ADVANCEMENT IN MANUFACTURING OF NON-GELATIN CAPSULE SHELL-A REVIEW

Author Name: - Dagadiye Ravindra B*, Kajale Archana D, Mahajan Vandana K, Joshi

Manisha H.

Affiliation:-1) Dagadiye Ravindra B* – Author2) Kajale Archana D – Guide3) Mahajan, Vandana K – Co guide4) Joshi Manisha H – Co guide

Dr.V.P.P.College of Pharmacy, Paithan road, Aurangabad, Maharashtra

Correspondence Details:-rickyravindra@gmail.com*

Address: - N-2, L-4-13/5, Ramnagar, CIDCO, Aurangabad, Maharashtra, 431006.

Contact no:-+919423467546.

Abstract:-

The gelatin cap-sule shell may be soft or hard depending on their formulation. Capsules are

intended to be swallowed whole by the patient. In instances where patients (especially

children) are unable to swallow capsules, the contents of the capsule can be removed and

added (e.g., sprinkled) on soft food immediately before ingestion. In the manufacture of

pharmaceuticals, encapsulation refers to a range of techniques used to enclose medicines in a

relatively stable shell known as a capsule, allowing them to, for example, be taken orally or

be used as suppositories. Hard-shelled capsules, which are normally used for dry, powdered

ingredients or miniature pellets, Both of these classes of capsules are made from aqueous

solutions of gelling agents like:Animal protein mainly gelatine And Non-gelatin such as Plant

polysaccharides or their derivatives like carrageenans and modified forms of starch and

cellulose. Despite the great advantages, of gelatin capsules’, gelatin has several drawbacks

that limit its use for capsules. The animal source of gelatin can be a problem for certain

consumers such as vegetarians or vegans and religious or ethnic groups, Since unmodified

gelatin is prone to cross linking when in contact with aldehydes, solubility problems might be

expected with certain fill formulations. The non-gelatin capsule shells are made up of such as

Starch, HPMC, PVA, and Alginate.

Key words: - Gelatin/Non-Gelatin Material, capsule shell, Starch, HPMC, PVA, Alginate.

GELATIN/NON-GELATIN CAPSULE SHELL

INTRODUCTION

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Capsules are solid dosage forms in which the drug is enclosed within either a hard or soft

soluble container or “shell.” The shells are usually formed from gelatin; however, they also

may be made from starch or other suitable substances. [1]

The gelatin capsule shell may be soft or hard depending on their formulation. Capsules are

intended to be swallowed whole by the patient. In instances where patients (especially

children) are unable to swallow capsules, the contents of the capsule can be removed and

added (e.g., sprinkled) on soft food immediately before ingestion. In this case, capsules are

used as a vehicle to deliver premeasured medicinal powder. [2]In the manufacture of

pharmaceuticals, encapsulation refers to a range of techniques used to enclose medicines in a

relatively stable shell known as a capsule, allowing them to, for example, be taken orally or

be used as suppositories. The two main types of capsules are:

Hard-shelled capsules, which are normally used for dry, powdered ingredients or miniature

pellets (also called beads that are made by the process of Extrusion and Spheronization) - or

mini tablets;

Soft-shelled capsules, primarily used for oils and for active ingredients that are dissolved or

suspended in oil.

Both of these classes of capsules are made from aqueous solutions of gelling agents like:

Animal protein mainly gelatin;

Plant polysaccharides or their derivatives like carrageenans and modified forms of starch and

cellulose.

Other ingredients can be added to the gelling agent solution like plasticizers such as glycerine

and/or sorbitol to decrease the capsule's hardness, colouring agents, preservatives,

disintegrants, lubricants and surface treatment.

TYPES OF CAPSULES

Gelatin capsules, informally called gel caps or gelcaps, are composed of gelatin

manufactured from the collagen of animal skin or bone. (Gelatin is not derivable from

ungulate hooves, which are composed of a different protein, keratin.)

Vegetable capsules are composed of hypromellose, a polymer formulated from cellulose.[3]

There are two types of capsules, “hard” and “soft”. The hard capsule is also called “two

pieces” as it consists of two pieces in the form of small cylinders closed at one end, the

shorter piece is called the “cap” which fits over the open end of the longer piece, called the

“body”. The soft gelatin capsule is also called as “one piece”. Capsules are available in many

sizes to provide dosing flexibility. Unpleasant drug tastes and odours can be masked by the

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tasteless gelatin shell. The administration of liquid and solid drugs enclosed in hard gelatin

capsules is one of the most frequently utilized dosage forms.

Advantages of Capsules

- Capsules mask the taste and odour of unpleasant drugs and can be easily administered.

- They are attractive in appearance

- They are slippery when moist and, hence, easy to swallow with a draught of water.

- As compared to tablets less adjuncts are required.

- The shells are physiologically inert and easily and quickly digested in the gastrointestinal

tract.

- They are economical

- They are easy to handle and carry.

- The shells can be opacified (with titanium dioxide) or colored, to give protection from light.

Disadvantages of Capsules

- The drugs which are hygroscopic absorb water from the capsule shell making it brittle and

hence are not suitable for filling into capsules.

- The concentrated solutions which require previous dilution are unsuitable for capsules

because if administered as such lead to irritation of stomach.[4][17]

Standard sizes of two-piece CAPSULES [3]

Size Volume (ml) Locked length (mm) External diameter (mm)

4

5 0.13 11.1 4.91

4 0.21 14.3 5.31

3 0.3 15.9 5.82

2 0.37 18 6.35

1 0.5 19.4 6.91

0 0.68 21.7 7.65

0E 0.7 23.1 7.65

00 0.95 23.3 8.53

000 1.37 26.14 9.91

13 3.2 30 15.3

12 5 40.5 15.3

12el 7.5 57 15.5

11 10 47.5 20.9

10 18 64 23.4

7 24 78 23.4

Su07 28 88.5 23.4

Raw materials used for capsule shell manufacturing

GELATIN CAPSULE SHELL

Development of capsule shell by Gelatin:-

Gelatin is the major component of the capsules and has been the material from which they

have traditionally been made. Gelatin has been the raw material of choice because of the

ability of a solution to gel to form a solid at a temperature just above ambient temperate

conditions, which enables a homogeneous film to be formed rapidly on a mould pin.

The reason for this is that gelatin possesses the following basic properties:

- It is non-toxic, widely used in foodstuffs and acceptable for use worldwide.

- It is readily soluble in biological fluids at body temperature.

- It is good film-forming material, producing a strong flexible film

- The gelatin films are homogeneous in structure, which gives them strength.

Some of the disadvantages with using gelatin for hard capsules include: it has a high moisture

content, which is essential because this is the plasticizer for the film and, under International

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Conference on Harmonization of Technical Requirements for Registration of

Pharmaceuticals for Human Use (ICH) conditions for accelerated storage testing, gelatin

undergoes a cross linking reaction that reduces its solubility. Gelatin is a translucent brittle

solid substance, colourless or slightly yellow, nearly tasteless and odourless, which is created

by prolonged boiling of animal skin connective tissue or bones. Type A gelatin is derived

from an acid-treated precursor and exhibits an isoelectric point in the region of pH 9, whereas

type B gelatin is from an alkali-treated precursor and has its isoelectric zone in the region of

pH 4.7. Capsules may be made from either type of gelatin, but mostly a mixture of both types

is used considering availability and cost. Difference in the physical properties of finished

capsules as a function of the type of gelatin used is slight. Blends of bone and pork skin

gelatins of relatively high strength are normally used for hard capsule production. The bone

gelatin produces a tough, firm film, but tends to be hazy and brittle. The pork skin gelatin

contributes plasticity and clarity to the blend, thereby reducing haze or cloudiness in the

finished capsule.[4][17]

I - HARD GELATIN CAPSULES

The majority of capsule products are made of hard gelatin capsules. Hard gelatin capsules are

made of two shells: the capsule body and a shorter cap. The cap fits snugly over the open end

of the capsule body. The basic hard gelatin capsule shells are made from mixtures of gelatin,

sugar, and water. They are clear, colourless, and essentially tasteless.

Gelatin is a product obtained by partial hydrolysis of collagen acquired from the skin, white

connective tissue, and bones of animals. Gelatin is a protein which is soluble in warm (or hot)

water, but insoluble in cold water. At low temperatures, gelatin dissolved in water becomes a

gel (which is insoluble in water). This property is used to prepare Jello and other gelatin

deserts. Gelatin capsules become dissolved in warm gastric fluid and release the contents.

Normally, hard gelatin capsules contain 13–16% of moisture. If additional moisture is

absorbed when stored in a high relative humidity environment, hard gelatin capsule shell

may lose their rigid shape and become distorted. In an opposite environment of extreme

dryness, capsules may become too brittle and may crumble during handling. Since moisture

can be absorbed or released by the gelatin capsules, capsules containing moisture-sensitive

drugs are usually packaged in containers. Gelatin for making hard shells is of bone origin and

has 220–280 g bloom strength (the weight required to depress a standard plunger 4 mm into

the gel).[5][15]

MANUFACTURING OF HARD CAPSULES

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Some of the major suppliers of empty gelatin capsules are: Eli Lilly and Company, Warner

Lambert’s Capsugel (formerly Park Davis) and R. P. Scherer Corporation.

The metal moulds at room temperature are dipped into a hot gelatin solution, which gels to

form a film. This is dried, cut to length, removed from the moulds and the two parts are

joined together, these processes are carried out as a continuous process in large machines.

The completely automatic machine most commonly used for capsule production consists of

mechanisms for automatically dipping, spinning, drying, stripping, trimming, and joining the

capsules.

• Stainless steel pins are used on which the capsule is formed and controls some of the final

critical dimensions of the capsule.

• One hundred and fifty pairs of these pins are dipped in to gelatin sol of carefully controlled

viscosity to form caps and bodies simultaneously. The pins are usually rotated to distribute

the gelatin uniformly, during which time the gelatin may be set or gelled by a blast of cool

air.

• The pins are moved through a series of controlled air drying kilns for the gradual and

precisely controlled removal of water. The capsules are striped from the pins by bronze jaws

and trimmed to length by stationary knives while the capsule halves are being spun in chuks

or collets. After being trimmed to exact length, the cap and body sections are joined and

ejected from the machine. The entire cycle of the machine lasts approximately 45 min.

• Thickness of the capsule wall is controlled by the viscosity of the gelatin solution and the

speed and time of dipping. Mold pin dimensions, precise drying, and machine control relating

to cut lengths are matters that are critical to the final dimensions. Precise control of drying

conditions is essential to the ultimate quality of the cast film.

The in-process quality controls include periodic monitoring, and adjustment when required,

of film thickness, cut lengths of cap and body, colour, and moisture content.

Inspection processes to remove imperfect capsules which were previously done visually, have

recently been automated following the development and patenting of a practical electronic

sorting mechanism by Eli Lilly and Company. This equipment mechanically orients the

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capsules and transports them past a series of optical scanners, at which time those having

detectable visual imperfections are automatically rejected. [5]

Excipients of Hard gelatin capsule

A) Gelatin

B) Colour & Opecifying agent

C) Preservatives (methyl paraben, propyl paraben, butylated hy-droxyaniline, EDTA,

sodium benzoate)

D) Dyes, pigments,

E) pH-adjusting additive

F) Flavour and fragrance

II- SOFT GELATIN CAPSULES

Soft gelatin (also called softgel or soft elastic) capsules consist of one-piece

hermetically-sealed soft shells. Soft gelatin capsules are prepared by adding a plasticizer,

such as glycerine or polyhydric alcohol (e.g., sorbitol), to gelatin. The plasticizer makes

gelatin elastic. Soft gelatin capsules come in various shapes such as spherical, elliptical,

oblong, and special tube shapes with and without twist off (see Figure 3.8). They can contain

non-aqueous liquids, suspensions, pasty materials, or dry powders. They are especially

important to contain volatile drug substances or drug materials susceptible to deterioration in

the presence of air.

MANUFACTURING OF SOFT CAPSULES

There are several procedures to prepare soft gelatin capsules, such as the plate process, the

rotary die process, and reciprocating die process. Most soft gelatin capsules produced in

industry are prepared by the rotary-die process (see Figures 3.9 and 3.10). In this process, two

continuous gelatin ribbons are brought together between twin rotating dies. At the moment

that the dies form pockets of the gelatin ribbons, metered-fill material is injected between the

ribbons. Then the pockets of fill-containing gelatin are sealed by pressure and heat. The

capsules are subsequently severed from the ribbon. As the capsules are cut from the ribbons,

they may be collected in a refrigerated tank to prevent capsules from adhering to one another

and from getting dull.

Soft gelatin capsules contain more moisture than the hard capsules. Since gelatin is subject to

microbic decomposition when it becomes moist, soft gelatin capsules may be prepared with

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preservatives to prevent the growth of fungi. Gelatin used for making soft capsules is usually

of bone and skin origin and has 150–175 g bloom strength.[5][6] [22]

Table:-Examples of commercial products prepared in soft gelatin capsules

Ethchlorvynol (Placidyl®, Abbott) Vitamin E (Aces®, J.R. Carlson Lab.)

Demeclocycline HCl (Declomycin®, Lederle) Neoral® capsule

Chlortrianisene (TACE®, Marion Merrell Dow) Zantac® Geldose capsule

Digoxin (Lanoxicaps®, Burroughs Wellcome) Procardia® capsule (PEG based)

Docusate calcium (Surfak®, Upjohn) Advil® liquicapsule

Figure, Schematic drawing of rotary-die soft gelatin capsule filler (R.P. Scherer: Detroit,

MI).

Excipients of Softgels [6] [7]

- Gelatin

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- Softener (plasticizer): sorbitol, xylose, maltitol, glycerin, PEG, wa-ter)

- Preservatives (methyl paraben, propyl paraben, butylated hy-droxyaniline, EDTA,

sodium benzoate)

- Dyes, pigments,

- Solvent

o Polar: glycerin, PEG, PEG 400, PEG 3350, ethanol, PPG, water

o Nonpolar: beeswax, coconut oil, triglycerin, corn oil, mineral oil, soybean oil, D,L-α-

tocopherol

- pH-adjusting additive

- flavor and fragrance

- Pigment: titanium oxide, ferric oxide

- Anticaking agent: Silicone dioxide

- Humectant: polyol

Important Factors in Soft Gelatin Capsule [6][7]

- Solubility

- Permeability

- Organic solubility

o Common organic solvents: DMSO

o Acceptable softgel excipients: fatty liquids, PEGs, propylene glycol, surfactants

- Drug-excipient compatibility

o Chemical stability

o Physical stability: Drug migration into shell, gelatin disintegration, recrystallization of gelatin

o Polymorphism

Advantages of Soft Gelatin Capsules [6][7]

- Ease of swallowing

- Dosage accuracy/uniformity: Precise fill volume of liquid fill unit delivers a greater degree of

accuracy and consistency from capsule-to-capsule and lot-to-lot.

- Consistent manufacturing requirements: More accurate compound-ing, blending, and

dispensing of liquid fill facilitates manufacturing. Liquid blends are more homogeneous.

- Increase in bioavailability: Absorption and bioavailability can be enhanced by formulating

compounds in solution including solubilizers and absorption enhancers, if necessary. Water-

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insoluble drugs may be formulated in a softgel. Clinical studies have shown enhanced

absorption and bioavailability with softgel forms. Examples are temazepam (Salonen et al.,

1986) and ibuprofen (Saano et al., 1991).

- Enhanced stability and security: The tight hermetical sealing protects fill from air and

environmental contamination. Gelatin shell can be formulated to block out ultraviolet light.

Streamlined, one-piece design is tamper-evident.

- Pliable shell: soft gel shell allows for custom shapes and sizes appropriate for oral, topical,

chewable and suppository delivery.

- Portability: Encapsulated liquid dosage formulations become highly portable for

consumers/patients.[17]

Raw materials used for capsule shell manufacturing

NON-GELATIN CAPSULE SHELL

Development of Non-gelatin capsules

Traditionally, gelatin has been used almost exclusively as shell-forming material of soft

capsules. This is due to its legal status and its unique physicochemical properties, namely its

oxygen impermeability and the combination of film forming capability and thermo reversible

sol/gel formation that favour its use for the industrial capsule production especially in the

rotary die process. Despite these great advantages, which have been described in detail in the

section above on ‘Soft gelatin capsules’, gelatin has several drawbacks that limit its use for

capsules:

- The animal source of gelatin can be a problem for certain consumers such as vegetarians or

vegans and religious or ethnic groups (Jews, Muslims, Hindus, etc.) who observe dietary

laws that forbid the use of certain animal products.

- Since unmodified gelatin is prone to cross linking when in contact with aldehydes, solubility

problems might be expected with certain fill formulations.

- Transparent low-colour capsules are difficult to produce owing to the effect of the intrinsic

Maillard reaction on gelatin colour.

- The temperature and moisture sensitivity of gelatin-based soft capsules is an issue that

complicates the use of soft gelatin capsules in very hot and humid regions and requires

special packaging and storage conditions to ensure product stability.

- For low-price health and nutrition products, pricing of commercially available gelatin might

be an additional problem.

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To address these concerns, there has been a great interest in the soft capsule industry in

looking for gelatin substitutes. Indeed, several concepts based on synthetic polymers and/or

plant-derived hydrocolloids have been described in the patent literature. [6]

A) DEVELOPMENT OF STARCH CAPSULES

PROPERTIES OF STARCH

- Moisture content:-

Moisture content in starch capsule lies between 12% to 14% w/w, with more than 50% being

tightly bound to starch. The presence of this bound moisture indicates that starch capsules

may provide better stability properties and reduces susceptibilities to change on storage.

- Dissolution

Similar to that of gelatine capsules.

Advantages:-

- Ready for filling immediately following manufacturing.

- Offer greater resistance to humidity and heat than gelatin and allow easy filling as they are

non-static.

- Dissolution is independent of pH.

- Good surface finish.

- Coating of hard gelatine capsule with aqueous spray formulations can lead to softening of

gelatin shell or gelatin shell may become brittle due to water evaporation and drying.

Especially at the onset of coating. On the contrary, the coating of starch capsules seems to be

less problematic because of smooth seal of the filled unit, together with the higher bulk

density of the capsules, which provide a more uniform coating bed.

MANUFACTURING OF STARCH HARD CAPSULES

- Hard gelatin capsules have been used most widely. Recently, however, starch capsules have

been used in various controlled-release products as well as in general use as demands for

non-animal based products increase. Starch capsules are more easily coated than gelatin

capsules. Gelatin shells may soften and solubilise when sprayed with aqueous dispersion of

coatings and can become brittle during the drying stage. The higher bulk density of the starch

capsule provides for a more uniform coating bed.

- Starch capsules are manufactured by an injection molding process that yields exact

dimensions and provides an excellent seal between “top” and “bottom.” The filling and

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sealing process is simultaneous, resulting in a finished product that is well-sealed, secure and

relatively resistant to further manipulation.

Starch and HPMC are good candidates for making not only hard but also soft gelatin

capsules. One of the limitations of using them is the initial high capital investment [7] [15] [23]

B) DEVELOPMENT CAPSULES OF HYDROXY PROPYL METHYL CELLULOSE (HPMC)

Hypromellose (INN), short for hydroxypropyl methylcellulose (HPMC), is a semisynthetic,

inert, viscoelastic polymer used as an ophthalmic lubricant, as well as an excipient and

controlled-delivery component in oral medicaments, found in a variety of commercial

products.

Product details:-[8]

Other names Hydroxypropyl methylcellulose;

hydroxypropyl methyl cellulose; HPMC;

E464

CAS number 9004-65-3

Chem Spider 21241863

UNII 36SFW2JZ0W

Molecular formula Variable

Molar mass Variable

Properties:

- Appearance: HPMC is white or similar to white fiber or granular powder; Odourless.

- Properties: Almost insoluble in ethanol, ether and acetone; Quickly dispersed in 80-90

centigrade water; Aqueous solution is very stable in room temperature; Has good wetting /

dispersing / adhesive / thickening / emulsifying / water preserving/film-forming properties;

Can prevent the infiltration of grease; Film formed has excellent flexibility and transparency;

Has good compatibility with other emulsifier; Easy salting-out. Its solution is stable with pH

2-12.

- Apparent density: 0.30-0.70g/cm3, density is 1.3G/cm3.

Dissolving process

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HPMC will agglomerate when directly added to water and then dissolve. In this way it

dissolves very slow and hard. Suggested methods as followers:

1. in hot water.

HPMC does not dissolve in hot water. The primary HPMC can be uniformly disperse in hot

water. Then cool down in two ways:

A) Add hot water in container and heated to over 70 centigrade. Add HPMC gradually while

slowly, stir. At the beginning, HPMC float on the top of water, then turns into slurry state stir

and cool down.

B) Add water in container to 1/3 or 2/3 of its content. Heated to over 70 centigrade add

HPMC by sequence of a). Make it disperse to form slurry state. Add cool water or ice to the

residual content, stir and cool down the mixture.

2. Powder combination.

Mix HPMC with identical volume of other powder, disperses them sufficiently then add

water to the. [9]

Despite the fact that most of pharmaceutical capsules available in market are made of gelatin,

several HPMC capsules for powdered herbs and dietary supplements have been available in

recent years. Many investigational new drugs with HPMC encapsulation are in clinical trials.

HPMC capsules may offer attractive alternative to gelatine capsules because of its vegetable

source. The cross linking of gelatin and drug incompatibilities and the strict regulations

regarding the use of animal derived gelatin requiring the absence of bovine spongiform

encephalopathy (BSE)/ transmissible spongiform encephalopathy (TSE) have encouraged the

search for gelatin replacement. Religious, cultural and personal issues may affect patients’

preference towards the medications presented in capsule dosage forms. Vegetarians for

example are becoming increasingly aware of the capsule shell materials which also

encouraged the companies to search for alternatives. As a result, the first vegetable capsules

with the trademark Vegicaps made of HPMC were produced in 1989 by G S Technologies

Inc. (now R.P. Scherer Technologies ownership).[10]

MANUFACTURING OF (HPMC) CAPSULES

- The results from the search were filtered to use information regarding the two-piece capsules

(hard capsules) only; since there are the soft capsules such as Vegicaps Soft (Catalent Pharma

Solutions), HPMC based soft capsules, which are available as alternative to soft gelatin

capsules. Hard gelatin and HPMC capsules are manufactured using similar equipments

developed by Eli Lilly (20).

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- In hard gelatin capsule manufacturing, pins (molds for making the capsules) at 22°C are

dipped in a dip pan or pot that holds a fixed quantity of gelatin at a constant temperature,

between 45° and 55°C. The level of solution is maintained automatically by a feed from the

holding hopper. Once the molds are dipped a film will be formed on them by gelling since

they are at lower temperature. The slowly withdrawn pins from the dipping pan are rotated to

maintain uniform film thickness, where they are passed through a series of drying kilns at

controlled temperature and humidity. The dried films (shells) are stripped of the pins, cut to

the correct length and the two pieces (cap and body) are joined together. The pins are then

cleaned and lubricated to start the next cycle.

- The manufacture of HPMC based capsules necessitates some modification to the molding

machine or to the formulation of the shell materials. HPMC gelling from solution occurs

when the temperature is raised while it is converted to its original solution as the temperature

is lowered, unlike gelatin solution. This means that the pins immersed in the dip pan

containing the HPMC solution must be of higher temperature (70°C) in order for the film to

be formed. To avoid liquefaction of the films formed on the pins, the temperature of the pins

must be further maintained post-dip to facilitate gelation until the films dry out in the kilns

(21-24).

- Because HPMC shell walls are much weaker than gelatin made shells, removal of the capsule

from the pins and subsequent handling and filling are in jeopardy. 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. The following gelling agents were experimented: tamarind seed

polysaccharide, carrageenan, pectin, curdlan, gellan gum and furcellaran.

C) DEVELOPMENT OF PVA COPOLYMER CAPSULES

Hard capsules have been developed as an edible container to mask the taste and odour of

medicines. Traditionally used for powder or granulated formulations, capsules have also been

adapted to contain oily liquids, tablets and even powders for inhalation. They are popular

because of their relative ease of manufacture (compared with other dosage forms such as

tablets) and their flexibility to accommodate a range of fill weights. Additionally, capsules

readily demonstrate bioequivalence between different strengths of the same formulation.

The solubility of many compounds used in potential new drugs is very low because they are

selected for their affinity to receptors, which increases as the lipophilicity of a compound

increases. Although these compounds are expected to have a high clinical performance, they

15

often fail to become new drug entities because of their low absorption in the gastro-intestinal

(GI) tract - a result of poor dissolution.

This suggests that pharmaceutical manufacturers could develop dosage forms of insoluble

drugs with macrogol 400, improving the solubility of such entities. Because the formulations

and manufacturing processes are simple, no scale-up studies would be required - possibly

reducing drug development times. Because of the large potential of capsules that can hold

macrogol 400, the developed new capsules, synthesizing materials that are suitable as capsule

shells. By copolymerizing acrylic acid (AA) and methyl methacrylate (MMA) on PVA as a

skeleton and then using the obtained PVA copolymer as capsule shells, the successfully

developed capsules that can be filled with macrogol 400.2,3 In this paper, the physical

properties of the PVA copolymer, and the characteristics and pharmaceutical applications of

PVA copolymer capsules, are given. [14]

Necessity of new materials:-

- Initially, examined why conventional capsule shells do not tolerate macrogol 400. When

gelatin capsules were filled with macrogol 400, they became brittle and broke easily because

the moisture in the shell was absorbed by the macrogol. When hydroxypropyl

methylcellulose (HPMC) capsules were filled with macrogol 400, the agent oozed out

through the capsule shell.

- It is believed that new synthetic polymers would be more suitable for capsule shell materials

rather than natural polymers or polysaccharides. Thus, different polymers were synthesized,

using styrene resin, polyurethane, acrylic polymer and chitosan as a skeleton.

Product Information:- [15]

Chemical Name Polyvinyl Alcohol

Commodity Name PVA

Category Linear polymer with hydroxyl group

Molecular formula (CH3CHCOOCH3)x(CH2CHOH)y

Molecular wt. n/a

H.S.Code 3905300000

CAS No. 9002-89-5

Hazard Class n/a

UN No. n/a

Packing Group: n/a

16

Technical Specification:-[15]

Appearance White granular

Viscosity by mPa.s 27.0~ 32.0

Alcohol degree by y/(x+y) x 100% 98.0~ 99.0

Sodium Acetate by wt % 2.5 max

Volatile by wt % 5.0 max

Ash by wt % 0.7 max

pH value 5~ 7

Particle size by mesh about 15

MANUFACTURING OF (PVA) CAPSULES

Dissolution of PVA copolymer:-

- Capsules made only of PVA are available, although they are easily softened by surrounding

moisture. In the PVA copolymer, MMA was used to increase the hardness of the capsule

shell; however, increasing the amount of MMA decreases the polymer solubility. Thus, AA

was copolymerized to increase the solubility at neutral pH. The composition ratios of PVA,

AA and MMA in the PVA copolymer can be modified; the best copolymer is formed when

the levels of PVA, AA and MMA are 70–80%, 2.5–5.0% and 15–25%, respectively.

- Drug capsules should dissolve in purified water, as well as in simulated gastric fluid (pH 1.2)

and simulated intestinal fluid (pH 6.8) of the disintegration test method listed in the Japanese

Pharmacopoeia (JP). The dissolution of PVA copolymer cast film in the above media was

examined. The result showed that the film was soluble in all three fluids, indicating that the

copolymer has suitable dissolution characteristics. The film showed no erosion, swelling or

dissolution in macrogol 400.

Film strength:-

- PVA copolymer film was formed in 100 μm thickness using the casting method. The

breaking strength and elongation rate of 40310 mm film segments were examined, which

showed the breaking strength of the PVA copolymer film to be 32.2 N/mm2. The value was

slightly lower than that of gelatin film (55.8 N/mm2), but comparable to that of HPMC film

(30.8 N/mm2); therefore, the PVA copolymer film was considered acceptable for practical

use.

17

- When the PVA copolymer film was moistened in a chamber (25 °C/75% relative humidity

[RH]), its strength decreased by approximately 25%. Gelatin and HPMC specimens showed

larger reductions (more than 50%) in strength when moistened at the same condition.

Although the gelatin and HPMC films showed a low elongation rate before and after moistening,

the PVA copolymer film showed a markedly higher rate before and particularly after

moistening (312% of the original rate).

Gas permeability of the film:-

- The 100 μm thick film was also used to examine gas permeability by the American Society

for Testing and Materials (ASTM) method. Water vapour permeability through PVA

copolymer film at 25 °C/90% RH was 323.2 g/m2/24 h, which was between the values of the

gelatin and HPMC films. There was no marked difference in water vapour permeability

between the three films. In contrast, oxygen permeability through PVA copolymer was

significantly less than through gelatin and HPMC films, indicating that it should be

impermeable to the PVA copolymer film.

- Moisture absorption and desorption isotherm. Generally, water-soluble polymers start to

absorb moisture when relative moisture increases by more than 70% and the absorption rate

dramatically increases when relative moisture exceeds 80%. The moisture absorption

isotherm curve of PVA copolymer is similar to that of gelatin. The moisture desorption of

PVA copolymer is similar to its absorption isotherm curve, whereas, for gelatin film, the

desorption rate is slower than its absorption rate.

Physical properties

- PVA copolymer capsules were prepared by the dipping and forming method. Carrageenan

(0.05-0.5%) was added as a gelling agent and potassium chloride (0.05-0.5%) was added as a

gelling promoter. This method requires no additional investment for capsule manufacturers

because conventional gelatin capsule manufacturing machines can be used. Prototype PVA

copolymer capsules were coloured showed a good gloss and were not different from

conventional capsules.

Disintegration and dissolution:-

- Prototype PVA copolymer capsules (size #0) were filled with macrogol 400 and the time

taken for the contents to begin to leak out was measured (Table IV). The capsules were filled

with the disintegrate croscarmellose sodium and the paddle method (50 rpm) was used to

measure the disintegration time as an index of the start of dissolution. The capsules opened in

less than 10 min in all the media.

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Capsule hardness:-

The relationships between the brittleness and moisture content of PVA copolymer, gelatin

and HPMC capsules were compared using a hardness tester (Shionogi Qualicaps, Japan). A

50 g weight was dropped at a height of 10 cm onto a capsule and the percentage of broken

capsule was determined (Figure 3). At a water content of 8%, the gelatin capsules became

brittle and the percentage of broken capsules was 100%. The HPMC capsules did not break,

even at 1% water content. PVA copolymer capsules became brittle when water content was

less than 4%, but were less brittle compared with gelatin capsules. PVA copolymer capsules

did not become brittle or break easily, even when filled with macrogol 400 (which absorbs

moisture from the capsule shell) or silica gel grains (desiccant). The authors concluded that

these test conditions were too severe to estimate capsule brittleness.

To evaluate capsule deformation, the load required to deform each capsule by 50% was

measured using a load cell. The results illustrate that PVA copolymer capsules can be

deformed by moisture absorption, but this can be prevented by controlling the water content

of the filling and the humidity of the environment, or with moisture-proof packaging.

Filling dissolution:-

- When dissolution testing PVA copolymer capsules (size #2) filled with macrogol 400, the

bottom of the capsules quickly dissolved (2 min) in purified water, JP 1st fluid (pH 1.2) and

JP 2nd fluid (pH 6.8), with the macrogol 400 leaking out from the bottom.

- Two sets of capsules for the insoluble drugs tolbutamide and indomethacin were prepared.

One capsule was filled with the drug as a solution of macrogol 400 and the other was filled

with a mixture of the drug, lactose (as filler) and croscarmellose sodium (as a disintegrant).

The dissolution behaviour of the capsules was compared using the JP paddle method (50

rpm). The tolbutamide/macrogol 400 capsules almost dissolved completely in 10 min in all

the test solutions. However, for the capsules filled with the drug, filler and disintegrant, only

80% of the drug had dissolved after 60 min.

Absorption of indomethacin in rats. Indomethacin PVA copolymer capsules were prepared

using either a solution of macrogol 400 or a mixed powder formulated with lactose and

croscarmellose sodium. Both sets were filled into mini-capsules (size #9) and administered to

rats to compare the plasma profiles of the drug .4 The results illustrate that between 180-360

min, the capsule containing the drug as a solution of macrogol 400 demonstrated a higher

plasma concentration (8 μg/mL) compared with the capsules containing the mixed powder (1

19

μg/mL). The data suggest that PVA copolymer capsules filled with macrogol 400 improve

the bioavailability of insoluble drugs.

Tolerance of PVA copolymer capsules. The solubilising agents macrogol 400, Tween 80 and

Labrasol were filled into PVA copolymer capsules and stored in accelerating conditions (40

°C/75% RH) in a sealed container to examine the tolerance of the capsules to the agents. The

capsules showed no change in appearance after 6 months.

When a solubilising agent with high water content is filled into a capsule, the moisture causes

the capsule shell to soften and/or deform. This can be prevented by controlling the water

content of the agent and the humidity of the manufacturing environment, and by using

moisture-proof packaging, as done for conventional capsules.[16][15][18]

D) DEVELOPMENT OF ALGINATE CAPSULES

Utilizing a novel patented process based on one of FMC core Biopolymers (alginate) this

technology provides a unique seamless, enteric, vegetarian alternative to gelatin soft capsules

in one unit process for pharmaceutical and nutraceutical applications.

Alginate capsules advantages

Globally acceptable regulatory compliance with Vegetarian (gelatin-free)

- Capsules easier to swallow:

- Smaller Capsule: Seamless thinner capsule shell, allowing for capsules 30% smaller than

traditional gelatin for a given fill volume

- No Fish Burps: Naturally enteric providing superior gastro resistant and enteric release

properties to film coated alternatives

- Superior elegance - high shell transparency

- Sugar and gluten free

Manufacture of capsules easier:

- Favourable unit cost - process does not produce waste ribbon as seen in traditional rotary die

processes and eliminates need/cost of enteric film coating maximizing production efficiency

- Process designed to provide oxidation protection

- QbD development philosophy

- Patented product and process enables product life cycle enhancement.[19]

Alginate Capsules Basic Formulation

Emulsion

…oil

…CaCl2•2H2O

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…emulsifier

…water

Gelling bath

…Alginate

Washing

…Water

> Plasticizer

> Regulatory evaluation of shell components:

…All of the excipients used in the algicaps shell are established excipients for use in oral

dose forms at levels used.

Alginate Capsules - Film thickness

Thinner films than conventional soft capsules, in the range of hard Capsules

…100-150 micron after drying

…Low film thickness variations

…Conventional seam variations avoided

…Smaller capsules

…Easier to swallow

…More product per capsule

…Film thickness determined by formulation and process conditions

…Amount of Ca2+ used

…Amount of alginate used

…Gelling temperature

…Gelling time

Manufacturing of alginate capsules:-[20]

Steps involved in alginate capsule shell formation:-

1. Extrude formation of Emulsion.

2. Introduce emulsion fragments into alginate bath.

3. CaCl2 diffuses through the emulsion and react with sodium alginate at the

interface.

4. The capsule shell wall is formed with the same thickness all around.

5. Washing and drying.

6. Dry capsule with transparent shell and transparent core.

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Fig. Alginate capsule shell manufacturing process

Continuous capsule shell manufacturing process:-

Fig. Continuous Alginate capsule shell manufacturing process.

22

Reference:-

1) http://www.pharmacopeia.cnArtical%20capsule/General%20Chapters_%20_1151_

%20PHARMACEUTICAL%20DOSAGE%20FORMS%20-%20CAPSULES.mht

2) LA Augsburger “Hard and soft gelatin capsules” in Modern Pharmaceutics GS Banker & CT

Rhodes, (1995) ,Eds., Marcel Dekker, Inc.: New York, NY, pp 395–440.

3) http://en.wikipedia.org/wiki/Capsule(pharmacy)

4) Dr. B.Bhatt,Prof. S.S. Agrawal "Pharmaceutical Technology Capsules(24-07-2007)" Delhi

Institute of Pharmaceutical Science and Research Sector – 3, ,Pushp Vihar ,New Delhi,page

no :-1 to 26.

5) Ogura T, Furuya Y, Matuura S. “HPMC capsules: an alternative to gelatin.” Pharm Tech

Europe, 1998; 10(11): 32-42.

6) MS Patel, FSS Morton, & H Seager “Advances in softgel formulation technology (1989)”

Manuf Chem, July 26–28.

7) M Salonen, E Aantaa, L Aaltonen, M Hovi-Viander, & J Kanto “A comparison of the soft

gelatin capsule and the tablet form of temazepam(1986)” Acta Pharmacol Toxicol 58 ,page

no:-49–54.

8) http://en.wikipedia.org/wiki/Hypromellose

9) http://kehongchem.en.made-in-china.com/product/obrnIVtMCdkD/China-Hydroxypropyl-

Methyl-Cellulose-HPMC-MHPC-.html

10) M. Moawia . Al-Tabakha,” HPMC Capsules: Current Status and Future Prospects”, College

of Pharmacy, Al Ain University of Science and Technology, Al-Ain, U.A.E.,J Pharm

Pharmaceut Sci (www.cspsCanada.org) 13(3) , 2010,428 – 442.

11) M. Sherry Kua,Weiyi Lia,,Wendy Dulina, Fran Donahuea, Dominique Cadeb, Hassan

Benameurb, Keith Hutchison,” Performance Qualification of a New Hypromellose Capsule”,

Pharmaceutical Development, Wyeth Research, 401 N. Middletown Road, Pearl River, NY

10965, USA.

12) Y. El-Malah; S.Nazzal;Carey B. Bottom”Hard Gelatin and Hypromellose (HPMC) Capsules:

Estimation of Rupture Time by Real-time Dissolution Spectroscopy”.Published in:Drug

Development and Industrial Pharmacy, Volume 33, Issue 1 January 2007 , pages 27 - 34

13) https://data.epo.org/publication-server/rest/v1.0/publicationdates/20081224/patents/

EP1693056NWB1/document.html

14) N.Hoshi, S.Uramatsu, T.Shimamoto, T.Ogura,” Development of PVA Copolymer Capsules”,

Pharmaceutical Technology Europe, Apr 1, 2004.

15) http://www.lukem.cn/en/ProductShow.asp?ID=62

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16) http://www.pharmtech.com/pharmtech/Raw+Materials/Development-of-PVA-Copolymer-

Capsules/ArticleLong/Article/detail/92479?contextCategoryId=2592&ref=25

17) Leon Lachman.,"The Theory and Practice of Industrial Pharmacy",varghese publication

house,mumbay,page no:-374-442.

18) http://www.capsugel.com

19) Magenta oral dosage formulation “Introduction to the Novel Alginate Capsules Technology”,

FMC.

20) http://www.fmcbiopolymer.com/Pharmaceutical/Products/AlginateCapsuleTechnology.aspx

21) http://www.trailab.net/Liam%20-%20Papers/23.pdf

22) www.liquidcapsules.com

23) http://www.google.com/patents/US5554385.pd

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