Now part of a larger pharmaceutical entity, a European company engaged Aptuit in the development of a Phase I oncology study focused on capsule formulation of a cytostatic highly potent compound. The project was designed to improve the bioavailability of an immediate release capsule.

An Aptuit scientific team of analytical, formulation, quality control and manufacturing experts was involved in extensive screening work, developing granulation processes for the multiple dosage strengths and evaluation of the lead formulation for pharmacokinetic and stability testing. An experimental design was developed for a trial formulation which met refined parameters of up to 13.5 kg for scale up in Phase I manufacturing.

Throughout the project, Aptuit’s project manager coordinated the team assigned to the project, ensuring the implementation of a strategy and schedule to deliver results within the predetermined timeline. As the project evolved (progressed from stage to stage), the reporting system that had been put in place kept the Aptuit team and the client aware of the progress that was being made.

The Challenge

Aptuit was challenged to develop an immediate release capsule that would improve bioavailability. The API was classified as cytostatic, requiring expert, safe handling of the hazard. Multiple aspects of the study had to be analyzed to ensure the efficacy of the improved tablet in two low dosage strengths, 0.5 mg and 4.0 mg.

The Aptuit Solution

The bioavailability workflow

The solution identified was to formulate as a hot melt granulation. The workflow process used to develop hot melt granules is outlined from its start (Figure 1) when the API was dispensed in an Aptuit isolator. The granules were tested in a Pharmacokinetic Study in Dogs.

Envair 2 glove A two-glove isolator, as seen in Figure 2, was used since the material was hazardous. The equipment is part of Aptuit’s range of tools for testing biohazardous products.

Diosna equipment Aptuit employs Diosna equipment (Figure 3) for wet and hot melt granulation. The hot melt granulation method was used to develop dosage strengths of 0.5 mg and 4.0 mg. Liquid filled/ semi solid granulation was also used in the same dosages. These granulation methods were chosen since the API was water soluble and no added water was needed for these processes. Both were filled on encapsulation equipment.

Dissolution profile

In Figure 4, the Dissolution Profile of the 0.5 mg dosage is compared with the 4.0 mg dosage. Comparative measures of label claim performance and rates of dissolution are indicated over a 100-minute timeframe.

Slide staining

After four months, the hot melt granulation method was selected for the lead formulation based on the findings of the Pharmacokinetic and Stability Studies. An example of slide staining from animal studies is shown in Figure 5.

Conclusion

The client was greatly satisfied that Aptuit developed a plan with multiple strategic elements, all leading to the development of a suitable capsule formulation. The client was impressed with Aptuit’s approach to project management which ensured that every step of the project was visible and ran efficiently. Ultimately, the application of the hot melt granulation was key to the overall success of the project. Bioavailability was improved, the desired doses formulated efficiently, and the hazard contained satisfactorily. After developing an experimental design, a trial batch was processed at manufacturing scale and was very successful in clinical production. At Aptuit, it’s all about the science..