The Concept

The most basic lipid-based formulations are simple fluids (e.g., low-viscosity oils, <50 cps) or suspensions with drug solids content varying from <0.04% to 40.0% and with viscosities ranging from 20 to over 25,000 cps. They may be thermo-softening products or self-emulsifying formulations. Additionally, they may include multi-phase formats designed to meet more complex and specific technical needs such as multi-step release-profiles. Certain products, specifically the multi-phase or thermo-softening formulations with high melting-points, are better suited to the hard gelatin capsule format as dictated by the processing needs. A limited number are better suited to soft gelatin capsule encapsulation due to the embrittling or plas-ticizing effects of the formulation excipients. Lipid-based formulations are well suited to processing in capsule format, especially as one-piece soft gelatin capsules or as the more commonly used two-piece hard gelatin capsules. A further type consists of spherical capsules containing an oil/active, which are formed by coextrusion of the core content and a gelatin/plasticizer solution through submerged nozzles, forming the so-called "seamless capsule" (5). While the soft gelatin capsule has been available for liquid-filled products for over 150 years, the liquid-filled, two-piece hard gelatin capsule has become well established only in the last 5 to 10 years. This has been due largely to the time required to generate sufficient stability and in vivo performance data and to gain regulatory approval for these formulations as well as recent technological developments, which allow for efficient, large-scale encapsulation of lipid-based products. Figure 1 shows the concept for liquid-filled two-piece capsules. The active component, as a liquid or as a solid, may be formulated with a liquid, thixotropic, or thermo-softening carrier to form a fluid, which is filled into hard capsules using capsule filling equipment in which a fluid-filling pump replaces the powder head. Certain products may require a further process of capsule sealing, while others require no further processing. Sealing may be required due to the physical nature of the fill material (e.g., low viscosity liquid), to improve stability or for regulatory or marketing reasons. The production process therefore is essentially a mix/fill/seal sequence, which can be simplified for particular products, for example, by the elimination of the need to seal.

MATERIALS Capsule Shells

Animal Gelatin

Animal gelatin represents the historical major material for two-piece capsules. Its properties and most recent issue, transmissible spongiform encephalopathy (TSE), are well understood (6,7). The major gelatin capsule manufacturers can provide

Figure 1 Unit operations involved in the production of liquid filled, two-piece gelatin or HPMC capsules. The active component, as a liquid or as a solid, may be formulated with a liquid, thixotropic, or thermo-softening carrier which is filled into hard capsules using capsule filling equipment in which a fluid-filling pump replaces the powder head. Certain products may require a further process of capsule sealing to ensure against leakage.

Figure 1 Unit operations involved in the production of liquid filled, two-piece gelatin or HPMC capsules. The active component, as a liquid or as a solid, may be formulated with a liquid, thixotropic, or thermo-softening carrier which is filled into hard capsules using capsule filling equipment in which a fluid-filling pump replaces the powder head. Certain products may require a further process of capsule sealing to ensure against leakage.

variants designed specifically for liquid-filling. While these can offer certain advantages, they are not necessary to all products, according to the nature of the fill material and the processing system being used. Issues of TSE, specific technical properties and consumer preference/religion-based market requirements drive a continuing effort to find substitutes (8). The current alternative material of choice to animal gelatin capsules are those prepared from hydroxypropyl methylcellulose (HPMC). Another recently introduced but less frequently applied alternative to animal gelatin is fish-skin-derived gelatin.

Hydroxypropyl Methylcellulose

Recent advances in capsule sealing technology have improved the commercial attractiveness of HPMC capsules. Many major pharmaceutical companies are proactively including them in their development programs. Their technical properties are compared with those for gelatin in Table 1. HPMC is a mixed-ether of cellulose containing variable proportions of methoxy- and 2-hydroxypropoxy groups. Various grades are suitable for preparing hard capsules and are accepted by the pharmacopoeia in the United States, Europe, and Japan (9). The grades used for capsule manufacture provide shells whose water solubility characteristics compare with those of gelatin. HPMC capsules compare closely in physical size and dimensions to gelatin capsules, allowing them to be processed on standard capsule-filling equipment. However, the various capsule shell manufacturers employ a variety of additives and production techniques, which influence the capsule physical properties and suitability for specific products, particularly

Table 1 Comparison of Gelatin and HPMC Capsule Shells

Selection factor

Gelatin capsule

HPMC capsule

International capsule

Widespread

Widespread for

acceptability

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