Application of image-based particle size and shape characterization systems in the development of small molecule pharmaceuticals.

With the introduction of Quality by Design (QbD) to the pharmaceutical industry, there has been an increased focus on understanding the nature of particles and composites, with the aim of understanding and modeling how they interact in complex systems, leading to robust dosage forms. Particle characterization tools have evolved and now enable a greater level of understanding of powder systems and blends. Tools that can elucidate the size and shape of particulate systems can provide significantly more information about the nature of the particles being analyzed, than a conventional particle size measurement. Although accurate size and shape analysis has always been regarded as the "gold standard" in understanding the nature of particulate systems, neither imaging systems nor IT infrastructure was sufficiently developed to allow this to be performed with sufficient accuracy in a timely manner. The aim of this review is to provide an insight into developments in the field of size and shape analysis of pharmaceutical systems, and how these can now realistically be used as robust development tools. Examples of current uses of such technologies will be explored as well as investigating future applications such as combined image/spectroscopic analyses to track single components within blended systems.

From bench to humans: formulation development of a poorly water soluble drug to mitigate food effect.

This study presents a formulation approach that was shown to mitigate the dramatic food effect observed for a BCS Class II drug. In vitro (dissolution), in vivo (dog), and in silico (GastroPlus®) models were developed to understand the food effect and design strategies to mitigate it. The results showed that such models can be used successfully to mimic the clinically observed food effect. GastroPlus® modeling showed that food effect was primarily due to the extensive solubilization of the drug into the dietary lipid content of the meal. Several formulations were screened for dissolution rate using the biorelevant dissolution tests. Surfactant type and binder amount were found to play a significant role in the dissolution rate of the tablet prototypes that were manufactured using a high-shear wet granulation process. The performance of the lead prototypes (exhibiting best in vitro dissolution performance) was tested in dogs and human subjects. A new formulation approach, where vitamin E TPGS was included in the tablet formulation, was found to mitigate the food effect in humans.

Processing challenges with solid dosage formulations containing vitamin E TPGS.

The objective of this study is to investigate processing challenges associated with the incorporation of Vitamin E TPGS (d-α tocopheryl polyethylene glycol 1000 succinate) into solid pharmaceutical dosage forms. For this work, a wet granulation process (high-shear and fluid bed) was used and Vitamin E TPGS was added as part of the binder solution during granulation. It was shown that Vitamin E TPGS can be incorporated into a prototype formulation at 10% w/w concentration without any significant processing challenges. However, the resulting granulations could only be compressed successfully at low tablet press speeds (dwell time ~100 ms). When compressed at low dwell times (<20 ms) representative of commercial tablet manufacturing, a significant loss in compactability was observed. In addition, several other tablet defects were observed. It was shown that intragranular incorporation of Aeroperl(®) 300, a granulated form of colloidal silicon dioxide, was able to overcome these compaction problems. The formulation consisting of Aeroperl(®) 300 showed significantly lower granule particle size, higher granule porosity and higher compactability as compared to the formulation without Aeroperl(®) 300.