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This paper considers the model predictive control (MPC) of critical quality attributes (CQAs) of products in an end-to-end continuous pharmaceutical manufacturing pilot plant, which was designed and constructed at the Novartis-MIT Center for Continuous Manufacturing. Feedback control is crucial for achieving the stringent regulatory requirements on CQAs of pharmaceutical products in the presence of process uncertainties and disturbances. To this end, a key challenge arises from complex plant-wide dynamics of the integrated process units in a continuous pharmaceutical process, that is, dynamical interactions between several process units. This paper presents two plant-wide MPC designs for the end-to-end continuous pharmaceutical manufacturing pilot plant using the quadratic dynamic matrix control algorithm. The plant-wide MPC designs are based on different modeling approaches - subspace identification and linearization of nonlinear differential-algebraic equations that yield, respectively, linear low-dimensional and high-dimensional state-space models for the plant-wide dynamics. The closed-loop performance of the plant-wide MPC designs is evaluated using a nonlinear plant simulator equipped with a stabilizing control layer. The closed-loop simulation results demonstrate that the plant-wide MPC systems can facilitate effective regulation of CQAs and flexible process operation in the presence of uncertainties in reaction kinetics, persistent drifts in efficiency of filtration units, temporary disturbances in purity of intermediate compounds, and set point changes. The plant-wide MPC allows for incorporating quality-by-design considerations into the control problem through input and output constraints to ensure regulatory compliant process operation.

The acquisition of enantioenriched organic molecules is crucial in processes where the enantiomeric purity of active ingredients impacts efficacy and safety. Temperature cycling-induced deracemization (TCID) can achieve deracemization, but its effectiveness can be hindered by degradation reactions that influence the kinetics and the achievable enantioenrichment. This work characterizes the impact of degradation on the dynamic development of enantiomeric excess during the TCID process for the p -synephrine hydrochloride salt. The pilot study demonstrates that a maximum enantiomeric excess of 86% R -(-)- p -synephrine can be achieved at an intermediate batch time among all tested conditions. Degradation promoted the crystallization of a dimer with novel solid-state form, disynephrine ether dihydrochloride, which led to a substantial decrease in the slurry density of synephrine, potentially contributing to the observed decline in enantiomeric excess during the TCID process. Batch-to-batch variability in process dynamics and maximum attainable enantiomeric excess was observed, potentially attributable to the sensitivity of the process to uncontrolled initial conditions. These findings underscore the importance of accounting for degradation kinetics in the design and optimization of TCID processes for enantioenrichment., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Cocrystals can be promising means of overcoming the poor aqueous solubility of many drugs. However, precipitation of the stable drug at the cocrystal surface or in the bulk medium is often provoked during cocrystal dissolution due to high drug supersaturation, which prevents sustaining high drug concentrations for enhanced bioavailability. There is a need for predictive in vitro models that can accurately describe this cocrystal dissolution-supersaturation-precipitation (DSP) process to aid drug development and formulation design. Consideration of surface precipitation is often essential for such models given the strong impact of surface precipitation on the drug concentration during cocrystal dissolution. However, DSP models that can explicitly account for the effect of surface precipitation are currently lacking. This work presents a population balance-based model to describe in vitro cocrystal DSP behavior, which accounts for cocrystal dissolution, surface precipitation, and bulk precipitation. Dissolution experiments with carbamazepine-succinic acid cocrystals are conducted for model development and validation. The developed model captures all of the principal experimental trends and predicts the dose-dependent DSP behavior outside the regression data set with reasonable accuracy. The results show that surface precipitation is an essential component of the model. Finally, the new model is integrated with numerical optimization to illustrate how it can be used to identify an optimal dose, particle size, and amount of predissolved coformer.

Engineered living materials (ELMs) are gaining traction among synthetic biologists, as their emergent properties and nonequilibrium thermodynamics make them markedly different from traditional materials. However, the aspiration to directly use living cells as building blocks to create higher-order structures or materials, with no need for chemical modification, remains elusive to synthetic biologists. Here, we report a strategy that enables the assembly of engineered Saccharomyces cerevisiae into self-propagating ELMs via ultrahigh-affinity protein/protein interactions. These yeast cells have been genetically engineered to display the protein pairs SpyTag/SpyCatcher or CL7/Im7 on their surfaces, which enable their assembly into multicellular structures capable of further growth and proliferation. The assembly process can be controlled precisely via optical tweezers or microfluidics. Moreover, incorporation of functional motifs such as super uranyl-binding protein and mussel foot proteins via genetic programming rendered these materials suitable for uranium extraction from seawater and bioadhesion, respectively, pointing to their potential in chemical separation and biomedical applications.

Assembly of DNA-coated colloids (DNACCs) provides a practical route to programming complex self-assembled materials at the micro/nanoscale. So far, the programmability of DNACC assembly has been extensively exploited internally using different DNA sequences or colloid geometry so that the assembly is mainly manipulated with single-particle spatial resolution such as in crystallization. In this Letter, we present an acoustic approach to externally programming the DNACC assembly with control of spatial resolution over larger scales. We demonstrate assembly of the DNACCs under different acoustic frequencies from stage to stage to produce hierarchical structures that are difficult to fabricate when using DNA coating alone. By programming the acoustic wave frequency, amplitude, and phase, colloidal structures with different morphologies can be assembled. The nonspecific driving force based on acoustic radiation forces at each stage allows our approach to be adopted for most colloidal systems without specific requirements on particle or medium properties.

Formulating pharmaceutical cocrystals as inhalable dosage forms represents a unique niche in effective management of respiratory infections. Favipiravir, a broad-spectrum antiviral drug with potential pharmacological activity against SARS-CoV-2, exhibits a low aqueous solubility. An ultra-high oral dose is essential, causing low patient compliance. This study reports a Quality-by-Design (QbD)-guided development of a carrier-free inhalable dry powder formulation containing a 1:1 favipiravir-theophylline (FAV-THP) cocrystal via spray drying, which may provide an alternative treatment strategy for individuals with concomitant influenza infections and chronic obstructive pulmonary disease/asthma. The cocrystal formation was confirmed by single crystal X-ray diffraction, powder X-ray diffraction, and the construction of a temperature-composition phase diagram. A three-factor, two-level, full factorial design was employed to produce the optimized formulation and study the impact of critical processing parameters on the resulting median mass aerodynamic diameter (MMAD), fine particle fraction (FPF), and crystallinity of the spray-dried FAV-THP cocrystal. In general, a lower solute concentration and feed pump rate resulted in a smaller MMAD with a higher FPF. The optimized formulation (F1) demonstrated an MMAD of 2.93 μm and an FPF of 79.3%, suitable for deep lung delivery with no in vitro cytotoxicity observed in A549 cells.

The present study aimed to investigate how cocrystal solution-state stability may affect the polymorphic drug formation and transition during dissolution. In this work, curcumin-resorcinol (CUR-RES), curcumin-hydroquinone (CUR-HYQ) and curcumin-phloroglucinol (CUR-PHL) cocrystals were employed for dissolution studies in three buffer systems to study the effects of solvent and cocrystal thermodynamic stability. The undissolved solids were collected at designed time points and characterized by powder X-ray diffraction, differential scanning calorimetry and scanning electron microscopy. In pH 1.2 buffer, three cocrystals generated > 94% of metastable CUR form III with trace amount of stable CUR form I, while the phase purity of CUR form III recrystallized from buffers containing ethanol (EtOH) were decreased dramatically. For the same cocrystal, the cocrystal form maintained longer in the pH 1.2 buffer when compared with buffers containing EtOH. The phase purity of recrystallized CUR form III in the metastable cocrystal systems followed a linear relationship against CUR solubility, while the thermodynamically stable cocrystal resulted in a non-linear relationship. Due to different intermolecular interactions analyzed by 1 H NMR, the stable cocrystal required a higher supersaturation level to precipitate pure CUR form III, in comparison to two metastable cocrystals. Our study offers important insights into mitigating the risk of recrystallization of drug polymorphs during cocrystal dissolution and demonstrates the potential use of cocrystals for drug polymorph preparation, both of which are crucial to the pharmaceutical cocrystal development and reformulation of existing drugs., (Copyright © 2021 Elsevier B.V. All rights reserved.)

We present a simple and effective scheme of a dynamic switch for DNA nanostructures. Under such a framework of toehold-free strand displacement, blocking strands at an excess amount are applied to displace the complementation of specific segments of paired duplexes. The functional mechanism of the scheme is illustrated by modelling the base pairing kinetics of competing strands on a target strand. Simulation reveals the unique properties of toehold-free strand displacement in equilibrium control, which can be leveraged for information processing. Based on the controllable dynamics in the binding of preformed DNA nanostructures, a multi-input-multi-output (MIMO) Boolean function is controlled by the presence of the blockers. In conclusion, we implement two MIMO Boolean functions (one with 4-bit input and 2-bit output, and the other with 16-bit input and 8-bit output) to showcase the controllable dynamics., (© 2021. The Author(s).)

Characterization of cell physical biomarkers is vital to understand cell properties and applicable for disease diagnostics. Current methods used to analyze physical phenotypes involve external forces to deform the cells. Alternatively, internal tension forces via osmotic swelling can also deform the cells. However, an established assumption contends that the forces generated during hypotonic swelling concentrated on the plasma membrane are incapable of assessing the physical properties of nucleated cells. Here, we utilized an osmotic swelling approach to characterize different types of nucleated cells. Using a microfluidic device for cell trapping arrays with truncated hanging micropillars (CellHangars), we isolated single cells and evaluated the swelling dynamics during the hypotonic challenge at 1 s time resolution. We demonstrated that cells with different mechanical phenotypes showed unique swelling dynamics signature. Different types of cells can be classified with an accuracy of up to ∼99%. We also showed that swelling dynamics can detect cellular mechanical property changes due to cytoskeleton disruption. Considering its simplicity, swelling dynamics offers an invaluable label-free physical biomarker for cells with potential applications in both biological studies and clinical practice.

Directed self-assembly has great potential for the precise manufacture of structured materials at the micro/nano-scale. A local particle density often has to be controlled to make the assembly of complicated structures with no defects attainable. However, the control of spatial particle density distributions is challenged by the need for multiple actuators, kinetic trapping and the stochastic nature of self-assembly systems. In this paper, a novel feedback control approach for shaping spatial density distributions of colloidal particles is presented. The control objective is to maintain the ratio of the particle densities of two adjacent regions close to a desired value. A microfluidic device with a triple-parallel microelectrode is fabricated to provide multiple actuators for particle manipulation. The multiple-electrode actuators can be operated flexibly to either direct particles between two adjacent regions or to maintain particles within regions by preventing undesired particle movements. A feedback control scheme is implemented to control the density ratio over a broad range of tested set points. The method is generic and can be extended to include additional parallel electrodes for the control of density distributions at higher resolutions due to a modular design.

Precise alignment of small-scale building blocks into specific structural features is important for the manufacture of novel materials. Directed self-assembly is a promising route to align such small-scale building blocks with single-particle resolution. However, reliable alignment via directed self-assembly is challenging due to design uncertainty, randomness and potential disturbances acting on the system. This paper presents an integrated feedback control strategy to align colloidal particles reliably using directed self-assembly with electric field properties as manipulated variables in a microfluidic device. First, the particle density is controlled to make assembly of a defect-free structure attainable. Subsequently, a novel control method for particle alignment is implemented to self-assemble lines with single-particle resolution. The system's ergodicity is restricted systematically to assure that the density-control step at the higher hierarchy restricts the alignment-control step at the lower hierarchy. The method exploits several electrokinetic phenomena and all steps are fully automated. The approach is generic and can in principle be extended to include more density control steps to self-assemble more complicated structures.

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.

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., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

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.