Ch14 Liquid- Filled and Sealed Hard Gelatin Capsule Technologies

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14Liquid-Filled and -Sealed HardGelatin Capsule Technologies

Ewart T. Cole

CAPSUGEL, a Division of Pfizer Inc., Arlesheim, Switzerland

I. INTRODUCTION

The hard gelatin capsule has been used for many years as an oral delivery form.

Initially drugs in powdered or granular form were usually filled into the capsuleto provide a unit dose that effectively masked the bitter taste of drugs in an easy-

to-swallow container. With the advent of pellet technology to modify the release

properties of drugs, the capsule provided an ideal vehicle into which multiparticu-

lates could be filled without risk of modifying the release characteristics by com-

pression into tablets [1]. More recently, technology has been developed to accu-

rately dose and seal liquids into hard gelatin capsules [2–4] and this chapter will

review the areas of application of this technology, outline the requirements of

the formulation, compare it with soft gelatin capsule technology, and describe a

process for sealing hard gelatin capsules.

II. DRUG CHARACTERISTICS RELEVANT TO LIQUID

FILLING TECHNOLOGY

Table 1 summarizes the various characteristics of drugs for which liquid filling

technology is applicable. For almost all categories of drugs examples of marketed

products are given to illustrate that several companies are already using the tech-

nology. Many more products are in various phases of the development process.

177

Copyright © 2003 Marcel Dekker, Inc.



178 Cole

Table 1 Drug Characteristics for Which Liquid-Filling Technology Is Relevant

Examples of Characteristic References marketed products

Poorly soluble [5–11] Nifedipine (Aprical)

Ibuprofen (Solufen)

Short half-life requiring frequent [12–18] Captopril (Captoril)

dosing

Low melting point [19] Oils of avocado and soya

(Piascledine)

Danthron (Co-danthramer)

Low dose/high potency [12,19–21] Products in development

Critical stability [22–24] Vancomycin hydrochloride(Vancocin)

III. THE EMPTY HARD GELATIN CAPSULE IN

COMPARISON TO SOFT GELATIN CAPSULES

The hard gelatin capsule for liquid filling is identical in composition to the capsule

used for filling powders and comprises gelatin, water, and coloring and opacify-

ing agents. For an efficient sealing process, however, it is important that the fillmaterial does not penetrate into the zone between the body and cap before the

sealing operation. A capsule with a special configuration has been designed to

eliminate this (Licaps) and a range of capsule sizes from approximately 0.3 to

0.85 mL is available. In contrast to the hard gelatin capsule, the soft gelatin

capsule contains a plasticizer in addition to gelatin and water, and commonly

glycerol at a level of approximately 30% is used. The soft gelatin capsule process

has been reviewed by Jimerson [25] and a comparison of the two capsule types

is given in Table 2.

IV. SUITABILITY OF FILL MATERIALS

As the tendency for poorly water-soluble drugs to enter the pipeline increases,

so does the challenge to find innovative ways of developing bioavailable and

stable dosage forms. Excipient suppliers, encouraged by the potential opportuni-

ties in this field, are developing new materials comprising mixtures of functional

excipients. An example is the introduction of SMEDDS (Self-Emulsifying Drug

Delivery System) by Gattefosse. Undoubtedly this approach was stimulated by

the work performed by Sandoz, on the microemulsion formulation of cyclosporin

A [10,11]. Bowtle [29] has described a process for selection of bases for thermo-

setting formulations.




Liquid-Filled Hard Gelatin Capsules 179

Table 2 Characteristics of Hard and Soft Gelatin Capsules

Hard gelatin Soft gelatinAspect capsule capsule Reference

Inhouse develop- Yes Difficult

ment and manu-

facture

Ability to manufac- Yes No

ture small bat-

ches

Scale-up Simple and in- Requires large

house quantities of

drug substanceand must be out-

sourced

Temperature of fill Max. ϳ70°C Max. ϳ35°C [25]

Plasticizer in shell No Yes [25,26]

Risk of drug mi- Low High for drugs sol- [27]

gration uble in plasti-

cizer

Permeability of Low High due to plasti- [21,28]

shell to oxygen cizera

Sensitivity to heat Low High due to plasti- [26]

and humidity cizerLimitation on ex- High concentra- Hygroscopic excip- [25,26]

cipients for for- tions of hygro- ients can be tol-

mulation scopic excipi- erated due to

ents such as presence of plas-

glycerol must be ticizer in shell

avoided

Capsule dimen- Constant May vary

sions

a Dependent on moisture content of shell.

As the potential for interactions between the capsule shell and fill are

greater than is the case with a powder-filled capsule, techniques have been devel-

oped to monitor this.

A. Moisture Exchange Fill Shell

Typically a hard gelatin capsule contains 13.5–15.5% moisture, which acts as a

plasticizer for gelatin. A hygroscopic material, when filled into the capsule, could

extract moisture from the shell thereby inducing embrittlement. The potential for




180 Cole

Figure 1 Equilibrium moisture content of empty gelatin capsules shells stored at variousrelative humidities for 2 weeks at 20°C. (From Ref. 31.) (See color insert.)

this is checked by storing capsules filled with the product under various condi-

tions of relative humidity from 2.5 to 65% and measuring the weight change as

already described by Cade and Madit [30].

B. Mechanical Properties

The relationship between relative humidity during storage, gelatin moisture con-tent, and capsule properties was reported by Bond et al. [31] and is shown in

Figure 1. The change in capsule brittleness with relative humidity has also been

studied by Kontny and Mulski [32]. It follows that monitoring of the mechanical

properties of capsules stored at various relative humidities is of critical impor-

tance in determining compatibility between the fill material and the capsule shell.

The methodology to determine this is described by Cade and Madit [30].

C. Dissolution Stability Indicator

The potential for interaction of an excipient or active with the capsule shell that

can result in a change in dissolution behavior has been described by Dey et al.





[33] for capsules filled with powders. Dissolution of gelatin capsules was also

the topic of an FDA/Industry Working Group, and a modified dissolution testing

procedure allowing the use of enzymes has been accepted when a delay in disso-

lution is a result of pellicle formation [34]. No relevance to the in vivo behavior

of the capsules was established [35,36].

Certain excipients used in the formulation of liquid-filled capsules may

have, or may generate during storage, low levels of aldehydes, which can poten-

tially react with gelatin. The technique to monitor any interaction is described

by Cade and Madit [30].

Particularly in the case of hot-melt fills the effect of melting temperature

and time held at this temperature on the potential for formation of aldehydes

needs to be investigated. The rate of cooling can also have an influence on thestructure of certain excipients, which in turn may modify the drug release charac-

teristics from the matrix itself [37].

D. Recommended Properties (Temperature and Viscosity)

of Fill Materials

The important factors to bear in mind during a liquid filling operation are temper-

ature and viscosity of fill material and, in the case of a suspension, the particle

size of the suspended drug. Whereas in principle any excipient found to be com-

patible with the gelatin shell can be used, in practice in a manufacturing environ-ment the viscosity of the fill material is important. If the viscosity is too low,

splashing of the bushings may occur, which could contaminate the area of overlap

between the capsule body and cap and prevent a good seal from being formed.

Absence of a clean break during dosing (stringing) can have the same effect. The

guidelines for problem-free filling are given in Table 3.

E. Excipients Compatible with Hard Gelatin Capsules

The materials listed have been tested according to the procedures described

above. Excipients that, from the aspect of compatibility, can be considered to be

Table 3 Recommended Guidelines for Dosing Liquids/Semisolids into

Hard Gelatin Capsules

Parameter Recommendation

Temperature of fill material Max. ϳ70°C

Viscosity at the temperature of dosing 0.1–1 Pa s

Dosing characteristics Clean break from dosing nozzle

Absence of “stringing”Particle size of suspended drug Յ50 µm




182 Cole

Table 4 Lipophilic Liquid Vehicles Compatible with

Hard Gelatin Capsules

Refined specialty oils MCTsa and related esters

Arachis oil Akomed E

Castor oil Akomed R

Cottonseed oil Captex 355

Maize (corn) oil Labrafac CC

Olive oil Labrafac PG

Sesame oil Lauroglycol FCC

Soybean oil Miglyol 810

Sunflower oil Miglyol 812

Miglyol 829Miglyol 840

Softisan 645

a Medium-chain triglycerides.

Note: The quality may vary between different suppliers and also

from batch to batch and should be routinely checked. The ther-

mal history of excipients during manufacture should be re-

corded.

suitable for formulation of drugs into hard gelatin capsules are shown in Tables

4, 5, and 6. They have been classified into three arbitrary groups: lipophilic liquid

vehicles, semisolid lipophilic vehicles/viscosity modifiers for lipophilic liquid

vehicles, and solubilizing agents, surfactants, emulsifying agents, and adsorption

enhancers.

Excipients shown in Table 7 are considered to be incompatible with hard

gelatin capsules and should be avoided at high concentrations. They may, how-

ever, be used in mixed systems, in which case the critical concentration above

which compatibility could become an issue must be determined experimentally.

The compatibility screening of the final formulation including the drug substancemust be monitored as part of the routine development process.

V. FILLING AND SEALING EQUIPMENT

A. Capsule-Filling Machines

Most of the modern European capsule-filling machines can be modified to allow

hard gelatin capsules to be filled with hot or cold liquids. The machine require-

ments to allow an industrial manufacture of liquid-filled capsules are reported

by Cole [38] and the models available are given in Table 8.





Table 5 Semisolid Lipophilic Vehicles and Viscosity-Modifying

Substances Compatible with Hard Gelatin Capsules

Hydrogenated speciality oils

Arachis oil Groundnut 36

Castor oil Cutina HR

Cottonseed oil Sterotex

Palm oil Softisan 154

Soybean oil Akosol 407

Aerosil

Cetosteryl alcohol

Cetyl alcohol

Gelucires 33/01, 39/01, 43/01

Glyceryl behenate (Compritol 888 ATO)Glyceryl palmitostearate (Precirol ATO 5)

Softisans 100, 142, 378, 649

Stearic acid

Steryl alcohol

Note: The quality may vary between different suppliers and also from batch to batch and

should be routinely checked. The thermal history of excipients during manufacture should

be recorded.

B. Equipment for Sealing Hard Gelatin Capsules

An essential part of a liquid-filling operation is the ability to effectively seal the

capsule. Various methods are available to seal hard gelatin capsules and these

have been reviewed by Wittwer [39]. The two most studied methods are banding

using a gelatin band and sealing using a hydroalcoholic solution, and both meth-

ods are described in the General Information section of the USP on capsules [40].

Banding of hard gelatin capsules has been described by Bowtle [29].

The capsule sealing process, which was first described by Wittwer [39] and

subsequently by Cade et al. [21], uses the principle of lowering of the meltingpoint of gelatin by the application of moisture to the area between the capsule

body and cap. Figure 2 illustrates the process to bring the sealing fluid to the

area of capsule overlap. The various stages of the process are outlined in Table 9.

The machine for industrially sealing hard gelatin capsules, shown in Figure

3, is commercially available and is marketed under the name LEMS 30* (Liquid

Encapsulation by MicroSpray). The machine is free standing and in practice is

connected to the output of a capsule-filling machine by means of a conveyor.

To allow manufacture of small batches for technical or clinical testing Cap-

* LEMS is a registered trademark of the Capsugel Division of Pfizer Inc.




184 Cole

Table 6 Solubilizing Agents, Surfactants,

Emulsifying Agents, and Adsorption Enhancers

Compatible with Hard Gelatin Capsules

Capryol 90

Gelucire 44/14, 50/13

Cremophor RH 40

Imwitor 191, 308,a 380, 742, 780 K, 928, 988

Labrafil M 1944 CS, M 2125 CS

Labrasol

Lauric acid

Lauroglycol 90

Oleic acid

PEG MW Ͼ 4000Plurol Oleique CC 497

Poloxamer 124 and 188

Softigen 701, 767

Tagat TO

Tween 80

a Glycerin content Ͻ 5%.

Note: The quality may vary between different suppliers and also

from batch to batch and should be routinely checked. The ther-

mal history of excipients during manufacture should be re-

corded.

Table 7 Excipients that Are Incompatible with Hard

Gelatin Capsules when Tested Alone

Ethanol

Cremophor EL

Glycerin

Glycofurol 75MCMs

Akoline MCM, Capmul MCM, Imwitor 308a

PEGs of MW Ͻ 4000

Pharmasolve

Propylene glycol

Span 80

Transcutol P

a Glycerin content Ͼ 5%.

Note: Mixtures with compatible excipients may allow these to

be used in lower concentrations. Limit must be determined ex-

perimentally.




186 Cole

Table 9 Stages During the Sealing of Liquid-Filled Hard Gelatin Capsules

Stage Process

1. Moisturizing 50: 50 water/ethanol mixture sprayed onto the join and capillary ac-

tion draws liquid into the space between body and cap.

Excess fluid removed by suction. Melting point of gelatin lowered

by presence of water.

2. Warming Application of gentle heat of approx. 45°C completes the melting

over a period of about 1 min and the two gelatin layers are fused

together to form a complete 360° seal.

3. Setting Gelatin setting or hardening process is completed while the product

returns to room temperature. This process is best carried out on

trays.

sugel has developed a bench top machine (CFS 1000) which is shown in Fig.

4. This machine automatically fills and seals up to 1000 capsules per hour.

Numerous companies familiar with the hard gelatin capsule banding opera-

tion have evaluated the capsule sealing technology using LEMS and over a period

of time a neutral comparison of the two processes has been possible. This compar-

ison is shown in Table 10.

Figure 3 LEMS 30 machine for sealing hard gelatin capsules. (See color insert.)





Figure 4 CFS 1000 capsule liquid filling and sealing machine. (See color insert.)

Table 10 Comparison of the Hard Gelatin Capsule Sealing and Banding

Technologies

Capsule sealing

Aspect using Lems Capsule bandinga

Installation and startup Easy, quick Difficult, time consuming

Machine operation User friendly User unfriendly

Initial capital costs Low High

Time for size change ϳ1 h ϳ8 h

Capsule rectification No Yes

Cleaning time 2–3 h ϳ12 h

Sealed area Large Small area of band

Gelatin handling No Yes

Current maximum machine 30,000 /h 80,000 /h

output

Solvent exhaust Yes No

a Quali-seal, S-100 Shionogi.




188 Cole

VI. CONCLUSIONS

For drugs requiring modified formulations, sealed hard gelatin capsules are a

viable option to soft gelatin capsules, providing the formulation scientist with an

inhouse possibility during the early stages of development to rapidly prepare

products for clinical trials. The process can also be readily scaled-up to produc-

tion level.

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Ch14 Liquid- Filled and Sealed Hard Gelatin Capsule Technologies

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