Tablets & Capsules


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18 July/August 2021 Tablets & Capsules Functional performance Reta M has a shelf life of 24 months and requires no specific storage conditions, other than room temperature and a dry and clean environment. It has the following functional characteristics: Flowability. The excipient's angle of repose is 39 degrees, which according to the powder flow classifica- tion system found in USP-NF, falls into the flow property range of "Fair—aid not needed." Compactibility. Coprocessing two or more excipients generally improves the resulting excipient's compactibility compared to a physical admixture of the same ingredients. Figure 1 compares the compactibility of Reta M with a 50/50 physical admixture of mannitol and hypromellose. As the figure shows, the coprocessed excipient achieves up to 100 percent greater compactibility than the admix- ture. Further, the admixture shows a rather flat curve with increasing compaction pressure, which limits the process window for its proper selection. Reta M, on the other hand, shows a quite linear increase of tablet hardness as a function of compaction pressure, allowing for reliable and predictable product performance. Dissolution. To achieve sustained release of the active pharmaceutical ingredient (API), the coprocessed excip- ient is made with hypromellose K4M, which means its viscosity at 2 percent (m/m) in aqueous solution is approximately 4,000 mPa∙s. API release from hydrophilic gel matrices such as hypromellose is governed by either diffusion when hydrophilic APIs are used or by erosion of the gel matrix and subsequent API release. The latter mechanism is mainly applicable to hydrophobic APIs. In either case, researchers found that using high- viscosity hypromellose does not necessarily lead to slower API release and can compromise important functional charac- teristics of the excipient, which led to the decision to use K4M-type hypromellose. Due to their ease of use and reliable performance, such lactose-based coprocessed excipients have been very well received by the pharmaceutical industry. The nutraceu- tical industry, on the other hand, has been reluctant to use lactose or lactose-based excipients, and has, there- fore, largely missed out on the benefits these coprocessed excipients can provide. However, Meggle recently intro- duced a lactose-free excipient comprising 50 percent mannitol and 50 percent hypromellose that is designed for the same use case as RetaLac: sustained-release, direct-compression tablet formulation. Manufacture Reta M is manufactured using spray agglomeration and is considered a coprocessed excipient. When working with hypromellose, spray agglomeration is an excel- lent method to achieve the specific functional attributes required for direct compression, which a physical admix- ture of mannitol and hypromellose lacks. The tricky part is to introduce enough moisture to ensure proper gran- ulation and then immediately and thoroughly dry the granules to limit subsequent hypromellose swelling. While spray drying provides a great degree of freedom to manufacture the porous structures that are preferable for tablet compaction, with spray agglomeration, such struc- tures are harder to achieve. Careful equipment selection and balanced airflow control are needed to create granules with the compactibility necessary for direct compression. Powder characterization Reta M is fine in particle size, providing an x10 of 58 micrometers, an x50 of 148 micrometers, and an x90 of 356 micrometers. The typical bulk density is in the range of 350 to 450 g/l. Its particle size and bulk density are right in the range of providing free flow and good blend- ing capabilities and compaction behavior. Loss on drying is described with NMT 3 percent (105°C, 4 hours). Figure 1 Comparison of compactibility between coprocessed excipient (Reta M) and physical admixture of 50 percent mannitol and 50 percent hypromellose Tablet hardness (newtons) 300 200 100 0 Compaction pressure (megapascals) Reta M Physical admixture 0 100 200 300 400 500 Figure 2 Ascorbic acid release in water of 1,000-milligram fixed-dose combination tablets Ascorbic acid 29.7% (300 mg) Zinc gluconate 10.4% Histidine 9.9% Reta M 48.5% Drug release (percentage) 100 50 0 Time (minutes) 0 500 1,000 1,500

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