Preparation of Amorphous Solid Dispersions by Cryomilling: Chemical and Physical Concerns Related to Active Pharmaceutical Ingredients and Carriers

Mol Pharm. 2020 Mar 2;17(3):1001-1013. doi: 10.1021/acs.molpharmaceut.9b01265. Epub 2020 Feb 12.


In this work, a chemical (and physical) evaluation of cryogenic milling to manufacture amorphous solid dispersions (ASDs) is provided to support novel mechanistic insights in the cryomilling process. Cryogenic milling devices are considered as reactors in which both physical transitions (reduction in crystallite size, polymorphic transformations, accumulation of crystallite defects, and partial or complete amorphization) and chemical reactions (chemical decomposition, etc.) can be mechanically triggered. In-depth characterization of active pharmaceutical ingredient (API) (content determination) and polymer (viscosity, molecular weight, dynamic vapor sorption, Fourier transform infrared spectroscopy, dynamic light scattering, and ANS and thioflavin T staining) chemical decomposition demonstrated APIs to be more prone to chemical degradation in case of presence of a polymer. A significant reduction of the polymer chain length was observed and in case of BSA denaturation/aggregation. Hence, mechanochemical activation process(es) for amorphization and ASD manufacturing cannot be regarded as a mild technique, as generally put forward, and one needs to be aware of chemical degradation of both APIs and polymers.

Keywords: (semi)synthetic polymers; amorphous solid dispersions (ASD); biopolymers; bovine serum albumin (BSA); cryomilling; decomposition; degradation; gelatin; mechanochemical activation; protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cinnarizine / chemistry
  • Crystallization
  • Drug Carriers / chemistry*
  • Drug Compounding / methods*
  • Drug Stability
  • Dynamic Light Scattering
  • Fenofibrate / chemistry
  • Gelatin / chemistry*
  • Glass / chemistry
  • Hypromellose Derivatives / chemistry*
  • Indomethacin / chemistry
  • Molecular Structure
  • Molecular Weight
  • Naproxen / chemistry
  • Povidone / chemistry*
  • Serum Albumin, Bovine / chemistry*
  • Solubility
  • Spectroscopy, Fourier Transform Infrared
  • Transition Temperature
  • Viscosity


  • Drug Carriers
  • Serum Albumin, Bovine
  • Cinnarizine
  • Hypromellose Derivatives
  • Naproxen
  • Gelatin
  • Povidone
  • Fenofibrate
  • Indomethacin