In Situ Crystal Growth Rate Distributions of Active Pharmaceutical Ingredients

Mol Pharm. 2020 Mar 2;17(3):769-776. doi: 10.1021/acs.molpharmaceut.9b00937. Epub 2019 Dec 16.

Abstract

Single-particle tracking of crystal growth performed in situ enables substantial improvements in the signal-to-noise ratio (SNR) for recovered crystal nucleation and growth rates by nonlinear optical microscopy. Second harmonic generation (SHG) is exquisitely sensitive to noncentrosymmetric crystals, including those produced by many homochiral active pharmaceutical ingredients (APIs). Accelerated stability testing at elevated temperatures and relative humidity informs design of pharmaceutical formulations. In the present work, we demonstrate reduction in the Poisson noise associated with the finite number of particles present in a given field of view through continuous monitoring during stability testing. Single-particle tracking enables recovery of crystal growth rates of individual crystallites and enables unambiguous direct detection of nucleation events. Collectively, these capabilities provide significant improvements in the signal-to-noise for nucleation and crystal growth measurements, corresponding to approximately an order of magnitude reduction in anticipated measurement time for recovery of kinetics parameters.

Keywords: amorphous solid dispersions; crystal growth kinetics; microscopy; second harmonic generation; single particle tracking.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Colloids
  • Crystallization
  • Drug Compounding / methods*
  • Drug Design*
  • Drug Stability
  • Hexoses / chemistry*
  • Humidity
  • Kinetics
  • Pyrrolidines / chemistry*
  • Ritonavir / chemistry*
  • Second Harmonic Generation Microscopy / methods
  • Signal-To-Noise Ratio
  • Silicon Dioxide / chemistry*
  • Solubility
  • Temperature
  • Vinyl Compounds / chemistry*
  • Water / chemistry

Substances

  • Colloids
  • Hexoses
  • Pyrrolidines
  • Vinyl Compounds
  • poly(vinylpyrrolidone-co-vinyl-acetate)
  • Water
  • sorbitan monolaurate
  • Silicon Dioxide
  • Ritonavir