Modeling of pharmaceutical filtration and continuous integrated crystallization-filtration processes

Nagy, Brigitta; Szilágyi, Botond; Domokos, András; Tacsi, Kornélia; Pataki, Hajnalka; Marosi, György; Nagy, Zsombor Kristóf; Nagy, Zoltán K.

doi:10.1016/j.cej.2020.127566

Cited by 28 publications

(27 citation statements)

References 47 publications

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“…Nagy et al developed the model of an integrated continuous crystallization-filtration system in 2020. 180 In this publication the effect of slurry properties on filtration performance was studied, and simulations were carried out with the integrated system which showed good correspondence with experimental data. 4.3.…”

Section: Integrated Continuous Crystallization and Filtrationmentioning

confidence: 95%

“…A unique impeller was applied to enhance the processability of needle-like crystals of ciprofloxacin hydrochloride, and this way they successfully reduced the amount of lumps in the material following filtration and drying. Nagy et al developed the model of an integrated continuous crystallization-filtration system in 2020 . In this publication the effect of slurry properties on filtration performance was studied, and simulations were carried out with the integrated system which showed good correspondence with experimental data.…”

Section: Recent Progress In Continuous Pharmaceutical Technologiesmentioning

confidence: 99%

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Integrated Continuous Pharmaceutical Technologies—A Review

Domokos

Nagy

Szilágyi

et al. 2021

Org. Process Res. Dev.

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103

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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 batchwise technologies, has not changed to date. As has already been demonstrated in several other industrial sectors, continuous manufacturing (CM) has many advantages over batch processes. Faster, cheaper, and more flexible production can be developed with a significantly higher level of quality assurance. In the recent years the main regulatory agencies recognized the need for a change in drug production and started to promote continuous technologies and encourage pharmaceutical companies to develop and adapt such processes. As a result, by today extensive research was conducted in the various fields of pharmaceutical technologies from drug substance to drug product manufacturing. Many publications deal with synthetic steps carried out in flow reactors and crystallizations implemented in a continuous manner, and on the formulation side continuous filtration, drying, granulation, and blending have all been studied to a lesser or greater extent. Moreover, besides the modification of these traditional processes to continuous operation, novel, intrinsically continuous technologies are being studied as well. In order to entirely exploit the advantages of CM, the mainly separately developed processes need to be integrated to form end-to-end systems from the raw materials to the final dosage forms. However, even the integration of two technological steps is a challenging task. The development of end-to-end systems requires deep process understanding and a holistic approach toward process development and optimization. The aim of this work is to give insight into the state-of-the-art and new directions in integrated continuous pharmaceutical technologies by critically reviewing the recent literature of the broad field.

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Section: Integrated Continuous Crystallization and Filtrationmentioning

confidence: 95%

Section: Recent Progress In Continuous Pharmaceutical Technologiesmentioning

confidence: 99%

Integrated Continuous Pharmaceutical Technologies—A Review

Domokos

Nagy

Szilágyi

et al. 2021

Org. Process Res. Dev.

Self Cite

103

View full text Add to dashboard Cite

show abstract

“…Alconbury Weston Ltd. launched the continuous filter carousel (CFC) to the market. A multitude of current publications shows the potential of automated, cyclic batch filtration in the CFC [9,[15][16][17][18][19][20][21][22]. A second concept, the continuous rotary plate filter (CRPF) was invented as part of an integrated continuous manufacturing pilot plant of Continuus Pharmaceuticals.…”

Section: Introductionmentioning

confidence: 99%

Continuous Isolation of Particles with Varying Aspect Ratios up to Thin Needles Achieving Free-Flowing Products

2022

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The continuous vacuum screw filter (CVSF) for small-scale continuous product isolation of suspensions was operated for the first time with cuboid-shaped and needle-shaped particles. These high aspect ratio particles are very common in pharmaceutical manufacturing processes and provide challenges in filtration, washing, and drying processes. Moreover, the flowability decreases and undesired secondary processes of attrition, breakage, and agglomeration may occur intensively. Nevertheless, in this study, it is shown that even cuboid and needle-shaped particles (l-alanine) can be processed within the CVSF preserving the product quality in terms of particle size distribution (PSD) and preventing breakage or attrition effects. A dynamic image analysis-based approach combining axis length distributions (ALDs) with a kernel-density estimator was used for evaluation. This approach was extended with a quantification of the center of mass of the density-weighted ALDs, providing a measure to analyze the preservation of the inlet PSD statistically. Moreover, a targeted residual moisture below 1% could be achieved by adding a drying module (Tdry = 60 °C) to the modular setup of the CVSF.

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“…with regard to final residual moisture reduction [16]. In further studies carried out by DOMOKOS ET AL., NAGY ET AL., and LIU ET AL., emphasis was put on a systematic analysis of the relations between operational parameters and CQAs [17][18][19]. The second approach of creating a full-continuous apparatus for solid-liquid separation was introduced by MASCIA ET AL.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, the definition of CQAs and the systematic manipulation by varied operating parameters is the main part of the quality-by-design (QbD) approach [8]. Regarding filtration performance, filter clogging is reported in several cases as a challenge of connecting a continuous crystallization with a solid-liquid separation step [4,[16][17][18][19]. This phenomenon was not quantified towards potential influence factors (fine fraction, supersaturation) affecting the clogging of the apparatuses used.…”

Section: Introductionmentioning

confidence: 99%

Towards Continuous Primary Manufacturing Processes—Particle Design through Combined Crystallization and Particle Isolation

et al. 2021

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Integrated continuous manufacturing processes of active pharmaceutical ingredients (API) provide key benefits concerning product quality control, scale-up capability, and a reduced time-to-market. Thereby, the crystallization step, which is used in approximately 90% of API productions, mainly defines the final API properties. This study focuses on the design and operation of an integrated small-scale process combining a continuous slug flow crystallizer (SFC) with continuous particle isolation using the modular continuous vacuum screw filter (CVSF). By selective adjustment of supersaturation and undersaturation, the otherwise usual blocking could be successfully avoided in both apparatuses. It was shown that, during crystallization in an SFC, a significant crystal growth of particles (Δd50,3≈ 220 µm) is achieved, and that, during product isolation in the CVSF, the overall particle size distribution (PSD) is maintained. The residual moistures for the integrated process ranged around 2% during all experiments performed, ensuring free-flowing particles at the CVSF outlet. In summary, the integrated setup offers unique features, such as its enhanced product quality control and fast start-up behavior, providing a promising concept for integrated continuous primary manufacturing processes of APIs.

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Modeling of pharmaceutical filtration and continuous integrated crystallization-filtration processes

Cited by 28 publications

References 47 publications

Integrated Continuous Pharmaceutical Technologies—A Review

Integrated Continuous Pharmaceutical Technologies—A Review

Continuous Isolation of Particles with Varying Aspect Ratios up to Thin Needles Achieving Free-Flowing Products

Towards Continuous Primary Manufacturing Processes—Particle Design through Combined Crystallization and Particle Isolation

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