The development of rational pharmaceutical polymorph control systems from crystallization requires the experimental manipulation of both thermodynamic and kinetic factors. Herein, we discuss the interplay between thermodynamics and kinetics on the formation mechanism responsible for concomitant polymorphs and their subsequent phase transformations. The polymorphic system studied is gestodene, which exhibits two enantiotropic polymorphs, I and II. The thermodynamic stability in ethanol is I > II above 18.5 °C and I < II below. At low supersaturation (1.09 to 1.25), plate-like crystals corresponding to form I become the dominant polymorph at T ≥ 19 °C, while at T ≤ 17 °C, needle-like solids corresponding to form II predominate. Solution crystallization at 5 ≤ T ≤ 25 °C and high supersaturation (1.36 to 1.81) results in concomitant polymorphs of forms I and II. The assessments of nucleation and growth kinetics indicate that at lower supersaturations, both nucleation and growth rates of the stable form are higher than that of the metastable one, while at higher supersaturations, the reverse occurs. It is therefore concluded that at lower supersaturations the stable form is favored by both thermodynamics and kinetics and at higher supersaturations concomitant polymorphism is the result of a balance between these competing driving forces. A semiempirical model that displays the influence of initial supersaturation and crystallization temperature on the relative nucleation rate of the two forms was derived and could be used to predict the polymorphic form resulting from nucleation with good accuracy. As the solvent-mediated polymorphic transformation kinetics between forms I and II is relatively fast at 5, 10, 30, and 35 °C, it can reasonably be expected that one can use a slurrying procedure to obtain the pure stable form when concomitant polymorphs appear at conditions of relatively high supersaturations.

The development of rational pharmaceutical polymorph control systems from crystallization requires the experimental manipulation of both thermodynamic and kinetic factors. Herein, we discuss the interplay between thermodynamics and kinetics on the formation mechanism responsible for concomitant polymorphs and their subsequent phase transformations. The polymorphic system studied is gestodene, which exhibits two enantiotropic polymorphs, I and II. The thermodynamic stability in ethanol is I > II above 18.5 °C and I < II below. At low supersaturation (1.09 to 1.25), plate-like crystals corresponding to form I become the dominant polymorph at T ≥ 19 °C, while at T ≤ 17 °C, needle-like solids corresponding to form II predominate. Solution crystallization at 5 ≤ T ≤ 25 °C and high supersaturation (1.36 to 1.81) results in concomitant polymorphs of forms I and II. The assessments of nucleation and growth kinetics indicate that at lower supersaturations, both nucleation and growth rates of the stable form are higher than that of the metastable one, while at higher supersaturations, the reverse occurs. It is therefore concluded that at lower supersaturations the stable form is favored by both thermodynamics and kinetics and at higher supersaturations concomitant polymorphism is the result of a balance between these competing driving forces. A semiempirical model that displays the influence of initial supersaturation and crystallization temperature on the relative nucleation rate of the two forms was derived and could be used to predict the polymorphic form resulting from nucleation with good accuracy. As the solvent-mediated polymorphic transformation kinetics between forms I and II is relatively fast at 5, 10, 30, and 35 °C, it can reasonably be expected that one can use a slurrying procedure to obtain the pure stable form when concomitant polymorphs appear at conditions of relatively high supersaturations.

The solubility of 4-(4-hydroxyphenyl)-2-butanone (raspberry ketone) in six pure solvents was experimentally determined at temperatures ranging from 283.15 to 313.15 K under the pressure 0.10 MPa by employing a gravimetrical method. The experimental results indicate that the solubility of raspberry ketone in all studied solvents is temperature dependent, a rise in temperature brings about an increase in solubility. The experimental solubility data of raspberry ketone in six pure solvents (acetone, ethanol, ethyl acetate, n-propyl alcohol, n-butyl alcohol, and distilled water) was correlated by using several commonly used thermodynamic models, including the Apelblat, van’t Hoff and λh equations. The results of the error analysis indicate that the van’t Hoff equation was able to give more accurate and reliable predictions of solubility with root-mean-square deviation less than 0.56%. Furthermore, the changes of dissolution enthalpies (ΔdissH°), dissolution entropies (ΔdissS°) and dissolution Gibbs energies (ΔdissG°) of raspberry ketone in the solvents studied were estimated by the van’t Hoff equation. The positive value of ΔdissH°, ΔdissS°, and ΔdissG° indicated that these dissolution processes of raspberry ketone in the solvents studied were all endothermic and enthalpy-driven.

In the current work, a systematic investigation on the thermal behavior of gestodene was carried out to understand temperature induced solid-state transitions between its polymorphs and amorphous phase. The focus was on polymorph identification, thermal stability analysis, and the nature of the phase transitions. These characteristics were compared to the complexity of the phase transitions, studied by differential scanning calorimetry (DSC) and variable temperature X-ray powder diffraction (VT-XRD) techniques. DSC studies indicated that the form II was enantiotropically related to form I, which melted at about 470 K. The temperature of polymorphic transition was 309 K, and form II was the more stable form between room temperature and the transition temperature. A schematic Gibbs free energy-temperature diagram was subsequently constructed to describe the thermal stability of the two forms. Amorphous phase converted exothermically to form I at 368 K on heating and was shown by VT-XRD to be accompanied by diffraction pattern changes. In addition, the crystallization kinetics studied by DSC heating technique followed by analysis using the Kissinger–Akahira–Sunose (KAS) method where values of apparent activation energy (Ea) were estimated as a function of extent of conversion (α). The variations in Ea with α on kinetic analysis from α = 0.10 to 0.88 for the amorphous to form I conversion suggested more complex processes, possibly liquid–solid and solid–solid transformations prior to formation of the form I.

•The solubility measurements were performed using the dynamic method.•The solubility data increases with rising temperature and initial mole fraction of ethanol.•The modified Apelblat equation is the best correlation model.•The dissolution process of DMHF is endothermic and enthalpy-driven.In the present study, the solubility and dissolution thermodynamics of 4-hydroxy-2,5-dimethyl-3(2H)-furanone (DMHF) in ethanol + water co-solvent mixtures were experimentally measured over the temperature range from 283.15 to 313.15 K under the atmospheric pressure of 0.1 MPa. Measurements were performed using the dynamic method coupled with a laser monitoring system as the observation technique. The onset fusion point temperature and enthalpy of fusion were determined by differential scanning calorimetry (DSC). The effects of temperature and co-solvent composition on the solubility data were discussed. The mole fraction solubility (42.71 × 10− 2 at 313.15 K) of DMHF was observed highest in pure ethanol. However, the lowest mole fraction solubility (0.9112 × 10− 2 at 283.15 K) of DMHF was found in distilled water. The experimental solubilities of DMHF were correlated with the modified Apelblat equation, van't Hoff equation, λh equation and Combined Nearly Ideal Binary Solvent/Redlich–Kister (CNIBS/R–K) model. The used correlation models were all proven to give good agreement with the experimental data and the modified Apelblat equation provided the best correlation results. Dissolution thermodynamic studies indicated that the dissolution process of DMHF was endothermic and enthalpy-driven. Based on the current solubility data, DMHF has been considered as freely soluble in pure ethanol and slightly soluble in distilled water.

•Measurements were performed using the dynamic method.•The solubility data increases with increasing temperature.•The modified Apelblat equation is the best thermodynamic method.•The dissolution process of DMHF is endothermic and enthalpy-driven.The objective of this work was to measure and correlate the solubility of 4-hydroxy-2,5-dimethyl-3(2H)-furanone (DMHF) in six pure solvents, including methanol, ethanol, n-propyl alcohol, n-butyl alcohol, n-hexane and distilled water, over the temperature range from 283.15 K to 313.15 K under atmospheric pressure of 0.10 MPa. Measurements were performed using the dynamic method coupled with a laser monitoring system as the observation technique. The solubility of DMHF in all the selected solvents was found to increase with rising temperature, and methanol has much more dissolving capacity for the DMHF solute. The experimental solubility of DMHF in pure solvents was well correlated with the modified Apelblat equation, van’t Hoff equation and λh equation. The results of the error analysis indicated that the modified Apelblat equation was able to give more accurate and reliable predictions of solubility with the relative average deviation (RAD) and root-mean-square deviation (RMSD) values being observed in the range of 0.21–0.67% and 0.01–0.13%, respectively. The modified Apelblat equation was therefore used to estimate the changes of dissolution enthalpy (ΔdissH°), dissolution entropy (ΔdissS°) and molar Gibbs free energy (ΔG°diss) of DMHF in the solvents investigated. The positive values of the ΔdissH°, ΔdissS° and ΔdissG° revealed the dissolution process of DMHF in the selected solvents was endothermic and enthalpy-driven.

A simple and direct method without a derivation step for routine analysis of tobramycin has been developed. This method used reversed-phase ion-pair high performance liquid chromatography (HPLC) with a refractive index (RI) detector and a C18 column which is stable at pH above 1.00. The presence of 4.50 mg·mL−1 trifluoroacetic acid (TFA) in the mobile phase improved the protonation of tobramycin and the formation of ionpairs, and thus reduced its hydrophility. This unique separation-detection combination showed good linearity with correlation coefficients 0.9996 in the concentration range of 0.25–2.50 mg·mL−1. The quantitation limit and detection limit were determined to be 0.23 mg·mL−1 and 0.071 mg·mL−1, respectively. Tobramycin was recovered in 98.00%, 98.84% and 99.64% for tobramycin solutions at concentrations of 2.25 mg·mL−1, 1.50 mg·mL−1 and 0.75 mg·mL−1, respectively. The relative standard deviations for six spiked samples ranged from 0.20% to 2.40%, indicating a good reproducibility of this method.