CAPSULEGeneral chapter

General introduction • Capsules are solid dosage forms in which the drug or a mixture of drugs is enclosed in

Hard Gelatin Capsule Shells, in soft, soluble shells of gelatin, or in hard or soft shells of any other suitable material, of various shapes and capacities.

• They usually contain a single dose of active ingredient(s) and are intended for oral administration.

• Excipients such as opaque fillers, antimicrobial preservatives, sweetening agents, flavoring agents and one or more coloring agents permitted under the Drugs and Cosmetic Rules, 1945 may be added.

• Capsules may bear surface markings.• The contents of capsules may be of solid, liquid or paste-like consistency. They consist of

the medicament(s) with or without excipients such as vehicles, solvents, diluents, lubricants, fillers, wetting agents and disintegrating agents.

• The contents do not cause deterioration of the shell, but the capsules are attacked by the digestive fluids thereby releasing the contents. The contents of capsules other than Modified-release (Sustained-release) Capsules do not contain any added coloring agent.

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CAPSULES• solid dosage form• the drug is enclosed within either a hard or

soft shell– shell is typically made of gelatin

• primarily intended for oral delivery• provide a rapid release of contents

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Filling

• operations involved– rectification of empty capsules– separation of caps from bodies– filling capsule bodies– replacing caps and ejecting filled capsules

• 3 basic methods for powder filling– auger or screw– dosator– dosing disc

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Capsule Filling

– auger• semi-automatic operation• filling based on volume• need good powder flow properties

– dosator• fill based on weight• continuous operation

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Capsule Filling– dosing disc• filled based on weight• continuous operation

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Hard Gelatin Capsules

• Advantages– tasteless and odourless– swallowing is easy– flexibility in formulating– uniquely suitable for blinded clinical trials– useful for extemporaneous compounding by pharmacist

• Disadvantages– tend to be more expensive to produce than tablets– not suitable for highly soluble salts

B. Amsden

Different size of hard gelatin capsule

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Soft Gelatin Capsules (Softgels)• consist of a continuous gelatin shell surrounding a liquid core• formed, filled, and sealed in one operation• shells are softened by addition of glycerin or polyhydric

alcohol (ex. sorbitol)• oblong, spherical, elliptical in shape

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Manufacture

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Soft Capsules• ADVANTAGES– may contain liquids, suspensions, pastes– rapid release of contents– useful for drugs prone to oxidation

• DISADVANTAGES– have a greater tendency to adhere to each other– more expensive– increased possibility of interactions between drug

and shell

B. Amsden

Types of capsule

• Hard Gelatin Capsules• Soft Gelatin Capsules• Modified-release Capsules• Enteric Capsules

Tests• Uniformity of container contents• Content of active ingredients• Uniformity of content• Uniformity of weight• Dissolution• Disintegration (not applied for • modified release capsule)

• Leak test • Locking length

Pharmacopoial

Non- Pharmacopoial

Uniformity of container contents / Contents of Packaged Dosage Forms (IP)

• The following tests and specifications apply to oral dosage forms and preparations intended for topical use that are packaged in containers in which the labeled net quantity is not more than 100 g or 300 ml or 1000 units, as the case may be

• For higher labeled quantities the test and limits given in the standards of Weights and Measures (Packaged commodities) Rules, 1977 may be followed.

Contents of Packaged Dosage Forms

• Test Method• Select a sample of 10 containers and count the number of capsules in each

container.

• The average number of the contents in the 10 containers is not less than the labeled amount and the number in any single container is not less than 98 per cent and not more than 102 per cent of the labeled amount

• If this requirements is not met, count the number of the contents in 10 additional containers. The average number in the 20 containers is not less than the labeled amount, and the number in not more than 1 of the 20 containers is less than 98 per cent or more than102 per cent of the labeled amount.

• This test is applicable to capsule that contain less than 10 mg or less than 10 per cent w/w of active ingredient (As per IP).

• This test is applicable to capsule that contain less than 25 mg or less than 25 per cent w/w of active ingredient (As per BP/USP ).

• For capsule containing more than one active ingredient carry out the test for each active ingredient that corresponds to the aforementioned conditions.

• The test for Uniformity of content should be carried out only after the content of active ingredient(s) in a pooled sample of the capsule has been shown to be within accepted limits of the stated content.

• The test for Uniformity of content is not applicable to capsule containing multivitamins and trace elements.

Uniformity of contant (IP)

• The test for uniformity of content of single-dose preparations is based on the assay of the individual contents of active substance(s) of a number of single-dose units to determine whether the individual contents are within limits set with reference to the average content of the sample.

• Method. • Determine the content of active ingredient(s) in each of 10 dosage units taken at

random using the method given in the monograph or by any other suitable analytical method.

• Acceptance limits• The preparation complies with the test if not more than one individual content is

outside the limits of 85 to 115 per cent of the average content and none is outside the limits of 75 to 125 per cent of the average content.

• The preparation fails to comply with the test if more than three individual contents are outside the limits of 85 to 115 per cent of the average content or if one or more individual contents are outside the limits of 75 to 125 per cent of the average content.

Uniformity of content (IP)

• If two or three individual contents are outside the limits of 85 to 115 per cent of the average content but within the limits of 75 to 125 per cent, repeat the determination using another 20 dosage units.

• The preparation complies with the test if not more than three individual contents of the total sample of 30 dosage units are outside the limits of 85 to 115 per cent of the average content and none is outside the limits of 75 to 125 per cent of the average content.

Uniformity of contents

Uniformity of Weight of Single-DosePreparations (IP/BP)• This test is not applicable to capsules that are required to comply

with the test for Uniformity of content for all active ingredients.• Weigh an intact capsule. Open the capsule without losing any part

of the shell and remove the contents as completely as possible. To remove the contents of a soft capsule the shell may be washed with ether or other suitable solvent and the shell allowed to stand until the odour of the solvent is no longer detectable. Weigh the shell. The weight of the contents is the difference between the weighing. Repeat the procedure with a further 19 capsules.

• Determine the average weight.• Not more than two of the individual weights deviate from the

average weight by more than the percentage shown in the table and none deviates by more than twice that percentage.

Disintegration Test• For the purpose of this test, disintegration does not imply complete

solution of the dosage unit or even of its active constituent.

• Disintegration is defined as that state in which no residue of the unit under test remains on the screen of the apparatus or, if a residue remains, it consists of fragments of disintegrated parts of capsule component parts such as insoluble coating of the of capsule shells, or of any melted fatty substance from the pessaries or suppository or is a soft mass with no palpable core.

• If discs have been used with capsules, any residue remaining on the lower surfaces of the discs consists only of fragments of shells.

• 28-32 cycle (strokes) per minute IP• 29-32 cycle (strokes) per minute BP/USP

Method• Unless otherwise stated in the individual monograph, introduce one

capsule into each tube and, if directed in the appropriate general monograph, add a disc to each tube. Suspend the assembly in the beaker containing the specified liquid and operate the apparatus for the specified time.

• Remove the assembly from the liquid. The capsules pass the test if all of them have disintegrated.

• If 1 or 2 capsules fail to disintegrate, repeat the test on 12 additional capsules; not less than 16 of the total of 18 capsules tested disintegrate.

• If the capsules adhere to the disc and the preparation under examination fails to comply, repeat the test omitting the disc. The preparation complies with the test if all the capsules in the repeat test disintegrate.

For enteric-coated capsule• Method. • If capsule having soluble external sugar coating, immerse the basket in

water at room temp for 5 min (USP).• Put one capsule into each tube, suspend the assembly in the beaker

containing 0.1M hydrochloric acid and operate without the discs for (2 hour as per IP/BP) (1 hour as per USP) , unless otherwise stated in the individual monograph. Remove the assembly from the liquid.

• No capsule shows signs of cracks that would allow the escape of the contents or disintegration, apart from fragments of coating.

• Replace the liquid in the beaker with mixed phosphate buffer pH 6.8, add a disc to each tube and operate the apparatus for a further 60 minutes.

• Remove the assembly from the liquid. If the capsule fails to comply because of adherence to the disc, repeat the test on a further 6 capsule without the discs. The capsule pass the test if all six have disintegrated.

Disintegration testing condition and interpretation (IP) Sr. No

Type of capsule Medium Temperature

Limit

1 Hard gelatin Water/buffer 37 °± 2 °C 30 min or as per individual monograph

2 Soft gelatin Water 37 °±2 °C 60 min or as per individual monograph

3 Enteric-coated 0.1 M HClmixed phosphate buffer pH 6.8

37 °±2 °C 02 hour in HCl: no disintegration60 min in buffer : disintegrate

Disintegration testing condition and interpretation (BP) Sr. No

Type of capsule Medium Temperature

Limit

1 Hard gelatin Water/0.1 M HCl/ Artificial gastric juice R

37 °± 2 °C 30 min or as per individual monograph

2 Soft gelatin Water/0.1 M HCl/ Artificial gastric juice R

37 °±2 °C 60 min or as per individual monograph

3 Enteric-coated 0.1 M HClmixed phosphate buffer pH 6.8

37 °±2 °C 02 hour in HCl: no disintegration60 min in buffer : disintegrate

Disintegration testing condition and interpretation (IP) Sr. No

Type of capsule Medium Temperature

Limit

1 Hard gelatin Water/buffer 37 °± 2 °C 30 min or as per individual monograph

2 Soft gelatin Water 37 °±2 °C 60 min or as per individual monograph

3 Enteric-coated 0.1 M HClmixed phosphate buffer pH 6.8

37 °±2 °C 02 hour in HCl: no disintegration60 min in buffer : disintegrate

Dissolution Test• Use Apparatus 1 unless otherwise directed.• Use the dissolution medium specified in• the individual monograph. If the medium is a buffered

solution, adjust the solution so that its pH is within 0.05 units of the pH specified in the monograph.

• Time. Where a single time specification is given in the monograph, the test may be concluded in a shorter period if the requirement for the minimum amount dissolved is met. If two or more times are specified, specimen are to be withdrawn only at the stated times, within a tolerance of ± 2 per cent.

• Assemble the apparatus and warm the dissolution medium to 36.5 ° to 37.5 °C unless otherwise stated

• Within the time interval specified, or at each of the times stated, withdraw a specimen from a zone midway between the surface of the dissolution medium and the top of the rotating blade or basket, not less than 10 mm from the wall of the vessel.

• Except in the case of single sampling, add a volume of dissolution medium equal to the volume of the samples withdrawn.

• Perform the analysis as directed in the individual monograph.

Acceptance criteriaConventional-release dosage forms (IP)

• Unless otherwise specified, the requirements are met if the quantities of active substance dissolved from the dosage units conform to Table below . If the results do not conform to the requirements at stage S1 given in the table, continue testing with additional dosage units through stages S2 and S3 unless the results conform at stage S2.

• Where capsule shells interfere with the analysis, remove the contents of not less than 6 capsules as completely as possible, and dissolve the empty capsule shells in the specified volume of the dissolution medium.

• Perform the analysis as directed in the individual monograph. Make any necessary correction.

• Correction factors should not be greater than 25 per cent of the stated amount.

As per IP

Acceptance criteria• Conventional-release solid dosage forms (BP/USP) • Unless otherwise specified, the requirements are met if the

quantities of active substance dissolved from the dosage units tested conform to Table below. Continue testing through the 3 levels unless the results conform at either S1 or S2.

• The quantity Q, is the specified amount of dissolved active substance, expressed as a percentage of the labeled content; the 5 per cent, 15 per cent, and 25 per cent values in the Table are percentages of the labeled content so that these values and Q are in the same terms.

As per (BP/USP)

Prolonged-release dosage forms (IP)

• Unless otherwise specified, the requirements are met if the quantities of active substance dissolved from the dosage units conform to Table below.

• If the results do not conform to the requirements at stage L1 given in the table, continue testing with additional dosage units through stages L2 and L3 unless the results conform at stage L2.

• The limits embrace each value of D, the amount dissolved at each specified dosing interval.

• Where more than one range is specified, the acceptance criteria apply to each range.

Prolonged-release dosage forms (BP/USP)

• Unless otherwise specified, the requirements are met if the quantities of active substance dissolved from the dosage units tested conform to Table below.

• Continue testing through the 3 levels unless the results conform at either L1 or L2.

• Limits on the amounts of active substance dissolved are expressed in terms of the percentage of labeled content. The limits embrace each value of Qi, the amount dissolved at each specified fractional dosing interval. Where more than one range is specified, the acceptance criteria apply individually to each range.

Modified-release dosage forms (IP)There are 2 method A & BMethod A & BAcid stage. • 750 ml/1000 ml of 0.1M hydrochloric acid • 36.5º to 37.5º. • 2 hours • Perform the analysis of the aliquot using a suitable assay method.Buffer stage. • Complete the operations of adding the buffer and adjusting the pH within 5 minutes. • 250 ml of a 0.2 M buffer and solution • 36.5º to 37.5º. • 6.8 ± 0.05• 45 minutes, or for the specified time.

Acceptance criteria (IP)• ACID STAGE • The requirements of the test are met if conform to Table below.

Continue the testing through the 3 levels unless the results of both acid and buffer stages conform at an earlier level

Acceptance criteria (IP)• BUFFER STAGE • The requirements of the test are met if conform to Table below. Continue

the testing through the 3 levels unless the results of both acid and buffer stages conform at an earlier level

• The value of D in Table is 75 per cent dissolved unless otherwise specified.• The quantity, D, is the specified total amount of active substance

dissolved in both the acid and buffer stages, expressed as a percentage of the labeled content.

Prolonged-release solid dosage forms (BP/USP)There are 2 method A & BMethod A & BAcid stage. • 750 ml/1000 ml of 0.1M hydrochloric acid • 36.5º to 37.5º. • 2 hours • Perform the analysis of the aliquot using a suitable assay method.Buffer stage. • Complete the operations of adding the buffer and adjusting the pH within 5 minutes. • 250 ml of a 0.2 M buffer and solution • 36.5º to 37.5º. • 6.8 ± 0.05• 45 minutes, or for the specified time.

Acceptance criteria (BP/USP)• ACID STAGE • Unless otherwise specified, the requirements of this portion of the test are met if the

quantities, based on the percentage of the labeled content of active substance dissolved from the units tested conform to Table 2.9.3.-3. Continue testing through the 3 levels unless the results of both acid and buffer stages conform at an earlier level.

Acceptance criteria (BP/USP)• BUFFER STAGE • The requirements are met if active substance dissolved from the units tested conform

to Table 2.9.3.-4. • Continue testing through the 3 levels unless the results of both stages conform at an

earlier level. • The value of Q in Table 2.9.3.-4 is 75 per cent dissolved unless otherwise specified. • The quantity, Q, is the specified total amount of active substance dissolved in both

the acid and buffer stages, expressed as a percentage of the labeled content. • The 5 per cent, 15 per cent and 25 per cent values in the Table are percentages of the

labeled content so that these values and Q are in the same terms.

Dissolution testing condition and interpretation (IP)Sr. No

Type of capsule Medium Temperature Limit

1 Hard gelatin Water/buffer 37 °± 5 °C As per tables shown before or As per individual monograph

2 Soft gelatin Water 37 °±5 °C As per tables shown before or As per individual monograph

4 Enteric-coated capsule

0.1 M HCl &Mixed phosphate buffer pH 6.8

37 °±2 °C 02 hour in HCl & 60 min in buffer

As per tables shown before or As per individual monograph

Defects of capsules