(M1330-06-33) Encapsulation of a Common Blend Formulation Using an Automatic Encapsulator: A Study on the Effect of Fill Weights on Weight Variation and Dissolution Behavior

Purpose: Capsules are one of the most common dosage forms in both developed and evolving markets, primarily because they are preferred by consumers. Poorly compressible powders can be easily formulated as capsule dosage forms with shorter development times and fewer units of operation, which is preferred for early phases of clinical trials, e.g. in Phase I and Phase II. Although encapsulation seems simple, the precise filling of powders into capsules requires considerable effort during development which mainly depends on the physical, chemical and mechanical properties of the powder, and especially on fillers. Innovative formulation strategies have been adopted to shorten formulation development time, optimize bulk drug requirements, and reduce overall resources to manufacture drug products. One early clinical study initiation strategy to simplify the manufacturing process is to use a common blend to prepare multiple dosage strengths using capsule shells of varying sizes for all the strengths of the product. Since the outbreak of the COVID-19 pandemic, capsule shells of all types and sizes have experienced extremely long lead times due to various supply and resource constraints. This study seeks to evaluate the possibility of filling capsules of two different strengths in the same size capsule shell that would normally be filled in two separate-sized capsule shells.

Methods: The capsule formulation consisted of 18.0 % w/w caffeine (API), 78.1% w/w microcrystalline cellulose (Filler), 2.9% w/w croscarmellose sodium (Disintegrant) and 1.0% w/w magnesium stearate (Lubricant). The formulation was evaluated for flow properties using bulk, tapped density and the compressibility index. The hard gelatin capsules (Size #0) were obtained from Capsugel. The common blend (18.0 % active) was formulated for both 55 mg and 75 mg capsules, with the net fill weights of 300 mg and 414 mg, respectively, to evaluate the capsule filling capabilities in the size #0 capsule for two different strengths. The capsule filling was performed using ACG AFTLab model automated encapsulator machine by varying the height of the tamping pins setting for a low and high fill weight using the common blend. The overview of the filling process is described in Figure 1. The study used two tamping pin settings in order to achieve the lowest tamping (fill weight- 300 mg) and highest tamping (fill weight-414 mg) to evaluate the performance of encapsulator for consistent filled weights. 60 capsules were collected at each time point, i.e., beginning (1 min), 10 minutes and 20 minutes and weighed individually to evaluate the net fill weight variation for both fill weights. The dissolution behavior of capsules was studied using Distek 6100 dissolution apparatus 2, 1000 mL water, 50 rpm at different time points of 5, 10, 15, 30, 45, and 60 minutes. The dissolution profiles for 55 mg and 75 mg formulation in size# 0 hard gelatin capsule are presented in Figure 2.

Results: The bulk density, tapped density, and the compressibility index for the formulation were found to be 0.45g/cc, 0.51 g/cc, and 11.76 respectively, suggesting good flow. Filled capsules were found to be acceptable in terms of appearance and capsule closing length without any dents, tips, holes, or joints. The weight variation for each time point (60 capsules) was calculated for a total of 6 sets (each set of 10 capsules X 6 = 60 for each time point) using mean and % CV for both fill weights. % CV for low fill weights were found to be higher than % CV for high fill weights. This could be attributed to the appropriate tamping force utilized in high fill weight to form a definitive slug inside the capsule body as compared to inadequate or not as consistent tamping force in the low fill weight capsules. Despite the greater difference in the fill weight, dissolution profile analysis showed that there was >95 % release of caffeine from both 55 mg and 75 mg strengths. Both strengths exhibited similar release profiles, suggesting that there was a negligible impact of the slug formation by tamping on dissolution for the common blend-based caffeine formulation.

Conclusion: The results of this study illustrated that with a common blend, %CV for low fill weight capsules is higher than %CV of high fill weight capsules filled by an automatic encapsulator equipped with tamping pins and a dosing disc due to the formation of a loose slug of blend compared to a more compressed slug that resulted from the two tamping forces utilized for the two fill weights evaluated. The study also suggested that there was a negligible impact on dissolution behavior for low and high fill weight capsules in the common blend formulation. This study could serve as a basis for early-stage development for clinical trial formulations which could be evaluated using different strengths, different capsule sizes, or different capsule types such as gelatin, HPMC, delayed-release or modified release capsules to optimize the manufacturing process.


Figure 1: Overview of the automated capsule filing process in ACG AFTLab Encapsulator


Figure 2: Dissolution profiles for 55 mg and 75 mg formulation in size# 0 hard gelatin capsule