Pharmaceutical Dosage Forms Capsules
Invented more than 160 years ago, the capsule today is second only to the compressed tablet among solid dosage in frequency of utilization for drug delivery, and its utilization is growing. According to one estimate,* approximately 10–15% of FDA-approved drugs in 2014 were capsule formulations, about double that in 2007. Originally intended to mask the unpleasant taste of certain medications, today there are many other advantageous reasons and drivers for selecting the capsule for drug delivery, as discussed in the various chapters of this book. Despite the growing utilization of the capsule and the important roles it plays as a dosage form, the capsule has been relatively under-served in the literature. To our knowledge, there have been only two prior published edited texts†,‡ devoted entirely to capsules, the most recent of which was published about 12 years ago. These books were intended to fulfill the need to provide in one place a concise summary of the making and filling of capsules, and of developing formulations for capsules. We are honored to have the opportunity to join the efforts of these prior editors in providing an updated discussion and description of capsule formulation and filling technology and the role of capsules in drug delivery. We are especially honored that Fridrun Podczeck, Brian E. Jones, and J. Michael Newton, editors and/or authors of chapters of those earlier books, have also contributed to this book.
Advances in Capsule Formulation Development and Technology
Among solid dosage forms, the capsule is second only to the compressed tablet in a frequency of utilization for drug delivery, and the hard shell capsule continues to be the more frequently used form. Because hard shell capsules are often perceived as “simpler” than other oral dosage forms, they are frequently the first dosage form administered to humans and sometimes the final marketed dosage form. Even when the marketed product is to be a tablet, firms may sometimes make a tablet formulation and initially fill it in hard shell capsules to facilitate clinical testing. During the past 15 years or so, there have been several interesting and important advances in capsule formulation science and technology, including (1) alternative (to gelatin) shell compositions and enhanced shell function such as enteric capsules, (2) unique drug delivery systems, (3) using capsules to manage poorly soluble drugs, (4) filling small doses of drugs into capsules without excipients, (5) capsule filling machine simulation, and (6) application of artificial intelligence and other modeling methods in support of formulation development and Quality by Design (QbD).
An Introduction to Two-Piece Hard Capsules and Their Marketing Benefits
Two-piece hard capsules are a well-established dosage form that provides solutions to many of today’s drug delivery and nutraceutical formulation challenges.1 Widely used in the pharmaceutical and nutritional industry for more than a century, two-piece capsules are still a recognized and trusted dosage form.2 When viewed as an empty container, they are highly flexible and amenable to many fill material types including powders, granulations, pellets, minitablets, semisolids, and liquids.3 Uses for two-piece capsules are equally flexible, including immediate release, sustained release, enteric release, clinical blinding, inhalation therapy, and vaccines.4,5 While the majority of hard capsules are composed of gelatin, hydroxypropylmethylcellulose (HPMC) has emerged as a naturally-sourced, lower water content alternative offering further flexibility to the formulator.
Modern drug discovery has yielded insoluble and complex molecules that challenge the pharmaceutical formulator to develop an orally available dosage form while meeting aggressive timelines. Likewise, the nutraceutical formulator is under even more aggressive development timelines and is usually constrained by the inability to use traditional formulation aids such as binders, flow aids, and disintegrants. For both formulators, the hard capsule typically offers a quicker and simpler developmental path than tablets, resulting in a faster time to market and considerable cost advantages.
Hard capsules are available in a wide range of sizes to meet most requirements. Colorants and printing options improve product identification and product branding, aid in anti-counterfeiting, and help improve patient compliance. For patients, hard capsules are frequently a preferred dosage form for their visual appeal, ease of swallowing, and taste and odor masking.
Hard Shell Capsules in Clinical Trials
The choice and use of capsule shell type in formulation and development for clinical trials are generally based on the drug delivery goals (gastrointestinal site-specific delivery), acceptable dietary norms and patient preferences, and ease of blinding in clinical trials. Another important reason for the choice is the need for use of a small number of actives in the early phase.
Capsule Shell Manufacture
Both hard and soft types of capsule shells were first patented and used in France in the first half of the nineteenth century.1 The manufacture of hard, two-piece, and soft, one-piece, capsule shells relies on the same basic phenomenon that solutions of certain polymers change their state from a liquid to a solid with a change in temperature. The polymer first used in their manufacture was gelatin, solutions of which, when their temperature drops below about 35°C, undergo a gelation process and change from a sol to a gel state, thus enabling homogeneous films to be formed rapidly on metal molds to produce hard capsules or to form sheets of material to produce soft capsules. The resulting shells are either filled with a formulated product at the point of the shell formation in the case of soft capsules or are filled in a totally separate operation in the case of hard capsules. The main formulation difference between the shells is that soft capsules contain a significant proportion of added plasticizer. This chapter describes their manufacturing processes and explains the properties of each.
Non-Gelatin-Based Capsules
Two-piece hard capsules are one of the most established dosage forms for pharmaceutical products. The concept of using hard capsules to deliver drugs was described as far back as 1846 when Jules César Lehuby was granted a patent for his “medicine coverings.” The patent described the manufacturing of two-piece capsules by dipping silver-coated metal pins into a gelatin solution and then drying them (Dorvault 1923). However, it wasn’t until 1931 that Arthur Colton, on behalf of Parke, Davis & Co., succeeded in designing a machine that simultaneously manufactured both halves of the gelatin capsule body and cap and fitted them together to produce a two-piece hard gelatin capsule (Colton 1931). This invention can be considered the starting point for one of the most important dosage form innovations used for pharmaceutical drug products, which is still being used to develop innovative solutions for a variety of different drug delivery systems and platforms.
Two-piece hard capsules have been traditionally made of gelatin, which exhibits unique physicochemical properties of gel and film formation within a very narrow temperature range. This feature is important for manufacturing purposes. Additionally, gelatin provides other important properties and characteristics for oral dosage forms such as fast capsule opening and dissolution in vivo, which are required for immediate-release dosage forms. Hard gelatin capsules are now an established pharmaceutical dosage form that are used as a delivery vehicle in 20% of all oral pharmaceutical products, several of which have been blockbuster drugs for many years. Through continuous improvements and advances in hard gelatin capsule manufacturing, these hard gelatin capsules are a state-of-the-art pharmaceutical delivery vehicle that are suited for modern Quality by Design-based pharmaceutical product development and manufacturing (Stegemann et al. 2014a).
In parallel to using gelatin for hard capsule production, scientists investigated the use of polymer-based two-piece hard capsules to broaden the applications of capsule technology for drug delivery. These resulting polymers had to display characteristics that can overcome some of the challenges associated with the delivery of specific drug molecules or that exhibit specific physicochemical characteristics. These new materials had to demonstrate utility with special drugs or delivery systems but at the same time be pharmaceutically acceptable. They also had to have manufacturing reproducibility and high capsule quality, be economically viability with respect to commercial-scale manufacturing, and be capable of being used in existing high-speed capsule filling machines. This polymer research led to the introduction of two-piece capsules made of two additional base polymers, HPMC (hypromellose, hydroxypropylmethylcellulose) and a polysaccharide, pullulan, which displays properties similar to those of gelatin. From these two polymers, HPMC capsules have gained regulatory approval for the formulation of orally as well as pulmonary delivered pharmaceutical products that are marketed in all major countries around the world. Furthermore, HPMC-based capsules have been developed for specific applications and with different release profiles.
Hard Shell Capsule Filling Machines
The history of capsule filling started in the United States around 1900 as a result of the development of large-scale manufacture of hard gelatin capsules. Many US pharmacists began manually filling capsules using devices composed of a funnel to fill the powder into the capsule body and a spring-loaded plunger to compact the powder. Modern high-speed capsule filling machines evolved from these devices.1
This chapter will describe the various types of capsule filling machines, their operations, processes and capabilities, and various types of capsule filling support equipment currently in use.
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