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20 July 2019 Tablets & Capsules content than HPMC capsules, which can cause chal- lenges with certain compounds. Gelatin capsules are manufactured with a consistent water content between 13 and 16 percent to ensure the shell's flexibility and ideal mechanical properties. To maintain this water content, gelatin capsules must be stored and used in environments between 35 and 65 percent relative humidity and between 15 and 25°C. However, some formulations suf- fer from stability challenges within these conditions. Moisture-sensitive compounds, for instance, are not com- patible with capsules that contain significant water con- tent, as degradation can occur. Capsules made from HPMC are more suitable for moisture-sensitive compounds, as they have an average water content within the 5 to 8 percent range and present fewer formulation concerns. The benefits of using HPMC capsules with moisture-sensitive compounds can be modeled well with acetylsalicylic acid formulations, as the moisture differential between hard gelatin and HPMC capsules has been shown to affect the extent of hydrolysis that occurs. When an acetylsalicylic acid formulation is loaded into both gelatin and HPMC shells and placed on stabil- ity at 25°C and 65 percent relative humidity in induc- tively sealed bottles, the amount of degradation over time is considerably different between the two polymers, as shown in Figure 2. Over 18 months, approximately 8 per- cent degradation of the acetylsalicylic acid formulation in the hard gelatin capsules occurred versus approximately 2 percent in the HPMC capsules. As the bottles were inductively sealed, environmental moisture can be dis- counted, leaving the moisture differential contained within the capsule shells as the primary source of water for the hydrolysis. This impact can be extrapolated to increased shelf-life stability for moisture-sensitive com- pounds in HPMC capsules. Dissolution and crosslinking performance Human bioequivalence studies have shown that next-generation HPMC capsules have comparable dissolu- tion profiles to gelatin capsules. For example, one human bioequivalence study showed equivalent performance between next-generation HPMC capsules and hard gelatin capsules with three Biopharmaceutical Drug Disposition and Classification System (BDDCS) Class 1 biomarkers— acetaminophen, acetylsalicylic acid, and caffeine [3]. In this study, fixed-dose combination Excedrin Extra Strength caplets containing three different rapidly- absorbed drugs over-encapsulated with gelatin capsules, and the same caplets over-encapsulated with HPMC cap- sules using a thermo-gelation process (Capsugel Vcaps Plus) were tested to compare the dissolution rates of the HPMC and gelatin excipients. Each excipient released 95 percent of its drug contents within 30 minutes and demonstrated similar delays in release compared to un-encapsulated dosage forms. There was no significant difference in in vivo pharma- cokinetics in 24 human subjects, showing the comparable performance of HPMC capsules without gelling systems and gelatin capsules. Similar studies done on HPMC cap- sules containing gelling systems showed greater intra- patient variability as well as a notable difference in onset time of drug absorption (tlag) [4]. HPMC capsules can also help formulators address potential chemical incompatibilities associated with gela- tin capsules. For instance, formulators have long known that gelatin capsules have the potential for crosslinking, a challenging phenomenon in which the contents of the gelatin capsule are released at a much slower rate than expected. Determining the cause of crosslinking can be complex but it occurs due to a chemical reaction with amino acids in the gelatin capsule. Crosslinking often causes costly delays in the development timeline when using gelatin capsules, but drug developers can avoid the issue entirely by using HPMC capsules, because the cel- lulose polymer does not contain amino acids. Similarly, formulations that can react with gelatin (such as reducing sugars, which produce a Maillard reaction) are more suit- able for HPMC capsules. Encapsulating moisture-sensitive APIs Water content is a critical factor in the successful use of capsule polymers. Gelatin capsules have a higher water Human bioequivalence studies have shown that next-generation HPMC capsules have comparable dissolution profiles to gelatin capsules. Figure 2 Degradation of acetylsalicylic acid over time in gelatin capsules (~14% moisture) versus HPMC capsules (~6% moisture) Initial 3 months 6 months 12 months 18 months 3 months 6 months Degradation (%) 8 7 6 5 4 3 2 1 0 Storage time Gelatin HPMC 25°C/60% RH 40°C/75% RH