Chapter 2: Kinetic and Stability of Drug

❖
The chemical breakdown of drugs:
✓
The main ways in which drugs break down are as follows:

1. Hydrolysis:
• Drugs containing ester, amide, lactam,imide or carbamate
groups are susceptible to hydrolysis.

• Hydrolysis can be catalysed by hydrogen ions (specific acid

catalysis) or hydroxyl ions (specific base catalysis).

• Solutions can be stabilised by formulating at the pH of

maximum stability or, in some cases, by altering the dielectric
constant by the addition of non-aqueous solvents.

45
 2. Oxidation:
• Oxidation involves the removal of an electropositive atom,
radical or electron, or the addition of an electronegative atom
or radical.
• Oxidative degradation can occur by autooxidation, in which
reaction is uncatalyzed and proceeds quite slowly under the
influence of molecular oxygen, or may involve chain processes
consisting of three concurrent reactions: initiation,
propagation and termination.

• Examples of drugs that are susceptible to oxidation include

steroids and sterols, polyunsaturated fatty acids, phenothiazines.

• Various precautions should be taken during manufacture and

storage to minimise oxidation:
– The oxygen in pharmaceutical containers should be replaced with
nitrogen or carbon dioxide.
46
– Contact of the drug with heavy-metal ions such as iron,
cobalt or nickel, which catalyse oxidation, should be avoided.
– Storage should be at reduced temperatures.
– Antioxidants should be included in the formulation.

3. Isomerization:
Isomerization is the process of conversion of a drug into its
optical or geometric isomers, which are often of lower
therapeutic activity.
Examples of drugs that undergo isomerisation include adrenaline
(epinephrine: racemisation in acidic solution), tetracyclines
(epimerisation in acid solution), cephalosporins (base-catalysed
isomerisation) and vitamin A (cis–trans isomerisation).
47
 4. Photochemical decomposition:
• Examples of drugs that degrade when exposed to light include
phenothiazines, hydrocortisone, prednisolone, riboflavin,
ascorbic acid and folic acid.

• Photodecomposition may occur not only during storage, but also

during use of the product. For example, sunlight is able to
penetrate the skin to a depth sufficient to cause
photodegradation of drugs.

• Pharmaceutical products can be adequately protected from

photo-induced decomposition by the use of coloured glass
containers (amber glass excludes light of wavelength < 470 nm)
and storage in the dark. Coating tablets with a polymer film
containing ultraviolet absorbers has been suggested as an
additional method for protection from light.
48
 5. Polymerization:
• Polymerisation is the process by which two or more identical
drug molecules combine together to form a complex molecule.

• Examples of drugs that polymerise include amino-penicillins,

such as ampicillin sodium in aqueous solution, and also
formaldehyde.

Kinetics of chemical decomposition

in solution
• Reactions may be classified according to the order of reaction,
which is the number of reacting species whose concentration
determines the rate at which the reaction occurs.
49
 Zero-orderreactions:
• The decomposition proceeds at a constant rate and is
independent of the concentrations of any of the reactants.

• The rate equation is: dx/dt = k0

• Integration of the rate equation gives: x = k0 t

• A plot of the amount decomposed (as ordinate) against time

(as abscissa) is linear with a slope of k0 (Figure 3.1).

• The units of k are concentration time-1.

0

• Many decomposition reactions in the solid phase or in

suspensions apparently follow zero-order kinetics.

50
51
 First-orderreactions:
• The rate depends on the concentration of one reactant.

• The rate equation is: dx/dt = k1(a – x)

• Integration of the rate equation gives:

• Rearrangement into a linear equation gives:

• A plot of time (as ordinate) against the logarithm of the

amount remaining (as abscissa) is linear with a slope = –
2.303/k1 (Figure 3.2).
• The units of k1 are time–1.
52
• If there are two reactants and one is in large excess, the
reaction may still follow first-order kinetics because the
change in concentration of the excess reactant is negligible.
This type of reaction is a pseudo first-order reaction.

• The half-life of a first-order reaction is t0.5 = 0.693/k1. The half-

life is therefore independent of the initial concentration of
reactants.

53
 Second-orderreactions:
• The rate depends on the concentration of two reacting species,
A and B.
• For the usual case where the initial concentrations of A and B
are different, the rate equation is: dx/dt = k2(a – x)(b – x)
• where a and b are the initial concentrations of reactants A and
B, respectively.
• The integrated rate equation is:

• Rearrangement into a linear equation gives:

54
• A plot of time (as ordinate) against the logarithm of [(a – x)/(b
– x)] (as abscissa) is linear with a slope = 2.303/k2(a – b) (Figure
3.3).
• The units of k2 are concentration–1 time–1.
• The half-life of a second-order reaction depends on the initial
concentration of reactants and it is not possible to derive a
simple expression to calculate it.

55
56
 Complex reactions
• These are reactions involving simultaneous breakdown by
more than one route or by a sequence of reaction steps.
Some examples include:
1. Reversible reactions:

• where kf is the rate of the forward reaction and kr is the rate of

the reverse reaction.
• For these reactions the rate constants can be calculated from a
plot of t (as ordinate) against log[(Ao – Aeq)/(A – Aeq)], where Ao,
A and Aeq represent the initial concentration, the concentration
at time t and the equilibrium concentration of reactant A,
respectively.
• The plot should be linear with a slope of 2.303/(kf + kr). kf and kr
may be calculated separately if the equilibrium constant K is also
determined, since K= kf /kr.
57
 2. Parallel reactions:
• Parallel reactions in which the decomposition involves two
or more pathways, the preference for each route
depending on the conditions. Values of the rate constants
kA and kB for each route may be evaluated separately by
determining experimentally the overall rate constant, kexp,
and also the ratio R of the concentration of products
formed by each reaction from R =[A]/ [B] = kA/kB. It is then
possible to calculate the rate constants from
kA = kexp (R/(R + 1)) and kB = kA/R.
3. Consecutive reactions:
• Consecutive reactions in which drug A decomposes to an
intermediate B which then decomposes to product C. Each of
the decomposition steps has its own rate constant but there
is no simple equation to calculate them.

58
 Factors influencing drug stability
of liquid dosage forms
1. pH
• pH has a significant influence on the rate of decomposition of drugs
that are hydrolysed in solution and it usual to minimise this effect
by formulating at the pH of maximum stability using buffers.
• The rate of reaction is, however, influenced not only by the
catalytic effect of hydrogen and hydroxyl ions (specific acid–base
catalysis), but also by the components of the buffer system
(general acid–base catalysis).

• The effect of the buffer components can be large. For example, the
hydrolysis rate of codeine in 0.05 M phosphate buffer at pH 7 is
almost 20 times faster than in unbuffered solution at this pH.

• The general equation for these two effects is:

59
• where kobs is the experimentally determined hydrolytic rate constant,
k0 is the uncatalyzed or solvent-catalysed rate constant, kH+ and kOH–
are the specific acid and base catalysis rate constants respectively,
kHX and kX– are the general acid and base catalysis rate constants
respectively and [HX] and [X–] denote the concentrations of protonated
and unprotonated forms of the buffer.

• The ability of a buffer component to catalyse hydrolysis is related to

its dissociation constant, K, by the Brønsted catalysis law. The
catalytic coefficient of a buffer component which is a weak acid is
given by;
• the catalytic coefficient of a weak base;
• where a, b, α, and β are constants, and α and β are positive and vary
between 0 and 1.

60
• To remove the influence of the buffer, the reaction rate should be
measured at a series of buffer concentrations at each pH and the data
extrapolated back to zero buffer concentration. These extrapolated rate
constants are plotted as a function of pH to give the required buffer-
independent pH–rate profile (Figure 3.4)

61
• The rate constants for specific acid and base catalysis can be
determined from the linear plots obtained when the corrected
experimental rate constants kobs are plotted against the hydrogen ion
concentration [H+] at low pH (gradient is kH+), and against the hydroxyl
ion concentration at high pH (gradient is kOH–).

• Complex pH rate profiles are seen when the ionisation of the drug
changes over the pH of measurement because of the differing
susceptibility of the unionised and ionised forms of the drug to
hydrolysis.

• The oxidative degradation of some drugs, for example, prednisolone

and morphine, in solution may be pH-dependent because of the effect
of pH on the oxidation-reduction potential, E0, of the drug.

• The photodegradation of several drugs, for example midazolam and

ciprofloxacin, is also pH-dependent.

62
 2. Temperature
• Increase in temperature usually causes a very pronounced increase in the
hydrolysis rate of drugs in solution. This effect is used as the basis for drug
stability testing.

• The equation which describes the effect of temperature on decomposition

is the Arrhenius equation:
log k = log A – Ea/(2.303RT)
• where Ea is the activation energy, A is the frequency factor, R is the gas
constant (8.314 J mol–1 K–1) and T is the temperature in kelvins.
• The Arrhenius equation predicts that a plot of the log rate constant, k,
against the reciprocal of the temperature should be linear with a gradient of
–Ea/2.303R.
• Therefore, assuming that there is not a change in the order of reaction with
temperature, we can measure rates of reaction at high temperatures
(where the reaction occurs relatively rapidly) and extrapolate the Arrhenius
plots to estimate the rate constant at room temperature (where reaction
occurs at a very slow rate) (Figure 3.5).
• This method therefore provides a means of speeding up the measurements of
drug stability during preformulation. 63
 Figure 3.5 A typical Arrhenius plot showing the determination of a
rate constant at room temperature by extrapolation of data at high
temperatures.

• If a drug formulation is particularly unstable at room temperature, for

example, injections of penicillin, insulin, oxytocin and vasopressin, it
should be labelled with instructions to store in a cool place. 64
 3. Ionic strength
• The equation which describes the infl uence of electrolyte on the rate
constant is the Brønsted–Bjerrum equation:

• where zA and zB are the charge numbers of the two interacting ions, A is a
constant for a given solvent and temperature and μ is the ionic strength.
• Figure 3.6 The variation of rate constant, k, with square root of ionic
strength, μ, for reaction between a: ions of similar charge, b: ion and
uncharged molecule and c: ions of opposite charge.

65
 4. Solvent effects

• The equation that describes the effect of the dielectric constant, ε, on the
rate of hydrolysis is:

• where K is a constant for a particular reaction at a given temperature, zA

and zB are the charge numbers of the two interacting ions and kε=∞ is the
rate constant in a theoretical solvent of infinite dielectric constant.

• This equation predicts that a plot of log k against the reciprocal of the
dielectric constant of the solvent should be linear with a gradient –KzAzB.
The intercept when 1/ε = 0 (i.e. when ε = ∞) is equal to the logarithm of
the rate constant, kε=∞, in a theoretical solvent of infinite dielectric
constant (Figure 3.7):

66
Figure 3.7 The variation of rate constant with reciprocal of dielectric
constant for reaction between a, ions of opposite charge, b, ion and
uncharged molecule and c, ions of similar charge.

67
68
5. Oxygen

• The susceptibility of a drug to the presence of oxygen can be tested by

comparing its stability in ampoules purged with oxygen to that when it is
stored under nitrogen.

• Drugs which have a higher rate of decomposition when exposed to oxygen

can be stabilised by replacing the oxygen in the storage container with
nitrogen or carbon dioxide. These drugs should also be kept out of contact
with heavy metals and should be stabilised with antioxidants.

6. Light
• The susceptibility of a drug to light can readily be tested by comparing its
stability when exposed to light to that when stored in the dark.

• Photolabile drugs should be stored in containers of amber glass and, as an

added precaution, should be kept in the dark.
69
 Chapter 3: Interfacial phenomena
• When phases exist together, the boundary between two of them is known
as an interface.

• The properties of the molecules forming the interface are often

sufficiently different from those in the bulk of each phase that they are
referred to as forming an interfacial phase.

• Interfaces are divided into two groups, namely, liquid interfaces and solid
interfaces. In the former group, the association of a liquid phase with a
gaseous or another liquid phase will be discussed. The section on solid
interfaces will deal with systems containing solid–gas and solid–liquid
interfaces.

• Although solid–solid interfaces have practical significance in pharmacy

(e.g., the adhesion between granules, the preparation of layered tablets,
and the flow of particles), little information is available to quantify these
interactions.
70
71
 Liquid Interfaces
Surface and Interfacial Tensions
• In the liquid state, the cohesive forces between adjacent molecules
are well developed. Molecules in the bulk liquid are surrounded in all
directions by other molecules for which they have an equal attraction,
as shown in Figure 15-1.

• On the other hand, molecules at the surface (i.e., at the liquid–air

interface) can only develop attractive cohesive forces with other liquid
molecules that are situated below and adjacent to them. They can
develop adhesive forces of attraction with the molecules constituting
the other phase involved in the interface, although, in the case of the
liquid–gas interface, this adhesive force of attraction is small.

• The net effect is that the molecules at the surface of the liquid
experience an inward force toward the bulk, as shown in Figure 15-1.
Such a force pulls the molecules of the interface together and, as a
result, contracts the surface, resulting in a surface tension.
72
• The tension in the surface is the force per unit length that must be
applied parallel to the surface so as to counterbalance the net
inward pull.
• This force, the surface tension, has the units of dynes/cm in the
cgs system and of N/m in the SI system.

• Interfacial tension is
the force per unit
length existing at the
interface between two
immiscible liquid
phases and, like
surface tension, has
the units of dynes/cm.

73
74
75
76
 Example 15-1
Calculating the Surface Tension of Water
If the length of the bar, L, is 5 cm and the mass required to break a soap film
is 0.50 g, what is the surface tension of the soap solution?

❖
Surface Free Energy
• To move a molecule from the inner layers to the surface, work needs to be
done against the force of surface tension.

• where W is the work done, or surface free energy increase, expressed in

ergs, γ is the surface tension in dynes/cm, and A is the increase in area
in cm2

77
78
Pressure Differences Across Curved Interfaces

79
 Measurement of Surface and Interfacial Tensions
1. Capillary Rise Method

80
81
(2) Drop Formation Method (3) Ring-detachment Method

82
(4) Maximum Bubble Pressure Method

83
 Adsorption at Liquid Interfaces
• Certain molecules and ions, when dispersed in the liquid, move of
their own accord to the interface.

• Their concentration at the interface then exceeds their concentration in

the bulk of the liquid. Obviously, the surface free energy and the
surface tension of the system are automatically reduced.

• Such a phenomenon, where the added molecules are partitioned in

favour of the interface, is termed adsorption, or, more correctly,
positive adsorption.

• Other materials (e.g., inorganic electrolytes) are partitioned in favour of

the bulk, leading to negative adsorption and a corresponding increase in
surface free energy and surface tension.

• Adsorption should not be confused with absorption. The former is solely

a surface effect, whereas in absorption, the liquid or gas being absorbed
penetrates into the capillary spaces of the absorbing medium.

• The taking up of water by a sponge is absorption; the concentrating of

alkaloid molecules on the surface of clay is adsorption.
84
 Surface-Active Agents
• It is the amphiphilic nature of surface-active agents that causes them to be
absorbed at interfaces, whether these are liquid–gas or liquid–liquid
interfaces.

• Thus, in an aqueous dispersion of amyl alcohol, the polar alcoholic group

is able to associate with the water molecules. The nonpolar portion is
rejected.

• Because the adhesive forces it can develop with water are small in
comparison to the cohesive forces between adjacent water molecules. As
a result, the amphiphile is adsorbed at the interface.

Adsorption of fatty
acid molecules at a
water–air interface
(left panel) and a
water–oil interface
(right panel).

85
 Systems of Hydrophile–Lipophile Classification
• Griffin devised an arbitrary scale of values to serve as a measure of the hydrophilic–
lipophilic balance of surface-active agents. By means of this number system, it is
possible to establish an HLB range of optimum efficiency for each class of surfactant.
The higher the HLB of an agent, the more hydrophilic it is.

• The HLB of a nonionic surfactant whose only hydrophilic portion is

polyoxyethylene is calculated by using the formula, where E is the
percentage by weight of ethylene oxide.:

• A number of polyhydric alcohol fatty acid esters, such as glyceryl

monostearate, can be estimated by using the formula

• where S is the saponification number of the ester and A is the acid number
of the fatty acid. The HLB of polyoxyethylene sorbitan monolaurate (Tween
20), for which S = 45.5 and A = 276, is

86
87
88
89
90
91
92
93
 Adsorption at Solid Interfaces
• Adsorption of material at solid interfaces can take place from either an adjacent
liquid or gas phase.

• The study of adsorption of gases arises in such diverse applications as the removal of
objectionable odors from rooms and food, the operation of gas masks, and the
measurement of the dimensions of particles in a powder.

• The principles of solid–liquid adsorption are used in decolorizing solutions, adsorption

chromatography, detergency, and wetting.

• The adsorption of materials from a gas or a liquid onto a solid surface is similar to that
discussed for liquid surfaces. Thus, adsorption of this type can be considered as an
attempt to reduce the surface free energy of the solid. The surface tensions of solids
are invariably more difficult to obtain.
• The average lifetime of a molecule at the water–gas interface is about 1 μ sec,
whereas an atom in the surface of a nonvolatile metallic solid may have an average
lifetime of 1037 sec.

• The surface of a solid may not be homogeneous, in contrast to liquid interfaces.

94
 1. The Solid–Gas Interface
• The degree of adsorption of a gas by a solid depends on the chemical
nature of the adsorbent (the material used to adsorb the gas) and the
adsorbate (the substance being adsorbed), the surface area of the
adsorbent, the temperature, and the partial pressure of the adsorbed gas.

❖ The types of adsorption

1. Physical adsorption, associated with van der Waals forces, is reversible,
the removal of the adsorbate from the adsorbent being known as
desorption. A physically adsorbed gas can be desorbed from a solid by
increasing the temperature and reducing the pressure.

2. Chemisorption, in which the adsorbate is attached to the adsorbent by

primary chemical bonds, is irreversible unless the bonds are broken.
• The relationship between the amount of gas physically adsorbed on a solid
and the equilibrium pressure or concentration at constant temperature
yields an adsorption isotherm when plotted as shown in Figure 15-18.
• The term isotherm refers to a plot at constant temperature. The number of
moles, grams, or milliliters, x, of gas adsorbed on, m, grams of adsorbent
at standard temperature and pressure is plotted on the vertical axis
against the equilibrium pressure of the gas in mm Hg on the horizontal
axis, as seen in Figure 15-18a. 95
 Fig. 15-18. Adsorption isotherms for a gas on a solid. (a) Amount, x, of gas
adsorbed per unit mass, m, of adsorbent plotted against the equilibrium pressure.
(b) Log of the amount of gas adsorbed per unit mass of adsorbent plotted against
the log of the pressure.

Freundlich isotherm

• where y is the mass of gas, x, adsorbed per unit mass, m, of adsorbent,

and k and n are constants that can be evaluated from the results of the
experiment. The equation is handled more conveniently when written in
the logarithmic form,

96
 Langmuir isotherm
• Langmuir developed an equation based on the theory that the molecules or
atoms of gas are adsorbed on active sites of the solid to form a layer one
molecule thick (monolayer).

• The fraction of centers occupied by gas molecules at pressure p is

represented by θ, and the fraction of sites not occupied is 1 - θ. The rate, r1,
of adsorption or condensation of gas molecules on the surface is
proportional to the unoccupied spots, 1 - θ, and to the pressure, p, or

• The rate, r2, of evaporation of molecules bound on the surface is

proportional to the fraction of surface occupied, θ, or

97
 • We can replace k1/k2 by b and θ by y/ym, where y is the mass of gas
adsorbed per gram of adsorbent at pressure p and at constant
temperature and ym is the mass of gas that 1 g of the adsorbent can
adsorb when the monolayer is complete. Inserting these terms into
equation (15-54) produces the formula

• which is known as the Langmuir isotherm. By inverting equation (15-55)

and multiplying through by p, we can write this for plotting as

• A plot of p/y against p should yield a straight line, and ym and b can be
obtained from the slope and intercept.
• Equations (15-49), (15-50), (15-55), and (15-56) are adequate for the
description of curves only of the type shown in Figure 15-18a. This is known
as the type I isotherm.

• Extensive experimentation, however, has shown that there are four other
types of isotherms, as seen in Figure 15-20, that are not described by these
equations.
98
 Fig. 15-20. Various types of adsorption isotherms.

• Type II isotherms are sigmoidal in shape and occur when gases undergo
physical adsorption onto nonporous solids to form a monolayer followed
by multilayer formation. The first inflection point represents the formation
of a monolayer; the continued adsorption with increasing pressure
indicates subsequent multilayer formation.
• Type II isotherms are best described by an expression derived by
Brunauer, Emmett, and Teller and termed for convenience the BET
equation. This equation can be written as

99
 2. The Solid–Liquid Interface
• Drugs such as dyes, alkaloids, fatty acids, and even inorganic acids and
bases can be absorbed from solution onto solids such as charcoal and
alumina. The adsorption of solute molecules from solution can be treated in
a manner analogous to the adsorption of molecules at the solid–gas
interface.

where c is the
Fig. 15-23.
equilibrium
Adsorption of
concentration in
strychnine on
milligrams of alkaloidal
various clays.
base per 100 mL of
solution, y is the
amount of alkaloidal
base, x, in milligrams
adsorbed per gram,
m, of clay (i.e., y =
x/m), and b and ymare
constants defined
earlier.
100
3. The Solid–Solid Interface

101
 Activated Charcoal
• An example of a substance that can adsorb enormous amounts of gases or
liquids is activated charcoal, the residue from destructive distillation of
various organic materials, treated to increase its adsorptive power.

• To adsorb more adsorbate, an adsorbent of a given mass should have the

greatest possible surface area. This might be achieved by the use of porous
or milled adsorbents.

• Consider the following example: A sphere with a diameter of 1.2 cm has a

volume of 1 cm3 and a surface area of 5 cm2. If the sphere is divided into
two spheres each with a diameter of 1 cm, together they will have the same
volume of 1 cm3 but an increased surface area of 6 cm2. 102
 Wetting Agent
• A wetting agent is a surfactant that, when dissolved in water, lowers the
advancing contact angle, aids in displacing an air phase at the surface,
and replaces it with a liquid phase.

• Examples of the application of wetting to pharmacy and medicine

include the displacement of air from the surface of sulfur, charcoal, and
other powders for the purpose of dispersing these drugs in liquid
vehicles; the displacement of air from the matrix of cotton pads and
bandages so that medicinal solutions can be absorbed for application to
various body areas; the displacement of dirt and debris by the use of
detergents in the washing of wounds; and the application of medicinal
lotions and sprays to the surface of the skin and mucous membranes.

• Figure 15-24, the contact angle between a liquid and a solid may be
0°,signifying complete wetting, or may approach 180°, at which wetting is
insignificant.

103
 Applications of Surface-Active Agents
• In addition to the use of surfactants as emulsifying agents, detergents,
wetting agents, and solubilizing agents, they find application as
antibacterial and other protective agents and as aids to the absorption of
drugs in the body, and foams and antifoaming agents.

104
• The cleansing action of soap is due to:

(1) Solubilisation of (2) Emulsification of grease

grease into the micelle

105
 ELECTRIC PROPERTIES OF INTERFACES
Electrical double layer

The double layer is made of:

1. A COMPACT LAYER of (+ve) and (-ve) charges which are fixed on the particle
surface.

2. A DIFFUSE LAYER of counterions diffused into the medium containing

positive ions.

106
• The combination of the compact and diffuse layer is referred to as the Stern
Double layer

• The difference in potential between the compact layer and the diffuse layer
called Zeta potential.

• Zeta potential = 0 when (+ve) = (-ve))

• The zeta potential can be calculated from the following properties: (a)
Electrophoresis (b) Electro-osmosis of colloids.

ORIGIN OF CHARGE ON SOL PARTICLES

1. Adsorption of ions from the aqueous medium:

107
2. Ionization of Surface groups

108
109
 Effect of Electrolytes

• As the concentration of electrolyte present in the system is increased,

the screening effect of the counterions is also increased.
• As a result, the potential falls off more rapidly with distance because the
thickness of the double layer shrinks.
• A similar situation occurs when the valency of the counterion is
increased while the total concentration of electrolyte is held constant.
• The overall effect frequently causes a reduction in zeta potential.

Negative sol (As2S3): Al3+> Ba2+>Na+

Positive sol (Fe (OH)3): [Fe(CN)6]3– > SO42– > Cl

110
 Chapter 4: Rheology
• The term―rheology, from the Greek rheo (to flow) and logos(science), was
suggested by Bingham and Crawford to describe the flow of liquids and
the deformation of solids.

• Viscosity is an expression of the resistance of a fluid to flow; the higher the

viscosity, the greater is the resistance. Simple liquids can be described in
terms of absolute viscosity.

• Rheologic properties of heterogeneous dispersions are more complex,

however, and cannot be expressed by a single value.

• Rheology study is important in pharmacy and suggested its application in

the formulation and analysis of such pharmaceutical products as
emulsions, pastes, suppositories, and tablet coatings.

• When classifying materials according to types of flow and deformation, it

is customary to place them in one of two categories: Newtonian or non-
Newtonian systems. The choice depends on whether or not their flow
properties are in accord with Newton's law of flow.

111
 Newtonian Systems
Newton's Law of Flow
• Consider a ―block of liquid consisting of parallel plates of molecules,
similar to a deck of cards, as shown in Figure 19-1.

Fig. 19-1. Representation of the shearing force required to produce a definite velocity
gradient between the parallel planes of a block of material.

112
• If the bottom layer is fixed in place and the top plane of liquid is moved
at a constant velocity, each lower layer will move with a velocity directly
proportional to its distance from the stationary bottom layer.

• The difference of velocity, dv, between two planes of liquid separated by

an infinitesimal distance,dr, is the velocity gradient or rate of shear, dv/dr.

• The force per unit area, F′/A, required to bring about flow is called the
shearing stress and is given the symbol F.

• Newton was the first to study flow properties of liquids in a quantitative

way. He recognized that the higher the viscosity of a liquid, the greater
is the shearing stress required to produce a certain rate of shear.

• Rate of shear is given the symbol G. Hence, rate of shear should be

directly proportional to shearing stress:

113
• where η is the coefficient of viscosity, usually referred to simply
as viscosity. where F = F′/A and G = dv/dr.

• A representative flow curve, or rheogram, obtained by plotting F versus

G for a Newtonian system is shown in Figure 19-2a. As implied by
equation (19-2), a straight line passing through the origin is obtained.

Fig. 19-2. Representative flow curves for various materials.

• The unit of viscosity is poise = dyne sec/cm2 or g/cm sec. (1 cp = 0.01 p)

• Fluidity, φ, is defined as the reciprocal of viscosity:

114
115
 Kinematic Viscosity
Kinematic viscosity is the absolute viscosity divided by the density of the
liquid at a specific temperature:

The units of kinematic viscosity are the stoke (s) and the centistoke(cs).
Arbitrary scales (e.g., Saybolt, Redwood, Engler, and others) for measurement
of viscosity are used in various industries; these are sometimes converted by
use of tables or formulas to absolute viscosities and vice versa.

116
 Temperature Dependence and the Theory of Viscosity
Viscosity of a gas increases with temperature, that of a liquid decreases as
temperature is raised.

analogous to the Arrhenius equation of chemical kinetics:

where A is a constant depending on the molecular weight and molar
volume of the liquid and Ev is an activation energy required to initiate flow
between molecules. 117
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 Non-Newtonian Systems
• The majority of fluid pharmaceutical products are not simple liquids and
do not follow Newton's law of flow. These systems are referred to as non-
Newtonian.
• Non-Newtonian behavior is generally exhibited by liquid and solid
heterogeneous dispersions such as colloidal solutions, emulsions, liquid
suspensions, and gels.
• When non-Newtonian materials are analyzed in a rotational viscometer
and results are plotted, various consistency curves, representing three
classes of flow, are recognized: plastic, pseudoplastic, and dilatant.

Plastic Flow
The slope of the rheogram is termed the mobility,
analogous to fluidity in Newtonian systems, and
its reciprocal is known as the plastic viscosity, U.
The equation describing plastic flow is

where f is the yield value, or intercept, on the shear

stress axis in dynes/cm2,
119
Pseudoplastic Flow
• Many pharmaceutical products, including liquid
dispersions of natural and synthetic gums (e.g,
sodium alginate, methylcellulose, and sodium
carboxymethyl cellulose) exhibit pseudoplastic
flow.

• Pseudoplastic flow is typically exhibited by

polymers in solution,

120
• N rises as flow becomes increasingly non-Newtonian. When N = 1 flow is
Newtonian. The term η′ is a viscosity coefficient.

Dilatant Flow

• N is always less than 1 and decreases as degree of

dilatancy increases. As N approaches 1, the system
becomes increasingly Newtonian in behavior.
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