DRUG PREFORMULATION

Once a lead New Molecular Entity (NME) has been identified during discovery, the screening and selection of solid forms is often a critical next step in the successful development of a new pharmaceutical product. Traditionally, solid form screening has focused on the isolation of the most stable crystalline form but as NMEs become more complex with challenging properties, alternative screening strategies are emerging. Different solid forms of an NME are referred to as polymorphs, which in the regulatory definition include different crystalline forms, amorphous forms and hydrates/solvates. Salt forms of NMEs with ionizable groups are considered to be a different molecular entities and may also be polymorphic in nature. Cocrystals and amorphous solid dispersions (ASD) offer alternate solid forms that can be utilized to improve critical attributes such as stability, solubility, and manufacturability.

During the investigation of different solid forms, analytical chemistry plays a vital role. Utilizing techniques such as X-ray Diffraction (XRD), Raman/IR spectroscopy and Thermal analysis (such as DSC) for structural characterization of the different solid forms.

In this early development stage, refinement of process chemistry and synthetic routes is a major component of ensuring purity and establishing appropriate manufacturing capability. Analytical chemistry again plays a significant role in optimizing process chemistry using elemental techniques like X-ray Fluorescence spectroscopy (XRF) and molecular techniques like Raman/IR spectroscopy to assay purity. The purity of the synthesized (or isolated) molecular entity will have a direct impact on the solid form landscape and crystalline forms are often utilized to help improve molecular purity, giving a synergistic relationship between process chemistry and solid form selection.

The drive to keep costs low in the early development stages, combined with the need to move swiftly through development and the high attrition rate of candidates, has sparked interest in a phase-appropriate solid form screening technique for small molecule candidates. Screening operations become more comprehensive as resources become available and technical needs alter in a phase-appropriate methodology, which is an iterative process. Limited screens are employed during early development to establish an appropriate solid form that would allow a speedy advance to the next milestone.

More material and resources become available later in development, after clinical proof-of-concept, and complete screening can be undertaken to locate all solid forms for intellectual property protection and determination of the best solid form for commercialization.