A small pharmaceutical company with an orphan drug in the early stages of drug development approached Aptuit to develop drug product for Phase I clinical trials. If successful, due to the orphan designation of the drug, it would then be possible to fast track the compound through to Phase III. A simple dry blend in capsule form was developed in doses of 5 mg, 20 mg and 100 mg.

Initial physical characterization of the API by Aptuit identified it as a single polymorph. The crystalline solid demonstrated poor aqueous solubility. An excipient compatibility study was performed by the Aptuit formulation development team. Three standard excipients were subsequently eliminated due to interactions with the compound. Probe formulations were prepared using a GMP batch of API at the lowest dose (5 mg). Three different formulations with various levels of diluents, lubricants and disintegrants were selected based on their flow characteristics.

A single rapid HPLC method, Aptuit’s “SuperMethod”, analyzed all samples. This accelerated method, with a sub-10 minute run-time, involving just one HPLC set up, analyzed the formulations for assay, related substances, content uniformity, content homogeneity and dissolution. The same method was also used for cleaning verification.

The Aptuit analytical team found that assay values were consistently low. After various investigations, it was found that the large rod-like crystals of the API were not dissolving sufficiently in the diluent. The process was amended to reduce the particle size and the analytical diluent was also modified. This resulted in product meeting specification.

Subsequently, assay and dissolution testing of 20 mg and 100 mg doses produced acceptable results also. Transfer to the clinical manufacturing stage followed to bring the project to a successful completion.

The Challenge

There were multiple issues that challenged Aptuit in developing a simple blend-in-capsule formulation that would take the client’s orphan drug to Phase I. The particle size of the API proved difficult to formulate due to the large rod-like crystals which resulted in processing and analytical problems. Across the range of formulation and analytical findings, Aptuit had to provide the varied solutions to reach the targeted goals within a designated timeframe.

The Solution

Microscopic examination: API in formulation

The API was studied by microscopic examination (Figure 1). Within the formulation, long rod-like crystals were found. These were then examined after grinding by mortar and pestle. This additional grinding step removed the long rod-like particles from the formulation, making it easier to process (Figure 2). The manufacturing process was then modified to include a grinding step as well as geometric blending to ensure content homogeneity in the blends.

The SuperMethod: all-in-one analysis

Following extensive analytical investigations, the diluent was modified to add the organic portion first to dissolve the API crystals.

A rapid HPLC method analyzed all samples and provided important advantages compared with typical procedures (Figure 3). The SuperMethod enabled the analyses of all samples in a single, accelerated method with a run-time of less than 10 minutes. This process necessitates a single HPLC set up for API assay and related substances, drug product assay and related substances, content uniformity, cleaning, and dissolution tests, resulting in reduced reporting timelines due to fast turnaround of results.

Conclusion

The client found unique value in Aptuit’s innovative approach to this study, confident that Aptuit conducted the project as a true partner, treated the compound as if it were their own, and advanced the work conscientiously and expeditiously.

After a thorough analytical investigation, it was found that the addition of organic solvent was an important factor in addressing the issues that challenged the successful completion of the project. In addition to this, reducing the particle size of the API to remove the large rod-like crystals proved critical in producing a homogeneous blend for filling into capsules.

Throughout the course of the project, the client was impressed with Aptuit’s flexibility, which demonstrated a consistent willingness to provide varied solutions as new findings were revealed. The client also recognized the seamless collaborative efforts of Aptuit Pharmaceutical Development and Manufacturing which was all managed by one Project Manager.

Manufacturing was completed in just two weeks, which the client recognized as an outstanding achievement. Aptuit continues to work with the client during the next stages to Phase IIa, which will be followed by Phase IIb, and then directly to Phase III. In every dimension of conducting this project and providing guidance for the future, one thing is clear: At Aptuit, it’s all about the science.