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Tablets & Capsules September 2019 31 with a liquid or by inserting small liquid-filled capsules into larger capsules that are also filled with liquid. Tech- nology and increased understanding of the self-emulsify- ing drug delivery system (SEDDS), coupled with the advances in commercial filling equipment, have reduced formulation difficulties. As a result, developing and com- mercializing liquid-nonliquid combination products is easier than ever and can benefit both consumer health and brand owners' commercial success. When combining APIs that demonstrate different mechanisms of action, the therapeutic effects may be additive and side effects may be decreased compared to delivering the APIs separately, which can exacerbate or increase the number of side effects [4]. A successful prod- uct that illustrates this benefit is Vimovo (AstraZeneca), which combines esomeprazole and naproxen. Vimovo age types into hard capsules is an attractive strategy for producing drug products that are able to achieve vital medicinal effects. Benefits of liquid-filled capsules Liquid filling of hard-shell capsules was developed in the late 1800s [1]. In its early development, the process experienced challenges with overall acceptance and leak- age issues. With advancements in capsule filling and new technology yielding improved repeatability, liquid-filled capsules have become easier to manufacture and more palatable to consumers. Several APIs currently under development show poor solubility and low bioavailability. Further, these APIs have complex structures when compared to previously developed drugs, as shown in Figure 1. This is partly because easier compounds have generally already been developed and commercialized, and only the more diffi- cult compounds remain. Solubilizing a complex API into a liquid fill for hard- shell capsules is an effective drug delivery tool that increases the API's bioavailability and may counteract its inherent limitations. As shown in Figure 2, only around 5 percent of new chemical entities under development are classified as having high bioavailability (Class I), under the Biopharmaceutics Classification System (BCS) [2]. Approximately 70 percent of APIs under development are classified as BCS Class II, indicating low bioavailability. These poorly bioavailable APIs will require bioavailability enhancements during development. Solubilization and liquid filling can increase this important parameter [3]. Benefits of combination capsule products Combination capsule products have naturally evolved from the advancements and innovations in capsule-filling technology, including easily integrated niche filling sta- tions and stricter quality controls. Formulation scientists can achieve combination liquid-filled capsule products in a number of ways, including by mixing beads and pellets Figure 1 Comparison of the molecular structures of gabapentin and cariprazine a. Gabapentin (Approved in 1993) b. Cariprazine hydrochloride (Approved in 2015) Source: https://pubchem.ncbi.nlm.nih.gov. Class I ~5% Class III ~5% Class II ~70% Class IV ~20% Permeability High Low Solubility High Low Figure 2 BCS classification of new chemical entities under development