Short-Cut Method To Predict the Solubility of Organic Molecules in Aqueous and Nonaqueous Solutions by Differential Scanning Calorimetry

Abstract

According to recent literature, − differential scanning calorimetry (DSC) is being proposed as an alternative technique for the determination of solubility curves with the advantage of requiring a small quantity of sample (in the order of milligrams), besides being a fast method: solubility data can be accessed in a few hours. In this work, DSC was applied for estimating the solubility of organic molecules in aqueous and nonaqueous solutions. The method was carried out using four organic substances, referred to here as substances A, B, C, and D, A and B being solubilized in water, C in a mixture of methanol−water 20 wt %, and D in acetone.

Isochronal Conditions—The Key To Maintain the Given Solubility Limit, of a Small Molecule within the Polymer Matrix, at Elevated Pressure

“… 26 As can be seen, the relaxation time of the system becomes shorter as the temperature increases, which is a well-known phenomenon. However, focusing on the solubility limits determined in ref ( 26 ), one can observe that besides the fact that with increasing temperature (at constant pressure) the solubility of FL in the polymer matrix increases (which is consistent with data reported in the case of different pharmaceuticals 5 , 10 , 11 , 15 , 17 − 19 , 42 , 43 ), the conditions that correspond to the longest relaxation time at the beginning of the recrystallization result in the lowest amount of the drug that can be successfully dissolved within the polymer (see Figure 1 d). This would also not be a surprising phenomenon considering mutual dependence between the temperature and relaxation time observed in Figure 1 c.…”

“…Comparing the solubility limit values obtained during the recrystallization at constant pressure, constant temperature, and constant relaxation time, one can notice some significant differences (see Figure 6 ). Namely, maintaining the constant pressure (either for 0.1 MPa or 50 MPa), while altering the temperature, we obtained the generally accepted dependence between temperature and solubility limits — the higher the temperature, the larger amount of the SMs (in our case FL) can be successfully dissolved within the polymer matrix 5 , 10 , 11 , 15 , 17 − 24 (e.g., 59 wt % of FL at 343 K and 64 wt % of FL at 363 K for 0.1 MPa). On the other hand, recrystallization conducted at a constant temperature (either 343 or 363 K—orange and green stars, respectively, in Figure 6 ), while applying different pressures, results in the following: with increasing pressure, the solubility of the FL within the polymer matrix is decreasing (e.g., 64 wt % of FL at 0.1 MPa and 57 wt % of FL at 50 MPa for 363 K) — effect similar to decreasing temperature at constant pressure.…”

“… 5 , 7 − 16 A great number of the experiments, performed under isobaric (ambient) conditions, allowed to explore the subject of drug–polymer solubility. 3 , 5 , 10 , 11 , 15 , 17 − 19 As a result of those efforts, our knowledge about this process increased. Namely, among many factors that affect the solubility of SMs within the polymer matrix, the temperature is assumed to be the most important one, governing this phenomenon.…”

Solubilities of Crystalline Drugs in Polymers: An Improved Analytical Method and Comparison of Solubilities of Indomethacin and Nifedipine in PVP, PVP/VA, and PVAc

“…There have been attempts to determine the solubilities of crystalline drugs in polymers by measuring the dissolution temperatures (depressed melting points) of mixtures of known compositions 4–6. In these attempts, differential scanning calorimetry (DSC) is used to detect the equilibrium solution temperature for a solute–solvent mixture of known composition 7, 8. To help attain solubility equilibrium, Tao et al6 used cryo‐milling to prepare uniform drug–polymer mixtures of small particle sizes and performed DSC at slow and various heating rates so that dissolution temperature could be estimated at “zero” heating rate by extrapolation.…”

Cosolvency approach for assessing the solubility of drugs in poly(vinylpyrrolidone)

“…However, the cryogenic milling process can induce crystal defects or phase transformations of the drug, leading to potential variation in the solubility determination. There are also reported investigations on the solubility of drugs in aqueous and organic solvents using DSC (Mohan et al, 2002;Park et al, 2003;Haddadin et al, 2009;Tamagawa et al, 2006).…”