and carbon dioxide. Ethylene oxide is a gas used to sterilize
or disinfect heat-labile objects.
3. In general, as the temperature of a substance increases, its heat content, or enthalpy,
increases as well.
a. Substances can undergo a change of state, or phase change, from the solid to the liquid
state (melting) or from the liquid to the gaseous state (vaporization).

b. Volatile liquids (e.g., ether, halothane, methoxy flurane) are used as inhalation
anesthetics. Amyl nitrite is a volatile liquid that is inhaled for its vasodilating effect in
acute angina.
c. Sublimation occurs when a solid is heated directly to the gaseous, or vapor, state
without passing through the liquid state (e.g., camphor, iodine). Ice sublimes at
pressures below 3 torr. The process of freeze-drying, or lyophilization, is a form of
vacuum drying in which water is removed by sublimation from the frozen product. It
is an especially useful process for drying aqueous solutions or dispersions of heat- or
oxygen-sensitive drugs and biological (e.g., proteins, peptides).

d. The reverse process (i.e., direct transition from the vapor state to the solid state) is also
referred to as sublimation, but the preferred term is deposition. Some forms of sulfur and
colloidal silicon dioxide are prepared in this way.

4. The intermolecular forces of attraction in gases are virtually nonexistent at room

temperature. Gases display little or no ordering.

B. Liquids
The intermolecular forces of attraction in liquids (van der Waals forces) are sufficient to
impose some ordering, or regular arrangement, among the molecules. Hydrogen bonding
increases the likelihood of cohesion in liquids and further affects their physicochemical
behavior. However, these forces are much weaker than covalent or ionic forces.
Therefore, liquids tend to display short range rather than long-range order.
Hypothetically, although molecules of a liquid would tend to aggregate in localized
clusters, no defined structuring would be evident.

1. Surface and interfacial tension

a. Molecules in the bulk phase of a liquid are surrounded by other molecules of the same
kind Molecules at the surface of a liquid are not completely surrounded by like molecules
As a result, molecules at or near the surface of a liquid experience a net inward pull from
molecules in the interior of the liquid. Because of this net inward intermolecular attraction,
the liquid surface tends to spontaneously contract. Thus, liquids tend to assume a spherical
shape (i.e., a volume with the minimum surface area). This configuration has the least
free energy.
b. Any expansion of the surface increases the free energy of the system. Thus, surface
free energy can be defined by the work required to increase the surface area A of the
liquid by 1 area unit. This value is expressed as the number of milli newtons (mN)
needed to expand a 1-m2 surface by 1 unit: work A
where _A is the increase in surface area and is the surface tension, or surface free
energy ,in mN m_1—equivalent to centimeter-gram-second (CGS) units of dynes
cm_1. At 20°C, water has a surface tension of 72 mN m_1, whereas n-octanol has a
surface tension of 27 mNm_1. Thus more work must be expended to expand the surface
of water than to expand the surface of n-octanol (i.e., to proceed from a given volume of
bulk liquid to the corresponding volume of small droplets).
c. At the boundary, or interface, between two immiscible liquids that are in contact with
one another, the corresponding interfacial tension (i.e., free energy or work required to
expand the interfacial area) reflects the extent of the intermolecular forces of attraction and
repulsion at the interface. When the interface is between two liquids, substantial molecular
interaction occurs across the interface between the two phases. Th is interaction reduces
the imbalance in forces of attraction within each phase. The interfacial tension between n-
octanol and water is reduced to 8.5 mN m_1 from 72 mN m_1 (_ air/water). Th is
reduction indicates, in part, the interfacial interaction between n-octanol and water.

2. The flow of a liquid across a solid surface can be examined in terms of the velocity, or
rate of movement, of the liquid relative to the surface across which it flows. More insight
can be gained by visualizing the flow of liquid as involving the movement of numerous
parallel layers of liquid between an upper, movable plate and a lower, fixed plate (Figure
2-3). The application of a constant force (F) to the upper plate causes both this plate and
the uppermost layer of liquid in contact with it to move with a velocity _y/_x. Th e
interaction between the fixed bottom plate and the liquid layer closest to it prevents the
movement of the bottom layer of liquid. The velocity (v)of the remaining layers of liquid
between the two plates is proportional to their distance from the immovable plate (i.e.,
_y/_x). Th e velocity gradient leads to deformation of the liquid with time. This
deformation is the rate of shear, dv/dx, or D. Newton defi ned fl ow in terms of the ratio
of the force F applied to a plate of area A—shear stress (_)—divided by the velocity
gradient (D)induced by _:F _ A _ _ dv _dxor_ _ D _ _Th e proportionality constant _ is the
coefficient of viscosity. It indicates the resistance to fl ow of
adjacent layers of fluid. The reciprocal of _ is fluidity. Units of viscosity in the CGS
system are dynes cm_2s_1, or poise. In the SI system, the units are Newtons m_2s_1,
which corresponds to10 poise. The viscosity of water at 20°C is approximately 0.01 poise,
or 1 centipoises (cps), which corresponds to 1 mN m_2s_1 or 1 mPa _ s (milliPascal
second).
a. Substances that fl ow in accordance with the equation in III.B.2 (Newton’s law) are
known as Newtonian substances. Liquids that consist of simple molecules and
dilute dispersions tend to be Newtonian. For a Newtonian fl uid, a plot of shear
stress as a function of shear rate (a fl ow curve or rheogram) yields a straight line
with a slope of

b. Non-Newtonian substances do not obey Newton’s equation of fl ow. Th ese substances

tend to exhibit shear-dependent or time-dependent viscosity. In either case, viscosity is
more aptly termed apparent viscosity because Newton’s law is not strictly obeyed.
Heterogeneous liquids and solids are most likely non-Newtonian.
(1) Shear-dependent viscosity involves either an increase in apparent viscosity (i.e.,
shear thickening or dilatancy) (Figure 2-4, Curve 3) or a decrease in apparent viscosity
(i.e., shear thinning or pseudo plasticity) (Figure 2-4, Curve 2) with an increase in the
rate of shear. Shear thickening is displayed by suspensions that have a high solid content
of small, deflocculated particles. Shear thinning is displayed by polymer or macromolecule
solutions. Plastic, or Bingham body, behavior (Figure 2-4, Curve 4) is exemplified by
flocculated particles in concentrated suspensions that show no apparent response to
low-level stress. Flow begins only after a limiting yield stress (yield value) is exceeded.
(2) Time-dependent viscosity
(a) The yield value of plastic systems may be time dependent (i.e., may depend on the
time scale involved in the application of force). Thixotropic systems display shear
thinning behavior but do not immediately recover their higher apparent viscosity
when the rate of shear is lowered. In a thixotropic system, structural recovery is relatively
slow compared with structural breakdown.

(b) Thixotropy occurs with heterogeneous systems that involve a three-dimensional

structure or network. When such a system is at rest, it appears to have a relatively
rigid consistency. Under shear, the structure breaks down and fluidity increases
(i.e., gel–sol transformation).

(c) Rheopexy (negative thixotropy, or antithixotropy) occurs when the apparent

viscosity of the system continues to increase with continued application of shear up to
some equilibrium value at a given shear rate. Th ese systems display a sol–gel
transformation. One explanation for anti thixotropic behavior is that continued shear
increases the frequency of particle or macromolecule interactions and leads to increased
structure in the system.
C. Solids. Intermolecular forces of attraction are stronger in solids than in liquids or gases.
Molecular arrangements in solids may be characterized as either crystalline or amorphous.
1. Crystalline solids have the following attributes:
a. Fixed molecular order (i.e., molecules occupy set positions in a specific array)
b. A distinct melting point
c. Anisotropicity (i.e., their properties are not the same in all directions), with the
exception of cubic crystals
2. Amorphous solids have the following attributes:
a. Randomly arranged molecules with the short-range order typical of liquids
b. No melting points
c. Isotropicity (i.e., properties are the same in all directions)
d. Less thermodynamic stability than the corresponding crystalline solid and
therefore more apt to exhibit chemical and physical instability, increased dissolution rate,

3. Polymorphism is the condition wherein substances can exist in more than one
crystalline form. These polymorphs have different molecular arrangements or crystal
lattice structures. As a result, the different polymorphs of a drug solid can have different
properties. For example, the melting point, solubility, dissolution rate, density, and stability
can differ considerably among the polymorphic forms of a drug. Many drugs exhibit
polymorphic behavior. Fatty (triglyceride) excipients
(e.g., theobroma oil, cocoa butter) are recognized for their polymorphic behavior.

4. The incorporation of solvent molecules into the crystal lattice of a solid results in a
molecular adduct known as a solvate or hydrate (the latter term is used when water
is the solvent). In general, solvates or hydrates exhibit different solubilities and
dissolution rates than their unsolvated/ anhydrous counterparts.

5. Melting point and heat of fusion. Th e melting point of a solid is the temperature at
which the solid is transformed to a liquid. When 1 g of a solid is heated and melts, the heat
absorbed in the process is referred to as the latent heat of fusion.
D. Phase diagrams and phase equilibria. A phase diagram represents the states of
matter (i.e., solid, liquid, and gas) that exist as temperature and pressure are varied (Figure
2-5). Th e data arrays separating the phases in Figure 2-5 delineate the temperatures and
pressures at which the phases can coexist. Th us, gas (or vapor) and liquid coexist along
“curve” BC, solid and liquid coexist along “curve” AB, and solid and gas (or vapor) coexist
along “curve” DB. Depending on the change in temperature and pressure, evaporation or
condensation occur along curve BC, fusion or melting along curve AB, and sublimation
or deposition along curve DB. Th e three “curves” intersect at point B. Only at this unique
temperature and pressure, known as the triple point, do all three phases exist in
equilibrium. (Th e triple point for water is 0.01°C and 6.04 _ 10_3 atm) Continuing along
curve BC, to higher temperatures and pressures, one ultimately reaches point C, known
as the critical point, above which there is no distinction between the liquid and the gas
phases.
Substances that exist above this critical point are known as supercritical fluids.
Supercritical fluids such as carbon dioxide (critical point, 30.98°C and 73.8 atm) oft en
exhibit markedly altered physicochemical properties (e.g., density, diffusivity, or solubility
characteristics) that render them useful as solvents and processing aids in the production of
pharmaceuticals and drug delivery systems.

IV. PHYSICOCHEMICAL BEHAVIOR

A. Homogeneous systems
1. A solution is a homogeneous system in which a solute is molecularly dispersed, or
dissolved, in a solvent. The solvent is the predominant species. Saturated solutions are
solutions that, at a given temperature and pressure, contain the maximum amount of solute
that can be accommodated by the solvent. If the saturation, or solubility, limit is exceeded,
a fraction of the solute can separate from the solution and exist in equilibrium with it.
a. Solutes can be gases, liquids, or solids, and non electrolytes or electrolytes.

(1) Nonelectrolytes are substances that do not form ions when dissolved in water.
Examples are estradiol, glycerin, urea, and sucrose. Their aqueous solutions do not
conduct electric current.

(2) Electrolytes are substances that do form ions in solution. Examples are sodium
chloride, hydrochloric acid, and atropine. As a result, their aqueous solutions
conduct electric current. Electrolytes are characterized as strong or weak. Strong
electrolytes (e.g., sodium chloride, hydrochloric acid) are completely ionized in
water at all concentrations. Weak electrolytes (e.g., aspirin, atropine) are partially
ionized in water.

b. Th e colligative properties of a solution depend on the total number of ionic and

nonionic solute molecules in the solution. Th ese properties depend on ionization
but are independent of other chemical properties of the solute.

2. Colligative properties include the following:

a. Lowering of vapor pressure. The partial vapor pressure of each volatile component
in a solution is equal to the product of the mole fraction of the component in the solution
and the vapor pressure of the pure component. This is Raoult’s law:
PA _ PA 0 _ xA where PA is the partial vapor pressure above a solution in which the mole
fraction of the solute A is xA and PA 0 is the vapor pressure of the pure component A. Th
e vapor pressure is the pressure at which equilibrium is established between the molecules
of A in the liquid state and the molecules of A in the gaseous (vapor) state in a closed,
evacuated container. The vapor pressure is temperature dependent, but independent of the
amount of liquid and vapor.
Raoult’s law holds for ideal solutions of non electrolytes. For a binary solution (i.e., a
solution of component B in component A) PA 0 _ PA _ PA 0 _ (1 _ xA ) _ xB
The lowering of the vapor pressure of the solution relative to the vapor pressure of the pure
solvent is proportional to the number of molecules of solute in the solution. The actual
lowering of the vapor pressure by the solute, _pA, is given by _pA _ (PA 0 _ pA) _ xB
PA0

b. Elevation of the boiling point. Th e boiling point is the temperature at which the vapor
pressure of a liquid equals an external pressure of 760 mm Hg. A solution of a nonvolatile
solute has a higher boiling point than a pure solvent because the solute lowers the vapor
pressure of the solvent. Th e amount of elevation of the boiling point (_Tb) depends on the
concentration of the solute:
_Tb _ RT2 0 M1m __ 1000 _ _Hvap
_ Kbm where Kb is the molal boiling point elevation constant, R is the molar gas constant,
T is absolutetemperature (degrees K), M1 is the molecular weight of the solute, m is the
molality of the solution, and _Hvap is the molal enthalpy of vaporization of the solvent.

c. Depression of the freezing point. Th e freezing point, or melting point, of a pure

compound is the temperature at which the solid and the liquid phases are in
equilibrium under a pressure of 1 atmosphere (atm). Th e freezing point of a solution
is the temperature at which the solid phase of the pure solvent and the liquid phase
of the solution are in equilibrium under a pressure of 1 atm. Th e amount of
depression of the freezing point (_Tf) depends on the molality of the solution:_ T f
_R T 02 M 1 m__ 1000 _ _ H fusion _ K f m where Kf is the molal freezing point
constant and _Hfusion is the molal heat of fusion.

d. Osmotic pressure. Osmosis is the process by which solvent molecules pass through
a semi permeable membrane (a barrier through which only solvent molecules may
pass) from a region of dilute solution to one of more concentrated solution. Solvent
molecules transfer because of the inequality in chemical potential on the two sides of
the membrane. Solvent molecules in a concentrated solution have a lower chemical
potential than solvent molecules in a more dilute solution.

(1) Osmotic pressure is the pressure that must be applied to the solution to prevent the
flow of pure solvent into the concentrated solution.

(2) Solvent molecules move from a region where their escaping tendency is high to one
where their escaping tendency is low. Th e presence of dissolved solute lowers the
escaping tendency of the solvent in proportion to the solute concentration.

(3) Th e van’t Hoff equation defi nes the osmotic pressureas a function of the number of
moles of solute n2 in the solution of volume V: V _ n2RT
 3. Electrolyte solutions and ionic equilibria
a. Acid–base equilibria

(1) According to the Arrhenius dissociation theory, an acid is a substance that liberates H
in aqueous solution. A base is a substance that liberates hydroxyl ions (OH_) in aqueous
solution. Th is defi nition applies only under aqueous conditions.

(2) Th e Lowry–Brønsted theory is a more powerful concept that applies to aqueous and
nonaqueous systems. It is most commonly used for pharmaceutical and biologic systems
because these systems are primarily aqueous.

(a) According to this defi nition, an acid is a substance (charged or uncharged) that is
capable of donating a proton. A base is a substance (charged or uncharged) that is
capable of accepting a proton from an acid. Th e dissociation of an acid (HA) always
produces a base (A_) according to the following formula: HA ↔ H A_

(b) HA and A_ are a conjugate acid–base pair (an acid and a base that exist in
equilibriumand diff er in structure by a proton). Th e proton of an acid does not exist
free in solution, but combines with the solvent. In water, this hydrated proton is a
hydronium ion (H3O).

(c) The relative strengths of acids and bases are determined by their ability to
donate or accept protons. For example, in water, HCl donates a proton more
readily than does acetic acid. Thus HCl is a stronger acid. Acid strength is also
determined by the affinity of the solvent for protons. For example, HCl may dissociate
completely in liquid ammonia, but only very slightly in glacial acetic acid. Thus, HCl is a
strong acid in liquid ammonia and a weak acid in glacial acetic acid.

(3) The Lewis theory extends the acid–base concept to reactions that do not involve
protons. It defi nes an acid as a molecule or ion that accepts an electron pair from
another atom and a base as a substance that donates an electron pair to be shared with
another atom.

b. H_ concentration values are very small. Th erefore, they are expressed in exponential
notation as pH. Th e pH is the logarithm of the reciprocal of the H concentration
pH _ log ( 1 _[H]) where [H] is the molar concentration of H. Because the logarithm of a
reciprocal equals the negative logarithm of the number, this equation may be rewritten as
pH _ _log [H]
or
[H] _ 10_pH
Thus, the pH value may be defined as the negative logarithm of the [H] value. For
example, if the H concentration of a solution is 5 _ 10_6, the pH value may be calculated
as follows:
 pH _ _log (5 _ 10_6)
log 5 _ 0.699
log 10_6 _ _6.0
pH _ _(_6 0.699)
_ _(_5.301)
_ 5.301

c. As pH decreases, H_ concentration increases exponentially. When the pH decreases

from 6 to 5, the H concentration increases from 10_6 to 10_5, or 10 times its original
value. When the pH falls from 5 to 4.7, the H concentration increases from 1 _ 10_5 to 2 _
10_5, or double its initial value.

e. Dissociation constants. Ionization is the complete separation of the ions in a crystal

lattice when the salt is dissolved. Dissociation is the separation of ions in solution
when the ions are associated by interionic attraction.

(1) For weak electrolytes, dissociation is a reversible process. The equilibrium of this
process can be expressed by the law of mass action. Th is law states that the rate of
the chemical reaction is proportional to the product of the concentration of the
reacting substances, each raised to a power of the number of moles of the substance
in solution.

(2) For weak acids, dissociation in water is expressed as HA ↔ H A_

The dynamic equilibrium between the simultaneous forward and reverse reactions is
indicated by the arrows. By the law of mass action,
rate of forward reaction _ K1[HA]
rate of reverse reaction _ K2[H][A_]
At equilibrium, the forward and reverse rates are equal. Therefore,
K1[HA] _ K2[H][A_] Thus, the equilibrium expression for the dissociation of a weak
acid is written as K a _K 1_ K 2 _ [H][A_] _ [HA]
where Ka represents the acid dissociation constant. For a weak acid, the acid dissociation
constant is conventionally expressed as pKa, which is _log Ka. For example, the Ka of
acetic acid at 25°C is 1.75 _ 10_5. T e pKa is calculated as follows:
pKa _ _log (1.75 _ 10_5)
log 1.75 _ 0.243
log 10_5 _ _5
pH _ _(_5 0.243) _(_4.757)_ 4.76

(3) For weak bases, dissociation may also be expressed with the Ka expression for the
conjugate acid of the base. Th is acid is formed when a proton reacts with the base. For a
base that does not contain a hydroxyl group, BH ↔ H B
Th e dissociation constant for this reaction is expressed as
K a _ [H][B] _ [BH]
However, a base dissociation constant is traditionally defined for a weak base with this
expression:
B H2O ↔ OH_ BH
K b _ [OH_][BH] __ [B]
where Kb represents the dissociation constant of a weak base. Th is dissociation constant
can be expressed as pKb as follows: pKb _ _log Kb

(3) Certain compounds (acids or bases) can accept or donate more than one proton.
Consequently, they have more than one dissociation constant.

e. Henderson–Hasselbalch equations describe the relation between the ionized and the
un-ionized species of a weak electrolyte.

(1) For weak acids, the Henderson–Hasselbalch equation is obtained from the equilibrium
relation described in IV.A.3d.(2). pH _ p K a log [salt] _ [acid]
(2) Similarly, the Henderson–Hasselbalch equation for weak bases is as follows:
pH _ p K a log [B] _ [BH]
where B is the un-ionized weak base and BH is the protonated base.

f. Th e degree of ionization (_), the fraction of a weak electrolyte that is ionized in

solution, is calculated from the following equation:_ _ [I] _[I] [U]
where [I] and [U] represent the concentrations of the ionized and un-ionized species,
respectively.

The degree of ionization depends solely on the pH of the solution and the pKa of the
weak electrolyte. When pH _ pKa, the Henderson–Hasselbalch equations are for a weak
acid and a weak base, respectively:
pH _ p K a _ 0 _ log [A_] _ [HA]
thus
[A_] _ [HA] _ 1
pH _ p K a _ 0 _ log [B] _
[BH]
thus
[B] _
[BH]
_1

In eff ect, when the pH of the solution is numerically equivalent to the pKa of the weak
electrolyte,
whether a weak base or a weak acid, [I] _ [U] and the degree of ionization _ _ 0.5
(i.e., 50% of the solute is ionized).
g. Solubility of a weak electrolyte varies as a function of pH.
(1) For a weak acid, the total solubility Cs is given by the expression
Cs _ [HA] [A_] where [HA] is the intrinsic solubility of the un-ionized weak acid and is
denoted as C0, whereas [A_] is the concentration of its anion. Because [A_] can be
expressed in terms of C0 and the dissociation constant Ka, C s _ C 0 K a C 0 _ [H]
Thus, the solubility of a weak acid increases with increasing pH (i.e., with an increasing
degree of ionization, as the anion is more polar and therefore more water soluble than the
un-ionized weak acid).

(2) Similarly, for weak bases,

C s _ C 0 C 0 [H] _ Ka Thus, the solubility decreases with increasing pH because more
of the weak base is in the unprotonated form. Th is form is less polar and therefore less
water soluble.

h. Buff ers and buff er capacity

(1) A buff er is a mixture of salt with acid or base that resists changes in pH when small
quantities of acid or base are added. A buff er can be a combination of a weak acid and
its conjugate base (salt) or a combination of a weak base and its conjugate acid (salt).
However, buff er solutions are more commonly prepared from weak acids and their salts.
Th ey are not ordinarily prepared from weak bases and their salts because weak bases are
oft en unstable and volatile.

(a) For a weak acid and its salt, the following buff er equation is satisfactory for
calculations with a pH of 4 to 10. It is important in the preparation of buff ered
pharmaceutical solutions: pH _ p K a log [salt] _ [acid]

(b) For a weak base and its salt, the buff er equation is similar but also depends on the
dissociation constant of water (pKw). Th e equation becomes pH _ p K w _ p K b log
[base] _ [salt]

(2) Buff er action is the resistance to a change in pH.

(3) Buff er capacity is the ability of a buff er solution to resist changes in pH. The smaller
the pH change caused by addition of a given amount of acid or base, the greater the
buffer capacity of the solution.
(a) Buff er capacity is the number of gram equivalents of an acid or base that changes the
pH of 1 L of buff er solution by 1 U.

(b) Buff er capacity is aff ected by the concentration of the buff er constituents. A higher
concentration provides a greater acid or base reserve. Buff er capacity (_) is related to
total concentration (C) as follows: _ _ 2.3 C K a [H] __ ( K a [H] ) 2
where C represents the molar concentrations of the acid and the salt.
(c) Th us, buff er capacity depends on the value of the ratio of the salt to the acid form.
It increases as the ratio approaches unity. Maximum buff er capacity occurs when
pH _ pKa and is represented by _ 0.576C.

B. Heterogeneous (disperse) systems

1. Introduction

a. A suspension is a two-phase system that is composed of a solid material dispersed

in an oily or aqueous liquid. Th e particle size of the dispersed solid is usually
0.5_m.

b. An emulsion is a heterogeneous system that consists of at least one immiscible

liquid that is intimately dispersed in another in the form of droplets. The droplet
diameter usually exceeds 0.1 _m. Emulsions are inherently unstable because the
droplets of the dispersed liquid tend to coalesce to form large droplets until all of the
dispersed droplets have coalesced. The third component of the system is an
emulsifying agent. This agent prevents coalescence and maintains the integrity of
the individual droplets.

2. Dispersion stability. In an ideal dispersion, the dispersed particles do not interact. The
particles are uniform in size and undergo no change in position other than the random
movement that results from Brownian motion. In contrast, in a real dispersion, the
particles are not uniformly sized (i.e., they are not monodisperse). The particles are
subject to particulate aggregation, or clumping, and the dispersion becomes more
heterogeneous with time. The rate of settling (separating or creaming) of the dispersed
phase in the dispersion medium is a function of the particle size, dispersion phase
viscosity, and difference in density between the dispersed phase and the dispersion
medium, in accordance with Stokes’s law: sedimentation rate _d2g ( _ 1 _ _ 2 )_ 18 _
where d is the particle diameter, g is the acceleration owing to gravity, _ is the viscosity of
the dispersion medium, and (_1 _ _2) is the diff erence between the density of the particles
(_1) and the density of the dispersion medium (_2). Although Stokes’s law was derived to
determine the settling, or sedimentation, of noninteracting spherical particles, it also
provides guidance for determining the stabilization of dispersion:
a. Particle size should be as small as possible. Smaller particles yield slower
sedimentation, or flotation, rates.

b. High particulate (dispersed phase) concentrations increase the rate of particle–

particle collisions and interaction. As a result, particle aggregation occurs, and
instability increases as the aggregates behave as larger particles. In the case of
liquid–liquid dispersions, particle–particle collisions can lead to coalescence (i.e.,
larger particles) and decrease dispersion stability.
 c. Avoidance of particle–particle interactions

(1) Aggregation can be prevented if the particles have a similar electrical charge. Particles
in an aqueous system always have some electrical charge because of ionization of
chemical groups on the particle surface or adsorption of charged molecules or ions at the
interface. If the adsorbed species is an ionic surfactant (e.g., sodium lauryl sulfate), the
charge associated with the surfactant ion (e.g., lauryl sulfate anion) will accumulate at the
interface. However, if a relatively non–surface-active electrolyte is adsorbed, the sign of
the charge of the adsorbed ion is less readily predicted.

(2) The magnitude of the charge is the diff erence in electrical potential between the
charged surface of the particle and the bulk of the dispersion medium. Th is magnitude
is approximated by the electrokinetic, or zeta, potential (_). Th e zeta potential
is measured from the fi xed, avidly bound layers of ions and solvent molecules on the
particle surface. When _ is high (e.g., _ 25 mV), interparticulate repulsive forces exceed
the attractive forces. As a result, the dispersion is deflocculated and relatively
stable to collision and subsequent aggregation (fl occulation). When _ is so low that
interparticulate attractive forces predominate, loose particle aggregates, or flocs, form
(i.e., fl occulation occurs).

d. Density can be manipulated to decrease the rate of dispersion instability. Th e

settling rate decreases as (_1 _ _2) approaches zero. However, the density of the
dispersion medium usually cannot be altered suffi ciently to halt the settling (or fl
otation) process. In the dispersed phase, the density of solid particles is not readily
altered; altering the density of liquid particles would require the addition of a
miscible liquid of higher (or lower) density. Altering the composition of suspensions
is also problematic because most solid particles are denser than the dispersion
medium. Additives of higher (or lower) density might alter the biopharmaceutical
characteristics of the formulation (e.g., rate of drug release, residence time at the site
of administration, or absorption).

e. The sedimentation, or flotation, rate is inversely proportional to the viscosity. An

increase in the viscosity of the dispersion medium decreases the rate of settling, or
flotation. However, although the rate of destabilization can be slowed by an increase
in viscosity, it cannot be halted.

3. Emulsion stability. Coalescence occurs in emulsion systems when the liquid particles
of the dispersed phase merge to form larger particles. Coalescence is largely prevented by
the interfacial fi lm of surfactant around the droplets. Th is fi lm prevents direct contact of
the liquid phase of the droplets. Coalescence of droplets in oil in water (o/w) emulsions is
also inhibited by the electrostatic repulsion of similarly charged particles. Creaming is
the reversible separation of a layer of emulsifi ed particles. Because mixing or shaking
may be suffi cient to reconstitute the emulsion system, creaming is not necessarily
unacceptable. However, cracking, or irreversible phase separation, is never acceptable.
Phase inversion, or emulsion-type reversal, involves the reversion of an emulsion from an
o/w to water in oil (w/o) form, or vice versa. Phase inversion can change the consistency or
texture of the emulsion or cause further deterioration in
its stability.
V. CHEMICAL KINETICS AND DRUG STABILITY

A. Introduction. The stability of the active component of a drug is a major criterion

in the rational design and evaluation of drug dosage forms. Problems with stability
can determine whether a given formulation is accepted or rejected.
1. Extensive chemical degradation of the active ingredient can cause substantial loss
of active ingredient from the dosage form.

2. Chemical degradation can produce a toxic product that has undesirable side effects.

3. Instability of the drug product can cause decreased bioavailability. As a result, the
therapeutic efficacy of the dosage form may be substantially reduced.

B. Rates and orders of reactions

1. Th e rate of a reaction, or degradation rate, is the velocity with which the reaction
occurs. Th is rate is expressed as dC/dt (the change in concentration, or C, within a given
time interval, or dt).

a. Reaction rates depend on certain conditions (e.g., reactant concentration,

temperature, pH, presence of solvents or additives). Radiation and catalytic agents (e.g.,
polyvalent cations) also have an effect.

b. The effective study of reaction rates in the body requires application of

pharmacokinetic principles (see Chapter 5).
2. Th e order of a reaction is the way in which the concentration of the drug or reactant in
a chemical reaction affects the rate. The rate of a reaction, dC/dt, is proportional to the
concentration to the nth power, where n is the order of the reaction—that is,
dC _ dt _ Cn Th e study of reaction orders is a crucial aspect of pharmacokinetics (see
Chapter 5). Usually, pharmaceutical degradation can be treated as a zero-order, first-
order, or higher order reaction. The first two are summarized as follows:

a. In a zero-order reaction, the rate is independent of the concentration of the

reactants (i.e., dC/dt _ C0) (see Chapter 5). Other factors, such as absorption of
light in certain photochemical reactions, determine the rate.
(1) A zero-order reaction can be expressed as
C _ _k0t C0 where C is the drug concentration, k0 is the zero-order rate constant in units
of concentration/ time, t is the time, and C0 is the initial concentration.

(2) When this equation is plotted with C on the vertical axis (ordinate) against t on the
horizontal axis (abscissa), the slope of the line is equal to _k0 (Figure 2-6). Th e negative
sign indicates that the slope is decreasing.

b. In a fi rst-order reaction, the rate depends on the fi rst power of the

concentration of a single reactant (i.e., dC/dt _ C1).

(1) In a first-order reaction, drug concentration decreases exponentially with time, in

accordance with the equation C _ C0e_k1t where C is the concentration of the reacting
material, C0 is the initial concentration, k1 is the fi rst-order rate constant in units of
reciprocal time, and t is time. A plot of the logarithm of concentration against time
produces a straight line with a slope of _k/2.303

(2) The half-life (t½) of a reaction is the time required for the concentration of a drug to
decrease by one-half. For a fi rst-order reaction, half-life is expressed by
t ½ _ 0.693 _ k 1 Concentration (C) versus time (t) for a zero order reaction. The slope of
the line equals _k0. The slope of the line is not equal to the rate constant because it
includes the minus sign. . Logarithm of concentration (log C) versus
time (t) for a fi rst-order reaction. The slope of the line equals _k/2.303.

(3) Th e time required for a drug to degrade to 90% of its original concentration (t90%)
is also important. Th is time represents a reasonable limit of degradation for the active
ingredients. Th e t90% can be calculated as t 90% _ 2.303 _ k 1 log 100 _ 90 _ 0.105 _ k 1
(a) because k 1 _ 0.693 / t ½
(b) then t 90% _ 0.105 _ 0.693 / t ½ _ 0.152 _ t ½

(4) Both t½ and t90% are concentration independent. Th us, for t½, it takes the same
amount of time to reduce the concentration of the drug from 100 to 50 mM as it does
from 50 to 25 mM.

C. Factors that affect reaction rates. Factors other than concentration can aff ect the
reaction rate and stability of a drug. These factors include temperature, the presence of a
solvent, pH, and the presence of additives.
1. Temperature. An increase in temperature causes an increase in reaction rate, as
expressed in the equation first suggested by Arrhenius:
k _ A _ e_Ea/RT
or
log k _ log A _ ( Ea _2.303 _ 1 _RT )
where k is the specific reaction rate constant, A is a constant known as the frequency factor,
Ea is the energy of activation, R is the molar gas constant (1.987 cal/degree _ mole), and T
is theabsolute temperature.

a. The constants A and Ea are obtained by determining k at several temperatures and then
plotting log k against 1/T. The slope of the resulting line equals _Ea/(2.303 _ R). Th e
intercept on the vertical axis equals log A.
b. The activation energy (Ea) is the amount of energy required to put the molecules in an
activated state. Molecules must be activated to react. As temperature increases, more
molecules are activated, and the reaction rate increases.

2. Presence of solvent.
Many dosage forms require the incorporation of a water-miscible solvent— for example,
low-molecular-weight alcohols, such as the polyethylene glycols (PEGs)—to stabilize the
drug.
a. A change in the solvent system alters the transition state and the activity coeffi cients of
the reactant molecules. It can also cause simultaneous changes in physicochemical
parameters, such as pKa, surface tension, and viscosity. Th ese changes indirectly aff ect
the reaction rate.
b. In some cases, additional reaction pathways are generated. For example, with an
increasing concentration of ethanol in an aqueous solution, aspirin degrades by an extra
route and forms the ethyl ester of acetylsalicylic acid. However, a change in solvent can
also stabilize the drug.
Change in pH
4. . Th e magnitude of the rate of a hydrolytic reaction catalyzed by H and OH_ can
vary considerably with pH.
a. H_ catalysis predominates at lower pH, whereas OH_ catalysis operates at higher pH.
At intermediate pH, the rate may be pH independent or may be catalyzed by both H_
and OH_. Rate constants in the intermediate pH range are typically less than those at
higher or lower pH.

b. To determine the eff ect of pH on degradation kinetics, decomposition is measured at

several H concentrations. Th e pH of optimum stability can be determined by plotting the
logarithm of the rate constant (k) as a function of pH (Figure 2-8). Th e point of infl ection
of the plot is the pH of optimum stability. Th is value is useful in the development of a
stable drug formulation.
4. Presence of additives
a. Buffer salts must be added to many drug solutions to maintain the formulation at
optimum pH. Th ese salts can aff ect the rate of degradation, primarily as a result of salt
increasing the ionic strength.
(1) Increasing salt concentrations, particularly from polyelectrolytes (e.g., citrate,
phosphate), can substantially affect the magnitude of pKa. In this way, they change the
rate constant.
(2) Buff er salts can also promote drug degradation through general acid or base
catalysis.
b. The addition of surfactants may accelerate or decelerate drug degradation.

(1) Acceleration of degradation is common and is caused by micellar catalysis.

(2) Stabilization of a drug through the addition of a surfactant is less common.

c. Complexing agents can improve drug stability. Aromatic esters (e.g., benzocaine,
procaine, tetracaine) increase in half-life in the presence of caff eine. Th is increased
stability appears to result from the formation of a less reactive complex between the
aromatic ester and the caff eine.
D. Modes of pharmaceutical degradation. Th e decomposition of active ingredients in a
dosage formoccurs through several pathways (e.g., hydrolysis, oxidation, photolysis;
1. Hydrolysis is the most common type of degradation because many medicinal
compounds are esters, amides, or lactams.
a. H_ and OH_ are the most common catalysts of hydrolytic degradation in solution.

b. Esters usually undergo hydrolytic reactions that cause drug instability. Because esters
are rapidly degraded in aqueous solution, formulators are reluctant to incorporate drugs
that have ester functional groups into liquid dosage forms.

2. Oxidation is usually mediated through reaction with atmospheric oxygen under ambient
conditions (auto-oxidation).

a. Medicinal compounds that undergo auto-oxidation at room temperature are aff ected
by oxygen dissolved in the solvent and in the head space of their packages. Th ese
compounds should be packed in an inert atmosphere (e.g., nitrogen) to exclude air
from their containers.

b. Most oxidation reactions involve a free radical mechanism and a chain reaction.
Free radicals tend to take electrons from other compounds.

(1) Antioxidants in the formulation react with the free radicals by providing electrons and
easily available hydrogen atoms. In this way, they prevent the propagation of chain
reactions.
(2) Commonly used antioxidants include ascorbic acid, butylated hydroxyanisole (BHA),
butylated hydroxytoluene (BHT), propyl gallate, sodium bisulfi te, sodium sulfi te, and the
tocopherols.

3. Photolysis is the degradation of drug molecules by normal sunlight or room light.

a. Molecules may absorb the proper wavelength of light and acquire suffi cient
energy to undergo reaction. Usually, photolytic degradation occurs on exposure to
 light of wavelengths _ 400 nm. Semilogarithmic plot of the rate constant (k) versus
pH. This plot is used to determine the pH of optimum stability.

b. An amber glass bottle or an opaque container acts as a barrier to this light, thereby
preventing or retarding photolysis. For example, sodium nitroprusside in aqueous
solution has a shelf life of only 4 hrs if exposed to normal room light. When
protected from light, the solution is stable for at least 1 year.
Determination of shelf life.
D. The shelf life of a drug preparation is the amount of time that the product can be
stored before it becomes unfi t for use, through either chemical decomposition or
physical deterioration.
1. Storage temperature affects shelf life. It is generally understood to be ambient
temperature unless special storage conditions are specifi ed.
2. In general, a preparation is considered fit for use if it varies from the nominal
concentration or dose by no more than 10%, provided that the decomposition products
are not more toxic or harmful than the original material.
3. Shelf life testing aids in determining the standard shelf life of a formulation.
a. Samples are stored at 3° to 5°C and at room temperature (20° to 25°C). The samples are
then analyzed at various intervals to determine the rate of decomposition. Shelf life is
calculated from this rate.
b. Because storage time at these temperatures can result in an extended testing time,
accelerated testing is conducted as well, with a range of higher temperatures. The rate
constants obtained from these samples are used to predict shelf life at ambient or
refrigeration temperatures. Temperature-accelerated stability testing is not useful if
temperature changes are accompanied by changes in the reaction mechanism or by
physical changes in the system (e.g., change from the solid to the liquid phase).

c. Stability at room temperature can be predicted from accelerated testing data by the
Arrhenius equation: log (k T2_ k T1 ) _Ea ( T 2 _ T 1 ) __ 2.303 _ R _ T 2 _ T 1
where kt2 and kt1 are the rate constants at the absolute temperatures T2 and T1,
respectively; R is the molar gas constant; and Ea is the energy of activation.

c. Alternatively, an expression of concentration can be plotted as a linear function of

time. Rate constants (k) for degradation at several temperatures are obtained. The
logarithm of the rate constant (log k) is plotted against the reciprocal of absolute
temperature (1/T) to obtain, by extrapolation, the rate constant for degradation at
room temperature

e. The length of time that the drug will maintain its required potency can also be
predicted by calculation of the t90% is method applies to chemical reactions with
activation energies of 10 to 30 kcal/mol—the magnitude of the activation energy for
many pharmaceutical degradations that occur in a solution.