Richard Lakerveld

End-to-End Continuous Manufacturing of Pharmaceuticals: Integrated Synthesis, Purification, and Final Dosage Formation†

A series of tubes: The continuous manufacture of a finished drug product starting from chemical intermediates is reported. The continuous pilot-scale plant used a novel route that incorporated many advantages of continuous-flow processes to produce active pharmaceutical ingredients and the drug product in one integrated system.

The application of a task-based concept for the design of innovative industrial crystallizers

A new task-based design approach [Menon, A. R., Pande, A. A., Kramer, H. J. M., Grievink, J., & Jansens, P. J. (2007). A task-based synthesis approach toward the design of industrial crystallization process units. Industrial & Engineering Chemistry Research, 46, 3979] is applied to design a crystallization process unit. Task-based design involves the conceptual built-up of a process (unit) from functional building blocks called tasks, which represent fundamental physical events. The motivation for developing this approach is to get a better control over the physical events governing crystalline product quality. To deliver a proof of concept, two lines of research are followed. First of all, several small scale experiments are designed to demonstrate practical feasibility of the approach. The new equipment allows for isolation and manipulation of individual crystallization tasks. Second, a model based on the experimentally tested tasks is developed for a crystallizer design and used in dynamic optimization of three case studies. The results show that completely different and tight product specifications can be achieved with the same design simply by changing the operational policy of the crystallizer. This remarkable increase in flexibility to achieve a broad range of product qualities is the result of the ability to control the rate at which individual crystallization tasks are executed as well as the material flows between those tasks.

A master-equation approach to simulate kinetic traps during directed self-assembly

Robust directed self-assembly of non-periodic nanoscale structures is a key process that would enable various technological breakthroughs. The dynamic evolution of directed self-assemblies towards structures with desired geometries is governed by the rugged potential energy surface of nanoscale systems, potentially leading the system to kinetic traps. To study such phenomena and to set the framework for the directed self-assembly of nanoparticles towards structures with desired geometries, the development of a dynamic model involving a master equation to simulate the directed self-assembly process is presented. The model describes the probability of each possible configuration of a fixed number of nanoparticles on a domain, including parametric sensitivities that can be used for optimization, as a function of time during self-assembly. An algorithm is presented that solves large-scale instances of the model with linear computational complexity. Case studies illustrate the influence of several degrees of freedom on directed self-assembly. A design approach that systematically decomposes the ergodicity of the system to direct self-assembly of a targeted configuration with high probability is illustrated. The prospects for extending such an approach to larger systems using coarse graining techniques are also discussed.

Plant-wide model predictive control for a continuous pharmaceutical process

Integrated continuous manufacturing offers ample opportunities for efficient and cost-effective pharmaceutical processes. Plant-wide control is required for meeting the stringent regulatory requirements on quality attributes of products in continuous pharmaceutical manufacturing processes. This paper investigates plant-wide model predictive control (MPC) of an end-to-end continuous pharmaceutical manufacturing process with nearly 8000 state variables. The process includes two series of chemical synthesis and crystallization steps, followed by tablet formation steps. A subspace identification approach is adopted to obtain a linear low-dimensional description of the complex plant-wide dynamics. Quadratic dynamic matrix control algorithm is used to enable input-output formulation of the control problem, whose online computational cost is independent of the state dimension. The performance of the plant-wide MPC system is evaluated in a closed-loop setting with an existing nonlinear plant simulator equipped with a stabilizing control layer. The closed-loop simulation results demonstrate the ability of plant-wide MPC to facilitate flexible process operation and effective regulation of quality attributes of tablets.

11-Azaartemisinin cocrystals with preserved lactam : acid heterosynthons

11-Azaartemisinin (11-Aza) is a potent anti-malarial drug more readily able to form cocrystals than its parent compound. 13 new 1 : 1 and 2 : 1 cocrystal phases from 25 mono- and bi-functional acids are reported here in excellent yield and purity by liquid assisted grinding. X-ray structures of several of these cocrystals reveal R22(8) heterosynthons with short OH–OC H-bonds ≤2.60 A between the 11-Aza lactam and the coformer acid groups. The new phases can show enhanced aqueous solubility of 11-Aza of 3× after 12 h. Notably diastereospecific cocrystal formation can occur, with the DL-mandelic acid system yielding solely the 11-Azaart : D-mandelic acid 1 : 1 product.

A review on recent technologies for the manufacture of pulmonary drugs

This review discusses recent developments in the manufacture of inhalable dry powder formulations. Pulmonary drugs have distinct advantages compared with other drug administration routes. However, requirements of drugs properties complicate the manufacture. Control over crystallization to make particles with the desired properties in a single step is often infeasible, which calls for micronization techniques. Although spray drying produces particles in the desired size range, a stable solid state may not be attainable. Supercritical fluids may be used as a solvent or antisolvent, which significantly reduces solvent waste. Future directions include application areas such as biopharmaceuticals for dry powder inhalers and new processing strategies to improve the control over particle formation such as continuous manufacturing with in-line process analytical technologies.

Towards robust fabrication of non-periodic nanoscale systems via directed self assembly

Abstract Robust directed self assembly of non-periodic nanoscale structures is a key tool that would enable various technological breakthroughs. The dynamics of directed self assembly face challenges as a result of the rugged potential energy surface of nanoscale systems. The development of a dynamic model involving a master equation to simulate directed self assembly is presented. The model describes the probability of each possible configuration of a fixed number of nanoparticles as function of time during self assembly. Two case studies demonstrate the ability of the model to represent kinetic traps. In future work, the approach presented will be used for dynamic optimization of self assembly in order to identify optimal routes towards desired nanoscale structures.

Control system implementation and plant-wide control of continuous pharmaceutical manufacturing pilot plant (end-to-end manufacturing process)

Abstract The integration of unit operations into an end-to-end continuous pharmaceutical process poses new challenges and opportunities for control compared to traditional batch processes. The continuous exchange of material and energy between unit operations call for a process control strategy that starts from the plant as a whole rather than from individual unit operations. This chapter discusses a systematic approach for such plant-wide control. A literature case is discussed, which involves systematic synthesis of the plant-wide control structure and dynamic simulations for validation. Furthermore, a simplified version of the synthesized control structure was applied experimentally to an end-to-end continuous pharmaceutical pilot plant. Finally, the application of more advanced control strategies is discussed for this case involving optimal averaging level control to utilize buffer capacity of mixed tanks in an automated way and MPC to improve control performance and enable the explicit definition of constraints.

CHAPTER 8:Photocatalysis: Past Achievements and Future Trends

Photocatalysis holds great promise to enable sustainable chemical processes related to, for example, the production of renewable fuels or prevention of pollution through advanced oxidation. However, despite significant progress and continuing interest from academia, industry and policy makers, key challenges have to be overcome. First, ideal photocatalytic materials should obey stringent requirements related to stability, cost, bandgap compatibility, availability of raw materials, and photon efficiency. In spite of certain limitations, such as an undesirable band gap, titania remains the frontrunner in terms of research and commercial applications. This chapter briefly discusses strategies to expand the allowable bandgap of photocatalytic materials. A key focus is on the use of metal–organic frameworks (MOFs). MOFs have an organic–inorganic structure, exhibit a high surface area and can be tuned with tremendous flexibility, which makes them promising candidates to advance photocatalysis. Second, the development of photocatalytic reactors is discussed. The design and operation of photocatalytic reactors is not trivial due to requirements for efficient contact of reactants with the catalyst and efficient utilization of photons. The former requirement is common for any heterogeneous catalytic reactor whereas the latter is unique for photocatalysis. Consequently, numerous reactor configurations have been designed specifically for photocatalysis of which a selection is reviewed in this chapter. Recent advances in simulation and optimization of mathematical models of photocatalytic reactors offer an important support for design. Furthermore, novel solid-state light sources provide opportunities for increased robustness, reduced costs and improved flexibility for the design and operation of future photocatalytic reactors.

The application of an automated plant-wide control strategy for a continuous pharmaceutical pilot plant

Continuous manufacturing has the potential to provide substantial improvements to the manufacturing of pharmaceutical products compared to traditional batch-wise manufacturing. A key challenge is the development of effective control strategies for this new type of process. This contribution presents the experimental application of an automated plant-wide control strategy for a continuous pharmaceutical pilot plant that produces a pharmaceutical product from start to finish in a continuous fashion. The performance of the automated control loops demonstrate the maintenance of the critical material attributes close to their desired setpoints for a sustained period of operation.