Xhale, Inc., a commercial stage medical technology company, had developed the SMART® Medication Adherence Monitoring System technology to non-invasively monitor adherence to oral medications. The system is based on detecting 2-butanol, a metabolite of the adherence marker, in patients’ breath and therefore can be used to definitively verify, monitor, and report how and when study participants are taking their medication in real time. By working with Catalent Pharma Solutions, Xhale, Inc. has developed SMART Softgels featuring a special shell to release quickly while still preventing evaporative loss during and after manufacturing. This softgel formulation also demonstrated excellent stability and compatibility with excipients. The small size of the softgel capsules allowed for incorporation into other dosage forms such as hard shell capsules.
Efficient encapsulation of 2-butanol has to overcome many challenges introduced by its physiochemical properties, such as low flash point, high volatility, low viscosity, and evaporative loss during and after manufacturing. This requires optimization of not only chemical composition, but also manufacturing parameters such as lower processing temperature and thinner softgel shell.
Multiple excipient formulations were previously screened but none could significantly increase the flash point. As shown in the stability graphs, GMP batches with the optimal excipient blend had high 2-butanol loading (%LC) and maintained capsule properties (%LC, hardness, and moisture). There was minimal change in these parameters during both long term (25°C/ 60% RH) and accelerated (40°C/ 75% RH) storage conditions.
In order for 2-butanol to be employed in Xhale’s Smart Medication Adherence Monitoring System, the capsule must have rapid disintegration and release of 2-butanol. The softgel technology offered great flexibility that allowed for manufacturing thin shell softgel capsules (0.02 inch shell thickness) at a low temperature. As a result, the softgel capsules rapidly disintegrated within 7 minutes without any change in disintegration time upon storage, as shown in the graph.
Figure 1 2-Butanol Softgel Stability at 25°C/60%RH
Figure 2 2-Butanol Softgel Stability at 40°C/75%RH
Catalent’s softgel technology demonstrated its versatility by overcoming the challenges of encapsulating the highly volatile, low flash point compound, 2-butanol. Further, the formulation had stable properties and displayed rapid release kinetics. The SMART Softgels are available for research use with the SMART Adherence System for the collection and reporting of medication adherence in clinical trials.