1. Size

Difficulty swallowing tablets and capsules can be a problem for many individuals and can lead to a variety of adverse events and patient noncompliance with treatment regimens. It is estimated that over 16 million people in the United States have some difficulty swallowing, also known as dysphagia. For these individuals, swallowing a tablet or a capsule can be particularly challenging. A survey of adults on difficulties swallowing tablets and capsules suggests that this problem goes well beyond the patient population with clinically recognized dysphagia and may affect as many as 40 percent of Americans. Of those who experience difficulty swallowing medications, less than a quarter discuss the problem with a healthcare professional, 8 percent admit to skipping a dose of prescribed medication, and 4 percent have discontinued therapy because the tablets and/or capsules were difficult to swallow. Individuals who find it difficult to swallow tablets and capsules frequently cite the size as the main reason for the difficulty in swallowing.

Size and shape of tablets and capsules affect the transit of the product through the pharynx and esophagus and may directly affect a patient's ability to swallow a particular drug product. Larger tablets and capsules have been shown to have a prolonged esophageal transit time. This can lead to disintegration of the product in the esophagus and/or cause injury to the esophagus, resulting in pain and localized esophagitis and the potential for serious sequelae including ulceration, stricture, and perforation. Other adverse events such as pain, gagging, choking, and aspiration are related to swallowing difficulties in the oropharyngeal phase of swallowing and increasingly occur at larger tablet and capsule sizes.

Studies in adults evaluating the effect of tablet and capsule size on ease of swallowing suggest that increases in size are associated with increases in patient complaints related to swallowing difficulties at tablet sizes greater than approximately 8 mm in diameter. The size of the tablet or capsule influences esophageal transit, irrespective of patient factors and administration techniques (i.e., use of fluids, patient position). Smaller tablets generally have been shown to have significantly faster transit times in these studies. Channer and Virjee specifically compared the transit time of 8-mm diameter round tablets to 11-mm diameter round tablets and 14-mm x 9 82-mm oval tablets and found the transit times for the 8-mm round tablet to be significantly shorter than for 11-mm round and 14-mm x 9-mm oval tablets (P<.02 and P<.04, respectively). In addition, significantly more patients were aware of the larger round tablets (>8 mm) sticking in the esophagus compared with the 8-mm round tablets. Although there has been less research quantifying the effects of size difference on the oropharyngeal phase of swallowing, increasing tablet or capsule size is believed to correlate with increasing difficulty with oropharyngeal transfer.

2. Shape

For any given size, certain shapes may be easier to swallow than others. In vitro studies suggest that flat tablets have greater adherence to the esophagus than capsule-shaped tablets. Studies in humans have also suggested that oval tablets may be easier to swallow and have faster esophageal transit times than round tablets of the same weight. Patient compliance with medication regimens may be influenced by the size and shape of a tablet or capsule.

3. Patient Factors

The Agency recognizes that a variety of other factors may affect a patient's ability to swallow a tablet or a capsule. For example, age could be a factor. Children and adolescents, as well as the elderly, are more likely to have difficulty swallowing tablets or capsules. Body position, fluid intake, and the presence of certain medical conditions (e.g., multiple sclerosis, muscular dystrophy, Parkinson's disease) may also affect a patient's ability to swallow tablets and capsules.

Although not all patient factors can be addressed through pharmaceutical design and manufacture, the physical characteristics of a product can be addressed. These physical characteristics influence the ability of certain patients to swallow the product, particularly in vulnerable populations. We believe that tablets and capsules can be effectively developed and manufactured to minimize swallowing difficulties, which can encourage and improve patient compliance with medication regimens. FDA recommends that applicants design and develop generic drugs with this in mind.

The presence and composition of a coating can also potentially affect the ease of swallowing tablets or capsules. The lack of a film coating can decrease or prevent tablet mobility compared with a coated tablet of the same size and shape. Coating also can affect other factors that contribute to patient acceptance, such as palatability and smell.

The weight of the tablet or capsule also may affect transit time, with heavier tablets or capsules having faster transit times compared to similarly-sized, lighter tablets or capsules. Surface area, disintegration time, and propensity for swelling when swallowed are additional parameters that can influence esophageal transit time and have the potential to affect the performance of the drug product for its intended use. These physical attributes should also be considered when developing a QTPP for generic drug products intended to be swallowed intact.