Effect of Milling on DSC Thermogram of Excipient Adipic Acid

Abstract

Abstract. The purpose of this research was to investigate why and how mechanical milling results in an unexpected shift in differential scanning calorimetry (DSC) measured fusion enthalpy (∆ fus H) and melting point (T m ) of adipic acid, a pharmaceutical excipient. Hyper differential scanning calorimetry (hyper-DSC) was used to characterize adipic acid before and after ball-milling. An experimental study was conducted to evaluate previous postulations such as electrostatic charging using the Faraday cage method, crystallinity loss using powder X-ray diffraction (PXRD), thermal annealing using DSC, impurities removal using thermal gravimetric analysis (TGA) and Karl Fischer titration. DSC thermograms showed that after milling, the values of ∆ fus H and T m were increased by approximately 9% and 5 K, respectively. Previous suggestions of increased electrostatic attraction, change in particle size distribution, and thermal annealing during measurements did not explain the differences. Instead, theoretical analysis and experimental findings suggested that the residual solvent (water) plays a key role. Water entrapped as inclusions inside adipic acid during solution crystallization was partially evaporated by localized heating at the cleaved surfaces during milling. The correlation between the removal of water and melting properties measured was shown via drying and crystallization experiments. These findings show that milling can reduce residual solvent content and causes a shift in DSC results.

Influence of Liquid‐Liquid Phase Separation on the Crystallization of L‐Menthol from Water

“…Since it is known that inclusions can depress a substance's melting point , , an investigation into solvent inclusions was also performed in parallel using the same base case experiment. The amount of water contained in the solid particles was quantified through Karl‐Fisher titration.…”

Solid-State Transformations of Sulfathiazole Polymorphs: The Effects of Milling and Humidity

“…These changes clearly have the potential to lead to a significant change in the physicochemical properties of pharmaceutical products [2][3][4][5][6][7]. Since milling may affect the mechanical properties of pharmaceutical dosage forms an ability to control these transformations would be highly valuable.…”

Characterization of nimesulide and development of immediate release tablets

“…The evaluation of the Tonset, Tpeak and ∆H values obtained in different heating rate showed slightly lower values to the micronized samples (NM2 and NM3, around 110-120 J/g). This phenomenon is widely described in the literature regarding DSC 21 .…”

“…The literature reports a study evaluating the dissolution profile of nimesulide tablets in a medium of phosphate buffer pH 7.4 containing different concentrations of polysorbate 80. The highest release value was in the presence of 2.5% surfactant, obtaining around 90% of dissolution in 60 min 21 . Another study evaluating the dissolution of commercial nimesulide tablets in sodium phosphate buffer pH 7.4 supplemented with 1.0% polysorbate 80 did not obtain values above 90% in 60 min 15 .…”