See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/285990404

Impact of capsules as a carrier for multiple unit drug delivery and the
importance of HPMC capsules

Article  in  Research Journal of Pharmacy and Technology · January 2013

CITATION READS

1 16,698

5 authors, including:

Mohd Abdul Hadi Srinivasa Rao Avanapu

66 PUBLICATIONS   250 CITATIONS   
Bhaskar Pharmacy College, Hyderabad, India
179 PUBLICATIONS   627 CITATIONS   
SEE PROFILE
SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Childhood Obesity View project

hepatoprotective and antioxidant activity of plant extracts View project

All content following this page was uploaded by Mohd Abdul Hadi on 13 December 2017.

The user has requested enhancement of the downloaded file.

 Research J. Pharm. and Tech. 6(1): January 2013

ISSN 0974-3618 www.rjptonline.org

REVIEW ARTICLE

Impact of Capsules as a Carrier for Multiple Unit Drug Delivery and the
Importance of HPMC Capsules
Mohd Abdul Hadi1*, N. G. Raghavendra Rao2, A. Srinivasa Rao1, Gaddam Shiva1,
J. Waseem Akram1
1
Dept of Pharmaceutics, Bhaskar Pharmacy College, Yenkapally (V), Moinabad (M), R.R. District, Hyderabad-
500075, India.
2
Dept of Pharmaceutics, Jyothismathi Institute of Pharmaceutical Sciences, Thimmapur, LMD Colony,
Karimnagar-505481, Andhra Pradesh, India.
*Corresponding Author E-mail: hadi.lcp@gmail.com

ABSTRACT:
The word ‘capsule’ is derived from the latin capsula, meaning a small box. It is a solid oral dosage form in which the
active ingredients and diluents are contained in a two-piece hard shell, usually made of gelatin. In the development of
new medicines, there are several problems to be solved. The formulation, and its important stability and release-
characteristics, control and reproducibility of the production process are other factors to be taken into account and,
increasingly, research costs and development timeframes have also to be considered. When it comes to a decision at
the end of phase II, which dosage form will be developed for the market, high production costs of hard gelatin capsule
products are generally assumed. Multiple unit dosage forms are mainly oral dosage forms consisting of a multiplicity
of small discrete units, each exhibiting some desired characteristics. It is even possible to include a number of dosage
forms – such as tablets, pellets, capsules, powders and granules – within a single formulation. In this way,
incompatibilities and interaction between the different drug substances in combination products can be prevented. Hard
gelatin capsules are particularly suitable for their development and manufacture. Hard gelatin capsules do have some
drawbacks. To overcome these problems, pharmaceutical scientists have developed capsules made of starch, cellulose
derivatives and polyvinyl alcohol copolymer. To date, HPMC capsules have been successfully utilized for
pharmaceutical products.

KEYWORDS: Capsule, Solid oral dosage form, Multiple unit dosage form, HPMC.

INTRODUCTION: [1]
The word ‘capsule’ is derived from the latin capsula,
meaning a small box. In current English usage it is applied
to many different objects, ranging from flowers to
spacecraft. In pharmacy, the word is used to describe an
edible package made from gelatin or other suitable material
which is filled with medicines to produce a unit dosage.1
These capsules are one of the oldest dosage forms in
pharmaceutical history, known to the ancient Egyptians.2
The earliest European reference is contained in a travel
account of 1730 which mentions the pharmacist de Pauli
from Vienna, who produced oval-shaped capsules in the
hope of covering up the unpleasant taste of the pure
turpentine he prescribed for people suffering from gout.
Received on 03.11.2012 Modified on 23.11.2012
Accepted on 28.11.2012 © RJPT All right reserved
Research J. Pharm. and Tech. 6(1): Jan. 2013; Page 34-43
A further 100 years were to pass before the first gelatin
capsule appeared. The first patent for such a product was
granted in 1834 to the pharmacist Joseph Gérard Auguste
Dublanc and the pharmacy student Francois Achille
Barnabe Mothes, who ended his collaboration with Dublanc
in 1837, continued to work on improving the gelatin
capsule and to take out patents for the manufacture and use
of capsules.3
The oral route of administration is considered as the most
widely accepted route because of its convenience of self
administration, compactness and easy manufacturing. 4, 5
Nevertheless, it is probable that at least 90% of all drugs
used to produce systemic effects are administered by oral
route (see Figure 1) 6

34
 Research J. Pharm. and Tech. 6(1): January 2013
Figure 1: Global drug delivery market by administration mode
A capsule is an solid oral dosage form in which the active
ingredients and diluents are contained in a two-piece hard
shell, usually made of gelatin. Gelatin capsules are available
in various sizes and colors. (see Figure 2) for capsule sizes.
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. Hard-shell capsules consist of two pieces: the body
and the cap (see Figure. 3). 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
Figure 2: Capsule size 00 is the largest capsule used for human oral
preparations and size 5 is the smallest.
35
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. 7
In the development of new medicines, there are several
problems to be solved. As well as the formulation, and its
important stability and release-characteristics, control and
reproducibility of the production process are other factors to
be taken into account and, increasingly, research costs and
development timeframes have also to be considered. When
it comes to a decision at the end of phase II, which dosage
form will be developed for the market, high production
costs of hard gelatin capsule products are generally
assumed. This assumption is valid if the production costs
are limited to the comparison of the excipient costs only.
When taking into account the total manufacturing costs,
which include the hidden costs coming from process
equipment, GMP space required, total production time, in-
process controls, analytical, cleaning and validation work
the comparison easily turns out in favor of the capsule
formulation8. More, as the development costs for new
medicines continue to rise, it is becoming imperative to
obtain international registration for the formulation.
Ensuring that all new entities conform to the various
pharmacopoeias and regulatory requirements is yet another
task for the formulation scientist. Companies are aiming at
achieving – reproducibly – a consistency of product quality
acceptable on a worldwide scale. The simplicity of hard
gelatin capsule formulation and manufacturing as well as
the versatility of this dosage form substantially supports
these requirements. 9
Figure 3: The cap of the capsule fits snugly over the body of the
capsule after the capsules are filled.
 Research J. Pharm. and Tech. 6(1): January 2013

Hard gelatin capsules: 7. Two or more active ingredients can be combined into a
Hard gelatin capsule shells are used in most commercial single capsule dosage form, improving patient
medicated capsules. The empty capsule shells are made of compliance.
gelatin, sugar and water. Gelatin is obtained by partial 8. One or more commercially manufactured tablets can be
hydrolysis of collagen obtained from the skin, white inserted into a capsule with the addition of a diluent,
connective tissue and bones of animals. Gelatin, being a such as lactose, to facilitate dosing.
protein, is digested by proteolytic enzymes and digested. As 9. They can be compounded easily in the pharmacy and
such they can be clear, colorless and essentially tasteless; or offer many advantages to patients.
they may be colored with various FD&C and D&C dyes 10. Capsules provide a rapid release of medication in the
and made opaque by adding agents such as titanium stomach because of their rapid disintegration.
dioxide. Most commercially available medicated capsules
contain combinations of colorants and opaquants to make Equipment13:
them distinctive, many with caps and bodies of different Hard Capsule Machine:
colors. They are commonly employed in clinical drug trials, SFR 901 FS6/7, In this model of capsule making machine,
to compare the effects of an investigational drug with those dipping action, transfer along upper deck, transfer from
of another drug product or placebo10. The hard gelatin upper to lower deck and transfer from lower deck to table
capsule has also been conventionally used as a dosage form are all performed by high precision programmable servo
for Rx and OTC drugs and herbal products, which are motors combined with precision ball screws.
formulated either as powder or pellets. 11
SFR 901D, In this model of capsule making machine,
A number of methods have also been developed to track the dipping action, separately for cap and body, is performed by
passage of capsules through the gastrointestinal tract to map high precision programmable servo motors combined with
their transit time and drug release patterns. Among these is precision ball screws.
gamma scintigraphy, a non-invasive procedure that entails
use of a gamma ray-emitting radiotracer incorporated into SFR 720, In this model of capsule making machine, follows
the formulation with a gamma camera coupled to a data the traditional system of capsule production where all
recording system. When scintigraphy is combined with movements and actions are performed by highly accurate
pharmacokinetic studies, the resultant mechanical components.
pharmacoscintographic evaluation provides information
about the transit and drug release patters of the dosage form Capsule filling machines:
as well as the rate of drug absorption from the various Below are few of the examples which can be used for filling
regions of the gastrointestinal tract.10 capsules---
Semi-Automatic SL90 Capsule Filling Machine
• Some of the examples of gelatin capsules are: Semi-Automatic SL 15 Capsule Filler Machine
• Clear Gelatin Capsules Semi-Automatic SL 60 Capsule Filler Machine
• Colored Gelatin Capsules -Red/White Semi-Automatic SL 180 Capsule Filler Machine
• Grape Flavored Gelatin Capsules -Purple/Purple
• Mint Flavored Gelatin Capsules -Green/Green Capsules as a carrier for Multiple Unit Drug Delivery
• Coffee Flavored Capsules -Brown/Brown Systems for Controlled Release:
• Strawberry Flavored Gelatin Capsules -Red/Red Oral controlled release drug delivery systems can be
classified in two broad groups: single unit dosage forms
• Orange Flavored Gelatin Capsules -Orange/Orange
(SUDFs), and multiple unit dosage forms (MUDFs). The
• Bubblegum Flavored Capsules -Pink/Pink
concept of MUDFs was initially introduced in the early
• Berry Flavored Gelatin Capsules -Dark Purple 1950s14. MUDFs have several performance advantages vs.
•
Clear Fish Gelatin Capsules12 SUDFs. After ingestion, MP units are released from the
capsule in the stomach, predictably transit to the small
Advantages of Capsule Formulations7, 12: intestine and spread along the gastro-intestinal. There is a
1. They are a professional looking, uniform, clean, and growing interest in MUDFs due to their consistent and
elegant dosage form. reliable in-vivo drug release, with a reduced risk of local
2. They effectively mask the odor and taste of substances. irritation along the gastrointestinal tract. 15, 16
3. They are a convenient dosage form in which an
individual dose can be accurately measured. MUDFs are mainly oral dosage forms consisting of a
4. They are easily packaged and transported, and can be multiplicity of small discrete units, each exhibiting some
easily administered to the patient. desired characteristics. In these systems, the dosage of the
5. They can be filled with a precise dose for a specific drug substances is divided on a plurality of subunit,
patient that may not be available commercially or may typically consisting of thousands of spherical particles with
be available only in another form. diameter of 0.05-2.00 mm. To deliver the recommended
6. They can contain ingredients that may be unpalatable total dose, these subunits are filled into a capsule. 17, 18
or toxic to the touch.

36
 Research J. Pharm. and Tech. 6(1): January 2013

Hard gelatin capsules are particularly suitable for their liquid or semi-solid formulation and, according to the
development and manufacture. Multiple-units might consist formulation or product requirements, either or both capsules
of a single pellet, or homogeneous granules, or a may be of gelatin or HPMC composition and can be coated,
combination of several pellets and granules with various if necessary. The inner and outer capsules may contain the
substances and different release characteristics. It is even same active drug, providing multiple release profiles from
possible to include a number of dosage forms – such as the dosage unit – for example, an immediate release
tablets, pellets, capsules, powders and granules – within a formulation from the outer capsule and a controlled release
single formulation. In this way, incompatibilities and formulation from the inner capsule. In addition to
interaction between the different drug substances in modifying release profiles, it is also possible to target the
combination products can be prevented19. inner and outer capsule to different areas of the GI tract
(small intestine or colon) with an appropriate coating.
The concept of MUDFs is characterized by the fact that the Alternatively, the inner and outer capsules may contain
dose is administered as a number of subunits, each one different actives for use with combination therapies or
containing the drug. The dose is then the sum of the actives that are incompatible. This method is suited for both
quantity of the drug in each subunit and the functionality of pharmaceutical and nutraceutical use. It is a simplified drug
the entire dose is directly correlated to the functionality of regimen. .23
the individual subunits.
Advantages of Capsule-in-capsule technology24:
This capsule design allows the filling of different types of 1. Provides both controlled and multi-phase release for
MUDFs formulations such as powder-filled-capsules, single or combination prescription and over the counter
granules-filled-capsules, beads-filled-capsule, tablets-filled- medicines.
capsule, caplets-filled- capsule and capsule-filled-capsule 2. Comprising of two independent compartments in one
(See Figure 4). Hard gelatin capsules therefore offer a single oral dosage unit.
highly flexible solution for MUDFs. 20-22 3. Patient convenience and compliance and cost effective
therapy can be achieved.
New technologies formulated as multiple unit drug: 4. Delivering of incompatible APIs are possible.
delivery Capsule formulations: 5. Sustained, pulsed or delayed release profiles can be
Capsule-in-a-capsule technology- achieved.
Single oral capsule dosage units comprising capsule-in-a- 6. Drug delivery can be targeted to two different regions
capsule technology (See Figure 5) offer a broad range of of the GI tract.
therapeutic applications. This method allows the insertion 7. Broad therapeutic applications can be achieved.
of a pre-filled, smaller capsule into a larger, liquid-filled
capsule. The smaller, inner capsule may contain either a

Figure 4: Capsule formulations

37
 Research J. Pharm. and Tech. 6(1): January 2013
Mini tablets-in-a-capsule technology:
Controlled release capsules often containing plurality of
coated pellets is yet another category of solid oral
formulation that offers analogous therapeutic benefits. A
relatively more recent approach that has come into
existence is the one that combines the features of both
controlled release tablets and modified release capsules in
one dosage form25.
Drugs are usually encapsulated in one way or another
within a barrier material, which is composed of an erodible
or biodegradable polymer. Depending on the barrier
material structure and thickness, different release lag times
can be achieved. After the barrier material is dissolved,
eroded or degraded, drugs are rapidly released from the
inner reservoir core. Based on the concept that a
formulation given once a time daily, a multifunctional and
multiple unit system for oral use can be developed by filling
versatile tablets in a hard capsule. This can be developed by
preparing Rapid-release Mini-Tablets (RMTs), Sustained-
release Mini-Tablets (SMTs), Pulsatile Mini-Tablets
(PMTs), and Delayed-onset Sustained-release Mini-Tablets
(DSMTs), each with various lag times of release. Based on
the combinations of mini-tablets, multiplied pulsatile drug
delivery system (DDS), site-specific DDS, slow/quick
DDS, quick/slow DDS, and zero-order DDS could be
obtained. This system can be used for achieving the
selective delivery of drugs at appropriate time, which is a
chronopharmaceutical approach for the better treatment of
disease with circadian rhythms. This novel system is a so-
called “mini-tablets-in-a-capsule technology”. (see Figure
6). The designed capsule device consists of an impermeable
capsule body and a soluble cap. The multi-layered tablets
formulation prepared is filled within the capsule body and
sealed with the water-soluble cap26, 27-30.
In this technology we can reduce the size of the tablet such
that it could be enclosed in a capsule, and then deploy
tablets with different release properties, within one single
dosage form. This technology may be achieved by fast/slow
delivery system. The proposed fast/slow delivery devices
Figure 6: Mini tablets-in-a-capsule technology
38
show a wide flexibility in the modulation of the delivery
program. The two different release phases can be easily
adjusted in a wide range of values of both delivery rate and
ratio of the dose fractions, on the basis of the
pharmacokinetics and therapeutic needs, to perform the
desired in-vivo profile31, 32.
Figure 5: Capsule-in-a-capsule technology
Advantages of tablets-in-a-capsule technology:
1. It causes significant savings, lower treatment failure
rate and lower case-fatality ratios.
2. Provides both controlled and multi-phase release for
single or combination prescription and over the counter
medicines.
3. Patient convenience and compliance and cost effective
therapy can be achieved.
4. Delivering of incompatible APIs are possible.
5. Sustained, pulsed or delayed release profiles can be
achieved.
6. Drug delivery can be targeted to two different regions
of the GI tract.
7. It has higher colonic residence time, more predictable
gastric emptying and consequently less money needed
for the development of new products in long-term
therapy.
8. It offers high drug loading, a wide range of release rate
designs, and fine tuning of these release rates. It has
less risk of dose dumping, less inter- and intra- subject
variability, high degree of dispersion in the digestive
tract thus minimizing the risks of high local drug
concentrations. Broad therapeutic applications can be
achieved. 25, 32
 Research J. Pharm. and Tech. 6(1): January 2013

Importance of HPMC Capsules: market. There are a few pharmaceutical products on the
Two-piece capsules have been used for almost a century in world market. Many giant companies are actively including
the pharmaceutical field, and gelatin has been adopted as HPMC capsules in their developmental studies. 34,
the main material of these capsules due to its excellent
characteristic as a gelatinizer. The gelatin dissolves under Some of the important properties of HPMC Capsules in
high concentration into water of a high temperature and comparison to gelatin capsules are:
quickly gels in room temperature. The thickness of the film Moisture Contents in Capsule Shell—
made by the gelatin becomes uniform. However, gelatin is Hard gelatin capsules contain 13% to 15% water, water-
one of the proteins derived from animals; therefore, it is sensitive drugs are not considered to be suitable to them.
unstable from a chemical viewpoint. 33 However, QUALI-V contains only 4% to 6% of water in
the shell and is able to be filled with water- sensitive drugs.
The success achieved by the hard gelatin capsules, The moisture content in the capsule shell also influences the
popularly known as HGC, is well known and is reflected by brittleness of hard capsules. When the moisture content in
the fact that hard gelatin capsule shells have been used in the gelatin capsule shell decreases to below 10%, the
the pharmaceutical field for more than 100 years and capsules can break easily. However, QUALI-V does not
continue to grow in acceptance as the preferred oral dosage crack even with 1% or less in the moisture content.
form. Hard gelatin capsules do have some drawbacks. The Moreover, upon storage in accelerated stability conditions
principal drawback of hard gelatin capsules is that capsule such as 40 °C/75% RH, gelatin capsules undergo cross-
shells have 13 to 16 per cent water content and therefore linking reactions which reduce water solubility and retard
may not be suitable for use with readily hydrolysable drugs. disintegration of the shell and thus slow down the drug
Some drugs react with amine groups of gelatin, causing release.33,34,35
formation of cross-link between gelatin molecules and
reducing the solubility of the capsule shell. Furthermore, Compatibility to Filled Substances:
gelatin products are avoided by many as a result of Gelatin is chemically active on the molecular level. Lysine
religious, cultural or vegetarian restrictions. In addition, residual is a typical example; therefore, some substances are
recent safety report suggests a theoretical risk of considered not to be suitable for gelatin capsules. In
transmitting spongiform encephalopathy via gelatin particular, hard gelatin capsules may not be suitable for the
capsules. 34, 36 accelerated stability test, 40 0C and relative humidity 75%.
Furthermore, it is thought that compounds that contain an
When starting to formulate a medicine in hard gelatin aldehyde group, reduction sugars, and ascorbic acid to
capsule form, the first thing to study is its compatibility name a few, are not suitable for the gelatin capsule.
with the gelatin shell. Incompatibilities are known to occur; However, QUALI-V is capable of being filled with
for instance, with certain substances that contain reactive numerous materials because HPMC is chemically inactive.
aldehydes. The aldehydes can react with the gelatin by 33
forming crosslinks. 35, 36 Dissolution Profiles of QUALI-V:
Dissolution profiles of HPMC and gelatin capsules are
To overcome these problems, pharmaceutical scientists comparable over a wide range of pH values. Studies
have been working for decades to develop capsules made of describing the bioavailability of drugs, as reported till date,
starch, cellulose derivatives and polyvinyl alcohol show that oral bioavailability in HPMC capsules is identical
copolymer. In 1998, Shionogi Qualicap successfully to that delivered in gelatin capsules 40, 42
manufactured HPMC capsules, Quali-V, with properties
suitable for pharmaceutical products and dietary Liquid and Semi-Solid Filling Into QAULI-V:
supplements. Quali-V is the first HPMC capsule developed QUALI-V can be filled with many liquid and semi-solid
for pharmaceutical market, can be filled with many kinds of ingredients in addition to powders or granules. The gelatin
liquid or semisolid dosage forms. Today, HPMC capsules capsules were easily broken after the storage. The suggested
are produced by many manufacturers; viz. Vcaps by reason is as follows: the moisture content in the capsule
Capsugel division of Pfizer, Cellulose capsules by Natural shell decreased by the preservation condition and/or the
Capsules Ltd., and Naturecaps by Associated Capsules. excipients, therefore the capsules were easily broken. The
QUALI-V has been submitted to the FDA and its DMF moisture content in QUALI-V also can be decreased but
number is 12900. Generally, the thickness of a hard two- QUALI-V hardly broken even at the low moisture content.44
piece capsule shell is about 0.1 mm, and the thickness of
QUALI-V's is the same. The capsule shell acts as a New drug development:
container and/or a protective wall. The important matter for The extension of use period for clinical supplies for IND
the former is a compatibility with ingredients to QUALI-V. filings heavily depends on the shelf-life extrapolation using
The important matter for the latter is a permeability of accelerated stability data, once the failure occurs, the
vapor water and oxygen through the capsule shell. 34, 37 program is delayed with crisis management. It is one of the
reasons some firms prefer tablets even though tablets
HPMC capsules have been widely used in the nutritional require additional encapsulation for blinding in clinical
market. To date, HPMC capsules have been successfully trials. In terms of risk management, HPMC shell is
utilized for pharmaceutical products on the Japanese
39
 Research J. Pharm. and Tech. 6(1): January 2013

preferred to gelatin shells for new

compound Because HPMC shell walls are much weaker than gelatin
development. 45 made shells, removal of the capsule from the pins and
subsequent handling and filling are difficult. To overcome
Sizes and selection of HPMC capsules: these problems, three approaches were adapted. These
HPMC capsules are odourless, flexible and exhibit similar approaches were to use a stripper jaw with depressions on
dissolution character to the hard gelatin capsules. HPMC the inner surface, increase the formed HPMC film thickness
capsules Generally, capsules of sizes “0” to “4” were and the use of gelling agents.50-53
readily available in the market and the relationship between
the capsule size and related body volume are shown in Capsule sealing:
Figure 7. It comes in crystal clear or colored as per the Some manufacturers make tamper evident capsules by
needs including a range of natural colors to complement the sealing the capsule between two joint parts. One
brand. The volume of material that was to be filled into the manufacturer makes distinctive-looking capsules by sealing
capsule determined the size of the capsule that was needed. them with a colored band of gelatin (kapseals, parked avis).
For pharmaceutical products it is unusual to use a size If removed, the band cannot be restored without expert
larger than “0” because of the difficulty in swallowing resealing with gelatin. Capsules may be sealed through a
larger size capsules, whilst size “5” is rarely used due to heat welding process that fuses the capsule cap to the body
difficulties in the automatic filling process. Various grades through the double wall thickness at their juncture. 6, 7. The
of HPMC are suitable for forming the two-piece shells and process results in a distinctive ring around the capsule
are accepted by the pharmacopoeias of the US, Europe and where heat welded see Figure 8.
Japan. HPMC capsules available are different from each
manufacturer because each uses own patented gelling Cleaning and polishing capsules:
system using different techniques and additives to solve Small amounts of powder may adhere to the outside of
specific issues related to gel formation. Thus HPMC capsules after filling. The powder may be bitter or
capsules, unlike gelatin capsules, from different otherwise unpalatable and should be removed after
manufacturers are not interchangeable. 38, 39, 46-48 packaging or dispensing. On a small scale, capsules may be
cleaned individually or in small numbers by rubbing them
with a clean gauze or cloth. On a large scale, many capsule
filling machines are affixed with cleaning vacuum that
removes any extraneous material from the capsules as they
exit the equipment.7

Quality control tests for capsules:

Added Substances—
Substances added to official preparations, including
capsules, to enhance their stability, usefulness, or elegance
or to facilitate their manufacture may be used only if they:
1. Are harmless in the quantities used.
2. Do not exceed the minimum amounts required to provide
their intended effect.
3. Do not impair the product's bioavailability, therapeutic
Figure 7: Size of the capsule to fill weight efficacy or safety.
4. Do not interfere with requisite compendial assays and
Manufacturing of HPMC Capsules: tests. 7
HPMC Capsules can be manufactured by the same dipping
and forming method that is employed for the manufacture Appearance and Shape:
of classic hard gelatin capsules. Hard gelatin and HPMC The general appearance of the capsules includes the
54
Capsules are produced by using similar equipments morphological characteristics like size, shape, colour, etc.
49
developed by Eli Lilly.
Containers for Dispensing Capsules:
The manufacturing of HPMC based capsules requires some The USP lists specifications prescribing the type of
modification to the molding machine or to the formulation container suitable for the repackaging or dispensing of each
of the shell materials. HPMC gelling from solution occurs official capsule. Depending on the item, the container may
7
when the temperature is increased while it is converted to be required to be tight, well-closed, and light resistant.
its original solution as the temperature is decreased, unlike
gelatin solution.it means that the pins immersed in the dip
pan containing the HPMC solution must be of higher
temperature (700C) in order for the film to be formed. The
temperature of the pins must be further maintained post-dip
to facilitate gelatin until the films dry out in the kilns.

40
 Research J. Pharm. and Tech. 6(1): January 2013
Figure 8: Capsule sealing process
Disintegration Test for Capsules:
The disintegration test for hard and soft gelatin capsules is
conducted in vitro using a testing apparatus. The apparatus
consists of a basket and rack assembly containing six open-
ended transparent tubes of USP-specified dimensions, held
vertically upon a 10-mesh stainless steel wire screen. The
capsules are placed in the basket rack assembly, which is
immersed 30 times per minute into a thermostatically
controlled fluid at 37°C and observed over the time
described in the individual monograph. The capsules pass
the test if no residue of drug or other than fragments of shell
remains on No.10 mesh screen of the tubes. Complete
disintegration is defined as "that state in which any residue
of the unit, except fragments of insoluble coating or capsule
shell, remaining on the screen of the test apparatus is a soft
mass having no palpably firm core".7,55
Dissolution Test for Capsules:
The dissolution test for capsules uses the same apparatus,
dissolution medium, and test as that for uncoated and plain
coated tablets. However, if the capsule shells interfere with
the analysis, the contents of a specified number of capsules
can be removed and the empty capsule shells dissolved in
the dissolution medium before proceeding with the
sampling and chemical analysis. The equipment consists of:
(a) a variable speed stirrer motor; (b) a cylindrical stainless
steel basket on a stirrer shaft (USP Apparatus 1) or a paddle
as the stirring element (USP Apparatus 2); (c) a 1000-mL
vessel of glass or other inert transparent material fitted with
a cover having a center port for the shaft of the stirrer and
three additional ports, two for removal of samples, and one
for a thermometer; and (d) a water bath to maintain the
temperature of the dissolution medium in the vessel. For
use of USP Apparatus 1, the dosage unit is placed inside the
basket. For use of USP Apparatus 2, the dosage, mit- placed
in the vessel. In each test, a volume of the dissolution
medium (as stated in the individual monograph) is placed in
the vessel and allowed to come to 37°C ± 0.5°C. Then the
stirrer is rotated at the speed specified, and at stated
intervals samples of the medium are withdrawn for
chemical analysis of the proportion of drug dissolved. The
41
capsule must meet the stated monograph requirement for
rate of dissolution, for example, "not less than 85% of the
labeled amount is dissolved in 30 minutes." 7,55
Weight Variation:
The uniformity of dosage units may be demonstrated by
determining weight variation and/or content uniformity.
The weight variation method is as follows: Ten capsules are
individually weighed and the contents removed. The
emptied shells are individually weighed and the net weight
of the contents calculated by subtraction. From the results
of an assay performed as directed in the individual
monograph, the content of active ingredient in each of the
capsules is determined. 7, 56, 57
Content Uniformity:
It is performed to ensure the proper mixing of the capsule
contents by Determining the content of active ingredient in
each of 10 capsules taken at random using the method given
in monograph or by any other suitable analytical method.
The capsules comply with the test if not more than one of
the individual values thus obtained is outside the limits 85
to 115 % of the average value and none is outside the limits
75 to 125 %. If 2 or 3 individual values are outside the
limits 85 to 115 % of the average values, repeat the
determination using the another 20 capsules. The capsules
comply with the test if in the total sample of 30 capsules not
more than 3 individual values are outside the limits 85 to
115 % and none is outside the limits 75 to 125 % of the
average value. 7,57-60
Uniformity of mass:
Weight an intact capsule. Open the capsule without loosing
any part of the shell and remove the contents as completely
as possible. Weigh the shell. The mass of the contents is the
difference between the weighing. Repeat the procedure with
another 19 capsules. The percentage deviation for
uniformity of mass is 10 % for less than 300 mg and 7.5%
for 300 mg or more. 57
 Research J. Pharm. and Tech. 6(1): January 2013

Content Labeling Requirement: several all the advantages including greater flexibility and
All official capsules must be labeled to express the quantity adaptability of microparticulate dosage forms which gives
of each active ingredient in each dosage unit. 7 clinicians and those engaged in product development
powerful new tools to optimize therapy. For
Stability Testing: Multiparticulate drug delivery systems, hard gelatin or
Stability testing of capsules is performed to determine the HPMC capsules are the ideal solution. Multiple-units in
intrinsic stability of the active drug molecule and the hard gelatin or HPMC capsules allow the combination of
influence of environmental factors such as temperature, different products with different release profiles, even if
humidity, light, formulative components, and the container they are incompatible with each other or of substances with
and closure system. The battery of stress testing, long-term different release profiles. HPMC capsules offer numerous
stability, and accelerated stability tests help determine the and unique benefits as dosage form for pharmaceuticals.
appropriate conditions for storage and the product's Increasing commercial availability, offer of overcoming
anticipated shelf life. 7,55 problems inherent with gelatin capsules coupled with their
rapid progress in manufacturing; make HPMC capsules an
Moisture Permeation Test: ideal alternative to classic gelatin capsules.
The USP requires determination of the moisture permeation
characteristics of single-unit and unit-dose containers to ACKNOWLEDGEMENTS:
ensure their suitability for packaging capsules. The degree The authors express his thanks to Mr. Joginpally Bhaskar
and rate of moisture penetration is determined by packaging Rao Garu, Chairman, and Dr. A. Srinivasa Rao, Principal,
the dosage unit together with a color-revealing desiccant Bhaskar Pharmacy College, R.R.District, Hyderabad for
pellet, exposing the packaged unit to known relative supporting us to do research and make this review article.
humidity over a specified time, observing the desiccant Based on the outcome results of our published research
pellet for color change (indicating absorption of moisture) works on capsules in various journals it has been possible
and comparing the pretest and posttest weight of the for us to publish this review article.
packaged unit. 7
REFERENCES:
Inspecting of capsules: 1. Michael Aulton E. Aultons Pharmaceutics: The design and
Capsules produced on a small or large scale should be manufacture of medicines. 3rd edn 2007.
uniform in appearance. Visual or electronic inspection 2. La Wall CH., 4000 years of pharmacy, an outline history of
should be undertaken to detect any flaws in the integrity pharmacy and the allied sciences, J. B. Lippincott Comp.,
Philadelphia/London/Montreal 1940.
and the appearance of the capsules. Defective capsules 3. Sven Stegemann, Capsugel Bornem. Hard gelatin capsules today
should be rejected. See Figure 9 for possibilities in defects. and tomorrow. Capsugel Library 2002; 2nd Edn.
7
4. Sastry SV, Nyshdham JR, Fix JA. Recent technological advances
in oral drug delivery: A review. Pharm Sci and Tech Today 2000;
3:138-45.
5. Seager H. Drug-delivery products and the Zydis fast-dissolving
dosage form. J. of Pharma and Pharmaco 1998; 50(4): 375-82.
6. Leon Lachman, Herbert Lieberman A. The theory and practice of
industrial pharmacy. Special Indian edition 2009; 293-373.
7. Allen LV, Popovich NG, Ansel HC. Ansel’s Pharmaceutical
Dosage Forms and Drug Delivery Systems. Philadelphia:
Lippincott, Williams and Wilkins 2004.
8. Cole GC. Evaluating development and production costs: tablets
versus capsules. Pharm Technol Eur 5 1998; 17-26.
9. Jones BE. The history of the gelatin capsule, in: Hard Capsules,
ed. Ridgway, K., The Pharmaceutical Press 1987.
10. Loyd Allen V, Nicholas Jr, Popovich G, Howard Ansel C. Ansels
pharmaceutical dosage forms and drug delivery systems. 8th
Edition.
11. Ewart Cole T. Liquid filled and sealed hard gelatin capsules.
Capsugel Library.
Figure 9: Possible defects in capsules
12. Karteek M, Bala Krishna K. A Review on capsules in pharmacy.
Int. J. Pharm. and Tech. 2011; 3(3):1189-1196.
Storage: 13. "History of dosage forms and basic preparations". Encyclopedia
Capules are packaged in glass or in plastic containers, some of Pharmaceutical Technology. 7. Informa Health Care 1998:
containing packets of a dessicant to prevent absorption of 304–306.
excessive moisture. 7, 55 14. Borgquist P, Nevsten P, Nilsson B, Wallenberg LR, Axelsson A.
Simulation of the release from a multiparticulate system validated
by single pellet and dose release experiments. J. of Cont. Rel.
CONCLUSION: 2004; 97: 453–465.
Today’s drug delivery technologies enable the 15. Khosla R, Feely LC, Davis SS. Gastrointestinal transit of non-
incorporation of drug molecules into a new delivery system, disintegration tablets in fed subjects. Int. J. Pharm 1989; 53:107-
117.
thus providing numerous therapeutic and commercial 16. Riis T, Bauer-Brandl A, Wagner T, Kranz H. pH independent
advantages. Multiparticulate drug delivery systems provide drug release of an extremely poorly soluble weakly acidic drug

42
 Research J. Pharm. and Tech. 6(1): January 2013
from multiparticulate extended release formulations. Eur. J.
Pharm/ Biopharm 2007; 65: 78-84.
17. Shaji J, Chadawar V,Talwalkar P. Multiparticulate Drug Delivery
System, The Indian Pharmacist 2007; 6(60): 21-28.
18. Preparing Modified Release Multiparticulate Dosage Forms With
Eudragit Polymers, Pharma Polymers 2002; 9: 2-3.
19. Cole G, Hogan J, Aulton M. Pharmaceutical Coating
Technology, London: Taylor and Francis 1995.
20. Gross ST, Hoffman A, Donbrow M, Benita S. Fundamentals of
the release mechanism interpretation in multiparticulate systems:
the prediction of the commonly observed release equations from
statistical population models for particle ensembles. Int. J. Pharm
1986; 29: 213–222.
21. Hoffman A, Donbrow M, Gross ST, Benita S, Bahat R.
Fundamentals of release mechanism interpretation in
multiparticulate systems: determination of substrate release from
single microcapsules and relation between individual and
ensemble release kinetics. Int. J. Pharm 1986; 29: 195–211.
22. Mathiowitz E, Brannon-Peppas L. In: Mathiowitz, E. (Ed.),
Encyclopedia of Controlled Drug Delivery. Wiley, New York
1999; 493–546.
23. Stephen Brown, Gary Norman, Alyn McNaughton. Liquid-Fill
Based Formulation: Advances and Challenges. Innovations in
Pharm. Technol. 64-68.
24. Duocap for controlled release combination products. Available at
http://www.encapdrugdelivery.com/assets/files/services/Encap%2
0DuoCap%20Technology.pdf
25. Mangesh Bhad E, Shajahan Abdul, Sunil Jaiswal B, Anil
Chandewar V, Jayesh Jain M, Dinesh Sakarkar M. MUPS Tablets
– A Brief Review. Int. J. of PharmTech Res . 2010; 2 (1): 847-
855.
26. Bin Li, JiaBi Zhu, ChunLi Zheng, Wen Gong. A novel system for
three-pulse drug release based on “tablets in capsule” device
2007; 1-6.
27. Ying-huan Li, Jia-bi Zhu. Modulation of combined-release
behaviors from a novel ‘‘tablets-in-capsule system. J. of Con.
Rel. 2004; 95: 381– 389.
28. N. G. Raghavendra Rao, Mohd Abdul Hadi, Harsh Panchal. A
Novel approach to sustained Montelukast sodium release:
Differentially coated mini-tablets in HPMC capsules. Int. J. of
Pharm. and Biomed. Sci. 2011; 2(2): 90-97.
29. Mohd Abdul Hadi, Raghavendra Rao NG, Sunil firangi. Mini-
tablets technology: An Overview. American J. of Pharm. Res.
2011; 2(2): 128-150.
30. Hitesh P. Patel, Nitesh J. Patel, Formulation and evaluation of
biphasic drug delivery system of diclofenac sodium using
compressed mini tablet. Int. J of Pharm Res. 2011; 3(1).
31. Mako to Ishida, Kenichi Abe., Munoru, Hashezime, Masco
Kawamura. A novel approach to sustained pseudoephedrine
release-Differentially coated Mini-tablets in HPMC capsules. Int.
J. of Pharm. 2008; 359: 46-52.
32. Raghavendra Rao NG, Mohd Abdul Hadi, Mansoori Wahid,
Munde MR, Shrishail M. Ghurghure, Development and
evaluation of tablets-filled-HPMC capsule system for
chronotherapeutic delivery of montelukast sodium. Int. J. of
Pharm. and Tech. 2011; 3(1):1702-1721.
33. Ogura T, Furuya Y, Matuura S. HPMC capsules: an alternative to
gelatin. Pharm Tech Europe , 2011; 10(11): 32-42.
34. Brown J, Madit N, Cole ET, Wilding IR, Cade D. Effect of cross-
linking on the in vivo disintegration of hard gelatin capsules.
Pharm. Res 1998; 15: 1026–1030.
35. Liebowitz, SM., Vadino WA., Ambrosio TJ. Determination of
hard gelatin capsule brittleness using a motorized compression
test stand. Drug Dev. Ind. Pharm 1990; 16: 995–1010.
36. Subal Basak C. The rise and rise of HPMC capsules. September
2007. Available at www.pharmabiz.com
37. Digenis GA, Gold TB, Shah VP. Crosslinking of gelatin capsules
and its relevance to their in-vitro in-vivo performance, J. Pharm.
Sci.1994; 83: 7.
38. Rowe, R.C., Sheskey, P.S. Weller, P.J.Handbook of
Pharmaceutical Excipients, 5th Edn. Pharmaceutical Press
43
View publication stats
(London, UK) and the American Pharmacists Association,
Washington DC, USA 2003.
39. Nature caps, cellulose (HPMC) capsules, product brochure, ACG
World wide. Available at www.acg-word.com
40. Nagata S, Tochio S, Sakuma S, Suzuki Y. Dissolution profiles of
drugs filled into HPMC capsule and gelatin capsule. Abstract
presented at: AAPS Annual Meeting in Denver; W4196,
41. Hard capsule for pharmaceutical drugs and method for producing
the same. US Patent No. 5264223; November 23, 1999.
42. Hard capsule for pharmaceutical drugs and method for producing
the same. U.S Patent No. 543917; July 11, 1995.
43. Capsule shell. May 26, 1998, US Patent No. 5756123.
44. Nagata S, Nishi N, Matsuura S. Characteristics of HPMC
capsules. Abstract 161 (Scientific to Regulatory Approaches)
presented at: International Symposium on Strategies for
Optimizing Oral Drug Delivery in Kobe 1999; 19-21:161.
45. Sherry Ku M, Weiyi Li,, Wendy Dulin, Fran Donahue,
Dominique Cade, Hassan Benameur, Keith Hutchison.
Performance Qualification of a New Hypromellose Capsule.
Capsugel Library. BAS 401.
46. Cole GC. Hard Capsules-development and technology, edited by
K Ridgway, The pharmaceutical Press. 1987; 93: 165-169.
47. David Edwards. Applications of capsule dosing techniques for
use in dry powder inhalers. Therapeutic del 2010; 1(1): 195-201.
48. Jones BE. Manufacture and properties of two piece hard capsules,
in: F. Podczek, BE. Jones (Eds.), Pharmaceutical Capsules,
Pharmaceutical Press, London 2004; 79–100.
49. Augsburger LL. Hard and Soft Shell Capsules, in Banker GS and
Rhodes CT (eds), Modern Pharmaceutics, 2002; Volume 121,
Marcel Dekker, Inc, New York.
50. Grosswald RR, Anderson JB and Andrew CS. Method for the
manufacture of pharmaceutical cellulose capsules. US Patent No.
1997; 5,698,155.
51. Grosswald RR, Anderson JB and Andrew CS. Apparatus for the
manufacture of pharmaceutical cellulose capsules. US Patent No.
5,750,157.
52. Grosswald RR, Anderson JB and Andrew CS. Method for the
manufacture of pharmaceutical cellulose capsules. US Patent No.
1998; 5,756,036.
53. Grosswald RR, Anderson JB and Andrew CS. Method for the
manufacture of pharmaceutical cellulose capsules. US Patent No.
2002; 6,337,045.
54. Dr Fahan Jalees ahmed, Sushma Drabu, Smriti Khatri, Sheveta
Babu. Formulation and Evaluation of Acyclovir Capsules. Int. J.
of Drug Dev. and Res. 2004;3(4): 162-167.
55. Ashok K. Gupta. Introduction to pharmaceutics-І, 3rd Edition ,
2006; 275-283.
56. Quality Control of solid dosage forms. Pharos University in
Alexandria. Faculty of pharmacy and drug manufacturing.
Industrial QC and GMP (PHR 505): 1-4.
57. Teja CH, Balamuralidhara V, Vinay S, Sudeendra Bhatt R,
Pramod Kumar TM. Comparative study of in-process and
finished products quality control tests of Indian pharmacopoeia,
british pharmacopoeia and united states pharmacopoeia for
capsules and liquid orals. Int. Res. J. of Pharm. 2011; 2(9): 65-69.
58. Yamamoto T, Matsuura S, Hashimoto K, Abe K and Akal A.
Hard capsules. European Patent No. EP0592130B1, 1999; 28.
59. US Pharmacopoeia 30-NF25, , 2007; May 1.
60. Kupiec TC, Vu N, Branscum D. Homogeneity of dosage forms.
Int. J. of Pharm. Comp. 2008;12(4): 340-343.