Predictive and Accelerated Formulation Design Using Synchrotron Methods.

Predictive formulation design and accelerated formulation design can lead to the discovery of useful formulations to support drug clinical studies and successful drug approval. Predictive formulation design can also lead to discovery of a path for commercialization, especially for poorly soluble drugs, when the target product profile is well defined and a "learning before doing" approach is implemented. One of the key components of predictive/accelerated formulation design is to understand and leverage the material properties of drug substance including solubility, BCS classification, polymorphs, salt formation, amorphous form, amorphous complex, and stability. In addition, utilizing synchrotron-based PDF (pair distribution function) analysis can provide important structural information for the formulation. This knowledge allows control of physical and chemical stability of the designed product. Finally, formulation design should link to process development following Quality by Design principles, and solid-state chemistry should play a critical role in many of the steps required to achieve Quality by Design, which can lead to successful product development.

Accelerating proof of concept for small molecule drugs using solid-state chemistry.

In this perspective we have shown that the process of "proof of concept" (POC) in the early part of drug development can be greatly accelerated by close attention to the underlying solid-state chemistry (SSC) of a new chemical entity. POC seeks data that provide confidence in the therapeutic activity and safety of a new chemical entity, which can rapidly lead to a key "GO/NO-GO" decision point for further development. Due to the high cost of the development of new chemical entities and the current low overall productivity of obtaining successful candidates, the pharmaceutical industry is being required to develop accelerated POC strategies. The success of accelerated approaches to POC depends on a full understanding of the SSC of drugs in relation to solubility and stability. Dissolution-limited absorption due to poor solubility of drug substances is particularly important because it can lead to low exposure in animals and undesired bioavailability in humans. Choosing a desirable solid form with sufficient solubility and acceptable stability is essential in developing formulations for POC with superior quality. In this perspective we present an approach that utilizes SSC as part of a novel 2-year development strategy for reaching the pivotal clinical trial stage of development.

Solid state characterization of mometasone furoate anhydrous and monohydrate forms.

Mometasone furoate is a potent glucocorticoid anti-inflammatory agent. Its anhydrous Form 1 and monohydrate form were characterized by X-ray crystallography, X-ray powder diffraction at ambient and elevated temperature, thermal analysis, FT-IR, and dynamic moisture adsorption. In Form 1, mometasone furoate molecules pack tightly with molecules interlocked in a space group of P2(1)2(1)2(1). The monohydrate form crystallizes in space group P1. The unit cell of the monohydrate contains one water molecule and one mometasone furoate molecule. The water molecules form channels along the a axis and mometasone furoate molecules pack in layers in the same direction. Dehydration was observed between 60 and 100 degrees C by thermogravimetric analysis with a heating rate of 10 degrees C/min. It corresponds to a broad endotherm over the same temperature range in the differential scanning calorimetry with the same heating rate. Variable temperature X-ray powder diffraction reveals that a new anhydrous form (Form 2) was fully produced above 90 degrees C. This crystalline form was converted to Form 1 after being heated above 150 degrees C; and was totally converted to the monohydrate after 1 day at 23 degrees C, 45% RH.