Get a little going a long way

Getting a lot of information from a small sample is the name of the game in pre-formulation research. Here we learn how implementing a screening approach can maximise ingredient characterisation

SIMPLY stated, the challenge in pre-formulation research is getting a little to go a long way. Early in discovery, researchers have only produced a small amount of active pharmaceutical ingredient (API). Determining the most druggable solid form of the material to progress into development requires extensive characterisation studies. The more information acquired about a material, the more certain the decision about which form to develop further. But when material is limited, so is the degree of characterisation that can be done.

“Limited preformulation studies ultimately limit formulation options,” says Shelia Colby, application manager at Symyx. At a minimum, API characterisation should include determining solubility, salt forms, crystal forms and hydrates and pKa values. Scientists typically use birefringence microscopy, Raman spectroscopy, x-ray diffraction and liquid chromatography to perform these investigations, techniques that must be conducted manually in low-throughput. Scientists invest excessive labor not just running the experiments, but also analysing the results. The studies also take time - completing a study design with 96 solvent and API combinations under several different conditions would produce hundreds of samples and might take several months to complete.

“A high-throughput screening approach to pre-formulation studies opens up a much larger playing field for a lead compound,” Colby says. “The ability to ‘screen’ key parameters offers time, breadth, and cost benefits and leads to better decisions about which formulations to develop further.”

Early in 2001, Symyx partnered with chemists at Merck Research Laboratories to develop an automated technology and informatics platform that would carry pre-formulation studies into the high-throughput age. The result is an integrated crystallisation workflow that miniaturises and parallelises critical pre-formulation experiments. Scientists can now screen hundreds of samples at once, shortening experiment cycles and producing more data points from less material.

The workflow developed through the Merck partnership integrates pre-formulation research activities from end to end. A variety of innovations were incorporated to give scientists control over different experimental variables while making the pre-formulation studies faster and easier to implement.

The centerpiece of the workflow is a configurable robotics station. This single

Figure 1: Preform software

system features a unique 96-well master plate that incorporates a universal substrate. Experiments run on this glass substrate can be easily assessed by any of the most common microscopic technologies used in pre-formulation work.

The system also incorporates a temperature controlled filtration assembly that gives scientists more certainty over experimental conditions. By eliminating temperature variance during experiments, the system provides robust investigation of the polymorphs and crystalline forms of APIs.

The robotic station is just one component of a fully integrated system that includes third-party instruments and Symyx Software. Symyx Software runs instrumentation and unifies all the experimental data generated from these instruments.

Scientists can use the integrated workflow system to set up and run experiments, collect data from birefringence microscopy, Raman spectroscopy, x-ray diffraction and liquid chromatography experiments, and analyse and report results.

Since delivering the crystallisation workflow at Merck in 2002, Symyx has implemented the system in over a dozen leading pharmaceutical companies. “It’s well on the way to becoming an industry standard,” says Colby, noting that customers have consistently reported completing in just four to five days projects that once took up to 40 days. And the success with this project is benefiting other areas of pharmaceutical R&D. Symyx integrated workflows for solubility, forced degradation, and excipient compatibility, for example, are changing the way pharmaceutical companies set and accomplish development goals.