❖
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.
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.
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.
50
51
First-orderreactions:
• The rate depends on the concentration of one reactant.
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:
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:
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.
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.
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.
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.
• 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:
• 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
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.
• 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.
• 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.
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.
• 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.
• 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 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.
Freundlich isotherm
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).
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
• 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.
• 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:
105
ELECTRIC PROPERTIES OF INTERFACES
Electrical double layer
1. A COMPACT LAYER of (+ve) and (-ve) charges which are fixed on the particle
surface.
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.
• The zeta potential can be calculated from the following properties: (a)
Electrophoresis (b) Electro-osmosis of colloids.
107
2. Ionization of Surface groups
108
109
Effect of Electrolytes
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.
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 force per unit area, F′/A, required to bring about flow is called the
shearing stress and is given the symbol F.
113
• where η is the coefficient of viscosity, usually referred to simply
as viscosity. where F = F′/A and G = dv/dr.
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.
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
120
• N rises as flow becomes increasingly non-Newtonian. When N = 1 flow is
Newtonian. The term η′ is a viscosity coefficient.
Dilatant Flow