Delivery of liquid formulations by fills in hard two piece capsules

With changing trends in the pharmaceutical industry, encapsulation technology has undergone a major change in the recent past. The challenge of the encapsulation technology is no longer restricted to solid formulations but has also extended to simple liquid and highly viscous semi-solid formulations. Liquid fill hard capsule technology is being increasingly accepted by the pharma industry and is expected to replace more conventional dosage forms such as tablets and powder-filled capsules. Dr Jnanadeva Bhat and Dr Surya N Singh, give an insight

The word ‘Capsule’ is derived from the Latin word ‘Capsula’, which means a small box or a container. Gelatin capsules were invented in the early 19th century. The hard gelatin capsule has historically been used as a dosage form for pharmaceutical and nutraceutical products that are formulated as powders or pellets. Liquid fill hard gelatin capsule technology was established in the early 1980s as an alternative to soft gelatin capsules. The technology offered a number of specific advantages such as lower moisture and gas transmission, permitting the use of high melting point excipients, freedom from plasticisers and preservatives, lower moisture content, ease of coating and choice of capsule composition (gelatin and hydroxypropylmethylcellulose, HPMC) (1-3).

Until recently, soft gelatin capsule was the only dosage form available to encapsulate liquid and poorly water-soluble drug formulations in liquid vehicles (4). For example, liquids like simple oils, semi-solids, suspensions, microemulsions, and nanosuspensions are major products, which are filled in soft gelatin capsules. To keep pace with the changing trends, ACG has introduced liquid filling and band sealing technology solutions. This technology enables the use of hard capsules (hard gelatin capsules or HPMC capsules) as an alternate dosage form to soft gelatin capsules for filling liquid/semi-solid formulations. This not only makes the encapsulation process easy and cost-effective but also eliminates numerous manufacturing and stability concerns associated with soft gelatin capsules.

After liquid filling, hard capsules would need to be band sealed in most of the cases.(5) Therefore, one has to make use of a stand-alone band sealing machine. The output of the automatic liquid filling machine is maximum 40,000 capsules/ hour and corresponding band sealing machine with 70,000 capsules/ hour output. Both the liquid filling and band sealing machines are available in R&D model as well as in production model. Both the machines are designed as per GMP standards.

Importance of hard liquid encapsulation technology

Technological perspective

This technology has advantages over the soft gelatin capsule such as in-house development and manufacturing, small batch production, scale up and combination filling. This technology can make a significant contribution to the overall development of efficacious pharma products.

Pharma perspective

This technology provides flexibility to the pharma formulation scientist for rapid development of new formulations and processes, which can be easily scaled up. The process is easy to handle with no containment of dust in and around the processing area as observed in conventional tablet and powder fill capsule processes. For example, this technology has been used for conversion of non-micronised form of Piroxicam to solubilised oily liquid formulation in hard capsule. Piroxicam is available in liquid form. It is believed that the liquid form has better absorption (with immediate onset of action) in comparison with the commercially available powder filled  capsules. Therefore, liquid filled capsules could be developed more cost-effectively with better quality and quantity. After the successful formulation of piroxicam as liquid-filled capsules, a combined formulation of Piroxicam and Rabeprazole was also developed using this technology.

Commercial perspective

First, band sealing renders the capsule tamper-proof, preventing counterfeiting in the marketplace. Second, as can be seen from the example of Piroxicam liquid filled capsules, the process required lesser steps during development and manufacturing. This ultimately led to a shorter time to market. Further, the combined formulation of Piroxicam and Rabeprazole is very helpful with respect to patient compliance as it is available as a single formulation for treating both ulcer and rheumatoid arthritis.

Comparison of hard capsules over the soft gelatin capsules

In case of hard capsules manufacturing process, pre-fabricated two piece empty hard gelatin/ HPMC capsules are used for encapsulation process. Whereas, in case of soft gelatin capsule process, the capsule shell formation and encapsulation take place simultaneously. The moisture content of the gelatin ribbon at this stage is around 30 per cent to 50 per cent and, the equilibrium moisture content is achieved only after several hours of drying and can stretch up to several days based on the formulation. During this period, migration and degradation can occur for few molecules either due to the presence of plasticiser in the shell or due to the higher moisture content in the shell before reaching equilibrium moisture content.

In contrast to hard capsule, the soft gelatin capsule contains a plasticiser (usually glycerol in approximately 15 per cent-30 per cent level) in addition to gelatin and water. As a result, the moisture uptake of soft gelatin capsules is considerably higher than that of hard capsules due to hygroscopic nature of glycerol. Another disadvantage in the usage of the plasticiser is that it aggravates migration of a drug from fill to shell, which ultimately results in chemical instability due to drug loss and degradation.

Advantages of hard capsules over the soft gelatin capsules

Oxygen transmission/ permeability rate

The oxygen transmission/ permeability rate of a soft gelatin capsule is proportional to the level of glycerol in the film and moisture content. As a hard capsule contains no plasticiser, the permeability of capsule wall is lower than that of the wall of a soft gelatin capsule. As a result, hard capsules containing even highly odorous products like fish oil, valerian oil, and garlic oil can be rendered odorless.

Dark spot

The dark spot on the soft gel capsule is an inherent problem, which occurs due to the basic nature of the encapsulation operation. This poor aesthetic issue of the drug product is a cause of worry for most of the brand owners. This problem is completely eliminated when the liquid formulation is encapsulated in hard capsules and band sealed. Moreover, it adds to the aesthetics of the product, offering a flexibility of colour and type of pre-printed capsule.

Contract manufacturers

The soft gelatin encapsulation process is usually outsourced to contract manufacturers due to the complexities of the process. Pharma companies rarely get involved in this operation. This means that from an early stage development, all activities must be contracted out. Many companies would prefer to keep these activities in-house for reasons of confidentiality, control over the development process, availability of drug substance at the early stage development trials and control over cost and quality. This is possible by adopting the new concept of liquid filling in hard capsules and band sealing.

In-house formulations

This technology can make a significant contribution to the overall development of efficacious pharma products. This technology provides the flexibility to rapidly develop and test in-house formulations when only small quantities of drug substance are available at initial pre-formulation and lab scale development stage. The process can be scaled up and also kept in-house similar to the operations of tableting or powder/ pellet filling of hard gelatin capsules.

The added advantage of this technology is extended to the very beginning of the development stage. New concepts can be evaluated for feasibility studies in an R&D lab without the involvement of in any machinery. The concept can be tried by filling capsules with a syringe and banding manually with the minimum amount of formulation. This is especially useful when the availability of API is restricted, or the API is available in small quantities, or the cost of API is exorbitantly high.

Development advantage of liquid filled hard capsules over soft gelatin capsules

Conventionally, the hard gelatin capsule has been used as a solid dosage form product, formulated either as powder or pellets. However, the market demands new and different ways of formulation to be developed and launched as quickly as possible. Liquids filled hard capsules can fulfil some of these demands. This is especially true for drugs, which are inherently liquid or semi-solid. This new concept can bring down the overall development time and, thereby, time to market.

Low melting point

Materials that have low melting points or are liquid at room temperature present difficulties when formulating as dry powders or tablet dosage form and often require high concentrations of excipients to avoid processing problems. The manufacturing process can be considerably simplified (five-step process to manufacture a tablet can be reduced to a simple mixing and filling operation) by filling as a hot melt into a hard capsule. Consumer acceptance is also enhanced due to the smaller size of the final dosage form. Products such as Validol tablets are made into solid dosage form by converting 60mg/100mg of liquid (Validol) with the addition of colloidal anhydrous silica (Aerosil 200) as a diluent or adsorbent, which can be directly filled in a hard capsule without any excipients.

Low dose/ high potency

Drugs in this category present two major challenges: achieving acceptable content uniformity and how to control cross-contamination and personnel protection. Invariably in a true solution format, the content uniformity is not a major concern. Further, owing to lesser/ no dust formation, the chances of cross-contamination are reduced considerably.

The liquid filling operation is capable of achieving fill weight variations of < 1%, especially if the drug product is in the form of true solution, microemulsion or uniformly dispersed stable suspension or nanosuspension in an oily vehicle. This contributes to the content uniformity of the finished dosage form in both fill-in hopper and in the encapsulated capsules due to volumetric filling principle (e.g.: Triamterene 25µg).

Companies manufacturing solid dosage forms of hormones and cytotoxic agents from powders are forced to install extremely elaborate systems (isolators) to reduce contamination. Incorporation of the highly potent drug substance into a liquid vehicle for filling into a hard capsule can reduce the dangers during handling such drug

Poor bioavailability

The bioavailability of the poorly water-soluble drug, such as Digoxin, could be significantly enhanced when formulated as a liquid in a hard capsule. This increases the effectiveness and efficacy of the drug.


Sensitivity to moisture is an aspect of drug substance and drug formulation, which can be minimised by incorporating the drug into either a hydrophilic or lipophilic matrix. For example, the Macrolid antibiotic, Vancomycin Hydrochloride, is a highly unstable molecule. To achieve acceptable stability, it requires to be formulated as a hot melt with a solid PEG matrix and filled in hard capsules.

Sustained release

By choosing appropriate excipients, the release property of a drug product 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 release profiles.

1. Bowtle W, Materials, process and manufacturing considerations for lipid-based hard-capsule formats, Lipid-based formulations for oral drug delivery, Ed: D Hauss, Informa Healthcare, New York: pp 79-106, 2007.
2. Cole ET, Challenges and opportunities in the encapsulation of liquid and semi-solid formulations into gelatin and non-gelatin capsules, Effective utilisation of lipid-based systems to enhance the delivery of poorly soluble drugs: physicochemical, biopharmaceutical and product development considerations, AAPS Workshop, Bethesda, 2007.
3. Rowley G, Filling of liquids and semi-solids into hard two-piece capsules, Pharmaceutical capsules, F Podczeck and BE Jones (eds), Pharmaceutical Press, London, 2nd edition, 9: pp 169-194, 2004
4. Brox W, Zande H, Meinzer A. Soft gelatin capsule manufacture. EP 1993: 0 649- 651.
5. Cade et al., Liquid filled and sealed hard gelatin capsules, Acta Pharm Technol 33 (2), 1987, 97-100.