RESUMEN
The recent and rapid increase in the discovery of new RNA therapeutics has created the perfect terrain to explore an increasing number of novel targets. In particular, antisense oligonucleotides (ASOs) have long held the promise of an accelerated and effective drug design compared to other RNA-based therapeutics. Although ASOs in silico design has advanced distinctively in the past years, especially thanks to the several predictive frameworks for RNA folding, it is somehow limited by the wide approximation of calculating sequence affinity based on RNA-RNA/DNA sequences. None of the ASO modifications are taken into consideration, losing hybridization information particularly fundamental to ASOs that elicit their function through RNase H1-mediated mechanisms. Here we present an inexpensive and enhanced biophysical screening strategy to investigate the affinity of ASOs for their target RNA using several biophysical techniques such as high throughput differential scanning fluorimetry (DSF), circular dichroism (CD), isothermal calorimetry (ITC), surface plasmon resonance (SPR) and small-angle X-ray scattering (SAXS).
RESUMEN
Granule structure has a key influence on tablet critical quality attributes. The ability to control this structure through excipient choice is an important part of formulation development. Mannitol is a popular diluent and the choice of input grade has been shown to impact granule properties. Allopurinol formulations containing two grades of mannitol (Pearlitol 160C and 200SD) were prepared by wet-granulation (twin-screw and high-shear) at different liquid/solid ratios (0.3 and 0.6 g/g). The particle and bulk properties were characterised by a range of techniques and linked to flow performance and tablet tensile strength during compression on a rotary tablet press. During granulation, 200SD underwent a polymorphic transition from a mixture of α and ß to predominantly ß. This transition was accompanied by a morphology change. Mannitol needles were formed, giving more porous granules with a higher specific surface area, which led to poorer flow properties but higher tablet tensile strength. This study concludes that understanding the effect of mannitol grade is a crucial part of formulation selection.
