Pressurized-Synthetic Methodology for Solubility Determination at Elevated Temperatures with Application to Paracetamol in Pure Solvents

Abstract

This paper describes a new nonintrusive method for the determination of high-temperature solubility data. Accurate high-temperature solubility data is vital to many industrial manufacturing processes such as cooling crystallization with direct implications for yield, throughput, and solvent usage. However, the provision of such data is notably absent from published literature for many active pharmaceutical ingredients. Pressurized-synthetic methodology is presented as a new technique for determining high-temperature solubility data. Paracetamol (acetaminophen) is used as a reference active pharmaceutical ingredient to validate the methodology. Solubility data determined using the pressurized-synthetic approach is reported for several pure solvents across a significantly extended temperature range. In the case of methanol, solubility data is obtained up to 354.15 K, above the atmospheric boiling point of the solvent, 337.65 K, and far in excess of the temperature range for which data exists in the literature, 268.15–303.15 K. The data obtained using the pressurized-synthetic method is validated against an extended gravimetric data set at temperatures up to the atmospheric boiling point for each solvent. Sensitivity studies were conducted to determine the influence of factors such as temperature gradient on the ultimate solubility determination. A temperature-based standard deviation of 0.1 K was established for paracetamol in 2-propanol at 303.15 K, comparing favorably with the temperature-based equivalent standard deviation of 0.2 K for the gravimetric approach. Binary interaction parameters for the pressurized-synthetic solubility data are derived and estimated for four different activity coefficient models, namely Margules, Van-Laar, Wilson, and non-random two-liquid (NRTL), along with the empirical solubility equation of Apelblat. For each solvent, the quality of fit of each of the activity coefficient models is analyzed. The NRTL model was found to best fit the experimental data for methanol, ethanol, 2-propanol, and acetone with mean square errors of 5.73 × 10–5, 3.00 × 10–4, 1.70 × 10–4, and 7.35 × 10–5, respectively. The pressurized-synthetic approach provides a nonintrusive, validated, and readily automated approach for the provision of valuable high-temperature solubility data that can be readily extended to binary and ternary systems.

Secondary Nucleation from Nuclei Breeding and Its Quantitative Link with Fluid Shear Stress in Mixing: A Potential Approach for Precise Scale-up in Industrial Crystallization

“…The solubility of paracetamol in cyclohexane is negligible (0.0539 g/kg at 298.15 K) and was therefore suitable to use without the risk of any dissolution of paracetamol . Solubility plays an important role to interpret the mechanism of a given crystallization system which was, therefore, taken from well-established literature …”

“…17 Solubility plays an important role to interpret the mechanism of a given crystallization system which was, therefore, taken from wellestablished literature. 30 The crystallization experiment was initially carried out at a small scale of 120 mL solution (paracetamol in propan-2-ol) at a low level of initial supersaturation ratio of S o = 1.0, measured in g of solute/kg of solvent, over the range of saturation temperatures, 30 to 60 °C. At each saturation temperature, the solution was crystallized at 300 and 370 rpm under a constant cooling rate of 0.1 °C/min.…”

Quantitative Link between Secondary Nucleation and Mixing Hydrodynamics in Batch Cooling Crystallization: A New Approach in Process Development

“…The results presented in terms of supersaturation ratio ( S r ) have been calculated using eq , where C is the concentration of the solution measured through FTIR and C eq is the concentration at solubility which was taken from the literature …”

“…A saturated solution was prepared at 50 °C with a low level of initial supersaturation ratio of S o = 1.0, measured in g of solute/kg of solvent. A solution was prepared in accordance with solubility data which was taken from a well-established literature . The solution was crystallized at a constant cooling rate of 0.1 °C/min.…”

Solubility of N-tert-Butylbenzothiazole-2-sulfenamide in Several Pure and Binary Solvents

“…Gibson33 reported that the effect of pressure on the solubility of a solid was significant only in very rare cases, which were concluded by the empirical and theoretical considerations Therefore, the modified Apelblat equation, the h equation and the NRTL model can also be applied to correlate the solubility data of TBBS in tert-butylamine at temperature from 318.2 K to 343.2 K34 . The fitting parameters of the models together with ARD and RMSD were listed inTable 12.…”