Hajnalka Pataki | Budapest University of Technology and Economics (original) (raw)
Papers by Hajnalka Pataki
Acta Pharmaceutica Hungarica, 2011
Crystallization processes can be evaluated from both kinetic and thermodinamic point of view with... more Crystallization processes can be evaluated from both kinetic and thermodinamic point of view with real-time analitical methods, effects of production parameters on the final quality can be estimated as well. Consequently there is an increasing emphasis on analytical devices being applicable for real-time detection. Among these techniques Raman spectrometry is advantageously utilizable for real-time monitoring of crystallizations. Impurities can dramatically change the nucleation and crystal growth, thus they can alter the physical and chemical properties of the final product. The use of different additives (polymers;surface active ingredients) in the crystallization step in order to modify the product morphology methodically is a new direction in the scientific literature. This study provides an overview of crystallization processes in the presence of additives as well as a summary concerning the monitoring of the drug crystallizations by real-time Raman spectrometry. Furthermore the effect of polyvinyl-pyrrolidone was examined in the course of cooling crystallization of Donepezil HCl, while the process was monitored by in-line Raman spectrometry.
International Journal of Pharmaceutics, 2015
Three solvent based methods: spray drying (SD), electrospinning (ES) and air-assisted electrospin... more Three solvent based methods: spray drying (SD), electrospinning (ES) and air-assisted electrospinning (electroblowing; EB) were used to prepare solid dispersions of itraconazole and Eudragit E. Samples with the same API/polymer ratios were prepared in order to make the three technologies comparable. The structure and morphology of solid dispersions were identified by scanning electron microscopy and solid phase analytical methods such as, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and Raman chemical mapping. Moreover, the residual organic solvents of the solid products were determined by static headspace-gas chromatography/mass spectroscopy measurements and the wettability of samples was characterized by contact angle measurement. The pharmaceutical performance of the three dispersion type, evaluated by dissolution tests, proved to be very similar. According to XRPD and DSC analyses, made after the production, all the solid dispersions were free of any API crystal clusters but about 10 wt% drug crystallinity was observed after three months of storage in the case of the SD samples in contrast to the samples produced by ES and EB in which the polymer matrix preserved the API in amorphous state.
Acta pharmaceutica Hungarica, 2011
Crystallization processes can be evaluated from both kinetic and thermodinamic point of view with... more Crystallization processes can be evaluated from both kinetic and thermodinamic point of view with real-time analitical methods, effects of production parameters on the final quality can be estimated as well. Consequently there is an increasing emphasis on analytical devices being applicable for real-time detection. Among these techniques Raman spectrometry is advantageously utilizable for real-time monitoring of crystallizations. Impurities can dramatically change the nucleation and crystal growth, thus they can alter the physical and chemical properties of the final product. The use of different additives (polymers;surface active ingredients) in the crystallization step in order to modify the product morphology methodically is a new direction in the scientific literature. This study provides an overview of crystallization processes in the presence of additives as well as a summary concerning the monitoring of the drug crystallizations by real-time Raman spectrometry. Furthermore th...
International Journal of Pharmaceutics, 2011
Isoptin SR-E (Meltrex ®) extruded tablets were assumed in a recent paper to be prepared with a co... more Isoptin SR-E (Meltrex ®) extruded tablets were assumed in a recent paper to be prepared with a composition different from a conventional (Isoptin SR) formulation. This study reveals, however, using Raman mapping and chemometric evaluation, that in fact the same composition, comprising Na alginate as polymer matrix, is used in both products. It means that only the difference in the manufacturing technology causes the reported sustained release of verapamil hydrochloride even in ethanol containing dissolution media. The products are compared based on the obtained Raman chemical images, which allowed concluding in a new structure-based explanation for the differences in the dissolution profiles in the presence of ethanol. It is also shown that extrusion technology influences the dissolution profile effectively, even in the cases when solid solution is formed only partially.
Journal of pharmaceutical and biomedical analysis, 2014
Raman spectrometry was utilized to estimate degraded drug percentage, residual drug crystallinity... more Raman spectrometry was utilized to estimate degraded drug percentage, residual drug crystallinity and glass-transition temperature in the case of melt-extruded pharmaceutical products. Tight correlation was shown between the results obtained by confocal Raman mapping and transmission Raman spectrometry, a PAT-compatible potential in-line analytical tool. Immediate-release spironolactone-Eudragit E solid dispersions were the model system, owing to the achievable amorphization and the heat-sensitivity of the drug compound. The deep investigation of the relationship between process parameters, residual drug crystallinity and degradation was performed using statistical tools and a factorial experimental design defining 54 different circumstances for the preparation of solid dispersions. From the examined factors, drug content (10, 20 and 30%), temperature (110, 130 and 150°C) and residence time (2.75, 11.00 and 24.75min) were found to have significant and considerable effect. By forming...
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 2012
This article appeared in a journal published by Elsevier. The attached copy is furnished to the a... more This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright
Journal of pharmaceutical sciences, 2014
Melt electrospinning (MES) was used to prepare fast dissolving fibrous drug delivery systems in t... more Melt electrospinning (MES) was used to prepare fast dissolving fibrous drug delivery systems in the presence of plasticizers. This new method was found promising in the field of pharmaceutical formulation because it combines the advantages of melt extrusion and solvent-based electrospinning. Lowering of the process temperature was performed using plasticizers in order to avoid undesired thermal degradation. Carvedilol (CAR), a poorly water-soluble and thermal-sensitive model drug, was introduced into an amorphous methacrylate terpolymer matrix, Eudragit® E, suitable for fiber formation. Three plasticizers (triacetin, Tween® 80, and polyethylene glycol 1500) were tested, all of which lowered the process temperature effectively. Scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, and Raman microspectrometry investigations showed that crystalline CAR turned into an amorphous form during processing and preserved it for longer time. In vitro dissolution st...
Journal of Pharmaceutical Sciences, 2013
The solvent-free melt electrospinning (MES) method was developed to prepare a drug delivery syste... more The solvent-free melt electrospinning (MES) method was developed to prepare a drug delivery system with fast release of carvedilol (CAR), a drug with poor water solubility. To the authors knowledge, this is the first report for preparing drug-loaded melt electrospun fibers. Cationic methacrylate copolymer of Eudragit R E type was used as a fiber forming polymer matrix. For comparison, ethanol-based electrospinning and melt extrusion (EX) methods were used to produce samples that had the same composition as the melt electrospun system. According to the results of scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, and Fourier transformed infrared spectrometry investigations, amorphous solid nanodispersions/solutions of CAR in Eudragit R E matrix were obtained in all cases with 20 m / m % drug content. In vitro drug release in acidic media from the extrudates was significantly faster (5 min) than that from crystalline CAR. Moreover, ultrafast drug release was achieved from the solvent-free melt and ethanol-based electrospun samples because of their huge surface area and the soluble polymer matrix in the acidic media. These results demonstrate that solvent-free MES is a promising, novel technique for the production of drug delivery systems with enhanced dissolution because it can combine the advantages of EX (e.g., solventfree, continuous process, and effective amorphization) and solvent-based electrospinning (huge product surface area).
Journal of Pharmaceutical and Biomedical Analysis, 2011
Raman chemical imaging was used in the characterization of drug-excipient interactions between a ... more Raman chemical imaging was used in the characterization of drug-excipient interactions between a drug and different types of cyclodextrins. Detailed analysis was carried out regarding the interactions between the active ingredient (API) and the cyclodextrins and the heterogeneity of the samples was studied using multivariate curve resolution-alternating least squares algorithm. The amount of recrystallized pure API was also estimated using the same curve resolution method. The Raman mapping results were validated via scanning electron microscopy-energy dispersive X-ray spectroscopy and X-ray powder diffraction. Raman mapping was found to be suitable to detect traces of pure crystalline API below the detection limit of X-ray powder diffraction.
Chemical Engineering & Technology, 2014
Carvedilol precipitation by combined antisolvent‐cooling crystallization was performed in the pre... more Carvedilol precipitation by combined antisolvent‐cooling crystallization was performed in the presence of polyvinylpyrrolidone (PVP) of different molecular weight. Drug emulsion was formed as a result of water addition and crystal growth occurred after cooling. In the absence of the additive, the kinetically preferred Form II polymorph crystallized while PVP facilitated the formation of the thermodynamically stable Form III (hemihydrate) polymorph. Crystallization was monitored by real‐time Raman spectrometry to indicate the polymorphic form and the endpoint of the process. The thermodynamic relationship between these polymorphs was established also by real‐time Raman spectrometry using ethanol and water as solvent mixture. In all cases, just a small amount of PVP, adsorbed on the crystal surface, was sufficient to affect the crystal form advantageously and induce excellent flowability of the products. The modification of crystal morphology assisted by the applied additives is ascri...
Analytica Chimica Acta, 2012
Chemical imaging is a rapidly emerging analytical method in pharmaceutical technology. Due to the... more Chemical imaging is a rapidly emerging analytical method in pharmaceutical technology. Due to the numerous chemometric solutions available, characterization of pharmaceutical samples with unknown components present has also become possible. This study compares the performance of current state-of-the-art curve resolution methods (multivariate curve resolution-alternating least squares, positive matrix factorization, simplex identification via split augmented Lagrangian and self-modelling mixture analysis) in the estimation of pure component spectra from Raman maps of differently manufactured pharmaceutical tablets. The batches of different technologies differ in the homogeneity level of the active ingredient, thus, the curve resolution methods are tested under different conditions. An empirical approach is shown to determine the number of components present in a sample. The chemometric algorithms are compared regarding the number of detected components, the quality of the resolved spectra and the accuracy of scores (spectral concentrations) compared to those calculated with classical least squares, using the true pure component (reference) spectra. It is demonstrated that using appropriate multivariate methods, Raman chemical imaging can be a useful tool in the non-invasive characterization of unknown (e.g. illegal or counterfeit) pharmaceutical products.
Organic Process Research & Development, 2016
The development of real-time monitoring and improved control system were performed according to P... more The development of real-time monitoring and improved control system were performed according to Process Analytical Technology (PAT) initiative focusing on the benefits of pharmaceutical industry. Extending the results of pioneer Raman-based closed loop feedback control of crystallization and synthesis, a bioprocess, namely the enzymatic hydrolysis of lactose was investigated in this work. For this purpose an effective control system was developed to maintain the lactose concentration at a level of 20 g/L. Real-time Raman spectra evaluation was accomplished using classical least squares (CLS) and partial least squares (PLS) multivariate data analysis methods. Formation of oligosaccharides during the hydrolysis of lactose causes inaccuracy in the CLS evaluation, thus optimization of lactose hydrolysis was needed to decrease oligosaccharide formation. After optimization, the control of lactose hydrolysis could be achieved. To improve real-time evaluation, PLS method was used resulting in better evaluation of spectra during control experiments.
Journal of pharmaceutical and biomedical analysis, Jan 5, 2016
This work demonstrates how nonlinearity in Raman spectrometry of pharmaceuticals can be handled a... more This work demonstrates how nonlinearity in Raman spectrometry of pharmaceuticals can be handled and accurate quantification can be achieved by applying certain chemometric methods including variable selection. Such approach proved to be successful even if the component spectra are very similar or spectral intensities of the constituents are strongly different. The relevant examples are: blends of two crystalline forms of carvedilol ("CRYST-PM" blend) and a three-component pharmaceutical model system ("PHARM-TM" blend). The widely used classical least squares regression (CLS) and partial least squares regression (PLS) quantification methods provided relatively poor root mean squared error of prediction (RMSEP) values: approximately 2-4% and 4-10% for CRYST-PM and PHARM-TM respectively. The residual plots of these models indicated the nonlinearity of the preprocessed data sets. More accurate quantitative results could be achieved with properly applied variable sele...
Ultrasonics Sonochemistry, 2016
The diastereomeric salt resolution of racemic tetramisole was studied using ultrasound irradiatio... more The diastereomeric salt resolution of racemic tetramisole was studied using ultrasound irradiation. We examined the effect of power and duration of ultrasonic irradiation on the properties of the crystalline phase formed by ultrasound-assisted crystallization and the result of the whole optical resolution. The results were compared with reference experiment without using ultrasound. The US time (5-30min) caused higher enantiomeric excess. Although yield was lower continuously high resolving efficiency could have been reached through ultrasound. We had the best results with 4.3W ultrasound power when resolvability was even higher than the best of reference. Furthermore, we accomplished a deep and thorough examination of the salts that possibly could form in this resolution. One of the four diastereomeric salts, which have been identified by powder X-ray diffraction, FTIR-spectroscopy, and differential scanning calorimetry (DSC) in the ternary system of the two tetramisole enantiomers and the resolving agent, namely the bis[(S)-tetramisole]-dibenzoyl-(R,R)-tartrate salt have been proven the key compound in the resolution process, and presented the highest melting point of 166°C (dec.) among the four salts. The originally expected diastereomeric bitartrate salts with 1:1M base:acid ratio [(S)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt and (R)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt] and their 'racemic' co-crystal [(RS)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt] showed somewhat lower melting points (152, 145, and 150°C, respectively) and their crystallization was also prevented by application of ultrasound. Based on the melting points and enthalpies of fusion measured by DSC, all the binary and ternary phase diagrams have been newly established and calculated in the system with help of classical modelling equations of liquidus curves.
European Journal of Pharmaceutical Sciences
Polymers for Advanced Technologies, 2015
Suitability of electrospinning for biodrug formulation was investigated in order to develop an el... more Suitability of electrospinning for biodrug formulation was investigated in order to develop an electrospinning‐based method for producing oral dosage form of β‐galactosidase. β‐Galactosidase‐loaded polymeric (polyvinyl alcohol, polyvinylpyrrolidones with two different molar masses, and polyethylene glycol) nanofibers were prepared by electrospinning in order to lengthen the shelf life of the enzyme (providing an alternative technology to drying). Based on the activity of the encapsulated β‐galactosidase, the most suitable polymer was polyvinylpyrrolidone with higher molecular weight (1,200,000 Da), because 97% of the original activity remained in this case. Kinetic behavior of β‐galactosidase did not show any alteration after encapsulation, and the pH and temperature profiles were not changed either. Time course of viability testing showed that the nanofibrous formulation can provide long‐term stability for β‐galactosidase; the activity of the enzyme decreased only 4% after a year. ...
European Polymer Journal, 2015
Two continuous processes, the spray drying method, producing microparticles in presence of hot ga... more Two continuous processes, the spray drying method, producing microparticles in presence of hot gas flow, and the electrospinning technology, producing continuous polymer nanofibers at low temperature under high electric fields, were investigated and compared the first time. Both techniques were used to prepare slow release caffeine (as a model of rapidly water-soluble drug) using water-insoluble, biocompatible and bioresorbable PLGA and PLA as polymeric matrix. The structural characterization of the obtained samples was performed using SEM, XRD, DSC and at-line Raman mapping, while in vitro dissolution was detected by UV spectrophotometer. We found that the release profile of a highly water soluble drug can be adjusted to the requirements through the investigated continuous technologies. Solid molecular dispersion of caffeine at colloidal level could be prepared in PLA matrix using electrostatic spinning. Furthermore the continuous nonwoven structure of ultrafine fibers, produced this way, allows easer handling than that of independent fine particle's. On the other hand continuous production of drug loaded microspheres with slightly less performance can be performed with the conventional technology of spray drying which is well known in the pharmaceutical industry.
Journal of Raman Spectroscopy, 2015
ABSTRACT Chemical imaging was used in this study as a powerful analytical tool to characterize ph... more ABSTRACT Chemical imaging was used in this study as a powerful analytical tool to characterize pharmaceuticals in solid form. The majority of analyses are evaluated with bilinear modelling using only the pure component spectra or just the chemical images themselves to estimate the concentrations in each pixel, which are far from true quantitative determination. Our aim was to create more accurate concentration images using regression methods. For the first time in chemical imaging, variable selections with interval partial least squares (PLS) and with genetic algorithms (PLS-GA) were applied to increase the efficiency of the models. These were compared to numerous bilinear modelling and multivariate linear regression methods such as univariate regression, classical least squares (CLS), multivariate curve resolution–alternating least squares (MCR-ALS), principal component regression (PCR) and partial least squares (PLS). Two component spray-dried pharmaceuticals were used as a model. The paper is shown that, in contrast to the usual way of using either external validation or cross-validation, both should be performed simultaneously in order to get a clear picture of the prediction errors and to be able to select the appropriate models. Using PLS with variable selection, the root mean square errors were reduced to 3% per pixel by keeping only those peaks that are truly necessary for the estimation of concentrations. It is also shown that interval PLS can point out the best peak for univariate regression, and can thereby be of great help even when regulations allow only univariate models for product quality testing. Variable selection, besides yielding more accurate overall concentrations across a Raman map, also reduces the deviation among pixel concentrations within the images, thereby increasing the sensitivity of homogeneity studies. Copyright © 2015 John Wiley & Sons, Ltd.
Organic Process Research & Development, 2015
Although the process analytical technology for ensuring constant product quality and tight contro... more Although the process analytical technology for ensuring constant product quality and tight control over the manufacturing process, which is especially important in the case of hazardous chemical reactions, has initiated extensive use of real-time spectroscopic methods (ATR-UV/vis, ATR-FTIR, or Raman) for monitoring of chemical reactions, control of chemical syntheses on the basis of inline Raman spectroscopic detection has not been implemented yet. The present paper reports the development of an effective feedback control on the basis of Raman spectroscopy governing a potentially hazardous, exothermic model reaction. The control approach allowed the quantification of reaction components and an unstable intermediate and, furthermore, determined the end point of the reaction. The spectrum of the unstable intermediate was identified using the multivariate curve resolution-alternating least-squares (MCR-ALS) method. The implementation of the feedback control required the development of a program operating the Raman spectrometer and coordinating the real-time CLS chemometric evaluation, while another program was designed to communicate with the previous one and was responsible for the closed-loop control of the process.
International journal of pharmaceutics, Jan 14, 2015
High speed electrospinning (HSES), compatible with pharmaceutical industry, was used to demonstra... more High speed electrospinning (HSES), compatible with pharmaceutical industry, was used to demonstrate the viability of the preparation of drug-loaded polymer nanofibers with radically higher productivity than the known single-needle electrospinning (SNES) setup. Poorly water-soluble itraconazole (ITRA) was formulated with PVPVA64 matrix polymer using four different solvent-based methods such as HSES, SNES, spray drying (SD) and film casting (FC). The formulations were assessed in terms of improvement in the dissolution rate of ITRA (using a "tapped basket" dissolution configuration) and analysed by SEM, DSC and XRPD. Despite the significantly increased productivity of HSES, the obtained morphology was very similar to the SNES nanofibrous material. ITRA transformed into an amorphous form, according to the DSC and XRPD results, in most cases except the FC samples. The limited dissolution of crystalline ITRA could be highly improved: fast dissolution occurred (>90% within 10...
Acta Pharmaceutica Hungarica, 2011
Crystallization processes can be evaluated from both kinetic and thermodinamic point of view with... more Crystallization processes can be evaluated from both kinetic and thermodinamic point of view with real-time analitical methods, effects of production parameters on the final quality can be estimated as well. Consequently there is an increasing emphasis on analytical devices being applicable for real-time detection. Among these techniques Raman spectrometry is advantageously utilizable for real-time monitoring of crystallizations. Impurities can dramatically change the nucleation and crystal growth, thus they can alter the physical and chemical properties of the final product. The use of different additives (polymers;surface active ingredients) in the crystallization step in order to modify the product morphology methodically is a new direction in the scientific literature. This study provides an overview of crystallization processes in the presence of additives as well as a summary concerning the monitoring of the drug crystallizations by real-time Raman spectrometry. Furthermore the effect of polyvinyl-pyrrolidone was examined in the course of cooling crystallization of Donepezil HCl, while the process was monitored by in-line Raman spectrometry.
International Journal of Pharmaceutics, 2015
Three solvent based methods: spray drying (SD), electrospinning (ES) and air-assisted electrospin... more Three solvent based methods: spray drying (SD), electrospinning (ES) and air-assisted electrospinning (electroblowing; EB) were used to prepare solid dispersions of itraconazole and Eudragit E. Samples with the same API/polymer ratios were prepared in order to make the three technologies comparable. The structure and morphology of solid dispersions were identified by scanning electron microscopy and solid phase analytical methods such as, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and Raman chemical mapping. Moreover, the residual organic solvents of the solid products were determined by static headspace-gas chromatography/mass spectroscopy measurements and the wettability of samples was characterized by contact angle measurement. The pharmaceutical performance of the three dispersion type, evaluated by dissolution tests, proved to be very similar. According to XRPD and DSC analyses, made after the production, all the solid dispersions were free of any API crystal clusters but about 10 wt% drug crystallinity was observed after three months of storage in the case of the SD samples in contrast to the samples produced by ES and EB in which the polymer matrix preserved the API in amorphous state.
Acta pharmaceutica Hungarica, 2011
Crystallization processes can be evaluated from both kinetic and thermodinamic point of view with... more Crystallization processes can be evaluated from both kinetic and thermodinamic point of view with real-time analitical methods, effects of production parameters on the final quality can be estimated as well. Consequently there is an increasing emphasis on analytical devices being applicable for real-time detection. Among these techniques Raman spectrometry is advantageously utilizable for real-time monitoring of crystallizations. Impurities can dramatically change the nucleation and crystal growth, thus they can alter the physical and chemical properties of the final product. The use of different additives (polymers;surface active ingredients) in the crystallization step in order to modify the product morphology methodically is a new direction in the scientific literature. This study provides an overview of crystallization processes in the presence of additives as well as a summary concerning the monitoring of the drug crystallizations by real-time Raman spectrometry. Furthermore th...
International Journal of Pharmaceutics, 2011
Isoptin SR-E (Meltrex ®) extruded tablets were assumed in a recent paper to be prepared with a co... more Isoptin SR-E (Meltrex ®) extruded tablets were assumed in a recent paper to be prepared with a composition different from a conventional (Isoptin SR) formulation. This study reveals, however, using Raman mapping and chemometric evaluation, that in fact the same composition, comprising Na alginate as polymer matrix, is used in both products. It means that only the difference in the manufacturing technology causes the reported sustained release of verapamil hydrochloride even in ethanol containing dissolution media. The products are compared based on the obtained Raman chemical images, which allowed concluding in a new structure-based explanation for the differences in the dissolution profiles in the presence of ethanol. It is also shown that extrusion technology influences the dissolution profile effectively, even in the cases when solid solution is formed only partially.
Journal of pharmaceutical and biomedical analysis, 2014
Raman spectrometry was utilized to estimate degraded drug percentage, residual drug crystallinity... more Raman spectrometry was utilized to estimate degraded drug percentage, residual drug crystallinity and glass-transition temperature in the case of melt-extruded pharmaceutical products. Tight correlation was shown between the results obtained by confocal Raman mapping and transmission Raman spectrometry, a PAT-compatible potential in-line analytical tool. Immediate-release spironolactone-Eudragit E solid dispersions were the model system, owing to the achievable amorphization and the heat-sensitivity of the drug compound. The deep investigation of the relationship between process parameters, residual drug crystallinity and degradation was performed using statistical tools and a factorial experimental design defining 54 different circumstances for the preparation of solid dispersions. From the examined factors, drug content (10, 20 and 30%), temperature (110, 130 and 150°C) and residence time (2.75, 11.00 and 24.75min) were found to have significant and considerable effect. By forming...
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 2012
This article appeared in a journal published by Elsevier. The attached copy is furnished to the a... more This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright
Journal of pharmaceutical sciences, 2014
Melt electrospinning (MES) was used to prepare fast dissolving fibrous drug delivery systems in t... more Melt electrospinning (MES) was used to prepare fast dissolving fibrous drug delivery systems in the presence of plasticizers. This new method was found promising in the field of pharmaceutical formulation because it combines the advantages of melt extrusion and solvent-based electrospinning. Lowering of the process temperature was performed using plasticizers in order to avoid undesired thermal degradation. Carvedilol (CAR), a poorly water-soluble and thermal-sensitive model drug, was introduced into an amorphous methacrylate terpolymer matrix, Eudragit® E, suitable for fiber formation. Three plasticizers (triacetin, Tween® 80, and polyethylene glycol 1500) were tested, all of which lowered the process temperature effectively. Scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, and Raman microspectrometry investigations showed that crystalline CAR turned into an amorphous form during processing and preserved it for longer time. In vitro dissolution st...
Journal of Pharmaceutical Sciences, 2013
The solvent-free melt electrospinning (MES) method was developed to prepare a drug delivery syste... more The solvent-free melt electrospinning (MES) method was developed to prepare a drug delivery system with fast release of carvedilol (CAR), a drug with poor water solubility. To the authors knowledge, this is the first report for preparing drug-loaded melt electrospun fibers. Cationic methacrylate copolymer of Eudragit R E type was used as a fiber forming polymer matrix. For comparison, ethanol-based electrospinning and melt extrusion (EX) methods were used to produce samples that had the same composition as the melt electrospun system. According to the results of scanning electron microscopy, X-ray diffraction, differential scanning calorimetry, and Fourier transformed infrared spectrometry investigations, amorphous solid nanodispersions/solutions of CAR in Eudragit R E matrix were obtained in all cases with 20 m / m % drug content. In vitro drug release in acidic media from the extrudates was significantly faster (5 min) than that from crystalline CAR. Moreover, ultrafast drug release was achieved from the solvent-free melt and ethanol-based electrospun samples because of their huge surface area and the soluble polymer matrix in the acidic media. These results demonstrate that solvent-free MES is a promising, novel technique for the production of drug delivery systems with enhanced dissolution because it can combine the advantages of EX (e.g., solventfree, continuous process, and effective amorphization) and solvent-based electrospinning (huge product surface area).
Journal of Pharmaceutical and Biomedical Analysis, 2011
Raman chemical imaging was used in the characterization of drug-excipient interactions between a ... more Raman chemical imaging was used in the characterization of drug-excipient interactions between a drug and different types of cyclodextrins. Detailed analysis was carried out regarding the interactions between the active ingredient (API) and the cyclodextrins and the heterogeneity of the samples was studied using multivariate curve resolution-alternating least squares algorithm. The amount of recrystallized pure API was also estimated using the same curve resolution method. The Raman mapping results were validated via scanning electron microscopy-energy dispersive X-ray spectroscopy and X-ray powder diffraction. Raman mapping was found to be suitable to detect traces of pure crystalline API below the detection limit of X-ray powder diffraction.
Chemical Engineering & Technology, 2014
Carvedilol precipitation by combined antisolvent‐cooling crystallization was performed in the pre... more Carvedilol precipitation by combined antisolvent‐cooling crystallization was performed in the presence of polyvinylpyrrolidone (PVP) of different molecular weight. Drug emulsion was formed as a result of water addition and crystal growth occurred after cooling. In the absence of the additive, the kinetically preferred Form II polymorph crystallized while PVP facilitated the formation of the thermodynamically stable Form III (hemihydrate) polymorph. Crystallization was monitored by real‐time Raman spectrometry to indicate the polymorphic form and the endpoint of the process. The thermodynamic relationship between these polymorphs was established also by real‐time Raman spectrometry using ethanol and water as solvent mixture. In all cases, just a small amount of PVP, adsorbed on the crystal surface, was sufficient to affect the crystal form advantageously and induce excellent flowability of the products. The modification of crystal morphology assisted by the applied additives is ascri...
Analytica Chimica Acta, 2012
Chemical imaging is a rapidly emerging analytical method in pharmaceutical technology. Due to the... more Chemical imaging is a rapidly emerging analytical method in pharmaceutical technology. Due to the numerous chemometric solutions available, characterization of pharmaceutical samples with unknown components present has also become possible. This study compares the performance of current state-of-the-art curve resolution methods (multivariate curve resolution-alternating least squares, positive matrix factorization, simplex identification via split augmented Lagrangian and self-modelling mixture analysis) in the estimation of pure component spectra from Raman maps of differently manufactured pharmaceutical tablets. The batches of different technologies differ in the homogeneity level of the active ingredient, thus, the curve resolution methods are tested under different conditions. An empirical approach is shown to determine the number of components present in a sample. The chemometric algorithms are compared regarding the number of detected components, the quality of the resolved spectra and the accuracy of scores (spectral concentrations) compared to those calculated with classical least squares, using the true pure component (reference) spectra. It is demonstrated that using appropriate multivariate methods, Raman chemical imaging can be a useful tool in the non-invasive characterization of unknown (e.g. illegal or counterfeit) pharmaceutical products.
Organic Process Research & Development, 2016
The development of real-time monitoring and improved control system were performed according to P... more The development of real-time monitoring and improved control system were performed according to Process Analytical Technology (PAT) initiative focusing on the benefits of pharmaceutical industry. Extending the results of pioneer Raman-based closed loop feedback control of crystallization and synthesis, a bioprocess, namely the enzymatic hydrolysis of lactose was investigated in this work. For this purpose an effective control system was developed to maintain the lactose concentration at a level of 20 g/L. Real-time Raman spectra evaluation was accomplished using classical least squares (CLS) and partial least squares (PLS) multivariate data analysis methods. Formation of oligosaccharides during the hydrolysis of lactose causes inaccuracy in the CLS evaluation, thus optimization of lactose hydrolysis was needed to decrease oligosaccharide formation. After optimization, the control of lactose hydrolysis could be achieved. To improve real-time evaluation, PLS method was used resulting in better evaluation of spectra during control experiments.
Journal of pharmaceutical and biomedical analysis, Jan 5, 2016
This work demonstrates how nonlinearity in Raman spectrometry of pharmaceuticals can be handled a... more This work demonstrates how nonlinearity in Raman spectrometry of pharmaceuticals can be handled and accurate quantification can be achieved by applying certain chemometric methods including variable selection. Such approach proved to be successful even if the component spectra are very similar or spectral intensities of the constituents are strongly different. The relevant examples are: blends of two crystalline forms of carvedilol ("CRYST-PM" blend) and a three-component pharmaceutical model system ("PHARM-TM" blend). The widely used classical least squares regression (CLS) and partial least squares regression (PLS) quantification methods provided relatively poor root mean squared error of prediction (RMSEP) values: approximately 2-4% and 4-10% for CRYST-PM and PHARM-TM respectively. The residual plots of these models indicated the nonlinearity of the preprocessed data sets. More accurate quantitative results could be achieved with properly applied variable sele...
Ultrasonics Sonochemistry, 2016
The diastereomeric salt resolution of racemic tetramisole was studied using ultrasound irradiatio... more The diastereomeric salt resolution of racemic tetramisole was studied using ultrasound irradiation. We examined the effect of power and duration of ultrasonic irradiation on the properties of the crystalline phase formed by ultrasound-assisted crystallization and the result of the whole optical resolution. The results were compared with reference experiment without using ultrasound. The US time (5-30min) caused higher enantiomeric excess. Although yield was lower continuously high resolving efficiency could have been reached through ultrasound. We had the best results with 4.3W ultrasound power when resolvability was even higher than the best of reference. Furthermore, we accomplished a deep and thorough examination of the salts that possibly could form in this resolution. One of the four diastereomeric salts, which have been identified by powder X-ray diffraction, FTIR-spectroscopy, and differential scanning calorimetry (DSC) in the ternary system of the two tetramisole enantiomers and the resolving agent, namely the bis[(S)-tetramisole]-dibenzoyl-(R,R)-tartrate salt have been proven the key compound in the resolution process, and presented the highest melting point of 166°C (dec.) among the four salts. The originally expected diastereomeric bitartrate salts with 1:1M base:acid ratio [(S)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt and (R)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt] and their 'racemic' co-crystal [(RS)-tetramisole-dibenzoyl-(R,R)-hydrogen-tartrate salt] showed somewhat lower melting points (152, 145, and 150°C, respectively) and their crystallization was also prevented by application of ultrasound. Based on the melting points and enthalpies of fusion measured by DSC, all the binary and ternary phase diagrams have been newly established and calculated in the system with help of classical modelling equations of liquidus curves.
European Journal of Pharmaceutical Sciences
Polymers for Advanced Technologies, 2015
Suitability of electrospinning for biodrug formulation was investigated in order to develop an el... more Suitability of electrospinning for biodrug formulation was investigated in order to develop an electrospinning‐based method for producing oral dosage form of β‐galactosidase. β‐Galactosidase‐loaded polymeric (polyvinyl alcohol, polyvinylpyrrolidones with two different molar masses, and polyethylene glycol) nanofibers were prepared by electrospinning in order to lengthen the shelf life of the enzyme (providing an alternative technology to drying). Based on the activity of the encapsulated β‐galactosidase, the most suitable polymer was polyvinylpyrrolidone with higher molecular weight (1,200,000 Da), because 97% of the original activity remained in this case. Kinetic behavior of β‐galactosidase did not show any alteration after encapsulation, and the pH and temperature profiles were not changed either. Time course of viability testing showed that the nanofibrous formulation can provide long‐term stability for β‐galactosidase; the activity of the enzyme decreased only 4% after a year. ...
European Polymer Journal, 2015
Two continuous processes, the spray drying method, producing microparticles in presence of hot ga... more Two continuous processes, the spray drying method, producing microparticles in presence of hot gas flow, and the electrospinning technology, producing continuous polymer nanofibers at low temperature under high electric fields, were investigated and compared the first time. Both techniques were used to prepare slow release caffeine (as a model of rapidly water-soluble drug) using water-insoluble, biocompatible and bioresorbable PLGA and PLA as polymeric matrix. The structural characterization of the obtained samples was performed using SEM, XRD, DSC and at-line Raman mapping, while in vitro dissolution was detected by UV spectrophotometer. We found that the release profile of a highly water soluble drug can be adjusted to the requirements through the investigated continuous technologies. Solid molecular dispersion of caffeine at colloidal level could be prepared in PLA matrix using electrostatic spinning. Furthermore the continuous nonwoven structure of ultrafine fibers, produced this way, allows easer handling than that of independent fine particle's. On the other hand continuous production of drug loaded microspheres with slightly less performance can be performed with the conventional technology of spray drying which is well known in the pharmaceutical industry.
Journal of Raman Spectroscopy, 2015
ABSTRACT Chemical imaging was used in this study as a powerful analytical tool to characterize ph... more ABSTRACT Chemical imaging was used in this study as a powerful analytical tool to characterize pharmaceuticals in solid form. The majority of analyses are evaluated with bilinear modelling using only the pure component spectra or just the chemical images themselves to estimate the concentrations in each pixel, which are far from true quantitative determination. Our aim was to create more accurate concentration images using regression methods. For the first time in chemical imaging, variable selections with interval partial least squares (PLS) and with genetic algorithms (PLS-GA) were applied to increase the efficiency of the models. These were compared to numerous bilinear modelling and multivariate linear regression methods such as univariate regression, classical least squares (CLS), multivariate curve resolution–alternating least squares (MCR-ALS), principal component regression (PCR) and partial least squares (PLS). Two component spray-dried pharmaceuticals were used as a model. The paper is shown that, in contrast to the usual way of using either external validation or cross-validation, both should be performed simultaneously in order to get a clear picture of the prediction errors and to be able to select the appropriate models. Using PLS with variable selection, the root mean square errors were reduced to 3% per pixel by keeping only those peaks that are truly necessary for the estimation of concentrations. It is also shown that interval PLS can point out the best peak for univariate regression, and can thereby be of great help even when regulations allow only univariate models for product quality testing. Variable selection, besides yielding more accurate overall concentrations across a Raman map, also reduces the deviation among pixel concentrations within the images, thereby increasing the sensitivity of homogeneity studies. Copyright © 2015 John Wiley & Sons, Ltd.
Organic Process Research & Development, 2015
Although the process analytical technology for ensuring constant product quality and tight contro... more Although the process analytical technology for ensuring constant product quality and tight control over the manufacturing process, which is especially important in the case of hazardous chemical reactions, has initiated extensive use of real-time spectroscopic methods (ATR-UV/vis, ATR-FTIR, or Raman) for monitoring of chemical reactions, control of chemical syntheses on the basis of inline Raman spectroscopic detection has not been implemented yet. The present paper reports the development of an effective feedback control on the basis of Raman spectroscopy governing a potentially hazardous, exothermic model reaction. The control approach allowed the quantification of reaction components and an unstable intermediate and, furthermore, determined the end point of the reaction. The spectrum of the unstable intermediate was identified using the multivariate curve resolution-alternating least-squares (MCR-ALS) method. The implementation of the feedback control required the development of a program operating the Raman spectrometer and coordinating the real-time CLS chemometric evaluation, while another program was designed to communicate with the previous one and was responsible for the closed-loop control of the process.
International journal of pharmaceutics, Jan 14, 2015
High speed electrospinning (HSES), compatible with pharmaceutical industry, was used to demonstra... more High speed electrospinning (HSES), compatible with pharmaceutical industry, was used to demonstrate the viability of the preparation of drug-loaded polymer nanofibers with radically higher productivity than the known single-needle electrospinning (SNES) setup. Poorly water-soluble itraconazole (ITRA) was formulated with PVPVA64 matrix polymer using four different solvent-based methods such as HSES, SNES, spray drying (SD) and film casting (FC). The formulations were assessed in terms of improvement in the dissolution rate of ITRA (using a "tapped basket" dissolution configuration) and analysed by SEM, DSC and XRPD. Despite the significantly increased productivity of HSES, the obtained morphology was very similar to the SNES nanofibrous material. ITRA transformed into an amorphous form, according to the DSC and XRPD results, in most cases except the FC samples. The limited dissolution of crystalline ITRA could be highly improved: fast dissolution occurred (>90% within 10...