Spatial Distribution of Trehalose Dihydrate Crystallization
in Tablets by X‑ray Diffractometry
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Abstract
Crystallization
of trehalose dihydrate (C<sub>12</sub>H<sub>22</sub>O<sub>11</sub>·2H<sub>2</sub>O) was induced by storing tablets
of amorphous anhydrous trehalose (C<sub>12</sub>H<sub>22</sub>O<sub>11</sub>) at 65% RH (RT). Our goal was to evaluate the advantages
and limitations of two approaches of profiling spatial distribution
of drug crystallization in tablets. The extent of crystallization,
as a function of depth, was determined in tablets stored for different
time-periods. The first approach was glancing angle X-ray diffractometry,
where the penetration depth of X-rays was modulated by the incident
angle. Based on the mass attenuation coefficient of the matrix, the
depth of X-ray penetration was calculated as a function of incident
angle, which in turn enabled us to “calculate” the extent
of crystallization to different depths. In the second approach, the
tablets were split into halves and the split surfaces were analyzed
directly. Starting from the tablet surface and moving toward the midplane,
XRD patterns were collected in 36 “regions”, in increments
of 0.05 mm. The results obtained by the two approaches were, in general,
in good agreement. Additionally, the results obtained were validated
by determining the “average” crystallization in the
entire tablet by using synchrotron radiation in the transmission mode.
The glancing angle method could detect crystallization up to ∼650
μm and had a “surface bias”. Being a nondestructive
technique, this method will permit repeated analyses of the same tablet
at different time points, for example, during a stability study. However,
split tablet analyses, while a “destructive” technique,
provided comprehensive and unbiased depth profiling information