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Open accessJournal ArticleDOI: 10.1021/ACS.OPRD.0C00504

Integrated Continuous Pharmaceutical Technologies—A Review

02 Mar 2021-Organic Process Research & Development (American Chemical Society (ACS))-Vol. 25, Iss: 4, pp 721-739
Abstract: Innovation in the pharmaceutical industry has been limited for a long time to the research and development of new active compounds; meanwhile, the structure of the production, dominated by batchwis...

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Topics: Tableting (52%)
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8 results found


Open access
13 Oct 2016-
Abstract: The pharmaceutical industry is starting to adopt continuous processing; however one missing component is an appropriately scaled unit for continuous isolation which can filter, wash and dry active pharmaceutical ingredients (APIs). This gap is particularly pressing in process development where API is available in limited quantities yet it is desirable to develop the isolation using continuous equipment which matches the equipment to be used in manufacturing to minimise scale up risks. This paper explores what such a unit must achieve and evaluates a prototype system.

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3 Citations



Journal ArticleDOI: 10.1016/J.CHERD.2021.09.013
Abstract: This paper describes a case study on integrating a continuous flow reaction and continuous crystallization. For the synthesis of Fmoc- l -Phe- l -Phe-OMe, we previously reported that this coupling reaction via acid chloride could be completed in approximately 1 min under continuous conditions. However, the crystals of Fmoc- l -Phe- l -Phe-OMe were obtained by batch crystallization. The quenched solution was unstable and rapid transfer to the crystallization step was desirable. Under such circumstances, continuous crystallization was considered to be the most reliable strategy for a robust scalable synthesis methodology. For this, we tested a mixed-suspension mixed-product-removal (MSMPR) crystallizer that allows for rapid crystallization without seeding and clogging. The steady state for the continuous crystallization could be monitored by particle size distribution using in-line monitoring. As a result, the integration of a continuous flow reaction and continuous crystallization worked smoothly for 2 h, which showed the feasibility of manufacturing using this integration system.

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Topics: Crystallization (59%)

1 Citations


Open accessJournal ArticleDOI: 10.3390/PR9091502
25 Aug 2021-
Abstract: Toward further implementation of continuous tablet manufacturing, one key issue is the time needed for start-up operation because it could lead to lower product yield and reduced economic performance. The behavior of the start-up operation is not well understood; moreover, the definition of the start-up time is still unclear. This work investigates the effects of process parameters on the start-up operation in continuous wet granulation, which is a critical unit operation in solid drug manufacturing. The profiles of torque and granule size distribution were monitored and measured for the first hour of operation, including the start-up phase. We analyzed the impact of process parameters based on design of experiments and performed an economic assessment to see the effects of the start-up operation. The torque profiles indicated that liquid-to-solid ratio and screw speed would affect the start-up operation, whereas different start-up behavior resulted in different granule size. Depending on the indicator used to define the start-up operation, the economic optimal point was significantly different. The results of this study stress that the start-up time differs according to the process parameters and used definition, e.g., indicators and criteria. This aspect should be considered for the further study and regulation of continuous manufacturing.

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Topics: Unit operation (53%)

1 Citations


Open accessJournal ArticleDOI: 10.3390/PR9091537
29 Aug 2021-
Abstract: Continuous small-scale production is currently of utmost interest for fine chemicals and pharmaceuticals. For this purpose, equipment and process concepts in consideration of the hurdles for solids handling are required to transfer conventional batch processing to continuous operation. Based on empirical equations, pressure loss constraints, and an expandable modular system, a coiled flow inverter (CFI) crystallizer with an inner diameter of 1.6 mm was designed. It was characterized concerning its residence time behavior, tested for operation with seed crystals or an ultrasonic seed crystal unit, and evaluated for different purging mechanisms for stable operation. The residence time behavior in the CFI corresponds to ideal plug flow behavior. Crystal growth using seed crystals was demonstrated in the CFI for two amino acids. For fewer seed crystals, higher crystal growth rates were determined, while at the same time, secondary nucleation was observed. Feasibility for the interconnection of a sonicated seeding crystal unit could be shown. However, the hurdles are also identified and discussed. Prophylactic flushing combined with a photosensor for distinguishing between solvent and suspension phase can lead to stable and resource-efficient operation. The small-scale CFI technology was investigated in detail, and the limits and opportunities of the technology are presented here.

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Topics: Continuous operation (54%), Seed crystal (51%)

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226 results found


Journal ArticleDOI: 10.1002/ADMA.200400719
Dan Li1, Younan XiaInstitutions (1)
19 Jul 2004-Advanced Materials
Abstract: Electrospinning provides a simple and versatile method for generating ultrathin fibers from a rich variety of materials that include polymers, composites, and ceramics. This article presents an overview of this technique, with focus on progress achieved in the last three years. After a brief description of the setups for electrospinning, we choose to concentrate on the mechanisms and theoretical models that have been developed for electrospinning, as well as the ability to control the diameter, morphology, composition, secondary structure, and spatial alignment of electrospun nanofibers. In addition, we highlight some potential applications associated with the remarkable features of electrospun nanofibers. Our discussion is concluded with some personal perspectives on the future directions in which this wonderful technique could be pursued.

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Topics: Nanofiber (56%), Electrospinning (56%)

4,798 Citations


Open accessJournal ArticleDOI: 10.1016/J.JHEALECO.2016.01.012
Abstract: The research and development costs of 106 randomly selected new drugs were obtained from a survey of 10 pharmaceutical firms. These data were used to estimate the average pre-tax cost of new drug and biologics development. The costs of compounds abandoned during testing were linked to the costs of compounds that obtained marketing approval. The estimated average out-of-pocket cost per approved new compound is $1395 million (2013 dollars). Capitalizing out-of-pocket costs to the point of marketing approval at a real discount rate of 10.5% yields a total pre-approval cost estimate of $2558 million (2013 dollars). When compared to the results of the previous study in this series, total capitalized costs were shown to have increased at an annual rate of 8.5% above general price inflation. Adding an estimate of post-approval R&D costs increases the cost estimate to $2870 million (2013 dollars).

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Topics: Cost estimate (56%)

1,657 Citations


Journal ArticleDOI: 10.1007/S11095-007-9511-1
Abstract: The purpose of this paper is to discuss the pharmaceutical Quality by Design (QbD) and describe how it can be used to ensure pharmaceutical quality. The QbD was described and some of its elements identified. Process parameters and quality attributes were identified for each unit operation during manufacture of solid oral dosage forms. The use of QbD was contrasted with the evaluation of product quality by testing alone. The QbD is a systemic approach to pharmaceutical development. It means designing and developing formulations and manufacturing processes to ensure predefined product quality. Some of the QbD elements include: Using QbD, pharmaceutical quality is assured by understanding and controlling formulation and manufacturing variables. Product testing confirms the product quality. Implementation of QbD will enable transformation of the chemistry, manufacturing, and controls (CMC) review of abbreviated new drug applications (ANDAs) into a science-based pharmaceutical quality assessment.

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Topics: Critical quality attributes (57%), Quality by Design (55%), New product development (53%) ... read more

916 Citations


Journal ArticleDOI: 10.1002/ANIE.201409318
01 Jun 2015-Angewandte Chemie
Abstract: In the past few years, continuous-flow reactors with channel dimensions in the micro- or millimeter region have found widespread application in organic synthesis. The characteristic properties of these reactors are their exceptionally fast heat and mass transfer. In microstructured devices of this type, virtually instantaneous mixing can be achieved for all but the fastest reactions. Similarly, the accumulation of heat, formation of hot spots, and dangers of thermal runaways can be prevented. As a result of the small reactor volumes, the overall safety of the process is significantly improved, even when harsh reaction conditions are used. Thus, microreactor technology offers a unique way to perform ultrafast, exothermic reactions, and allows the execution of reactions which proceed via highly unstable or even explosive intermediates. This Review discusses recent literature examples of continuous-flow organic synthesis where hazardous reactions or extreme process windows have been employed, with a focus on applications of relevance to the preparation of pharmaceuticals.

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Topics: Microreactor (55%)

877 Citations


Journal ArticleDOI: 10.1021/ACS.CHEMREV.7B00183
01 Jun 2017-Chemical Reviews
Abstract: Flow chemistry involves the use of channels or tubing to conduct a reaction in a continuous stream rather than in a flask Flow equipment provides chemists with unique control over reaction parameters enhancing reactivity or in some cases enabling new reactions This relatively young technology has received a remarkable amount of attention in the past decade with many reports on what can be done in flow Until recently, however, the question, “Should we do this in flow?” has merely been an afterthought This review introduces readers to the basic principles and fundamentals of flow chemistry and critically discusses recent flow chemistry accounts

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846 Citations