Figure 2.1Capsule shells being formed on mold pins.
Figure 2.2Dried capsule shells on mold pins just before removal.
After formation, the capsule shells can be printed to improve identification. Printing can be achieved using one or two colors, containing information such as the following:
Product name or code number
Manufacturer’s name or logo
Dosage details
Printing reduces the risk of product confusion by the numerous handlers and users of the product including manufacturers, pharmacists, nurses, doctors, caregivers, and patients. Capsule printing will be further covered in a later section.
Quality Control
The capsule manufacturing process is carried out according to Good Manufacturing Practices during all phases of production from gelatin preparation through printing and packaging. A large number of quality control tests are conducted at each stage to ensure that the finished product meets all specifications.
In the raw material stage, gelatin is tested for Bloom strength (gelling properties), viscosity, solubility, pH value, chemical purity, heavy metals, and microbial count. Water is tested for electrolyte content, pH value, and microbial count. Coloring agents are tested for identity, solubility, heavy metals, and microbial count. The final gelatin solution is tested for viscosity, temperature, color composition, and color shade. Finished capsules are tested for capsule characteristics including water content, shell wall thickness, cap and body length, open and closed shell length, ovality, separation force, color shade, and print quality/defects.
Modern capsule manufacturing processes yield capsules with highly consistent critical quality attributes including weight, length, and shell wall thickness. Studies have demonstrated that the hard capsule is a suitable excipient for QbD drug development and manufacturing with acceptable variability within a consistent and narrow range, and is well defined by its specifications.
Capsule Materials
Gelatin
Gelatin is by far the most common and most well-known material used to produce two-piece hard capsules. Its origin has been previously described.9 Gelatin has a long history of safety and possesses excellent performance characteristics, making it an excellent polymer for producing capsules. It is nontoxic, widely used in foods, acceptable for use worldwide, and recognized in all pharmaceutical pharmacopeia.
Hypromellose
Alternatives have been investigated to gelatin either for reasons of stability or objections to animal-derived materials.10,11 The most common gelatin alternative is HPMC, which has been extensively studied and successfully developed into two-piece capsules for use in the pharmaceutical and nutritional industries. Important benefits of HPMC include a water content of approximately 4–7% as compared to gelatin capsules, which are typically in the range of 13–16%. This makes HPMC capsules an excellent container for water-sensitive drugs; as a result, they are also less prone to brittleness owing to drying. However, capsules made with HPMC have a higher gas permeation rate than those from gelatin, which may be a consideration for oxygen-sensitive compounds.
HPMC is a cellulose ether of vegetable origin and therefore answers the need for religious, cultural, and dietary restrictions. HPMC capsules are available from most capsule suppliers, but unlike gelatin capsules, HPMC capsules may differ somewhat among suppliers. Consequently, these capsules may not be readily interchangeable between suppliers and it is therefore important for the formulator to fully understand the composition of the capsule being procured. The following description will lead to a fuller understanding of this issue.
HPMC capsules are molded according to a steel pin dipping process as described above for gelatin capsules. However, the solution preparation and film formation will vary depending on the manufacturer. To produce gelatin capsules, steel pins at room temperature are dipped into a hot gelatin solution. This approach may also be used for HPMC capsules; however, doing so requires the addition of a gelling aid. Common gelling agents include gellan gum and various types of carrageenan. Each of these gelling agents imparts unique performance characteristics that may affect capsule dissolution.
An alternative approach is to dip hot steel pins into a room temperature solution of HPMC solution, thus eliminating the need for a gelling agent. The value of this approach is a reported improvement in capsule dissolution. Each approach, hot steel pin or gelling agent, has its advantages and disadvantages that may affect the rate of dissolution as well as capsule dimensions. It then becomes clear that supplier interchangeability is not as simple as for gelatin capsules. Switching among suppliers will likely require additional manufacturing trials and stability studies and may affect any regulatory documents.
Capsule Shell Features (Capsule Design)
Hard capsules are designed not only to contain pharmaceutical and nutritional formulations but also to withstand the rigors of handling on high-speed filling machines, packaging, and shipping. The filling machine process involves feeding of capsules into the machine, rectification, separation of cap and body, filling, closing of cap and body, and ejection. These steps may occur at rates in excess of 200,000 capsules per hour, making the design and integrity of the capsule of paramount importance. Figure 2.3 shows the operational steps of a capsule filling machine.
Figure 2.3The basic operational steps of all capsule filling machines.
Capsule designs are often patented by their respective manufacturers, the net result being a capsule sufficiently robust for all phases of handling. Figure 2.4 shows a capsule design containing a prelocking feature, a locking mechanism, air venting, and an alignment feature on the body. The following will discuss each of these features to fully understand their function.2,12
Figure 2.4Capsugel Coni-Snap® Capsule: (1) dimples maintain body and cap in pre-joined position; (2) rings lock cap and body together after closing; (3) vents allow air to escape during closing; (4) tapered rim provides additional closing tolerance.
Capsules were originally produced as simple caps and bodies with no additional locking features or design elements to support filling at commercial scale. However, with the advent of high-speed filling machines, it quickly became apparent that this design was inadequate to meet the needs of the industry. One common problem was the ease with which cap and body would separate after filling and during shipping. After some study, it was discovered that this was often attributed to air entrapment in the capsule during the filling process, thus creating sufficient internal pressure to cause separation of the cap and body. To remedy this problem, matching lock-rings were introduced onto the cap and body to assure a tight closure. There are multiple methods for achieving this, and these vary by manufacturer, but all perform the same function of locking the cap and body together. As capsule filling became ever more efficient and faster, the lock-rings alone were often not sufficient to withstand internal forces. To further improve the capsule design, air vents were introduced onto the body. These allow air to escape at the closing station and thus eliminate a common cause of cap–body separation.
As described earlier, after the molding step, the cap and body are joined together for packaging and shipping. The separation of caps and bodies during shipping and handling was initially a common occurrence. Unfortunately, shipping capsules in the fully closed or locked position is not feasible as this requires excessive separation force on the filling machine, which results in capsule damage. To address this challenge, indentations are molded into the cap that provides a firmer fit known as the prelock force. The placement, depth, and number of indentations are optimized to assure that the cap and body are sufficiently held in place during shipping and handling but not so much so that separation on the filling machine is difficult. As with the other capsule features, the various manufacturers offer different approaches to address this challenge.
An alignment feature on the body was another productivity enhancement made to the original capsule design. Similar to the other design features, an alignment feature was introduced in response to the demands of high-speed filling machines. Previously, even slight variances in lateral cap–body alignment would cause improper closing, resulting in split and deformed capsules. The alignment feature provides for additional tolerance during this operational step. Unique approaches have been taken by various manufacturers to enhance closing variance. These include tapered body rims that increase variance or circular grooves indented into the body near the end to maintain circularity. Of course, proper filling machine setup is still critical to ensure an efficient and smooth filling operation.
Capsule Sizes
Capsule sizes are designated numerically from sizes 000 to 5, with 000 being the largest size and 5 being the smallest. Table 2.1 lists commonly available capsule sizes and their respective fill capacities based on tapped density.12 Determination of the optimal capsule size for a given product is straightforward. First, determine the density of the formulation using tapped density for powders and bulk density for pellets, minitablets, and granules. Refer to a capsule volume chart such as Table 2.1; this type of information is available from the capsule supplier.12 The appropriate capsule size may then be calculated using the measured density of the formulation, the target fill weight, and capsule volume.
Size | 000 | 00el | 00 | 0el | 0 | 1 el | 1 | 2el | 2 | 3 | 4 | 5 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
Capsule volume (mL) | 1.37 | 1.02 | 0.91 | 0.78 | 0.68 | 0.54 | 0.50 | 0.41 | 0.37 | 0.30 | 0.21 | 0.13 |
Powder tapped density | Capsule capacity (mg) | |||||||||||
0.6 g/mL | 822 | 612 | 546 | 468 | 408 | 324 | 300 | 246 | 222 | 180 | 126 | 78 |
0.8 g/mL | 1096 | 816 | 728 | 624 | 544 | 432 | 400 | 308 | 296 | 240 | 168 | 104 |
1.0 g/mL | 1370 | 1020 | 910 | 780 | 680 | 540 | 500 | 410 | 370 | 300 | 210 | 130 |
1.2 g/mL | 1644 | 1224 | 1092 | 936 | 816 | 648 | 600 | 492 | 444 | 360 | 252 | 156 |
Specialized capsule sizes have also been developed to overencapsulate dosages for blinding in clinical trial administration.13 Two important requirements for blinded clinical trial materials are that the patient not being able to see the contents of the capsule and that it would be difficult for the patient to open the capsule and thus break the blind. A unique capsule design was developed to support these requirements with a cap that covers most of the body, creating a double layer of shell so that only the rounded end is visible, as shown in Figure 2.5. This dual layer not only ensures the opacity of capsule contents but also makes it extremely difficult to open, maintaining the integrity of the blind. As the size and cost of clinical studies increase, the need to maintain study integrity becomes ever more critical. The two-piece capsule can be an invaluable tool in preventing patient bias by making it difficult for the patient to break the blind, thus assuring study integrity. Another unique capsule was developed specifically to contain liquids using special design and locking features. Such capsules are typically sealed after filling either by applying a band across the seam or by a hydroalcoholic seal.14,15
Figure 2.5Capsule for clinical blinding.
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