In the present work the induction time for nucleation of ethyl paraben (EP) and propyl paraben (PP) in ethanol, ethyl acetate and acetone has been measured at different levels of supersaturation. The induction time shows a wide variation among repeat experiments, indicative of the stochastic nature of nucleation. The solid-liquid interfacial energy and the size of the critical nucleus have been determined according to the classical nucleation theory. Combined with previous results for butyl paraben (BP), the nucleation behaviour is analysed with respect to differences in the solid phase of the three pure compounds, and with respect to differences in the solution. The results indicate that the difficulty of nucleation in ethanol and acetone increases in the order BP < PP < EP, but is approximately the same in ethyl acetate. For each of the three parabens the difficulty of nucleation increases in the order acetone < ethyl acetate < ethanol. The Gibbs energy of melting increases in the order BP < PP < EP, but the crystal structures are quite similar resulting in the basic crystal shape being very much the same. The solid-liquid interfacial energy is reasonably well correlated to the solvation energy, and even better correlated to the deformation energy, of the solute molecule within the first solvation shell as obtained by density functional theory calculations.
The influence of agitation and fluid shear on nucleation of mhydroxybenzoic acid polymorphs from 1-propanol solution has been investigated through 1160 cooling crystallization experiments. The induction time has been measured at different supersaturations and temperatures in two different crystallizer setups: small vials agitated by magnetic stir bars, for which experiments were repeated 40−80 times, and a rotating cylinder apparatus, for which each experiment was repeated five times. The nucleating polymorph has in each case been identified by FTIR spectroscopy. At high thermodynamic driving force for nucleation, only the metastable polymorph (form II) was obtained, while at low driving force both polymorphs were obtained. At equal driving force, a higher temperature resulted in a larger proportion of form I nucleations. The fluid dynamic conditions influence the induction time, as well as the polymorphic outcome. Experiments in small vials show that the agitation rate has a stronger influence on the induction time of form II compared to form I. The fraction of form I nucleations is significantly lower at intermediate agitation rates, coinciding with a reduced induction time of form II. In experiments in the rotating cylinder apparatus, the induction time is found to be inversely correlated to the shear rate. The difference in polymorphic outcome at different driving force is examined in terms of the ratio of the nucleation rates of the two polymorphs, calculated by classical nucleation theory using determined values of the preexponential factor and interfacial energy for each polymorph. A possible mechanism explaining the difference in the influence of fluid dynamics on the nucleation of the two polymorphs is based on differences between the two crystal structures. It is hypothesized that the layered structure of form II is comparatively more sensitive to changes in shear flow conditions than the more isotropic form I structure. ■ INTRODUCTIONA pure substance with the potential to crystallize as more than one crystalline phase with different ordered arrangements of molecules is said to exhibit polymorphism.1 Polymorphs of active pharmaceutical ingredients (APIs) are of great importance to the pharmaceutical industry, since they can exhibit significantly different solubility and dissolution rates, and thereby have different bioavailability. At each given set of conditions, except for transition points, there is one thermodynamically stable polymorph, with the lowest free energy and solubility of all potential polymorphs. Which polymorph will actually crystallize first is subject to both thermodynamic and kinetic factors, however.2 Thermodynamically, the stable polymorph is preferred as it will have a higher driving force for nucleation. The driving force is defined as the difference in chemical potential between the supersaturated and equilibrium states of the compound in solution, and is often approximated as RT ln S, where S is the supersaturation ratio on mole fraction basis. In practice, however, ...
ABSTRACT. The polymorphism of m-aminobenzoic acid has been investigated. Two polymorphs have been identified and characterized by XRPD, FTIR, microscopy and thermal analysis. The melting properties and isobaric heat capacities of both polymorphs have been determined calorimetrically, and the solubility of each polymorph in several solvents at different temperatures has been determined gravimetrically. The solid-state activity (i.e. the Gibbs free energy of fusion) of each polymorph has been determined through a comprehensive thermodynamic analysis based on experimental data. It is found that the polymorphs are enantiotropically related, with a stability transition temperature of 156.1°C. The published crystal structure belongs to the polymorph that is metastable at room temperature. Energy-temperature diagrams of both polymorphs have been established by determining the free energy, enthalpy and entropy of fusion as a function of temperature. A total of 300 cooling crystallizations have been carried out at constant cooling rate using different saturation temperatures and solvents, and the visible onset of primary nucleation recorded. The results show that for this substance, the polymorph that will nucleate depends chiefly on the solvent. In water and methanol solutions, the stable form I was obtained in all experiments, whereas in acetonitrile, a majority of nucleation experiments resulted in the isolation of the metastable form II. It is shown how this can be rationalised by analysis of solubility, solution speciation and nucleation relationships. The importance of carrying out multiple experiments at identical conditions in nucleation studies of polymorphic systems is demonstrated.
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. QC 20131119
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PostprintThis is the accepted version of a paper published in Journal of Pharmaceutical Sciences. This paper has been peer-reviewed but does not include the final publisher proof-corrections or journal pagination.Citation for the original published paper (version of record):Svärd, M., Gracin, S., Rasmuson, Å C. (2007) Oiling out or molten hydrate-liquid-liquid phase separation in the system vanillin-water. Journal of Pharmaceutical ABSTRACTVanillin crystals in a saturated aqueous solution disappear and a second liquid phase emerges when the temperature is raised above 51°C. The phenomenon has been investigated with crystallization and equilibration experiments, using DSC, TGA, XRD and hot-stage microscopy for analysis. The new liquid solidifies on cooling, appears to melt at 51°C, and has a composition corresponding to a dihydrate. However, no solid hydrate can be detected by XRD, and it is shown that the true explanation is that a liquid-liquid phase separation occurs above 51°C where the vanillin-rich phase has a composition close to a dihydrate. To our knowledge, liquid-liquid phase separation has not previously been reported for the system vanillin-water, even though thousands of tonnes of vanillin are produced globally every year.
Nucleation of m-hydroxybenzoic acid crystals in different pure solvents has been investigated, and the thermodynamic interrelationship between two polymorphs analysed. The melting properties and specific heat capacities of both polymorphs have been determined by differential scanning calorimetry and the solubility in several solvents at different temperatures measured gravimetrically. Absolute values of the Gibbs free energy, enthalpy and entropy of fusion, and the activity of the polymorphs have been determined as functions of temperature. It is established that the polymorphs are monotropically related, with differences in enthalpy and Gibbs free energy of approximately one kJ/mol at room temperature. In a total of 539 nucleation experiments, in six solvents and with different cooling rates, the visible onset of nucleation was recorded and the nucleating polymorph isolated. It is found that the degree of supersaturation required for nucleation and the polymorphic outcome depend strongly on the solvent. The metastable polymorph is kinetically favoured under all evaluated experimental conditions, and for most of the conditions it is also statistically the most probable outcome. Nucleation of the stable polymorph is increasingly promoted in solvents of increasing solubility. It is shown how this can be rationalized by analysis of solubility and rate of supersaturation generation.
The influence of agitation on nucleation of butyl paraben and m-hydroxybenzoic acid polymorphs has been investigated through 330 cooling crystallization experiments. The induction time has been measured at different supersaturation and temperature in three parallel jacketed vessels equipped with different overhead stirring agitators. In each case, the nucleating polymorph of mhydroxybenzoic acid has been identified by infrared spectroscopy. The influence of agitation rate, impeller type, impeller diameter, impeller to bottom clearance and the use of baffles have been investigated. A general trend in all the experiments is that the induction time decreases with increasing agitation rate. Across all experiments with different fluid mechanics for the butyl paraben system, the induction time is correlated to the average energy dissipation rate raised to the power -0.3. It is shown that this dependence is consistent with a turbulent flow enhanced cluster coalescence mechanism. In experiments with m-hydroxybenzoic acid, the metastable form II was always obtained at higher nucleation driving force while both polymorphs were obtained at lower driving force. In the latter case, form I was obtained in the majority of experiments at low agitation rate (100 rpm) while form II was obtained in all experiments at higher agitation rate (≥300 rpm).
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