Attila Farkas | Budapest University of Technology and Economics (original) (raw)

Papers by Attila Farkas

Journal of Pharmaceutical Innovation

Purpose In continuous manufacturing (CM), the material traceability and process dynamics can be i... more Purpose In continuous manufacturing (CM), the material traceability and process dynamics can be investigated by residence time distribution (RTD). Many of the unit operations used in the pharma industry were characterized by dead time–dominated RTD. Even though feasible and proper feedback control is one of the many advantages of CM, its application is challenging in these cases. This study aims to develop a feedback control, implementing the RTD in a Smith predictor control structure in a continuous powder blender line. Methods Continuous powder blending was investigated with near-infrared spectroscopy (NIR), and the blending was controlled through a volumetric feeder. A MATLAB GUI was developed to calculate and control the concentration of the API based on the chemometric evaluation of the spectra. The programmed GUI changed the feeding rate based on the proportional integral derivative (PID) and the Smith predictor, which implemented the RTD of the system. The control structures ...

Biotechnology Journal, 2022

An innovative, Raman spectroscopy-based monitoring and control system is introduced in this paper... more An innovative, Raman spectroscopy-based monitoring and control system is introduced in this paper for designing dynamic feeding strategies that allow the maintenance of key cellular nutrients at an ideal level in Chinese hamster ovary cell culture. The Partial Least Squares calibration models built for glucose, lactate and 16 (out of 20) individual amino acids had very good predictive power with low root mean square errors values and high square correlation coefficients. The developed models used for real-time measurement of nutrient and by-product concentrations allowed us to gain better insight into the metabolic behavior and nutritional consumption of cells. To establish a more beneficial nutritional environment for the cells, two types of dynamic feeding strategies were used to control the delivery of two-part multi-component feed media according to the prediction of Raman models (glucose or arginine). As a result, instead of high fluctuations, the nutrients (glucose together with amino acids) were maintained at the desired level providing a more balanced environment for the cells. Moreover, the use of amino acid-based feeding control enabled to prevent the excessive nutrient replenishment and was economically beneficial by significantly reducing the amount of supplied feed medium compared to the glucose-based dynamic fed culture. This article is protected by copyright. All rights reserved.

International Journal of Pharmaceutics, 2021

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

International Journal of Pharmaceutics, 2020

Novel combination of non-invasive morphological and solid-state characterisation of drug-loaded c... more Novel combination of non-invasive morphological and solid-state characterisation of drug-loaded coreshell electrospun fibres,

Pharmaceutics, 2019

The aims of this work were to develop a processable, electrospun formulation of a model biopharma... more The aims of this work were to develop a processable, electrospun formulation of a model biopharmaceutical drug, β-galactosidase, and to demonstrate that higher production rates of biopharmaceutical-containing fibers can be achieved by using high-speed electrospinning compared to traditional electrospinning techniques. An aqueous solution of 7.6 w/w% polyvinyl alcohol, 0.6 w/w% polyethylene oxide, 9.9 w/w% mannitol, and 5.4 w/w% β-galactosidase was successfully electrospun with a 30 mL/h feeding rate, which is about 30 times higher than the feeding rate usually attained with single-needle electrospinning. According to X-ray diffraction measurements, polyvinyl alcohol, polyethylene oxide, and β-galactosidase were in an amorphous state in the fibers, whereas mannitol was crystalline (δ-polymorph). The presence of crystalline mannitol and the low water content enabled appropriate grinding of the fibrous sample without secondary drying. The ground powder was mixed with excipients commonl...

International Journal of Pharmaceutics, 2020

The present paper reports the first monitoring and control of ultra-low dose powder feeding using... more The present paper reports the first monitoring and control of ultra-low dose powder feeding using a camera image-based mass flow measurement system. Caffeine was fed via a single-screw microfeeder as a model active pharmaceutical ingredient (API). The mass, mass flow and sizes of the particles were successfully monitored in real-time by the developed videometric system consisting of a high-speed process camera coupled with an image analysis software. The system was also tested in feedback control mode to automatically reach the desired mass flow values by adjusting the feeder speed based on the mass flow measured by the image analysis system. Based on these features, the developed videometric system can serve as a multipurpose PAT-tool and can provide valuable real-time information about the process which is indispensable for modern continuous pharmaceutical manufacturing.

Materials, 2021

In this paper we report the synthesis of a N, S co-doped metal free carbon cryogel obtained from ... more In this paper we report the synthesis of a N, S co-doped metal free carbon cryogel obtained from a marine biomass derived precursor using urea as nitrogen source. Natural carrageenan intrinsically contains S and inorganic salt. The latter also serves as an activating agent during the pyrolytic step. The overall 11.6 atomic % surface heteroatom concentration comprises 5% O, 4.6% N and 1% S. The purified and annealed final carbon (CA) has a hierarchical pore structure of micro-, meso- and macropores with an apparent surface area of 1070 m2/g. No further treatment was applied. The gas adsorption potential of the samples was probed with H2, CO2 and CH4, while the electrocatalytic properties were tested in an oxygen reduction reaction. The atmospheric CO2 and CH4 storage capacity at 0 °C in the low pressure range is very similar to that of HKUST-1, with the CO2/CH4 selectivity below 20 bar, even exceeding that of the MOF, indicating the potential of CA in biogas separation. The electroca...

International Journal of Pharmaceutics, 2021

The present paper serves as a demonstration how an in-line PAT tool can be used for rapid and eff... more The present paper serves as a demonstration how an in-line PAT tool can be used for rapid and efficient process development in a fully continuous powder to granule line consisting of an interconnected twin-screw wet granulator, vibrational fluid bed dryer, and a regranulating mill. A new method was investigated for the periodic in-line particle size measurement of high mass flow materials to obtain real-time particle size data of the regranulated product. The system utilises a vibratory feeder with periodically altered feeding intensity in order to temporarily reduce the mass flow of the material passing in front of the camera. This results in the drastic reduction of particle overlapping in the images, making image analysis a viable tool for the in-line particle size measurement of high mass-flow materials. To evaluate the performance of the imaging system, the effect of several milling settings and the liquid-to-solid ratio was investigated on the product's particle size in the span of a few hours. The particle sizes measured with the in-line system were in accordance with the expected trends as well as with the results of the off-line reference particle size measurements. Based on the results, the in-line imaging system can serve as a PAT tool to obtain valuable real-time information for rapid process development or quality assurance.

Powder Technology, 2021

Comprehensive understanding of an integrated continuous pharmaceutical technology was achieved in... more Comprehensive understanding of an integrated continuous pharmaceutical technology was achieved in this study by a combining design of experiments and mechanistic modeling-based simulations. The powder to granule line consisted of twin-screw wet granulation, vibrational fluid-bed drying and milling. A Partial Least Squares (PLS) regression model was built using Near-infrared (NIR) spectroscopy for the real-time monitoring of the product moisture content after the milling step. A split-plot full factorial experimental design was set up and executed to help the understanding of the relationships between the moisture content and process parameters. Furthermore, a mechanistic model was built, involving heat transfer between the drying air and the solid material. The unknown kinetic model parameters were estimated using the results of the experimental study resulting in good calibration and validation performance. The simulations not only reinforced the experimental observations but also paves the way for model-based process monitoring and optimal control.

International Journal of Pharmaceutics, 2020

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

International Journal of Pharmaceutics, 2020

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Crystal Growth & Design, 2019

The aim of this study was developing a new easily performable feedback control of crystallization... more The aim of this study was developing a new easily performable feedback control of crystallization based on exact polymorphic concentration (mass ratio of polymorph/solvent). The efficiency of the developed process control, utilizing combined signals of inline Raman and ATR-UV/Vis sensors, was tested in a cooling crystallization of carvedilol. The solution concentration was determined according to multivariate calibration results of UV/Vis spectroscopic detection, while the evaluation

Biotechnology Progress, 2019

Raman spectroscopy as a process analytical technology tool was implemented for the monitoring and... more Raman spectroscopy as a process analytical technology tool was implemented for the monitoring and control of ethanol fermentation carried out with Saccharomyces cerevisiae. The need for the optimization of bioprocesses such as ethanol production, to increase product yield, enhanced the development of control strategies. The control system developed by the authors utilized noninvasive Raman measurements to avoid possible sterilization problems. Real-time data analysis was applied using partial least squares regression (PLS) method. With the aid of spectral pretreatment and multivariate data analysis, the monitoring of glucose and ethanol concentration was successful during yeast fermentation with the prediction error of 4.42 g/L for glucose and 2.40 g/L for ethanol. By Raman spectroscopy-based feedback control, the glucose concentration was maintained at 100 g/L by the automatic feeding of concentrated glucose solution. The control of glucose concentration during fed-batch fermentation resulted in increased ethanol production. Ethanol yield of 86% was achieved compared to the batch fermentation when 75% yield was obtained. The results show that the use of Raman spectroscopy for the monitoring and control of yeast fermentation is a promising way to enhance process understanding and achieve consistently high production yield.

International Journal of Pharmaceutics, 2019

Corona alternating current electrospinning (C-ACES), a scaled-up productivity electrospinning met... more Corona alternating current electrospinning (C-ACES), a scaled-up productivity electrospinning method was developed by combining the intense forces of the alternating electrostatic field and a sharp-edged spinneret design with increased free surface. C-ACES reached two orders of magnitude higher productivity (up to 1200 mL/h) than the classical single needle direct current electrospinning (DCES) without any alteration of fiber properties.

Chemical Engineering Journal, 2018

Based on the concept of continuous manufacturing an end-to-end benchtop device was developed unpr... more Based on the concept of continuous manufacturing an end-to-end benchtop device was developed unprecedented for the production of solid drug dosage forms by connecting flow synthesis and formulation via electrospinning (ES). Together with the optimized two-step continuous-flow synthesis of acetylsalicylic acid (ASA) a water-soluble polymeric excipient (polyvinylpyrrolidone K30, PVPK30) was introduced. The resulting polymeric solution could be readily electrospun into solid nanofibers with high purity in one single step due to the excellent yet gentle drying effect of ES. The ASA-loaded fibers were electrostatically deposited onto a water-soluble pullulan sheet and the obtained double-layered films were continuously cut into orally dissolving webs (ODWs) as final dosage formulation. The synthesis as well as the dosing of the fibrous films were monitored by Process Analytical 2 Technology (PAT) tools (IR and Raman spectroscopy) with active feedback on product quality. The successful coupling of flow synthesis and fiber formation confirms that ES enables versatile formulation of pharmaceuticals in future continuous production systems.

Journal of Chemometrics, 2016

Raman mapping and chemometrics are proposed to accurately characterize the composition of tablets... more Raman mapping and chemometrics are proposed to accurately characterize the composition of tablets. The most critical step of the state-of-art curve resolution methods (such as multivariate curve resolution-alternating least squares [MCR-ALS]) is the determination of the number of constituents, when chemical imaging is coupled with multivariate data analysis. However, it is usually performed in a considerably subjective way. We propose a variable clustering approach for the identification of the main dimensionality of vibrational spectral data. The method was tested on a Raman map of a complex pharmaceutical tablet that contained 4 major components with high spectral resemblance, and a low-dose lubricant was also added for tableting purposes. Using a variable clustering algorithm called VARCLUS we were able to construct clusters from the Raman mapping data corresponding to the real constitution of the sample. The modeled clusters were analyzed by the "sum of ranking differences" method. All 4 major components could be identified. The potential of the clustering algorithm was further assessed by applying MCR-ALS and spectral angle mapper-orthogonal projection methods. We have shown that variable clustering corresponded with MCR-ALS results and that it can be used to characterize the qualitative composition of an unknown pharmaceutical sample by combining the clustering algorithm with a pure component resolution method. Therefore, this method is well applicable to analyze and interpret the curve resolution of complex samples. Testing of the previously studied spectral angle mapper-orthogonal projection method, which relies on spectral reference libraries and even the low-dose lubricant (approximately 1% w/w), was identified through the chemical imaging.

Advanced Powder Technology, 2017

This work was carried out to explore the unknown area of converting non-woven fibres, prepared by... more This work was carried out to explore the unknown area of converting non-woven fibres, prepared by high 35 speed electrospinning, into a directly compressible blend by mixing with excipients. An experimental 36 design, with independent variables of compression force and fillers fraction, was realized to investigate 37 tabletability of electrospun material (EM) and to produce hard tablets with appropriate disintegration 38 time. The models proved to be adequate; fitted to the results and predicted values well for the optimal 39 tablet, which was found to be at 76.25% fillers fraction and 6 kN compression force. Besides standard 40 characterizations, distribution of EM was investigated by Raman mapping and scanning electron micro-41 scopy revealing the propensity of EM to cover the surface of microcrystalline cellulose and not of man-42 nitol. These analytical tools were also found to be useful at investigating the possible formation of the so-43 called gelling polymer network in tablets. Scanning electron microscopic pictures of tablets confirmed 44 the maintenance of fibrous structure after compression. The moisture absorption of EM under increasing 45 humidity was studied by dynamic vapour sorption measurement, which suggested good physical stabil-46 ity at 25°C and 60% relative humidity (corroborated by modulated DSC). These results demonstrate the 47 feasibility of a pharmaceutically acceptable downstream processing for EMs. 48

Green Chemistry, 2017

An immobilization engineering approach using bioinformatics and experimental design tools was app... more An immobilization engineering approach using bioinformatics and experimental design tools was applied to improve the sol–gel enzyme entrapment methodology.

European Polymer Journal, 2017

Eudragit® FS (EudFS), a novel anionic metachrylate terpolymer with pH dependent solubility was pr... more Eudragit® FS (EudFS), a novel anionic metachrylate terpolymer with pH dependent solubility was processed using electrospinning (ES) for the first time and melt extrusion (EX) for controlled delivery of a poorly water-soluble model drug, spironolactone (SPIR). Optimization of ES showed good spinnability of EudFS. Nanofibrous products could be obtained using fairly polar solvents (acetone, dichloromethane-ethanol (1:1), dimethylformamide). Drug-loaded nanofibers were prepared using novel alternating current electrospinning at multiple times higher throughput than direct current electrospinning. Melt extrusion proved to be also a feasible technique to prepare EudFS-based solid dispersions above 100°C. The viscoelasticity of EudFS melts was characterized in terms of temperature, frequency and heating time dependence. Solid state analyses revealed amorphous SPIR content in the electrospun fibers, however, signs of residual crystallinity could be detected in the extruded sample with 20% SPIR according to XRPD and EDS mapping. In vitro dissolution of the EudFS-based solid dispersions showed superior control of drug release compared to the physical mixture of crystalline SPIR and EudFS. At gastric pH where the polymer is insoluble the drug was more restrained in the ground extrudates than in the electrospun fibers. This state was followed by a quick burst as the pH rose to 7.4. EudFS, well-processed by electrospinning or melt extrusion, proved to be a promising matrix for oral drug delivery applications especially targeting the colon.

Periodica Polytechnica Chemical Engineering, 2018

Novel medicated straws were developed based on drug-loaded electrospun fibers prepared by direct ... more Novel medicated straws were developed based on drug-loaded electrospun fibers prepared by direct current electrospinning (DCES) and high-speed electrospinning (HSES) of scaled-up productivity. Good quality micro- and nanofibers were electrospun using both techniques despite the multiple times higher throughput rate of HSES based on the scanning electron microscopic imaging (SEM). Solid state analyses revealed that the poorly soluble model drug carvedilol (CAR) was dispersed in an amorphous form in the electrospun polyvinylpyrrolidone (PVPK30) fibers. In vitro dissolution studies revealed ultrafast drug release from the prepared fibrous formulations inserted into plastic straws. Based on the results the developed drug delivery system is suitable for storing the formulation in a solid dosage form and in situ turning it into liquid form when administered.

Journal of Pharmaceutical Innovation

Purpose In continuous manufacturing (CM), the material traceability and process dynamics can be i... more Purpose In continuous manufacturing (CM), the material traceability and process dynamics can be investigated by residence time distribution (RTD). Many of the unit operations used in the pharma industry were characterized by dead time–dominated RTD. Even though feasible and proper feedback control is one of the many advantages of CM, its application is challenging in these cases. This study aims to develop a feedback control, implementing the RTD in a Smith predictor control structure in a continuous powder blender line. Methods Continuous powder blending was investigated with near-infrared spectroscopy (NIR), and the blending was controlled through a volumetric feeder. A MATLAB GUI was developed to calculate and control the concentration of the API based on the chemometric evaluation of the spectra. The programmed GUI changed the feeding rate based on the proportional integral derivative (PID) and the Smith predictor, which implemented the RTD of the system. The control structures ...

Biotechnology Journal, 2022

An innovative, Raman spectroscopy-based monitoring and control system is introduced in this paper... more An innovative, Raman spectroscopy-based monitoring and control system is introduced in this paper for designing dynamic feeding strategies that allow the maintenance of key cellular nutrients at an ideal level in Chinese hamster ovary cell culture. The Partial Least Squares calibration models built for glucose, lactate and 16 (out of 20) individual amino acids had very good predictive power with low root mean square errors values and high square correlation coefficients. The developed models used for real-time measurement of nutrient and by-product concentrations allowed us to gain better insight into the metabolic behavior and nutritional consumption of cells. To establish a more beneficial nutritional environment for the cells, two types of dynamic feeding strategies were used to control the delivery of two-part multi-component feed media according to the prediction of Raman models (glucose or arginine). As a result, instead of high fluctuations, the nutrients (glucose together with amino acids) were maintained at the desired level providing a more balanced environment for the cells. Moreover, the use of amino acid-based feeding control enabled to prevent the excessive nutrient replenishment and was economically beneficial by significantly reducing the amount of supplied feed medium compared to the glucose-based dynamic fed culture. This article is protected by copyright. All rights reserved.

International Journal of Pharmaceutics, 2021

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

International Journal of Pharmaceutics, 2020

Novel combination of non-invasive morphological and solid-state characterisation of drug-loaded c... more Novel combination of non-invasive morphological and solid-state characterisation of drug-loaded coreshell electrospun fibres,

Pharmaceutics, 2019

The aims of this work were to develop a processable, electrospun formulation of a model biopharma... more The aims of this work were to develop a processable, electrospun formulation of a model biopharmaceutical drug, β-galactosidase, and to demonstrate that higher production rates of biopharmaceutical-containing fibers can be achieved by using high-speed electrospinning compared to traditional electrospinning techniques. An aqueous solution of 7.6 w/w% polyvinyl alcohol, 0.6 w/w% polyethylene oxide, 9.9 w/w% mannitol, and 5.4 w/w% β-galactosidase was successfully electrospun with a 30 mL/h feeding rate, which is about 30 times higher than the feeding rate usually attained with single-needle electrospinning. According to X-ray diffraction measurements, polyvinyl alcohol, polyethylene oxide, and β-galactosidase were in an amorphous state in the fibers, whereas mannitol was crystalline (δ-polymorph). The presence of crystalline mannitol and the low water content enabled appropriate grinding of the fibrous sample without secondary drying. The ground powder was mixed with excipients commonl...

International Journal of Pharmaceutics, 2020

The present paper reports the first monitoring and control of ultra-low dose powder feeding using... more The present paper reports the first monitoring and control of ultra-low dose powder feeding using a camera image-based mass flow measurement system. Caffeine was fed via a single-screw microfeeder as a model active pharmaceutical ingredient (API). The mass, mass flow and sizes of the particles were successfully monitored in real-time by the developed videometric system consisting of a high-speed process camera coupled with an image analysis software. The system was also tested in feedback control mode to automatically reach the desired mass flow values by adjusting the feeder speed based on the mass flow measured by the image analysis system. Based on these features, the developed videometric system can serve as a multipurpose PAT-tool and can provide valuable real-time information about the process which is indispensable for modern continuous pharmaceutical manufacturing.

Materials, 2021

In this paper we report the synthesis of a N, S co-doped metal free carbon cryogel obtained from ... more In this paper we report the synthesis of a N, S co-doped metal free carbon cryogel obtained from a marine biomass derived precursor using urea as nitrogen source. Natural carrageenan intrinsically contains S and inorganic salt. The latter also serves as an activating agent during the pyrolytic step. The overall 11.6 atomic % surface heteroatom concentration comprises 5% O, 4.6% N and 1% S. The purified and annealed final carbon (CA) has a hierarchical pore structure of micro-, meso- and macropores with an apparent surface area of 1070 m2/g. No further treatment was applied. The gas adsorption potential of the samples was probed with H2, CO2 and CH4, while the electrocatalytic properties were tested in an oxygen reduction reaction. The atmospheric CO2 and CH4 storage capacity at 0 °C in the low pressure range is very similar to that of HKUST-1, with the CO2/CH4 selectivity below 20 bar, even exceeding that of the MOF, indicating the potential of CA in biogas separation. The electroca...

International Journal of Pharmaceutics, 2021

The present paper serves as a demonstration how an in-line PAT tool can be used for rapid and eff... more The present paper serves as a demonstration how an in-line PAT tool can be used for rapid and efficient process development in a fully continuous powder to granule line consisting of an interconnected twin-screw wet granulator, vibrational fluid bed dryer, and a regranulating mill. A new method was investigated for the periodic in-line particle size measurement of high mass flow materials to obtain real-time particle size data of the regranulated product. The system utilises a vibratory feeder with periodically altered feeding intensity in order to temporarily reduce the mass flow of the material passing in front of the camera. This results in the drastic reduction of particle overlapping in the images, making image analysis a viable tool for the in-line particle size measurement of high mass-flow materials. To evaluate the performance of the imaging system, the effect of several milling settings and the liquid-to-solid ratio was investigated on the product's particle size in the span of a few hours. The particle sizes measured with the in-line system were in accordance with the expected trends as well as with the results of the off-line reference particle size measurements. Based on the results, the in-line imaging system can serve as a PAT tool to obtain valuable real-time information for rapid process development or quality assurance.

Powder Technology, 2021

Comprehensive understanding of an integrated continuous pharmaceutical technology was achieved in... more Comprehensive understanding of an integrated continuous pharmaceutical technology was achieved in this study by a combining design of experiments and mechanistic modeling-based simulations. The powder to granule line consisted of twin-screw wet granulation, vibrational fluid-bed drying and milling. A Partial Least Squares (PLS) regression model was built using Near-infrared (NIR) spectroscopy for the real-time monitoring of the product moisture content after the milling step. A split-plot full factorial experimental design was set up and executed to help the understanding of the relationships between the moisture content and process parameters. Furthermore, a mechanistic model was built, involving heat transfer between the drying air and the solid material. The unknown kinetic model parameters were estimated using the results of the experimental study resulting in good calibration and validation performance. The simulations not only reinforced the experimental observations but also paves the way for model-based process monitoring and optimal control.

International Journal of Pharmaceutics, 2020

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

International Journal of Pharmaceutics, 2020

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Crystal Growth & Design, 2019

The aim of this study was developing a new easily performable feedback control of crystallization... more The aim of this study was developing a new easily performable feedback control of crystallization based on exact polymorphic concentration (mass ratio of polymorph/solvent). The efficiency of the developed process control, utilizing combined signals of inline Raman and ATR-UV/Vis sensors, was tested in a cooling crystallization of carvedilol. The solution concentration was determined according to multivariate calibration results of UV/Vis spectroscopic detection, while the evaluation

Biotechnology Progress, 2019

Raman spectroscopy as a process analytical technology tool was implemented for the monitoring and... more Raman spectroscopy as a process analytical technology tool was implemented for the monitoring and control of ethanol fermentation carried out with Saccharomyces cerevisiae. The need for the optimization of bioprocesses such as ethanol production, to increase product yield, enhanced the development of control strategies. The control system developed by the authors utilized noninvasive Raman measurements to avoid possible sterilization problems. Real-time data analysis was applied using partial least squares regression (PLS) method. With the aid of spectral pretreatment and multivariate data analysis, the monitoring of glucose and ethanol concentration was successful during yeast fermentation with the prediction error of 4.42 g/L for glucose and 2.40 g/L for ethanol. By Raman spectroscopy-based feedback control, the glucose concentration was maintained at 100 g/L by the automatic feeding of concentrated glucose solution. The control of glucose concentration during fed-batch fermentation resulted in increased ethanol production. Ethanol yield of 86% was achieved compared to the batch fermentation when 75% yield was obtained. The results show that the use of Raman spectroscopy for the monitoring and control of yeast fermentation is a promising way to enhance process understanding and achieve consistently high production yield.

International Journal of Pharmaceutics, 2019

Corona alternating current electrospinning (C-ACES), a scaled-up productivity electrospinning met... more Corona alternating current electrospinning (C-ACES), a scaled-up productivity electrospinning method was developed by combining the intense forces of the alternating electrostatic field and a sharp-edged spinneret design with increased free surface. C-ACES reached two orders of magnitude higher productivity (up to 1200 mL/h) than the classical single needle direct current electrospinning (DCES) without any alteration of fiber properties.

Chemical Engineering Journal, 2018

Based on the concept of continuous manufacturing an end-to-end benchtop device was developed unpr... more Based on the concept of continuous manufacturing an end-to-end benchtop device was developed unprecedented for the production of solid drug dosage forms by connecting flow synthesis and formulation via electrospinning (ES). Together with the optimized two-step continuous-flow synthesis of acetylsalicylic acid (ASA) a water-soluble polymeric excipient (polyvinylpyrrolidone K30, PVPK30) was introduced. The resulting polymeric solution could be readily electrospun into solid nanofibers with high purity in one single step due to the excellent yet gentle drying effect of ES. The ASA-loaded fibers were electrostatically deposited onto a water-soluble pullulan sheet and the obtained double-layered films were continuously cut into orally dissolving webs (ODWs) as final dosage formulation. The synthesis as well as the dosing of the fibrous films were monitored by Process Analytical 2 Technology (PAT) tools (IR and Raman spectroscopy) with active feedback on product quality. The successful coupling of flow synthesis and fiber formation confirms that ES enables versatile formulation of pharmaceuticals in future continuous production systems.

Journal of Chemometrics, 2016

Raman mapping and chemometrics are proposed to accurately characterize the composition of tablets... more Raman mapping and chemometrics are proposed to accurately characterize the composition of tablets. The most critical step of the state-of-art curve resolution methods (such as multivariate curve resolution-alternating least squares [MCR-ALS]) is the determination of the number of constituents, when chemical imaging is coupled with multivariate data analysis. However, it is usually performed in a considerably subjective way. We propose a variable clustering approach for the identification of the main dimensionality of vibrational spectral data. The method was tested on a Raman map of a complex pharmaceutical tablet that contained 4 major components with high spectral resemblance, and a low-dose lubricant was also added for tableting purposes. Using a variable clustering algorithm called VARCLUS we were able to construct clusters from the Raman mapping data corresponding to the real constitution of the sample. The modeled clusters were analyzed by the "sum of ranking differences" method. All 4 major components could be identified. The potential of the clustering algorithm was further assessed by applying MCR-ALS and spectral angle mapper-orthogonal projection methods. We have shown that variable clustering corresponded with MCR-ALS results and that it can be used to characterize the qualitative composition of an unknown pharmaceutical sample by combining the clustering algorithm with a pure component resolution method. Therefore, this method is well applicable to analyze and interpret the curve resolution of complex samples. Testing of the previously studied spectral angle mapper-orthogonal projection method, which relies on spectral reference libraries and even the low-dose lubricant (approximately 1% w/w), was identified through the chemical imaging.

Advanced Powder Technology, 2017

This work was carried out to explore the unknown area of converting non-woven fibres, prepared by... more This work was carried out to explore the unknown area of converting non-woven fibres, prepared by high 35 speed electrospinning, into a directly compressible blend by mixing with excipients. An experimental 36 design, with independent variables of compression force and fillers fraction, was realized to investigate 37 tabletability of electrospun material (EM) and to produce hard tablets with appropriate disintegration 38 time. The models proved to be adequate; fitted to the results and predicted values well for the optimal 39 tablet, which was found to be at 76.25% fillers fraction and 6 kN compression force. Besides standard 40 characterizations, distribution of EM was investigated by Raman mapping and scanning electron micro-41 scopy revealing the propensity of EM to cover the surface of microcrystalline cellulose and not of man-42 nitol. These analytical tools were also found to be useful at investigating the possible formation of the so-43 called gelling polymer network in tablets. Scanning electron microscopic pictures of tablets confirmed 44 the maintenance of fibrous structure after compression. The moisture absorption of EM under increasing 45 humidity was studied by dynamic vapour sorption measurement, which suggested good physical stabil-46 ity at 25°C and 60% relative humidity (corroborated by modulated DSC). These results demonstrate the 47 feasibility of a pharmaceutically acceptable downstream processing for EMs. 48

Green Chemistry, 2017

An immobilization engineering approach using bioinformatics and experimental design tools was app... more An immobilization engineering approach using bioinformatics and experimental design tools was applied to improve the sol–gel enzyme entrapment methodology.

European Polymer Journal, 2017

Eudragit® FS (EudFS), a novel anionic metachrylate terpolymer with pH dependent solubility was pr... more Eudragit® FS (EudFS), a novel anionic metachrylate terpolymer with pH dependent solubility was processed using electrospinning (ES) for the first time and melt extrusion (EX) for controlled delivery of a poorly water-soluble model drug, spironolactone (SPIR). Optimization of ES showed good spinnability of EudFS. Nanofibrous products could be obtained using fairly polar solvents (acetone, dichloromethane-ethanol (1:1), dimethylformamide). Drug-loaded nanofibers were prepared using novel alternating current electrospinning at multiple times higher throughput than direct current electrospinning. Melt extrusion proved to be also a feasible technique to prepare EudFS-based solid dispersions above 100°C. The viscoelasticity of EudFS melts was characterized in terms of temperature, frequency and heating time dependence. Solid state analyses revealed amorphous SPIR content in the electrospun fibers, however, signs of residual crystallinity could be detected in the extruded sample with 20% SPIR according to XRPD and EDS mapping. In vitro dissolution of the EudFS-based solid dispersions showed superior control of drug release compared to the physical mixture of crystalline SPIR and EudFS. At gastric pH where the polymer is insoluble the drug was more restrained in the ground extrudates than in the electrospun fibers. This state was followed by a quick burst as the pH rose to 7.4. EudFS, well-processed by electrospinning or melt extrusion, proved to be a promising matrix for oral drug delivery applications especially targeting the colon.

Periodica Polytechnica Chemical Engineering, 2018

Novel medicated straws were developed based on drug-loaded electrospun fibers prepared by direct ... more Novel medicated straws were developed based on drug-loaded electrospun fibers prepared by direct current electrospinning (DCES) and high-speed electrospinning (HSES) of scaled-up productivity. Good quality micro- and nanofibers were electrospun using both techniques despite the multiple times higher throughput rate of HSES based on the scanning electron microscopic imaging (SEM). Solid state analyses revealed that the poorly soluble model drug carvedilol (CAR) was dispersed in an amorphous form in the electrospun polyvinylpyrrolidone (PVPK30) fibers. In vitro dissolution studies revealed ultrafast drug release from the prepared fibrous formulations inserted into plastic straws. Based on the results the developed drug delivery system is suitable for storing the formulation in a solid dosage form and in situ turning it into liquid form when administered.