Purdue University Graduate School
Scott Griffin_Thesis_2020.pdf (3.47 MB)

Optical Techniques for Analysis of Pharmaceutical Formulations

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posted on 2020-05-01, 18:48 authored by Scott R GriffinScott R Griffin

The symmetry requirements of both second harmonic generation (SHG) and triboluminescence (TL) provide outstanding selectivity to noncentrosymmetric crystals, leading to high signal to noise measurements of crystal growth and nucleation of active pharmaceutical ingredients (API) within amorphous solid dispersions (ASD) during accelerated stability testing. ASD formulations are becoming increasingly popular in the pharmaceutical industry due to their ability to address challenges associated with APIs that suffer from poor dissolution kinetics and low bioavailability as a result of low aqueous solubility. ASDs kinetically trap APIs into an amorphous state by dispersing the API molecules within a polymer matrix. The amorphous state of the API leads to an increase in apparent solubility, faster dissolution kinetics, and an increase in bioavailability. Both SHG and TL are used to quantitatively and qualitatively detect the crystal growth and nucleation within ASD formulations at the parts per million (ppm) regime. TL is the emission of light upon mechanical disruption of a piezoelectrically active crystal. Instrumentation was developed to rapidly determine the qualitative presence of crystals within nominally amorphous pharmaceutical materials in both powders and slurries. SHG was coupled with a controlled environment for in situ stability testing (CEiST) to enable in situ accelerated stability testing of ASDs. Single particle tracking enabled by the CEiST measurements provided insights into crystal growth rate distributions present due to local differences within the material. Accelerated stability testing monitored by in situ measurements increased the signal to noise in recovered nucleation and crystal growth rates by suppressing the Poisson noise normally present within conventional accelerated stability tests. The disparities between crystal growth and nucleation kinetics on the surface versus within bulk material were also investigated by single particle tracking and in situ measurements. Crystals were found to grow faster in the bulk compared to single crystals growing on the surface while total crystallinity was found to be higher on the surface due to radial growth habits of crystals on the surface compared to columnar growth within the bulk. To increase the throughput of the in situ measurements, a temperature and relative humidity array (TRHA) was developed. The TRHA utilizes a temperature gradient and many individual liquid wells to enable the use of a multitude of different conditions at the same time which can reduce time required to inform formulations design of stability information.






Degree Type

  • Doctor of Philosophy


  • Chemistry

Campus location

  • West Lafayette

Advisor/Supervisor/Committee Chair

Garth Simpson

Additional Committee Member 2

Lynne Taylor

Additional Committee Member 3

Corey Thompson

Additional Committee Member 4

Julia Laskin

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