<p>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 <i>in situ</i> stability testing
(CEiST) to enable <i>in situ</i> 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 <i>in situ</i> 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 <i>in situ </i>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 <i>in situ </i>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. </p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/12227369 |
| Date | 01 May 2020 |
| Creators | Scott R Griffin (8788166) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/Optical_Techniques_for_Analysis_of_Pharmaceutical_Formulations/12227369 |
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