Formulation, Evaluation and Recent advancements in capsule

Capsules are solid dosage forms in which drug substance is enclosed within hard or soft soluble shell. The shells are generally formed from gelatin.

INTRODUCTION

Capsules are of two types

1. Hard gelatin capsules

2. Soft gelatin capsules

Tasteless, odorless and can easily be administered.

Combination of powders we can use

There are attractive in appearance.

The drugs having un-pleasant odor and taste are

enclosed in a tasteless shell.

They can be filled quickly and conveniently.

Physician can change the dose and combination of

drug according to patient requirement.

They are economical.

They are easy to handle and carry.

Advantages

Hygroscopic drugs are not suitable for filling into capsules, because they absorb water present in capsule shell makes shell very brittle and ultimately lead to crumble into pieces.

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

Disadvantages:-

For human use, empty capsules ranging in size from 000 the largest to 5 the smallest. Generally, hard gelatin capsule are used to encapsulate between 65 mg to 1 gram.

Capsule size

GELATIN

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

The sources of gelatins including animal bones, hide portions and frozen pork skin.

TYPES OF GELATIN

Type A

Type B

Types of gelatin

TYPE A Derived from acid treated precursor that

exhibits an iso electric point at pH-9. It is manufactured mainly from pork skin.

TYPE B Derived from alkali treated precursor that

exhibits an iso electric point at pH-4.7. It is manufactured mainly from animal bones

Preparation Of Gelatin

Steps involved in making empty gelatin capsules…

1.Dipping2.Spinning3.Drying4.Stripping5.Trimming and Joining6.Polishing

Manufacturing of hard gelatin capsules

Dipping :Pairs of the stainless steel pins are dipped into the dipping solution to simultaneously form the caps and bodies.The dipping solution is maintained at a temperature of about 500C in a heated, jacketed dipping pan.

Spinning :The pins are rotated to distribute the gelatin over the pins uniformly and to avoid the formation of a bead at the capsule ends.

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Drying :The gelatin is dried by a blast of cool air to form a hard shells.The pins are moved through a series of air drying kilns to remove water

Stripping :A series of bronze jaws strip the cap and body portions of the capsules from the pins

Trimming and joining:The stripped cap and body portions are trimmed to the required length by stationary knives.After trimming to the right length, the cap and body portion are joined and ejected from the machine.

Polishing:

Pan Polishing : Acela-cota pan is used to dust and polish.Cloth Dusting : Capsule are rubbed with cloth.Brushing : Capsule are feed under soft rotating brush.

In large scale or small preparations of filled hard gelatin

capsules divided into the following general steps: Developing and preparing formulation. Filling the capsule shell. Capsule sealing

Cleaning and polishing the filled capsules.

Filling hard gelatin capsules:

Developing and preparing the formulation

Diluents and fillers: lactose, microcrystaline cellulose, starch.

Disintegrants: sodium starch glicolate ,pregelatinised starch

Gligants and lubricants: silicon dioxide,magnesium stearte,calcium stearate

Wetting agents: SLS

Methods of filling:16

• Hand Operated methods. ex: feton capsule filling machine

• Semi Automatic Capsules Devices. • Automatic filling machine. ex: osaka capsule filling machine ,macofar

capsule filling machine

Hand Operated Capsule Filling Machine:

It is having following parts:-

a)Bed having 200-300 holes.

b)Loading tray having 200-300 holes.

c)Powder tray.

d)Pin Plate having 200-300 pins.

e)Sealing plate having rubber top.

f) Lever

g) Cam handle

JAANSUN CAPSULE FILLING MACHINE

SEMI AUTOMATIC MACHINE

MG2 MODEL 60

POWDERS w/ capseal GRANULES

BEADS TABLETS

1. Tamper evident capsules by sealing the joint between the 2 capsule parts

2. Distinctive looking capsules by sealing them with colored band of gelatin (Kapseals). If removed, the band cannot be restored without expert sealing with gelatin

3. Through a heat welding process that fuses the capsule cap to the ring around the capsule where heat welded

Example: Weld’s gelatin seal

CAPSULE SEALING:

4. Lightly coating the inner surface of the cap with a warm gelatin solution immediately prior to placement on the filled capsule body.

SOFT GELATIN CAPSULE

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

Soft gelatin is mainly composed of gelatin, plasticizers, preservative, colouring and opacifying agents, flavoring agents and sugars.

Definition:

Shape of capsule25

The shape of soft gelatin capsule are round, oval, oblong, tube.

The basic component of soft gelatin shell is gelatin; however, the shell has been plasticize

The ratio of dry plasticizer to dry gelatin determines the “hardness” of the shell and can vary from 0.3-1.0 for very hard shell to 1.0-1.8 for very soft shell

Up to 5% sugar may be included to give a “chewable” quality to the shell

The residual shell moisture content of finished capsules will be in the range of 6-10%.

Composition of the shell:

Bloom strengthA measure of cohesive strength of gelatin filmTypically 150-280 "bloom-grams“The weight in g required to depress a plunger 12.7

mm diameter 4 mm into a 6.67% gel held for 17 hours at 10 degrees (O.T. Bloom, 1925)

Viscosity Single most important factor controlling shell

thicknessCapillary viscometer; 6.67% soln.Typical range 25-45 millipoise.

Properties of gelatin:

Formulation :

Formulation for soft gelatin capsules involves liquid, rather than powder technology.

Materials are generally formulated to produce the smallest possible capsule consistent with maximum stability, therapeutic effectiveness and manufacture efficiency.

The liquids are limited to those that do not have an adverse effect on gelatin walls.

Emulsion can not be filled because water will be released that will affect the shell

The pH of the liquid can be between 2.5 and 7.5.

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Is manufactured by four methods

1)Plate process

2)Rotary die process

3)Reciprocating die

4)Accogel machine

Manufacturing of Soft Gelatin Capsule

Plate process:30

•Place the gelatin sheet over a die plate containing numerous die pockets.

•Application of vacuum to draw the sheet in to the die pockets.

•Fill the pockets with liquid or paste.

•Place another gelatin sheet over the filled pockets, and

•Sandwich under a die press where the capsules are formed and cut out.

1) In this machine the soft gelatin capsules are prepared & then filled immediately with liquid medicaments it is having two hoppers & two rotating dies  2) Liquid mixture is placed in one hopper & the liquid medicament in other Hooper.

3) The two rotating dies rotate in opposite directions when the fluid gelatin mixture enters the machine from the hopper it produces two continuous ribbons .

4) These half shell of the capsule is formed.

ROTARY DIE PROCESS:

5) At this stage the measured quantity of the medicament is filled in to it with the stroke of a pump with the subsequent movement of the dies the other half capsule is formed.6) The two halves' of the capsules are sealed together by the heat & pressure of the rotating dies. 7) As the die rolls rotate, the convergence of the

matchingdie pockets seals and cuts out the filled capsules

ROTARY DIE PROCESS

Accogel Capsule Machine Or Stern machine, uses a system of rotary dies but is unique in that it is the only machine that can successfully fill dry powder into a soft gelatin capsule.

Acogel Capsule Machine

Formulation of soft gelatin capsule:

vehicles used in soft gelatin capsules: Two main groups :

1)Water immiscible, volatile or more likely more volatile liquids such as vegetable oils, mineral oils, medium-chain triglycerides and acetylated glycerin.

2)Water miscible, nonvolatile liquids such as low molecular weight PEG have come in to use more recently because of their ability to mix with water readily and accelerate dissolution of dissolved or suspended drugs.

All liquids used for filling must flow by gravity at a temperature of 350C or less.

The sealing temperature of gelatin films is 37-400C

1) Two piece (large body & short cap)

2) Cylindrical shape.

3) Powder drug or pallets coated with drug are encapsulated.

4) Gelatin in Hard form is used.

5) Capsules are sealed after they are filled to ensure that the medicaments may not come out of the capsule due to rough handling.

6) 8 different type of sizes are available

SOFT GELATIN CAPSULESSOFT GELATIN CAPSULES

1) One piece & hermetically sealed.

2) Available in round , oval & tube like shapes.

3) Liquid & Semi liquid fill & unstable substances are encapsulated.

4) Molten gelatin are used.

5) Filling & sealing of soft gelatin capsules are done in a combined operation on machine.

6) No specific sizes are available.

HARD GELATIN CAPSULESHARD GELATIN CAPSULES

Steps Of Capsule ManufacturingSteps Of Capsule Manufacturing

Mfg of Gelatin Shell.

Drying of shells in controlled humidity.

Mfg of granules/spanzules.

Filling of Shells.

Packaging & Labeling.

Mfg of Gelatin Shell.

Drying of shells in controlled humidity.

Mfg of granules/spanzules.

Filling of Shells.

Packaging & Labeling.

IPQC Checks During Gelatin Shell Manufacturing

IPQC Checks During Gelatin Shell Manufacturing

% purity of gelatin Viscosity of gelatin solution 25-45 millipoise Bloom strength of gelatin solution 150-250 gm Iron content NMT 15 ppm pH of gelatin A=9; B=4.7 Film Thickness Color, surface, appearance of empty shells Temperature of hot air, for drying of shells Length of Capsule & Body of the shell Moisture content 12-15%

% purity of gelatin Viscosity of gelatin solution 25-45 millipoise Bloom strength of gelatin solution 150-250 gm Iron content NMT 15 ppm pH of gelatin A=9; B=4.7 Film Thickness Color, surface, appearance of empty shells Temperature of hot air, for drying of shells Length of Capsule & Body of the shell Moisture content 12-15%

Sorting of defective shells After the capsules have been inspected either electronically or manually, they are sampled by the QA inspector & checked for the defects and then sorted out. Printing inspection on shell Inspection of defects like:-

• Hardening of shells• Softening of shells• Swelling of shells• Cracking of shells• Discoloration of shells • Misprinting of logo on shells

Sorting of defective shells After the capsules have been inspected either electronically or manually, they are sampled by the QA inspector & checked for the defects and then sorted out. Printing inspection on shell Inspection of defects like:-

• Hardening of shells• Softening of shells• Swelling of shells• Cracking of shells• Discoloration of shells • Misprinting of logo on shells

IPQC Checks During Filling Of Empty Capsule Shells

IPQC Checks During Filling Of Empty Capsule Shells

During filling process equipment should be labeledwith :-product name, Batch No, Time of starting, Sign

During Filling: flow property of granules or powders

Weight Variation : For hard gel caps-

Limit NMT 2 caps should deviate from avg wt.

AVG WT %DEVIATION <300mg 10% >300mg or more 7.5%

During filling process equipment should be labeledwith :-product name, Batch No, Time of starting, Sign

During Filling: flow property of granules or powders

Weight Variation : For hard gel caps-

Limit NMT 2 caps should deviate from avg wt.

AVG WT %DEVIATION <300mg 10% >300mg or more 7.5%

MACHINE OUTPUT INSPECTION:

•Machine output is monitored in a specific time interval•Total batch or number of caps filled are counted in a specific time interval & then machine is calibrated and speed is maintained.

MACHINE OUTPUT INSPECTION:

•Machine output is monitored in a specific time interval•Total batch or number of caps filled are counted in a specific time interval & then machine is calibrated and speed is maintained.

APPEARANCE:Inspection of capsules checked with a standard

stripSORTING DEFECTS:

Electronic automated or manual inspection is made to sort out & reject the defected caps.

Overprinting

PRINTING & LABELING:Inspection of overprinting, logo, labeling are checked with the standard shade cards.Defective ones are sorted out & rejected.

APPEARANCE:Inspection of capsules checked with a standard

stripSORTING DEFECTS:

Electronic automated or manual inspection is made to sort out & reject the defected caps.

Overprinting

PRINTING & LABELING:Inspection of overprinting, logo, labeling are checked with the standard shade cards.Defective ones are sorted out & rejected.

EVALUVATION OF CAPSULES

1. STABILITY TESTS.

a) Shell integrity test

b) Determination of shelf life

2.INVARIABILITY TESTS.

a ) Weight variation

b) Content uniformity

3. DISINTEGRATION TEST.

4. DISSOLUTION TEST. 5. MOISTURE PERMEATION TEST.

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1.STABILITY TESTS

Stability tests for capsules are performed to know the integrity of gelatin capsule shell ( but not to know the stability of therapeuticallay active agent ) and for determining the shelf life of capsules.

The tests helps in improving the quality of contents of capsule shell and for choosing the appropriate retail package.

BEFORE ACTUALLY PERFORMING THE TESTS FOLLOWING FACT:

(i).the capsule shell are to be stabilized to know atmospheric condition with relative humidity about 20-30 % and temperature about 21-24⁰c .

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A ) SHELL INTEGRITY TEST : This test is performed to find out the integrity of

capsule shell.The standard capsule shells kept at the room

temperature 40 ⁰c and 80% RH becomes more soft, sticky and swollen .

B) DETERMINATION OF SHELF LIFE :

Shelf life or the expiry date of packed capsules is

determined under normal storage conditions.

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INVARIABILITY TESTS

The invariabilty in the medicaments packed in the

capsule shells can be determined by performing the

following tests :a)Weight variation test

b) Content uniformity test

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DISINTEGRATION TEST

Disintegration test is a method to evaluate the rate of disintegration of solid dosage forms .

disintegration is defined as the breakdown of solid dosage form into small particles after it is ingested .

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DISSOLUTION TEST

▪ Dissolution test is an official method to determine the dissolution rate of a solid dosage form .

▪ Dissolution rate is defined as the rate at which the drug is released into the systemic circulation from the dosage from .

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Apparatus-1 (rotating basket dissolution apparatus ) :- ▪Small wire mesh size basket – 22

▪Temperature – 37 +/- 5⁰c ▪Rotated speed – 25 -150 rpm ▪Dissolution medium height from the bottom of the vessel :- 23-27 mm

MOISTURE PERMEATION TEST

To assure the suitability of containers forpackaging capsules .The moisture permeating feature of capsules packaged in ▪ single unit containers – blister pack or strip

pack ▪ unit dose containers – glass or plastic

bottlesAre to be determined .

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Disadvantages of conventional capsule:

1) Gelatin shells are permeable for moisture and air.2) Some persons give vometic response to gelatin capsules due to its odor.

Innovations In Capsule Shells:1) Improve in Shell Property and provide physical

strength.2) Protection From light, moisture, and microbial

contamination.3) Encapsulation of various kinds of material.

4) Improve Compatibility of fill material with shell.

Recent advancements in capsule

NON GELATIN CAPSULES

Gelatin Alternatives:-HPMC CapsulesStarch CapsulesAlginate capsules.

IDEAL REQUIREMENTS-Good film forming property.Good gelation property so that capsule film can be

cast or dipped.Fast dissolution in biological fluids at 37⁰C.Low toxicity.

HPMC and starch capsules are also called vegetable capsules.Raw material contain the basic contents of polysaccharide and vegetable cell wall.Beside natural concept, superiority, these capsules can also promote digestion of proteins, fats and carbohydrate .

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HGC made from potato starch were developed by Capsugel.

Steps-Starch containing 13-14% is heated at a temp of

140-190⁰C .Glassy mass formed which flow without degradation.Injection molded separately to form cap and body

portions and finally dried.Moisture content in starch capsules lies between 12-

14% w/w with more than 50% being tightly bound to starch.This bound water indicates that the syarch capsules may provide better stability properties and reduced susceptibility to changes on storage.

Starch Capsules

Advantages- Ready for filling immediately following

mfg. pH independent dissolution. Offers greater resistance to humidity and

heat than gelatin. Good surface finish.

Consists cap and body; which are sealed together at the time of filling to prevent separation.Sealing is achieved by applying a hydro alcoholic solution to inner section of the cap, immediately prior to placing on to the body.Coating with aqueous spray formulation doesn’t pose any problem with respect to softening and shell doesn’t become brittle due to water evaporation and drying.

TARGET TECHNOLOGY –Based on applying enteric polymer coatings to the starchcapsule.Used for site specific delivery to colon.Coating of starch capsules appear to be less problematic becauseof the smooth seal together with the higher bulk density ofcapsules which provide more uniform coating bed.

HPMC CAPSULES

HPMC Capsules (Hypromellose)

QUALI-V developed by Shinogi Qualicapsis the first HPMC capsule developed for use in pharmaceutical products.

Advantages:-Cross-linking-HPMC hard capsules avoid the issues of

gelatin cross-linking & product vulnerability to aldehydes (no Maillard reaction)

Moisture content-HPMC hard capsules(Quali-v) have low moisture content. These doesn’t crack even with 1% or low in moisture content. HGCs breaks easily when moisture drops below 10%.)

Water vapor permeability-Water vapor permeated more rapidly through gelatin film than HPMC film. ( Gelatin>PEG-Gelatin>HPMC)

Dissolution:-Disso profiles of HPMC hard capsules doesn’t change even when the capsules were stored under diff conditions of temp and humidity i.e30⁰C and 60% RH ,40⁰C and 75% RH(for 6 months) and 60⁰C (for 1 week).Disso profiles of gelatin capsules changed when stored under similar conditions.

High tolerance to temperature. Non aqueous fill materials can be filled into HPMC hard

capsules. Not the substrate for Protease.

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QUALI-V®-I:

Superior physical performance and moisture contents.Content could easily arise in the usage of DPIs with capsules. Elimination of the generation of shell particles in use. Excellent microbiological quality. Higher weight specification available if required. Suitable for use in all types of DPIs.

A New Key for Dry Powder Inhalers

Alginate soft capsule

• Appearance: spherical, smooth and uniform with diameter of 1-10mm, •Oil based core(non-water soluble liquid) within the capsule comprise at least 80% by weight of the capsule.• Shell of the capsule is alginate gel.

•Shell of the capsules will turn into alginic acid in stomach under the effect of gastric acid which can protect the API in the core from decomposing by gastric acid.• In intestine, shell of the capsules will turn into soluble sodium alginate or potassium alginate when meet with sodium or potassium ion then release the API in the core.

Advantages-Alginate, the major material of the shell, is

extracted from algae which is cheap and is full of human necessary microelement.

Shell of the capsule comprise at most 15% by weight of the capsule which can improve the loading capacity of the API within the capsule.

Alginates shell with little water content has antibiotic property which means there is no need or less need for preservatives.