Hydration and dehydration behavior of aspartame hemihydrate

Article abstract of DOI:10.1021/js970250m

Previous studies have shown that aspartame in the solid state can exist as a hemihydrate which occurs in two different polymorphic forms (I and II). The present work shows that equilibration of either hemihydrate at 25 °C with water vapor at relative humidities ≤58% or with liquid water produces a 2.5-hydrate. Upon subjecting each of these crystalline hydrates to increasing temperature, the same crystalline anhydrate is formed which thermally cyclizes at a higher temperature to form the known compound 3- (carboxymethyl)-6-benzyl-2,5-dioxopiperazine. The activation energy of the cyclization reaction appears to depend on the degree of crystallinity of the anhydrate that is formed at a lower temperature. On increasing the temperature of the 2.5-hydrate, a hemihydrate intervenes before the anhydrate is formed. This intervening hemihydrate is similar to the commercial form (11) of aspartame hemihydrate but exhibits greater amorphous character. The techniques employed were Karl Fischer titrimetry, powder X-ray diffractometry, differential scanning calorimetry, thermogravimetric analysis, solid-state ¹³C nuclear magnetic resonance spectroscopy, and Fourier transform infrared absorption spectroscopy.

Full text of DOI:10.1021/js970250m

Hydration and Dehydration Behavior of Aspartame Hemihydrate
†,‡
§
§
,†
SUZANNE S. LEUNG, BRIAN E. PADDEN, ERIC J. MUNSON, AND DAVID J. W. GRANT*
Contribution from the Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Weaver-Densford Hall,
3
08 Harvard Street S.E., Minneapolis, Minnesota 55455-0343, and the Department of Chemistry, University of Minnesota,
Minneapolis, Minnesota 55455-0343.
Received June 24, 1997.
Final revised manuscript received November 3, 1997.
Accepted for publication December 29, 1997.
Materials and Methods
Abstract 0 Previous studies have shown that aspartame in the solid
state can exist as a hemihydrate which occurs in two different
polymorphic forms (I and II). The present work shows that equilibration
of either hemihydrate at 25 °C with water vapor at relative humidities
g58% or with liquid water produces a 2.5-hydrate. Upon subjecting
each of these crystalline hydrates to increasing temperature, the same
crystalline anhydrate is formed which thermally cyclizes at a higher
temperature to form the known compound 3-(carboxymethyl)-6-benzyl-
Ma ter ia lssCommercial aspartame hemihydrate was a gift
from the NutraSweet Kelco Co., Mount Prospect, IL. The phases
of aspartame hemihydrate that come into equilibrium with water
vapor at various relative humidities were determined by examina-
tion of samples equilibrated over saturated salt solutions at
constant relative humidities of 0.0, 15.0, 32.3, 42.0, 58.0, 80.0, and
8.0 at 22.5 °C7 for as long as four months.
P a r ticle Size An a lysissSamples were suspended in 1,1,1-
9
2
,5-dioxopiperazine. The activation energy of the cyclization reaction
trichloroethane with mechanical stirring and analyzed in a particle
size analyzer (Brinkmann, model 2010, Westbury, NY). The mean
number-length particle size of each powder sample was measured
and is given by ∑nd /∑nd, where n is the number of particles of
mean diameter, d.
appears to depend on the degree of crystallinity of the anhydrate that
is formed at a lower temperature. On increasing the temperature of
the 2.5-hydrate, a hemihydrate intervenes before the anhydrate is
formed. This intervening hemihydrate is similar to the commercial
form (II) of aspartame hemihydrate but exhibits greater amorphous
character. The techniques employed were Karl Fischer titrimetry,
2
Ka r l F isch er Tit r im et r y (KF T)sThe water content of the
various solid forms of aspartame was determined by Karl Fischer
titrimetry using a Mitsubishi Moisture Meter (model CA-05,
Mitsubishi Chemical Industries Ltd., Tokyo, J apan). Samples
(2-7 mg) were accurately weighed and quickly transferred to the
titration vessel containing anhydrous methanol prior to titration.
P ow d er X-r a y Diffr a ctom etr y (P XRD)sRoom-temperature
powder X-ray diffraction patterns were determined using an X-ray
diffractometer (Siemens, model D-500, Germany) at 30 mA, 45 kV,
with Cu KR radiation. Counts were measured using a scintillation
counter. Samples were packed into an aluminum holder and
scanned from 5° to 35° 2θ, increasing at a step size of 0.02° with
a counting time of 1 s. Elevated temperature PXRD patterns were
obtained under ambient atmosphere using an X-ray diffractometer
powder X-ray diffractometry, differential scanning calorimetry, ther-
mogravimetric analysis, solid-state 13C nuclear magnetic resonance
spectroscopy, and Fourier transform infrared absorption spectroscopy.
Introduction
Because drugs are frequently crystallized from water and
because of the presence of water vapor in the atmosphere,
many drugs that are capable of hydrogen bonding in the
solid state incorporate water into their crystal lattices to
form hydrates.1 The formation of a hydrate can be achieved
by absorption of water vapor at a relative humidity (water
(Scintag model 2000, Sunnyvale, CA) with a hot stage attachment
at 40 mA, 45 kV, with Cu KR radiation. Samples were packed
into a copper holder and scanned from 5° to 35° 2θ, at a rate of
4
°/min with a counting time of 1 s.
Differ en tia l Sca n n in g Ca lor im etr y (DSC)sThe DSC curves
were determined using a differential scanning calorimeter (Du-
Pont, model 910, TA Instruments, New Castle, DE) equipped with
a data station (Thermal Analyst 2000, TA Instruments, New
Castle, DE). The temperature axis and the cell constant were
calibrated using indium. Samples (2.40-2.70 mg) in nonhermeti-
cally crimped or open aluminum pans were heated at rates of 1,
activity) greater than the equilibrium value between the
anhydrate and the hydrate.2
-4
The presence of water
molecules in the lattice structure of the solid usually affects
its pharmaceutically important physical properties, such
as melting point, solubility, dissolution rate, physical and
chemical stability, powder flow, and tableting behavior. In
particular, solid-state solvation may change the dissolution
rate of the solid and may therefore affect the bioavailabil-
ity.2 In this continuation of our studies on aspartame, a
dipeptide sweetener that is finding increasing use in
pharmaceuticals, we here determine the susceptibility of
aspartame hemihydrate to undergo dehydration and hy-
dration. Previous studies have shown that aspartame
hemihydrate undergoes chemical degradation and poly-
2
, 4, 7, and 10 °C/min under nitrogen purge at 3-4 mL/min. The
crimped pan allows the pressure of the released solvent to build
up inside the pan, thereby shifting the desolvation process to a
higher temperature. The peak temperature was noted as the point
on the temperature scale corresponding to maximum deviation
from the baseline.
,4
Th er m ogr a vim etr ic An a lysis (TGA)sThe TGA curves were
obtained using a thermogravimetric analyzer (DuPont, model 951,
TA Instruments, New Castle, DE) linked to a data station
(Thermal Analyst 2000, TA Instruments, New Castle, DE). All
5
,6
TGA runs were performed on samples in open aluminum pans
with a nitrogen purge at 3-4 mL/min. Nonisothermal TGA was
performed on samples (2.30-2.50 mg) at a heating rate of 10 °C/
min. Isothermal TGA was performed on samples (2.30-2.50 mg)
at various temperatures to determine the kinetics of cyclization
for the different solid forms of aspartame by monitoring the loss
in weight due to the splitting-off of methanol.
Solid -St a t e Nu clea r Ma gn et ic R eson a n ce (SSNMR )
Sp ectr oscop ysThe 13C solid-state NMR spectra of aspartame
hemihydrate (II) and 2.5-hydrate were acquired at 75.7 MHz using
a Chemagnetics CMX-300 spectrometer (Fort Collins, CO). The
morphic transition in the solid state.
hydrate forms of aspartame are here also evaluated with
respect to the thermally induced degradation reaction.
The various
*
Corresponding author. Telephone: (612) 624-3956. Facsimile:
(612) 625-0609. E-mail: grant001@maroon.tc.umn.edu.
†
Department of Pharmaceutics.
Present address: 3M Pharmaceuticals, 260-4N-12, 3M Center, St.
‡
Paul, MN 55144.
§
Department of Chemistry.
5
08 / Journal of Pharmaceutical Sciences
S0022-3549(97)00250-5 CCC: $15.00
Published on Web 03/12/1998
© 1998, American Chemical Society and
American Pharmaceutical Association
Vol. 87, No. 4, April 1998

Figure 1sPowder X-ray diffraction patterns of aspartame forms at elevated temperatures, showing dehydration and cyclization: (a) hemihydrate form I, (b)
hemihydrate form II, and (c) 2.5-hydrate.
samples were packed in 7.5 mm zirconia rotors and spun at the
magic angle (MAS) at a speed of 6 kHz. All spectra were acquired
with high-power H decoupling, cross polarization (CP), and total
suppression of sidebands (TOSS). A minimum of 256 scans were
acquired with a pulse delay of 3 s and a contact time of 5 ms.
not observed in crimped pans (Figure 2a). However, a
recrystallization exotherm was not seen during the dehy-
dration of the ball-milled form (I), suggesting that the
recrystallization event is not separated from the dehydra-
tion or reaction event. The absence of the recrystallization
exotherm in DSC of the ball-milled form (I) by both crimped
pans (Figure 2a) and open pans (Figure 2b) and the
similarity of the enthalpy change suggests that the recrys-
tallization and dehydration events are occurring simulta-
neously. Neither DSC nor PXRD showed any conversion
of form II to form I on heating in the absence of water
vapor.
The water content of the samples after dehydration was
determined by Karl Fischer titrimetry to be 0.50 ( 0.12%
w/w (0.082 mol of H O/mol of aspartame). This small
2
amount of residual water may be held either by strong ion-
dipole interactions between zwitterionic aspartame and
dipolar water molecules or by occlusion onto the surface of
the tiny crystallites in the mosaic structure of the crystals.
The theoretical water content of aspartame hemihydrate
is 2.97% w/w and that of the dihemihydrate is 13.27% w/w.
1
F ou r ier
Tr a n sfor m
In fr a r ed
Ab sor p t ion
(F TIR )
Sp ectr oscop ysSpectra of mulls in Nujol (Aldrich Chemical Co.,
Milwaukee, WI) were obtained from a Fourier transform infrared
spectrophotometer (Nicollet, model 5DXC, Madison, WI).
Results and Discussion
Commercial aspartame hemihydrate, as received, cor-
responds to form II (untreated form), described earlier by
6
Leung et al. Form II, when milled, transforms to form I
ball-milled form).6 The thermally induced dehydration of
(
both polymorphs of aspartame hemihydrate are here
evaluated. Desolvation may be accompanied either by
retention of the crystal structure of the solvate, by creation
of an amorphous form, or by transformation into a new
crystal structure.1 In this study both polymorphs (I and
II) of aspartame hemihydrate are found to undergo thermal
dehydration to a crystalline anhydrate phase, as observed
at 150° by variable temperature PXRD (Figure 1a,b). The
diffraction pattern of the anhydrate phase (Figure 1a,b) is
different from that of the hemihydrate forms, an indication
that it is a new crystalline form, and consists of sharp
peaks, suggesting appreciable crystallinity, but without
significant baseline separation corresponding to an under-
lying amorphous halo and suggesting some amorphous
character. The anhydrate form of aspartame cyclizes to
A lower dehydration temperature of the ball-milled form
(I) than of the untreated form (II) of aspartame in either
type of DSC pan (Figures 2a and b) may have significant
consequences for formulation. The released water, even
in small amounts, may be transferred to other components
of the formulation, affecting the chemical and physical
stability.8 The observed improvement in flow may provide
a sufficient reason for milling commercial aspartame
hemihydrate, but if the aspartame formulation is moisture-
sensitive, the greater ease of dehydration of the ball-milled
polymorph (I) should also be considered.
Leung and Grant5 found that aspartame anhydrate at
about 180-190 °C undergoes a cyclization reaction which
involves an intramolecular aminolysis with release of
methanol to form the cyclic compound DKP and which
3
-(carboxymethyl)-6-benzyl-2,5-dioxopiperazine (DKP) at
5
higher temperatures (e.g., 200 °C in Figure 1a,b).
When samples of untreated aspartame hemihydrate (II)
were heated in open pans without lids, recrystallization of
the anhydrate after dehydration was observed as an
exotherm in DSC at about 133 °C (Figure 2b), but this was
Journal of Pharmaceutical Sciences / 509
Vol. 87, No. 4, April 1998

Figure 2sDSC curves of aspartame hemihydrate polymorphs (I and II) and of aspartame 2.5-hydrate in (a) crimped pans and (b) open pans. The arrow points
to the lowest temperature endotherm for the 2.5-hydrate heated in an open pan.
9
follows Prout-Tompkins kinetics. Evidently, the reactant
of the cyclization reaction of both aspartame hemihydrate
polymorphs is really the anhydrate that is formed by their
dehydration. Similar sigmoidal progress curves were
observed for both the untreated (II) and ball-milled (I)
forms, for which Figure 3a is an example. The activation
energy of the cyclization reaction is 267.6 kJ /mol for the
5
untreated hemihydrate (II) and 262.1 kJ /mol for the ball-
milled hemihydrate (I) (Figure 3b). Because Prout-
9
Tomkins kinetics suggests that the reaction is nucleation-
controlled, the similarity of these activation energies
suggests that the anhydrate that is formed from the
dehydration of the two hemihydrate polymorphs may have
similar defect contents that arise from the loss of 0.5 mol
of water from each polymorph.
For untreated (II) and ball-milled (I) samples of aspar-
tame hemihydrate, which had been exposed to air contain-
ing water vapor at various relative humidities (RH) at 22.5
°
C for up to four months, the water content values were
determined by KFT and are plotted against RH in Figure
The data points for the two forms in Figure 4 are
4
.
indistingishable within the standard deviations stated in
the following two sentences. At 0-42% RH, the water
content (0.629 ( 0.010 mol of water/mol of aspartame)
corresponds closely with that of the hemihydrate with some
adsorbed water. At 58-98% RH, the water content (2.643
(
0.038 mol of water/mol of aspartame) corresponds closely
with that of the 2.5-hydrate with additional absorbed
water. At 58% RH this conversion was much slower than
at other RH values, taking four months to approach
completion. The water content did not fall below that of
the hemihydrate even after four months at 0% RH, imply-
ing that the hemihydrate polymorphs are kinetically stable
at 22.5 °C. While a crystalline anhydrate was observed in
situ at 150 °C by variable temperature PXRD (Figure 1),
attempts to isolate crystalline anhydrous aspartame, by
heating in a vacuum or by crystallization from anhydrous
organic solvents, were unsuccessful, suggesting that the
Figure 3s(a) Reaction-time profiles of aspartame hemihydrate form I at
-
1
elevated temperatures and (b) Arrhenius plot, where k has units of min and
4
is found by fitting the reaction profiles to the Prout-Tompkins equation.
hemihydrate is more stable than the anhydrate in the
presence of the slightest trace of water. Using a VTI
moisture sorption apparatus, the weight of aspartame
hemihydrate II was monitored at RH values from 5% to
95% in 5% increments. Adopting 1.0 µg/min as the
5
10 / Journal of Pharmaceutical Sciences
Vol. 87, No. 4, April 1998

Figure 4sWater stoichiometry−relative humidity phase diagram for aspartame
after four months at 22.5 °C. The points represent experimental points, the
lines represent theoretical stoichiometries, and the difference may be attributed
to adsorbed water. The dotted line between 42% and 58% RH denotes the
uncertainty in the exact transition point. The choice of RH for the transition
point is explained in the text.
threshold criterion for equilibrium, no significant weight
change was observed until 60% RH was reached. There-
fore, the critical RH for equilibrium betwen aspartame
hemihydrate II and the dihemihydrate is depicted as 55%-
Figure 5sTGA curves of aspartame hemihydrate polymorphs (I and II) and
aspartame 2.5-hydrate in open pans. The beginning of each plot at 22.5 °C
corresponds to a weight of 100%. The subsequent weight losses at higher
temperatures are indicated by the arrows.
6
0% in Figure 4.
PXRD (Figure 1c) at ambient temperature (22.5 °C)
confirms that the 2.5-hydrate is a new crystalline phase
with a lattice that differs from those of the hemihydrate
polymorphs. The thermally induced dehydration behavior
of the 2.5-hydrate was monitored by variable temperature
PXRD (Figure 1c). At 70 °C the overlaid diffraction
patterns in Figure 1 show that the 2.5-hydrate has changed
to a phase similar to the untreated hemihydrate (II),
without significant baseline separation of the peaks and
with an underlying amorphous halo, suggesting significant
amorphous character. At 150 °C a pattern similar to the
anhydrous form appears but again with an underlying
amorphous halo, suggesting significant amorphous char-
acter. These changes indicate that the thermal dehydra-
tion of the 2.5-hydrate proceeds via the hemihydrate to the
anhydrous form.
(2 Fb i) g ua nr ed 1r ce ) c. rystallizes at ∼133 °C to give the anhydrate
The weight losses during heating the various hydrates
(discussed above and below) were monitored by open pan
TGA (Figure 5) as well as by KFT (above). The first weight
loss step at 58 °C for hemihydrate form I and at 113 °C for
hemihydrate form II (Figure 5) arises from dehydration of
the hemihydrate, while the second weight loss step at 189
and 196 °C, respectively, is attributed to the loss of
5
methanol with the formation of DKP from the anhydrate
and is unchanged with varying initial amounts of water.
After equilibration of the original aspartame hemihydrate
(II, Figure 4) with water vapor at RH G 58% to produce
the 2.5-hydrate, the TGA curve showed significant weight
loss (10.3% measured), corresponding to 2 mol of water
(10.6% theoretical), on increasing the temperature from
ambient (22.5 °C) to about 35 °C. The subsequent weight
loss (about 1.5%) at 100-110 °C is less distinct, perhaps
corresponding very approximately to the loss of the final
0.5 mol of water (theoretically 2.65%), and occurs over a
wider temperature range. The final weight loss step at 200
°C is again attributed to the loss of methanol with the
formation of DKP.
The dehydration of either hemihydrate (I or II) and
subsequent recrystallization to the anhydrate are difficult
to discern by open pan TGA (Figure 5) and by crimped pan
DSC (Figure 2a) but are clearly shown by open pan DSC
(Figure 2b). During heating in a crimped pan, the water
vapor is not lost immediately to the environment but
remains to surround the solid, moderating the loss of the
remaining water. The DSC results (Figure 2) show that
three dehydration events may be observed, depending on
the method. The measured enthalpy of dehydration of the
hemihydrate formed from the 2.5-hydrate (16.3 ( 2.6 J /g
of aspartame) is smaller than that for the untreated
hemihydrate (38.08 ( 0.87 J /g of aspartame), confirming
the greater amorphous character of the former, as deduced
from PXRD (Figure 1).
DSC of the 2.5-hydrate in crimped pans (Figure 2a)
shows a large and broad endotherm with a shoulder at
lower temperatures (about 90 °C) than for the hemihydrate
polymorphs. Open pan conditions shifted the lowest en-
dotherm to even lower temperatures (about 30 °C, just
above room temperature) and revealed an endotherm at
∼
98 °C and an exotherm at ∼133 °C. The endotherm at
∼
98 °C is in the same temperature range as that for the
dehydration of hemihydrate form II in an open pan (95-
1
13 °C, Figure 5, weight loss of about 2%, corresponding
to 3% loss for 0.5 mol of water). The water content of cooled
samples previously heated to 90 °C in open pans, above
the lower temperature endotherms, was 0.532 mol of H O/
2
mol of APM (not shown), corresponding to the hemihydrate
with a small amount of adsorbed water. When the 2.5-
hydrate was heated to 150 °C, above the second dehydra-
tion and subsequent recrystallization, the water content
2
was only 0.10 mol of H O/mol of aspartame (0.6%), similar
to that for the anhydrate formed from the dehydration of
either of the two hemihydrate polymorphs (0.5-1.0%). This
small amount of residual water is again attributed to
adsorbed water. Thus, on heating the 2.5-hydrate in open-
pan DSC (Figure 2b) the endotherm just above room
temperature corresponds to the loss of 2 mol of water
Scanning electron microscopy and helium pycnometry
could not be performed on the 2.5-hydrate because exposure
of the sample to reduced pressures may cause dehydration.
However, measurement of the particle size distribution
(theoretically 10.6%, corresponding to 10.3% by TGA in
Figure 5) to give the hemihydrate (form II). The hemihy-
drate then dehydrates at ∼98 °C in open pan DSC (Figure
Journal of Pharmaceutical Sciences / 511
Vol. 87, No. 4, April 1998

Figure 6sFourier transform infrared absorption spectra of aspartame
hemihydrate form II and aspartame 2.5-hydrate.
using the Brinkman particle size analyzer showed no
significant difference between the number-length particle
size of the 2.5-hydrate (8.41 ( 3.33 µm) and that of the
hemihydrate (8.28 ( 3.28 µm). Macroscopically, significant
agglomeration of the particles was observed that may be
attributed to adsorbed moisture and to the inherent surface
characteristics of the particles.
1
3
Figure 7s C Solid-state NMR spectra of aspartame hemihydrate form II
and aspartame 2.5-hydrate. Each asterix denotes a spinning sideband that
was not completely suppressed by the TOSS sequence.
suggest that they have similarities in their crystal struc-
tures. The hydrates have two or more inequivalent sites
for some carbons and three or more inequivalent sites for
other carbons. It is possible that the basic molecular
arrangement of the hemihydrate (I) is maintained by both
the hemihydrate (II) and the 2.5-hydrate. Since there are
some carbons which have three peaks in both spectra, the
crystal structure may correspond to three layers of the four
molecules, with 12 molecules per unit cell. This can be
confirmed when a crystal structure can be determined for
either the hemihydrate (II) or the 2.5-hydrate.
The anhydrate formed from dehydration of the 2.5-
hydrate, designated A2.5, undergoes the same intramolecu-
lar cyclization reaction to form DKP6 and at a similar
temperature (∼188 °C) as the anhydrate formed from the
hemihydrate forms (I and II) of aspartame, designated A0.5
(Figures 2 and 5). The kinetic progress curves for the
cyclization reaction of A2.5, monitored by isothermal TGA
at various temperatures, are shown in Figure 8. These
The interactions of the aspartame molecules in the 2.5-
1
3
hydrate were investigated by FTIR and C SSNMR
spectroscopy. The FTIR spectrum of the 2.5-hydrate
(Figure 6) is similar to that of the ball-milled form (I) of
the hemihydrate. These spectra showed no splitting of
absorption peaks as was seen with the untreated hemihy-
5
drate form. The broad absorption band at 2600-360100
-
1
cm , which can be attributed to O-H stretch in water,
is more pronounced for the 2.5-hydrate than for the
hemihydrate forms.
The 13C solid-state NMR spectra of the hemihydrate (II)
and the 2.5-hydrate are shown with tentative peak assign-
ments in Figure 7. The assignments were based primarily
1
3
on the solution C NMR assignments of phenylalanine and
aspartic acid.11 The differences in the spectra of the
hemihydrate (II) and the 2.5-hydrate demonstrate that
solid-state NMR can be used to identify these hydrates.
The 13C solid-state NMR spectra (Figure 7) of both the
hemihydrate (II) and the 2.5-hydrate show multiple reso-
nances for each carbon due to crystallographically in-
equivalent sites in the unit cell. The existence of more than
one peak for each carbon indicates that the hemihydrate
curved plots of the fraction, x, of the anhydrate, A2.5 or A0.5
,
reacted against time, t, are sigmoidal, suggesting nucle-
ation control, but are not symmetrical. The acceleratory
period of these progress curves (e.g. Figure 8) is exagger-
ated with the point of inflection at x ≈ 0.6, unlike the curves
for the reaction of A0.5, which are quite well-fitted by the
Prout-Tompkins9 equation. The acceleratory period of
(
II) and the dihemihydrate have less symmetric crystal
1
4
structures than the hemihydrate (I) reported elsewhere.
The spectrum of the hemihydrate (II) exhibits resonances
with a peak intensity ratio of approximately 2:1 for carbons
C1, C2, and C6. This indicates that there are at least two
inequivalent sites per unit cell. The spectrum shows three
peaks of approximately equal intensity for carbon C7,
indicating at least three inequivalent sites in the unit cell.
The spectrum of the 2.5-hydrate has three peaks of
approximately equal intensity for each carbon C1 and C7.
This result indicates that there are at least three inequiva-
lent sites per unit cell.
solid-state reactions can be described more closely by a
power rate law x ) (kt) .
n 12,13
As the product is formed, it
can act as a site of nucleation to induce the reaction of
neighboring molecules. This autocatalytic effect gives rise
to a nonlinear x versus time plot. Unlike the Prout-
Tompkins9 equation, the exponential and power laws of
nucleation do not take into account the mutual interference
of nuclei at higher fractions reacted and therefore do not
approximate well the deceleratory portion of the reaction
progress curve (Figure 8) which occurs after the point of
inflection in the curve.5 For the reaction of A2.5, the fit with
The similarities between the 13C solid-state NMR spectra
of the hemihydrate (II) and the 2.5-hydrate (Figure 7)
5
12 / Journal of Pharmaceutical Sciences
Vol. 87, No. 4, April 1998

Scheme 1.sConversions of aspartame hydrates upon heating. The
temperatures of phase conversion are approximate and are derived from
variable temperature powder X-ray diffraction.
tion energy and with more acceleratory kinetic profiles,
confirming its greater defect content.
Acknowledgments
We thank the American Foundation for Pharmaceutical Educa-
tion and the Pharmaceutical Research and Manufacturers of
America Foundation, Inc., for consecutive predoctoral fellowhips
for S.S.L., and the NutraSweet Kelco Co., Mount Prospect, IL, for
gifts of aspartame and 3-(carboxymethyl)-6-benzyl-2,5-dioxopip-
erazine.
Figure 8s(a) Reaction-time profiles, determined by isothermal TGA, for the
cyclization of aspartame from aspartame 2.5-hydrate and (b) Arrhenius plot,
-
1
where k has units of min and is found by fitting the reaction profiles to a
References and Notes
12
13
power law model (Young, Bamford and Tipper ).
1
. Byrn, S. Solid-State Chemistry of Drugs; Academic Press:
New York, 1982; pp 149-186.
the power rate law is justified by the pronounced accel-
eratory period and provides correlation coefficients greater
than 0.993 for the data at various temperatures. Arrhenius
plots of ln k against 1/T provide a value of the activation
energy of A2.5 (from the 2.5-hydrate, 177.1 kJ /mol), signifi-
cantly less than that for the reaction of A0.5 (from the
untreated hemihydrate [II], 267.6 kJ /mol; from the ball-
milled hemihydrate [I], 262.1 kJ /mol).
2. Shefter, E.; Higuchi, T. Dissolution behavior of crystalline
solvated and nonsolvated forms of some pharmaceuticals. J .
Pharm. Sci. 1963, 52, 781-791.
3
. Khankari, R. K.; Grant, D. J . W. Prediction of nedocromil
sodium hydrate phases in 2-propanol + water mixtures form
the relative humidity phase diagram. Pharm. Res. 1993, 10
(10), S153, PT 6106.
4
. Khankari, R. K.; Grant, D. J . W. Pharmaceutical hydrates.
Thermochim. Acta 1995, 248, 61-79.
The differences between the two anhydrates, A2.5 and
A
0.5, in the kinetic profile and activation energy of their
5. Leung, S. S.; Grant, D. J . W. Solid-state stability studies of
model dipeptides: aspartame and aspartylphenylalanine. J .
Pharm. Sci. 1997, 86 (1), 64-71.
intramolecular cyclization reactions may arise from the
differences in the nature of the defects. The pronounced
acceleratory region for A2.5 implies a slow initial rate of
nucleation and delayed interference between the nuclei
until the latter stages of the reaction. The differences
between A2.5 and A0.5 were not detected by PXRD.
6
. Leung, S. S.; Padden, B.; Munson, E.; Grant, D. J . W. Solid-
state characterization of two polymorphs of aspartame
hemihydrate. J . Pharm. Sci. 1998, 87, 501-507 (preceding
paper in this issue).
7
. Nyqvist, H. Saturated salt solutions for maintaining specified
relative humidities. Int. J . Pharm. Technol. Prod. Manuf.
1
983, 4, 47-48.
Conclusions
8. Carstensen, J . Effect of moisture on the stability of solid
dosage forms. Drug Dev. Ind. Pharm. 1988, 14, 1927-1968.
A summary of the thermally induced transformations of
aspartame hydrates is shown in Scheme 1. Equilibration
of either hemihydrate polymorph (I or II) with water vapor
at relative humidities g 58% RH yields a 2.5-hydrate,
which, when heated, undergoes the following sequence of
conversions: 2.5-hydrate f hemihydrate f anhydrate f
DKP. The hemihydrate II formed by dehydration of the
9. Prout, E.; Tompkins, F. The thermal decomposition of
potassium permanganate. Trans. Faraday Soc. 1944, 40,
4
88-498.
1
1
0. Campbell, I.; Dwek, R. Biological Spectroscopy; Benjamin
Cummings: Menlo Park, CA, 1984; p 46.
1. Pretsch, P.; Seibl, J .; Simon, W.; Clerc, T. Tables of Spectra
Data for Structure Determination of Organic Compounds;
Springer-Verlag: New York, 1983; pp C170, C210.
2
.5-hydrate has the same crystal structure as the hemi-
1
2. Young, D. The International Encyclopedia of Physical Chem-
istry and Chemical Physics, Topic 21, Vol. 1, Decomposition
of Solids; Pergamon Press: New York, 1966; pp 10-14.
13. Bamford, C.; Tipper, C. Chemical Kinetics, Vol. 22, Reactions
in the Solid State; Elsevier: New York, 1980; pp 42-47.
14. Hatada, M.; J ancarik, J .; Graves, B.; Kim, S.-H. Crystal
structure of aspartame, a peptide sweetener. J . Am. Chem.
Soc. 1985, 107, 4279-4282.
hydrate form II but shows greater amorphous character
or defect content which corresponds to a lower crystallinity.
Dehydration of both hemihydrate polymorphs (I and II) and
of the 2.5-hydrate gives anhydrates with the same crystal
structures. The anhydrate formed by dehydration of the
2
.5-hydrate undergoes cyclization to DKP at a temperature
similar to that for cyclization of the anhydrate formed by
dehydration of the hemihydrates but with a lower activa-
J S970250M
Journal of Pharmaceutical Sciences / 513
Vol. 87, No. 4, April 1998