Tablets Capsules

TC0321

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Tablets & Capsules March/April 2021 13 Softgel capsules are widely compatible with excipients commonly used for LBFs and can accurately dose products in the microgram dose range with excellent content uni- formity. Softgels are also well-suited to small-scale batch manufacture with minimal effort and API consumption yet are easily scaled to commercial levels with minimal risk. Potent APIs can be contained easily within the liquid fill material, and the manufacturing process and shell systems are well suited to protect APIs and excipients from oxidation. Since the shell is essentially a container for the fill material, there is minimal impact on in vitro/in vivo fill formulation performance such as dissolution and dispersion. In cases where softgel manufacture is incompatible with the API, the predictable interchangeability between softgels and hard-shell capsules is straightforward. Selecting one versus the other can be based on TPP, technical limitations, or development phase. Empty hard- shell capsules are readily available from several vendors, making in-house formulation studies practical for compa- nies that do not have access to softgel manufacturing, and this can be extended to in-house manufacturing for early animal or clinical studies. On the other hand, softgels are typically manufactured by an experienced CDMO, allowing rapid development and a choice of dosage form designs. The ability to modify the softgel's composition offers greater flexibility in tailoring the shell to the fill to improve compatibility, and softgel manufacturing has a well-established and extensive knowl- edge base and history of regulatory acceptance. Hard-shell capsule technology is less mature and has experienced sev- eral issues, such as spontaneous cracking with hygroscopic fills. Selection depends on the API, the properties of the fill formulation, and ultimately, which technology best meets the defined TPP. T&C References 1. Savla R, Browne J, Plassat V, Wasan KM, Wasan EK. "Review and analysis of FDA approved drugs using lipid-based formulations." Drug Dev Ind Pharm. 2017;43(11):1743-1758. 2. Pouton CW. "Formulation of poorly water-soluble drugs for oral administration: physicochemical and phys- iological issues and the lipid formulation classification system." Eur J Pharm Sci. 2006;29(3-4):278-287. 3. Gullapalli RP, Mazzitelli CL. "Gelatin and Non-Gela- tin Capsule Dosage Forms." Journal of Pharmaceutical Sciences. 2017;106(6):1453-1465. 4. Rayaldee (calcifediol) [package insert]. Miami, FL: OPKO Pharmaceuticals, 2016. 5. Tanner KE, Shelley R, Stroud N, Youngblood E, inventors; Catalent Pharma Solutions, assignee. Non-gel- atin soft capsule system, 2012. Jeffrey E. Browne is director, science & technology and David Fulper is director, technology support at Catalent (877 587 1835, www.catalent.com). points. Calcifediol is an example of an approved product that incorporates a semi-solid lipid formulation into a polysac- charide-based softgel with extended-release properties [4]. Polysaccharide softgels are also compatible with alka- line fills up to pH 12.0 [5], and because they eliminate the potential for cross-linking associated with gelatin capsules, further expand the number of materials that can be filled into a softgel format. LFC selection Selecting which type of LFC to use for the final dosage form begins with the TPP, which defines the product's desired properties. However, if the TPP does not explic- itly define the choice between LFCs, developers should consider compatibility and stability data when selecting the LFC type and material. Both business and development considerations may influence the choice with respect to the amount of work that can be performed in-house versus work that must be outsourced to a contract development and manufacturing organization (CDMO) that specializes in a platform. Manufacturers should perform a preliminary risk analysis with respect to commercial viability within the project's development scope and the optimization of the project's time and resource needs. For the most part, hard-shell capsules and softgels are equivalent, but there are subtle practical differences between them. Generally, softgels are manufactured by experienced CDMOs that can apply their expertise early in the process to avoid problems later in development. This knowledge, coupled with the ability to adjust and fine-tune the shell formulation, provides greater flexibility in solving problems— particularly those associated with challenging APIs—when working with softgels compared with hard-shell capsules. The most common issues associated with softgels involve compatibility problems with the plasticizer system, or an API in the fill that cannot tolerate exposure to water. If developers identify and address these issues early, transitioning the prod- uct to a hard-shell capsule is a viable and economical option. Summary LBFs are well established as an enabling technology for challenging APIs. They offer flexible approaches for early stage formulation development, generally require only min- imal API for formulation development, and are easily scaled up to commercial volumes. Although a liquid-in- bottle approach may be a good option for early development work, such as animal and first-in-human testing, commercially it is limited to specific markets, such as pediatrics.

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