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20 March/April 2021 Tablets & Capsules Specialized wet granulation methods can ensure the sta- bility of effervescent tablets by enabling the production of more stable effervescent bases compared to other common tableting techniques such as direct compression. For example, Hermes Pharma's proprietary TOPO granulation method uses a vacuum granulation step to produce a homogeneous, moisture-resistant granulate, which can be easily processed into a tablet form. Such methods not only improve the stability of effer- vescent aspirin tablets—as assessed by testing of products under long-term and accelerated conditions—but also enable the stable production of other medicines that could not be achieved in effervescent form otherwise, such as cimeti- dine, ranitidine, ambroxol, and acetylcysteine. Specialized granulation techniques have also enabled the production of tablets free from discoloration, a common moisture-related problem encountered with effervescent tablets produced using direct compression. Brown spots are a disconcerting sight on tablets, so their absence is welcomed by manufac- turers and consumers alike (Figure 2). For dosage forms such as ODGs, hot melt coating is a key technique for improving the stability of products prone to unwanted discoloration. For example, when exposed to oxygen, ascorbic acid (vitamin C) ODGs become covered in brown spots. Hot melt coating prevents such discoloration because the coating material is melted prior to its application and forms a lipid layer around the ascorbic acid particles, protecting them from environmental oxygen. Creating the right environment Managing the environmental conditions within a man- ufacturing facility is important for minimizing potential instability issues as well as for optimizing efficiency. For example, applying UV filters to glass windows can help manufactured under normal atmosphere (in the presence of oxygen) became appalling in terms of taste and odor within weeks, even when stored at long-term conditions. Companies considering outsourcing the manufacture of products requiring inert atmosphere filling must ask the following questions when selecting an outsourcing partner: • Is the potential manufacturing partner experienced in handling nitrogen? • If not, do they know how to modify their equipment and processes to make this possible while also secur- ing staff safety? • Are they aware of the special handling considerations required for oxygen-sensitive raw materials? Handling omega-3 raw materials immediately or soon after opening is important, but this requirement can be overcome by using precautionary measures, such as creat- ing a nitrogen "seal" to exclude oxygen once drums have been opened. Partnering with a contract manufacturer that is confident about nitrogen filling and about working with nitrogen in general can help avoid costly and avoidable product degradation. Harnessing technology to stabilize ingredients and APIs Effervescent aspirin tablets are another example of a user-friendly product with inherent production challenges. Aspirin in any form is highly sensitive to moisture and, as previously mentioned, the same can be said for effervescent tablets. The degradation products of aspirin are salicylic acid and acetic acid—the latter of which is known for its sharp and undesirable vinegar smell. Effervescent aspirin tablets present particular stability challenges and require tailored technologies to prevent customers from encountering aspirin products that smell like vinegar. Figure 2 Comparison of effervescent tablets manufactured using direct compression versus TOPO granulation when stored unprotected under different conditions Zinc and vitamin C effervescent tablets manufactured using direct compression and showing yellow discoloration Vitamin C effervescent tablets manufactured with TOPO technology Fresh After 16 hours at 25°C and 60% RH (stored without primary packaging) After 16 hours at 30°C and 65% RH (stored without primary packaging)