Advances in drug potency and tailored therapeutics are promoting pharmaceutical manufacturing to transition from a traditional batch paradigm to more flexible continuous processing. Here we report the development of a multistep continuous-flow CGMP (current good manufacturing practices) process that produced 24 kilograms of prexasertib monolactate monohydrate suitable for use in human clinical trials. Eight continuous unit operations were conducted to produce the target at roughly 3 kilograms per day using small continuous reactors, extractors, evaporators, crystallizers, and filters in laboratory fume hoods. Success was enabled by advances in chemistry, engineering, analytical science, process modeling, and equipment design. Substantial technical and business drivers were identified, which merited the continuous process. The continuous process afforded improved performance and safety relative to batch processes and also improved containment of a highly potent compound.

The densest amorphous packing of rigid particles is known as random close packing. It has long been appreciated that higher densities are achieved by using collections of particles with a variety of sizes. For spheres, the variety of sizes is often quantified by the polydispersity of the particle size distribution: the standard deviation of the radius divided by the mean radius. Several prior studies quantified the increase of the packing density as a function of polydispersity. A particle size distribution is also characterized by its skewness, kurtosis, and higher moments, but the influence of these parameters has not been carefully quantified before. In this work, we numerically generate many sphere packings with different particle radii distributions, varying polydispersity and skewness independently of one another. We find that the packing density can increase significantly with increasing skewness and in some cases skewness can have a larger effect than polydispersity. However, the packing fraction is relatively insensitive to the higher moment value of the kurtosis. We present a simple empirical formula for the value of the random close packing density as a function of polydispersity and skewness.

Studies of random close packing of spheres have advanced our knowledge about the structure of systems such as liquids, glasses, emulsions, granular media, and amorphous solids. When these systems are confined their structural properties change. To understand these changes we study random close packing in finite-sized confined systems, in both two and three dimensions. Each packing consists of a 50-50 binary mixture with particle size ratio 1.4. The presence of confining walls significantly lowers the overall maximum area fraction (or volume fraction in three dimensions). A simple model is presented which quantifies the reduction in packing due to wall-induced structure. This wall-induced structure decays rapidly away from the wall, with characteristic length scales comparable to the small particle diameter.

Mussels are well known for their ability to generate and maintain strong, long-lasting adhesive bonds under hostile conditions. Many prior studies attribute their adhesive strength to the strong chemical interactions between the holdfast and substrate. While chemical interactions are certainly important, adhesive performance is also determined by contact geometry, and understanding the coupling between chemical interactions and the plaque shape and mechanical properties is essential in deploying bioinspired strategies when engineering improved adhesives. To investigate how the shape and mechanical properties of the mussel's plaque contribute to its adhesive performance, we use a custom built load frame capable of fully characterizing the dynamics of the detachment. With this, we can pull on samples along any orientation, while at the same time measuring the resulting force and imaging the bulk deformations of the plaque as well as the holdfast-substrate interface where debonding occurs. We find that the force-induced yielding of the mussel plaque improves the bond strength by two orders of magnitude and that the holdfast shape improves bond strength by an additional order of magnitude as compared to other simple geometries. These results demonstrate that optimizing the contact geometry can play as important a role on adhesive performance as optimizing the chemical interactions as observed in other organisms and model systems.

We experimentally study the jamming of quasi-two-dimensional emulsions. Our experiments consist of oil-in-water emulsion droplets confined between two parallel plates. From the droplet outlines, we can determine the forces between every droplet pair to within 8% over a wide range of area fractions φ . We study three bidisperse samples that jam at area fractions φ c ≈ 0.86. Our data show that for φ > φ c , the contact numbers and pressure have power-law dependence on φ − φ c in agreement with the critical scaling found in numerical simulations. Furthermore, we see a link between the interparticle force law and the exponent for the pressure scaling, supporting prior computational observations. We also observe linear-like force chains (chains of large interdroplet forces) that extend over 10 particle lengths, and examine the origin of their linearity. We find that the relative orientation of large force segments are random and that the tendency for force chains to be linear is not due to correlations in the direction of neighboring large forces, but instead occurs because the directions are biased towards being linear to balance the forces on each droplet.