The hard gelatin capsule has been conventionally used as a dosage form for Rx and OTC drugs and herbal products, which are formulated either as powder or pellets. Various categories of drugs, however, demand new and different ways of formulation and the market demands that these products are developed and launched in an ever decreasing time period.

This article will review how liquids filled into hard gelatin capsules can fulfill some of these demands and in particular will review the categories of drugs for which the liquid and semi-solid filled capsule is particularly relevant, examine the compatibility issues associated with excipients, compare the liquid filled and sealed hard gelatin capsule with soft gelatin capsules and also describe a new process for sealing hard gelatin capsules.


1.Drug categories

Figure 1 shows the different categories of drugs for which a conventional dry powder dosage form may be either unsuitable or impractical.














1.1. Poor bioavailability

Ghirardi et al.  reported in 1977 that the bioavailability of the poorly water soluble drug digoxin could be significantly enhanced when formulated as a liquid in a soft gelatin capsule, which at the time was the only available way to formulate a liquid unit dosage form. It was not until the early 80‘s when workers reported studies in which hard gelatin capsules can be filled with molten formulations of drug substances that an alternative to soft gelatin capsules became a reality. One of the first commercial products to be developed as a liquid filled hard gelatin capsule was the poorly water soluble calcium antagonist nifedipine as described by Lahr . Bioequivalence with a drop solution and a soft gelatin capsule was achieved and the product was marketed in Germany as Aprical®.

Since the early 80’s the number of poorly water soluble drugs exiting from screening programs has increased sharply. Lipinski recently reportedthat 35% of NCE’s from the current Pfizer screening program are poorly soluble which agrees with the estimate given by Robinson .

Formulation of microemulsions is a technique, which has already been used to improve the bioavailability of poorly water soluble drugs and a continuation of this approach can be expected.


1.2 Low melting point

Materials which have low melting points or are liquid at room temperature present difficulties when formulating as dry powders, often requiring high concentrations of excipient to avoid processing problems. The product Piascledine® 300, which was originally marketed in France as a tablet, is a good example of how a manufacturing process can be considerably simplified by filling as a hot melt into a hard gelatin capsule. The product contains a mixture

of oils of avocado and soya for the treatment of skin disorders and the five step process to manufacture a tablet was reduced to a simple mixing and filling operation. Consumer acceptance was also enhanced due to the smaller size of the final dosage form.

Other actives with low melting points, which could benefit from this process include ibuprofen and the oily vitamins.


1.3 Low dose / High potency

Drugs in this category present two main challenges; how to achieve acceptable content uniformity and how to control cross-contamination and worker protection.


Content uniformity

Duerr et al. and Cadé et al. have reported that the liquid filling operation is capable of achieving fill weight variations of < 1%. If a drug substance is in solution or is uniformly dispersed in a liquid vehicle then it follows that good drug contentuniformity can also be achieved as has been reported by Walker et al. for the model drug triamterene at a dose level of 25μg.



Companies manufacturing solid dosage forms ofhormones and cytotoxic agents from powders are forced to install extremely elaborate systems to reduce contamination. Incorporation of the highly potent agent into a liquid for filling into a hard gelatin capsule can reduce the dangers when working with such drugs. A study carried out by Bowtle using phenacetin as a model drug, demonstrated that in a swab test of the bushings on a capsule filling machine operating with liquids, no detectable level ofphenacetin was found. Those familiar with capsule filling operations will realize that such clean conditions rarely exist when working with dry powders.


1.4 Critical stability

Sensitivity to moisture is an aspect of formulation which can be minimized by incorporating the drug into either a hydrophilic or lipophilic matrix. For example, the antibiotic vancomycin hydrochloride is highly hygroscopic and to achieve acceptable stability it needed to be formulated as a lyophilized powder for reconstitution. Bowtle et al. successfully developed a hard gelatin capsule filled with a PEG 6000 matrix of the drug. This capsule formulation produced faecal, plasma and urine levels of the antibiotic that were similar to those obtained with the solution and is marketed by Eli Lilly as Vancocin® HCL.


1.5 Sustained release

By choosing an appropriate excipient the release rate of an active can be modified. For example Gelucire, which is available as a semi-solid with a range of melting points and HLB values, can be mixed to obtain different drug release rates .

Seta et al. compared the bioavailability of an oily semi-solid matrix of captopril in hard gelatin capsules with that of a tablet. They concluded that the oily semi-solid matrix of captopril containing soybean oil and glyceryl  monostearate b.i.d. provided antihypertensive action that was comparable tothe conventional tablet t.i.d., the total daily dose being equal. This product is marketed by Sankyo in Japan as Captoril®‚ and provides the patient with a more convenient dosage regime.

2.The empty hard gelatin capsule and 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, colouring and opacifying agents. For an efficient sealing process, however, it is important that the fill material 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 problem and the range of capsule sizes available is given in Table 1.


Table 1.


In contrast to the hard gelatin capsule the soft gelatin capsule contains a plasticizer in addition to gelatin and water. Usually glycerol at a level of approx. 30% is used. As described by Bauer , the moisture uptake of soft gelatin capsules plasticized with glycerol is considerably higher than that for hard gelatin capsules. Another effect of the plasticizer has been reported by Armstrong et al. They found that migration of a drug into the shell of a soft gelatin capsule can occur which may result in drug degradation and difficulties in assay.

One basic difference exists between the hard and soft gelatin encapsulation processes. In the hard gelatin capsule process, the capsule is pre-fabricated and supplied empty, whereas in the soft gelatin capsule process the encapsulation and filling take place simultaneously. The moisture content of the gelatin/plasticizer mass at this stage can be around 50%, the equilibrium moisture level only being reached after several days storage on trays. It is conceivable that this is the most critical period during which migration and degradation of moisture sensitive drugs, which are readily soluble in glycerol, can occur.

Hom et al. reported that the oxygen transmission rate of a soft gelatin capsule film decreased with the level of glycerol in the film and also with the moisture content. As the hard gelatin capsule wall contains no plasticizer one may expect that the permeability of the hard gelatin capsule wall will be lower than that of a soft gelatin capsule. Cadé et al. reported on the smell assessment of soft and hard gelatin capsules containing the highly odorous products fish oil, valerian and garlic oil. Their resultsagree with the conclusions of Hom et al. , in that the permeability of the gelatin shell without plasticizer was found to be lower than that of the soft gelatin capsule with plasticizer. This higher permeability could have consequences for oxygen sensitive drugs filled into soft gelatin capsules.

The soft gelatin encapsulation process is in the hands of a few contract manufacturers, and rarely, due to the complexities of the process, do pharmaceutical companies get involved in this operation. This means, that from an early stage of development,once it has been established that a unit liquid/semi-solid dosage form is necessary, all development activities must be contracted out. Many companies would prefer to keep these activities inhouse for reasons of confidentiality, control over the development process, availability of drug substance at the early stages of development and not least control over costs.



















3.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 opportunities 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 Gattefossé. Undoubtedly this approach was stimulated by the work performed by Sandoz, on the microemulsion formulation of cyclosporin A .

The area of contact between the capsule shell and a liquid fill material is greater than is the case with a powder filled capsule. The potential for interactions must therefore be checked.


3.1. Moisture exchange fill-shell

A hard gelatin capsule contains 14-16% moisture(Figure 2), 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 this is checked by storing capsules filled with the product under various conditions of relative humidity from 2.5 to 65% and measuring the weight change as already described by Cadé and Madit .

The acceptance criteria have been set at a change in weight of plus or minus 2%.










                                                     Figure 2 Hard Gelatin Capsule Water Permeability


3.2. Mechanical properties

The relationship between relative humidity during storage, gelatin moisture content and capsule properties was reported by Bond et al. and is shown in Figure 3.









                                         Figure 3 Equilibrium moisture content of empty gelatin

                                      capsule shells stored at various relative humidities

                                                     for two weeks at 20°C.


The change in capsule brittleness with relative humidity has also been studied by Kontny and Mulski . It follows that monitoring of the mechanical properties of capsules stored at various relative humidities is of critical importance in determining compatibility between the fill material and the capsule shell. The methodology to determine this is described by Cadé and Madit . Acceptance criteria proposed are that significant capsule brittleness should not be detected in capsules stored at 30% and 50% relative humidity for four weeks.


3.3. Dissolution stability indicator

The potential for interaction of an excipient or active with the capsule shell which can result in a change in dissolution behaviour has been described by Dey et al. 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 dissolution is a result of pellicle formation . No relevance to the in vivo behaviour of the capsules was established.

Certain excipients used in the formulation of liquid filled capsules may have, or may generate during storage, low levels of aldehydes, which can potentially react with gelatin. As a means to evaluate potential interactions with the gelatin shell, capsules are filled with the test material and stored in closed HDPE bottles at 40°/75% RH for periods of up to six months. After the appropriate time has elapsed the capsules are emptied and cleaned. Acetaminophen is used as a dissolution reference material and is filled into the capsules which have been stored and the dissolution rate determined using the USP method 2. Comparison of the acetaminophen dissolution profiles from the stored and from a reference capsule gives an indication of a potential interaction between the fill material and the capsule shell.

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 the structure of certain excipients which in turn may modify the drug release characteristics from the matrix itself .


3.4. Recommended Properties(Temperature And Viscosity) of Fill Materials

The important factors to bear in mind during a liquid filling operation are temperature 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 compatible with the gelatin shell can be used, in practice in a manufacturing environment 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.

                  Table 3.

3.5. Excipients compatible with hard gelatin capsules

The materials listed have been tested according to the procedures described above. Excipients which, from the aspect of compatibility, can considered to be suitable for formulation of drugs into hard gelatin capsules, are shown in Tables 3 They have been classified into three arbitrary groups:

            • Lipophilic liquid vehicles

• Semi-solid lipophilic vehicles/viscosity modifiers for lipophilic liquid vehicles

• Solubilizing agents, surfactants, emulsifying agents and adsorption enhancers

Excipients shown in Table 4are 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.

 It appears that the incompatibility of the medium chain monoglycerides may be due to the presence of quantities of glycerol remaining from the synthesis of these products. If the MCM’s are to be considered the glycerol level must be < 5%.

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










Lipophilic liquid vehicles

Semi-solid lipophilic vehicles / Viscosity modifiers for lipophilic liquid vehicles

Solubilizing agents, surfactants,

emulsifying agents adsorption enhancers

Refined speciality oils

MCT’s(1) and related esters

Hydrogenated speciality oils

Capryol 90

Arachis oil

Akomed E

   Arachis oil: Groundnut 36

   Castor oil: Cutina HR

   Cottonseed oil: Sterotex

   Palm oil: Softisan 154

   Soybean oil: Akosol 407

Gelucire 44/14, 50/13

Castor oil

Akomed R

Cremophor RH 40

Cottonseed oil

Captex 355

Imwitor 191, 308(1), 380, 742, 780 K, 928, 988

Maize (corn) oil

Labrafac CC

Labrafil M 1944 CS, M 2125 CS

Olive oil

Labrafac PG

Lauroglycol 90

Sesame oil

Lauroglycol FCC


PEG MW > 4000

Soybean oil

Miglyol 810

Cetosteryl alcohol

Plurol Oleique CC 497

Sunflower oil

Miglyol 812

Cetyl alcohol

Poloxamer 124 and 188


Miglyol 829

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

Softigen 701, 767


Miglyol 840

Glyceryl behenate (Compritol 888 ATO)

Tagat TO


Softisan 645

Glyceryl palmitostearate (Precirol ATO 5)

Tween 80



Softisans 100, 142, 378, 649




Steryl alcohol



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.

(1) Medium chain triglycerides.


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.


(1) Glycerin content < 5%

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.

Tables 3 Excipients compatible with hard gelatin capsule shells


Table 4Considered to beincompatible with hard gelatin capsules and should be avoided at high concentrations.


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