Tablets & Capsules

TC0321

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12 March/April 2021 Tablets & Capsules As a result, it is important to evaluate the choice of plasticizer as a part of the shell compatibility process. If this evaluation determines that the plasticizer is prevent- ing suitable stability, a hard-shell capsule may be a more appropriate delivery method. A big advantage of softgels is that they offer a wide range of options in terms of shapes and colors for market and product differentiation, with rounds, oblongs, and ovals being the most common shapes for oral delivery. The practical fill volume limit for softgels is approximately 1.2 milliliters before the capsule becomes too large to swallow. Softgels provide a fast route of development, as manufac- turers typically have a library of gel-mass formulas that they can either apply directly or modify slightly to accommodate the fill composition. This library approach leverages knowl- edge of shell performance across a broad base of products. Changes to the library, such as a change in the gelatin source, undergo rigorous evaluation to ensure that the change doesn't alter product performance. An organization that has built and diligently maintains a shell library spanning many LBFs is in a very strong position to offer innovators a stable and robust shell system, and this knowledge base and expertise is indicative of a successful softgel operation. Gelatin capsules have a longer developmental and manufacturing history than non-gelatin capsules, so most products on the market are gelatin-based. Gelatin shells are compatible with fill formulations in a 4 to 7 pH range [3]; however, the maximum processing temperature is approximately 40°C because of the relatively low melting point of the gel-mass used to form the capsule. Gelatin softgels are susceptible to crosslinking, which can impact in vitro dissolution testing. Formulators can min- imize crosslinking by using fill excipients with low levels of impurities known to catalyze the crosslinking reaction (such as peroxides and aldehydes) and reducing exposure to excessive heat and oxygen during processing. In instances where significant crosslinking cannot be avoided, either due to the API itself or to impurities in the formulation, gelatin-free capsules are a suitable alternative. Polysaccharide-based softgels that use starch and/or car- rageenan as capsule-forming polymers have a higher melting point than gelatin. This allows for fill temperatures up to 75°C, which expands the number of excipients that can be used compared with gelatin shells. It also opens up the possibility for modified-release applications, as formulators can control the rate of dissolution or dispersion of the fill material by including different excipients with varying melting Liquid-filled capsules The most common delivery vehicles for LBFs during early-stage development studies are liquid-in-bottle for- mulations and liquid-filled capsules (LFCs). LFCs, which can be either hard-shell capsules or softgels, are typically preferred for clinical studies because they are convenient for patients and widely accepted in both pharmaceutical and consumer health products. Formulation and scale up methodologies are widely understood, and LFCs are com- patible with most excipients used in LBFs. LFCs are an effective means of unit-dose delivery of liquid, semi-solid, and thermosetting formulations and allow for precise volumetric filling of liquid formulations, providing increased dose uniformity compared to other delivery vehicles. Also, LFCs enhance product stability because the capsule shell protects the API from exposure to oxygen or water. The encapsulation technology also has negligible adverse impacts on the fill formulation's performance properties (such as dispersion and digest- ibility) or the API release from the dosage form over time (dissolution rate). From a practical, manufacturing point of view, small-scale batches of a few dozen LFCs are easy to produce, which saves API, time, and money and makes development fast and efficient. Both hard-shell and softgel capsules can be either animal- based (gelatin) or non-animal-based. Non-animal-based shells use a variety of polysaccharides, such as hydroxypro- pyl methylcellulose (HPMC), starch, and carrageenan. The choice of shell material is based on the final dosage form's target product profile (TPP), as well as the formulation's physicochemical properties. Hard-shell capsules offer some advantages over soft- gels, such as the ability to fill at higher temperatures. Also, HPMC hard capsules can encapsulate compounds and fills that are very moisture sensitive, acidic, or alkaline. How- ever, hard-shell capsules also have some drawbacks, such as sensitivity to crosslinking and a maximum fill volume of only approximately 0.9 milliliter. Also, HPMC films have a relatively high rate of oxygen permeability compared to gelatin films, which can limit the applicability of HPMC capsules in the development of oxygen-sensitive compounds. Softgel manufacturing Softgel manufacturing technology has a long history in the pharmaceutical industry and produces a plasticized, hermetically sealed shell. While softgels are typically com- posed of gelatin, non-gelatin shells, usually made from polysaccharide (starch and/or carrageenan), are becoming more common because of their appeal to populations whose cultural or religious beliefs preclude the use of gelatin. Softgel formulations include plasticizers—typically glycerin, sorbitol, maltitol, or mannitol—however, these materials can sometimes be reactive with the fill formulation and may result in the formation of glycerol esters when used with weakly acidic APIs. Such reactions can impact the APIs chemical stability within the drug product.

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