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Liquid-Filled and -Sealed Hard Gelatin Capsule Technologies

Ewart T. Cole
CAPSUGEL, a Division of Pzer 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 lled into the capsule to provide a unit dose that effectively masked the bitter taste of drugs in an easyto-swallow container. With the advent of pellet technology to modify the release properties of drugs, the capsule provided an ideal vehicle into which multiparticulates could be lled without risk of modifying the release characteristics by compression into tablets [1]. More recently, technology has been developed to accurately dose and seal liquids into hard gelatin capsules [24] 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 lling technology is applicable. For almost all categories of drugs examples of marketed products are given to illustrate that several companies are already using the technology. Many more products are in various phases of the development process.

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

References
[511] [1218] [19]

Cole

Characteristic
Poorly soluble Short half-life requiring frequent dosing Low melting point

Examples of marketed products

Nifedipine (Aprical) Ibuprofen (Solufen) Captopril (Captoril) Oils of avocado and soya (Piascledine) Danthron (Co-danthramer) Products in development Vancomycin hydrochloride (Vancocin)

Low dose/high potency Critical stability

[12,1921] [2224]

III. THE EMPTY HARD GELATIN CAPSULE IN COMPARISON TO SOFT GELATIN CAPSULES The hard gelatin capsule for liquid lling is identical in composition to the capsule used for lling powders and comprises gelatin, water, and coloring and opacifying agents. For an efcient sealing process, however, it is important that the ll material does not penetrate into the zone between the body and cap before the sealing operation. A capsule with a special conguration 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 nd innovative ways of developing bioavailable and stable dosage forms. Excipient suppliers, encouraged by the potential opportunities in this eld, are developing new materials comprising mixtures of functional excipients. An example is the introduction of SMEDDS (Self-Emulsifying Drug . Undoubtedly this approach was stimulated by Delivery System) by Gattefosse 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 thermosetting formulations.

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Liquid-Filled Hard Gelatin Capsules Table 2

Aspect
Inhouse development and manufacture Ability to manufacture small batches Scale-up

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Characteristics of Hard and Soft Gelatin Capsules

Hard gelatin capsule
Yes

Soft gelatin capsule

Difcult

Reference

Yes

No

Simple and inhouse

Temperature of ll Plasticizer in shell Risk of drug migration Permeability of shell to oxygen Sensitivity to heat and humidity Limitation on excipients for formulation

Max. 70C No Low

Low Low High concentrations of hygroscopic excipients such as glycerol must be avoided Constant

Requires large quantities of drug substance and must be outsourced Max. 35C Yes High for drugs soluble in plasticizer High due to plasticizera High due to plasticizer Hygroscopic excipients can be tolerated due to presence of plasticizer in shell May vary

[25] [25,26] [27]

[21,28] [26] [25,26]

Capsule dimensions
a

Dependent on moisture content of shell.

As the potential for interactions between the capsule shell and ll are greater than is the case with a powder-lled capsule, techniques have been developed to monitor this. A. Moisture Exchange Fill Shell Typically a hard gelatin capsule contains 13.515.5% moisture, which acts as a plasticizer for gelatin. A hygroscopic material, when lled into the capsule, could extract moisture from the shell thereby inducing embrittlement. The potential for

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

this is checked by storing capsules lled with the product under various conditions of relative humidity from 2.5 to 65% and measuring the weight change as and Madit [30]. already described by Cade B. Mechanical Properties

The relationship between relative humidity during storage, gelatin moisture content, 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 importance in determining compatibility between the ll material and the capsule shell. and Madit [30]. The methodology to determine this is described by Cade 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.

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[33] for capsules lled with powders. Dissolution of gelatin capsules was also the topic of an FDA/Industry Working Group, and a modied dissolution testing procedure allowing the use of enzymes has been accepted when a delay in dissolution 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-lled capsules may have, or may generate during storage, low levels of aldehydes, which can potentially react with gelatin. The technique to monitor any interaction is described and Madit [30]. by Cade Particularly in the case of hot-melt lls 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 inuence on the structure of certain excipients, which in turn may modify the drug release characteristics from the matrix itself [37]. D. Recommended Properties (Temperature and Viscosity) of Fill Materials The important factors to bear in mind during a liquid lling operation are temperature and viscosity of ll material and, in the case of a suspension, the particle size of the suspended drug. Whereas in principle any excipient found to be compatible with the gelatin shell can be used, in practice in a manufacturing environment the viscosity of the ll 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 lling 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
Temperature of ll material Viscosity at the temperature of dosing Dosing characteristics Particle size of suspended drug

Recommendation
Max. 70C 0.11 Pa s Clean break from dosing nozzle Absence of stringing 50 m

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182 Table 4 Lipophilic Liquid Vehicles Compatible with Hard Gelatin Capsules
Rened specialty oils
Arachis oil Castor oil Cottonseed oil Maize (corn) oil Olive oil Sesame oil Soybean oil Sunower oil

Cole

MCTsa and related esters

Akomed E Akomed R Captex 355 Labrafac CC Labrafac PG Lauroglycol FCC Miglyol 810 Miglyol 812 Miglyol 829 Miglyol 840 Softisan 645

Medium-chain triglycerides. 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.

suitable for formulation of drugs into hard gelatin capsules are shown in Tables 4, 5, and 6. They have been classied into three arbitrary groups: lipophilic liquid vehicles, semisolid lipophilic vehicles/viscosity modiers 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, however, 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 nal formulation including the drug substance must be monitored as part of the routine development process.

V. A.

FILLING AND SEALING EQUIPMENT Capsule-Filling Machines

Most of the modern European capsule-lling machines can be modied to allow hard gelatin capsules to be lled with hot or cold liquids. The machine requirements to allow an industrial manufacture of liquid-lled capsules are reported by Cole [38] and the models available are given in Table 8.

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Liquid-Filled Hard Gelatin Capsules 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.

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B. Equipment for Sealing Hard Gelatin Capsules An essential part of a liquid-lling 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 methods 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 rst described by Wittwer [39] and et al. [21], uses the principle of lowering of the melting subsequently by Cade point 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 uid 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-lling 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 Pzer Inc.

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184 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 Labral M 1944 CS, M 2125 CS Labrasol Lauric acid Lauroglycol 90 Oleic acid PEG MW 4000 Plurol Oleique CC 497 Poloxamer 124 and 188 Softigen 701, 767 Tagat TO Tween 80
a Glycerin content 5%. 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.

Cole

Table 7 Excipients that Are Incompatible with Hard Gelatin Capsules when Tested Alone
Ethanol Cremophor EL Glycerin Glycofurol 75 MCMs Akoline MCM, Capmul MCM, Imwitor 308a PEGs of MW 4000 Pharmasolve Propylene glycol Span 80 Transcutol P
a Glycerin content 5%. Note: Mixtures with compatible excipients may allow these to be used in lower concentrations. Limit must be determined experimentally.

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Table 8 European Automatic Capsule-Filling Machines for Liquid Filling of Hard Gelatin Capsules
Machine type
Robert Bosch GmbH GKF 400 L GKF 800 L GKF 1500 L (2 pumps) Harro Hoeiger GmbH KFM III-I KFM III IMA Zanasi Division Z 12 Z 48 Plus Z 85 Plus MG2 Compact Futura

Number of capsules/segment
3 6 6

Approximate lling rate (capsules/h)

10,000 30,000 60,000

1 3 2 6 11 Continuous motion Continuous motion

3,500 10,000 9,000 35,000 60,000 4,00035,000 4,00060,000

Figure 2 Illustration of spraying process to moisturize the space between cap and body of the capsule. (See color insert.)

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186 Table 9
Stage
1. Moisturizing

Cole Stages During the Sealing of Liquid-Filled Hard Gelatin Capsules

Process
50: 50 water/ethanol mixture sprayed onto the join and capillary action draws liquid into the space between body and cap. Excess uid removed by suction. Melting point of gelatin lowered by presence of water. Application of gentle heat of approx. 45C completes the melting over a period of about 1 min and the two gelatin layers are fused together to form a complete 360 seal. Gelatin setting or hardening process is completed while the product returns to room temperature. This process is best carried out on trays.

2. Warming

3. Setting

sugel has developed a bench top machine (CFS 1000) which is shown in Fig. 4. This machine automatically lls and seals up to 1000 capsules per hour. Numerous companies familiar with the hard gelatin capsule banding operation 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 comparison is shown in Table 10.

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

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

Table 10 Comparison of the Hard Gelatin Capsule Sealing and Banding Technologies
Aspect
Installation and startup Machine operation Initial capital costs Time for size change Capsule rectication Cleaning time Sealed area Gelatin handling Current maximum machine output Solvent exhaust
a

Capsule sealing using Lems

Easy, quick User friendly Low 1 h No 23 h Large No 30,000/h Yes

Capsule bandinga
Difcult, time consuming User unfriendly High 8 h Yes 12 h Small area of band Yes 80,000/h No

Quali-seal, S-100 Shionogi.

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VI. CONCLUSIONS For drugs requiring modied 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 production level. REFERENCES
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35. RM Mhatre, H Malinowski, H Nguyen, MC Meyer, AB Straughn, L Lesko, RL Williams. The effects of cross-linking in gelatin capsules on the bioequivalence of acetaminophen. Pharm Res 14:3251, 1997. . The effect of cross-linking on 36. J Brown, N Madit. ET Cole, IR Wilding, D Cade the in vivo disintegration of hard gelatin capsules. Pharm Res 15:10261030, 1998. 37. SM Chatham. The use of bases in semi-solid matrix formulations. STP Pharma 3: 575582, 1987. 38. ET Cole. Liquid lled hard gelatin capsules. Pharm Technol Int Sept/Oct 1989, pp. 2933. 39. F Wittwer. New developments in hermetic sealing of hard gelatin capsules. Pharm Manufac 2:2427, 1985. 40. USP 23, General Information. Pharmaceutical Dosage Forms 1151, 1995, pp. 1942 1943.

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