Pharmaceutical Research, Vol. 18, No. 3, 2001
Research Paper
simultaneously evolved, thermal analysis alone is not very
helpful in the study of reaction kinetics (4). In such cases,
thermal analysis should be used in conjunction with other
techniques for evolved gas analysis (e.g., infrared spectros-
copy, mass spectroscopy or gas chromatography). It is often
realized that solid-state reactions take place through complex
mechanisms involving intermediates and the same end prod-
uct is obtained through multiple pathways (5,6). In such cases,
thermoanalytical techniques yield complex profiles due to
overlapping thermal events. Often, it is difficult to separate the
reaction steps and study the kinetics of the individual steps.
Variable temperature X-ray powder diffractometry is a
technique where X-ray diffraction patterns are obtained while
the sample is subjected to a controlled temperature program.
While the weight and the heat flow in the sample can be
monitored using TGA and DSC respectively, XRD provides
information about alterations in the solid-state of the sample.
Thus, XRD is an excellent complement to thermoanalytical
techniques. Numerous transitions such as dehydration, poly-
morphic transformation, formation of amorphous phase and
recrystallization can be observed using variable temperature
XRD. Since the solid-state of the intermediates (if any) can
be readily characterized, the technique has the potential to
provide information about the reaction mechanism. For ex-
ample, the dehydration of theophylline monohydrate was in-
vestigated by this technique (7). The study revealed the for-
mation of a metastable anhydrous phase, which then trans-
formed to the stable anhydrate. Recent advances in
instrumentation have enabled simultaneous and independent
control of the temperature and the water vapor pressure in
the sample chamber (4,8).
Investigation of Solid-State Reactions
Using Variable Temperature X-Ray
Powder Diffractrometry. I.
Aspartame Hemihydrate
Suneel Rastogi,1,2 Marek Zakrzewski,3,4 and
Raj Suryanarayanan1,5
Received August 29, 2000; accepted December 12, 2000
Purpose. The object of this study was to demonstrate the applicability
of variable temperature X-ray powder diffractometry (XRD) to in-
vestigate solid-state reactions using aspartame as a model compound.
Methods. Aspartame exists as a hemihydrate (ASH) under ambient
conditions and converts to aspartame anhydrate (ASA) at 130°C.
ASA on further heating to 180°C undergoes decomposition (intra-
molecular cyclization) to form a diketopiperazine derivative (DKP).
The dehydration as well as the decomposition kinetics were studied
isothermally at several temperatures. The unique feature of this tech-
nique is that it permits simultaneous quantification of the reactant as
well as the product.
Results. While the dehydration of ASH appeared to follow first-order
kinetics, the cyclization of ASA was a nucleation controlled process.
The rate constants were obtained at various temperatures, which
permitted the calculation of the activation energies of dehydration
and cyclization from the Arrhenius plots. The activation energy of
dehydration was also calculated according to the method described
by Ng (Aust. J. Chem., 28:1169–1178, 1975) and the two values were
in good agreement.
The object of this investigation was to develop and vali-
date an XRD method to study the kinetics of a multi-step
decomposition of a pharmaceutical solid. Two reactions were
studied: the dehydration of aspartame hemihydrate to form
anhydrous aspartame followed by its cyclization to form
DKP. Aspartame hemihydrate was used as the model com-
pound since its dehydration followed by decomposition has
been studied in detail (9–12). Leung and Grant demonstrated
that in the solid-state, anhydrous aspartame (ASA) under-
goes intramolecular cyclization to form a single crystalline
product (9). This involves nucleophilic attack of the N-
terminal nitrogen on the carbonyl group of the phenylalanyl
residue yielding a diketopiperazine derivative (DKP: 3-car-
boxymethyl-6-benzyl-2,5-diketopiperazine, C13H14O4N2)
along with the evolution of gaseous methanol. State-of-the-
art instrumentation was used, the features of which are de-
scribed below. (i) A high temperature attachment that per-
mitted us to carry out the reactions at temperatures ranging
from room temperature to 300°C. (ii) A position sensitive
detector (PSD), which enabled very rapid data collection.
This was invaluable while monitoring fast reactions. For ex-
ample, even in a fast reaction that was complete in 15 min-
utes, over 10 data points were obtained. (iii) Reliable data
(peak) analysis program, which was particularly useful to de-
compose asymmetric and overlapping X-ray peaks.
Conclusions. The study demonstrates that XRD is an excellent
complement to thermal analysis and provides direct information
about the solid-states of various reaction phases.
KEY WORDS: kinetics; solid-state reaction; X-ray powder diffrac-
tometry; aspartame; dehydration; decomposition.
INTRODUCTION
The present investigation is concerned with two types of
solid-state decomposition reactions. The first type involves
loss of solvent of crystallization while the second is a chemical
decomposition reaction. The kinetics of solid-state decompo-
sition reactions is conventionally studied by thermoanalytical
techniques (1,2) such as thermogravimetric analysis (TGA)
and differential scanning calorimetry (DSC). However, these
techniques have several drawbacks. They do not unambigu-
ously identify crystalline solid phases and provide little or no
information about their degree of crystallinity (3). Since in-
termediate phases (if any) may not be readily identified, these
techniques are not necessarily useful for discerning the reac-
tion mechanism. When two or more gaseous products are
1 College of Pharmacy, 308, Harvard St. S.E., University of Minne-
sota, Minneapolis, Minnesota 55455.
2 Present address, Forest Laboratories, Inc., 300, Prospect St., In-
wood, New York 11096.
3 Philips Analytical X-ray, Almelo, The Netherlands.
4 Present address, Advanced Solid State Characterization, Inc., 520 MATERIALS AND METHODS
Anthony’s Drive, Exton, Pennsylvania 19341.
5 To whom correspondence should be addressed. (e-mail: surya001@
tc.umn.edu)
Aspartame hemihydrate (C14H18O5N2и0.5H2O) was a gen-
erous gift from the NutraSweet Kelco Co., Mount Prospect, IL.
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0724-8741/01/0300-0267$19.50/0 © 2001 Plenum Publishing Corporation