Gpd unit ii

GPD-UNIT - II
 Design of dosage form to meet equivalence to
reference listed drug,
 Product development steps,
 Formula optimization,
 Process optimization and
 Packaging selection.

Introduction to Dosage Form Design
2

1. PRINCIPLES
• Drugs are
substances
rarely administered as pure chemical
alone and are almost always given as
formulated preparations or medicines. These can vary
from relatively simple solutions to complex drug delivery
systems through the use of appropriate additives or
excipients in the formulations. The excipients provided
varied and specialized pharmaceutical functions. It is the
formulation additives that, amongst other things,
solubilize, suspended, thicken, preserve, emulsify, modify
dissolution, improve the compactability and flavour drug
substances to form various medicines or dosage forms.
3

CONSIDERATIONS
difference in• Consideration should be given to
bioavailability between apparently similar
formulations and possible causative reasons.
• In recent years, increasing attention has therefore
bioavailability characteristics, particularly
been directed towards eliminating variation in
for
medicinal products containing an equivalent dose of a
drug substance, as it is recognized that formulation
factors can influence their therapeutic performance.
4

Biopharmaceutical considerations
• Drug substance must be in solution form before it can be absorbed
via the absorbing membranes and epithelia of skin, gastrointestinal
tract and lungs into body fluids.
Drug administered via buccal, respiratory, rectal, intramuscular or
subcutaneous routes, it passes directly into the blood-stream from
absorbing tissues, but the intravenous route is the most direct of all.
Drug administered by oral route the onset of drug action will be
delayed because of the transit time in the gastrointestinal tract, the
absorption process and hepatoenteric blood circulation features.
The physical form of oral route influences the absorption rate and
onset of action, with solutions acting faster than suspensions, which
in turn generally act faster than capsules and tablets.
•
•
•
5

Biopharmaceutical considerations
6

• The absorption pattern of drugs varies considerably
between individual drug substances as well as between
the different administration routes. Dosage forms are
designed to provide the drug in a suitable form for
absorption from each selected route of administration.
Oral route
Rectal route
Parenteral route
Topical route
Respiratory route
•
•
•
•
•
2. ROUTES OF ADMINISTRATION
7

ORAL ROUTE
• The oral route is the most frequently used route for
drug administration. Oral dosage forms are intended
usually for systemic effects resulting from drug
absorption through the various epithelia and mucosa
of the gastrointestinal tract. A few drugs, however,
are intended to dissolve in the mouth for rapid
absorption or for local effect in the tract due to poor
absorption by this route or low aqueous solubility.
Compared with other routes, the oral route is the
simplest, most convenient and safest means of drug
administration.
8

RECTAL ROUTE
• Drugs given rectally in solution, suppository or emulsion
form are generally administered for local rather than
systemic effects. Suppositories are solid forms intended
for introduction into body cavities (usually rectal but also
vaginal and urethral) where they melt, releasing the drug
and the choice of suppository base or drug carrier can
greatly influence the degree and rate of drug release. This
route of drug administration is also indicated for drugs
inactivated by the gastrointestinal fluids when given
orally or when the oral route is precluded, as for example
when a patient is vomiting or unconscious.
10

PARENTERAL ROUTE
• A drug administered parenterally is one injected via a
hollow needle into the body at various sites and to
varying depths. The three main parenteral routes are
subcutaneous (s.c.), intramuscular (i.m) and
intravenous (i.v). Other routes such as intracardiac
and intrathecal are used less frequently. The
parenteral route is preferred when rapid absorption is
essential, as in emergency situations or when patients
are unconscious or unable to accept oral medication,
and in cases when drugs are destroyed, inactivated or
poorly absorbed following oral administration.
11

PARENTERAL ROUTE
IV:
Intravenous,
IM:
Intramuscular,
SC:
Subcutaneous
12

TOPICAL ROUTE
• Drugs are applied topically, that is to the skin, mainly
for local action. Whilst this route can also be used for
systemic drug delivery, percutaneous absorption is
often poor and erratic, although several transdermal
patches delivering drug for systemic distribution (e.g.
glyceryl trinitrate patches for the prophylaxis and
treatment of angina) are available. Drugs applied to
the skin for local effect include antiseptics,
antifungals, antiinflammatory agents, as well as skin
emollients for protective effects.
• E.g. ointments, creams and pastes
13

RESPIRATORY ROUTE
• The lungs provide an excellent surface for absorption
when the drug is delivered in gaseous, aerosol mist or
ultrafine solid particle form, For drug particles
presented as an aerosol or solid form, particle size
largely determines the extent to which they penetrate
the alveolar region, the zone of rapid absorption.
• Drug particles that are in the region 0.5-1m diameter
reach the alveolar sacs. Particles smaller than this
range are either exhaled or, if larger, deposited upon
larger bronchial airways.
1
5

ROUTES OF ADMINISTRATION
Administration route Dosage form
Oral Solutions, syrups, suspensions, emulsions, gel, powders,
granules, capsules, tablets
Rectal Suppositories, ointments, creams, powders, solutions.
Topical Ointments, creams, pastes, lotions, gels, solutions, topical
aerosols, transdermal patches
Parenteral Injections (Solutions, suspensions, emulsion forms),
implants, irrigation and dialysis solutions.
Respiratory/Lungs Aerosols (Solutions, suspension, powder form), inhalations,
sprays and gases.
Nasal Aerosols (Solutions), inhalations
Eye Solutions, ointments, solutions
Ear Solutions, suspensions, ointments, creams.
1
7

3. DRUG FACTORS IN DOSAGE FORM DESIGN
1. Particle size and surface area
2. Solubility
3. Dissolution
4. Partition coefficient pKa
5. Crystal properties: polymorphism
6. Stability
7. Organoleptic properties
8. Other drug properties 18

PARTICLE SIZE AND SURFACE AREA
• Particle size reduction results in an increase in the
specific surface (i.e. surface area per unit weight) of
powders.
• Drug dissolution rate, absorption rate, dosage form
content uniformity and stability are all dependent to
varying degrees on particle size, size distribution and
interactions of solid surface.
• In many cases, for both drugs and additives, particle
size reduction is requires to achieve the desired
physiochemical characteristics.
19

SURFACE AREA
• The fine material, often in micrometer or
submicometer (nanometer) form with large specific
surface, dissolves at faster rates which can lead to
improved drug absorption by passive diffusion.
• On the other hand, with formulated nitrofurantoin
preparations an optimal particle size of 150 m
reduced gastrointestinal distress whilst still permitting
sufficient urinary excretion of this urinary
antibacterial agent.
20

SOLUBILITY
• Relatively insoluble compounds can exhibit erratic or
incomplete absorption, and it might be appropriate to
use more soluble salt or other chemical derivatives.
• Alternatively, micronizing, complexation or solid
dispersion technique might be employed.
• Solubility, and especially degree of saturation in the
vehicle, can also be important in the absorption of
drugs already in solution in liquid dosage forms since
precipitation in the gastrointestinal tract can occur,
modifying bioavailability.
21

DISSOLUTION
• During dissolution, the drug molecules in the surface
layer dissolve, leading to a saturated solution around
the particles to form the diffusion layer.
• Dissolved drug molecules then pass throughout the
dissolving fluid to contact absorbing mucosa and are
absorbed.
• Replenishment of diffusing drug molecules in the
diffusion layer is achieved by further drug dissolution
and the absorption process continues.
22

PARTITION COEFFICIENT pKa
• One of the first properties of a molecule that should
be predicted or measured is its partition coefficient
between an oil and a water phase (log P).
• This gives a measure of the lipophilicity of a
molecule, which can be used as a prediction as to how
it will be able to cross a biological membrane.
• One of the most common ways of measuring partition
coefficient is to use the shake flask method.
23

CRYSTAL PROPERTIES:
polymorphism
• Practically all drug substances are handled in powder
form at some stage during manufacturing into dosage
forms.
• Many drug substances can exist in more than one form
with different molecular packing arrangements in the
crystal lattice.
• This property is termed polymorphism and different
polymorphs my be prepared by manipulation of
conditions of particle formation during crystallization
such as solvent, temperature and rate of cooling.
2
4

STABILITY
• The chemical aspects of formulation generally centre
on the chemical stability of the drug and its
compatibility with the other formulation ingredients.
• It should be emphasized that the packaging of the
dosage form is an important factor contributing to
product stability and must be an integral part of
stability testing programmes.
physical modifications to the
• Chemical changes involving additives and any
product must be carefully monitored to optimize
formulation stability.
25

ORGANOLEPTIC PROPERTIES
• Modern medicines require that pharmaceutical dosage
forms are acceptable to the patient. Unfortunately, many
drug substances in use today are unpalatable and
unattractive in their natural state and dosage forms
containing such drugs, particularly oral preparations, may
require the addition of approved flavours and/or colours.
The use of flavours applies primarily to liquid dosage
forms intended for oral administration.
Colours are employed to standardize or improve an
•
•
existing drug colour, to mask a colour change or
complement a flavour.
26

OTHER DRUG PROPERTIES
• At the same time as ensuring that dosage forms are
chemically and physically
therapeutically efficacious, it is
stable
also
and are
relevant to
establish that the selected formulation is capable of
efficient and, in most cases, large-scale manufacture.
• Hygroscopic drugs can require low moisture
manufacturing environments and need to avoid water
during preparation.
• Poorly flowing formulations may require the addition
of flow agents (e.g. fumed silica).
27

4. OTHER FACTORS
(diss., part.coef., stability)
• Studies of the compactability of drug substances are
frequently undertaken using instrumented tablet
machines in formulation laboratories to examine the
tableting potential of the material in order to foresee
any potential problems during compaction, such as
lamination or sticking, which may require
modification to the formulation or processing
conditions.
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5. THERAPEUTIC
CONSIDERATIONS IN DESIGN
• The nature of the clinical indication, disease or illness
against which the drug is intended is an important
factor when selecting the range of dosage forms to be
prepared.
• Factors such as the need for systemic or oral therapy
duration of action required, and whether the drug will
be used in emergency situations, need to be considered.
• Patients requiring urgent relief from angina pectoris, a
coronary circulatory problem, place tablets of
nitroglycerin sublingually for rapid drug absorption
directly into the blood capillaries there.
29

VARIOUS STAGES OF NEW
PRODUCT DEVELOPMENT
'New products' can be:
 Products that your business has never made or sold
before but have been taken to market by others
 Product innovations created and brought to the market
for the first time. They may be completely original
products, or existing products that you have modified and
improved.
 New products are responsible for employment,
economic growth, technological progress, and
high standards of living.

8 - STEPS OF
NEW PRODUCT DEVELOPMENT

1. Idea generation
The first step in new-product development is idea
generation.
New ideas can be generated by:
•Conducting marketing research to find out the
consumers' needs and wants.
•Inviting suggestions from consumers.
•Inviting suggestions from employees.
•Brainstorming suggestions for new-product ideas.
•Searching in different markets viz., national and
international markets for new-product ideas.
•Getting feedback from agents or dealers about
services offered by competitors.
•Studying the new products of the competitors.

2. Idea screening
Most companies have a "Idea Committee." This committee
studies all the ideas very carefully. They select the good ideas
and reject the bad ideas.
Before selecting or rejecting an idea, the following questions are
considered or asked:
•Is it necessary to introduce a new product?
•Can the existing plant and machinery produce the new
product?
•Can the existing marketing network sell the new product?
•When can the new product break even?
If the answers to these questions are positive, then the idea of a
new-product development is selected else it is rejected. This
step is necessary to avoid product failure

The screeners should ask
several questions:
Marketing factors:
Potential market size
Compatibility of market image with company's product
lines
Relationship to competing products
Compatibility with existing or specified market
channels
Access to suitable physical distribution systems
Fits into an acceptable pricing structure
Relationship to promotional methods and resources
Marketing resources needed to produce success

Production factors:
Compatibility with existing product lines
Availability of processing equipment
Availability of raw materials and ingredients
Availability of technical skills to produce the product
Availability of production time
Agreement with any legal requirements
Cost and availability of new resources required

Development factors:
Knowledge needed for development
Available knowledge and skills
Available time and human resources
Development funds needed and
available
Compatibility with existing strengths
Development difficulties and risks of
failure

Financial factors:
Compatibility of development costs with
financial resources
Capital investment resources needed and
available
Finance needed and available for market
launch and on-going product support
Profits or returns on investment required
By answering these questions, the company can
get a better idea of the likelihood of a product
becoming a commercial success.

3. CONCEPT TESTING
Concept testing is done after idea screening. It is different from
test marketing.
In this stage of concept testing, the company finds out:
•Whether the consumers understand the product idea or not?
•Whether the consumers need the new product or not?
•Whether the consumers will accept the product or not?
Here, a small group of consumers is selected. They are given
full information about the new product. Then they are asked
what they feel about the new product. They are asked whether
they like the new product or not. So, concept testing is done to
find out the consumers' reactions towards the new product. If
most of the consumers like the product, then business analysis
is done.

4. BUSINESS ANALYSIS
Business analysis is a very important step in new-product
development. Here, a detailed business analysis is done. The
company finds out whether the new product is commercially profitable
or not.
Under business analysis, the company finds out...
•Whether the new product is commercially profitable or not?
•What will be the cost of the new product?
•Is there any demand for the new product?
•Whether this demand is regular or seasonal?
•Are there any competitors of the new product?
•How the total sales of the new product be?
•What will be the expenses on advertising, sales promotion, etc.?
•How much profit the new product will earn?
So, the company studies the new product from the business point of
view. If the new product is profitable, it will be accepted else it will be
rejected.

IDENTIFY BUSINESS GOALS:
To develop marketing strategy, identify overarching business goals, so
that set of marketing
goals can be defined to support them. Business goals might include:
Increasing awareness of the products and services
Selling more products from a certain supplier
Reaching a new customer segment.
When setting goals it's critical to be as targeted as possible so that
outcomes can be effectively measure against what the targets are set out
to achieve. A simple criterion for goal-setting is the SMART method:
 Specific - state clearly what you want to achieve
 Measurable - set tangible measures so you can measure your results
 Achievable - set objectives that are within your capacity and budget
 Relevant - set objectives that will help you improve particular aspects
of your business
 Time-bound - set objectives you can achieve within the time you need
them.

5. PRODUCT DEVELOPMENT
At this stage, the company has decided to introduce a new
product in the market. It will take all the necessary steps to
produce and distribute the new product.
The production department will make plans to produce
the product.
The marketing department will make plans to distribute
the product.
The finance department will provide finance for
introducing the new product.
The advertising department will plan the advertisements
for the new product.
However, all this is done as a small scale for Test Marketing.

6. TEST MARKETING
Test marketing means to introduce the new product on a very
small scale in a very small market. If the new product is
successful in this market, then it is introduced on a large scale.
However, if the product fails in the test market, then the
company finds out the reasons for its failure. It makes
necessary changes in the new product and introduces it again
in a small market. If the new product fails again the company
will reject it.
Test marketing reduces the risk of large-scale marketing. It is a
safety device. It is very time-consuming. It must be done
especially for costly products.

7. COMMERCIALIZATION
If the test marketing is successful, then the company
introduces the new product on a large scale, say all over
the country. The company makes a large investment in the
new product. It produces and distributes the new product
on a huge scale. It advertises the new product on the mass
media like TV, Radio, Newspapers, and Magazines, etc.

8. REVIEW OF MARKET PERFORMANCE
The company must review the marketing performance of the
new product.
It must answer the following questions:
•Is the new product accepted by the consumers?
•Are the demand, sales and profits high?
•Are the consumers satisfied with the after-sales-service?
•Are the middlemen happy with their commission?
•Are the marketing staffs happy with their income from the new
product?
•Is the Marketing manager changing the marketing mix
according to the changes in the environment?
•Are the competitors introducing a similar new product in the
market?
The company must continuously monitor the performance of the
new product. They must make necessary changes in their
marketing plans and strategies else the product will fail.

Optimization Techniques in
pharmaceutical Formulation
and Processing
Optimization Techniques in pharmaceutical
Formulation and Processing

1. CONCEPT OF OPTIMIZATION:
 The term optimize is defined as “ to make perfect”.
 In terms of sentence it is defined as choosing the best element
from some set of available alternatives.
 According to Merriam Webster dictionary, optimization
means, “ An act, process or methodology of making something
(as a design, system or a decision) as a fully perfect, functional
or effective as possible; specially the mathematical procedures.
 Optimization is also defined as “The process of finding the
best values for the variables of a particular problem to
minimize or maximize an objective function.”

 It is used in pharmacy relative formulation and processing.
 It is involved in formulating drug products in various forms.
 Final product not only meets the requirements from the bio-
availability but also from the practical mass production
criteria.
 It helps the pharmaceutical scientist to understand theoretical
formulation and the target processing parameters which ranges
for each excipients & processing factors.
 In development projects, one generally experiments by a series
of logical steps, carefully controlling the variables & changing
one at a time, until a satisfactory system is obtained

“It is not a screening technique.”
Optimization is necessary because,
1. It reduces the cost.
2. It provides safety and reduces the error.
3. It provides innovation and efficacy.
4. It saves the time.

2.PARAMETERS OF OPTIMIZATION:
Parameters of optimization is divided into two
main types which is shown schematically:
optimization parameters
problem type variables
constrained unconstrained dependent independent
formulating processing

A. Problem type:
There are two generaltype are there in the problem type of
optimization technique:
1. Constrained
2. Un constrained
3. Constrained :
Theseare the restrictions placed on the system by physical
limitations or perhaps by simple practicality.
Example : Economical considerations
2.Un constrained:
Here there are no restrictions.
With the help of flow chart we can predict these two
problem type very easily viz.,

B. Variables:
Mathematically, they can be divided into two groups
a. Independent or primary variables
b. Dependent or secondary variables
a. Independent or primary variables:
Formulations and process variables directly under control of the
formulator.
Example: Ingredients
Mixing time for given process step.

B. Dependent or secondary variables:
These are the responses or the characteristics of the in-
progress material or the resulting drug delivery system.
Example: Direct result of any change in the formulation or process.

 If greater the variables in a given system, then greater will be
the complicated job of optimization.
 But regardless of the no.of variables, there will be relationship
between a given response and independent variables.
 Once we know this relationship for a given response, then will
able to define a response surface i.e.,

 It involves application of calculus to basic problem for
maximum/minimum function.
 Limited applications
i. Problems those are not too complex.
ii. They do not involve more than two variables.
 For more than two variables, graphical representation is
impossible, but it is possible mathematically.

3.OPTIMIZATION TECHINQUES IN
PHARMACEUTICAL
FORMULATION & PROCESSING
Deming and king presented a general optimization techniques:

Considering the changes in input and effect on output,
the optimization techniques are categorized into five types:
1. Evolutionary operations
2. Simplex method
3. Lagrangian method
4. Search method
5. Canonical analysis

1.EVOLUTIONARY OPERATIONS
(EVOP):
 It is the one of the most widely used methods of experimental
optimization in fields other than pharmaceutical technology is
the evolutionary operation(EVOP),
 It is well suited to production situation.
 The basic idea is that the production procedure(formulation
and process) is allowed to evolve to the optimum by careful
planning and constant repetition.

Method:
This process is run in a such a way that
A. It produces a product that meets all specifications.
B. Simultaneously, it generates information on product
improvement.
 Experimenter makes a very small change in the formulation
or process but makes it so many times i.e., repeates the
experiment so many times.
 Then he or she can be able to determine statistically whether
the product has improved.
 And the experimenter makes further any other change in the
same direction, many times and notes the results.
 This continues until further changes do not improve the
product or perhaps become detrimental.

Applications:
1. It was applied to tablets by Rubinstein.
2. It has also been applied to an inspection system for parenteral
products.
Drawbacks:
1. It is impractical and expensive to use.
2. It is not a substitute for good laboratory scale investigation.

2. SIMPLEX METHOD:
Formulation and
Processing
 It is most widely applied technique.
 It was proposed by Spendley et.al.
 This technique has even wider appeal in areas other than
formulation and processing.
 A good example to explain its principle is the application to
the development of an analytical method i.e., a continuous
flow anlayzer, it was predicted by Deming and king.
 Simplex method is a geometric figure that has one or more
point than the number of factors.
 If two factors or any independent variables are there, then
simplex is represented triangle.
 Once the shape of a simplex has been determined, the method
can employ a simplex of fixed size or of variable sizes that are
determined by comparing the magnitude of the responses after
each successive calO
cp
utim
laiza
tt
iio
onT
nec
.hniquesin pharmaceutical

Graph representing theOpstiimmizaptiloenxTemchnoiqvueesminpehanrmtsacteoutictahl e optimum
conditions
Formulation and
Processing

Explaination:
 The two axes in the figure are nothing but two independent
variables show the pump speeds for the two reagents required
in the analysis reaction.
 The initial simplex is represented by the lowest triangle.
 The vertices represent the spectrophotometric response.
 The strategy is moves towards a better response.
 The worst response is 0.25, conditions are selected at the
vertex, 0.6 and indeed improvement is obtained.
 Then the experiment path is followed to obtain optimum,
0.721.

Applications of method:
1. This method was used by Shek.et.al. to search for an capsule
formula.
2. This was applied to study the solubility problem involving
butaconazolenitrate in a multicomponent system.
3. Bindschaeder and Gurny published an adaptation of the
simplex technique to a TI-59 calculator and applied
successfully to a direct compression tablet of acetaminophen.
4. Janeczeck applied the approach to a liquid system i.e., a
pharmaceutical solution and was able to optimize physical
stability.

3. THE LAGRAGIAN METHOD:
 This optimization method represents the mathematical
technique, is an extension of the classic method.
 Fonner.et.al gave ideas of understanding this technique by
applying it to a tablet formulation and by considering two
independent variables.

Explaination :
 The active ingredient, phenylpropanolamine HCl , was kept at
a constant level, and the levels of disintegrant (corn starch)
and lubricant (stearic acid) were selected as the independent
variables x1 and x2 .
 The dependent variables include tablet hardness, friability,
volume, in vitro release rate and urinary excretion rate in
human subjects.
 This techniques requires that the experimentation to be
completed before optimization so that mathematical models
can be generated.

The experimental data for the taken
example : Tablet formulation:

 The analysis is performed on a polynomial form.
6 1 2 7 1y = B0 + B1x1+ B2x2+ B3x1
2+ B4x2
2 + B5x1 x2 + B x x 2 + B x 2
x2+ B8x1
2x2
2
And these terms were retained and eliminated according to stand
stepwise regression techniques.
In above equation ,
y = Any given response
Bi = The regression co-efficient for the various terms containing
levels of the independent variables,
 Each response have its own equation.
 A graphic technique may be obtained from the polynomial
equations.

Figure a.
It shows the contours for tablet hardness as the levels of the
independent variables are changed.

Figure: b
It shows similar contour for the dissolution response t50%

Figure c.
The above graph shows the feasible space with the limits of
hardness be 8-10 kg and t50 % be 20-33 min.
This figure is obtained by superimposing a and b.

In the mathematical technique slightly different constraints are
used.
In this example.
The constrained optimization problem is to locate levels of stearic
acid (x1) and starch (x2)
That minimizes the time of invitro release (y2)
Such that the average tablet volume (y4) did not exceed 9.422
cm2 and the average friability (y3) did not exceed2.72%.

To apply the Lagrangian method, this problem must be expressed
mathematically as follows:
……………..(1)Minimize y2 = F2 (x1 , x2)
such that
y3 = F3 (x1 , x2) ≤ 2.72
y4 = F4 (x1 , x2) ≤ 0.422
……………...(2)
………………(3)
And 5 ≤ x1 ≤ 45 ………….. (4)
1 ≤ x2 ≤ 41 ………….. (5)
Equation (4) and (5) are the solution within the experimental
range.

 The foregoining inequality constraints must be converted to
equality constraints before the operation begins and this is
done by introducing a slack variable ‘q’ foreach.
 The several equations are then combined into a Lagrange
function F and this necessitates the introduction of a Lagrange
multiplier ⅄for eachconstraint.
 The partial differentiation of Lagrange function and solving
the resulting set of six simultaneous equations, value are
obtained for x1 and x2 to yield an optimum invitro time of
17.9mm (t50 %).
 The solution to a constrained optimization program may
depend heavily on the constraints applied to the secondary
objectives.

 A technique called “sensitive analysis” can provide
information so that the formulator can further trade off one
property for another.
 For sensitivity analysis the formulator solves the constrained
optimization problem for systemic changes in the secondary
objectives.

Explaination:
The foregoing problem restricted tablet friability, y3 to maximum
of 2.72 %.
The graph illustrates the invitro release profile as constraint is
tightened or relaxed and demonstrates that substantial
improvement in the t50 % can be obtained up to 1- 2%.

The several steps in the Lagrangian method can be written as
follows:
Step-1 : Determine objective function.
Step-2 : Determine constraints.
Step-3 : Change inequality constraints to equality constraints.
Step-4 : Form the Lagrange function, F
a. One Lagrange multiplier ⅄for eachconstraint.
b. One slack variable q for each inequality constraint.
Step-5 : Partially differentiate the Lagrange function for each
variable and set derivatives equal to zero.
Step-6 : Solve the set of simultaneous equations.
Step-7 : Substitute the resulting values into the objective
functions.

This can be phased into four phases, this was given by Buck et.al
The phases are:
a. A preliminary planning phase
b. An experimental phase
c. An analytical phase
d. A verificationphase

4.SEARCH METHODS:
 It is defined by appropriate equations. It does not require
continuity or differentiability of function. It is applied to
pharmaceutical system
For optimization 2 major steps are used
• Feasibility search-used to locate set of response constraints
that are just at the limit of possibility.
• Grid search – experimental range is divided in to grid of
specific size & methodically searched

STEPS INVOLVED IN SEARCH METHOD
 Select a system
 Select variables
 Perform experiments and test product
 Submit data for statistical and regression analysis
 Set specifications for feasibility program
 Select constraints for grid search
 Evaluate grid search printout

Example:

• Five independent variables dictates total of 32 experiments.
This design is known as five-factor, orthogonal, central,
composite, second order design.
• First 16 formulations represent a half-factorial design for five
factors at two levels.
• The two levels represented by +1 & -1, analogous to high &
low values in any two level factorials.
Translation of statistical design in to physical units

Experimental conditions:

Then the data is subjected to statistical analysis followed by
multiple regression analysis.
The equation used in this design is second order polynomial.
y = a0+a1x1+…+a5x5+a11x12+…+a55x25+a12x1x2+a13x1x3+a45x4x5
 A multivariate statistical technique called principle
component analysis (PCA) is used to select the best
formulation.
 PCA utilizes variance-covariance matrix for the
responses
involved to determine their interrelationship.

For single variable:

Plots for five variables

Advantages of search method:
It takes five independent variables in to account.
Persons unfamiliar with mathematics of
optimization & with no previous computer
experience could carry out an optimization
study.

5. Canonical analysis
 It is a technique used to reduce a second order regression
equation. This allows immediate interpretation of the
regression equation by including the linear and interaction
terms in constant term.
 This was firstly adopted by Box and Wilson,
 It is used to reduce second order regression equation to an
equation consisting of a constant and squared terms as follows:
Y = Y0 +λ1W1
2 + λ2W2
2 +…
 It is described as an efficient method to explore an empherical
response.

PACKAGING SELECTION.
What is Packaging?
Selection criteria for Packaging material
Characteristics of Packaging material
Uses of Packaging
Types of Packaging
1.Primary
2.Secondary
3.Tertiary
Types of Packaging material
1.glass
2.Metals
3.Rubber
4.Plastic
5.Fibrous materials
6.Films,Foils & Laminates

PACKAGING
93
Packaging is the science, art, and technology of
enclosing or protecting products for distribution,
storage, sale, and use.
Packaging also refers to the process of design,
evaluation, and production of packages.
Packaging may also be deﬁned as the collection of
different components (e.g. bottle, vial, closure, cap,
ampoule, blister) which surround the pharmaceutical
product from the time of production until its use.

SELECTION CRITERIA FOR
PACKAGING MATERIAL
94
There are many factorswhichneed to considerwhen selecting a
suitable type of pack for the product:
• The product or pack contents
• The application of the product
• Content stability, and the need of protection from any
environmental factors
• Content reactivity
(with relevant to the packaging material)
• Acceptibilty of the pack to the consumer or user
• The packaging process
• Regulatory, legal and quality issues

CHARACTERISTICS OF
PACKAGING MATERIAL:
95
The material selected must have the following
characteristics:
•Must meet tamper-resistance requirements
•Must be FDAapproved
•Must be non-toxic
•Must not impart odor/taste to the product
•Must not reactive with the product
•They must protect the preparation from environmental
conditions

USES OF PACKAGING:
96
•Physical protection: It protects from, among other things, mechanical
shock, vibration, electrostatic discharge, compression, temperature, etc.
•Information transmission: Packages and labels communicate how to use,
transport, recycle, or dispose of the package or product. With pharmaceuticals,
food, medical, and chemical products, some types of information are required
by governments.
•Marketing: The packaging and labels can be used by marketers to encourage
potential buyers to purchase the product.
•Convenience: Packages can features that add convenience in
distribution, handling, display,
have
sale, opening, re-closing, use, reuse,
recycling, and ease of disposal.

•Security: Packaging can play an important role in reducing the security
risks of shipment. Packages can be made with improved tamper
resistance to deter tampering and also can have tamper-evident features to
help indicate tampering. Packages can be engineered to help reduce the
risks of package pilferage.
97

TYPES OF PACKAGING
Primary packaging is the material that first envelops the product
and holds it. This usually is the smallest unit of distribution or
use and is the package which is in direct contact with the
contents.
Examples: Ampoules,Vials ,Containers ,Dosing dropper
,Closures (plastic, metal) ,Syringe ,Strip package, Blister
packaging.
98

Secondary packaging
It is outside the primary packaging– perhaps used to
group primary packages together.
Example: Paper and boards, Cartons ,Corrugated
fibers ,Box
99

Tertiary packaging
It is used for bulk handling , warehouse storage
and transport shipping. The most common form is a
palletized unit load that packs tightly into
containers.
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TYPES OF PACKAGING MATERIAL
10
1
I) Glass
II) Metals
III) Rubbers
IV) Plastics
V) Fibrous material
VI) Films, Foils and laminates

GLASS:
Glass has been widely used as a drug packaging
material.
glasses are made from three main materials—sand
(silicon dioxide, or SiO2), limestone (calcium carbonate,
or CaCO3), and sodium carbonate (Na2CO3). ... By
adding about 25 percent of the sodium oxide to silica,
the melting point is reduced from 1,723 to 850 °C
(3,133 to 1,562 °F).
Si, Al, Na, K, Ca, Mg, Zn & Ba are generally used
into preparation of glass
10
2

13
Advantages
• They are hygienic and suitable for sterilization
• They are relatively non reactive ( depending on the
grade chosen)
• It can accept a variety of closures
• They can be used on high speed packaging lines
• They are transparent.
• They have good protection power.
• They can be easily labeled.
Disadvantages
• It is relatively heavy
• Glass is fragile so easily broken.
• Release alkali to aqueous preparation

METALS
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4
 Metal containers are used solely for medicinal products
for non-parenteral administration.
 Metal is strong, opaque, impermeable to moisture, gases,
odors, light, bacteria, and shatterproof, it is the ideal
packaging material for pressurized containers.
 It is resistant to high and low temperatures
 They include tubes, packs made from foil or blisters,
cans, and aerosol and gas cylinders.
 Aluminium and stainless steel are the metals of choice for
both primary and secondary packaging for medicinal
products.
 Form an excellent tamper evident containers.

• Thickest aluminium is used for rigid containers such as
aerosol cans and tubes for effervescent tablets.
• Intermediate thickness are when mechanical integrity is still
important but the pack should be capable of being reformed
under a reasonable force.
e.g. Collapsible tubes for semi solid preparations or roll on
screw caps.
• Thinnest aluminium is used in flexible foil that are usually a
component of laminated packaging material.
10
5
For e.g. ALUMINIUM

RUBBERS (Elastomers):
10
6
• Excellent material for forming seals, used to form closures
such as bungs for vials or in similar applications such as
gaskets in aerosol cans.
Categories of Rubbers:
1) NATURAL RUBBERS
• Suitable for multiple use closures for injectable products as
rubber reseals after multiple insertion of needle.
• Disadvantages are;
i. It doesn't well tolerate multiple autoclaving becoming
brittle and leads to relative degree of extractable material
in presence of additives.
ii. Risk of product absorbing on or in to a rubber.
iii. It has certain degree of moisture & gas permeation.

17
2) SYNTHETIC RUBBER:
• Have fewer additives and thus fewer extractable and
tends to experience less sorption of product
ingredients.
• Are less suitable for repeated insertions of needle
because they tend to fragment or core pushing small
particles of the rubber in to the product.
• E.g. Silicone, butyl, bromobutyl, chlorobutyl etc.
• Silicone is least reactive but it does experience
permeability to moisture and gas.
Softer rubbers experience less coring and reseal better,
harder rubbers are easier to process on high speed
packaging lines.

PLASTICS
Classes of plastics:
There are two classes of plastics, reflecting the behavior with
respect to individual or repeated exposure to heating and cooling.
1. Thermoplastics
2. Thermosets
Thermoplastics
Capable of being shaped after initial heating and
solidifying by cooling.
Resistant to breakage and cheap to produce and providing the right
plastics are chosen will provide the necessary protection of the
product in an attractive containers.
E.g. Polystyrene, polyethylene and polyvinyl chloride.
18

19
Thermosets
They need heat for processing into a permanent
shape. During heating such materials form permanent
crosslinks between the linear chains, resulting in solidification
and loss of plastic flow.
E.g. Phenolic, urea and melamine are representative of
thermosets.
Uses
Used for many types of pack including;
rigid bottles for tablets and capsules, squeezable bottles for
eye drops and nasal sprays, jars, flexible tubes and strip and
blister packs.

Advantages
• Least expensive than glasses
• Ease of transportation
• No risk of breakage
• Flexible
• Light in weight
Disadvantages
• They are not as chemically inert .
• They are not as impermeable to gas and vapour as
glass.
• They may possess an electrostatic charge which will
attract particles.
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FIBROUS MATERIALS
 The fibrous materials are the important part of
pharmaceutical packaging.
 Fibrous materials include: Papers, Labels, Cartons,
Bags, Outers, Trays For Shrink Wraps, Layer Boards
On Pallets, etc.
Paper
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1
Corrugated Fiber board

22
 The Applications aswell as Advantages of Cartons
include:
Increases display area
Provides better stacking for display of stock items
Assembles leaflets
Provides physical protection especially to items like
metal collapsible tubes.
Fiberboard outers either as solid or corrugated board
also find substantial application for bulk shipments.
Regenerated cellulose film, trade names Cellophane &
Rayophane, is used for either individual cartons or to
assemble a no. of cartons.

FOILS,FILMS & LAMINATES
23
4/5/201123
FOILS:
The most important metal for pharmaceutical
application is aluminium.
FILMS
Cellophane is an attractive transparent film which
can be colored and printed upon so it useful as
outer wrap.
LAMINATES
Laminates are used to combine the properties of
individual foil and films and strictly are made by
bonding the layer with adhesive.

• Uses of films, foils, laminations:
Strip packs
Blister packs
Diaphragm seals for bottles
Liners for boxes either attached or loose bag-in-box
systems & bags.
• Foil blisters:
When sealed with a metal foil-cover, the blister can
provide a hermetic pack i.e. an isolated system, which
excludes any exchange of gases between the product &
surrounding atmosphere.
24

BLISTER PACK
Blister packs are commonly used as unit dose packaging
for pharmaceutical tablets, capsules.
Blister packs consist of two principal components :
1) a formed base web creating the cavity inside which
the product fits and
2) the lidding foil for dispensing the product out of the
pack.
There are two types of forming the cavity into a base
web sheet: thermoforming and cold forming
25

26
Thermoforming
In the case of thermoforming, a plastic film
or sheet is unwound from the reel and
guided though a pre-heating station on the
blister line
The temperature of the pre-heating plates (upper
and lower plates) is such that the plastic will soften
and become moldable.

• Cold forming
• In the case of cold forming, an aluminum-based
laminate film is simply pressed into a mold by
means of a stamp.
• The aluminum will be elongated and maintain the
formed shape.
• Advantage of cold form foil blisters is that the use
of aluminum is offering a near complete barrier for
water and oxygen, allowing an extended product
expiry date.
• The disadvantages of cold form foil blisters are the
slower speed of production compared to
thermoforming and the lack of transparency of the
package and the larger size of the blister card
27

Aluminium Foils for Blister Packing
Aluminium Foil suitable for blister packing of
Pharmaceutical Products such as Tablet, Capsules, etc.
28

STRIP PACKING
It is commonly used for the packaging of tablets and
capsules. A strip package is formed by feeding two webs
of a heat sealable flexible film through a heated
crimping roller .The product is dropped into the pocket
formed before forming the final set of seals. A
continuous strip of packets is formed which is cut to the
desired number of packets in length.
The materials used for strip package are cellophane,
polyester, polyethylene, polypropylene,
polyvinylchloride.
11
9

SYMBOLS USED ON PACKAGES
AND LABELS
Many types of symbols for package labeling are nationally and
internationally standardized. For product certifications,
trademarks, proof of purchase, etc. identification code .
Fragile This way up Keep away from sunlight Keep away from water
12
0

THANK YOUDr.V.Ravikumar
whatsup: 9246806227
E-mail: drvrkpharmacy@gmail.com
12
1

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