Jacek Żegliński - Academia.edu (original) (raw)

Papers by Jacek Żegliński

Crystal Growth & Design, Jul 26, 2017

Controlling pharmaceutical polymorphism in crystallization processes represents a major challenge... more Controlling pharmaceutical polymorphism in crystallization processes represents a major challenge in pharmaceutical science and engineering. For instance, CO 2-antisolvent crystallization typically favors the formation of metastable forms of carbamazepine (CBZ), a highly polymorphic drug, with impurities of other forms. This work demonstrates for the first time that a supercritical CO 2antisolvent crystallization process in combination with certain molecular additives allows control of the polymorphic outcome of carbamazepine. We show herein that in the presence of sodium stearate and Eudragit L-100, needle-shaped crystals of CBZ form II are obtained, while blocky-shaped crystals of CBZ form III are obtained in the presence of Kollidon VA64, sodium dodecyl sulfate, ethyl cellulose and maltitol. This selectivity for pure forms in this supercritical set up contrasts to the results when the same set of additives where used in a solvent evaporation method that yielded mixtures of form I, II and III. The type of additive used in the CO 2-antisolvent crystallization process impacted both the product crystals polymorphic form and size. A detailed molecular-level analysis along with DFT calculations allowed us to give a mechanistic insight into the role of sodium stearate and Eudragit L-100 in facilitating nucleation of the metastable form II.

International Journal of Pharmaceutics, 2021

Multivariate Curve Resolution (MCR) was used to determine the phase purity of pharmaceutical co-c... more Multivariate Curve Resolution (MCR) was used to determine the phase purity of pharmaceutical co-crystals from mid infrared spectra. An in-silico coformer screening was used to choose one of ten potential coformers. This analysis used quantum chemistry simulation to predict which coformers are thermodynamically inclined to form cocrystals with the model drug, hydrochlorothiazide. The coformer chosen was nicotinamide. An experimental solvent screening by ultrasound assisted slurry co-crystallization was performed to evaluate the capacity of the method to determine phase purity. Afterwards, slurry and slow evaporation co-crystallizations were performed at 10, 25, and 40 °C using 7 solvent systems, and two levels of agitation for the evaporation co-crystallization (on and off). Mid infrared spectroscopy (MIRS) analysis of the products of these co-crystallizations was used to develop an MCR model to determine co-crystal phase purity. The MCR results were compared with a reference co-crystal. Experimental design (DoE) was used to investigate the effect of solvents, temperature, and agitation on the purity of co-crystals produced by slurry and evaporation co-crystallization. DoE revealed that evaporation co-crystallization with agitating at 65 rpm formed co-crystals with greater phase purity. The optimal temperature varied with the solvent used.

Electrically Active Materials for Medical Devices, 2016

By using the sol-gel method, silica gels were prepared with embedded hydrogen peroxide. Altogethe... more By using the sol-gel method, silica gels were prepared with embedded hydrogen peroxide. Altogether 18 systems were investigated with variable hydrogen peroxide contents and different stabilizers. Orthophosphoric acid(V) at a concentration of 0.05 per cent turned out to be an effective stabilizer of the hydrogel system H 1 3 containing 10 per cent of hydrogen peroxide. Drying hydrogels afforded the so-called xerogels with hydrogen peroxide contents as high as up to 74 per cent. The most stable xerogel systems were those labelled K 5 and K 3 stabilized respectively with 0.23 per cent.orthophosphoric acid(V) and 0.83 per cent tartaric acid. The least effective stabilizer was disodium ethylenediaminetetraacetate (Na 2 EDTA) which even decomposed hydrogen peroxide at its higher concentrations in the gels. A study of thermal stability of the systems carried out by employing differential scanning calorimetry and thermogravimetry showed their decomposition over the temperature range 80 - 150 °C with accompanying 75 per cent loss in weight of the xerogels. The highest rate of decomposition was recorded at 126.7 °C.

Journal of Molecular Structure, 2006

The FTIR spectra of the silica xerogel–H2O2 composite, obtained by the sol–gel technique, were ex... more The FTIR spectra of the silica xerogel–H2O2 composite, obtained by the sol–gel technique, were examined. To support interpretation of the experimental data, vibrational frequencies were calculated using density functional theory (DFT) and B3LYP functional for low-molecular-weight models of solvated silica gel: H4SiO4–H2O2–H2O and [(HO)3SiOSi(OH)3]–H2O2. The role of water in stabilizing the hydrogen peroxide adsorbed on silica surface was discussed. The

Excipient Applications in Formulation Design and Drug Delivery, 2015

Smart polymers or stimuli-responsive polymers typically change their physical properties and/or s... more Smart polymers or stimuli-responsive polymers typically change their physical properties and/or structure in response to relatively minor changes in the stimulus. Changes in the environment that affect polymer properties can be called as the stimuli, while the resulting changes in the polymer and the system (such as dissolved state of the polymer in a solvent) has been termed as the response. The changes in the environment that have been exploited for biopharmaceutical applications are exemplified by pH, ionic strength, temperature, light,and magnetic or electric field. This chapter will highlight most popular smart polymers used in drug delivery.

Acta Crystallographica, Dec 1, 2017

Using Artificial Neural Networks (ANNs),1 a model has been developed for prediction of the meltin... more Using Artificial Neural Networks (ANNs),1 a model has been developed for prediction of the melting point (Tm)2 of unsynthesized co-crystals (CCs). The model uses four input parameters for the pure Active Pharmaceutical Ingredient (APIs) and four for the pure coformer. In addition, as input parameters the model uses the 1:1 gas phase binding energy in the anticipated main synthon of the cocrystal as calculated by a force field method and ΔpKa value of the respective cocrystals2 (mostly extracted from the literature). The model is trained using known cocrystal melting temperatures giving an average relative deviation of 1.98%, and can then predict the melting point of a validation set to a relative deviation of 3.37%. In total, 61 CCs (two-component molecular cocrystals3) Tm were used to construct the model, and the Tm values were extracted from the literature for four APIs, namely, i.e. caffeine (CAF), theophylline (THP), nicotinamide (NA) and isonicotinamide (INA). The number of CCs included were: 14-CAF, 9-THP, 29-INA and 9-NA. The advantage of our model is that, it could be possible to set the melting point of the new solid form of the respective drug molecules within the target range by a selection of an ideal coformer for cocrystal formation. Hence, it will reduce the cost, manpower and time in the pharmaceutical industry.

European Journal of Pharmaceutics and Biopharmaceutics, Oct 1, 2017

Piracetam was investigated as a model API which is known to exhibit a number of different polymor... more Piracetam was investigated as a model API which is known to exhibit a number of different polymorphic forms. It is freely soluble in water so the possibility exists for polymorphic transformations to occur during wet granulation. Analysis of the polymorphic form present during lab-scale wet granulation, using water as a granulation liquid, was studied with powder X-ray diffraction and Raman spectroscopy as offline and inline analysis tools respectively. Different excipients with a range of hydrophilicities, aqueous solubilities and molecular weights were investigated to examine their influence on these solutionmediated polymorphic transitions and experimental results were rationalised using molecular modelling. Our results indicated that as an increasing amount of water was added to the as-received piracetam FIII, a greater amount of the API dissolved which recrystallised upon drying to the metastable FII(6.403) via a monohydrate intermediary. Molecular level analysis revealed that the observed preferential transformation of monohydrate to FII is linked with a greater structural similarity between the monohydrate and FII polymorph in comparison to FIII. The application of Raman spectroscopy as a process analytical technology (PAT) tool to monitor the granulation process for the production of the monohydrate intermediate as a precursor to the undesirable metastable form was demonstrated.

Physical Chemistry Chemical Physics, 2018

Molecular clustering and solvent-solute interactions in isopropanol solutions of fenoxycarb have ... more Molecular clustering and solvent-solute interactions in isopropanol solutions of fenoxycarb have been thoroughly and systematically investigated by dynamic light scattering, small-angle X-ray scattering, and nanoparticle tracking, supported by infrared spectroscopy and molecular dynamics simulations. The existence of molecular aggregates, clusters, ranging in size up to almost a micrometre is clearly recorded at undersaturated as well as supersaturated conditions by all three analysis techniques. The results systematically reveal that the cluster size increases with solute concentration and time at stagnant conditions. For most concentrations the time scale of cluster growth is of the order of days. In undersaturated solutions the size appears to eventually reach a maximum value, higher the higher the concentration. Below a certain concentration threshold clusters are significantly smaller. Clusters are found to be smaller in solutions pre-heated at a higher temperature, which offers a possible explanation for the so-called ''history of solution'' effect. The cluster distribution is influenced by filtration through membranes with a pore size of 0.1 mm, offering an alternative explanation for the ''foreign particle-catalysed nucleation'' effect. At moderate concentrations larger clusters appear to be sheared into smaller ones, but the original size distribution is rapidly re-established. At higher concentrations, although still well below solubility, the cluster size as well as solute concentration are strongly affected, suggesting that larger clusters contain at least a core of more organized molecules not able to pass through the filter.

Crystal Growth & Design, Sep 19, 2018

The crystallization of seven active pharmaceutical ingredients (APIs) (acetaminophen (AAP), carba... more The crystallization of seven active pharmaceutical ingredients (APIs) (acetaminophen (AAP), carbamazepine (CBMZ), caffeine (CAF), phenylbutazone (PBZ), risperidone (RIS), clozapine base (CPB) and fenofibrate (FF)) was studied in the absence and presence of microcrystalline cellulose (MCC) which acted as a heterosurface. Two of the APIs, namely AAP and CBMZ, possess hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA)

Crystal Growth & Design, Mar 8, 2019

Induction time experiments, spectroscopic and calorimetric analysis, and molecular modelling were... more Induction time experiments, spectroscopic and calorimetric analysis, and molecular modelling were used to probe the influence of solvent on the crystal nucleation of fenoxycarb (FC), a medium-sized, flexible organic molecule. 800 induction times covering a range of supersaturations and crystallisation temperatures in four different solvents were measured to elucidate the relative ease of nucleation. To achieve similar induction times, the required thermodynamic driving force, RTlnS, increases in the order: ethyl acetate < toluene < ethanol < isopropanol. This is roughly matched by the order of interfacial energies calculated using the Classical Nucleation Theory. Solvent-solute interaction strengths were estimated using three methods: solvent-solute enthalpies derived from calorimetric solution enthalpies, solvent-solute interactions from Molecular Dynamics simulations, and the FTIR shifts in the carbonyl stretching corresponding to the solvent-solute interaction. The three methods gave an overall order of solvent-solute interactions increasing in the order: toluene < ethyl acetate < alcohols. Thus, with the exception of FC in toluene, it is found that the nucleation difficulty increases the stronger the solvent binds the solute.

Crystal Growth & Design, Nov 13, 2018

A new 1:1 drug-drug cocrystal of theophylline (THP) and aspirin (ASP) was successfully prepared b... more A new 1:1 drug-drug cocrystal of theophylline (THP) and aspirin (ASP) was successfully prepared by liquid assisted grinding, evaporative crystallization and slurry conversion crystallization. The obtained cocrystal was comprehensively characterized by Single Crystal X-ray Diffraction, Powder X-ray diffraction, Differential Scanning Calorimetry, Thermogravimetric analysis, Scanning Electron Microscopy and Fourier Transform Infrared analysis. Ternary phase diagrams (TPDs) were constructed for the obtained cocrystal in isopropyl alcohol at two different temperatures, i.e. 20 and 40°C. A narrow stability region was found for the pure THP-ASP cocrystal in the phase diagram at both temperatures. By proper selection of the ratios between THP, ASP and IPA from the stability region, THP-ASP cocrystals could be purely produced by isothermal slurry conversion in IPA. In addition, molecular modelling was deployed to provide mechanistic insights into the formation of this THP-ASP cocrystal system.

Crystal Growth & Design, Jun 15, 2018

In this work, the influence of the structurally related impurities, Demethoxycurcumin (DMC) and B... more In this work, the influence of the structurally related impurities, Demethoxycurcumin (DMC) and Bisdemethoxycurcumin (BDMC) on the primary nucleation of Curcumin (CUR) has been investigated in propan-2-ol. The induction time for nucleation was measured at different CUR driving forces and impurity concentrations 0.10 mmol.dm-3 , 0.30 mmol.dm-3 and 0.60 mmol.dm-3 and the results are analysed by the classical nucleation theory (CNT). The nucleation rate for the impure systems was noticeably lower than the nucleation rate of the pure system, and the times of growth to visibility were much longer for the impure systems. The pre-exponential factors are clearly lower for the impure system compared to the pure CUR system, while the increase in the solid-liquid interfacial energy is small. DFT and Metadynamic molecular modelling reveal that the 1:1 bonding between CUR and an impurity molecule is stronger than to another CUR molecule, thus suggesting that the developing CUR nucleus has to overcome a certain energy barrier in order to remove the impurity molecules from their surface, which may explain why nucleation of CUR is more difficult in presence of the structurally related impurities; DMC and BDMC.

CrystEngComm, 2022

The crystal growth of curcumin in pure 2-propanol containing two structurally related impurities,... more The crystal growth of curcumin in pure 2-propanol containing two structurally related impurities, demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC), has been investigated by seeded isothermal desupersaturation experiments at 283, 293 and 308 K.

Crystal Growth & Design, Dec 1, 2017

Using Artificial Neural Networks (ANNs), four distinct models have been developed for the predict... more Using Artificial Neural Networks (ANNs), four distinct models have been developed for the prediction of solid-state properties of cocrystals: melting point, lattice energy, and crystal density. The models use three input parameters for the pure model compound (MC) and three for the pure coformer. In addition, as input parameter the model uses the pKa difference between the MC and the coformer, and a 1:1 MC-conformer binding energy as calculated by a force field method. Notably the models require no data for the actual cocrystals. In total, 61 CCs (two-component molecular cocrystals) were used to construct the models, and melting temperatures and crystal densities were extracted from the literature for four MCs: caffeine, theophylline, nicotinamide and isonicotinamide. The data set includes 14 caffein cocrystals, 9 theophylline cocrystals, 9 nicotinamide cocrystals and 29 isonicotinamide cocrystals. The model-I is trained using known cocrystal melting temperatures, lattice energies and crystal densities, to predict all three solid-state properties simultaneously. The average relative deviation for the training set is 2.49%, 6.21% and 1.88% for the melting temperature, lattice energy and crystal density, respectively, and correspondingly 6.26%, 4.58% and 0.99% for the valdation set. Model-II, model-III and model-IV were built using the same input neurons as in model-I, for separate prediction of each respective output solid-state property. For these models the average relative deviation for the traning sets becomes 1.93% for the melting temperature model-II, 1.29% for the lattice energy model-III and 1.03% for the crystal density model-IV, and correspondingly 2.23%, 2.40% and 1.77% for the respective validation sets.

Journal of Drug Delivery Science and Technology, 2018

In this study, a set of 24 experiments was designed to understand the combined effect of differen... more In this study, a set of 24 experiments was designed to understand the combined effect of different process parameters, i.e. material feed rate, liquid-to-solid (L/S) ratio, screw speed, and screw configuration on the residence time distribution, granule morphology, and particle size distribution in twin screw wet granulation of microcrystalline cellulose. It was shown that residence times were longer at higher L/S and lower screw speeds. However, the most dominant effect on mean residence time had screw configuration, with longer residence times observed with increasing complexity of the screws employed. Scanning electron microscopy and laser diffraction measurements showed accordingly that the most important quality attribute affecting size of granules is L/S ratio. The relationships between input and output parameters observed for our low throughput setup generally match those concerning higher throughput granulators described in literature.

European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, Jan 27, 2017

Piracetam was investigated as a model API which is known to exhibit a number of different polymor... more Piracetam was investigated as a model API which is known to exhibit a number of different polymorphic forms. It is freely soluble in water so the possibility exists for polymorphic transformations to occur during wet granulation. Analysis of the polymorphic form present during lab-scale wet granulation, using water as a granulation liquid, was studied with powder X-ray diffraction and Raman spectroscopy as off-line and inline analysis tools respectively. Different excipients with a range of hydrophilicities, aqueous solubilities and molecular weights were investigated to examine their influence on these solution-mediated polymorphic transitions and experimental results were rationalised using molecular modelling. Our results indicated that as an increasing amount of water was added to the as-received piracetam FIII, a greater amount of the API dissolved which recrystallised upon drying to the metastable FII(6.403) via a monohydrate intermediary. Molecular level analysis revealed tha...

Faraday Discussions, 2015

Sarah Price opened a general discussion of the paper by Sven Schroeder: I have been generating th... more Sarah Price opened a general discussion of the paper by Sven Schroeder: I have been generating the thermodynamically plausible crystal structures of organic molecules for many years, and back in 2004 we did a crystal structure prediction (CSP) study on imidazole1 and found that it was relatively straightforward. Following your paper, we have reclassified the low energy structures according to the tilt within the hydrogen-bonded chain and the relative direction of the chains. Although the observed structure was the global minimum, two other structures with a displacement of otherwise identical layers are very close in energy. Do you think that if imidazole had crystallised in one of these alternative structures it would be distinguishable by NEXAFS? This would be a very sensitive test of whether NEXAFS combined with CSP could be used in characterising crystal structures.

Crystal Growth & Design, Jul 26, 2017

Controlling pharmaceutical polymorphism in crystallization processes represents a major challenge... more Controlling pharmaceutical polymorphism in crystallization processes represents a major challenge in pharmaceutical science and engineering. For instance, CO 2-antisolvent crystallization typically favors the formation of metastable forms of carbamazepine (CBZ), a highly polymorphic drug, with impurities of other forms. This work demonstrates for the first time that a supercritical CO 2antisolvent crystallization process in combination with certain molecular additives allows control of the polymorphic outcome of carbamazepine. We show herein that in the presence of sodium stearate and Eudragit L-100, needle-shaped crystals of CBZ form II are obtained, while blocky-shaped crystals of CBZ form III are obtained in the presence of Kollidon VA64, sodium dodecyl sulfate, ethyl cellulose and maltitol. This selectivity for pure forms in this supercritical set up contrasts to the results when the same set of additives where used in a solvent evaporation method that yielded mixtures of form I, II and III. The type of additive used in the CO 2-antisolvent crystallization process impacted both the product crystals polymorphic form and size. A detailed molecular-level analysis along with DFT calculations allowed us to give a mechanistic insight into the role of sodium stearate and Eudragit L-100 in facilitating nucleation of the metastable form II.

International Journal of Pharmaceutics, 2021

Multivariate Curve Resolution (MCR) was used to determine the phase purity of pharmaceutical co-c... more Multivariate Curve Resolution (MCR) was used to determine the phase purity of pharmaceutical co-crystals from mid infrared spectra. An in-silico coformer screening was used to choose one of ten potential coformers. This analysis used quantum chemistry simulation to predict which coformers are thermodynamically inclined to form cocrystals with the model drug, hydrochlorothiazide. The coformer chosen was nicotinamide. An experimental solvent screening by ultrasound assisted slurry co-crystallization was performed to evaluate the capacity of the method to determine phase purity. Afterwards, slurry and slow evaporation co-crystallizations were performed at 10, 25, and 40 °C using 7 solvent systems, and two levels of agitation for the evaporation co-crystallization (on and off). Mid infrared spectroscopy (MIRS) analysis of the products of these co-crystallizations was used to develop an MCR model to determine co-crystal phase purity. The MCR results were compared with a reference co-crystal. Experimental design (DoE) was used to investigate the effect of solvents, temperature, and agitation on the purity of co-crystals produced by slurry and evaporation co-crystallization. DoE revealed that evaporation co-crystallization with agitating at 65 rpm formed co-crystals with greater phase purity. The optimal temperature varied with the solvent used.

Electrically Active Materials for Medical Devices, 2016

By using the sol-gel method, silica gels were prepared with embedded hydrogen peroxide. Altogethe... more By using the sol-gel method, silica gels were prepared with embedded hydrogen peroxide. Altogether 18 systems were investigated with variable hydrogen peroxide contents and different stabilizers. Orthophosphoric acid(V) at a concentration of 0.05 per cent turned out to be an effective stabilizer of the hydrogel system H 1 3 containing 10 per cent of hydrogen peroxide. Drying hydrogels afforded the so-called xerogels with hydrogen peroxide contents as high as up to 74 per cent. The most stable xerogel systems were those labelled K 5 and K 3 stabilized respectively with 0.23 per cent.orthophosphoric acid(V) and 0.83 per cent tartaric acid. The least effective stabilizer was disodium ethylenediaminetetraacetate (Na 2 EDTA) which even decomposed hydrogen peroxide at its higher concentrations in the gels. A study of thermal stability of the systems carried out by employing differential scanning calorimetry and thermogravimetry showed their decomposition over the temperature range 80 - 150 °C with accompanying 75 per cent loss in weight of the xerogels. The highest rate of decomposition was recorded at 126.7 °C.

Journal of Molecular Structure, 2006

The FTIR spectra of the silica xerogel–H2O2 composite, obtained by the sol–gel technique, were ex... more The FTIR spectra of the silica xerogel–H2O2 composite, obtained by the sol–gel technique, were examined. To support interpretation of the experimental data, vibrational frequencies were calculated using density functional theory (DFT) and B3LYP functional for low-molecular-weight models of solvated silica gel: H4SiO4–H2O2–H2O and [(HO)3SiOSi(OH)3]–H2O2. The role of water in stabilizing the hydrogen peroxide adsorbed on silica surface was discussed. The

Excipient Applications in Formulation Design and Drug Delivery, 2015

Smart polymers or stimuli-responsive polymers typically change their physical properties and/or s... more Smart polymers or stimuli-responsive polymers typically change their physical properties and/or structure in response to relatively minor changes in the stimulus. Changes in the environment that affect polymer properties can be called as the stimuli, while the resulting changes in the polymer and the system (such as dissolved state of the polymer in a solvent) has been termed as the response. The changes in the environment that have been exploited for biopharmaceutical applications are exemplified by pH, ionic strength, temperature, light,and magnetic or electric field. This chapter will highlight most popular smart polymers used in drug delivery.

Acta Crystallographica, Dec 1, 2017

Using Artificial Neural Networks (ANNs),1 a model has been developed for prediction of the meltin... more Using Artificial Neural Networks (ANNs),1 a model has been developed for prediction of the melting point (Tm)2 of unsynthesized co-crystals (CCs). The model uses four input parameters for the pure Active Pharmaceutical Ingredient (APIs) and four for the pure coformer. In addition, as input parameters the model uses the 1:1 gas phase binding energy in the anticipated main synthon of the cocrystal as calculated by a force field method and ΔpKa value of the respective cocrystals2 (mostly extracted from the literature). The model is trained using known cocrystal melting temperatures giving an average relative deviation of 1.98%, and can then predict the melting point of a validation set to a relative deviation of 3.37%. In total, 61 CCs (two-component molecular cocrystals3) Tm were used to construct the model, and the Tm values were extracted from the literature for four APIs, namely, i.e. caffeine (CAF), theophylline (THP), nicotinamide (NA) and isonicotinamide (INA). The number of CCs included were: 14-CAF, 9-THP, 29-INA and 9-NA. The advantage of our model is that, it could be possible to set the melting point of the new solid form of the respective drug molecules within the target range by a selection of an ideal coformer for cocrystal formation. Hence, it will reduce the cost, manpower and time in the pharmaceutical industry.

European Journal of Pharmaceutics and Biopharmaceutics, Oct 1, 2017

Piracetam was investigated as a model API which is known to exhibit a number of different polymor... more Piracetam was investigated as a model API which is known to exhibit a number of different polymorphic forms. It is freely soluble in water so the possibility exists for polymorphic transformations to occur during wet granulation. Analysis of the polymorphic form present during lab-scale wet granulation, using water as a granulation liquid, was studied with powder X-ray diffraction and Raman spectroscopy as offline and inline analysis tools respectively. Different excipients with a range of hydrophilicities, aqueous solubilities and molecular weights were investigated to examine their influence on these solutionmediated polymorphic transitions and experimental results were rationalised using molecular modelling. Our results indicated that as an increasing amount of water was added to the as-received piracetam FIII, a greater amount of the API dissolved which recrystallised upon drying to the metastable FII(6.403) via a monohydrate intermediary. Molecular level analysis revealed that the observed preferential transformation of monohydrate to FII is linked with a greater structural similarity between the monohydrate and FII polymorph in comparison to FIII. The application of Raman spectroscopy as a process analytical technology (PAT) tool to monitor the granulation process for the production of the monohydrate intermediate as a precursor to the undesirable metastable form was demonstrated.

Physical Chemistry Chemical Physics, 2018

Molecular clustering and solvent-solute interactions in isopropanol solutions of fenoxycarb have ... more Molecular clustering and solvent-solute interactions in isopropanol solutions of fenoxycarb have been thoroughly and systematically investigated by dynamic light scattering, small-angle X-ray scattering, and nanoparticle tracking, supported by infrared spectroscopy and molecular dynamics simulations. The existence of molecular aggregates, clusters, ranging in size up to almost a micrometre is clearly recorded at undersaturated as well as supersaturated conditions by all three analysis techniques. The results systematically reveal that the cluster size increases with solute concentration and time at stagnant conditions. For most concentrations the time scale of cluster growth is of the order of days. In undersaturated solutions the size appears to eventually reach a maximum value, higher the higher the concentration. Below a certain concentration threshold clusters are significantly smaller. Clusters are found to be smaller in solutions pre-heated at a higher temperature, which offers a possible explanation for the so-called ''history of solution'' effect. The cluster distribution is influenced by filtration through membranes with a pore size of 0.1 mm, offering an alternative explanation for the ''foreign particle-catalysed nucleation'' effect. At moderate concentrations larger clusters appear to be sheared into smaller ones, but the original size distribution is rapidly re-established. At higher concentrations, although still well below solubility, the cluster size as well as solute concentration are strongly affected, suggesting that larger clusters contain at least a core of more organized molecules not able to pass through the filter.

Crystal Growth & Design, Sep 19, 2018

The crystallization of seven active pharmaceutical ingredients (APIs) (acetaminophen (AAP), carba... more The crystallization of seven active pharmaceutical ingredients (APIs) (acetaminophen (AAP), carbamazepine (CBMZ), caffeine (CAF), phenylbutazone (PBZ), risperidone (RIS), clozapine base (CPB) and fenofibrate (FF)) was studied in the absence and presence of microcrystalline cellulose (MCC) which acted as a heterosurface. Two of the APIs, namely AAP and CBMZ, possess hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA)

Crystal Growth & Design, Mar 8, 2019

Induction time experiments, spectroscopic and calorimetric analysis, and molecular modelling were... more Induction time experiments, spectroscopic and calorimetric analysis, and molecular modelling were used to probe the influence of solvent on the crystal nucleation of fenoxycarb (FC), a medium-sized, flexible organic molecule. 800 induction times covering a range of supersaturations and crystallisation temperatures in four different solvents were measured to elucidate the relative ease of nucleation. To achieve similar induction times, the required thermodynamic driving force, RTlnS, increases in the order: ethyl acetate < toluene < ethanol < isopropanol. This is roughly matched by the order of interfacial energies calculated using the Classical Nucleation Theory. Solvent-solute interaction strengths were estimated using three methods: solvent-solute enthalpies derived from calorimetric solution enthalpies, solvent-solute interactions from Molecular Dynamics simulations, and the FTIR shifts in the carbonyl stretching corresponding to the solvent-solute interaction. The three methods gave an overall order of solvent-solute interactions increasing in the order: toluene < ethyl acetate < alcohols. Thus, with the exception of FC in toluene, it is found that the nucleation difficulty increases the stronger the solvent binds the solute.

Crystal Growth & Design, Nov 13, 2018

A new 1:1 drug-drug cocrystal of theophylline (THP) and aspirin (ASP) was successfully prepared b... more A new 1:1 drug-drug cocrystal of theophylline (THP) and aspirin (ASP) was successfully prepared by liquid assisted grinding, evaporative crystallization and slurry conversion crystallization. The obtained cocrystal was comprehensively characterized by Single Crystal X-ray Diffraction, Powder X-ray diffraction, Differential Scanning Calorimetry, Thermogravimetric analysis, Scanning Electron Microscopy and Fourier Transform Infrared analysis. Ternary phase diagrams (TPDs) were constructed for the obtained cocrystal in isopropyl alcohol at two different temperatures, i.e. 20 and 40°C. A narrow stability region was found for the pure THP-ASP cocrystal in the phase diagram at both temperatures. By proper selection of the ratios between THP, ASP and IPA from the stability region, THP-ASP cocrystals could be purely produced by isothermal slurry conversion in IPA. In addition, molecular modelling was deployed to provide mechanistic insights into the formation of this THP-ASP cocrystal system.

Crystal Growth & Design, Jun 15, 2018

In this work, the influence of the structurally related impurities, Demethoxycurcumin (DMC) and B... more In this work, the influence of the structurally related impurities, Demethoxycurcumin (DMC) and Bisdemethoxycurcumin (BDMC) on the primary nucleation of Curcumin (CUR) has been investigated in propan-2-ol. The induction time for nucleation was measured at different CUR driving forces and impurity concentrations 0.10 mmol.dm-3 , 0.30 mmol.dm-3 and 0.60 mmol.dm-3 and the results are analysed by the classical nucleation theory (CNT). The nucleation rate for the impure systems was noticeably lower than the nucleation rate of the pure system, and the times of growth to visibility were much longer for the impure systems. The pre-exponential factors are clearly lower for the impure system compared to the pure CUR system, while the increase in the solid-liquid interfacial energy is small. DFT and Metadynamic molecular modelling reveal that the 1:1 bonding between CUR and an impurity molecule is stronger than to another CUR molecule, thus suggesting that the developing CUR nucleus has to overcome a certain energy barrier in order to remove the impurity molecules from their surface, which may explain why nucleation of CUR is more difficult in presence of the structurally related impurities; DMC and BDMC.

CrystEngComm, 2022

The crystal growth of curcumin in pure 2-propanol containing two structurally related impurities,... more The crystal growth of curcumin in pure 2-propanol containing two structurally related impurities, demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC), has been investigated by seeded isothermal desupersaturation experiments at 283, 293 and 308 K.

Crystal Growth & Design, Dec 1, 2017

Using Artificial Neural Networks (ANNs), four distinct models have been developed for the predict... more Using Artificial Neural Networks (ANNs), four distinct models have been developed for the prediction of solid-state properties of cocrystals: melting point, lattice energy, and crystal density. The models use three input parameters for the pure model compound (MC) and three for the pure coformer. In addition, as input parameter the model uses the pKa difference between the MC and the coformer, and a 1:1 MC-conformer binding energy as calculated by a force field method. Notably the models require no data for the actual cocrystals. In total, 61 CCs (two-component molecular cocrystals) were used to construct the models, and melting temperatures and crystal densities were extracted from the literature for four MCs: caffeine, theophylline, nicotinamide and isonicotinamide. The data set includes 14 caffein cocrystals, 9 theophylline cocrystals, 9 nicotinamide cocrystals and 29 isonicotinamide cocrystals. The model-I is trained using known cocrystal melting temperatures, lattice energies and crystal densities, to predict all three solid-state properties simultaneously. The average relative deviation for the training set is 2.49%, 6.21% and 1.88% for the melting temperature, lattice energy and crystal density, respectively, and correspondingly 6.26%, 4.58% and 0.99% for the valdation set. Model-II, model-III and model-IV were built using the same input neurons as in model-I, for separate prediction of each respective output solid-state property. For these models the average relative deviation for the traning sets becomes 1.93% for the melting temperature model-II, 1.29% for the lattice energy model-III and 1.03% for the crystal density model-IV, and correspondingly 2.23%, 2.40% and 1.77% for the respective validation sets.

Journal of Drug Delivery Science and Technology, 2018

In this study, a set of 24 experiments was designed to understand the combined effect of differen... more In this study, a set of 24 experiments was designed to understand the combined effect of different process parameters, i.e. material feed rate, liquid-to-solid (L/S) ratio, screw speed, and screw configuration on the residence time distribution, granule morphology, and particle size distribution in twin screw wet granulation of microcrystalline cellulose. It was shown that residence times were longer at higher L/S and lower screw speeds. However, the most dominant effect on mean residence time had screw configuration, with longer residence times observed with increasing complexity of the screws employed. Scanning electron microscopy and laser diffraction measurements showed accordingly that the most important quality attribute affecting size of granules is L/S ratio. The relationships between input and output parameters observed for our low throughput setup generally match those concerning higher throughput granulators described in literature.

European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V, Jan 27, 2017

Piracetam was investigated as a model API which is known to exhibit a number of different polymor... more Piracetam was investigated as a model API which is known to exhibit a number of different polymorphic forms. It is freely soluble in water so the possibility exists for polymorphic transformations to occur during wet granulation. Analysis of the polymorphic form present during lab-scale wet granulation, using water as a granulation liquid, was studied with powder X-ray diffraction and Raman spectroscopy as off-line and inline analysis tools respectively. Different excipients with a range of hydrophilicities, aqueous solubilities and molecular weights were investigated to examine their influence on these solution-mediated polymorphic transitions and experimental results were rationalised using molecular modelling. Our results indicated that as an increasing amount of water was added to the as-received piracetam FIII, a greater amount of the API dissolved which recrystallised upon drying to the metastable FII(6.403) via a monohydrate intermediary. Molecular level analysis revealed tha...

Faraday Discussions, 2015

Sarah Price opened a general discussion of the paper by Sven Schroeder: I have been generating th... more Sarah Price opened a general discussion of the paper by Sven Schroeder: I have been generating the thermodynamically plausible crystal structures of organic molecules for many years, and back in 2004 we did a crystal structure prediction (CSP) study on imidazole1 and found that it was relatively straightforward. Following your paper, we have reclassified the low energy structures according to the tilt within the hydrogen-bonded chain and the relative direction of the chains. Although the observed structure was the global minimum, two other structures with a displacement of otherwise identical layers are very close in energy. Do you think that if imidazole had crystallised in one of these alternative structures it would be distinguishable by NEXAFS? This would be a very sensitive test of whether NEXAFS combined with CSP could be used in characterising crystal structures.