Hard choice

Brian Jones from Shionogi Qualicaps highlights the advantages of using non-gelatine materials in capsules

Taking cold drinks to help down a capsule is not a good idea – not because of any adverse reaction with the drug, but because the cold reduces the dissolution rate of the gelatine from which the capsule is made.

The hard two-piece gelatine-based capsule has a long history, and during this time there have been many small changes made to improve its performance¹. Over the years much effort has been expended in looking for gelatine replacements, to improve either the efficiency of manufacturing process or capsule performance.

The three major pharmacopoeias, Ph Eur, JP and USP/USNF, already permit the use of suitable materials besides gelatine for capsule production. The problem is to find a suitable material that forms strong, flexible films by some sort of gelling process, which would allow the standard machines for gelatine to be used.

More recently, the development and use of modified celluloses for pharmaceutical applications has made available polymers with potentially suitable properties. Methylcellulose was used during the 1950s for capsule manufacture, but these capsules had poor in vivo performance. Since then other polymers with more suitable properties have been developed, such as hydroxypropyl methylcellulose (HPMC). However, HPMC solutions do not undergo a sol gel transformation in the same way as gelatine and thus it is more difficult to form a film rapidly on a stainless steel mould pin.

Two processes have been developed to overcome this problem. The first relies on the increase in HPMC solution viscosity with temperature, and GS Technologies has patented a process that involves significant machine modifications, heating the mould pins and dipping them into an HPMC solution, which is at room temperature². These capsules are thicker than standard gelatine capsules to give them sufficient mechanical strength to withstand handling. The second involves adding a gelation aid, carrageenan, and a promoter, potassium chloride, into the HPMC solution so that it undergoes a gelling process similar to gelatine. Shionogi Qualicaps first patented this in the early 1990s^3,4. These Quali-V capsules are produced on standard machines and have the same dimensional specifications as gelatine ones.

inherent differences

Like conventional capsules, HPMC two-piece capsules made by this latter technique can be processed on high-speed filling and packaging machines. The differences in their properties are due to the inherent difference between gelatine and HPMC films. HPMC films are less lustrous than gelatine and the capsules appear to have a matt rather than a gloss surface. HPMC films are less permeable to water vapour than gelatine and water does not act as a plasticiser for the film as it does for gelatine.

general properties

Ogura et al have described the general properties of these HPMC capsules⁵. They demonstrated that they retained their strength and flexibility even when dried down to moisture contents of less than 1%, showing that HPMC could be used for labile compounds by reducing the moisture content or used with hygroscopic formulation without risk of embrittlement. This is important when considering blister packaging of products because HPMC capsules can be pushed through the film without breaking even after storage under conditions that make gelatine capsules brittle.

The difference in water vapour permeability influences the way in which the capsules release their contents. The process by which capsules dissolve is the same for both polymers (see figure 1). Water first penetrates through the shell wall, the polymer hydrates and swells, starts to dissolve, and the shell splits at its weakest point, which is normally the base of the hemisphere, at each end. Dissolution of the shell continues and the last part to dissolve is the overlap between the cap and body because of the film thickness.

comparative tests

For HPMC capsules it takes longer for the water to penetrate through the walls and thus the time for the first split is longer than for gelatine. Chiwele et al compared the dissolution of gelatine and HPMC capsules by measuring the time for a ball bearing to drop from the body of a capsule suspended in a liquid (see figure 2)⁶. They carried this out over a range of temperatures from 10-55°C. HPMC capsules were not influenced by the temperature, whereas the solubility of gelatine capsules was significantly more rapid at temperatures above 28°C. Below this value gelatine capsules are insoluble.

The significance of this finding could be that in those countries where they drink lots of iced beverages consumers should not use them in order to help swallow their gelatine capsules. Podczeck and Jones⁷ studied the effect of this finding on the dissolution of a model compound, theophylline, from capsules. They found that although it took longer for dissolution to start, after 15-20 minutes there was no significant difference in the amount released (see figure 3). This they attributed to the more rapid dispersion HPMC capsule shell after the initial split.

One of the problems that have affected gelatine capsules in the last decade has been the problem of 'cross-linking'. This is the phenomenon of a decrease in in vitro capsule solubility after accelerated storage testing.

Nagata et al, in a poster shown at the last AAPS conference in Denver, compared the changes in dissolution rate of two model compounds, acetaminophen and pyridoxine hydrochloride, filled into HPMC and gelatine capsules and stored under different conditions⁸.

All trials met compendial requirements initially. They compared standard accelerated storage conditions of 40°C and 75% RH for six months, with 30°C and 60% RH for one year and 60°C for one week. In the HPMC capsules there was no significant change from the initial values under any storage condition.

In the gelatine capsules there was a significant reduction in dissolution under accelerated conditions but not at 30°C and 60% relative humidity. There was a significant difference between the two compounds at 60°C for one week, which was related to the radical scavenging activity (RSA) of the compounds.

These results agreed with a proposed mechanism for cross-linking initiated by peroxide radicals. Acetaminophen, which had the higher RSA value, showed the smallest change in dissolution rate. In further experiments with HPMC capsules from three different manufacturers, only Quali-V capsules released acetaminophen satisfactorily when tested in three standard dissolution media.