Åke C. Rasmuson

Prediction of solubility curves and melting properties of organic and pharmaceutical compounds

The relationships between solubility, temperature dependence of solubility, melting temperature and melting enthalpy are investigated for the purpose of finding relations that can significantly reduce the need for experimental work in the selection of the solvent for processing of organic fine chemicals and pharmaceuticals. The relationships are investigated theoretically and by evaluation of experimental data for 41 organic and pharmaceutical compounds comprising a total of 115 solubility curves in organic and aqueous solvents. The work considers (i) selection of the equation for correlation of solubility data based on thermodynamic considerations and ability to predict melting properties of the solute from solubility data, (ii) prediction of the temperature dependence of solubility, and (iii) prediction of solubility curves in new solvents. While it is a simple task to find an equation to obtain a decent fit of experimental solubility data, it is more challenging to find relations that are sufficiently sound thermodynamically to allow for extrapolation to the melting temperature. However, with a proper choice of equation it is shown that the melting temperature of the solute can readily be predicted from solubility data in organic solvents (average accuracy of -5K, standard deviation of 26K). Relationships are identified by which the entire solubility curve can be predicted of the compound in a new solvent using only the melting properties and a single solubility data point in that solvent.

Primary nucleation of paracetamol in acetone}water mixtures

The influence of solvent composition on primary nucleation of 4-hydroxyacetanilide (paracetamol) in acetone-water mixtures is investigated. The induction time for primary nucleation is determined, ...

Influence of different scales of mixing in reaction crystallization

Experiments on semibatch reaction crystallization of benzoic acid are reported. The conditions in an agitated tank are simulated by a loop reactor by which feed point mixing conditions can be controlled separately from the macroscale circulation rate. Hydrochloric acid is fed into a circulating solution of sodium benzoate and the influence of macromixing, mesomixing and micromixing on the product crystal mean size is evaluated. The product mean size increases with increasing circulation rate in the loop, with increasing feed point mixing intensity, with decreasing feed rate and with decreasing feed pipe diameter. Increased mixing intensity on any level leads to larger product crystals, but especially the rate of mesomixing is of importance. The influence of the feed pipe diameter is opposite to predictions by available theories and cannot be explained by backmixing into the feeding pipe. All results can be correlated quite well against a dimensionless mixing efficiency defined as the ratio of the reactant feeding time to the mixing time. The mixing time is the sum of the time constants for mesomixing and micromixing. A new mesomixing time constant is defined as being proportional to the ratio of the feed pipe diameter and the velocity of the bulk flow passing the feed pipe.

Characterization of paracetamol agglomerates by image analysis and strength measurement

Paracetamol is crystallized in different solvents and techniques are developed and used to characterize the product. The product particles from three different solvent compositions: ethylene glycol, acetone and an acetone-water mixture (30-70 wt.%) have been examined. Product properties visually observed are quantified by image analysis and evaluation of measured image descriptors with Principal Component Analysis (PCA). The agglomerate strength has been determined by crushing single agglomerates. Depending on the solvent, the content of single crystals and agglomerates differ. Agglomerates differ by the number and size of crystals grown together, as well as by the strength.

THE FORMATION OF SUBMICRON ORGANIC PARTICLES BY PRECIPITATION IN AN EMULSION

Submicron organic particles are produced by precipitation in an emulsion. The poorly water soluble organic substance is dissolved in a non-polar solvent. This solution is dispersed in an aqueous ph ...

On the mechanisms of formation of spherical agglomerates

Spherical agglomerates of benzoic acid have been successfully prepared by semi-batch, agitated vessel, drowning-out crystallization in water-ethanol-toluene mixtures. Benzoic acid is dissolved in ethanol, toluene is added and this mixture is fed at constant rate to the agitated crystallizer containing water. The influence of the amount of bridging liquid and the feeding rate on the product particle size distribution, morphology, and mechanical compression characteristics have been investigated. Compression characteristics for single agglomerates are compared with data on bed compression. With increasing amount of bridging liquid the particle size and strength increases and morphology improves. Particle size decreases and the fracture force increases with increasing feeding rate but the morphology remains unchanged. Using toluene as opposed to chloroform as the bridging liquid leads to improved product properties. Experiments have also been performed to reveal the mechanisms of the formation of the agglomerates. The results show that along the course of the process the properties of the particles change gradually but substantially. Particle size and number increases along with increasing feed. The spherical shape does not appear immediately but develops gradually, and is shown to be very much the result of the agitation of the slurry.

Investigating the role of solvent-solute interaction in crystal nucleation of salicylic acid from organic solvents.

In previous work, it has been shown that the crystal nucleation of salicylic acid (SA) in different solvents becomes increasingly more difficult in the order: chloroform, ethyl acetate acetonitrile, acetone, methanol, and acetic acid. In the present work, vibration spectroscopy, calorimetric measurements, and density functional theory (DFT) calculations are used to reveal the underlying molecular mechanisms. Raman and infrared spectra suggest that SA exists predominately as dimers in chloroform, but in the other five solvents there is no clear evidence of dimerization. In all solvents, the shift in the SA carbonyl peak reflecting the strength in the solvent-solute interaction is quite well correlated to the nucleation ranking. This shift is corroborated by DFT calculated energies of binding one solvent molecule to the carboxyl group of SA. An even better correlation of the influence of the solvent on the nucleation is provided by DFT calculated energy of binding the complete first solvation shell to the SA molecule. These solvation shell binding energies are corroborated by the enthalpy of solvent-solute interaction as estimated from experimentally determined enthalpy of solution and calculated enthalpy of cavity formation using the scaled particle theory. The different methods reveal a consistent picture and suggest that the stronger the solvent binds to the SA molecule in solution, the slower the nucleation becomes.

The theophylline–oxalic acid co-crystal system: solid phases, thermodynamics and crystallisation

The solid phases in the theophylline–oxalic acid co-crystal system have been investigated by thermal analysis techniques, X-ray diffraction analysis (XRD) and solubility measurements. The work includes the 2 : 1 co-crystal of theophylline and oxalic acid, polymorphs of theophylline, the theophylline monohydrate and solid oxalic acid. The DSC curve of the co-crystal presents two endothermic peaks, one at about 230 °C where the oxalic acid in the co-crystal decomposes and carbon dioxide is liberated, and another one at 279 °C where the remaining theophylline melts. At equilibrium with the solid co-crystal, the theophylline concentration is only 60% of the corresponding value for the pure solid theophylline. Using the solubility data, the standard Gibbs free energy of formation of the co-crystal from the pure solid phases is estimated to be approximately −6.0 kJ mole−1. In a chloroform/methanol mixture (4 : 1 v : v) the commercial form of pure theophylline (Form II) has been observed to transform into a more stable non-solvated form (Form I). The data suggest that the polymorphs are enantiotropically related with an approximate transition temperature of 70 °C. The 2 : 1 theophylline–oxalic acid co-crystal can be successfully produced by cooling crystallisation in chloroform/methanol mixture (4 : 1 v : v) and by slurry conversion crystallisation also in more benign solvents.

Precipitation of calcium carbonate in the presence of citrate and EDTA

The influence of process conditions such as feed rate, calcium/carbonate ratio, pH, complexing agents [ethylenediaminetetraacetic acid (EDTA), citrate (CIT)] and their concentration on the average particle size and shape of precipitated calcium carbonate was studied. The precipitation was performed in a semi-batch operated agitated vessel at constant pH by adding sodium hydrogen carbonate to a solution containing calcium chloride. In the absence of a complexing agent, agglomerates of needle-shaped crystals, probably aragonite, are obtained. Increasing feed time and the calcium/carbonate ratio increases the average particle size, whereas the opposite effect is observed for increasing pH. The observations can be related to the level of supersaturation. In the presence of complexing agents and at a concentration ratio of calcium vs. a complexing agent of 6, differently shaped and smaller particles were obtained. Furthermore, the effect of the other parameters on particle size becomes much weaker in the presence of complexing agents. In the presence of EDTA mostly spherical particles were obtained, and in the presence of citrate mainly rhombic particles corresponding to calcite were obtained. The effect on particle shape and size is attributed to interactions of the complexing agents with the faces of the crystalline calcium carbonate.

Thermodynamics and nucleation of the enantiotropic compound p-aminobenzoic acid

In this work, the thermodynamic interrelationship of the two known polymorphs of p-aminobenzoic acid has been explored, and primary nucleation in different organic solvents investigated. The solubility of both polymorphs in several solvents at different temperatures has been determined and the isobaric solid-state heat capacities have been measured by DSC. The transition temperature below which form α is metastable is estimated to be 16 °C by interpolation of solubility data and the melting temperature of form β is estimated to be 140 °C by extrapolation of solubility data. Using experimental calorimetry and solubility data the thermodynamic stability relationship between the two polymorphs has been estimated at room temperature to the melting point. At the transition temperature, the estimated enthalpy difference between the polymorphs is 2.84 kJ mol−1 and the entropy difference is 9.80 J mol−1 K−1. At the estimated melting point of form β the difference in Gibbs free energy and enthalpy is 1.6 kJ mol−1 and 5.0 kJ mol−1, respectively. It is found that the entropic contribution to the free energy difference is relatively high, which explains the unusually low transition temperature. A total of 330 nucleation experiments have been performed, with constant cooling rate in three different solvents and with different saturation temperatures, and multiple experiments have been carried out for each set of conditions in order to obtain statistically significant results. All performed experiments resulted in the crystallization of the high-temperature stable α-polymorph, which is kinetically favoured under all evaluated experimental conditions. The thermodynamic driving force required for nucleation is found to depend chiefly on the solvent, and to be inversely correlated to both solvent polarity and to solubility.