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Ans. 5: Enlist the physical instability markers of emulsion and discuss any two.
Physical Instability Markers
1. Flocculation
2. Creaming
3. Coalescence
4. Breaking
5. Phase Inversion

Flocculation:
In this case, neighboring globules come closer to each other and form colonies in the external phase (Figure
a). This aggregation of globules is not clearly visible. This is probably the initial stage that leads to
instability.

The extent of flocculation of globules depends on

(a) Globule size distribution
(b) Charge on the globule surface
(c) Viscosity of the external medium

To Prevent Flocculation:
 Uniform sized globules prevent flocculation. This can be achieved by proper size reduction process.
 A charge on the globules exerts repulsive forces with the neighboring globules. This can be achieved by
using ionic emulsifying agent, electrolytes etc.
 If the viscosity of the external medium is increased, the globules become relatively immobile and
flocculation can be prevented. This can be obtained by adding viscosity improving agents (bodying
agents or thickening) such as hydrocolloids or waxes.

Flocs slowly move either upward or downward leading to creaming. Flocculation should not be confused
with creaming. Flocculation is due to the interaction of attractive and repulsive forces, whereas creaming is
due to density differences in the two phases.

Creaming:
Creaming is the concentration of globules at the top or bottom of the emulsion. The floccules move either
upward or downward leading to creaming. Creaming may also be observed on account of the movement of
individual globules (Figure a). It can be observed by a difference in colour shade of the layers.

It is a reversible process, i.e., cream can be redispersed easily by agitation. This is possible because the oil
globules are still surrounded by the protective sheath of the emulsifier. This is a potential step towards
complete coalescence of internal phase. Hence, this stage is also considered to be the mark of instability.

In creaming, the drug is not uniformly distributed. This leads to variable dosage. Therefore, the emulsion
should be shaken thoroughly before use.

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Creaming is of two types.

 Upward creaming, this is due to the less denser internal phase (Figure b). This is normally observed
in o/w emulsions.
 On the other hand, downward creaming is also possible if the internal phase is heavier. Due to
gravitational pull, the globules settle down. This is normally the case in w/o emulsions.

Since creaming process involves the movement of globules in an emulsion, Stokes' law can be applied.
Therefore, creaming is influenced by:
• Globule size
• Viscosity of the dispersion medium
• Difference in the densities of dispersed phase and dispersion medium

Creaming can be reduced / prevented by:

1. Reducing the particle size by homogenisation. Doubling the diameter of oil globules increases
the creaming rate by a factor of four.
2. Increasing the viscosity of the external phase by adding the thickening agents such as tragacanth
or sodium alginate.
3. Reducing the difference in the densities between the dispersed phase and dispersion medium.

In general, the density of aqueous phase is higher than the oil phase. To make densities equal, oil soluble
substances such as β-bromonaphthalene, bromoform are added to the oil phase. This technique is rarely used
in practice.

Figure a: Different stages of Instability of Emulsion

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Coalescence:
A few globules tend to fuse with each other and form bigger globules (Figure a). In this process, the
emulsifier film around the globules is destroyed to a certain extent. This step can be recognised by increased
globule size and reduced number of globules. Coalescence is followed by creaming stage.

Coalescence is observed due to:

 Insufficient amount of the emulsifying agent
 Altered partitioning of the emulsifying agent
 Incompatibilities between emulsifying agents

Phase volume ratio represents the relative volume of water to oil in an emulsion. At higher ratio (>74% of
oil to water), globules are closely packed, wherein small globules occupy the void spaces between bigger
globules. Thus, globules get compressed and become irregular in shape, which leads to fusion of adjacent
globules.

Breaking:
This is indicated by complete separation of oil and aqueous phases (Figure b). It is an irreversible process,
i.e., simple mixing fails to resuspend the globules into an uniform emulsion. In breaking, the protective
sheath around the globules is completely destroyed.

Phase Inversion:
This involves the change of emulsion type from o/w to w/o or vice versa. When we intend to prepare one
type of emulsion say o/w, and if the final emulsion turns out to be w/o, it can be termed as a sign of
instability.

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Ans. 6: Write a note on factor affecting stability of suspension.

The ideal characteristics of suspensions have highlighted the need to prevent the settling of particles. The
study of theories relating to sedimentation provides information regarding factors that affect the settling of
solids.

These factors enable the pharmacist to take appropriate action in the manufacture of suspensions.
The following are the factors affecting stability of Suspension.
1. Particle size
2. Viscosity of Medium
3. Density of the medium
4. Brawonian movement

Theory of Sedimentation
To derive factor affecting stability of suspension, stokes’ Law is important to understand. According to
theory of sedimentation, the rate of sedimentation of particles can be expressed by the Stokes' Law, using
the following formula:

𝒅𝒅𝟐𝟐(𝝆𝝆𝝆𝝆− 𝝆𝝆𝟐𝟐)𝒈𝒈 .....................................

𝑹𝑹𝑹𝑹𝑹𝑹𝑹𝑹 𝒐𝒐𝒐𝒐 𝑺𝑺𝑹𝑹𝒅𝒅𝒅𝒅𝒅𝒅𝑹𝑹𝒅𝒅𝑹𝑹𝑹𝑹𝑹𝑹𝒅𝒅𝒐𝒐𝒅𝒅 = Equation 1
𝝆𝝆𝟏𝟏𝟏𝟏
Where,
d = Diameter of the particles, cm
ρ1 = Density of the dispersed phase, g/cm3
ρ2 = Density of the dispersion medium, g/cm3
η = Viscosity of the dispersion medium, poise
g = Acceleration due to gravity (980.7 cm/sec2)

Stokes law is applicable in the following conditions:

(i) Particles should be spherical, but in the suspension, particles are largely irregular.
(ii) Particles should settle freely and independently. Such a condition can be satisfied by dilute
suspensions (0.5 to 2% solids per 100 ml). But most suspensions contain dispersed solids in concentrations
of 5 to 10% or higher.

In these suspensions, solids exhibit hindered settling, i.e., particles interfere the free settling of other
particles. Therefore, Stokes law cannot be applied to these types of suspensions. Stokes law is applicable to
deflocculated systems, wherein particles settle independently. However, this law is useful, in a qualitative
sense, in fixing factors which can be utilized in formulation of suspensions.

So according to stokes’ law, Factors affecting stability are as under:

(1) Particle size:

If the particle size is reduced to half of its original size, the rate of sedimentation decreases by a factor of
four (equation 1). Smaller particles facilitate rapid absorption.

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(2) Viscosity of the medium:

The viscosity of suspension should be optimum. From equation (1), it is inferred that higher the viscosity,
lower is the rate of sedimentation.

Selection of high viscosity has several advantages and disadvantages.

The advantages of high viscosity are as follows.

A. High viscosity enhances the physical stability, because sedimentation is retarded.
B. High viscosity inhibits the crystal growth, because movement of particles is diminished.
C. High viscosity prevents the transformation of metastable crystals to stable crystals.

The disadvantages of high viscosity are as follows.

A. High viscosity hinders the redispersibility of the sediment.
B. High viscosity retards the absorption of drugs from the suspension.
C. High viscosity creates problems in the handling of materials during manufacture.

(3) Density of the medium:

The densities of solid used in pharmacy are generally from 1.5 to 2.0 g/cc. According to equation (1), if the
density of the medium is equal to the density of solids, the rate of settling becomes zero.

In general, the density of medium is about 1.0 g/cc on account of aqueous phase. Therefore, there is a need
to increase the density of the medium, so that the difference in densities will be minimal.

The density of a medium can be increased by including the ingredients such as polyvinylpyrrolidone (PVP),
sugars (sorbitol or dextrose), polyethyleneglycols, glycerin etc. A combination of these adjuvants yields
improved suspension. However, these should be used in high concentrations, but improvement in density
will be less. Hence, this is not a viable factor to decrease the settling.

(4) Brownian Movement:

Brownian movement of particles prevents sedimentation. In general, particles are not in a state of Brownian
movement in suspensions, due to larger particle size and higher viscosity' of the medium.

Brownian movement can be observed, if the size of the particles is about 2 to 5 µm, provided densities of the
particles, and viscosity of the medium are favourable.

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Ans. 7: Write a note on suspending agent.

A pharmaceutical suspension, like other disperse systems, is thermodynamically unstable, thus, making it
necessary to include in the dosage form, a stabilizer or suspending agent which reduces the rate of settling
and permits easy redispersion of any settled particulate matter both by protective colloidal action and by
increasing the consistency of the suspending medium.

Suspending agents are substances that are used to keep finely diveded insoluble materials suspended in a
liquid media by preventing there agglomeration (Coming together) and by imparting viscosity to the
dispersion media so that the particle settle more slowly.

Care must be taken when selecting a suspending agent for oral preparations as the acid environment of
the stomach may alter the physical characteristics of the suspension and thererfore the rate of release of the
drug from suspension.

The selection of amount of suspending agent is dependent on the presence of other suspending agent,
presence or absence of other ingredients which have an ability to act as a suspending agent or which
contributes viscosity to the medium. Stability of the suspensions depends on the types of suspending agents
rather than the physical properties of the drugs.

The sedimentation rate is slowed down by increasing the viscosity of liquid vehicle, and slowing down
settling in accordance to skokes law.

They usually prevent caking at the base of an suspension. On long storage if caking forms, it could be
resuspended by agitation due to the presence of suspending agent. It is majorly used as an excipients to help
active pharmaceutical indgredients stay suspended in formulation.

Types of Suspending agent: Type your text

A. Polysaccharides
B. Inorganic salts
C. Synthetic componds

Above types are discussed as under:

A. POLYSACCHARIDES:
The official suspending agents were natural polysaccharides but nowadays semi synthetic compounds are
increasingly used.

Following are some examples of it:

Acacia, Tragacanth, Starch, Alginates, Xanthamn gums

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Ans. 8: Give a brief account on theories of emulsification.

A variety of emulsifying agents are used, each probably act by different mechanisms. Irrespective of their
chemical nature, they tend to concentrate at the interface and form a tough film around the globules. Based
on the type of the films they form, emulsifying agents are classified as:

A. Surface active agents, which are adsorbed at oil-water interfaces to form monomolecular films and
reduce interfacial tension. Examples are soaps, spans, tweens.

B. Hydrophilic colloids, which form a multimolecular film around the dispersed droplets of oil in and o/w
emulsion. Examples are acacia, gelatin.

C. Finely divided solids particles, which are adsorbed at the interface between two immiscible liquid
phases and form what amounts to a film of particles around the dispersed globules. Examples are bentonite,
veegum.

Based on the nature of films formed at the interface, the mechanisms of action of emulsifying agents can be
discussed under the following headings.

Monomolecular Adsorption and Film Formation

1. Surfactants adsorb at the oil-water interface and form a monomolecular film. This film rapidly envelopes
the droplets as soon as they are formed. Agents having higher interfacial activity are better suited for this
purpose.

The monomolecular film should be

 Compact and strong enough so that it cannot be easily disturbed or broken.
 For any reason, if the film is broken, it should be elastic and flexible enough, so that it can be
reformed rapidly on moderate agitation.

The physical, chemical and mechanical properties of the interfacial films are of importance in stabilising
emulsions. Attempts have been made to use a combination of surfactants rather than a single one to impart
these characteristics to the interface. It is assumed that they support each other and strengthen the
monomolecular film (Shown in Figure).

The surfactant blend consists of a water-soluble and an oil-soluble surfactants. The hydrophilic surfactant
approaches the interface from aqueous phase-side, while the oil-soluble surfactant approaches from the oil
phase-side. At the interface, the two surfactants interact to form a complex and condense as a
monomolecular film.

The interaction within a mixture of emulsifying agents at the interface and nature of film formed is depicted
in Figure.

A combination of sodium cetyl sulfate (hydrophilic) and cholesterol (lipophilic) leads to a close packed,
complex film at the interface that produces an excellent emulsion (Figure a). Thus, a blend of surface active
agents produce good emulsions.

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Figure a: The interaction within a mixture of emulsifying agents at the interface and nature of film
formed depicted in figure (a) – Excellent emulsion

However, it should be stressed that a blend of surfactants may also produce poor quality emulsion, if the
interaction between them is not stronger at the interface.

Sodium cetyl sulfate and oleyl alcohol do not form a close packed film and therefore, their combination
produces a poor emulsion (Figure b).

Figure b: The interaction within a mixture of emulsifying agents at the interface and nature of film
formed depicted – Poor emulsion

Cetyl alcohol and sodium oleate produce a close packed film, but complexation is negligible and,
therefore, again produces poor emulsions (Figure c).

Figure c: The interaction within a mixture of emulsifying agents at the interface and nature of film
formed depicted – Poor emulsion

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2. Surfactants are capable of reducing the interfacial tension. This facilitates the immediate formation of
small droplets. Furthermore, its importance can be understood by considering the surface free energy
changes during emulsification. In equation ∆G = Yo/w ∆A, ∆A is increased due to formation of small
globules.

Usually, these small globules tend to combine with each other and form separate phases. But formation of
smaller droplets is important in the preparation of an emulsion. So, ∆A cannot be altered to get ∆G = 0. The
only option is to reduce the interfacial tension, Yo/w.

Surfactants achieve this objective and produce stable emulsions. This factor is of secondary importance in
stabilisation.

3. Ionic surfactants impart charges on interfacial films. These films exert repulsive forces between two
approaching globules and prevent their coalescence. This mechanism is of minor importance.

Nonionic surfactants also produce good emulsions. In such cases, ions present in the aqueous phase often
get adsorbed onto the monomolecular film, thereby preventing the coalescence of droplets.

Multimolecular Adsorption
The emulsifying agents such as acacia and gelatin, (isoelectric point) tend to form a multimolecular film
around the globules and prevent coalescence (Figure d). They also reduce the interfacial tension moderately,
though it is of secondary importance.

They are effective at high concentrations and promote the formation of o/w emulsion owing to their
hydrophilicity. They also have affinity towards the oil phase and this facilitates interfacial adsorption.
Normally, the stability is improved by adding viscosity inducing agents such as tragacanth, methyl cellulose,
CMC etc.

Figure d: Film formation at the o/w interface – Multimolecular film

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Solid Particle Adsorption

The finely divided solid particles adsorb at the oil-water interface and form a rigid film of closely packed
solids (Figure c). This film acts as a mechanical barrier and prevents the coalescence of globules. These tend
to produce coarse emulsions. Depending on the affinity of the emulsifier to a particular phase, one can
prepare both types of emulsions.

Figure e: Film formation at the o/w interface – Solid Particle film

Examples are:
 Bentonite (hydrated aluminum silicate, pH-9) — o/w and w/o
 Veegum (magnesium aluminum silicate, > 1%) — o/w

The stability of an emulsion depends on the finer state of subdivision of solid particles, irregular surface and
charge on the surface.

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Ans. 9: Write a short not on accelerated stability study

Stability is officially, defined as the time lapse. during which the drug product retains the same properties
and characteristics that it possessed at the time of manufacture.

The stability of a product is expressed as the expiry period or technically as shelf life. Expiration period is a
valuable quality—attribute for all pharmaceutical dosage forms.

Stability studies are necessary for the following reasons:

1. Product instability or chemical degradation of active drug may lead to under-medication due to lowering
of the concentration of the drug in the dosage form. Examples are digoxin and theophylline. If concentration
of drug is not maintained in the body (or blood) through an appropriate dose, the dosage form becomes
ineffective.

2. During decomposition of active drug toxic products may be formed. For example, p-aminosalicylic acid
(PAS) is converted into p- aminophenol, which is toxic.

3. Instability may be due to change in physical appearance. Examples of this type are, mottling of tablets,
creaming of emulsions or caking of solids in a suspension.

Accelerated Stability Studies

The objective of accelerated stability studies is to predict the shelf life of a product by accelerating the rate
of decomposition, preferably by increasing the temperature. Accelerated stability studies are experimental
designs.

Stability method :

Drug liquid preparations (solution dosage forms) are stored at elevated temperatures, viz., 50, 60, 70, 85,
100 and 121°C.

In addition, the samples should be studied at 40°C, 75% RH and incubator temperature (35-37°C). To
confirm the results obtained from accelerated stability studies, it is necessary to simultaneously conduct
experiments at room temperature (i.e., 30°C, 70% RH) and or refrigerator temperature (4-5°C). During
different time intervals, samples are withdrawn.
The sampling may be done at:
3 month intervals during the first year,
6 month intervals during the second, and yearly thereafter.
For drug products which may degrade rapidly (examples are certain radiopharmaceuticals) more frequent
sampling is necessary.

Due to diverse climatic conditions prevalent in different countries, mentioning of ambient temperature may
be relevant here. For this purpose, four climatic zones are proposed as listed here.
Temperate zone = 21°C (45% RH)
Mediterranean zone = 25°C (60% RH)
Tropical moist = 30°C (70% RH)
Desert zone = 30°C (35% RH)

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2. Accelerated stability studies are valid only when the energy of activation obtained in the study is about 10
to 30 kcal/mole. Reactions in solution phase, in general, have heat of activationin this range. If Ea is less
than 10 kcal/mole, the rate would be fast at normal storage conditions.

The elevated temperature has little influence on the decomposition. If Ea is higher than the 30 kcal/mole,
very high temperatures are required to enhance the degradation. Reaction at such high temperatures may not
have any relevance because they do not reflect ambient storage conditions.

3. The results (shelf life etc.,) obtained for one set of conditions for a preparation cannot be applied to other
preparations of the same drug.

4. Whenever slight changes in the formula is made, kinetic study at one elevated temperature will be
sufficient (helpful) to predict the stability. In such cases, the literature value cf Ea can be used.

5. Stability predictions at elevated temperatures are of little use when the degradation is due to
Diffusion
Microbial contamination
Photochemical reactions (Ea range from 2 to 3 kcal/mole)
Excessive agitation (stress)

6. Stability studies are meaningless, when the product looses its physical integrity at higher temperatures.
For example
Coagulation of suspending agent (Methylcellulose)
Denaturation of proteins
Breaking of an emulsion or change in the distribution
Coefficient of emulsifier at the high temperatures
Loss of consistency of ointments

The product should retain its physical properties which are generally seen in normal shelf conditions.
Predictions based on elevated temperature studies are generally satisfactory for solution dosage forms.

7. Predictions will become erroneous when the order changes at elevated temperature. For example, a
suspension follows a zero order at room temperature, but may become a solution that will follow first order
at elevated temperatures.

8. Predictions will become erroneous when the reaction changes its order during the period of study.

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Ans. 10: Describe the various methods of determination of reaction order.

There is no straight forward method to theoretically know the order of a reaction. Molecularity
provides a rough estimate of the number of molecules participating in the reaction. So, the order will be
either equal to or less than this number (molecularity). The exact order can be determined experimentally.
The following methods are employed to decide the order of a reaction.

1. Graphic Method

This pictorial method may be more reliable because deviations from the best fit line can be easily observed.
Conduct the kinetic experiment and collect the data on the time course of changes in the concentration of the
reactants.
Plot the data on a graph paper as per the general principles of each order. The patterns are shown in Figure
(Figure: a, b and c). Decide which graph gives a better fit for a straight line. The reaction is considered to be
of that order.

Figure: The graphs that are to be compared for differentorders to decide theorder of a chemical
reaction. (a) Zero Order (b) First order and (c) Second order

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2. Substitution Method
Conduct a kinetic experiment and collect the data on the time course of changes in the concentration of
reactants. Substitute the data in the integral equations of zero, first, and second order reactions to get the k
values.
𝑨𝑨𝟎𝟎− 𝑨𝑨𝑹𝑹
Zero order : 𝒌𝒌𝟎𝟎 =
𝑹𝑹

𝟐𝟐.𝟑𝟑𝟎𝟎𝟑𝟑 𝒄𝒄𝟎𝟎
First order : 𝑲𝑲𝝆𝝆 = 𝑳𝑳𝒐𝒐𝒈𝒈
𝑹𝑹 𝒄𝒄𝑹𝑹

Second order : 𝒌𝒌 = 𝝆𝝆 𝒙𝒙
𝟐𝟐 𝑹𝑹𝑹𝑹 (𝑹𝑹−𝒙𝒙)

Select the order in which k values at different time periods remain constant within the experimental errors.
The reaction is considered to be of that order.

3. Half Life Method

Calculate the average k value using the data for zero, first, and second orders as given in substitution method
or graphic method. Then, estimate the t1/2, values for each time period in the kinetic study. Equations are as
follows.
𝑹𝑹
Zero order : 𝑹𝑹𝝆𝝆/𝟐𝟐 =
𝟐𝟐𝒌𝒌𝑹𝑹

𝟎𝟎.𝟔𝟔𝟔𝟔𝟑𝟑
First order : 𝑹𝑹𝝆𝝆/𝟐𝟐 =
𝒌𝒌𝝆𝝆

Second order : 𝑹𝑹 =
𝝆𝝆 (where a = b)
𝝆𝝆/𝟐𝟐 𝑹𝑹𝒌𝒌𝟐𝟐

From the above equations, following relationships may be established.

Zero order : Half life is proportional to the initial concentration of the reactants.
First order : Half life is independent of the initial concentration of the reactants.
Second order : Half life is inversely proportional to initial concentration of the reactants (a = b).

In general, the relationship between half life and initial concentration is as follows.
𝝆𝝆
𝑹𝑹𝝆𝝆/𝟐𝟐 𝜶𝜶
𝑹𝑹𝒅𝒅−𝝆𝝆

Alternatively, conduct the experiments at two different initial concentration levels, a1, and a2 under
identical conditions. Then, the half lives t1/2(1) and t1/2(2) are related as follows.

𝒍𝒍𝒐𝒐𝒈𝒈 [𝑹𝑹𝝆𝝆(𝝆𝝆)] / [𝑹𝑹𝝆𝝆(𝟐𝟐)]

𝟐𝟐
𝒅𝒅 = 𝑹𝑹 𝟐𝟐 + 𝝆𝝆
𝒍𝒍𝒐𝒐𝒈𝒈( 𝟐𝟐)
𝑹𝑹𝝆𝝆

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Ans. 11: Enlist the different type of densities of powder. Write the experimental method
for the determination of true density.
Types of densities of powder:
1. True densities
2. Bulk densities
3. Granule densities

Experimental method for the determination of true density:

1. Helium displacement method (for porous powders)
2. Liquid displacement method (for non porous powders)

1. Helium displacement method (for porous powders) :

Helium penetrates the smallest pores and crevices. Therefore, this method gives a value closer to its true
density. This is a valuable tool to estimate the true density, particularly for porous solids.

Method :
 The schematic representation of helium pycnometer is shown in Figure.
 It consists of a sample holder (A), which can be sealed after placing the sample.
 The valve (B) is connected to the sample holder. It has provisions for removing the air from
the sample holder and introducing the helium gas.
 Helium gas is selected as it does not adsorb on the solid sample.
 A pressure detector (C) is included in order to maintain preset constant pressure. It has sealed
bellows which maintains the electric contact at a particular pressure.
 A piston (D) is attached in order to read the corresponding pressure, which is also related to the
volume of the powder.

Figure a: Parts and arrangement of helium pycnometer for determining the true volume of a
powder

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Procedure:

 Initially, the volume of empty pycnometer is determined. The air present in the sample holder is
removed by applying vacuum. Then, helium gas is passed into the apparatus through the valve
(B).
 The pressure is adjusted and set a particular value with the help of a movable piston (D). At
this position, the reading on the scale denotes U1. This represents the volume of empty cell.
 In the next step, pycnometer is calibrated by placing a standard sample of known true volume (Vc)
(stainless steel spheres) in the sample holder.
 The sample holder is sealed and air is removed. The same amount (as used in the first step) of
the helium gas is introduced. Pressure is adjusted to preset value by moving the piston suitably.
 At this stage, the scale reading is denoted by U2. The difference between U1 and U2 gives the
volume occupied by the sphere.
 The last step involves the determination of volume of the sample. The stainless steel sphere is
replaced by the test sample powder. The air in the pycnometer is replaced by helium gas (same
quantity as used in earlier steps). The pressure is adjusted with the help of piston.
 At this state, the piston reading is denoted by Us. The difference between U1 and Us gives the
volume occupied by the sample.
 The operating equation for the instrument is:
𝑽𝑽𝒄𝒄
𝑽𝑽𝑹𝑹 = [𝑼𝑼𝝆𝝆 − 𝑼𝑼𝒔𝒔]
𝑼𝑼𝝆𝝆 − 𝑼𝑼𝟐𝟐
Where, Vt = true volume of the sample

2. Liquid displacement method (for non porous powders):

 Liquids such as water and ethyl alcohol cannot occupy the pores and crevices. If the powder is
nonporous, this method is used.
 Select a solvent in which the powder is insoluble and heavy. Normally, the values obtained are
somewhat lower than the helium displacement method.

Method : Pycnometer or specific gravity bottle may be used.

Weight of pycnometer = W1
Weight of pycnometer + sample (or glass beads) = W2
Weight of sample = W3 = W2 – W1
Weight of pycnometer with powder and filled with solvent = W4
Weight of the liquid displaced by solids (related to volume of liquid displaced) = W4 - W2

𝒘𝒘𝟐𝟐 − 𝒘𝒘𝝆𝝆
𝑻𝑻𝑻𝑻𝑻𝑻𝑹𝑹 𝒅𝒅𝑹𝑹𝒅𝒅𝒔𝒔𝒅𝒅𝑹𝑹𝒅𝒅 =
𝒘𝒘𝒘𝒘 − 𝒘𝒘𝟐𝟐

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Ans. 12: Explain method for determining particle surface area.

There are two methods used for directly measuring the surface area of powder:

1. Adsorption method and,

2. Air permeability method.

1. Adsorption method:

 Particles having large specific surfaces are good adsorbents of gases and solutes from solution.

 Amount of gas that is adsorbed to form a monomolecular layer on the adsorbent is a function of surface
area of the powder.

 This principle is used to estimate the specific surface. This method is also used to estimate surface
diameter, ds.

2. Air permeability method:

 The instrumentation is simple and determination is quick. This method also used to estimate surface
diameter, ds.

 This method is useful in controlling batch to batch variations in production of powders. It is official in
I.P. Bephenium hydroxynaphthoate (An anthelmintic) is administered as a suspension.

 The I.P. prescribes the specific surface area limit of not less than 7000 cm2/g. As the specific
surface is reduced, the activity of the drug also falls.

 According to I.P., griseofulvin, an antifungal antibiotic, should have the surface area of not less than
13000 to 17000 cm2/g. If it is less, the absorption of the drug will fall.

Principle:

Powder is packed in the sample holder as a compact plug. In this packing, surface-surface contacts between
particles appear as a series of capillaries.

 The surface of these capillaries is a function of the surface area of the powder.

 The air, when allowed to pass, travel through these capillaries and thus this method is related to
surface area of powder. When air is allowed to pass through the powder bed at a constant pressure,
the bed resists the flow of air.

 This results in a pressure drop. The greater the surface area per gram of the powder, Sw the greater the
resistance to flow. The permeability of air for a given pressure drop is inversely proportional to specific
surface.

 The Kozeny-Carman equation is used to estimate the surface area by this method.

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Practical considerations :

The flow rate through the plug or bed is affected by:

1. Degree of compression: The more compact the plug, the lower the porosity, and greater is the
resistance to air flow.

2. Irregularity of the capillaries: Capillaries are not circular and are longer than the length of the
bed.

 Non-compliance with above equation may be due to bridging of the particles in the plug, i.e., the
powder bed is not homogeneous. When powders are compacted firmly, the bed becomes uniform. In
such cases, dvs reaches a minimum value.

Method:
 This method is official in I.P. Fisher subsieve sizer instrument is commercially abilable. Assemblin of th
apparatur is shown in fugure. It consists of a sample tube containingthe packed powder samplewith one
end connected to an pump through a constant pressure regulator.

 The other end is attached to a calibrated manometer containing a suitable liquid of low viscosity and
negligible vapor pressure.

 The air pump builds up air pressure and is connected to a constant pressure regulator.

 Air is passed through the dryer to remove any moisture. Air is then allowed to flow through the
packed powder in the sample tube.

 The flow of air is measured by the manometer. The level of the fluid in the manometer indicates the
average diameter of the particles. Commercial equipment is standardized to eliminate the
mathematical computation.

 Average particle diameter can be read from the calculator charts supplied with the equipment.

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Ans. 13: Give factors affecting powder flow

Factors affecting the flow properties of powder

1. Alteration of Particle’s size & Distribution

2. Alteration of Particle shape & texture

3. Alteration of Surface Forces

4. Formulation additives (Flow activators)

5. Moisture content

6. Packing property

7. Adhesion and cohesion

8. Humidity

9. Temperature

10. Pressure

1. Alteration of Particle’s size & Distribution:

 There is certain particle size at which powder’s flow ability is optimum. Coarse particles are more
preferred than fine ones as they are less cohesive.
 The size distribution can also be altered to improve flow ability by removing a proportion of the fine
particle fraction or by increasing the proportion of coarser particles such as occurs in granulation.

2. Alteration of Particle shape & texture Particle’s Shape:

 Irregular shapes can have markedly different flow properties due to difference contact areas. A group of
spheres has minimum interparticle contact and generally optimum flowability, whereas flakes or
irregular particles have a very high surface area and poor flow properties.

Figure: Characteristic particle shapes related to geometric shape and surface irregularity

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 Generally, more spherical particles have better flow properties than more irregular particles.
 Spherical particles are obtained by spray drying, or by temperature cycling crystallization.
 Particles with very rough surfaces will be more cohesive and have a greater tendency to interlock than
smooth surfaced particles.

3. Alteration of Surface Forces:

 Reduction of electrostatic charges can improve powder flow ability. Electrostatic charges can be reduced
by altering process conditions to reduce frictional contacts.
 Moisture content of particle greatly affects powder’s flow ability.
 Adsorbed surface moisture films tend to increase bulk density and reduce porosity.
 Drying the particles will reduce the cohesiveness and improve the flow. Hygroscopic powder’s stored
and processed under low humidity conditions.

4. Formulation additives (Flow activators):

 Flow activators are commonly referred as a glidants. Flow activators improve the flowability of powders
by reducing adhesion and cohesion.
 e. g. Talc, maize starch and magnesium stearate.

5. Moisture content:
 Absorbed moisture in solids can exist either in the unbound state or as part of crystal structure.
 Its effect directly change surface properties of the particles. It can also affect flow properties indirectly
and permanently through the granules formulation, which are held together by solid bridges generated by
hydration and dehydration.
 At higher moisture content and higher packing densities liquid bridges may progress. The effect of
moisture varies, depending on the degree of packing or the porosity of the powder bed.
 In a porous and cohesive material, flowability is not affected by moisture because the moisture can
penetrate to the inside of particle without the formation of liquid bridge

6. Packing property:
 A set of particles can be filled into a volume of space to produce a powder bed which is in static
equilibrium due to the interaction of gravitational and adhesive/cohesive forces.
 The change in bulk volume has been produced by rearrangement of the packing geometry of the
particles. In general, such geometric rearrangements result in a transition from loosely packed to more
tightly pack. More tightly packed powders require a higher driving force to produce powder flow than
more loosely packed particles.

7. Adhesion and cohesion:

 Cohesion occurs between like surfaces, such as component particles of a bulk solid, whereas adhesion
occurs between two unlike surfaces like between a particle and a hopper wall.
 Cohesion and other particle properties affect flow property of powder. Vander Waals, surface tension
and electrostatic forces are important properties related with powder flow.
 Adhesive/cohesive forces acting between a single pair of particle and substrate can be accurately
determined using a ultracentrifuge to apply very high forces strong enough to separate the two surfaces.

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Ans. 14: Enlist methods of particle size estimation. Explain conductivity method in
detail.
Methods to estimate particle sizes are:

a. Optical Microscopy

b. Sieving Method

c. Sedimentation Method

d. Conductivity Method

CONDUCTIVITY METHOD

 Particle size ranging from 0.5 to 500 µm is measured by conductivity method.

 This method gives number distribution. In fact, particle volume is measured and converted into
particle diameter, coulter counter is used to measure the particle volume.

 Thus, in this method, size is expressed as volume diameter, dv, which describes the diameter of
the sphere having the same volume as that of the asymmetric particle. This is a quick and accurate
method, but the instrument is expensive.

This method finds applications in the study of…..

(a) Particle growth in suspensions and solutions,

(b) Dissolution of drugs in a desired medium, and

(c) Effect of antibacterial agents on the growth of micro-organisms.

Principle:
 Working principle of the Coulter counter may be explained with the help of Figure. Particles
are suspended in a conducting electrolyte (say sodium chloride).

 This dispersion is filled in the sample cell, that has an orifice and maintains contact with the
external medium. Electrodes are placed in the solution (inside the cell) and suspension (outside)
as shown in Figure.

 A constant voltage is applied across the two electrodes. In this position current passes. When a
suspended particle travels through the orifice, it displaces its own volume of electrolyte into the
beaker.

 The net result is a change in electrical resistance. This change in electric resistance is termed as
voltage pulse, which is related to the particle volume.

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Ans. 16: Discuss the derived properties of powder

Derived properties of powders are:

1. Porosity
2. Densities of particles
3. Flow properties

1. Porosity:
The term porosity is used to define the number of small space or voids present within a solid material.

True volume = Volume of the powder itself.

Granule volume = Volume of the powder itself + volume of intraparticle spaces (represented by the
pores and crevices).
Bulk volume = Volume of the powder itself + volume of intraparticle spaces + volume of inter-particles
spaces (voids).

 If the powder is nonporous i.e., no internal pores or capillary spaces, the bulk volume consists of true
volume plus the volume of spaces between the particles, i.e., void volume.

The porosity or voids, ε, of the powder is defined as:

Prosity is frequently expressed in per cent

Above equation can aslo be expressed in terms of density values

𝛒𝛒𝐩𝐩− 𝛒𝛒𝐛𝐛
Per cent, 𝛆𝛆 = × 𝝆𝝆𝟎𝟎𝟎𝟎
𝛒𝛒𝐩𝐩

Above equation is valid for porous solids

Application:

Certain powders contribute immensely to the porosity of the tablet. Porosity influences the rate of
disintegration and dissolution. The higher the porosity, the faster the rate of dissolution. Based on porosity
values, solids can be classified as porous and nonporous. Porosity is applied in the studies on adsorption and
diffusion of drug materials.

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Packing arrangement:

The arrangement of particle in a powder influences the volume occupied by it. As a result bulk density and
subsequently porosity are affected.

When the particles are considered to be uniform size of spheres, then any one of the following packing
arrangements are possible theoretically…
Closest or rhombohedral packing, and
Most open, loosest or cubic packing

The arrangement of packing systems is shown in figure:

In practice, particles in a powder are neither spherical nor uniform in size. Therefore, any type of
packing between these ideal suituation is possible.

a. porosities of powder (spherical particles) are about 26%. It means closed packing.
b. porosities of powder (spherical particles) are about 48%. It means loose packing.

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c. porosities of powder, in general, are between 30% and 50%.

d. Porosities below 30 are possible, if the particles differ greatly iin the size distribution. The small particles
accommodate the voids between large particles.
e. porosities above 50% are possible, when the particles are aggregated and flocculated.

3. Densities of particle:

a. True density

 The density is dependent on the type of atoms in a molecule, arrangement of the atoms in a
molecule and the arrangement of molecules in the sample. Apart from true density, powder is
also characterized by granule density and bulk density. Their differences are shown in Figure.

b. Granule Density:

Granule density is determinedfor the granules that are employed in the manufacture of tablets.
It is defined as:

The volume of granulescan be measured by mercury displacement method. Mercury is suitable because it
fillst the voids, but fails to penetrate the internal pores of the particles. The use ofmercury is also based on its
high contact angle of about 140o and its nonwetting characteristics.

Granule volume is related to weight of the mercury that is displaced by the granules in pycnometer.

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c. Bulk density

 When particles are packed loosely, lots of gaps between particles are observed. Hence, bulk
volume increases making the powder light. Based on bulk volume, powders are classified as
“light” and “heavy”. Light powders have high bulk volume. On the other hand, smaller particles
may shift between the larger particles, the powder assume low bulk volume or high bulk density. Such
powders are called heavy powders.

3. Flow Properties:

- Angle of repose
- Carr’s index

Angle of repose:
Angle of the repose is the maximum angle possible between the surface of a pile of powder and the
horizontal plane. It can be mathematically expressed as:

Figure a: Angle of repose apparatus

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Figure b: Angle of repose for Fine sand, Coarse sand, Angular pebbles

Relationship between angle of Repose (θ) and powder flow:

Angle of repose (θ) Flow

(degrees)
< 25 Excellent
25-30 Good
30-40 Passable
>40 Very poor

Carr’s index:

It is defined as
𝑻𝑻𝑹𝑹𝑻𝑻𝑻𝑻𝑹𝑹𝒅𝒅 𝒅𝒅𝑹𝑹𝒅𝒅𝒔𝒔𝒅𝒅𝑹𝑹𝒅𝒅−𝒐𝒐𝒍𝒍𝑻𝑻𝒐𝒐𝒐𝒐 𝒅𝒅𝑹𝑹𝒅𝒅𝒔𝒔𝒅𝒅𝑹𝑹𝒅𝒅
Consolidation index =
𝑻𝑻𝑹𝑹𝑻𝑻𝑻𝑻𝑹𝑹𝒅𝒅 𝒅𝒅𝑹𝑹𝒅𝒅𝒔𝒔𝒅𝒅𝑹𝑹𝒅𝒅

This property is also known as compressibility. It is indirectly related to the relative flow rate,cohesiveness
and particle size. It issimple,fast and popular mehod of predicting powder flow characteristics.

Grading of the powders for their flow properties according to Carr Index:

Consolidation indix Flow

(Carr, %)
5-15 Excellent
12-16 Good
18-21 Fair to passable
23-35 Poor
33-38 Very Poor
>40 Very very poor

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Ans. 17: Derive equation of rate of reaction and half life for first order kinetics.
First Order Reaction
First order reaction is defined as a reaction in which the rate of reaction depends on the concentration
of one reactant. Mathematically, the first order rate equation can be written as:
−𝑠𝑠𝑓𝑓 −𝑠𝑠𝑓𝑓
∝ 𝑓𝑓 = 𝑘𝑘 1 𝑓𝑓 ..................... Equation 1
𝑠𝑠𝑈𝑈 𝑠𝑠𝑈𝑈

where c is the concentration of the reactant and k1 is the specific rate constant for first order.

Examples:
Decomposition of hydrogen peroxide catalyzed by 0.02M potassium iodide.

 The stoichiometric equation involves 2 molecules, i.e., molecularit is two. But the order is found
to be first order, based on experimental observation. In the presence of stabilisers, this reaction
follows zero order kinetics. In other words, same drug may exhibit different orders of decomposition
under different experimental conditions.
Acid hydrolysis of ethylacetate and methylacetate.
Inversion of sugar (sucrose).
Disintegration of radioactive elements.

 Examples of biological importance are as follows:

Diffusion of drug across biological membranes
Absorption, distribution, metabolism and excretion of drugs Growth of microorganisms
Rate of killing of microorganisms by heat

Derivation : Consider the reaction

A Product

 According to the definition of first order, rate expression is written as:

−𝑠𝑠𝑓𝑓 (2)
𝑘𝑘1𝑓𝑓
𝑠𝑠𝑈𝑈

Integrating equation (2) between concentration Co at time t=o and conc. Ct at time t=t gives

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 Equation (5) permits the calculation of rate constant. Specific rate constant can at best be obtained
from a plot of log concentration vs. time (Figure a). Slope of the line is equal to k1/2.303, from
which k1 can be calculated. The unit for k1 is reciprocal time, i.e., hours-1, minutes-1etc.

Figure a: A typical plot for a first order reaction. Drawn as per equation (4)

 The k1 value explains the fraction of the reactant consumed per unit time. For example, if k1= 0.01 sec-1,
the rate of reaction is 1 per cent per second.
 If a straight line is obtained for any set of data as indicated in Figure, then that reaction must follow
first order. Equation (5) can be used to estimate the concentration of reactant remained at the end of a
definite period of time.
 Sometimes equation (5) is written as,

where
‘a’ is same as Co and ‘x’ is the concentration of the reactant consumed during time t. Now, (a - x) is Ct.
The exponential form of the first order rate equation is:

The exponential form in the logarithms to the base 10 is:

 Equations (7) and (8) indicate that the decrease in the concentration of the reactant is
monoexponential with time. The representative plot for equation (8) is given in Figure b.

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 In other words, when a graph is plotted by taking concentration on y axis and time on jt axis,
a curve will be obtained. The trend is described as asymptotic i.e., it takes infinite time for the
concentration to reach zero level (Figure b). This is typical first order.

Figure b: An asymptotic (or monoexponential) plot for a reaction that follows first order. Drawn as
per equation (8)

Half life :
It is the time required to reduce the concentration of the reactant to half of its initial concentration.
As per the definition, the terms in equation (5) change to,

 The half life of a reaction can be determined by equation (9). Half life, at best, can be obtained by
reading the time scale in the plot for the concentration to decrease to half of its starting point on
the y axis (Figure c).
 The units are time units, i.e., hours, minutes or seconds. According to equation (9), the half life
period is independent of the initial concentration in a first order reaction.
 It is important to mention here a comment on the concept of half life. Theoretically, the first order
equation (7 or 8) is asymptotic, i.e., it takes an infinite period of time for the reaction to
complete.

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Figure c: Estimation of half life and shelf life directly from the graph

Shelf life:
It is the time required to reduce the concentration of the reactant to 90 per cent of its initial concentration.
As per the definition, the terms in equation (5) change to:
90
𝑓𝑓 = ( ) 𝑓𝑓 t = 𝑈𝑈
𝑈𝑈 100 0 90

Substituting these terms in equation (5) and rearranging it gives

2.303 𝑓𝑓0
𝑈𝑈90 = log
𝑘𝑘1 0.9𝑓𝑓0

2.303 10
𝑈𝑈90 = log
𝑘𝑘1 9

0.105
𝑈𝑈90 =
𝑘𝑘1

The relation between shelf life and half life is

𝑈𝑈90 = 0.152𝑈𝑈1
2

Above equation indicates that the shelf life values are lesser compared to the half life (Figure c)

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Ans. 18: Write a short note on second order reaction.

Second order Reaction
Second order reaction is defined as a reaction in which the rate depends on the concentration terms of
two reactants each raised to the power one.

Consider the following reaction

A + B ------- > Products

 The rate equation can be written as,

−𝑠𝑠𝑑𝑑 𝑠𝑠𝑑𝑑
=− = k2[A]1[b]1 (1)
𝑠𝑠𝑈𝑈 𝑠𝑠𝑈𝑈

 Where [A] and [B] are the concentration of A and B, respectively, and k2 is the specific rate constant for
second order. In other words, the rate of reaction is first order with respect to A, and again first order
with respect to B. So the overall order of this reaction is second order.

 Proof of a second order reaction can be verified by plotting log concentration of A vs. time. A
straight line indicates that it is a first order with respect to A. Similarly, we can establish a linear
relationship by plotting an appropriate graph with respect to B. This is the proof for a second order
reaction.

Examples :
(a) Alkaline hydrolysis of esters such as methylacetate or ethylacetate.
(b) Hydrolysis of chlorbutanol in presence of sodium hydroxide.

Derivation :
As per the definition, the rate equation for second order is:
−𝑠𝑠𝑑𝑑 𝑠𝑠𝑑𝑑
=− = k2[A][b] (1)
𝑠𝑠𝑈𝑈 𝑠𝑠𝑈𝑈

Let a and b be the initial concentrations of A and B, respectively, and ‘x’ be the concentration of each
species reacting in time t. Substituting these terms in equation (1) gives;
−𝑠𝑠𝑑𝑑 𝑠𝑠𝑑𝑑
=− = k2(a-x)(b-x)
𝑠𝑠𝑈𝑈 𝑠𝑠𝑈𝑈

Now consider a case where a = b (both A and B have the same concentration). Then the above equation
changes to equation (2)
𝑠𝑠𝑑𝑑
= k2 (a-x)2 (2)
𝑠𝑠𝑈𝑈

Integrate equation (2) employing the conditions x = 0 at t = 0 and x = x at t = t.

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(3)

Equation (3) is the integral equation for second order reaction, where a= b. If x/a(a-x) is plotted against time,
t (on x axis), a straight line with a positive slope is obtained. Intercept will not be zero. This graph permits
the estimation of k2.

Since ‘a’ is defined as the initial concentration of the reactant which is normally a constant, plot of x/(a-x)
vs. time also gives a straight line with a positive slope. The slope is equal to k2/a.

 The units for k2 are conc-1 time-1 . When the concentration of reactants is expressed as moles/liter, then
k2 has units liter/mol.time (min).

When a≠b, the integral equation is:

2.303 𝑏𝑏(𝑈𝑈−𝑑𝑑)
K2 = log (4)
𝑈𝑈(𝑈𝑈−𝑏𝑏) 𝑈𝑈(𝑏𝑏−𝑑𝑑)

 When log[{b{a-x)}/{a{b-x)}) is plotted against t, a straight line with a positive slope can be obtained
(Figure b). The slope is equal to k2(a-b)/2.303. thus, k2 can be calculated.
 In pharmaceutical dosage forms, second order reactions are pretty rare. The reaction conditions
will be suitably modified to follow pseudo first order.

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Half life:
It is the time required to reduce the concentration of the reactant to half of its initial
concentration.
As per the definition, the terms in equation (3) change to

(5)

 Equation (5) is valid for a second order reaction when a = b. Similarly when a≠b, the half life
equation can be derived. The units for half life for second order are time/conc.

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Ans. 19: Enumerate Physical and chemical factors influencing the chemical
degradation of pharmaceutical product and explain any one
The different Physical and chemical factors which influencing the chemical degradation of pharmaceutical
products are:

Physical Factor:
1. Loss of Volatile constitutents
2. Loss of Water
3. Absorption of water
4. Crystal Growth
5. Polymorphism
6. Colour changes

Chemical Factor:
1. Temperature
2. Solvent
3. Ionic Strength
4. Dielectric constant, and
5. Specific and general acid-base catalysis.

Temperature:

The speed of many reactions increases about two or three times with every 10° rise in temperature.
Arrhenius equation explains the effect of temperature on the rate of a reaction.

k=Ae-Ea/RT (1)
Where,
k = Specific reaction rate constant
A = Arrhenius factor
Ea = Energy of activation
R = Gas constant (1.987 calories/deg mole)
T = Absolute temperature

Take logarithms both sides

ln k = ln A - 𝑬𝑬𝑹𝑹 (2)
𝑹𝑹𝑻𝑻

Converting equation (2) to log base 10 gives

log k = log A - 𝑬𝑬𝑹𝑹

(3)
𝟐𝟐.𝟑𝟑𝟎𝟎𝟑𝟑𝑹𝑹𝑻𝑻

Energy’ of activation is defined as the minimum energy that a molecule should possess so that
molecular collisions produce the product.

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Arrhenius factor is defined as the frequency of collisions which can occur between molecules.

‘A’ is the product (multiplication) of the number of molecular collisions and probability factor of collisions
which give a reaction product. The collision theory takes into account of the fact that not every molecular
collision between molecules leads to product-formation.

Mechanism :
 The collision theory postulates that collisions must occur between molecules for the reaction to proceed.
Furthermore, the reaction between molecules does not take place unless the colliding molecules possess
certain energy.

 These two factors are appropriately included in the Arrhenius equation (equation 1). At any given
temperature a fixed number of molecules possess a certain energy. As the temperature rises, more
molecules absorb energy and get activated. These activated molecules arc responsible for increased rate
of reaction. By and large, these principles are applicable to all orders of reactions.

 The decomposition may sometimes increase rather than decrease when a product is stored at low
temperature. In cool place, the dissolved oxygen content in the solution increases. This will enhance the
rate of oxidation. While low temperature reduces the rate, high oxygen content enhances it. The net
effect is to be evaluated.

 In frozen solutions, the rate of the reaction is high, if the concentration of reactants in liquid phase is
more. Normally, the solute molecules being excluded from the ice lattice and thus become concentrated.

 An increase in rate may sometimes be observed due to change in pH on freezing. For example, proteins
are particularly sensitive to changes in pH. Folding or unfolding of structure may occur to a varying
degree. Proteins tend to be most stable at their isoelectric point, owing to electrostatic interaction. When
optimum pH is adjusted with buffer at room temperature, the pH may not be maintained throughout the
lyophilization cycle. Thus proteins may aggregate.

Estimation of k :
The reaction is conducted at several temperatures. The concentration ol reactant is determined at different
time periods at each temperature. Appropriate graphs are drawn for the kinetic data. As per the principles of
kinetics, data is processed for all the orders for each temperature. The order of reaction is identified. From
the slopes of the lines, k values are calculated for all temperatures.

Estimation of energy of activation :

Equation (3) represents a linear pattern. So, a graph can be drawn by taking log k on y axis and reciprocal
temperature (1/T) on x axis. When data are plotted, a straight line will be obtained (Figure a).

To get a line, we need log k values at least at three temperatures. For a better fit, data at more than three
temperatures are required. The slope of the line is negative and the magnitude is equal to Ea/2.303R. The
intercept corresponds to log A. Thus all the constants in the Arrhenius equation may be obtained from the
graph.

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Figure a: A plot of log k vs. Reciprocal temperature for the fhermal decomposition of aspire. Drawn
as per equation (3)

Ea can also be obtained by substituting data in equation (3). Write the equation for a temperature, T2
𝑬𝑬𝑹𝑹
log k2 = log A - (4)
𝟐𝟐.𝟑𝟑𝟎𝟎𝟑𝟑𝑹𝑹𝑻𝑻𝟐𝟐
For another temperature, T1, the equation is
𝑬𝑬𝑹𝑹
log k1 = log A - (5)
𝟐𝟐.𝟑𝟑𝟎𝟎𝟑𝟑𝑹𝑹𝑻𝑻𝝆𝝆

Subtracting equation (5) from equation (4) gives

𝑬𝑬𝑹𝑹
log k2 - log k1 = log A - - log A + 𝑬𝑬𝑹𝑹
𝟐𝟐.𝟑𝟑𝟎𝟎𝟑𝟑𝑹𝑹𝑻𝑻𝟐𝟐 𝟐𝟐.𝟑𝟑𝟎𝟎𝟑𝟑𝑹𝑹𝑻𝑻𝝆𝝆

𝑬𝑬𝑹𝑹 𝝆𝝆 𝝆𝝆
log 𝒌𝒌𝟐𝟐 = [ − ]
𝒌𝒌𝝆𝝆 𝟐𝟐.𝟑𝟑𝟎𝟎𝟑𝟑𝑹𝑹 𝑻𝑻𝝆𝝆 𝑻𝑻𝟐𝟐

𝑬𝑬𝑹𝑹 𝑻𝑻𝟐𝟐−𝑻𝑻𝝆𝝆
log 𝒌𝒌𝟐𝟐 = [ ] (6)
𝒌𝒌𝝆𝝆 𝟐𝟐.𝟑𝟑𝟎𝟎𝟑𝟑𝑹𝑹 𝑻𝑻𝝆𝝆𝑻𝑻𝟐𝟐

 Data for two different temperatures are substituted in equation (6) and solved for Ea. The Ea value is
substituted in any one equation (4 or 5) of specific temperature to get Arrhenius factor.

 Ea can also be estimated by using half-life values (instead of k values) vs. reciprocal temperature. This
method requires the derivation of an appropriate equation for each order based on the relationship
between k and t1/2. For example, the half-life for a first order reaction is related to k.
𝟎𝟎. 𝟔𝟔𝟔𝟔𝟑𝟑
𝑹𝑹𝝆𝝆/𝟐𝟐 =
𝒌𝒌𝝆𝝆

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Take logarithms on both sides

𝐥𝐥𝐥𝐥𝐥𝐥 𝑹𝑹𝝆𝝆/𝟐𝟐 = 𝐥𝐥𝐥𝐥𝐥𝐥 𝟎𝟎. 𝟔𝟔𝟔𝟔𝟑𝟑 − 𝐥𝐥𝐥𝐥𝐥𝐥 𝒌𝒌𝝆𝝆

Substituting log k1 value in equation (3) gives

𝑬𝑬𝑹𝑹
𝐥𝐥𝐥𝐥𝐥𝐥 𝟎𝟎. 𝟔𝟔𝟔𝟔𝟑𝟑 − 𝐥𝐥𝐥𝐥𝐥𝐥 𝑹𝑹𝝆𝝆/𝟐𝟐 = 𝒍𝒍𝒐𝒐𝒈𝒈𝑨𝑨 −
𝟐𝟐. 𝟑𝟑𝟎𝟎𝟑𝟑𝑹𝑹𝑻𝑻

𝑬𝑬𝑹𝑹
𝒍𝒍𝒐𝒐𝒈𝒈𝑹𝑹𝝆𝝆/𝟐𝟐 = 𝐥𝐥𝐥𝐥𝐥𝐥 𝟎𝟎. 𝟔𝟔𝟔𝟔𝟑𝟑 − 𝐥𝐥𝐥𝐥𝐥𝐥 𝑨𝑨 +
𝟐𝟐. 𝟑𝟑𝟎𝟎𝟑𝟑𝑹𝑹𝑻𝑻

In this equation, ‘A’ is a constant, therefore

𝑬𝑬𝑹𝑹
𝐥𝐥𝐥𝐥𝐥𝐥 𝑹𝑹𝝆𝝆/𝟐𝟐 = 𝟐𝟐.𝟑𝟑𝟎𝟎𝟑𝟑𝑹𝑹𝑻𝑻
+ 𝑪𝑪𝒐𝒐𝒅𝒅𝒔𝒔𝑹𝑹𝑹𝑹𝒅𝒅𝑹𝑹 (7)

According to equation (7) a graph is drawn by plotting log t1/2 against 1/T. A straight line with a positive
slope will be obtained (Figure b).

Slope is equal to Ea/2.303R. It is possible to derive similar expressions for zero and second order (where a =
b). These expressions will be similar to equation (7). Arrhenius factor can be estimated using Ea.

Application of temperature and estimation of energy of activation are important to predict the product
stability.

Figure b: A plot of half life vs. reciprocal temperatue for the hydrolysisof aspirin in 0.1N hydrochloric
acid. Drawn as perequation (7)

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Ans. 20: Discuss the various means of stabilization of product which is sensitive to
oxidation
 Oxidation involves the removal of electrons from a molecule. The reaction between the
compounds and molecular oxygen is called autooxidation.

 In fats and oils, autooxidation of unsaturated fatty acids proceeds in the presence of atmospheric
oxygen, light and traces of heavy metals or organic peroxides. For example, the rate of oxidation of
ascorbic acid is increased by a factor of 105, when copper ions are present in the concentration
of 0.002 M.

 Similarly hydroperoxides contained in polyethylene glycol suppository bases have been implicated in
the oxidation of codeine to codeine-N-oxide.

The general principles that govern an oxidation reaction may be listed as follows.

 The presence of atomospheric oxygen (also air) promotes the rate of oxidation.

 Since oxidation frequently involves free radicals, chain reactions occur. Light provides the necessary
energy to initiate the oxidation process.

 The presence of trace metals also accelerate the rate of oxidation.

 Organic peroxides promote the chain initiation and propagate the oxidation reaction.

 Drugs are either weak acids or bases. Therefore, these may be available as ionic forms or
neutral molecules. Oxidation reaction between ionic species proceeds faster than with neutral
molecules (to a large extent it is solubility related phenomenon).

 Oxidation reactions are catalysed by H+ and OH- ions. Hydroxyl ions catalyse oxidation faster than
hydrogen ions. Alkaline solutions are known to react with atmospheric oxygen and form oxides.

Drugs which decompose by oxidation pathways are given below.

 Arachis oil, Ethyl oleate, Clove oil, Cinnamon oil, Promethazine, epinephrine, Vitamin A,
Riboflavin, Vitamin B12, Ascorbic acid, Morphine, Prednisolone

The autooxidation kinetics of ascorbic acid has been extensively studied. The overall reaction may be
represented as:

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Influence of Trace Metals : The scheme of oxidation of ascorbic acid by cupric ion is as follows:

When solutions are fee from traces of copper, ascorbic acid is not oxidized by molecular oxygen to a
measurable extent, except in alkaline solutions. However, even traces of copper lead to the rapid oxidatiton
of ascorbic acid. When CO and KCN are added to the above reaction mixture, they form complexes with
metal ions, and therefore, oxidation of ascorbic acid is inhibited. These reactions demonstrate the influence
of cupric ion on theocidation ofascorbic acid.

Influence of air on oxidation : The rate of decomposition decreases when higher concentration of
ascorbic acid is used. It is presumed that a part of the ascorbic acid reacts with oxygen and
thus depletes free oxygen. When air is bubbled through the reaction mixture, the rate of oxidation
is enhanced. When dissolved oxygen is maintained at saturation level, the reaction rate remains
constant. Therefore, oxygen is responsible for the autooxidation reactions.

Influence of ionic species of drugs : Ascorbic acid can exist as a singly charged or doubly
charged ion. In the absence of copper ions, oxygen is found to react with divalent ions at about
105 times faster compared to its reaction with monovalent ascorbate ion. When copper ions are
added, oxidation of the singly charged ascorbate ion alone is found to be catalysed.

Influence of acidic and basic ion species : The acid and base catalysed oxidation on ascorbic acid
proceeds as follows. Dehydroascorbic acid (degradation product) further degrades to give ketogulonic
acid, which in turn gives threonic acid and oxalic acid.

In general, autooxidation proceeds more readil in alkaline medium than in acidic solution. Alkaline solutions
are known to react with atmospheric oxygne and form oxides.

Protection against Oxidation:

Oxidation reactions take place in the presence of oxygen, trace metals, and H+ and OH- ions, therefore,
many protective steps has to be taken to terminate the factors promoting oxidation:

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Anti-Oxidants:
 Many natural (e.g., tocopherols, ascorbic acid, etc.) and synthetic anti-oxidants (e.g., butylated
hydroxyl anisole, butylated hydroxy toluene, propyl gallate, etc.) are widely used in foods,
cosmetics, and drugs to inhibit oxidation reactions. Mechanism of these agents is to break the
free radical chain reactions at the chain propagation step. Most of these compounds are oil soluble
antioxidants.
 Water-soluble antioxidants act by preferentially undergoing oxdition instead of the drug itself. Example
is ascorbic acid. Compound having –SH groups molecular oxygen present in solution. Examples are
cysteine, acetylcysteine, thioglycolic acid etc.

Chelating Agents:
 Addition of chelating agent to a product will be useful when traces of heavy metals catalyse the
oxidation. Substances such as EDTA (ethylendediamine tetraacetic acid) citric acid and tartaric
acid, form complexes with heavy metals. Thus, metal ions are notavailable to catalyse the oxidation.
For example, addition of EDTA to buffer system prevents the degradation of drugs such as prednisolone
and ascorbic acid.
 Another variation is that boric acid forms a one-to-one chelate directly with the drug, epinephrine. The
chelated epinephrine is far less susceptible to sulfite attack than free epinephrine. Thus oxidation of
epinephrine is inhibited.

Vehicles:
 Usually water is used as a solvent for most products. The replacement of water by other solvents is often
employed as a means of stabilizing drugs. But, other solvents when used in combination with water, they
have catalyzing effect on oxidation. Production of hydroperoxides through these solvents is implicated in
the degradation. Some empirical generalisations are enumerated below.

o If the internal pressure (polarity) of solvents is high, these favour the formation of products with high
internal pressure, On the other hand, if the internal pressure of reactants is higher than the products,
solvents with high internal pressure retard the rate of reaction. Similar relationship is observed with
solubility parameters.
o In a dilute solution, if one of the reactants is neutral molecule, the rate of reaction is independent of
the ionic strength.
o The use of solvent mixture, which lowers the dielectric constant, may increase the rate of reaction. If
the solution contains ions of like charges, an increase in the dielectric constant results in an increase
in the rate of the reaction.
o If the solution contains ions of opposite signs, solvents with high dielectric constant decreases the
rate constant.

Micellar solubilisation :

Surfactants such as polysorbate 80 enhance the rate of oxidation of ascorbic acid at low concentration, but
protect above its critical micelle concentration (cmc), presumably by entrapping the drugs in the spherical
micelles. Sometimes, spherical micelles offer a site for surface adsorption of catalytic ions and enhance rate
of reaction.

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Buffers :
Buffer system imparts stability when oxidation is catalysed by H+ or (OH)- ions. Choose a buffer with
appropriate pH to maintain maximum stability of the product.

Environmental control measures:

One or more of the following preventive measures are employed to stabilisethe product from oxidation.

Prevent the exposure to light: Light is responsible for oxidation. The preparation is protected from light by
employing amber coloured bottles or usig appropriate packaging material (cardboard). For example
morphine sulphate injection USP is proteted from light by using amber coloured ampoules.

Oxygen free enviromnemt: oxygen enhances ocidative degradation. Therefore, air is replaced with inert
gasees susch as nitrogen or caron dioxide. Similarly, use of oxygen free solvents in manufacture is
advisable.

Low temperature storage: since high temperature enhances the rate of reaction, the product is stored in a
cool place.

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