1.

Introduction

1. INTRODUCTION
Pharmaceuticals have made a major contribution to improving the health status
of patients over a past few decades. At the same time, its expenditure has increased
rapidly, with spending on medicines outpacing economic growth in many countries.
Many economists have speculated that, if spending on healthcare continues to increase
at the current rate, the economies of most countries will be severely affected. Most
governments have, therefore, begun to implement cost-containment measures to slow
the rate of healthcare spending and have concentrated to a larger degree on
pharmaceutical spending. Since generics are usually marketed at substantially lower
prices than the original brand-name products and, with the rising cost of healthcare; this
has made them an attractive option to healthcare providers and governments .
1.1 Generic drug
Generic medicines are those where the original patent has expired and which
may now be produced by manufacturers other than the original innovator (patent-
holding) company. The term “generic drug” a or “generic medicine” can have varying
definitions in different markets, however the term is commonly understood, as defined
by the World Health Organization (WHO), to mean a pharmaceutical product which is
usually2,
 Intended to be interchangeable with an innovator product
 Is manufactured without a licence from the innovator company, and
 Is marketed after the expiry date of the patent or other exclusive rights.

Need of generics
 Generic helps to keep the health insurance premium down.
 It encourages the research based drug companies to keep finding newer and better
medicines that have patent protection.
 Generic have long offered a safe and inexpensive alternative to the brand name drugs.
 Generic commutation helps to lower the cost of drugs down. Because generic drug
manufacturers do not have to spend as much as brand name drug manufacturers do for
extensive research and development, sales, advertising and marketing.
Requirements of generics
To gain FDA approval, a generic medicine must,
 Contain the same active ingredient as the originator medicine (inactive ingredients may
vary).

1
 1. Introduction

 Be identical in strength, dosage form, and route of administration.

 Have the same use indications.
 Be bioequivalent.
 Be meet the same batch requirements for identity, strength, purity, and quality.
 Be manufactured under the same strict standards of FDA's good manufacturing practice
regulations required for originator products.
1.2 Abbreviated new drug application (ANDA)
The ANDA is submitted to FDA's Centre for Drug Evaluation and Research,
Office of Generic Drugs, which provides for the review and ultimate approval of a
generic drug product. Once approved, an applicant may manufacture and market the
generic drug product to provide a safe, effective, low cost alternative to the American
public. Electronic submissions of ANDAs have grown by 70% since November
2008.The Section IV challenge has been credited with suppressing new drug
innovation.
A generic drug product is one that is comparable to an innovator drug product in
dosage form, strength, route of administration, quality, performance characteristics and
intended use. All approved products, both innovator and generic, are listed in FDA's
approved drug Products with therapeutic equivalence evaluations (Orange Book).
Generic drug applications are termed "abbreviated" because they are generally not
required to include preclinical (animal and in vitro) and clinical (human) trial data to
establish safety and effectiveness. Instead, generic applicants must scientifically
demonstrate that their product is bioequivalent (i.e., performs in the same manner as the
innovator drug). One way scientists demonstrate bioequivalence is to measure the time
it takes the generic drug to reach the bloodstream in 24 to 36 healthy volunteers. This
gives them the rate of absorption, or bioavailability, of the generic drug, which they can
then compare to that of the innovator drug. The generic version must deliver the same
amount of active ingredients into a patient's bloodstream in the same amount of time as
the innovator drug. In cases of topically active drugs, the bioequivalence of a drug can
be demonstrated by comparing drugs dissolution or transdermal drug absorption is
compared with the innovator drug. In cases of systemically active drugs, active drug
blood concentration of that drug is compared with the innovator drug.
1.3 Overview of Hatch-Waxman act
Congress adopted the Hatch-Waxman Act, formally known as the Drug Price
Competition and Patent Term Restoration Act of 1984 to expedite and streamline both

2
 1. Introduction

generic drug approvals and patent litigation involving generic drugs. Before its
adoption, no streamlined Food and Drug Administration approval process existed for
generic drugs. Rather, generic drug companies were required to conduct the same kinds
of expensive, time-consuming clinical trials that drug companies conducted for new
brandname drugs. In addition, the unlicensed investigation and testing of a patented
drug by the generic drug company to obtain FDA approval for a generic version could
subject the generic drug company to patent infringement liability. The Hatch-Waxman
Act changed this and, in doing so, is often credited with creating the modern generic
drug industry. The Hatch-Waxman Act has been amended several times since its
enactment. Nevertheless, its basic structure remains the same. This Note provides an
overview of the following four main features of the Hatch-Waxman system:
 An expedited FDA approval process for generic drug applications.
 Certain market and patent exclusivity periods for both branded and generic drug
companies.
 Patent term extension to adjust for delays caused by the FDA approval process.
 A unique patent litigation process triggered by a generic drug company’s submission of
an application for FDA approval.
Biologic drugs are subject to different FDA requirements and a different patent
litigation mechanism that are beyond the scope of this Note.
1.4 Types of ANDA filling

An ANDA must contain a certification regarding each patent listed in the

orange book covering a referred NDA. There are four types of certification as given
below:
 Filing with “Paragraph I Certification”: Certifying that patent information has not
been filed in connection with an NDA. The FDA may approve immediately an ANDA
making this certification.
 Filing with “Paragraph II Certification”: Certifying that a patent covering an NDA
has expired. Again, the FDA may approve immediately an ANDA making this
certification.
 Filing with “Paragraph III Certification”: Certifying that ANDA approval is sought
after a listed patent expires. The FDA may approve the ANDA only after such patent
expiration.

3
 1. Introduction

 Filing with “Paragraph IV Certification”: Certifying that a listed patent is either

invalid or will not be infringed by the generic drug for which the ANDA applicant
seeks approval.

Paragraph I FDA Generic entry One

No patent Approval or more generic
filed Immediate applicants may
enter the market
Paragraph II
Patent has
expired

FDA Approval May

Paragraph III approve. Valid after
Patent will patent expiry
expire on
“X”date

Paragraph IV Generic entry

Patent not FDA Approval May or may not
expired; May approve enter, Depends on
Generic claims before patent court ruling in
patent “invalid” expiry favour or against
or “not the generic
infringed” applicant

Figure 1.1: Paragraph certification

1.5 The Biopharmaceutical Classification System:
The Bio-pharmaceutics Classification System (BCS) was introduced by the
Food and Drug Administration (FDA) to assess oral drug products. In this system,
drugs are classified into four groups based on the ability of a given drug substance to
permeate biological membranes and aqueous solubility. A given drug substance is
considered ‘highly soluble’ when the highest dose strength is soluble in 250 ml water or
less over a pH range 1 to 7.5, and the substance is considered ‘highly permeable’ when
the extent of absorption in humans is determined to be 90% of an administered dose (in
solution), based on mass balance or related to an intravenous reference dose. For a
rapidly dissolving tablet 85% of the labelled amount of drug substance must dissolve
within 30 minutes.

4
 1. Introduction

Table 1.1:BCS Classification

Sr. No. Classes Parameter

1 Class I High solubility and high permeability

2 Class II Low solubility and high permeability

3 Class III High solubility and low permeability

4 Class IV Low solubility and low permeability

Class I
It consists of highly water-soluble drugs that are well absorbed from the
gastrointestinal tract. Drugs in Class I have high bioavailability after oral
administration.
Class II
It consists of water-insoluble drugs. The dissolution rate in vivo is usually the
rate limiting step in drug absorption. Commonly, drugs in this class have variable
absorption due to the insolubility and in vivo variables that can affect their dissolution
profile.
Class III
It consists of water-soluble drugs that do not permeate bio membranes readily.
Class IV
It consists of water-insoluble drugs that do not permeate bio membranes readily.

Granulation Technology
Active pharmaceutical Ingredients are pharmacologically active chemical substances
that are used to treat disease and symptoms. Excipients are vehicle that plays a huge

5
 1. Introduction

role in formulation. Earlier, it was thought that excipients are inert in the formulation,
but nowadays excipients are modified synthetically which can greatly modify the
intended effect of a drug and release characteristics from the dosage form.
Selection of excipients and processing (method of Granulation) of drug and excipients
mixture is a very important in the formulation. Success of formulation depends on the
selection of excipients and the order in which the formulation ingredients are mixed
with the drug, as well as how the process is carried out.
Granulation is universal unique unit operation in pharmaceutical oral solid dosage form
formulation. It is known for enlargement of particle size or process of conversion of
fine powders into dust free large free-flowing powders. Still novel granulation process
eliminate excessive amount of fine particles and will improve compression character,
flow property of powder and blend uniformity. Generally, granules can be in the size
range of 0.2 to 0.5 mm depending upon the process employed. Overall the purpose of
granulation is to enhance content uniformity of API in final product and to increase the
density of blend to occupy less volume in the unit dosage. It also plays a part in better
shipment, storage.
Ideal characters of granules:
Granules are spherical shaped smaller particle in the range of 0.2 to 0.5 mm with
sufficient fines property to fill void spaces present between granules. The granules
should have adequate moisture (between 1-2%) with good compressibility flow and
sufficient hardness.
Strength and size of granules depend on the
➢ Drug and excipients particle size
➢ Binder and solvent volume
➢ Binder type
➢ Wet massing time
➢Binder addition rate and amount of shear applied
➢ Time of drying (Polymorphism)
➢ Type of granulator
Reason for granulation:
✓ To enhance the property of powder flow
✓ To enhance the strength of granule.
✓ To improve compression ability.

6
 1. Introduction

✓ To improve drug stability.

✓ To regulate the drug release from its dosage form.
✓ To prevent the formation of dust during process of granulation

Methods of granulation:
API and excipients can be compressed into tablets from blend of powders processed
either by wet granulation or dry granulation. Granulation technique is broadly
classified as two types, dry granulation and wet granulation, a type of method used to
facilitate the agglomeration of powder particles. Physico-chemical property of API and
excipients helps to select the method of granulation. i.e. if API is heat sensitive dry
granulation is suitable and incase of bulk amount of API in a formulation, Wet
granulation is one of the methods for processing.

Stages of granulation:
a) Pendular stage: This is initial stage just after addition of binding agent.
b) Funicular stage: This is second stage where adequate binding solution incorporated
between the particles.
c) Capillary stage: In this stage binding solution entrapped by capillary action. This is
a perfect stage where good granules can be obtained.
d) Droplet stage: Here over wetting, particles may form. This stage is not desirable
stage.

7
 1. Introduction

Classification of Granulation Technologies

Basing upon the type of processing, that had been involved, GT can be classified as
follows:
1. Conventional methods
 Dry granulation
 Wet granulation
a) High-shear wet granulation
b) Low-shear wet granulation
2. Novel/advanced methods
 Moisture activated dry granulation
 Thermal adhesion granulation
 Pneumatic dry granulation
 Melt/thermoplastic granulation
 Fluidized bed granulation
 Extrusion-spheronization granulation
 Spray drying granulation
 Freeze granulation
 Foam binder granulation
 Steam granulation

1) Dry Granulation
This method is cheapest method of granulation and suitable for hydro-sensitive
products. In this method granules are prepared without binding solution and heat. This
method involves two steps. One is preparing large particles called slugging. Second one
is milling and screening of slugs into small granules.
Advantages
a) Less equipment’s are needed
b) Eliminate binding solution process
Disadvantages
a) Requires specialized heavy duty tablet press.
b) Does not permit uniform colour distribution.
c) Tends to create more dust with respect to wet granulation.
d) Increases the potentiality of cross contamination.

8
 1. Introduction

Applications
Suitable for hydrophobic andoily substances.

2) Wet granulation
This method involves several steps. Initially by the addition of binding agent
(hydrophilic or hydrophobic) to get wet mass. This wet mass is passed through the
sieves followed by drying.
Advantages
Easy process and no need of experts
Disadvantages
Time consuming, Labor cost is more, several steps are involved.

3) Moisture Activated Dry Granulation (MADG)

MADG is also known as ‘Single-Pot’ granulation or moist granulation. Here drying
step is eliminated because very less amount of binding agent is used to activate binding
process and moreover moisture absorbing agents like microcrystalline cellulose (MCC),
potato starch, a mixture of MCC and potato starch (50% w/w), silicon dioxide, Spress®
B818 Pregelatinized Corn Starch NF, Maltrin® maltodextrins, etc. used to remove
moisture present in the granules. This technology involves wet agglomeration of the
powder mixture to form a tacky mass followed by moisture absorption to dry the
granules.
In this technology small amount of water (1–4%) is added to agglomerate the powder
blend.
Advantages
a) A simple, clean, lean process that utilizes very little granulating fluid.
b) Produce granules with more uniform particle size distribution (particle size range
of 150-500 μm) and excellent flowability.
c) Economical and time efficient, as requires less energy and eliminates drying step.
d) Suitable for continuous processing, and for preparation of floating and sustained
release products.
Disadvantages
a) Unsuitable for thermo-labile, moisture sensitive, high moisture absorbing
substances.
b) Difficult to develop formulations with high drug loading.

9
 1. Introduction

Applications
Suitable for eutectic and hydro-phobic substances.

4) Thermal Adhesion Granulation (TAG)

It is a novel GT, patented by Wei-Ming Pharmaceutical Company (Taipei, Taiwan) that
involves granulation by adding very less amount of granulation fluid. In this process the
binder&/diluent mixture is first wetted by pouring water or ethanol (2.0–3.6%). Then
this blend is placed in a prewarmed glass bottle, sealed and then heated by an IR lamp
to raise surface temperature of the equipment to 900C–1050C for water as solvent,
700C–900C for ethanol as a binding agent and mixed under tumble rotation for 3–20
min until granules are formed. Resulted granules were immediately sifted with proper
sieve.
Advantages
a) Requires less amount of granulation fluid and forms granules with good flow
property
b) Reduces the dust generation during powder processing.
Disadvantages
a) Not suitable for substances with more than 1300C melting point andfor materials
with binding solvents other than water and ethanol.
Applications:
Applicable in R&D systems.

5) Pneumatic Dry Granulation (PDG):

It is a novel dry granulation method developed by Atacama Labs (Helsinki, Finland). It
involves production of compact mass by using roller compaction method with little
compression force. This material is introduced into a newly innovated fractionating
device that separates the granules and recycles rejected fraction.
Advantages
a) Can achieve high drug loading of traditionally proven difficult materials.
b) Faster development (within weeks) even with historically proven difficult
materials.
c) Decreases cost of product by minimizing waste through recycling and production
cost.
d) Excellent stability with enhanced shelf-life.

10
 1. Introduction

e) Compatible with other technologies like coating, sustained release, fast release.
f) Suitable for thermo-labile and moisture sensitive drugs.
g) Taste masking and tailoring of release rate and time can be achieved.
h) Produce soft and porous granules with high compressibility and Flowability.
i) Possesses potentiality to handle sterile products or toxic materials
j) Lowers scale-up cost and problems.
Disadvantages
a) Due to usage of double compression force materials used may undergo
degradation.
b) High cost due to novelty in process.
Applications
a) Applied widely because of compliment with regulatory bodies.
b) Suitable for drugs with high melting point.

6) High Shear Mixture Granulation

Rapid mixture granulator (RMG) is a simple and easily cleanable equipment developed
in accordance to Good Manufacturing environmental hazards and to get spherical and
well-compacted granules in a relatively short time. This equipment can be operated in a
closed unit and it involves mixing, primary and secondary granulation, drying steps.
Primary granulation step involves spraying of the binding agent onto the powder bed
while the secondary granulation involves kneading of the wet product to produce and to
enlarge the granules. Subsequent drying of final material is done suitably under low
pressure at moderate temperature. Impeller speed, chopper speed, water addition
method and rate, massing (mixing) time, load of the RMG, feed material characteristics,
drug substance particle size are the granulation process parameters that requires
monitoring to get granules with desired characteristics. Volume of load in RMG should
be less than two-thirds of its capacity
Advantages
a) It involves Short processing time.
b) Requires less amount of liquid binders required with respect to fluidized bed
granulation technology.
c) Highly cohesive material can be handled.
Disadvantages
a) Mechanical degradation could take place in case of fragile particles.

11
 1. Introduction

b) Results in the uneven distribution of binder solution throughout moving powder

bed during high-shear granulation.
c) Unsuitable for thermo-labile material.
d) Over wetting leads to formation of lumps and large size granules.
Applications
a) Used in pharmaceutical industry and as well as in paint, cosmetic industries

7) Fluidized Bed Granulation

It is an air suspension technique, of pharmaceuticals was first reported by Wurster to
coat tablets that are later used for granulating and drying of pharmaceuticals and
particle/granule coating. Fluidized bed granulation is a widely employed technique in
the manufacturing of solid pharmaceutical Dosage forms, providing efficient blending,
high thermal & mass transfer rates, and maintaining a uniform temperature throughout
the bed. This process involves the spraying of droplets of a granulating solution onto
the surface of fluidized granules. The particles undergo conversion into solid bridges,
adhering to each other and forming agglomerates or granules. The schematic
representation of Fluidized bed granulation. One of the primary advantages of fluidized
bed granulation is the uniform and consistent
formation of granules, ensuring homogeneity in the final product. The Complete
Advantages and disadvantages of Fluidised Bed Granulation. The technique also
facilitates the efficient mixing of ingredients, contributing to the overall quality of the
granulation. Additionally, fluidized beds offer high heat and mass transfer rates,
promoting desirable granule properties. The controlled temperature maintenance
prevents localized overheating, and the process reduces agglomeration issues through
the formation of solid bridges with the granulating solution.
Fluidized bed granulation is versatile and adaptable to various formulations, proving
particularly effective for solid dispersion manufacturing. However, it comes with
challenges, including the potentially high cost of equipment acquisition and
maintenance, the requirement for skilled operators, limited scalability, dust generation
necessitating additional safety measures, unsuitability for heat-sensitive Fluidized bed
granulation process involves spraying of binder solution onto the fluidized powder bed
(FPB) to get finer, free flowing and homogeneous granules employing single equipment
known as FBP. FBP contains air-handling unit, product container and air distributor,

12
 1. Introduction

spray nozzle, disengagement area and process filters, exhaust blower or fan, control
system, solution delivery system.

1. Top Spray Granulator:

Utilizes two Methods—hardening binder and crystallization. The powder material is
loaded into a product container through a spray nozzle and fine mesh retention screen.
Controlled spraying of the binding solution allows for proper drying.

2. Rotating Disk Granulator with Dryer Option:

Combines layering techniques with a coater & rotating disk granulator, providing
independent control of air velocity and volume. Fluidizing patterns in the rotor chamber
are regulated by centrifugal force, gravity, and fluidization. A spray nozzle applies the
solution tangentially to particles, employing the layering technique for pallet
manufacturing.
Advantages
a) Reduces dust formation during processing.
b) Improves housekeeping and worker safety.
c) Suitable for subsequent coating and controlled release products and reduces
product loss
Disadvantages
b) Cleaning was labor-intensive, time consuming and assuring reproducibility was
troublesome.
Applications:
Applicable for granulation, drying, coating, mixing, etc.

8) Spray Drying Granulation

It is a continuous process where a dry granular product is obtained by feeding a binding
solution or a suspension of active agent with or without excipients to the drying system
where the feed is atomized and dried with a heated gas stream followed by subsequent
separation of granular product from the gas stream. Alternately particle agglomeration
was brought about by spraying the binder solution onto bed of powder particles in
fluidized state achieved with the passage of air followed by drying using hot air.
Advantages
a) It is a fast and continuous process.

13
 1. Introduction

b) Low cost.
c) Reduces operator exposure to dust.
Disadvantages
a) Substances which are sensitive to heat are poor candidates.
b) Improper spray leads to inadequate sized particles.

Applications: Applicable in the preparation of dry syrups and dusting powders.

9) Freeze Granulation
Integrated Biosystems, Inc. (California, USA) had patented freeze GT that results in
spherical and free flowing granules with optimal homogeneity. FG involves spraying of
suspension containing powder into liquid nitrogen where the drops were
instantaneously frozen to form granules which upon subsequent freeze-drying yields
dry granules.
Advantages
a) Granule density can be controlled by the solid contents of the suspension.
b) Non-oxides and metals can be handled as mild drying prevents serious oxidation.
c) Results solid granules with no cavities.
d) High yield with low material waste.
e) Low to high quantities of granules can be produced with reproducibility.
f) Equipment can be easily cleaned up and Organic solvents can be recycled.
Disadvantages
There may be a chance of degradation of drug due to use of temperature which is less
than 0 °C.
Applications: In the formation of injectable granules.

1.6. CAPSULES
The most convenient and popular route of administration among all drug delivery routes
is oral drug delivery. The main goal of any dosage form is to keep up the therapeutic
amount of drug to the targeted site with minimum toxicity and side effects by providing
loading and maintenance dose. Tablets are most widely used solid dosage form and
there is always a possibility for improving the confines of tablets like delay in onset of
action and difficulty in swallowing and improves patient compliance and have many
advantages when compared with other dosage forms such as ease of transportation,

14
 1. Introduction

production and application, accurate dosing, stability, and controlled release patterns
were achieved The traditional solid dosage forms such as tablets and capsules
considered as not proper due to swallowing difficulties in young children. Due to lack
of its stability, dose accuracy, and dispensing faults, special attention is given to the
progress of mini tablets to overcome these problems, with the aim to improve drug
delivery for paediatrics. Mini tablets symbolize a new development in solid dosage
form design and can use as a flexible drug delivery tool for single or composite of
multiple units. Furthermore, mini tablets with well controlled quality features could be a
practical choice for administrating solid dosage forms of low potency drug substances
as capsules or stick packs. A capsule is an solid oral dosage form in which the active
ingredients and diluents aren contained in a two-piece hard shell, usually made of
gelatin. Gelatin capsules are available in various sizes and colors. The double-zero size
is the largest size for oral use in humans, although the zero size is more commonly
used. The zero-size capsule has a capacity of 0.5 to 0.8 grams of powder depending on
the density of the chemical being used. Hardshell capsules consist of two pieces: the
body and the cap. After the two pieces are separated, the body piece is filled with the
dry powder ingredients and the cap is then replaced. The smallest capsule that will hold
the ingredients can be chosen for the compound. When several ingredients are being
inserted into the capsule, a powder that is near the average weight of all the ingredients
can be chosen to determine the capsule size that will best accommodate the ingredients
in a slightly packed form. If the amount of drug needed for a single dose is below the
minimum weighable quantity, a diluent should be added. If the single dose is too large
for a capsule that can reasonably be swallowed by the patient, a diluent can be added
and the dose divided into two capsules

Capsule differ from tablets in that tablets are compressed forms of a medication, while
capsules contain a drug by putting active pharmaceutical ingredients and excipients
inside a capsule. There are a number of different capsule dosage forms, each with its
distinctive advantages, strengths, and weaknesses. They include Dosage forms in which
drug substance is enclosed within hard or soft soluble shell. The shells are generally
formed from gelatin. Capsules are of two types 1. Hard gelatin capsules 2. Soft gelatin
capsules. Capsules are tasteless, odourless and can easily be administered. Combination
of powders we can use. There are attractive in appearance. The drugs having un-
pleasant odour and taste are enclosed in a tasteless shell. They can be filled quickly and

15
 1. Introduction

conveniently. Physician can change the dose and combination of drug according to
patient requirement. They are economical. They are easy to handle and carry.
Hygroscopic are not suitable for filling into capsules, because they absorb water present
in capsule shell makes shell very brittle and ultimately lead to crumble into pieces. The
concentrated solutions which require previous dilution are unsuitable for capsules
because if administered as such lead to irritation into stomach. For human use, empty
capsules ranging in size from 000 the largest to 5 the smallest. Generally, hard gelatin
capsule is used to encapsulate between 65 mg to 1 gram.

Gelatin is heterogeneous product derived by hydrolytic extraction of animal's collagen.

The sources of gelatin including animal bones, hide portions and frozen pork skin.
There are two basic types of gelatin TYPE A Derived from acid treated precursor that
exhibits an iso electric point at pH-9. It is manufactured mainly from pork skin. TYPE
B Derived from alkali treated precursor that exhibits an iso electric point at pH-4.7. It is
manufactured mainly from animal bones. They are often believed as the primary oral
dosage form because of their manufacturing process compared to other dosage forms.
Gelatin has the property of disintegrating when it comes in contact with water, thereby
releasing the medicament completely. Instead, of gelatin, denatured gelatin, methyl
cellulose and polyvinyl alcohol can also be used to make the capsule shells.
Hard-shelled capsules, which contain dry, powdered ingredients or miniature pellets
made by e.g. processes of extrusion or spheronization. These are made in two halves: a
smaller-diameter “body” that is filled and then sealed using a larger-diameter “cap”.
Both of these classes of capsules are made from aqueous solutions of gelling agents,
such as animal protein (mainly gelatin) or plant polysaccharides or their derivatives
(such as carrageenans and modified forms of starch and cellulose). Other ingredients
can be added to the gelling agent solution including plasticizers such as glycerin or
sorbitol to decrease the capsule's hardness.

Advantages of Capsules dosage form

 Enclosing the medication within capsule shell provides mask the taste and odor of
unpleasant drugs and can be easily administered.

 They are attractive in appearance

16
 1. Introduction

 They are slippery when moist and, hence, easy to swallow with a draught of water.

 As compared to tablets less adjuncts are required.

 The shells are physiologically inert and easily and quickly digested in the
gastrointestinal tract.

 The shells can be opacified (with titanium dioxide) or colored, to give protection
from light.

 The solubility of gelatine at gastric Ph provides the rapid release of medication in the
stomach.

 The capsules are smooth and slippery in nature and easily swallowed.

 Packaged and shipped by manufacture at lower cost less breakage than liquids forms.

 The contents may be removed from the gelatine shell and employed as a
premeasured medicinal powder. The capsule shell being use to contain a dose of the
medicinal substance. E.g. Theo-dur sprinkle.

Disadvantages of Capsules

 The drugs which are hygroscopic absorb water from the capsule shell making it
brittle and hence are not suitable for filling into capsules.

 The concentrated solutions which require previous dilution are unsuitable for
capsules because if administered as such lead to irritation of stomach.

 Capsules are not suitable for liquids that dissolves gelatine, such as aqueous are
hydro alcoholic solutions.

 The concentrated solutions which require previous dilution is unsuitable for capsule
because if administered as such lead to irritation into stomach.

 Not useful for efflorescent or deliquescent materials. Efflorescent cause capsules to

soften and deliquescent may dry the capsule shell to brittleness.

 Very soluble salts such as bromides, iodides should not be dispensed in capsules, as
the rapid release of such materials may cause gastric irritation.

17
 1. Introduction

1.6.1 Evaluation tests for capsule drug products

Finished capsules are subjected to a number of tests in accordance with compendial
standards and regulatory requirements for unit dose capsule products. These batteries of
tests help identify whether the batch is acceptable for marketing or its intended usage,
the finished capsules are evaluated by the following tests:
1) Permeability and sealing
Soft gelatin capsules are tested for physical integrity (absence of leakage) by visual
inspection. Similarly, hard gelatin capsules are tested for any breach of physical
integrity (breakage or opened cap and body).
2) Potency and impurity content
All capsules are tested for drug content (potency, as a per cent of label claim). In
addition, most drug products are tested for related substances or impurities. These must
meet predefined specifications for a batch to be acceptable.
3) Weight variation test
The uniformity of dosage units may be demonstrated by determining weight variation
or content uniformity. The weight variation method is as follows.
4) Weight variation test for hard gelatin capsules
Ten hard gelatin capsules are usually weighed individually and the contents are
removed. The emptied shells are individually weighed and the net weight of the
contents is calculated by subtracting the weight of the shell from the respective gross
weight. The content of active ingredient in each capsule may be determined by
calculation based on the per cent drug content in the formulation.
5) Weight variation test for soft gelatin capsules
For soft gelatin capsules, the gross weight of 10 gelatin capsules is determined
individually. Then each capsule is cut open with a suitable clean, dry cutting instrument
(e.g., scissors or a sharp open blade), and the contents are removed by washing with a
suitable solvent (that dissolves the fill but not the shell). The solvent is allowed to
evaporate at room temperature over a period of about 30 minutes, followed by weighing
of the individual washed shells. The net contents are calculated by subtraction and the
content of active ingredient in each of the capsules can be determined by calculation
based on the per cent drug content in the formulation.

18
 1. Introduction

Fill-weight variation of capsules is often a function of equipment setup and filling

operation. An automated capsule sizing machine and/or weight checker is frequently
used to discard over- or underfilled capsules.
6) Uniformity of content
This test is performed only when the content is specified in the individual monographs
and when capsules fail weight variation test. If the weight of capsules is completely
filled no need of this test.
Unless otherwise stated in the monograph for an individual capsule, the amount of drug
substance, determined by assay, is within the range of 85.0% to 115.0% of the label
claim for nine (9) of ten (10) dosage units assayed, with no unit outside the range of
75.0% to 125.0% of the labelled drug content. Additional tests are prescribed when two
or three dosage units are outside of the desired range but within the stated extremes.
7) Disintegration time test for capsules
Disintegration of hard and soft gelatin capsules is evaluated to ensure that the drug
substance is fully available for dissolution and absorption from the gastrointestinal tract.
The compendial disintegration test for hard and soft gelatin capsules follows the same
procedure and uses the same apparatus described in the article “Quality Control Tests
for Tablets”.
The capsules are placed in the basket-rack assembly, which is repeatedly lowered 30
times per minute into a thermostatically controlled bath of fluid at 37 ± 2 ˚C and
observed over the time described in the individual monograph.
8) Dissolution test for capsules
Drug absorption and physiological availability depend on the drug substance being in
the dissolved state at the site of drug absorption. The rate and extent of dissolution of
the drug from the capsule dosage form is tested by a dissolution test. This test provides
means of quality control in ensuring that, different batches of the drug product have
similar drug release characteristics and also, a given batch has similar dissolution as the
batch of capsules that was shown initially to be clinically effective.
9) Moisture content
Water content of the entire capsule or the capsule contents are determined by Karl
Fisher titrimetry to enable the correlation of water content with the degradation profile
or drug-release characteristics of capsules.
10) Moisture permeation test

19
 1. Introduction

The USP requires determination of the moisture-permeation characteristics of single-

unit and unit dose containers to assure their suitability for packaging capsules. The
degree and rate of moisture penetration is determined by packaging the dosage unit
together with a colour-revealing desiccant pellet, exposing the packaged unit to known
relative humidity over a specified time, observing the desiccant pellet for colour change
(indicating absorption of moisture) and comparing the pre-test and post-test weight of
the packaged unit.
11) Microbial content
The capsules are tested to ensure lack of growth of bacteria and mould by
microbiological tests. These tests are usually carried out by incubation of the capsule
contents in a growth medium and counting the colonies formed after a predefined
period of time. Selection of the growth medium and duration of the test, as well as
maintenance of aseptic conditions during the testing, are critical to successful
assessment of microbial contamination by this method.

20