| 1. |
- Worku, Z. A., et al.
(författare)
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Modelling and understanding powder flow properties and compactability of selected active pharmaceutical ingredients, excipients and physical mixtures from critical material properties
- 2017
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Ingår i: International Journal of Pharmaceutics. - : Elsevier. - 0378-5173 .- 1873-3476. ; 531:1, s. 191-204
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Tidskriftsartikel (refereegranskat)abstract
- The development of solid dosage forms and manufacturing processes are governed by complex physical properties of the powder and the type of pharmaceutical unit operation the manufacturing processes employs. Suitable powder flow properties and compactability are crucial bulk level properties for tablet manufacturing by direct compression. It is also generally agreed that small scale powder flow measurements can be useful to predict large scale production failure. In this study, predictive multilinear regression models were effectively developed from critical material properties to estimate static powder flow parameters from particle size distribution data for a single component and for binary systems. A multilinear regression model, which was successfully developed for ibuprofen, also efficiently predicted the powder flow properties for a range of batches of two other active pharmaceutical ingredients processed by the same manufacturing route. The particle size distribution also affected the compactability of ibuprofen, and the scope of this work will be extended to the development of predictive multivariate models for compactability, in a similar manner to the approach successfully applied to flow properties.
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| 2. |
- Heffernan, C., et al.
(författare)
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Influence of Structurally Related Impurities on the Crystal Nucleation of Curcumin
- 2018
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Ingår i: Crystal Growth & Design. - : American Chemical Society (ACS). - 1528-7483 .- 1528-7505. ; 18:8, s. 4715-4723
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Tidskriftsartikel (refereegranskat)abstract
- In this work, the influence of the structurally related impurities, demethoxycurcumin (DMC) and bisde-methoxycurcumin (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 analyzed 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. Density functional theory and metadynamic molecular modeling 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 the presence of the structurally related impurities, DMC and BDMC.
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| 3. |
- Karpinska, J., et al.
(författare)
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Ethyl N-[2-(4-phenoxyphenoxy)ethyl]-carbamate
- 2012
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Ingår i: Acta Crystallographica Section E: Structure Reports Online. - : International Union of Crystallography (IUCr). - 1600-5368. ; 68:10, s. o2834-o2835
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Tidskriftsartikel (refereegranskat)abstract
- The title compound, C17H19NO4, which is a non-toxic insect growth regulator with the common name fenoxycarb, contains two independent and conformationally different molecules in the asymmetric unit. Although the inter-ring dihedral angles are similar [62.21 (15) and 63.00 (14)°], the side-chain orientations differ. In the crystal, the molecules are linked through N - H···O hydrogen-bonding associations, giving chains which extend along [110], while intra- and inter-molecular aromatic C - H···π interactions give sheet structures parallel to [110].
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| 4. |
- Lynch, A., et al.
(författare)
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Face indexing and shape analysis of salicylamide crystals grown in different solvents
- 2019
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Ingår i: CrystEngComm. - : Royal Society of Chemistry. - 1466-8033. ; 21:16, s. 2648-2659
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Tidskriftsartikel (refereegranskat)abstract
- The effect of solvent on salicylamide's crystal habit was investigated. Crystals grown experimentally in acetone, acetonitrile and methanol matched the attachment energy predicted rectangle plate vacuum habit. However, in ethyl acetate irregular hexagonal plate crystals form. This change in habit was found to be caused by the stunted growth of specific crystal faces during the crystallisation process. Single crystal and powder X-ray diffraction was carried out to rule out the possibility of a new polymorph. Given no new polymorphs were discovered, the changing habit makes face indexing of experimentally grown crystals difficult. A combination of experimental and modelling prediction tools was employed for the face indexing process. The interfacial angle between faces combined with preferred orientation P-XRD was found to be the most accurate and reliable method leading to successful identification of each salicylamide crystal face. The surface chemistry of each face was examined on a molecular level with insights into the possible growth attachment sites being made. It is deduced that ethyl acetate is adsorbed more strongly on the faces, the increased size of which, can explain the shape change.
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| 5. |
- Rama Krishna, G., et al.
(författare)
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Prediction of Solid State Properties of Cocrystals Using Artificial Neural Network Modeling
- 2018
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Ingår i: Crystal Growth & Design. - : American Chemical Society (ACS). - 1528-7483 .- 1528-7505. ; 18:1, s. 133-144
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Tidskriftsartikel (refereegranskat)abstract
- 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 an 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 caffeine cocrystals, 9 theophylline cocrystals, 9 nicotinamide cocrystals, and 29 isonicotinamide cocrystals. 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 training 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.
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| 6. |
- Abrahamsson, Per, 1985, et al.
(författare)
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Analysis of mesoscale effects in high-shear granulation through a computational fluid dynamics–population balance coupled compartment model
- 2018
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Ingår i: Particuology. - : Elsevier BV. - 2210-4291 .- 1674-2001. ; 36, s. 1-12
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Tidskriftsartikel (refereegranskat)abstract
- There is a need for mesoscale resolution and coupling between flow-field information and the evolution of particle properties in high-shear granulation. We have developed a modelling framework that compartmentalizes the high-shear granulation process based on relevant process parameters in time and space. The model comprises a coupled-flow-field and population-balance solver and is used to resolve and analyze the effects of mesoscales on the evolution of particle properties. A Diosna high-shear mixer was modelled with microcrystalline cellulose powder as the granulation material. An analysis of the flow-field solution and compartmentalization allows for a resolution of the stress and collision peak at the impeller blades. Different compartmentalizations showed the importance of resolving the impeller region, for aggregating systems and systems with breakage. An independent study investigated the time evolution of the flow field by changing the particle properties in three discrete steps that represent powder mixing, the initial granulation stage mixing and the late stage granular mixing. The results of the temporal resolution study show clear changes in collision behavior, especially from powder to granular mixing, which indicates the importance of resolving mesoscale phenomena in time and space.
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| 7. |
- Heffernan, C., et al.
(författare)
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Effects of structurally - related impurities on the crystal growth of curcumin spherulites
- 2022
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Ingår i: CrystEngComm. - : Royal Society of Chemistry (RSC). - 1466-8033. ; 24:28, s. 5156-5169
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Tidskriftsartikel (refereegranskat)abstract
- The crystal growth of curcumin in pure propan-2-ol and in this solvent containing two structurally related impurities, demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC), has been investigated by seeded isothermal desupersaturation experiments at 283, 293 and 308 K. In situ attenuated total reflectance UV-visible spectroscopy and focused beam reflectance measurement were used as process analytical technologies to monitor the solution concentration over time and to track the particle counts. Both impurities are found to slow down the growth of curcumin spherulites. The product particles collected after growth in the presence of the impurities present a rougher and more porous surface appearance in comparison to curcumin crystalline material grown in pure solutions. A detailed analysis of the powder X-ray diffraction patterns along with compositional analysis by high performance liquid chromatography of grown crystals reveals that impurities are not incorporated into the solid phase except at the highest impurity concentrations explored. By molecular modelling it is shown that the influence of impurities on the diffractograms of the material grown at high impurity concentrations is consistent with the formation of a solid solution. By fitting the Birth and Spread theory to the experimental growth data it is found that the interfacial energy for growth in the presence of the impurities is higher than that for growth of curcumin in the absence of impurities. Two scenarios are envisaged explaining the results. The first is that 3-D nucleation occurs on the impurity encumbered CUR crystallite generating new crystalline material on which crystal growth may continue. The second scenario envisages that a molecular cluster from the solution attaches to the impurity-encumbered surface and condenses into a crystalline surface nucleus without perfect lattice matching.
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| 8. |
- Ståhl, Marie
(författare)
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Process modeling of semibatch reaction crystallization
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis aims at increasing the fundamental understanding of reaction crystallization by modeling, simulations and parameter estimation. Benzoic acid is used as the model compound. A population balance model of single-feed semi-batch reaction crystallization is developed, accounting for chemical reaction, mixing, nucleation, growth, and growth rate dispersion. The model is evaluated by comparing the results with data from previously published semi-batch experiments. Two different mechanistic mixing models are used to describe mixing: the engulfment model with mesomixing and the segregated feed model. When the engulfment mixing model is used, the semi-batch model correctly captures the variation in weight mean size with varying agitation rate, feed point location, reactant concentration, feed pipe diameter, and total feed time. However, at scaling-up, a decrease in weight mean size with increasing crystallizer volume is predicted, which is not found experimentally. When the segregated feed model is used to describe mixing, the results are unsatisfactory. The crystallization kinetics have a great impact on the performance of the model, influencing both the final mean size, and the predicted influence of changes in the processing conditions. The kinetics of nucleation and growth are determined from T-mixer experiments. Three population balance models of increasing complexity are developed and used in parameter estimations by non-linear optimization. The T-mixer model accounts for nucleation, growth and growth rate dispersion. Five or six kinetic parameters are estimated using data from 14 experiments at 8 different initial supersaturation levels. Depending on the assumptions in the model, different kinetics are estimated. The main differences are found in the nucleation and growth rate constants. The T-mixer kinetics yields unsatisfactory results in the semi-batch simulations, with a predicted mean size that is significantly smaller than the experimental and a less pronounced influence of processing conditions that are related to mesomixing. An attempt is made to model aging of benzoic acid precipitates formed at high supersaturation. A model of Ostwald ripening gives a reasonably good description of the changes in the size distribution, provided that the observed shape change during aging is accounted for. However, significant deviations remain, in particular, the broadening of the aged size distribution is more pronounced in the experiments than in the simulations. There are indications that the observed aging might be caused by kinetic ripening, driven by a transformation to a more regular shape or a less strained crystal, rather than by Ostwald ripening.
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| 9. |
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