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Tablets & Capsules July 2020 21 Formulation benefits of HPMC To maintain their plasticity, gelatin capsules must have a rela- tively high water content. This has occasionally led to concerns when developing hygroscopic for- mulations due to water exchange between the gelatin capsule shell and the encapsulated formulation. HPMC capsules have a low mois- ture content and are not susceptible to water exchange, which improves their chemical and physical stabil- ity, increases their shelf life, and mitigates the challenges associated with moisture-sensitive APIs and excipients. HPMC polymer can also withstand a wider range of tempera- ture variation and fluctuation than gelatin, reducing the chance that the capsules will become brittle or break during storage or transit. With potent NMEs under development, the challenges of deploying APIs in gelatin-based capsules are contrib- uting to a shift toward the use of HPMC-based capsules. Currently, HPMC-based capsules are widely preferred in clinical trials and for many investigational NMEs because they have the added flexibility to accommodate a vast array of drug products and formulations [6]. The primary factors driving developers toward HPMC capsules are the difficulty of containing hygroscopic APIs in gelatin and issues with gelatin capsules suffering from cross-linking reactions, which are chemical alterations to the gelatin that can hinder dissolution. Other benefits of HPMC capsules include: • Reduced risk of interaction, resulting in less analysis and faster development; • Sourcing confidence and reliability; and • A broad range of applications. With fewer barriers and more application options, pharmaceutical buyers are increasingly moving toward HPMC-based capsules for their new drug products [7]. Patient-friendly dosing with capsules Most patient groups respond well to hard capsules because they are easy to swallow, require less frequent dosing, and reduce or eliminate unpleasant side effects. Advances in encapsulated medications and capsule mate- rial science are playing a prominent role in helping to achieve these benefits. For example, controlling the release profile by pelletizing the API is an effective way to prevent dose dumping—a major source of side-effects. Encapsulated multiparticulate forms such as multi- ple-unit pellet systems (MUPS), spheronized APIs, and fixed-dose combination (FDC) systems offer drug devel- opers effective ways to control and manipulate complex modified and controlled release of APIs. These formula- product developers as well due to their cost-effectiveness, rel- ative ease of manufacturing, and array of patient-friendly dosing options. As a result, the number of SODFs being approved and in development is increasing, with the SODF market expected to reach $926.3 billion by the end of 2027 [2]. In 2018, 53 per- cent of the new molecular enti- ties (NMEs) approved by the FDA were SODFs, an increase over the previous two years (50 percent in 2017 and 32 percent in 2016) [3]. Although compressed tablets currently dominate the SODF mar- ket, hard capsules come in a close second, and interest in their use is growing. This is largely driven by the fact that formulators view encapsulation as a reliable delivery method for a range of compounds, including highly potent APIs. In 2018, approximately 25 percent of new chemical entities were considered to be "potent," a trend largely attributed to the fact that about one-third of all drug candidates in development are oncology treatments [4, 5]. Of the 31 solid-dose onco- logical NMEs approved in 2018, seven were capsules. The shift to plant-based and clean label capsules Traditionally, hard capsules have been made from gelatin, which is manufactured using collagen protein, a natural by-product of the meat industry. Gelatin-based hard capsules offer traditional benefits such as swallow- ability, ease of manufacture, and cost-effectiveness, and they are proven to be compatible with a range of APIs and fill materials. For years, few alternatives could offer the same characteristics. However, advances in material science and organic chemistry over the past decade have produced capsule polymers derived from non-animal sources that offer performance and compatibility similar to that of gelatin. First and foremost, pharmaceutical companies look for the most compatible capsule technology they can find for a formulation to ensure the safety and efficacy of the final product. However, developers of all types of therapeutics, especially nutraceuticals, also respond to emerging social and cultural trends. In recent years, these trends have included increasing consumer demand for products that are free of any animal proteins and that contain only "clean label" colorants and ingredients from natural sources. Hard capsules made from hydroxypropyl methylcellulose (HPMC), which is derived from cel- lulose found in trees, show great potential for meeting these emerging consumer demands and becoming the best-practice alternative to gelatin-based capsules. HPMC capsules have a low moisture content and are not susceptible to water exchange, which improves their chemical and physical stability, increases their shelf life, and mitigates the challenges associated with moisture-sensitive APIs and excipients.