Solubility of crystalline organic compounds in high and low molecular weight amorphous matrices above and below the glass transition by zero enthalpy extrapolation

Abstract

Pharmaceutical applications which require knowledge of the solubility of a crystalline compound in an amorphous matrix are abundant in the literature. Several methods that allow the determination of such data have been reported, but so far have only been applicable to amorphous polymers above the glass transition of the resulting composites. The current work presents, for the first time, a reliable method for the determination of the solubility of crystalline pharmaceutical compounds in high and low molecular weight amorphous matrices at the glass transition and at room temperature (i.e. below the glass transition temperature), respectively. The solubilities of mannitol and indomethacin in polyvinyl pyrrolidone (PVP) K15 and PVP K25, respectively were measured at different temperatures. Mixtures of undissolved crystalline solute and saturated amorphous phase were obtained by annealing at a given temperature. The solubility at this temperature was then obtained by measuring the melting enthalpy of the crystalline phase, plotting it as a function of composition and extrapolating to zero enthalpy. This new method yielded results in accordance with the predictions reported in the literature. The method was also adapted for the measurement of the solubility of crystalline low molecular weight excipients in amorphous active pharmaceutical ingredients (APIs). The solubility of mannitol, glutaric acid and adipic acid in both indomethacin and sulfadimidine was experimentally determined and successfully compared with the difference between their respective calculated Hildebrand solubility parameters. As expected from the calculations, the dicarboxylic acids exhibited a high solubility in both amorphous indomethacin and sulfadimidine, whereas mannitol was almost insoluble in the same amorphous phases at room temperature. This work constitutes the first report of the methodology for determining an experimentally measured solubility for a low molecular weight crystalline solute in a low molecular weight amorphous matrix.

Polymeric Amorphous Solid Dispersions: A Review of Amorphization, Crystallization, Stabilization, Solid-State Characterization, and Aqueous Solubilization of Biopharmaceutical Classification System Class II Drugs

“…The most widely used method for the estimation of drug solubility in a polymer is by using the melting enthalpy of the crystalline drug in a drug-polymer system measured by hyper DSC. 142 This method is based on a simple principle that the fraction of drug dissolved in the polymer does not contribute to the melting endotherm. Therefore, by measuring the melting enthalpy of a series of drug concentrations in drug-polymer mixtures and extrapolating the plot to zero enthalpy, the solubility of a given drug in selected polymers could be estimated from the x-intercept of the plotted line as shown in Figure 9.…”

A Promising New Method to Estimate Drug-Polymer Solubility at Room Temperature

“…On account of increasing focus on the physical stability of amorphous solid dispersions, several experimental methods to predict the solubility of drugs in polymers at room temperature have been proposed. [1][2][3][4][5][6] As most pharmaceutically relevant drugs and polymers are solid or highly viscous at room temperature, measuring the drug solubility under these conditions is not feasible, 7 and therefore, the methods are based on equilibrium thermodynamics at elevated temperature and subsequent extrapolation to room temperature. Most of the methods are based on differential scanning calorimetry (DSC) measurements and are time consuming due to slow dissolution or crystallization kinetics of the drug into or from the polymer.…”

Physical stability of solid dispersions with respect to thermodynamic solubility of tadalafil in PVP-VA

“…Another, a slightly modified approach based on the melting point depression principle, which also could not be utilized in this work, is based on the measurement of the drug melting enthalpy reduction in a physical mixture [1]. In this method a crystalline drug dissolves in a polymer at a pre-set constant temperature and is subsequently heated up to the drug melting point to determine its enthalpy of fusion.…”