Spatial Distribution of Trehalose Dihydrate Crystallization in Tablets by X-ray Diffractometry

Abstract

Crystallization of trehalose dihydrate (C12H22O11·2H2O) was induced by storing tablets of amorphous anhydrous trehalose (C12H22O11) 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.

Controlling the Release of Indomethacin from Glass Solutions Layered with a Rate Controlling Membrane Using Fluid-Bed Processing. Part 1: Surface and Cross-Sectional Chemical Analysis

“…9 Glancing angle X-ray techniques can be used to measure varying sample thicknesses since penetration depths are lower and can be calculated according to the incident X-ray beam angle. 10,11 This leads us to conclude that mDSC and XRPD do not provide adequate information on the different layers of complex coated systems. It has even been shown recently that the phase behavior study of a single layer glass solution on an inert carrier is not straightforward.…”

“…Also, in reflection geometry, the penetration depth of the X-rays does not allow in depth resolution; spatial resolution can only be achieved in combination with other techniques . Glancing angle X-ray techniques can be used to measure varying sample thicknesses since penetration depths are lower and can be calculated according to the incident X-ray beam angle. , This leads us to conclude that mDSC and XRPD do not provide adequate information on the different layers of complex coated systems. It has even been shown recently that the phase behavior study of a single layer glass solution on an inert carrier is not straightforward …”

Investigation of Spatial Heterogeneity of Salt Disproportionation in Tablets by Synchrotron X-ray Diffractometry

“…In addition to providing a two-dimensional image, the use of 2D SXRD in transmission geometry, reduces errors in phase quantification due to preferred orientation because the complete Debye− Scherrer rings are captured. 19 As disproportionation is considered to be a solutionmediated transformation, storage of tablets under accelerated stability conditions (for example, 40 °C/75% RH) provides an avenue to understand disproportionation reaction mediated by water. When tablets are stored under high RH conditions, the sorbed water, initially present only at the surface, is expected to gradually penetrate through the tablet and progress toward the tablet core.…”

A New Frontier for Nondestructive Spatial Analysis of Pharmaceutical Solid Dosage Forms: Spatially Offset Low-Frequency Raman Spectroscopy

“…A nonintrusive multidimensional analysis can be useful in many pharmaceutical applications, especially for the analysis of solid dosage forms, where spatial information using conventional analytical methods can typically only be obtained after destructive manipulations with samples prior or during the measurements. Several recent studies have highlighted the heterospatial nature of solid-state transformations on the surfaces of pharmaceutical tablets and its potential implications. , The presence and severity of these changes (i.e., the quantitative extent of transformations) can alter the appearance of the solid dosage form, affect its physicochemical properties and ultimately result in product failure. Considering that such solid-state transformations (propagated by different environmental factors) usually proceed toward the core of the tablet, the information on the inner and outer layer structures such as their thickness and composition can be especially valuable, for example, to assess the process kinetics.…”