Long Term Compatibility of Excipients in Soft Gelatin Capsules

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ABSTRACT
Purpose
To study the compatibility of several excipients in soft gelatin capsules.

Methods/Materials
Diethylene Glycol Monoethyl Ether (Transcutol® HP), PEG-6 Caprylic/Capric Glycerides (Softigen® 767), Triethyl Citrate with and without 30% (w/w%) Ethyl Acetate NF, Dimethyl Isosorbide (Super Refined Arlasolve® DMI-LQ-(MH)), Triacetin (Kollisolv® GTA), Polyoxyl Castor Oil (Kolliphor® EL), Propylene Glycol Monocaprylate (Capryol™ 90) or Polyoxyl 15 Hydroxystearate (Kolliphor® HS 15) were filled into soft gelatin capsules. The capsules were packed into HDPE bottles, induction sealed and placed on stability at ambient and 40°C/75%RH. Appearance, hardness, disintegration and fill moisture were tested at multiple time points.

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Softgel Encapsulation
Fill materials were encapsulated into 8.5 Oval tooling (lot 14MC-18 sublots 1 through 6) and 10 Oval tooling (lot 14MC-30 Sublots A, B, and C) on a single pocket, lab-scale encapsulation machine at Catalent Pharma Solutions, Somerset, New Jersey. Both gel mass formulae used consisted of the same ingredients but slightly different proprietary ratios of Glycerin, Sorbitol, 195 Bloom Type A Gelatin and water.

Drying
All lots were dried until an average hardness of NLT 8.0N was recorded. Fill moisture content determinations were also performed. Drying data is provided in Table 2.

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Hardness
Hardness testing was performed using a Bareiss Durometer. Three (3) to five (5) softgels per lot were tested and an average was calculated.

Fill Moisture Testing
Fill material was extracted from the softgels used for hardness testing, combined into a single vial, and vortex mixed to ensure homogeneity prior to testing. The water content was determined using the Karl Fischer Titrator Model DL 38. The results were recorded as % water.

Finishing
After drying, the softgels were washed, re-trayed, and dried overnight.

Disintegration
Disintegration was tested on 6 softgels using a USP apparatus with deionized water at 37.0°C without discs. The mean disintegration time was reported.

Stability Protocol
Each softgel lot was packaged into 60cc or 30cc WM Pharma Round HDPE bottles with CR closures, induction sealed, and placed at ICH condition 40°C/75%RH and ambient condition. The capsule count for each lot was based on testing needs and total number of softgels available for the study.

RESULTS
Refer to Figures 1 through 6 for all stability pull point results recorded to date.

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After two months at 40°C/75%RH, the average disintegration time of all samples remained less than 15 minutes for all prototypes with the exception of Kolliphor EL filled capsules as shown in Figure 1.
Softgel cross-linking was only observed in Transcutol HP filled softgels after 6 months at 40°C/75%RH as no disintegration was observed after 120 minutes (this data was not listed in Figure 1). However, no cross-linking was observed in the same lot after 6 months at ambient conditions (average disintegration time of 7 minutes), as shown in Figure 2.
After 6 months at 40°C/75%RH, all samples had fill moisture content changes less than 0.5% water as compared to initial as shown in Figure 5. However, the fill moisture of Transcutol HP and Kolliphor HS15 filled softgels stored at ambient for 6 months had increased by 1.1% and 0.6 %, respectively, as shown in Figure 6.
After 2 months at 40°C/75%RH, the average hardness decreased for all samples except Softigen 767 filled capsules as shown in Figure 3. After 6 months at 40°C/75%RH, the hardness had decreased for all samples due to water and temperature impacts while all samples held at ambient conditions for the same amount of time remained fairly consistent as compared to T0, as shown in Figures 3 and 4.

CONCLUSION
All excipients tested are compatible with softgels at up to 100% fill level. All excipients were able to be encapsulated with relatively low difficulty.

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