Investigation into the Effect of Ageing of a Lipid Based Formulation on API Dissolution Release for Soft Gelatin Capsules

Ad Bernaerts; Martin Piest; Stefan de Cock

ABSTRACT SUMMARY

The goal was to investigate the effect of bulk storage time of a lipid based formulation on API dissolution release behavior for soft gelatin capsules. It was observed for current lipid based formulation that dissolution results were poorly reproducible. An extensive root cause investigation showed a correlation between the bulk storage time between medicine preparation and encapsulation that was further investigated. A new batch of bulk API lipid formulation was prepared and subsequently stored in a stainless steel mixing tank. After each  selected storage time, a part of the bulk formulation was used for manufacturing the capsules and conducting API dissolution release profiles.

INTRODUCTION: ENCAPSULATION OF SOLID FILLS

Soft gelatin based capsules (softgels) are manufactured using the rotary die process invented by R.P. Scherer in 1933, see Figure 1. In this process two gelatin sheets (ribbons) are led over a heated wedge. The pockets of the rotating dies are heated and the first leading seam is formed, next the fluid fill medicine is injected in the freshly filled capsule. Last step is sealing of the capsules after formation of the second receding seam.

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Figure 1. Schematic representation of the rotary die process.

This process requires the liquid to be of a viscosity that allows reproducible filling of the softgels. Consequently, fills with a higher melting temperature, such as waxes and semi-solids that are solid at ambient temperature are notoriously difficult to manufacture into soft gelatin based capsules and are usually only considered for filling into hard gelatin capsules. Whereas others have selected non-gelatin shell materials for hot-filling of capsules, Patheon has developed a method for encapsulation of semi-solids using a modified manufacturing process. Several products have been developed and one example of a solid wax mixture successfully encapsulated using this modified manufacturing process is shown in Figure 6.

EXPERIMENTAL METHODS

MANUFACTURING OF SOFTGELS WITH LIPID BASED FORMULATIONS

The medicine formulation was prepared according an in-house method. Solid waxes were molten and API was added and stirred until it was completely dissolved. Next, medicine was cooled and stored in a stainless steel mixing tank. Different storage times were selected at which a part of the bulk formulation was used for manufacturing the capsules. Capsule seam quality was verified using X-ray analysis on a Skyscan 1074 portable micro-CT scanner, see Figure 3.

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Figure 2. Solid wax mixture (top) successfully filled into softgels bottom).

DISSOLUTION METHOD

The validated dissolution test method conditions were: 900 ml, 0.005 M potassium phosphate buffer pH 7.2 containing 2.0% (w/v) SLS at 37°C as the dissolution medium, including a compendial compliant sinker for the capsules and using USP apparatus 2 with a paddle stirring speed of 150 rpm. Automatic sampling at the selected sampling points at 10, 15, 30, 45 and 60 minutes, including filtering of the sample solutions was performed. For each sample, 6 capsules were tested and the mean result was reported. The API content in the dissolution sample solutions were analyzed by HPLC. The HPLC conditions were: injection 5 μl on a reversed phase zorbax XDB-C8 column(2.1 x 50 mm/3.5μm), an isocratic flow at 1.0 ml/min, using a mobile phase of phosphate buffer and acetonitrile, running for 1.5 minutes and UV detection at 220 nm.

RESULTS AND DISCUSSION

White colored capsules where manufactured as shown in Figure 3. Capsules were of good quality and the seam quality was verified using X-ray analysis. Despite the fact of the complex manufacturing process good seam quality was observed, see Figure 3.

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Figure 3. Left: Capsules had good seam quality according to crosssectional analysis with X-ray analysis. Right: Prelimiinary DSC thermograms of soft gelatin capsules with bulk lipid formulation ageing times. Note that thermograms were offset for clarity.

EFFECT OF MEDICINE AGING ON DISSOLUTION RESULTS

The results presented in Figure 4 show a clear relationship between the bulk formulation ageing time and the dissolution profile. The API dissolution release rate of the capsules gradually improves with increased bulk lipid formulation storage ageing times at 34-38°C. The ageing process up to t5 of the lipid based formulation causes a significant increase in API dissolution release rate until 30 minutes.

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Figure 4. Comparative Dissolution Profiles of soft gelatin capsules with bulk lipid formulation ageing times increasing from t1 to t5.

A B C

Figure 5. A) Liquid molten samples with all API dissolved. B) Samples are pale yellow homogenous solid. C) Samples are becoming hazy/cloudy during aging.

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Figure 6. Example of soft gelatin capsules containing a solid wax mixture. Samples were cut in half to demonstrate that fill material is a solid at ambient temperature

VISUAL ASSESSMENT OF MEDICINE AGING

Five duplicate samples were prepared using the selected fill formulation. The results presented in Figure 5 show a clear solution wherein all API is dissolved in the lipid formulation. Upon cooling the material solidifies into a uniform pale yellow solid. Upon staging the material becomes cloudy and clear white turbid regions appear, suggesting a slow process. Most likely this is due to the crystallization of the lipid matrix, which is reported for other solid lipid materials as well, see reference 1.

CONCLUSION

The storage time of the bulk API lipid formulation for up to several days is covering the ageing process commonly reported for solid lipid excipients. It is observed that the drug dissolution kinetics from a lipid formulation can be controlled to yield a product with reproducible dissolution profile by controlling the bulk holding time. The API dissolution profile is not only controlled by the physicochemical characteristics of the API, but more importantly by those of the lipid excipients. For lipid based formulations it is important to consider the crystalline structures formed by this lipid excipient that can be modified during storage of the lipid formulation. These polymorphic transformations of the lipid crystalline structure have significant impact on dissolution rate of the excipients and thereby on the API release profile of the soft gelatin capsules.

REFERENCES

1) Mahmoud El-Badry, Gihan Fetih, Mohamed Fathy, Improvement of solubility and dissolution rate of indomethacin by solid dispersions in Gelucire 50/13 and PEG4000. Saudi Pharmaceutical Journal (2009) 17, 217–225

 

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