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.¹These capsules are one of the oldest dosage forms in pharmaceutical history, known to the ancient Egyptians.²The 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.

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

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 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 2: Capsule size 00 is the largest capsule used for human oral preparations and size 5 is the smallest.

Figure 3: The cap of the capsule fits snugly over the body of the capsule after the capsules are filled.

Hard gelatin capsules:

Hard gelatin capsule shells are used in most commercial medicated capsules. The empty capsule shells are made of gelatin, sugar and water. Gelatin is obtained by partial hydrolysis of collagen obtained from the skin, white connective tissue and bones of animals. Gelatin, being a protein, is digested by proteolytic enzymes and digested. As such they can be clear, colorless and essentially tasteless; or they may be colored with various FD&C and D&C dyes and made opaque by adding agents such as titanium dioxide. Most commercially available medicated capsules contain combinations of colorants and opaquants to make them distinctive, many with caps and bodies of different colors. They are commonly employed in clinical drug trials, to compare the effects of an investigational drug with those of another drug product or placebo¹⁰. The hard gelatin capsule has also been conventionally used as a dosage form for Rx and OTC drugs and herbal products, which are formulated either as powder or pellets. ¹¹

A number of methods have also been developed to track the passage of capsules through the gastrointestinal tract to map their transit time and drug release patterns. Among these is gamma scintigraphy, a non-invasive procedure that entails use of a gamma ray-emitting radiotracer incorporated into the formulation with a gamma camera coupled to a data recording system. When scintigraphy is combined with pharmacokinetic studies, the resultant pharmacoscintographic evaluation provides information about the transit and drug release patters of the dosage form as well as the rate of drug absorption from the various regions of the gastrointestinal tract.¹⁰

· Some of the examples of gelatin capsules are:

· Clear Gelatin Capsules

· Colored Gelatin Capsules -Red/White

· Grape Flavored Gelatin Capsules -Purple/Purple

· Mint Flavored Gelatin Capsules -Green/Green

· Coffee Flavored Capsules -Brown/Brown

· Strawberry Flavored Gelatin Capsules -Red/Red

· Orange Flavored Gelatin Capsules -Orange/Orange

· Bubblegum Flavored Capsules -Pink/Pink

· Berry Flavored Gelatin Capsules -Dark Purple

^·Clear Fish Gelatin Capsules¹²

Advantages of Capsule Formulations^7,
12:

1. They are a professional looking, uniform, clean, and elegant dosage form.

2. They effectively mask the odor and taste of substances.

3. They are a convenient dosage form in which an individual dose can be accurately measured.

4. They are easily packaged and transported, and can be easily administered to the patient.

5. They can be filled with a precise dose for a specific patient that may not be available commercially or may be available only in another form.

6. They can contain ingredients that may be unpalatable or toxic to the touch.

7. Two or more active ingredients can be combined into a single capsule dosage form, improving patient compliance.

8. One or more commercially manufactured tablets can be inserted into a capsule with the addition of a diluent, such as lactose, to facilitate dosing.

9. They can be compounded easily in the pharmacy and offer many advantages to patients.

10. Capsules provide a rapid release of medication in the stomach because of their rapid disintegration.

Equipment¹³:

Hard Capsule Machine:

SFR 901 FS6/7, In this model of capsule making machine, dipping action, transfer along upper deck, transfer from upper to lower deck and transfer from lower deck to table are all performed by high precision programmable servo motors combined with precision ball screws.

SFR 901D, In this model of capsule making machine, dipping action, separately for cap and body, is performed by high precision programmable servo motors combined with precision ball screws.

SFR 720, In this model of capsule making machine, follows the traditional system of capsule production where all movements and actions are performed by highly accurate mechanical components.

Capsule filling machines:

Below are few of the examples which can be used for filling capsules---

Semi-Automatic SL90 Capsule Filling Machine

Semi-Automatic SL 15 Capsule Filler Machine

Semi-Automatic SL 60 Capsule Filler Machine

Semi-Automatic SL 180 Capsule Filler Machine

Capsules as a carrier for Multiple Unit Drug Delivery Systems for Controlled Release:

Oral controlled release drug delivery systems can be classified in two broad groups: single unit dosage forms (SUDFs), and multiple unit dosage forms (MUDFs). The concept of MUDFs was initially introduced in the early 1950s¹⁴.MUDFs have several performance advantages vs. SUDFs. After ingestion, MP units are released from the capsule in the stomach, predictably transit to the small intestine and spread along the gastro-intestinal. There is a growing interest in MUDFs due to their consistent and reliable in-vivo drug release, with a reduced risk of local irritation along the gastrointestinal tract.^15,
16

MUDFs are mainly oral dosage forms consisting of a multiplicity of small discrete units, each exhibiting some desired characteristics. In these systems, the dosage of the drug substances is divided on a plurality of subunit, typically consisting of thousands of spherical particles with diameter of 0.05-2.00 mm. To deliver the recommended total dose, these subunits are filled into a capsule. ^{17, 18}

Hard gelatin capsules are particularly suitable for their development and manufacture. Multiple-units might consist of a single pellet, or homogeneous granules, or a combination of several pellets and granules with various substances and different release 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 prevented¹⁹.

The concept of MUDFs is characterized by the fact that the dose is administered as a number of subunits, each one containing the drug. The dose is then the sum of the quantity of the drug in each subunit and the functionality of the entire dose is directly correlated to the functionality of the individual subunits.

This capsule design allows the filling of different types of MUDFs formulations such as powder-filled-capsules, granules-filled-capsules, beads-filled-capsule, tablets-filled-capsule, caplets-filled- capsule and capsule-filled-capsule (See Figure 4). Hard gelatin capsules therefore offer a highly flexible solution for MUDFs. ^20-22

New technologies formulated as multiple unit drug: delivery Capsule formulations:

Capsule-in-a-capsule technology-

Single oral capsule dosage units comprising capsule-in-a-capsule technology (See Figure 5) offer a broad range of therapeutic applications. This method allows the insertion of a pre-filled, smaller capsule into a larger, liquid-filled capsule. The smaller, inner capsule may contain either a liquid or semi-solid formulation and, according to the formulation or product requirements, either or both capsules may be of gelatin or HPMC composition and can be coated, if necessary. The inner and outer capsules may contain the same active drug, providing multiple release profiles from the dosage unit – for example, an immediate release formulation from the outer capsule and a controlled release formulation from the inner capsule. In addition to modifying release profiles, it is also possible to target the inner and outer capsule to different areas of the GI tract (small intestine or colon) with an appropriate coating. Alternatively, the inner and outer capsules may contain different actives for use with combination therapies or actives that are incompatible. This method is suited for both pharmaceutical and nutraceutical use. It is a simplified drug regimen. .²³

Advantages of Capsule-in-capsule technology²⁴:

1. Provides both controlled and multi-phase release for single or combination prescription and over the counter medicines.

2. Comprising of two independent compartments in one single oral dosage unit.

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. Broad therapeutic applications can be achieved.

Figure 4: Capsule formulations

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 cap^{26, 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

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 profile^{31, 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}

Figure 6: Mini tablets-in-a-capsule technology

Importance of HPMC Capsules:

Two-piece capsules have been used for almost a century in the pharmaceutical field, and gelatin has been adopted as the main material of these capsules due to its excellent characteristic as a gelatinizer. The gelatin dissolves under high concentration into water of a high temperature and quickly gels in room temperature. The thickness of the film made by the gelatin becomes uniform. However, gelatin is one of the proteins derived from animals; therefore, it is unstable from a chemical viewpoint. ³³

The success achieved by the hard gelatin capsules, popularly known as HGC, is well known and is reflected by the fact that hard gelatin capsule shells have been used in the pharmaceutical field for more than 100 years and continue to grow in acceptance as the preferred oral dosage form. Hard gelatin capsules do have some drawbacks. The principal drawback of hard gelatin capsules is that capsule shells have 13 to 16 per cent water content and therefore may not be suitable for use with readily hydrolysable drugs. Some drugs react with amine groups of gelatin, causing formation of cross-link between gelatin molecules and reducing the solubility of the capsule shell. Furthermore, gelatin products are avoided by many as a result of religious, cultural or vegetarian restrictions. In addition, recent safety report suggests a theoretical risk of transmitting spongiform encephalopathy via gelatin capsules. ^{34, 36}

When starting to formulate a medicine in hard gelatin capsule form, the first thing to study is its compatibility with the gelatin shell. Incompatibilities are known to occur; for instance, with certain substances that contain reactive aldehydes. The aldehydes can react with the gelatin by forming crosslinks. ^{35, 36}

To overcome these problems, pharmaceutical scientists have been working for decades to develop capsules made of starch, cellulose derivatives and polyvinyl alcohol copolymer. In 1998, Shionogi Qualicap successfully manufactured HPMC capsules, Quali-V, with properties suitable for pharmaceutical products and dietary supplements. Quali-V is the first HPMC capsule developed for pharmaceutical market, can be filled with many kinds of liquid or semisolid dosage forms. Today, HPMC capsules are produced by many manufacturers; viz. Vcaps by Capsugel division of Pfizer, Cellulose capsules by Natural Capsules Ltd., and Naturecaps by Associated Capsules. QUALI-V has been submitted to the FDA and its DMF number is 12900. Generally, the thickness of a hard two-piece capsule shell is about 0.1 mm, and the thickness of QUALI-V's is the same. The capsule shell acts as a container and/or a protective wall. The important matter for the former is a compatibility with ingredients to QUALI-V. The important matter for the latter is a permeability of vapor water and oxygen through the capsule shell. ^34,
37

HPMC capsules have been widely used in the nutritional market. To date, HPMC capsules have been successfully utilized for pharmaceutical products on the Japanese market. There are a few pharmaceutical products on the world market. Many giant companies are actively including HPMC capsules in their developmental studies.^34,

Some of the important properties of HPMC Capsules in comparison to gelatin capsules are:

Moisture Contents in Capsule Shell—

Hard gelatin capsules contain 13% to 15% water, water-sensitive drugs are not considered to be suitable to them. However, QUALI-V contains only 4% to 6% of water in the shell and is able to be filled with water- sensitive drugs. The moisture content in the capsule shell also influences the brittleness of hard capsules. When the moisture content in the gelatin capsule shell decreases to below 10%, the capsules can break easily. However, QUALI-V does not crack even with 1% or less in the moisture content. Moreover, upon storage in accelerated stability conditions such as 40 °C/75% RH, gelatin capsules undergo cross-linking reactions which reduce water solubility and retard disintegration of the shell and thus slow down the drug release.^33,34,35

Compatibility to Filled Substances:

Gelatin is chemically active on the molecular level. Lysine residual is a typical example; therefore, some substances are considered not to be suitable for gelatin capsules. In particular, hard gelatin capsules may not be suitable for the accelerated stability test, 40 ⁰C and relative humidity 75%. Furthermore, it is thought that compounds that contain an aldehyde group, reduction sugars, and ascorbic acid to name a few, are not suitable for the gelatin capsule. However, QUALI-V is capable of being filled with numerous materials because HPMC is chemically inactive. ³³

Dissolution Profiles of QUALI-V:

Dissolution profiles of HPMC and gelatin capsules are comparable over a wide range of pH values. Studies describing the bioavailability of drugs, as reported till date, show that oral bioavailability in HPMC capsules is identical to that delivered in gelatin capsules ^{40, 42}

Liquid and Semi-Solid Filling Into QAULI-V:

QUALI-V can be filled with many liquid and semi-solid ingredients in addition to powders or granules. The gelatin capsules were easily broken after the storage. The suggested reason is as follows: the moisture content in the capsule shell decreased by the preservation condition and/or the excipients, therefore the capsules were easily broken. The moisture content in QUALI-V also can be decreased but QUALI-V hardly broken even at the low moisture content.⁴⁴

New drug development:

The extension of use period for clinical supplies for IND filings heavily depends on the shelf-life extrapolation using accelerated stability data, once the failure occurs, the program is delayed with crisis management. It is one of the reasons some firms prefer tablets even though tablets require additional encapsulation for blinding in clinical trials. In terms of risk management, HPMC shell is preferred to gelatin shells for new compound development.⁴⁵

Sizes and selection of HPMC capsules:

HPMC capsules are odourless, flexible and exhibit similar dissolution character to the hard gelatin capsules. HPMC capsules Generally, capsules of sizes “0” to “4” were readily available in the market and the relationship between the capsule size and related body volume are shown in Figure 7. It comes in crystal clear or colored as per the needs including a range of natural colors to complement the brand. The volume of material that was to be filled into the capsule determined the size of the capsule that was needed. For pharmaceutical products it is unusual to use a size larger than “0” because of the difficulty in swallowing larger size capsules, whilst size “5” is rarely used due to difficulties in the automatic filling process. Various grades of HPMC are suitable for forming the two-piece shells and are accepted by the pharmacopoeias of the US, Europe and Japan. HPMC capsules available are different from each manufacturer because each uses own patented gelling system using different techniques and additives to solve specific issues related to gel formation. Thus HPMC capsules, unlike gelatin capsules, from different manufacturers are not interchangeable. ^{38,
39, 46-48}

Figure 7: Size of the capsule to fill weight

Manufacturing of HPMC Capsules:

HPMC Capsules can be manufactured by the same dipping and forming method that is employed for the manufacture of classic hard gelatin capsules. Hard gelatin and HPMC Capsules are produced by using similar equipments developed by Eli Lilly.⁴⁹

The manufacturing of HPMC based capsules requires some modification to the molding machine or to the formulation of the shell materials. HPMC gelling from solution occurs when the temperature is increased while it is converted to 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.

Because HPMC shell walls are much weaker than gelatin made shells, removal of the capsule from the pins and subsequent handling and filling are difficult. To overcome these problems, three approaches were adapted. These approaches were to use a stripper jaw with depressions on the inner surface, increase the formed HPMC film thickness and the use of gelling agents.^50-53

Capsule sealing:

Some manufacturers make tamper evident capsules by sealing the capsule between two joint parts. One manufacturer makes distinctive-looking capsules by sealing them with a colored band of gelatin (kapseals, parked avis). If removed, the band cannot be restored without expert resealing with gelatin. Capsules may be sealed through a heat welding process that fuses the capsule cap to the body through the double wall thickness at their juncture. ^{6, 7}. The process results in a distinctive ring around the capsule where heat welded see Figure 8.

Cleaning and polishing capsules:

Small amounts of powder may adhere to the outside of capsules after filling. The powder may be bitter or otherwise unpalatable and should be removed after 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 efficacy or safety.

4. Do not interfere with requisite compendial assays and tests.⁷

Appearance and Shape:

The general appearance of the capsules includes the morphological characteristics like size, shape, colour, etc.⁵⁴

Containers for Dispensing Capsules:

The USP lists specifications prescribing the type of container suitable for the repackaging or dispensing of each official capsule. Depending on the item, the container may be required to be tight, well-closed, and light resistant.⁷

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 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

Content Labeling Requirement:

All official capsules must be labeled to express the quantity of each active ingredient in each dosage unit.⁷

Stability Testing:

Stability testing of capsules is performed to determine the intrinsic stability of the active drug molecule and the influence of environmental factors such as temperature, humidity, light, formulative components, and the container and closure system. The battery of stress testing, long-term stability, and accelerated stability tests help determine the appropriate conditions for storage and the product's anticipated shelf life.^7,55

Moisture Permeation Test:

The USP requires determination of the moisture permeation characteristics of single-unit and unit-dose containers to ensure their suitability for packaging capsules. The degree and rate of moisture penetration is determined by packaging the dosage unit together with a color-revealing desiccant pellet, exposing the packaged unit to known relative humidity over a specified time, observing the desiccant pellet for color change (indicating absorption of moisture) and comparing the pretest and posttest weight of the packaged unit.⁷

Inspecting of capsules:

Capsules produced on a small or large scale should be uniform in appearance. Visual or electronic inspection should be undertaken to detect any flaws in the integrity and the appearance of the capsules. Defective capsules should be rejected. See Figure 9 for possibilities in defects.⁷

Figure 9: Possible defects in capsules

Storage:

Capules are packaged in glass or in plastic containers, some containing packets of a dessicant to prevent absorption of excessive moisture. ^{7, 55}

CONCLUSION:

Today’s drug delivery technologies enable the incorporation of drug molecules into a new delivery system, thus providing numerous therapeutic and commercial advantages. Multiparticulate drug delivery systems provide several all the advantages including greater flexibility and adaptability of microparticulate dosage forms which gives clinicians and those engaged in product development powerful new tools to optimize therapy. For Multiparticulate drug delivery systems, hard gelatin or HPMC capsules are the ideal solution. Multiple-units in hard gelatin or HPMC capsules allow the combination of different products with different release profiles, even if they are incompatible with each other or of substances with different release profiles. HPMC capsules offer numerous and unique benefits as dosage form for pharmaceuticals. Increasing commercial availability, offer of overcoming problems inherent with gelatin capsules coupled with their rapid progress in manufacturing; make HPMC capsules an ideal alternative to classic gelatin capsules.

ACKNOWLEDGEMENTS:

The authors express his thanks to Mr. Joginpally Bhaskar Rao Garu, Chairman, and Dr. A. Srinivasa Rao, Principal, Bhaskar Pharmacy College, R.R.District, Hyderabad for supporting us to do research and make this review article. Based on the outcome results of our published research works on capsules in various journals it has been possible for us to publish this review article.

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Received on 03.11.2012 Modified on 23.11.2012

Research J. Pharm. and Tech. 6(1): Jan. 2013; Page 34-43