A series of tubes: The continuous manufacture a finished drug product starting from chemical intermediates is reported. pilot-scale plant used novel route that incorporated many advantages continuous-flow processes to produce active pharmaceutical ingredients and the in one integrated system. As service our authors readers, this journal provides supporting information supplied by authors. Such materials are peer reviewed may be re-organized for online delivery, but not copy-edited or...

The development and operation of the synthesis workup steps a fully integrated, continuous manufacturing plant for synthesizing aliskiren, small molecule pharmaceutical, are presented. started with advanced intermediates, two synthetic away from final active pharmaceutical ingredient, ended finished tablets. entire process was run on several occasions, data presented herein corresponding to 240 h at nominal throughput 41 g h–1 aliskiren. first reaction performed solvent-free in molten...

The pharmaceutical industry has historically benefited from high profit margins for their products, and over the years limited efforts have been made to change main manufacturing concept batch into continuous. However, past decade, as a result of an increased demand more efficient cost-effective processes, interest grown in application continuous address economical technical issues field. This option is becoming viable, particularly with implementation new process analytical technology...

The design of an effective plant‐wide control strategy is a key challenge for the development future continuous pharmaceutical processes. This article presents case study structure system inspired by end‐to‐end pilot plant. A hierarchical decomposition used to classify objectives. dynamic model process generate parametric sensitivities, which provide basis synthesis loops. Simulations selected disturbances illustrate that critical quality attributes (CQAs) final product can be kept close...

Eine Serie von Röhren: Ein kontinuierlicher Prozess für die Herstellung eines Medikaments aus chemischen Intermediaten wird beschrieben. Die Anlage im Pilotmaßstab nutzt viele Vorteile Flussverfahren, um aktiven pharmazeutischen Inhaltsstoffe und das Medikament in einem integrierten System herzustellen. As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed may be re-organized for online delivery, but...

Continuous manufacturing offers potential opportunities for the improved of pharmaceutical products. A key challenge is development an appropriate control strategy. The experimental application automated strategy presented end-to-end continuous pilot plant. process starts from advanced intermediate compound and finishes with tablet formation steps. focus results on design performance loops needed to produce a slurry active ingredient solvent specified material properties. demonstrate that...

Real-time control using process analytical technology (PAT) tools is required for the implementation of continuous crystallization within integrated manufacturing (ICM) pharmaceuticals. However, appropriate selection PAT challenging, and design operation automated loops a pharmaceutical brings forward important questions. This paper discusses reactive aliskiren hemifumarate as part an ICM pilot plant. Several were used to satisfy specifications on critical materials attributes process. The...

This paper considers the model predictive control (MPC) of critical quality attributes (CQAs) products in an end-to-end continuous pharmaceutical manufacturing pilot plant, which was designed and constructed at Novartis-MIT Center for Continuous Manufacturing. Feedback is crucial achieving stringent regulatory requirements on CQAs presence process uncertainties disturbances. To this end, a key challenge arises from complex plant-wide dynamics integrated units process, that is, dynamical...

Kenics static mixers enhance mixing under laminar flow conditions. The ideal mixer achieves efficient at a low pressure drop. A modified design of the is analyzed, featuring gaps between elements, which can achieve same level as conventional but with fewer elements and substantially lower effects entrances exits are enhanced by introduction elements. performances based on right–left right–right configurations different gap lengths characterized in terms drop, coefficient variance...

Formulating pharmaceutical cocrystals as inhalable dosage forms represents a unique niche in effective management of respiratory infections. Favipiravir, broad-spectrum antiviral drug with potential pharmacological activity against SARS-CoV-2, exhibits low aqueous solubility. An ultra-high oral dose is essential, causing patient compliance. This study reports Quality-by-Design (QbD)-guided development carrier-free dry powder formulation containing 1:1 favipiravir–theophylline (FAV-THP)...

Abstract A novel data‐driven methodology is presented for developing mathematical models crystallization processes. The approach based on the sparse identification of nonlinear dynamics (SINDy) method, which iterates between a partial least‐squares fit and sparsity‐promoting step leading to discovery interpretable models. performance SINDy characterized kinetics in mixed tank operated continuous mode, isothermal lysozyme batch stirred cooling paracetamol. method robust against noise. Good...

Cocrystallization represents an emerging approach to tackle the issues associated with pharmaceutical product performance and processing, owing its capability of modifying a variety physicochemical properties. In this study, we sought modify crystal form itraconazole (ITZ) suberic acid (SUB) via rapid solvent removal methods, namely rotary evaporation spray drying. A phase pure ITZ-SUB cocrystal, which could not be obtained by traditional cocrystallization was successfully prepared...

Crystallization is an attractive method for separation and purification of large biomolecules such as proteins due to inherent advantages related product composition, stability, process throughput. However, the lack control over nucleation growth protein crystals complicates design operation. Electric fields have been used improve location induction time in small batches. To adopt electric-field-assisted crystallization a method, novel device based on continuous flow presented. The...

The metastable needlelike form of lysozyme can be obtained from continuous crystallization in mixed-suspension mixed-product-removal (MSMPR) crystallizers for conditions at which the stable tetragonal is batch crystallization. A 3D-printed airlift crystallizer and stirred tank are used, both approximate an MSMPR well. influence residence time, precipitant concentration, agitation mechanism on attainable solid-state presented. crystals appear after nucleation form. An earlier transition to...

Abstract We present a simple and effective scheme of dynamic switch for DNA nanostructures. Under such framework toehold-free strand displacement, blocking strands at an excess amount are applied to displace the complementation specific segments paired duplexes. The functional mechanism is illustrated by modelling base pairing kinetics competing on target strand. Simulation reveals unique properties displacement in equilibrium control, which can be leveraged information processing. Based...

Direct nucleation control (DNC) is a feedback strategy, based on an in situ measurement of the number particles. In batch cooling crystallization processes, DNC approach utilizes temperature cycling to supersaturation profile during batch. As result this cycling, product crystals with large mean size and narrow distribution can be achieved due dissolution undesired fines. However, implementing cycles may come at expense significantly prolonged times conventional heat transfer limitations...

Solvent usage is a major source of environmental waste in pharmaceutical industry. The current paradigm shift toward continuous manufacturing industry has renewed the interest crystallization, which offers prospect easy solvent recycling. However, selection solvents for an integrated crystallization processes nontrivial due to likely trade‐off between optimal properties and separation A systematic approach simultaneous optimization process conditions including recycling presented. unified...

Secondary nucleation is suppressed in an air-lift crystallizer at levels of supersaturation where a stirred clear contribution secondary visible. A comparison batch crystallization l-ascorbic acid and presented. The results demonstrate that low supersaturation, can be both the crystallizer. At higher starts to dominate intermediate level final product obtained from However, experiments with similar conditions show significantly smaller nucleation. observed enlargement operating window terms...

The concept of membrane-assisted crystallization using reverse osmosis (MaC-RO) shows a high potential in decreasing energy conversion as compared to evaporative crystallization. A setup has been constructed for MaC-RO, two separate loops membrane separation and In this study we focus on the characterization performance solvent removal from an aqueous adipic acid solution under conditions. semiempirical model was developed flux function temperature, concentration, pressure difference across...