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HGC are physically incompatible with some of the lower molecular weight solubilizing excipients such as polyethylene glycol (PEG) 400, ethanol, water, and glycerol at concentrations greater than a few percent as higher concentrations of these excipients can result in capsule brittleness or softening (22).

The aqueous dissolution rate of HGC is temperature dependent, requiring a minimum of 35°C to occur at an appreciable rate. The dissolution profile of HGC drug products are also subject to change upon aging, particularly following exposure to a combination of elevated heat and humidity (23), certain chemicals (24), or trace levels of volatile substances contained in various packaging components (25,26). The chemical compatibility of the formulation with the capsule shell may be assessed, by dissolution testing following storage of the encapsulated formulation, placebo, and empty capsule shells for approximately one to two months under conditions of elevated temperature and humidity (50°C, 25°C/60%/RH, and 40°C/75% RH). A formulation that is incompatible with the capsule shell may show evidence of changes in appearance, physical integrity, and in vitro dissolution profile. It is helpful to videotape or photograph the dissolution process and scrutinize the visual appearance of the capsule shell as it dissolves. Careful observation of the difference between a poorly dissolving capsule shell containing formulation versus placepo and empty capsule shell stored under the same environmental conditions, may provide insight into whether the formulation or the storage condition has impaired dissolution.

Decreases in the in vitro dissolution performance are often attributed to "gelatin crosslinking," although physicochemical evidence of crosslinking may be difficult to provide. Despite this deficiency, the terms "internal" and "external" crosslinking are frequently used to describe the subjective visual appearance of an insoluble pellicle. Internal crosslinking describes the situation, where the inner surface of the dissolving capsule shell appears to be less soluble than the outer surface, suggesting incompatibility between gelatin and formulation. Changes in capsule dissolution that appear to originate on the external surface of the capsule shell may suggest that environmental factors (e.g., excessive heat, humidity, or exposure to packaging components) are responsible for the change. Interaction between the formulation and capsule gelatin can be confirmed by replacing the capsule contents with a rapidly dissolving formulation and repeating the dissolution test; an altered dissolution profile is confirmatory of this type of interaction (27). Alternatively, empty capsules that were stored for equivalent time periods under identical conditions of temperature and humidity can be used for this test.

The water content of a HGC is critical for maintaining gelatin plasticity and overall capsule shell integrity, and must be kept within a narrow range (13-16% w/w). Inadequate control of HGC moisture content during processing can result in capsule swelling, shrinkage, turned edges, or accumulation of a static charge, all of which can lead to compromised handling on automated filling and sealing equipment and result in batch failures. These deficiencies may go unnoticed during hand-filling of small test batches and can lead a formulator to incorrectly conclude that problems encountered during scale-up are due to a faulty formulation or improper set-up of processing equipment. Hence, it is wise to confirm that the initial moisture content of the HGC shell is within the limits specified by the manufacturer and is maintained within that range during every step of product manufacture and packaging.

Capsule shell moisture content can be estimated by comparing the average weight of a sample of empty capsules to the acceptance range supplied by the manufacturer or by assessing the weight loss on drying at 105°C for 17 hours

(28). A useful, shorter screening test may be developed by correlating the 17-hour "loss on drying" results with those generated at slightly elevated temperatures

(29) (between 105°C and 120°C) for shorter time periods (e.g., 5-10 minutes) using a gravimetric analyzer such as the Computrac® 2000 (Arizona Instruments, Phoenix, Arizona, U.S.A.). The relationship between HGC brittleness and moisture content is shown in Figure 1 (30). These data were generated by spreading 100 capsules on a 4-inch diameter circular sample test pan, which was subsequently compressed with a platen and held at 1500 psi for 5 to 15 seconds. The number of capsules broken under these conditions represents the percent brittleness of the sample. Empty capsule shells that have remained outside of controlled environmental conditions (between 68°F and 77°F, and 40% and 60% RH), either in the laboratory or in the manufacturing environment, should be discarded prior to resumption of filling operations. During manufacturing operations, empty capsule shells should not remain in the hopper overnight, during lunch breaks, or over other extended periods of work stoppage.

Since excipients can also significantly influence capsule moisture content and physical integrity, formulations need to be selected with regard to their relative humectant properties. Hygroscopic materials such as glycerol, low molecular weight polyethylene glycols (<1000 molecular weight), and propylene glycol are generally unsuitable for HGC products in appreciable levels since they tend to draw

Figure 1 Relationship between hard gelatin capsule shell moisture content and capsule brittleness.

moisture into the capsule shell from humid environments, leading to capsule softening. Conversely, under conditions of low environmental humidity, these excipients can dehydrate the capsule shell leading to brittleness. A variety of simple screening tests can be performed during formulation development to evaluate the moisture affinity profiles of various excipients and their respective compatibilities with the HGC shell (31). One method that requires relatively long periods of time (several weeks), involves evaluating differences in weight gain or loss between small groups or 10 to 20 filled or empty control capsule shells stored under a range of humidity conditions (2.5-65%). Those formulations that maintain their weight within a range of ±2%, relative to the empty capsule control, are considered to be hygroscopically compatible with the capsule.

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