Hard capsules have traditionally been used for most of the initial phases for the development of new active entities (NCE) because of the ease with which small quantities can be filled, the ability to accommodate a range of doses in a single capsule, and the masking effects of the shell for double blind trials.
Often after the development stage the dosage form was switched to tablets due to their perceived advantages in large-scale production. In early regulatory times this was a comparatively simple step. However, the regulatory climate has changed significantly and if such changes are made now, extensive testing is required to justify the change. This extensive testing considerably adds to the development time, and when combined with quality and risk assessments to the process, there has been a change in how decisions are made in selecting the form for solid oral dosage forms.
In the past, hard capsules were hindered by their simplicity of use, which led them to be considered a non-serious dosage form. Another contributory factor has been the lack of academic studies for capsules compared to tablets because capsule use is restricted to pharmaceuticals and nutraceuticals. Tablets are used in many industries, so there is a large science base to draw upon. The situation described has changed and the under-valued hard capsule now has an important part to play in getting products to market as quickly as possible.
Animals, mainly small rodents, are used in pre-clinical toxicological studies. The challenge is to dose the animals with a quantity adjusted to their weight. A special small capsule, size 9 with a fill volume of 0.05 mL, was developed by Elanco Qualicaps in the 1980s for this purpose. There are special devices for administration, which assures that the dose material is delivered into the animal’s stomach.
Early phase safety and proof-of-concept studies face a similar challenge in requiring a variable dose of active. In the past, capsules were filled manually in a very labor intensive process. Automatic machines are now available that can dose capsules gravimetrically with the active from quantities of 50 micrograms upward. These machines have software that monitors fill weights and continuously adjusts the machine to meet the target, thus taking the tedium out of the activity and making it an efficient process.
The next phases of development require a formulated product that can be manufactured. There are two schools of thought on how to do this. The quickest is by developing a formulation that will work on the small-scale, realizing that further work will have to be done on the formulation later to produce a commercial product. The other slightly longer process is to spend more time at this stage and develop a commercial formulation. This second formulation method would then gain time on the first later on in the development cycle as it would require no further large-scale effort.
The formulation of standard release capsules is a simple exercise and can be performed on small quantities of material because the capsule filling process remains the same on machines of all different outputs. Increases are achieved by using multiple dosing devices. On tabletting machines, higher outputs are achieved by operating the machines faster, resulting in a significantly shorter time that the maximum compression force is applied. If there are any time-dependent factors in the compaction, the tablets will be different from those made on the small-scale.
Capsule powder mixtures can be made and assessed on the small-scale by using tapped bulk density testers to optimize glide levels and powder plug devices, such as the H&K rig by Bosch, which can make powder plugs with similar properties to those made on large-scale machines. These powder plugs can be used for assessing lubricant levels and dissolution testing. Automatic filling machines are manufactured in a range of outputs, from bench-top to full scale-production, sufficient to meet the requirements of most potential users. Scale-up to larger machines is not a problem because these have larger powder dosing hoppers. As a result, powders flow more easily than in those on smaller machines, thus giving confidence to R&D people that their formulations will work well on the large-scale.
The highest output capsule filling machines produce 200,000/hour. Tablet machines have speeds in excess of 1,000,000/hour and this number often is used to compare capsules unfavorably with tablets. However, what is often forgotten in comparing these numbers is that the second one only represents part of the process. The majority of tablets are coated and thus there is a further process step, which involves a significant amount of labor, space and utilities. The extra steps involved in the process also increase quality risks. It has been demonstrated that if all the processes involved in making tablet and capsule products are compared, the costs are less for hard capsules.
Current Formulation Trends
Currently, the trends in formulation are to make products with special release characteristics that may be required because of the poor solubility of the active or to deliver the active to specific sites in the body. In this instance the hard capsule has significant advantages over the other oral dosage forms because they can be filled with formulations with a wide range of properties, including powders, liquids, pellets and other solid oral dosage forms. Thus they provide the formulator with a wide-range of options to meet the challenges of the newer NCEs with very low aqueous solubility. Filling machines are available that can handle these products and with the use of more than one dosing head, are able to fill combinations of formulations into each capsule, extending the formulator’s options.
In the last decade liquid-fill formulations have become more popular because of their ability to overcome the challenges posed by handling very potent actives and in the development of formulations that are able to take NCEs across the gut wall barrier. Handling liquid formulations that are mobile at ambient temperatures requires the capsules are sealed after filling. Qualicaps was one of the first in this field when in the mid-1980s they introduced high-speed band-sealing machines capable of making liquid-tight seals. Sealing machines are available for all scales, including bench-top, lab-scale and full production. These have been in extensive use because the band has a secondary function of being a tamper-evident seal.
The hard capsule shell has also been improved to better meet the needs of users. Gelatin has been the main polymer used since capsules were first made in the 19th century. It is an excellent film-forming material but has some draw backs: high moisture content, brittleness when dried, under goes cross-linking reactions at elevated storage conditions and is of animal origin. The 1990s saw the launch of capsules made from hypromellose, which overcome these drawbacks. However, to convert solutions of this material into a form in which they could be used on standard gelatin capsule filling machines it is necessary to modify them in some way either by using gelling additives or by extensive machine modification to reverse the process from a cold mold dip/warm solution to a hot mold dip/cold solution. The pharmaceutical grade hypromellose capsule with the longest history of usage is Qualicaps' Quali-V®, which uses a carrageenan/potassium chloride gelling system.
The hard gelatin capsule offers companies the means of producing marketable products of NCEs in the shortest period of time. This is due to their relative simplicity of formulation and the machine filling process.