A small French company that has since become part of a large European pharmaceutical entity sought Aptuit’s assistance in the development of a dual antibiotic tablet. An important factor in choosing Aptuit was the submission of a detailed, comprehensive strategy to be implemented over the targeted timeline.

An Aptuit team comprised of formulation, analytical development, manufacturing and quality control professionals was assigned to the project which was conducted at the company’s site in Riccarton, Edinburgh, Scotland. The project began with the development of a tablet form of two combined antibiotics at a 70:30 ratio with a dosage strength of 100 mg. The ongoing reporting during the entire project created a communications environment that expanded the project to the development of a dosage strength of 500 mg.

To examine the compaction behavior of the APIs, a compaction simulation study was initially performed. The APIs were considered “plastic” and an evaluation was required to determine if the two antibiotic formulations would compress on tablet compression equipment. Two lead formulations were the basis of the expanded studies. Experimental design packages identified the most suitable granulation properties. Increasing the concentration to 500 mg necessitated a tablet weight of 825 mg which, in turn, led to the development of oval shaped tablets, most suitable for a larger size, dual antibiotic product. These were film coated with a PVA-based coat to mask bitter taste. A placebo matching the appearance, hardness and thickness of the active tablets was developed. The performance of the API and dosage strengths were investigated. Six different ratios were studied for processing on a single compression machine while simultaneous bioequivalent studies in humans were also undertaken.

A seamless, smooth transfer to clinical trial manufacturing was achieved. The project’s success led to the client’s commitment to additional studies.

The Challenge

The client came to Aptuit with an existing capsule formulation. Due to the dose required, between 100 mg and 800 mg, a tablet formulation was requested. Several problems became apparent in the very early stages of the project. The client was uncertain regarding the ratio of the two actives required for therapeutic dose. The two API’s had very different properties and both were poorly soluble, also batch to batch variation was high in each API and the API manufacture process led to high levels of impurities. As these problems presented themselves to the formulation and analytical method development teams, both were required to work closely to find a solution to successfully develop a dual antibiotic tablet.

Dual antibiotic tablet project workflow

At the start, Aptuit agreed upon a careful step by step approach to meet these challenges. An Aptuit Project Manager led a carefully structured work flow, as shown in Figure 1, to ensure a seamless process and on time results.

The Aptuit Solution

In parallel with the initial analytical method development, the formulation team assessed the API properties and reviewed the data available from the existing capsule formulation.

Aptuit developed a wet granulation process to produce a 100 mg active tablet with a 70:30 ratio of the two APIs. These were used in initial safety studies (Phase I). The project expanded to look at a higher dose (500 mg). A compaction simulation study was performed. The APIs were considered “plastic”, therefore the formulation team evaluated the dual formulations to see if tablets would compress on tablet compression equipment. Two lead formulations were selected for further investigation. A package of experiments were performed using an experimental design matrix to identify the most suitable granulation properties. Increasing the active dose to 500 mg required a tablet weight of 825 mg, this led to the development of an oval shaped tablet, most suitable for larger sizes. The tablets were film coated with a PVA-based coat to mask the bitter taste of the antibiotics. A placebo was developed to match the appearance, hardness and thickness of the active tablets. This work was supported by the analytics team who developed methods to test the formulations prepared. This information allowed the formulation and analytics teams, together with the client, to make a decision regarding the formulation with the most chance of success.

Having achieved a suitable formulation, Aptuit looked at adjusting the ratios of the two APIs so that the client could assess the appropriate dose combination of the two antibiotics in bioequivalence studies in clinic. Clinical batches for these studies were manufactured at a small scale using a single station compression machine. (Figure 2). This minimized the quantities of API required which were in short supply, due to the long processing time required to manufacture the API. The formulation team ensured a seamless and smooth transfer with their continual involvement in the initial clinical manufactures. To provide larger batches for further clinical work, the process was scaled-up and transferred to the clinical trial manufacturing group.

Manesty F3 single station press

Clinical batches were manufactured on a Manesty F3 single station press seen in Figure 2.

Tablet compression equipment

Aptuit routinely relies on a broad range of compression equipment such as Fette 2200 as shown in Figure 3.

Dual antibiotic dissolution profile

Dissolution profiles of the two antibiotics were compared as seen in Figure 4.

Conclusion

Client bioequivalence studies found that the API combined ratio of 41.7/58.3 was most suitable. The project has since carried forward to later clinical phases with Aptuit conducting clinical trial manufacture and QC release. The success of the initial tablet formulation has led to the client’s commitment to additional studies for the same dual active project. These include an enteric coated dual active formulation, a pediatric suspension, smaller tablets suitable for older children and an IV formulation.

The client was especially impressed with the knowledge of the project team and their ability to work closely together. The team included a Project Manager who maintained ongoing client communication that was seen to be very advantageous.

The project started in 2004 for Phase I formulation and is currently moving towards Phase III. At Aptuit, it’s all about the science, the people and the service coming together.