From a pharmaceutical manufacturing point of view, there is some disadvantage in the fact that output rates (e.g., capsules/hr) of even the fastest automatic capsule-filling machines are substantially slower than the rates at which modern high-speed production tablet presses can produce tablets, which is a factor that adds to the cost of capsule production. Another factor is the cost of the shells. Although hard-shell capsule products may thus tend to be more costly to produce than tablets, the relative cost-effectiveness of capsules and tablets must be judged on a case-by-case basis. This cost disadvantage diminishes as the cost of the active ingredient increases or when the tablets must be coated (19). Furthermore, it may be possible to avoid the cost of a granulation step by choosing encapsulation in lieu of tableting.

Highly soluble salts (e.g., iodides, bromides, chlorides) generally should not be dispensed in hard capsules. Their rapid release may cause gastric irritation because of the formation of a high drug concentration in localized areas. A somewhat related concern is that hard-gelatin capsules may become lodged in the esophagus where the resulting localized high concentration of certain drugs (doxycycline, potassium chloride, indomethacin, and others) may cause damage (20). Marvola (20) measured the force required to detach various dosage forms from isolated pig esophagus mounted in an organ bath and found that gelatin capsules tended to adhere more strongly than tablets. However, the detachment forces were greatly reduced for both after a water rinse (to simulate drinking) and when there was a slow continuous flow of artificial saliva. In an in vivo study, Hey et al. (21) studied the esophageal transit of barium sulfate tablets and gelatin capsules radiologically in 121 healthy volunteers. The subjects' position (standing or lying down) and the volume of water taken (25 or 100 mL) during swallowing were considered. The majority (60%) of the volunteers had some difficulty in swallowing one or more of the preparations: Many preparations were shown to adhere to the esophagus and to begin to disintegrate in the lower part of the esophagus. Delayed transit time occurred more frequently with large round tablets than with small tablets or capsules. In contrast to tablets, patient position or the volume of water taken had less influence on the passage of capsules. Despite their findings, Hey et al. did not prefer capsules because of their potential for esophageal adhesion. In general, it was recommended that patients should remain standing 90 seconds or more after taking tablets or capsules and that they should be swallowed with at least 100 mL water. In a study considering only the esophageal transit of barium sulfate-filled hard-gelatin capsules, Channer and Virjee (22) found that 26 of 50 patients exhibited sticking; however, only three of these patients were aware that a capsule had lodged in their esophagus. These investigators also concluded that drugs should be taken with a drink while standing. Evans and Roberts (23) compared barium sulfate tablets and capsules and found a greater tendency for esophageal retention with tablets than with capsules. Fell (24) pointed to the large difference in density between barium sulfate and typical pharmaceutical preparations as a complicating factor in drawing conclusions about any differences in esophageal retention between tablets and capsules from such studies.

Few studies have compared the mucosal adhesion of HPMC and gelatin hard-shell capsules. In an in vitro study, Ponchel and Degobert (25) compared the force required to detach gelatin and HPMC hard-shell capsules from isolated porcine esophageal mucosa. They found that the adhesiveness of the two types of capsules was comparable. But later a similar study revealed that the force required to detach HPMC capsules was significantly lower (p < 0.001) than that for gelatin capsules (26). On the basis of scintigraphic evidence gathered in a study of esophageal transit involving 11 human volunteers, Cole et al. (7) questioned the relevance of isolated tissue studies. They found the esophageal transit of HPMC and gelatin capsules to be quite rapid (<20 sec) in most cases, with no significant difference between the two types of capsules.

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