Factors Influencing the Crystallization-Onset Time of Metastable ASDs

Friederike Wolbert; Ineke-Katharina Fahrig; Tobias Gottschalk; Christian Luebbert; Markus Thommes; Gabriele Sadowski

doi:10.3390/pharmaceutics14020269

Factors Influencing the Crystallization-Onset Time of Metastable ASDs

Pharmaceutics. 2022 Jan 23;14(2):269. doi: 10.3390/pharmaceutics14020269.

Authors

Friederike Wolbert^{1

2}, Ineke-Katharina Fahrig², Tobias Gottschalk^{1

3}, Christian Luebbert², Markus Thommes³, Gabriele Sadowski²

Affiliations

¹ Drug Delivery innovation Center (DDiC), INVITE GmbH, 51368 Leverkusen, Germany.
² Laboratory of Thermodynamics, Department of Biochemical and Chemical Engineering, TU Dortmund University, Emil-Figge-Str. 70, 44227 Dortmund, Germany.
³ Laboratory of Solids Process Engineering, Department of Biochemical and Chemical Engineering, TU Dortmund University, Emil-Figge-Str. 68, 44227 Dortmund, Germany.

Abstract

In formulation development, amorphous solid dispersions (ASD) are considered to improve the bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). However, the crystallization of APIs often limits long-term stability and thus the shelf life of ASDs. It has already been shown earlier that the long-term stability of ASDs strongly depends on the storage conditions (relative humidity, temperature), the manufacturing methods, and the resulting particle sizes. In this work, ASDs composed of the model APIs Griseofulvin (GRI) or Itraconazole (ITR) and the polymers poly (vinylpyrrolidone-co-vinyl acetate) (PVPVA) or Soluplus^® were manufactured via spray drying and hot-melt extrusion. Each API/polymer combination was manufactured using the two manufacturing methods with at least two different API loads and two particle-size distributions. It was a priori known that these ASDs were metastable and would crystallize over time, even in the dry stage. The amount of water absorbed by the ASD from humid air (40 °C/75% relative humidity), the solubility of the API in the ASD at humid conditions, and the resulting glass-transition temperature were predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) and the Gordon-Taylor approach, respectively. The onset of crystallization was determined via periodic powder X-ray diffraction (PXRD) measurements. It was shown that simple heuristics such as "larger particles always crystallize later than smaller particles" are correct within one manufacturing method but cannot be transferred from one manufacturing method to another. Moreover, amorphous phase separation in the ASDs was shown to also influence their crystallization kinetics. Counterintuitively, phase separation accelerated the crystallization time, which could be explained by the glass-transition temperatures of the evolving phases.

Keywords: PC-SAFT; amorphous solid dispersion; crystallization kinetics; hot-melt extrusion; particle size distribution; spray drying; stability; water sorption.