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Singh, AK., Chaurasiya, A., Singh, M., Upadhyay, SC., Mukherjee, R. and Khar, RK.;
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development and optimization; AAPS Pharm. Sci.Tech.; vol. 9, no. 2, pp. 628–634,
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(c)
(d)
4.
(a)
(b)
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Great Britain. Volume II, 6th ed.; 2010, 650210.
Exercises
Multiple Choice Questions Carrying 01 Mark
An excipient is used in a formulation for which of the following purpose?
To alter the dose.
To facilitate the manufacturing process
To alter stability characteristics of the formulation
None of the above
During manufacture of a product which of the following point must be kept in mind?
Properties and limitation of excipients used
Properties and limitation of the drug substance
Advantages and limitations of the method used
All of the above
Which of the following components is not generally used in a capsule dosage form?
Sucrose powder
Dry starch powder
Starch powder
Talcum
Complexing agent is generally used for the purpose of
Decreasing the bioavailability of poorly water soluble drugs.
Increasing the bioavailability of water soluble drugs.
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(c)
(d)
5.
(a)
(b)
(c)
(d)
6.
(a)
(b)
(b)
(d)
7.
(a)
(b)
(c)
(d)
8.
(a)
(b)
(b)
(d)
9.
(a)
(b)
(b)
(d)
10.
(a)
Increasing the bioavailability of drugs which are very soluble in water.
Increasing the bioavailability of poorly water soluble drugs.
A volatile substance can be formulated by using
Macromolecule
Maintaining a particular pH
Suitable viscosity imparting agent
Diluent
Pseudo polymorphism generally occurs
On grinding
After crystallization
Before crystallization
After heating
Solvolysis is which type of interaction between two or more components in the
formulation
Physical interaction between drug and solvent
Physical interaction between drug and cosolvent
Chemical interaction between drug and solvent
Chemical interaction between solvent and cosolvent
Which of the functional groups mentioned are not involved in solvolysis
Imide
Amide
Lactam
Carboxylic acid
Which of the following impurities is commonly found in talcum powder?
Heavy metals
Peroxides
Chlorides
Formaldehyde
A chemical degradation of the drug having smaller therapeutic windows, causes
The plasma concentration become too high to exert toxic effect
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(b)
(c)
(d)
11.
(a)
(b)
(b)
(d)
12.
(a)
(b)
(c)
(d)
13.
(a)
(b)
(c)
(d)
14.
(a)
(b)
(b)
(d)
15.
(a)
(b)
(c)
(d)
The plasma concentration become too less to make them therapeutically
ineffective.
All of the above
None of the above
Which of the following dosage form is subjected to degradation under humid
condition?
Solution
Tablets
Suspension
Aerosol
Which of the following statements is correct?
Pearl is a dispersion of solid in solid
Pearl is a dispersion of solid in liquid
Pearl is a dispersion of liquid in liquid
Pearl is a dispersion of liquid in solid
Thermodynamic equilibrium of a dispersion system depends on
Surface free energy of the system
Surface tension of the dispersed phase
Surface tension of the dispersion medium
Interfacial tension of the system
The size of the dispersed particles/globules is the lowest, in case of
Microemulsion
Nanoemulsion
Colloidal emulsion
Emulsion
Which of the following is not considered a reason for instability of drug?
Keeping the size of package unchanged
No modification of the formula
Changes in the sterilization method
Changes in the manufacturing process
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16.
(a)
(b)
(c)
(d)
17.
(a)
(b)
(c)
(d)
18.
(a)
(b)
(b)
(d)
19.
(a)
(b)
(c)
(d)
20.
(a)
(b)
(c)
(d)
In an injection the color of the injectable solution may changes due to
Presence of nitrogen in the head space
Addition of EDTA in the product
Presence of air in the head space
None of the above
The free energy of a self- emulsifying formulation can be calculated as
Free
energy=∑(Number of droplets × diameter of droplet × interfacial energy)
Free
energy=∑(Number of droplets × radius of droplet × interfacial energy)
Free
energy=∑(Number of droplets × diameter of droplet × interfacial energy)/4
Free
energy=∑(Number of droplets × diameter of droplet × interfacial energy)/2
Which of the following ingredients should be present in dispersed phase of a
suspension?
Buffers
Thickeners
Osmotic agents
Preservatives
Non-aqueous emulsion systems are widely used
For making topical emulsion only
As a dosage form only
As solvents for drugs
None of the above
An emulsion becomes stable and uniform when
The particle size of the droplets varies from 1 – 1000 µm
The particle size of the droplets varies from 10 – 1000 µm
Its internal phase contains the droplets varies from 0.10 – 1000 µm
Its internal phase contains fine and mono-sized droplets,
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2.
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4.
5.
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7.
8.
9.
10.
1.
2.
3.
4.
5.
6.
7.
8.
Short Questions Carrying 3-5 Marks
What are the reasons for which different excipients are incorporated in a
pharmaceutical formulation?
What are different classes of excipients in solid dosage forms and mention the
function of each.
What is pseudopolymorphism? Give an example of pseudopolymorphism
What is oxidative stress testing in stability testing?
What are different classes of the dispersion?
What are factors related to thermodynamic equilibrium of dispersion?
How the wetting of particles is related to dispersion?
Explain briefly the Newtonian flow of liquid.
Under what circumstances an emulsion remains stable and uniform?
What is the principle behind the formulation of self-micro emulsifying drug delivery
system?
Long Questions Carrying 7-9 Marks
Explain how oxygen and water can decompose a drug in its formulation?
Explain in brief the mechanisms of drug degradation.
Explain in short how the drug and excipient physically interact.
Discuss briefly what happens in photo degradation.
Describe briefly salient features of different types of dispersion classified on the basis
of particle size.
How the non-Newtonian flows of liquid is related to stability of suspensions?
Explain the mechanism of self emulsifying drug delivery system.
On what basis the excipients for SMEDDS are selected?
Answers
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
b d a d a b c d a c b d a b d c a b c d
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CHAPTER 2
Optimization Techniques
Concept and parameters of optimization, IU-Optimization techniques in pharmaceutical
formulation and processing. Statistical design, Response surface method, Contour designs,
Factorial designs and application in formulation.
Concept of Optimization
The term, optimization is defined as selecting the best one among the set of available
alternatives . Alternatively it means to make as possible as perfect, effective, or functional .
The phrase, “as possible” raises the following questions subsequently.
What is meant by perfect?
For which characteristics?
Under what conditions?
What are the quantities of ingredients to be taken?
Which ingredients?
When to be added?
How to be added?
Under which environment?
Since long, pharmaceutical manufacturing has been practiced on the basis of individual
knowledge and experience to develop dosage forms. The formulations have been developed
based on intuitive and subjective judgment. No rational operation was available. Thus, the
entire process may or may not be optimal. Sometimes, formulation scientists face different
problems in manufacturing a drug product –
Meeting the biopharmaceutical requirements,
Commercial production methods, and
Process reproducibility within a limited time and funds.
’Trial and error method’ is primarily costly and inefficient; extrapolations, if done, have not
been found to be accurate and practical. The regulations circulated by the Food and Drug
Administration are strict and rigorous; for example, manufacturing process to be used for
commercial production of a product must be well characterized and validated. Moreover, for
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•
•
•
•
obtaining the approval of a product of a New Drug molecule, it is must be demonstrated that
the product shall exhibit its therapeutic effect in a predictable manner as expected.
The concept of optimization has been originated from the field of chemical engineering and
mathematics 1 . It provides the required information efficiently without spending much effort
in experimentation. It has been reported
2-5
that this concept can be used in pharmaceutical
cases where more than two variables are there. It started with optimization of convention
dosage forms. However, least data have been published demonstrating the application of
optimization methods to relatively difficult job such as preparation of high dose
acetaminophen tablets using microcrystalline cellulose
6,7
by wet granulation method.
Optimization technique requires minimal knowledge about computer programming and
optimization mathematics. The formulator should find out the solutions to the problems by
using the process of optimization, otherwise it will be unrealistic. The optimization method
can also be used to get some desirable pharmaceutic and pharmacokinetic parameters by
varying the process and formulation parameters.
Physical, chemical, and biological properties of a dosage form must be considered during
selection of ingredients and processing step for that dosage form. In pharmaceutical
development work the researcher performs the experiment logically in a series of steps,
controls the variables and changes one at a time until satisfactory results are obtained. In this
way, the optimization is done in pharmaceutical industries. It is a technique of choosing the
best possible way to use the most suitable resource taking into account of all the factors that
influence the design or decisions in any experiment. The objective of designing the quality
formulation by using different optimization techniques such as design of experiment (DOE)
is to produce a product with almost ‘zero defects’. The concept is to arrive at the design by
quality (QbD), formulation by design (FbD). The FbD has replaced the concept of one
variable at a time (OVAT) for optimization 8 . To understand the concept of optimization the
following should be understood.
Design of Experiment (DOE)
It is primarily a mathematical means used for systematic planning and performing scientific
studies that change experimental variables to determine their effect on a given response
9-14
.
It allows changing the variables of input in a controlled manner to get maximum information
about the relationship between cause and effect for optimizing the formulation with
minimum sample size. Usually four steps are associated with DOE:
Design of the experiment (By using various models)
Collection of the data
Statistical analysis of the data, and
Conclusions and recommendations made on the experiment.
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The process of optimization involves various steps. In general, it involves the following
steps as shown below.
There are various models used for optimization, from screening of factors to section of their
levels and finally studying their effects. Hence, it depends on the formulation scientist to
select the most suitable model for the study and to help in minimizing the experimentation
time.
Experimental Design
It is a statistical design prescribing and advising a set of combination of variables. Within the
experimental region, the number and layout of these design points, depend on the number of
effects that must be estimated. Various experimental designs are selected on the basis of (1)
the number of factors, (2) their levels, (3) possible interactions, and (4) order of the model.
Within the domain of experiment, each experiment can be expressed as a point; the point
should be defined by its value given to the variable (co-ordinate)
15-17
.
There are various types of methods of experimental design.
Screening Designs are used to recognize the important factor and to select their levels which
can influence the quality of the product. Generally, this supports only linear responses.
Response Surface Designs are used when (1) exact image of the response, (2) estimation of
interaction, and (3) quadratic effects are required. Generally, this type of design supports
non-linear and quadratic response is able to detect the curvatures.
Factorial designs (FDs) are commonly used as response surface designs. In factorial
designs all levels of a particular factor are combined with all levels of every factor in an
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experiment. Generally, these are based on first-degree mathematical models. Complete
factorial designs involve examining of the effect of all the factors (k) at different levels (x).
When the interactions are included among these, the total numbers of experiments become x
k
. In the optimization study, if the number of levels is same for each factor, the factorial
designs are considered as symmetric. In case of a different number of levels for different
factors, the factorial designs are called asymmetric. For example, in a study of three factors
at two levels, the total number of run will be 2 3 = 08 and for two factors at three-level, the
total number of run will be 3 2 = 09.
Fractional Factorial Design (FFD) is commonly used to screen the factor. Since the
number of run is less, this design has low resolution. In terms of number of experiments, this
design is economical. The ability to differentiate some of the factor effects is partially
avoided by reducing the number of trials.
Plackett-Burman Designs (PBD) is special two-level design used for screening of factors.
This type of design is generally used when there are high numbers of factors. For example,
to study the effect of 7 factors, it becomes necessary to show 4 dummy factors. The PlackettBurman Design and Taguchi design are to be drawn with the help of Pareto chart and half
normal plot for interpretation of the results in FFD.
Central Composite Design (CCD) is used for nonlinear responses that require second-order
models and under such circumstances central composite designs (CCDs) are the most
frequently used. With rectangular experimental domain a two-factor CCD is identical to a 32
FD at α = ±1, On the other hand, the experimental domain is spherical in shape for α = √2 =
1.414. The CCD is fairly popular in response surface optimization during pharmaceutical
product development.
Box-Behnken Designs (BBD) is a specially made design which requires only three levels
for each factor –l, 0 and +1. It requires 15 experiments to run with three factors at three
levels. It is economical than CCD, because it requires less number of trial.
Taguchi Design is an experimental design usually referred to as "offline quality control",
because it is a method which can ensure good performance in the development of products
or processes. It is also used for screening of factors, and it provides 8 experimental run for 7
factors.
Mixture Designs are commonly used when the characteristics of the finished product
usually depends moderately on the quantity of each substance present; that is, on their
proportions. The total of the proportions of all the excipients becomes unity, and none of the
fractions can be negative. Therefore, the levels of different components can be varied with
the restriction that the sum should not be more than one.
Parameters of Optimization
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