Use of high-intensity X -radiation in solid-state characterization of pharmaceuticals

2005 2005

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Abstract (summary)

The overall goal of this project was to develop new approaches to characterize pharmaceutical phase transitions and to quantify solid phases. The investigations were classified into three categories: (i) Amorphous → crystalline transition, (ii) phase transitions during dehydration, and (iii) anhydrate → hydrate transition. The use of synchrotron X-rays allowed diffraction patterns to be acquired with a time resolution of 40 milliseconds. The 2-dimensional detector and transmission geometry allowed X-ray patterns to be obtained as ‘snapshots’ over a wide angular (2&thetas;) range and minimized preferred orientation effects. For crystallinity quantification, a novel algorithm was developed for objective separation of crystalline and amorphous intensities from an X-ray pattern. An in situ crystallization approach was used to overcome the problem of inhomogeneity in mixing, which is a particularly serious issue at extreme mixture compositions. The estimated limit of detection, of crystalline sucrose in an amorphous matrix, was 0.2% w/w. The dehydration kinetics of theophylline monohydrate (M) was investigated using 2-dimensional XRD. Modeling of the dehydration profiles revealed that M dehydrated via a two-step pathway. The dehydration initiated with the M → metastable anhydrate (A*) transition, followed by the M → stable anhydrate (A) transition. The activation energies of the two processes were 110 and 146 kJ·mol −1, respectively. Polyvinylpyrrolidone (crystallization inhibitor) retarded the formation of A, which led to the build-up of A* in the dehydrated product. The activation energy for the MA transition was higher in the presence of PVP. A decrease in the dehydration temperature and an increase in the PVP concentration, facilitated the build-up of A*. A pressure differential scanning calorimetric technique was developed for quantification of betaine hydrate when present as a mixture with anhydrous betaine. The limits of detection and quantification of this technique were 0.15% and 1.5% w/w, respectively. The effect of annealing on betaine anhydrate → monohydrate transformation was studied. The water uptake rate constant (k), based on the three-dimensional nucleation and growth model, for unannealed anhydrous betaine (0.075 ± 0.002 min−1) was significantly higher than that for the annealed material (0.052 ± 0.004 min−1).

Indexing (details)

0572: Pharmaceuticals
0491: Pharmacology
Identifier / keyword
Health and environmental sciences; Pure sciences; Crystallinity; Pharmaceuticals; Synchrotron radiation; Theophylline monohydrate; X-radiation
Use of high-intensity X -radiation in solid-state characterization of pharmaceuticals
Nunes, Cletus
Number of pages
Publication year
Degree date
School code
DAI-B 66/02, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
9780542012976, 0542012979
Suryanarayanan, Raj
University of Minnesota
University location
United States -- Minnesota
Source type
Dissertations & Theses
Document type
Dissertation/thesis number
ProQuest document ID
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
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