Technology of Solid Dosage Forms &Disperse Systems

Facilitated by/

Mekaiel Amiel Mekaiel M.Sc. Pharmaceutical Technology

National University

Capsules

Outline

1. Introduction & definition

2. Advantages and disadvantages

3. Types of capsules

4. Capsules ingredients

5. Capsules manufacturing

6. Quality control tests (hard and soft capsules)

Learning outcomes

By the end of this session student should be able to:

1. Explain the detailed formulation and manufacturing

unit operation involved in the manufacture of

Capsules.

2. Identify the excipients used and their role/function in

the formula.

3. Describe different techniques employed in production

of Capsules.

Capsules

defined as:

Solid dosage form in which the medicament

contained is enclosed in a water-soluble,

biodegradable small shell or container made up

mostly of gelatin.

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Types of capsules

They are of two types:

1. Hard gelatin capsules (HGC): consist of two

pieces, made and filled in two separate steps

2. Soft gelatin capsules (SGC):

consist of a single piece made and filled in a

one step process

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Advantages of Capsule Dosage Form:

1. Capsules are elegant and hence more acceptable to patients,

2. Easy to swallow due to their smooth and slippery nature.

3. Easy to handle and carry.

4. Can mask the unpleasant taste, colour and odour of drug using tasteless shell.

5. Better bioavailability than tablets and faster onset of action than tablets. The assumption derived from the fact that the gelatin shells are physiologically inert and easily and quickly dissolve and rupture and digested in the gastrointestinal tract.

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Continue Advantages

6. They are easier to formulate. because there is no requirement that

powder be formed in coherent compact form.

7. HGC are uniquely suitable for blinded clinical tests & are widely

used in preliminary drug studies.

8. Capsule is ideally suited to the dispensing of modified release

formulation.

9. The shells can be opacified (with titanium dioxide) or coloured,

to give protection from light.

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Limitations of Capsule Dosage Form:

1. They are not suitable for aqueous or hydro alcoholic

solutions which dissolve gelatin, and

2. No. of supplies are limited & more over filling

equipment is slower than tableting and so generally

HGC tends to be costly to produce, than that of tablet.

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Continue Limitations

3. Highly soluble salt (e.g. Iodides, Bromides, and Chlorides)

generally should not be dispersed in HGC as their rapid release may

cause gastric irritation owing to the formation of a higher drug

concentration in localized areas.

4. HGC may become lodged in esophagus, where the resulting

localized high concentration of certain drugs.(e.g. doxacyclin,

indomethacin) may cause damage.

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Continue Limitations

5. Difficult to swallow in case of children and older people

6. May be bitter

7. Less or no flexibility of dose

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Hard Gelatin Capsules (HGC):

They consists of two pieces in the form of cylinders closed at one

end,

the shorter piece called the „cap‟, fits over the open end of the

longer piece called the „body‟.

The shell is made of gelatin as the main component, suitable

colorant and sodium lauryl sulphate as a wetting agent,

the finished capsules contain 13-16% w/v moisture that acts as a

plasticizer for the gelatin film (less amount of plasticizer).

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Empty capsules are available in 8 (000 - 5) sizes selected

on the basis of the amounts of powder formulations that

can be contained in these sizes.

SIZE AND CAPACITIES SIZE: 000 0 1 2 3 4 5

Capacity: 1gm 650mg 300mg 250mg 200mg 150mg 100mg

The capsules most commonly used for human medicines

range from (0 - 5).

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Gelatin

“Gelatin is obtained by partial hydrolysis of collagen

obtained from the skin , white connective tissue , and

bones of animals”.

Available in form of powder , flakes or sheets and

sometimes in form of granules.

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Types of gelatin

Pharmagel A (type A):

is produced by an acid hydrolysis and is

manufactured mainly from the pork skin.

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Continue types of gelatin:

Pharmagel B (type B):

which is produced by alkaline hydrolysis is

manufactured mainly from the animal bones.

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They differ only in that:

Pharmagel-A: pH 4.8-5.2

Pharmagel-B: pH 6.5-9.2 and by their viscosity building & film

forming characteristics.

Either type of gelatin may be used, but combination of pork

skin & bone gelatin is often used to optimize shell characteristics.

Bone gelatin- contributes firmness where as Pork skin-

contributes plasticity & clarity.

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Gelatin alternatives

Some hard shell capsules are made from materials

other than gelatin...

Starch hydrolysate: "Capill"

Hydroxypropyl methyl cellulose ("Vegicaps" and others)

Such alternatives to gelatin will be of interest to those who, for

religious, cultural or other reasons wish to avoid capsules made

from animal derived components.

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The physiochemical properties of gelatin of most

interested to the shell manufactures are-

1) Bloom strength

2) Viscosity

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Bloom strength-

It is an empirical gel strength measure, that gives an

indication of the firmness of the gel.

It is measure in a bloom gelometer which determine

the weight in grams required to depress a standard plunger

a fixed distance into the surface of a 6.67 % w/w gel under

standard condition.

Bloom strength in the range of 150-280 is considered

suitable for capsule.

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Viscosity-

The viscosity of the gelatin is vital to control the

thickness of the cast film.

Viscosity is measured on a standard 6.67% w/w

solution at 600 C in a capillary pipette & generally in the

range of 30-60 millipoise.

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Stability of gelatin

Gelatin is stable in air when dry but is subject to

microbial decomposition when it becomes moist.

Moisture content and humidity must be controlled during

the production of gelatin shells.

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Shell should have moisture content of 13-15%

If too dry – become brittle/easily fractured

If too moist – become too soft and can get sticky

Unprotected capsules are best stored at 45-65%RH.

Caution using strongly hygroscopic drugs.

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Formulation of Capsules:

formulations to be filled in HGC can contain:

1. One API or more,

2. Different excipient e.g.:

3. Fillers (Diluents),

4. Lubricants,

5. Glidents,

6. Wetting agents (surfactants & hydrophilic agents),

7. Disintegrants,

8. Stabilizers (protectives). Anti-dusting agents

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ACTIVE INGREDIENTS :-

The amount and type of active ingredients influence capsule

size and the nature and amount to be used in the formulation.

Active ingredients tends to make up to the high percentage of

the contents of a capsule as compared to tablet.

Smaller the size of active ingredients, larger will be the surface

area of the active ingredients, hence greater will be the rate of

dissolution of the active ingredients.

Granulation of the active ingredient in the case of hard gelatin

capsule is carried out to

Increase the flow properties.

Increase Drug dissolution.

FILLERS(DILUENTS):-

Fillers are used to increase the bulk of the

formulation.

The most common capsule diluents are starch,

lactose & dicalcium phosphate.

These substances improve flow properties and

compatibility.

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GLIDENTS:-

Glidents are used to improve the fluidity of powders.

Glidents include the colloidal silica, corn starch, talc

and magnesium stearate.

They are fine particles that appear to coat the surface

of the bulk powder and enhance fluidity by reducing

roughness by filling surface irregularities reducing

attractive force by ….

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Continue Glidents

Physically separating the host particles.

Modifying electrostatic charges.

Acting as moisture scavengers.

Serving as ball bearing between host particles.

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Continue Glidents

Optimum concentration for flow is less then 1% &

typically lies between 0.25-0.50 percent. Exceeding this

concentration will result in no further improvement in

flow.

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LUBRICANTS:-

Capsule formulation usually requires lubricants :

To ease the ejection of plugs.

To reduce filming on piston and adhesion of powders to metal

surface.

Reduce the friction between sticking surfaces in contact with

powder.

Ex:- magnesium stearate and stearic acid.

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DISINTEGRANTS:-

In capsule formulation, the substances which have

superior swelling or moisture absorbing properties are

generally used as disintegrants. Such disintegrants are

called “super disintegrants”.

E.g. croscarmellose sodium, sodium starch glycolate

and crospovidone.

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HYDROPHILIC AGENTS:-

Hydrophilic agents are used to improve the

wettability of poorly soluble drug present in hard gelatin

capsule.

E.g.:- Both wettability of the drug and the rate of

dissolution of hexobarbital from hard gelatin capsule could

be enhanced if the drug is treated with methyl cellulose or

hydroxyl ethyl cellulose.(hydrophilic agents).

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Requirements of Capsule Filling

Formulations :

All formulations for filling into capsules have to meet the following requirements:

i. Capable of being filled uniformly,

ii. Release their active contents in a form that is available for absorption,

iii. Should not react with gelatin or interact with shell integrity, and

iv. Comply with the pharmacopoeial and official requirements.

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HGC can be filled by:

powder,

granules,

pellets or

mini-tablets

the filling powder weight is calculated by the equation:

Cap. filling weight =

Tapped bulk density of the powder x cap. volume

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Filling Process of HGC:

The process consists of three steps:

1. Decapping: removal of the cap from the body,

2. Filling of the body with filling material,

3. Recapping: closing the filled capsule,

in small scale operation drugs (with or without additives) could be compounded into hard gelatin dosage form using the manual capsule filling machine (extemporaneous preparation).

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Soft gelatin capsule DEFINITION:-

soft Gelatin capsules are one piece, hermetically sealed, soft gelatin shells containing a liquid, a suspension, or a semisolid.

The Nomenclature for this dosage form has now

been changed to soft gel

They have long been preferred dosage form for

those, taking Health & Nutritional supplements.

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ADVANTEGES 1) Soft gelatin capsules permit liquid medicament to be easily

portable.

2) Accuracy and uniformity of the dosage are predominant

advantages with soft capsules. Since the liquid fill is metered into

individual capsule by a positive displacement pump. Moreover a

higher degree of homogeneity is possible in the liquid system than

can be achieved in powder blend.

3) The bioavailability of drugs is often improved since these

capsules contain drug in liquid form i.e. as liquid drug substance,

drug in solution or drug in suspension.

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Continue Advantages

4)Since soft gelatin capsules are hermetically sealed in

nature, these are best suited for liquid or volatile drugs.

Many drugs which are liable to atmospheric oxidation can

be safely formulated as soft gelatin capsule. Since the soft

gelatin shell acts as all effective barrier to oxygen.

5)The gastric irritation or ulcerogenecity of some drugs

such as dexamethasone can be minimized by formulating

them as liquids in soft capsules, when compared to hard

capsule formulation.

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DISADVANTEGES

Water soluble material are difficult to incorporate

Highly Moisture sensitive

Efflorescent material cannot be incorporated, they may

cause softening / leaching

Deliquescent materials cannot be incorporated, they may

cause hardening or brittle capsules.

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Hard Gelatin vs Soft Gelatin

"Softgels" Capsules Criterion Soft gelatin

Capsules

Hard Gelatin

Capsules

Shell Plasticized (glycerin,

propylene glycol,

sorbitol)

Not plasticized

Content Usually liquids or

suspensions (dry

solids possible)

Usually dry solids

(liquids/semi-solid

matrices possible)

Manufacture Formed/filled in one

operation

Shells made in one

operation and filled in

a separate process

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Criterion Soft gelatin

Capsules

Hard Gelatin

Capsules

Closure Hermetically sealed

(inherent)

Traditional friction-fit;

mechanical interlock,

banding and liquid

sealing possible

Sizes and Shapes Many Limited

Formulation

Technology

Liquids Solids

Fill Accuracy 1-3% 2-5% (with modern

automatic machines)

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Capsule content

Content may be liquid, or a combination of miscible

liquids,

A solution of a solid(s) in a liquid(s) or a suspension of a

solid(s) in a liquid(s).

It can be a liquid like a volatile oil composition

e.g.Pudin hara.

Vegetable oils like arachis oil or aromatic or aliphatic

hydrocarbons, ethers, esters, or alcohols.

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Soft gelatin contain more moisture -up to 45% of capsule

weight- than hard capsule therefore we use preservatives

such as methylparaben and propylparaben to retard the

microbial growth.

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Modified-release capsules

They are hard or soft capsules in which the contents or

the shell or both contain excipients or are prepared by

special procedures such as microencapsulation which,

separately or together, are designed to modify the rate,

place or time of release of the active ingredient(s) in the

gastrointestinal tract.

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Sustained-release capsules

(Extended- or Prolonged-release capsules) are designed to

slow the rate of release of the active ingredient(s) in the

gastrointestinal tract.

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Delayed-release capsules

(gastro-resistant/enteric capsules) are hard or soft

capsules prepared in such a manner that either the shell

or the contents resist the action of gastric fluid but

release the active ingredient(s) in the presence of

intestinal fluid.

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Microcapsule is a small sphere with a uniform

wall around it.

Micro-encapsulation is a process in which tiny particles or droplets are surrounded by a coating to give small capsules many useful properties.

The material inside the microcapsule is referred to as the core, internal phase, or fill, whereas the wall is sometimes called a shell, coating, or membrane.

Most microcapsules have diameters between a few micrometers and a few millimeters.

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The reasons for microencapsulation

In some cases, the core must be isolated from its surroundings, as in isolating vitamins from the deteriorating effects of oxygen,

retarding evaporation of a volatile core,

improving the handling properties of a sticky material, or isolating a reactive core from chemical attack.

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Continue the reasons for

microencapsulation

In other cases, the objective is not to isolate the core completely but to control the rate at which it leaves the microcapsule, as in the controlled release of drugs or pesticides.

The problem may be as simple as masking the taste or odor of the core, or as complex as increasing the selectivity of an adsorption or extraction process

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Controlled Release Capsules:

Capsules can be formulated to give controlled release as follows:

1. Delayed release (enteric coating):

After preparation the hall capsules are inserted in enteric coating polymer solution to give enteric coated capsules.

2. Sustained release:

o using particles of different sizes,

o Coating particles by different polymers,

o Coating particles with different thickness of the polymer.

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Quality control tests (hard and soft

capsules) 1. Weight variation test: 20 capsules are individually weighed, average weight and

percentage deviation from the average weight is determined. Weight

variation limits are average weight ± 10%. If the weight variations are

beyond the limits, net weights (weight of the contents) are determined.

The net weights of the not more than 2 capsules should fall outside the

average net weight ± 10% values and net weight of no capsule should

be outside the average net weight ±25% limit.

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If the net weights of 2-6 capsules deviate by ±10 to

25%, the net weights of 40 more capsule determined .

out of the 60 capsules tested, the net weights of not more

the 6 capsules should deviate from the average net

weight by 10- 25% and none by more than 25%. If limits

are ±10% when average weight < 300 mg and 7.5%

when average weight is 300mg or more.

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2. Uniformity of the drug content:-

A sample of 30 capsule is taken and 10 are assayed

individually. The drug content of a capsule should be

within the limits of average drug content ±15% and the

drug content of none of the capsule fall outside the average

drug content ±25%.

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If 1-3 capsules falls outside the average drug content

±15%, the remaining 20 are assayed. The drug content of

at least 27 out of 30 assayed should be within the

average drug content ±15% limits. and the drug content

of none of the capsules falls outside the average drug

content ±25% limits. The test is prescribed for capsules

when active ingredient is <10 mg or 10% of fill weight.

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3. Disintegration test:-

Capsules are not generally tested for disintegration,

particularly, when the dissolution test is prescribed in the

monograph, except when they are designed to be enteric by

treatment of their shell with formaldehyde, which should

be tested to ensure they do not disintegrate in the simulated

gastric fluid. usual disintegration time limit is 60 min.

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4. Dissolution test:-

Carried out by means of tablet dissolution test apparatus.

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Quality Control of capsules:

QC tests of capsules are similar to those of tablets,

except:

In wt variation test the shell is empted and its content is

weighed,

No need for hardness and friability tests.

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Thank you