Engineering Processing Properties of Acetaminophen by Cosolvent Screening - Pharmaceutical Technology

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Engineering Processing Properties of Acetaminophen by Cosolvent Screening
The authors used common solvents to develop an initial solvent-screening method for laboratory-scale research to determine the solubility, polymorphism, and crystal properties of various active ingredients.

Pharmaceutical Technology
Volume 34, Issue 8, pp. 61-68

The apparent differential heat of solution, ΔH d, of acetaminophen in the 92 cosolvent systems was calculated from the 92 solubility curves based on the following van't Hoff equation if acetaminophen and the cosolvent system were assumed not to behave ideally (17):

in which x is the mole fraction of acetaminophen solute in the cosolvent solution, T is the solution temperature, R is the gas-enthalpy constant (8.314 J/mol K), ΔH d is the apparent differential heat of solution, which was obtained from the slope of the plot of ln x versus 1/T, and C is a constant. Using the solubility data, the standard Gibbs free energy of the dissolution process, ΔG d, at 25 C was calculated using the following equation (18):

Table II (Continued).
Because the cosolvent systems were all real systems, the calculated ΔG d at a given temperature T might not equal ΔH dTΔS d. Therefore, only values of ΔG d and ΔHd are listed in Table II. The positive values of ΔH d indicated that dissolution was an endothermic process. The energy of attraction of acetaminophen-solute molecules with each other and the energy of attraction of cosolvent molecules with each other were lower than the energy attraction of the acetaminophen solute and the cosolvent molecules in the solution. Therefore, the solubility of acetaminophen in different cosolvent systems increased with temperature. The negative values of ΔG d at 25 C also revealed that dissolution was a spontaneous process at 25 C. Only three systems seriously deviated from the linearity of Equation 2. They were ethyl acetate and acetone, THF and acetonitrile, and MEK and 1,4-dioxane. These solvent pairs seemed to have a large difference in their Hansen polar parameter values only (8).

Optical micrographs of acetaminophen crystals grown from 88 cosolvent systems were taken because four other systems (i.e., THF and 1,4-dioxane, MEK and acetone, IPA and DMF, and IPA and 1,4-dioxane) had failed to produce acetaminophen solids. Perhaps the high affinity of acetaminophen solutes for those four cosolvent systems through hydrogen bonding more than compensated for their crystal interactions. As expected, increases in temperature generally increased the solubility of acetaminophen solutes in those four cosolvent systems to a lesser extent than in the other 88 cosolvent systems, probably because it reduced the cosolvent–cosolvent interactions in those four cosolvent systems less than it reduced the other cosolvent–cosolvent interactions in the other 88 cosolvent systems (19).


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