(203p) The Pressurized-Synthetic Methodology for Solubility Determination at Elevated Temperatures, with Application to Paracetamol in Pure Solvents

Authors: 
Keshavarz, L., SSPC, University of Limerick
de Souza, B., SSPC, University of Limerick
Frawley, P., SSPC, University of Limerick
In the present work, a new non-intrusive methodology is presented for determining high temperature solubility data using a new approach to be known as the pressurized-synthetic method. 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, far in excess of the atmospheric boiling point of the solvent. The data obtained using the pressurized-synthetic method is validated against an extended gravimetric dataset at temperatures up to the atmospheric boiling point for each solvent.

Sensitivity studies were conducted in order 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 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 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 pressurized-synthetic approach provides a non-intrusive and readily automated approach for the provision of valuable high temperature solubility data which can be readily extended to binary and ternary systems.

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