Cryogenic Grinding of Indomethacin Polymorphs and
Solvates: Assessment of Amorphous Phase Formation
and Amorphous Phase Physical Stability
KIERAN J. CROWLEY, GEORGE ZOGRAFI
School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, Wisconsin 53705
Received 11 May 2001; revised 6 September 2001; accepted 11 September 2001
ABSTRACT: The effect of cryogenic grinding on ®ve crystal forms of indomethacin
(IMC) was investigated with particular interest in the formation of amorphous phase.
Powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) demonstrated that amorphous phase formation took place for all three polymorphs (g, a, and d)
and one solvate (IMC methanolate). In the latter case, a postgrinding drying stage was
needed to remove desolvated methanol from the ground amorphous product because
methanol destabilized amorphous IMC presumably via a plasticizing effect. The crystal
structure of another solvate, IMC t-butanolate, was unaffected by grinding, indicating
that amorphous phase formation on grinding does not occur in all cases. Ground
amorphous materials possessed similar glass transition temperatures but signi®cant
differences in physical stability as assessed by both isothermal and nonisothermal
crystallization. It is argued that physical factors, namely residual crystal phase and
speci®c surface area, determine the isothermal and nonisothermal crystallization
behavior of ground amorphous samples as opposed to intrinsic differences in the
structure of the amorphous phase. ß 2002 Wiley-Liss, Inc. and the American Pharmaceutical
Association J Pharm Sci 91:492±507, 2002
Keywords: cryogenic grinding; polymorphs; solvates; amorphous phase; isothermal
and nonisothermal crystallization
INTRODUCTION
Grinding is regularly used in pharmaceutical
solid processing to reduce particle size. High
levels of mechanical energy are used to generate
suf®cient strain in solid substrate particles so as
to cause crystal lattice disruption (defect formation), followed by crack formation, crack propagation, and particle fracture. Grinding is an
inef®cient process in energetic terms, with the
ratio of energy consumed in lattice bond breaking
and crack formation versus mechanical energy
input thought to be of the order of 1%.1 Large
amounts of heat, sound, and vibrational energy
Correspondence to: George Zogra® (Telephone: 608-2622991; Fax: 608-262-3397; E-mail: gzogra®@facstaff.wisc.edu)
Journal of Pharmaceutical Sciences, Vol. 91, 492±507 (2002)
ß 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association
492
are also generated during grinding. The combination of grinding-induced crystal lattice disruption,
also referred to in the pharmaceutical literature
as process-induced disorder,2 mechanical activation,3 and the generation of excess energy can lead
to additional physical and chemical changes in a
crystalline solid. These include intra-and intermolecular chemical reactions, chemical complexation, polymorphic transition, and melting and
amorphous phase formation,4 all of which can
seriously affect the ef®cacy of a pharmaceutical
solid dosage form.5
Formation of amorphous phase on grinding is
the focus of this study. The term amorphous phase
describes a condensed solid state without longrange three-dimensional molecular order. The
amorphous state possesses greater molecular
mobility compared to the more stable crystalline
state, so it is often more susceptible to chemical
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 2, FEBRUARY 2002
CRYOGENIC GRINDING OF IMC POLYMORPHS AND SOLVATES
degradation. The amorphous state can also offer
pharmaceutical advantages, primarily an enhanced dissolution rate above the crystalline state.
For this application, grinding provides an alternative method of preparing amorphous phase for
materials that have heat or solvent sensitivities that preclude other preparation methods.
Whether one is interested in amorphous phase
formation on grinding from the perspective of the
detrimental effect on stability or the bene®cial
effect on drug dissolution, a better understanding
of crystal to amorphous phase transformation is
essential. Pertinent issues include: Which crystal
properties determine whether transformation
takes place? Under what conditions and at what
rate does transformation take place? What are the
properties of the amorphous phase formed and
how do they compare to amorphous phase generated via other methods?
The two leading theories of crystal to amorphous phase transformation have been described
using the concepts of mechanical and thermodynamic destabilization.6,7 The mechanical mechanism describes how greater anharmonicity of
lattice vibrations (phonons) under increased
compression will eventually violate the Born
stability criteria of a crystal lattice at a critical
pressure, above which the lattice collapses to yield
an amorphous structure.6 The thermodynamic
mechanism declares that mechanical energy
input continuously increases the concentration
of defects in a crystal lattice to a critical limit,
beyond which the amorphous phase has greater
thermodynamic stability than the disordered
crystal and so transformation takes place.7,8
Amorphous phase formation by mechanical
energy input and by quench melting can be considered to occur by opposite routes in energetic
terms, that is, energy input to the ground crystalline state and energy loss on cooling the high
energy liquid state. Comparison of amorphous
phases generated by mechanical energy input and
those generated by quench melting have shown
differences in con®gurational heat capacity,9
differences in vibrational spectra,10 and also
``memory'' effects that cause crystallization back
to the original crystal phase.6 Such differences are
unrelated to the rare phenomenon of polyamorphism.11 Instead, they emphasize that the amorphous state is not a tightly de®ned energetic state
but can possess different dynamic and energetic
properties according to the method of preparation
and sample history. It is possible that amorphous
phase formation on grinding can occur via a
493
quench melting mechanism if large increases in
sample temperature take place. When attempting
to investigate crystal to amorphous transformation on grinding, therefore, it is imperative that
simultaneous melting to yield liquid phase is
avoided, and so grinding must be performed at
temperatures substantially below the melting
temperature.
The objectives of this study are to investigate
cryogenic crystal to amorphous transformation
in different crystal forms of indomethacin (IMC)
and to establish the physical properties of the
ground amorphous phase. IMC is a well-characterized glass-former with a glass transition
temperature (Tg) of approximately 438C (measured for a rapidly quenched glass by thermal
analysis at 108C/min).12 Previous work has shown
that, below Tg, melt-quenched amorphous IMC
crystallizes to the most stable g polymorph but
forms the metastable a polymorph or a mixture of
g and a above Tg.13±17 Crystallization of a third
polymorph from supercooled IMC at 908C has
been reported by Borka18 and will be classi®ed as
d form in this article. The notations I, II, and IV
were used for g, a, and d IMC, respectively, in the
earlier study. To our knowledge, the only previous
studies on IMC grinding were performed by
Otsuka and coworkers.14,19 It was reported that
grinding of IMC g and a polymorphs in the proximity of Tg yielded partially amorphous material
but low temperature grinding yielded X-ray
amorphous material. Interestingly, the starting
crystal form affected the physical stability of
ground amorphous material. In this study, cryogenic grinding was performed on three IMC
polymorphs (g, a, and d) and two IMC solvates
(methanol and t-butanol). Substrates were ground
for different lengths of time and phase analysis
was performed using powder X-ray diffraction
(PXRD) and differential scanning calorimetry
(DSC) accompanied by speci®c surface area analysis before and after grinding. The same methods
were used to examine crystallization of ground Xray amorphous materials under both isothermal
and nonisothermal conditions with reference to
quenched IMC reference samples.
EXPERIMENTAL
Materials
Gamma IMC obtained from Sigma (St. Louis, MO)
was used without further treatment in grinding
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494
CROWLEY AND ZOGRAFI
studies and also for preparation of all other
crystal forms. Alpha IMC was precipitated from
ethanol solution using distilled water as previously described.20 Delta IMC was prepared by
desolvation of IMC methanolate under vacuum at
308C for 10 days.21 DSC analysis yielded melting
temperature (Tm) and enthalpy (DHm) values of
157.98C (0.4) and 109.5 J/g (4.3) for g IMC,
151.48C (0.6) and 103.5 J/g (2.6) for a IMC, and
130.68C (0.3) for d IMC. DHm was not calculated
for d IMC as immediate recrystallization took
place on melting, affecting the enthalpy measurement. IMC methanolate (MeOH) and IMC
t-butanolate (tBA) solvates were prepared as described by Joshi.21 Measurement of desolvation
temperature (Td) and enthalpy (DHd) by DSC gave
values of 82.98C (0.4) and 93.0 J/g (4.3) for MeOH
and 86.18C (5.8) and 148.1 J/g (6.6) for tBA.
Changes in DSC sample weight following desolvation of MeOH and tBA were 7.5% w/w (0.4)
and 16.9% w/w (0.3), in good agreement with
calculated solvent contents for 1:1 solvate stoichiometry (8.2 and 17.1 w/w, respectively). Meltquenched amorphous IMC was prepared by
heating g IMC at approximately 1808C for 5 min
and then rapidly cooling by immersion in liquid
nitrogen. The amorphous product was then
lightly ground using a pestle and mortar and
passed through a 250 mm screen.
Grinding Methodology
Grinding was performed using a cryogenic impact
mill (Model 6750; SPEX CertiPrep, Metuchen,
NJ) consisting of a stainless steel vessel immersed
in liquid nitrogen, within which a stainless steel
rod is vibrated by means of a magnetic coil. Grinding of 2-g samples was performed at an impact
frequency of 10 cycles per s for 2 min periods
separated by 2 min cool-down periods. To assess
the effect of grinding time on crystallinity, the
sample vessel was removed at 6 min intervals,
transferred to a glove bag purged with nitrogen
gas, and allowed to warm to room temperature for
sampling. When preparing amorphous IMC for
investigation of isothermal and nonisothermal
crystallization studies, the sample was kept in
liquid nitrogen for a total grinding time of 60 min
without intermittent removal of the sample
vessel. Amorphous samples used in isothermal
and nonisothermal crystallization studies were
stored at 208C over P2O5 desiccant before analysis and the water content of each of these samples
was shown to be below 0.1% w/w by Karl-Fisher
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titration (Aquastar C2000; EM Science, Cherry
Hill, NJ).
PXRD
PXRD was used to examine changes in crystallinity and polymorphic/solvate form on grinding
and on aging of ground samples. A PXRD method
was sought that did not require additional sample
trituration or mixing with a crystalline reference,
steps that may further alter the properties of
the processed sample. The equipment found to be
most suited to this application was the General
Area Detector Diffraction System (Siemens,
Madison, WI). This equipment comprises a twodimensional detector that measures the entire
cone of diffracted X-rays, providing diffraction
data of reproducible peak intensity unaffected by
preferred orientation, allowing more accurate and
precise measurement of percentage crystal phase.
Sample was gently packed into a glass capillary
(2 mm i.d.; Charles Supper, Natick, MA), positioned in the X-ray beam path, and rotated
through 3608 during the 5 min diffraction data
collection. For quantitative measurement of crystal phase, calibration curves were constructed
using duplicate PXRD measurements for physical
mixtures of crystalline and amorphous IMC.
Gamma and a IMC samples described in the
Materials section were taken to be 100% crystalline based on the agreement of Tm and DHm data
for both polymorphs with literature values.15,18,20
Raw data for g/amorphous IMC physical mixtures
are given in Figure 1. The diffraction peak at 11.88
2y could be detected in mixtures containing as low
as 2% crystal phase and so this peak was chosen
for quantitative analysis of g IMC. The capability
of detecting low levels of crystal phase arises from
low detector noise and was of particular value for
investigating the effects of grinding on IMC
crystallinity. Although diffraction peak resolution
was much lower than that of a conventional
Bragg-Brentano powder diffraction apparatus,
differences between diffraction patterns were
suf®cient to permit identi®cation of all crystal
forms of IMC used in this study. Diffraction peaks
at 8.6, 9.8, 7.2, and 12.18 2y were used to quantify
a, d, MeOH, and tBA, respectively, using peak
height values corrected for the diffuse diffraction
of the amorphous component. Calibration curves
for g/amorphous IMC and a/amorphous IMC physical mixtures are shown in Figure 2. Isothermal
crystallization studies were performed at 308C
and approximately 0% relative humidity (RH) in
CRYOGENIC GRINDING OF IMC POLYMORPHS AND SOLVATES
495
Figure 2. PXRD calibration plots of corrected peak
height against percentage crystal phase for g/quenched
amorphous and a/quenched amorphous physical mixtures.
Figure 1. PXRD analysis of g/quenched amorphous
IMC physical mixtures.
temperature of the crystallization exotherm (Tp)
was also recorded to permit kinetic analysis of
the nonisothermal crystallization process. DSC
numerical data reported in this article are the
average of three measurements (with standard
deviation in parentheses) and were obtained at a
heating rate of 108C/min.
Measurement of Speci®c Surface Area
evacuated glass desiccators containing P2O5.
Duplicate PXRD measurements were made at
each time point.
DSC
DSC was performed using a Seiko SSC220C
instrument (Haake, Paramus, NJ). Four- to sixmg samples were crimped in Seiko Al pans
(SSCE030) with lids in a glove bag purged with
nitrogen gas and accurately weighed. Pan lids
were pierced for analysis of unground and ground
solvate samples. DSC measurements were carried
out from 10 to 1908C at heating rates of 5, 10,
20, and 308C/min with a nitrogen purge gas ¯ow
rate of 100 mL/min. Temperature and enthalpy
calibration was carried out at each heating rate
using high purity indium and gallium (Aldrich,
Milwaukee, WI). Tg was measured using the
extrapolated onset temperature of the glass
transition region. The extrapolated onset temperature was used to calculate Tc (crystallization
temperature), Td, and Tm values. The peak
Speci®c surface area measurements were made
with the Quantasorb apparatus (Quantachrome,
Boynton Beach, FL) using nitrogen adsorbate
unless otherwise stated. Accurately weighed
samples were degassed under a nitrogen purge
for a minimum of 12 h at a temperature below 08C
to avoid crystallization of amorphous sample.
Monolayer desorption data were collected in
triplicate for each sample. For samples with low
speci®c surface area (< 1 m2/g), a modi®ed sample
holder with a narrow bore diameter was used in
order to minimize thermal diffusion effects. PXRD
analysis was used to ensure that no crystallization had taken place during degassing and
speci®c surface area measurement of each amorphous sample.
RESULTS
Effect of Grinding on c, a, and d IMC Polymorphs
PXRD data for g, a, and d IMC following different
grinding times are given in Figure 3a±c. A rapid
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496
CROWLEY AND ZOGRAFI
Figure 3. PXRD analysis of IMC polymorphs and solvates following different
grinding times: (a) g polymorph (b) a polymorph (c) d polymorph (d) methanol solvate
(MeOH) (e) t-butanol solvate (tBA). PXRD for a 2/1 physical mixture of g/a IMC has been
included in (d) to assist identi®cation of the phase composition following 60 min
grinding.
decrease in diffraction peak intensities was observed for all three IMC polymorphs during the ®rst
30 min of grinding. In each case, there was no
detectable crystal phase present after 60 min, so
all materials were classi®ed as X-ray amorphous.
There was no evidence of polymorphic changes
during g, a, or d IMC grinding, indicating direct
crystal to amorphous phase transformation. Crystallinity reduction took place at comparable rates
for each crystal form. The changes in speci®c
surface area following 60 min grinding of g, a,
and d IMC are given in Table 1. Grinding produced large increases in speci®c surface area for g
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 2, FEBRUARY 2002
and a IMC, but, surprisingly, a moderate decrease
in speci®c surface area for d IMC.
Figure 4a±c contains DSC heating data for
g, a, and d IMC measured following varying
grinding times. For each polymorph, formation
of amorphous phase on grinding was con®rmed by
the presence of a glass transition event in the
temperature range of 39 to 458C, which was
accompanied by an exothermic crystallization
event between Tg and the melting region. As the
quantity of amorphous phase increased on
extended grinding, the enthalpy of crystallization
(DHc) became larger, as re¯ected in the exotherm
CRYOGENIC GRINDING OF IMC POLYMORPHS AND SOLVATES
497
Table 1. The Effect of 60 min Grinding on the Speci®c Surface Area and Phase Properties (Identi®ed by PXRD)
of g, a, and d IMC, MeOH, tBA, and Quenched IMC
Material
Speci®c Surface Area
Pregrinding [m2/g]
Speci®c Surface Area
Postgrinding [m2/g]
g
a
d
MeOH
0.38 (0.02)a
4.22 (0.15)
2.69 (0.01)
2.20 (0.30)
TBA
0.17 (< 0.01)b
1.13 (0.14)
Quenched/6 min ground
0.35 (< 0.01)
1.74 (0.02)
Quenched/60 min ground
0.35 (< 0.01)
2.02 (0.03)
6.69 (0.09)
12.36 (0.86)
1.71 (0.05)
5.23 (0.11)
Phase Properties Postgrinding
X-ray amorphous
X-ray amorphous
X-ray amorphous
X-ray amorphous if drying
stage is followed by grinding
No change (tBA intact even
with drying stage)
No change (remains X-ray
amorphous)
No change (remains X-ray
amorphous)
Standard deviation values are given in parentheses.
a
The speci®c surface area of g IMC measured using krypton sorption was 0.35 0.01 m2/g, con®rming that nitrogen adsorption
data yield reasonably accurate data for samples with low speci®c surface area.
b
Measurement made using krypton adsorption.
magnitude. For g and a, the peak temperature
of nonisothermal crystallization (Tp) also rose
on grinding by 10 to 158C (Figure 4a±b). DSC
analysis of ground d IMC samples no longer
identi®ed a d IMC melting event but two exothermic events following 12 and 30 min grinding
that exhibited contrasting temperature relationships (Figure 4c). Increased grinding time caused
a rise in the ®rst exotherm transition temperature
but a fall in the second exotherm transition
temperature. Most likely, the ®rst exotherm
represented crystallization of amorphous phase
and so exhibited a relationship with grinding time
comparable to that observed for g and a substrates. The second exotherm was probably a
phase transformation from d to the more stable g
polymorph that took place before the d melting
temperature was reached.
Effect of Grinding on IMC Solvates
The effects of grinding on solvate crystal structure and speci®c surface area are shown in
Figure 3d±e and Table 1, respectively. Grinding
of MeOH and tBA solvates did not produce X-ray
amorphous phase. In the case of MeOH, signi®cant changes in PXRD data were apparent.
A reduction in MeOH diffraction peak intensity
took place after 12 min grinding. The diffraction
peak at 7.28 2y, unique to MeOH, was almost
absent by 30 min with g IMC the principal phase.
Following 60 min grinding, a mixture of g and a
IMC was present, with only a trace amount of
MeOH remaining. For con®rmation of the phase
composition at 60 min, a PXRD pattern of a 2/1 g/a
physical mixture has been included in Figure 3d
with diffraction peaks at 11.88 2y (g) and 8.68 2y (a)
prominent.
Changes in the nonisothermal desolvation behavior of ground MeOH were identi®ed by DSC
analysis (Figure 4d). Grinding caused reduction
in both Td and DHd in agreement with the loss of
MeOH shown by PXRD. The d melting endotherm
was no longer evident in ground MeOH samples, a
change also seen with pure d IMC in Figure 4c.
A small ``desolvation'' endotherm (now thought to
be a desorption phenomenon) remained after
30 and 60 min grinding even though MeOH was
undetected by PXRD and detectable weight loss
was noted on DSC analysis. These observations
indicated that desolvated methanol was still
present in the sample.
The effect of desolvated methanol on the outcome of cryogenic grinding was considered. With a
melting temperature of 988C, methanol may be
present either as a solid or liquid during grinding
depending on the ability of the cryogenic mill to
maintain low temperature. IMC may dissolve
liquid methanol from which crystallization of IMC
polymorphs could occur. With a Tg of 1708C,22
methanol could act as a potent plasticizer of
any amorphous IMC formed during grinding.
Plasticization could lower the Tg of IMC to
below room temperature, resulting in rapid
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498
CROWLEY AND ZOGRAFI
Figure 4. DSC analysis of IMC polymorphs and solvates following different grinding
times: (a) g polymorph (b) a polymorph (c) d polymorph (d) methanol solvate (MeOH) (e)
t-butanol solvate (tBA).
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CRYOGENIC GRINDING OF IMC POLYMORPHS AND SOLVATES
crystallization from the amorphous state before
PXRD and DSC analysis. The 8.2% w/w concentration of methanol in MeOH is low but signi®cant
as the plasticizing effect is greatest at low solvent
levels,23 and solvent will probably concentrate in
amorphous regions of the partially ground sample. The formation of a IMC at longer grinding
times gave a strong indication that phase changes
took place above Tg, as the metastable a form
is known to crystallize only above Tg unless
a seeds are present.13 The Couchman-Karasz
Equation (a modi®cation of the Gordon-Taylor
Equation) can be used to estimate Tg of an ideal
mixture of two components 1 and 224:
Tg12 ˆ
…w1 Tg1 † ‡ …K w2 Tg2 †
w1 ‡ …K w2 †
…1†
where w is weight fraction of each component and
K ˆ DCp1/DCp2 (DCp represents the heat capacity
change at Tg). Using Tg and DCp values of 458C
and 0.41 J/g/8C for IMC, respectively,25 and
1708C and 0.81 J/g/8C for methanol, respectively,22 predicted Tg of an 8.2% w/w methanol in
IMC mixture was 138C.
A modi®ed grinding experiment was performed
to establish if less stable amorphous phase was
formed on cryogenic grinding of MeOH. MeOH
was ground for 60 min using the same protocol as
before except that sample was not brought to
room temperature for intermittent analysis. Following 60 min grinding, sample was transferred
directly to a freeze dryer precooled to
408C
(Dura-Stop; FTS Systems, Stone Ridge, NY). This
temperature should have been substantially
below Tg of plasticized systems of 8.2% w/w
methanol in IMC, even allowing for nonideal
mixing. Ground samples were subjected to 24 h
drying under vacuum at 50 mTorr. PXRD analysis of ground and dried MeOH identi®ed an X-ray
amorphous product and a Tg value of 39.58C was
measured by DSC analysis. No measurable
weight loss was recorded following DSC analysis,
con®rming that the drying step had been successful. The modi®ed grinding experiment con®rms
that cryogenic grinding of MeOH formed an
amorphous phase containing residual solvent
that required solvent removal under high vacuum
to yield an amorphous phase stable at room
temperature.
Grinding of tBA did not cause signi®cant
changes in PXRD patterns (Figure 3e), suggesting
that the solvate crystal structure remained intact
throughout 60 min of processing. DSC analysis of
499
ground tBA identi®ed a reduction in both temperature and enthalpy of desolvation at an early
grinding time (Figure 4e), but additional grinding
did not cause further changes in desolvation
behavior. The change in DSC nonisothermal desolvation behavior on initial grinding was probably
due to particle size decrease that altered the rate
and/or mechanism of desolvation.26 Thus, DSC
analysis con®rmed that the tBA solvate lattice
remained intact following grinding. The possibility that cryogenic grinding produced a less stable
amorphous phase that immediately recrystallized
prior to PXRD and DSC analysis must be considered. t-Butanol Tg and DCp values could not be
found in the literature so eq. 1 could not be used to
estimate the Tg of a t-butanol/IMC mixture. A
crude estimate of t-butanol Tg can be made using
its Tm of 299 K (268C) and the general rule that Tg/
Tm ˆ 0.7 for small organic glass-formers.27 Tg is
predicted to be in the region of 209 K ( 648C),
indicating that t-butanol could also plasticize IMC
but to a lesser extent than methanol.
tBA was also subjected to a two stage process of
cryogenic grinding (without intermittent temperature increase) and vacuum drying identical
to the process used to produce X-ray amorphous
MeOH. In the case of tBA, combined grinding and
drying failed to produce an amorphous phase,
with tBA solvate found to be intact as shown by
both PXRD and DSC. tBA appeared to resist
desolvation or crystal to amorphous phase transformation on cryogenic grinding.
Isothermal and Nonisothermal Crystallization
Behavior of Ground Amorphous IMC
The isothermal and nonisothermal crystallization
behaviors of 60 min ground amorphous g, a, and d
IMC polymorphs (abbreviated GA-g, -a, and -d)
and 60 min ground and dried amorphous MeOH
(abbreviated GDA-MeOH) are now presented.
Crystallization was also investigated in two meltquenched amorphous IMC samples for reference
purposes. The ®rst reference sample was prepared by grinding < 250 mm melt-quenched
amorphous IMC for 60 min, providing a material
with speci®c surface area and mechanical energy
input that was comparable to ground amorphous
materials. It was noted that the greatest changes
in speci®c surface area took place during the early
stages of grinding. Thus, it was possible to prepare
a second reference sample with comparable
speci®c surface area to all other ground materials
following a much shorter grinding time and so
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500
CROWLEY AND ZOGRAFI
having experienced much lower mechanical
energy input. Six minute grinding of < 250 mm
melt-quenched amorphous IMC achieved this
objective, as seen by the similar speci®c surface
areas for both reference samples (Table 1). The
term ``quenched/ground'' is used to describe
the reference samples.
Isothermal crystallization of X-ray amorphous
IMC samples was studied at 308C and 0% RH,
conditions that are known to yield the g crystal
form from melt-quenched amorphous IMC13,14
unless crystal seeds are present.15 Figure 5a±c
contains plots of percent crystal phase versus
time. Samples displayed in Figure 5a all crystallized to the g polymorph (GA-g, -d, and quenched/
ground reference samples) and percent crystal
phase at the ®nal time points was greater than
90% w/w in each case. Quenched/ground reference samples that were subjected to different
grinding times of 6 and 60 min exhibited comparable crystallization rates, reaching 90% w/w
crystallinity following approximately 45±50 h.
GA-g and GA-d samples both crystallized at faster
rates relative to the quenched/ground IMC references, crystallizing to 90% w/w g IMC after
approximately 13±15 h. Solid lines calculated by
nonlinear regression analysis are shown for each
data set, the details of which are described in the
Discussion section.
In Figure 5b, GA-a crystallization produced
both g and a polymorphs. Only a IMC crystallization was identi®ed at early time points (0±11
h) after which time its rate of formation decreased.
Gamma IMC was ®rst identi®ed at 11 h and
crystallized to a value of 38% w/w after 100 h, by
which time crystallization of both a and g appeared to have slowed greatly. At 100 h, the
concentration of a IMC was measured at 23% w/
w, therefore the total percent crystal phase was in
the region of 60% w/w. PXRD analysis following
2 months aging identi®ed minor changes in the
levels of a (18% w/w) and g (48% w/w), demonstrating that a signi®cant portion of amorphous
phase present in GA-a resisted crystallization
over extended time periods. These ®ndings
are consistent with crystallization data for GA-a
previously reported.14 Crystallization from GDAMeOH also produced a mixture of g and a
(Figure 5c). The rate of g formation was much
greater than that observed for GA-a, although it
was again found that a portion of amorphous
GDA-MeOH did not crystallize after 100 h, with
concentrations of g and a leveled off at values of
83% w/w and 2% w/w, respectively. Thus, samples
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Figure 5. Isothermal crystallization of ground amorphous IMC samples at 308C and 0% RH. (a) Quenched/
ground for 6 min, quenched/ground for 60 min, GA-g
and GA-d. (b) GA-a: ^ crystallizing to g polymorph; }
crystallizing to a polymorph. (c) GDA-MeOH: ^ crystallizing to g polymorph; } crystallizing to a polymorph.
Solid lines represent KJMA kinetics (®t to eq. 2).
CRYOGENIC GRINDING OF IMC POLYMORPHS AND SOLVATES
501
DISCUSSION
that crystallized to produce a mixture of polymorphs both possessed a quantity of amorphous
phase that resisted crystallization during the
time scale of this investigation.
Nonisothermal crystallization data (Tc, Tp, and
DHc values) measured by DSC analysis for ground
and quenched/ground amorphous materials are
reported in Table 2 along with Tg values. Differences in nonisothermal crystallization behavior were evident with Tp values for ground
amorphous materials (GA-g, -a, and -d and GDAMeOH) equal to or less than the quenched/ground
references. A direct correlation between Tp and
speci®c surface area was evident.
On grinding, it was found that Tp varied as the
ratio of crystalline to amorphous phase changed
(Figure 4a±c). Amorphous samples undergoing
isothermal crystallization below Tg will also
contain different ratios of crystalline and amorphous phase. To see if Tp was altered in partially
crystalline sample formed on isothermal crystallization, DSC analysis was performed on GA-a
following different aging times at 308C and
0% RH. DSC data presented in Figure 6 show
an expected decrease in DHc as isothermal
crystallization proceeded, but there was little
variation in Tp. Comparing Figures 4b and 6
demonstrates that the nonisothermal crystallization behavior of partially crystalline samples
varies according to how the partially crystalline
sample was prepared: by generating amorphous
phase in a crystal substrate on grinding or by
isothermal crystallization of an amorphous substrate.
Otsuka et al.19 ®rst demonstrated that low
temperature grinding of g and a IMC produced Xray amorphous material. The current work
extends the earlier ®ndings in reporting that
d IMC and the methanol solvate MeOH are also
rendered X-ray amorphous by such treatment,
although ground solvate requires additional lowtemperature vacuum drying to stabilize the amorphous phase. An increase in speci®c surface area
accompanies crystal to amorphous phase transformation for most materials following 60 min grinding, with the exception of d IMC (see Table 1). It is
assumed that these increases in speci®c surface
area are brought about by reduction in particle
size. The surprising decrease in speci®c surface
area seen on d IMC grinding was dif®cult to
explain. Delta IMC was prepared by isothermal
desolvation of a solvate while all other crystal
substrates (g and a IMC, MeOH and tBA) were
prepared by crystallization from solution. We
speculate that d IMC prepared by desolvation
may possess more coarse crystal surfaces compared to those harvested from solution, a property
that could counter the effect of particle size reduction on speci®c surface area and produce an overall
decrease in this parameter. Alternatively, d IMC
crystals prepared by desolvation may exhibit
different fracture behavior on grinding. Another
explanation is that the presence of low levels of
residual methanol in the d IMC sample interfered
with the N2 gas desorption signal and affected the
accuracy of speci®c surface area calculation.
Table 2. DSC Analysis of 60 min Ground IMC and Quenched/Ground IMC References (6 and 60 min Grinding):
Tg and Nonisothermal Crystallization Behavior (Tc, Tp and DHc). Speci®c Surface Areas of Ground Materials are
Also Listed
Material
Quenched/6 min
ground
Quenched/60 min
ground
GA-g
GA-a
GA-d
GDA-MeOH
Crystallized
Phase
Surface Area
Postgrinding
[m2/g]
Tg [8C]
Tc [8C]
44.3 (0.1)
87.3 (0.1)
94.0 (0)
68.1 (2.7)
a
1.74
43.1 (0.4)
84.8 (0.1)
90.8 (0.1)
72.4 (0.3)
a
2.02
41.8
41.0
41.1
39.5
68.5 (0.1)
67.6 (0.4)
84.7 (0)
72.2 (0.5)
77.6
73.1
90.8
78.4
46.5
45.8
74.2
49.7
a
a
a
a
6.69
12.36
1.71
5.23
(0.6)
(0.1)
(0.9)
(0.3)
Tp [8C]
(0.1)
(0.1)
(0.1)
(0)
DHc [J/g]
(3.0)
(3.2)
(0.1)
(0.6)
Standard deviation values are given in parentheses.
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502
CROWLEY AND ZOGRAFI
Figure 6. DSC analysis of GA-a following isothermal aging at 308C and 0% RH. Only
the temperature region 20±1008C is shown to facilitate visualization of Tg and Tp.
The differing behavior of MeOH and tBA
solvates on grinding is of particular interest.
Grinding of MeOH causes desolvation and formation of a mixture of IMC polymorphs. Grinding
followed by drying of MeOH leads to amorphous
phase formation. In contrast, no phase changes
are observed on tBA grinding or following the twostage grinding and drying process.
Solvate lattice properties are likely to be a
factor in determining susceptibility to amorphous phase formation on grinding. Previous
work has demonstrated that MeOH and tBA
exhibit different rates and mechanisms of isothermal desolvation.21 Optical microscopy demonstrated anisotropic desolvation of MeOH but not
tBA that points to the presence of distinct solvent
channels in the crystal structure of MeOH but not
tBA. The more ready desolvation of MeOH under
isothermal conditions and ease of crystal structure collapse on grinding may be related. Once
amorphous phase is generated on grinding,
different solvents will exert different plasticizing
effects based on the solvent Tg and miscibility of
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 2, FEBRUARY 2002
the two amorphous components. The large differences in Tg and size of methanol and t-butanol
molecules could also contribute to the different
behavior of MeOH and tBA on grinding and on
grinding/drying. Interestingly, 60 min grinding
produces a large increase in tBA speci®c surface
area from 0.17 to 1.13 m2/g, presumably due to
particle size reduction. Changes in DSC desolvation temperature are in agreement with such
particle size decrease. It is anticipated that grinding of tBA leads to formation of defects prior to
crack formation, propagation, and particle fracture, in which case defect formation in tBA is not
accompanied by amorphous phase formation.
Such behavior can be explained using either the
thermodynamic or mechanical destabilization
mechanisms of crystal to amorphous phase transformation. In terms of the thermodynamic mechanism, grinding produces some lattice disorder but
the critical concentration of defects is not reached.
In terms of the mechanical mechanism, the mechanical energy generated on grinding does
not exceed the lattice stability limit. As both
CRYOGENIC GRINDING OF IMC POLYMORPHS AND SOLVATES
transformation theories can be used to explain
these ®ndings, identi®cation of the most applicable mechanism of amorphous to crystal phase
transformation is not possible.
Sixty minute ground amorphous IMC samples
(GA-g, -a, and -d and GDA-MeOH) possess Tg
values ranging from 39.5 to 41.88C, slightly below
the Tg values for the reference quenched/ground
samples of 43.1 and 44.38C. These small differences can be explained by differing enthalpy
relaxation behavior at the glass transition that
affects Tg calculation, indicating variation in
amorphous phase energetics according to processing history but not inherent structural differences. Despite similar Tg values, isothermal
stability of ground amorphous materials differs
both in terms of polymorph selection and rate of
crystallization. Crystallization kinetics are often
described using the Kolmogorov-Johnson-MehlAvrami (KJMA) Equation:28
x ˆ 1
exp… …k…t
t o ††n †
…2†
where x represents the fraction crystallized
following time t and induction time to, yielding a
rate constant k and exponent n that re¯ects the
dimension of transformation. KJMA crystallization rate constants were calculated using
nonlinear regression analysis (SigmaPlot 5TM)
for samples that crystallized to a single polymorph, namely, quenched/ground references
GA-g and GA-d. KJMA k and n values and R2
regression coef®cients are reported in Table 3
solid lines in Figure 5a represent calculated
KJMA kinetic pro®les. In all cases, crystal phase
is present by the ®rst time point and so to is
zero. KJMA crystallization rate constants of
503
3.3 10 2 h 1 and 3.1 10 2 h 1 were calculated
for 6 and 60 min quench/ground reference
samples, respectively, and 1.62 10 1 h 1 and
1.00 10 1 h 1 for GA-g and GA-d, respectively.
Values of n fall between 1.0 and 2.7, a range that
is lower than predicted for classic nucleation
mechanisms (n ˆ 4 for continuous nucleation,
n ˆ 3 for nucleation from a ®xed number of nuclei
or via a site-saturated mechanism).28 Considering
both the wide range of n and the absence of a trend
linking GA-g and GA-d samples and/or quenched/
ground reference samples, mechanistic interpretation of KJMA n is not possible. KJMA n calculated for amorphous state crystallization is often
reduced relative to the predicted value, suggesting deviation from KJMA theory, which demands
that nucleation is random and that nucleation
and growth rate constants do not change during
the isothermal crystallization process.29 Nonrandom nucleation (due to chemical impurities, residual crystal phase, or mechanical strains) or the
changing energy difference between amorphous
and crystalline phases (due to enthalpic relaxation of amorphous phase) may have contributed to
the apparent deviation from KJMA kinetics.
Consequently, eq. 2 is utilized solely for calculation of a crystallization rate constant in this work.
An effect of speci®c surface area on isothermal
crystallization below Tg is known for meltquenched amorphous IMC.15,17 Previous crystallization studies performed at 308C and 0% RH
show that the larger surface area of a triturated
sample screened to < 250 mm gives a KJMA rate
constant of 3.7 10 3 h 1 (KJMA n ˆ 1.2), an
order of magnitude above 2.9 10 4 h 1 (KJMA
n ˆ 2.8) for an undisturbed ®lm. KJMA rate
constants for the quenched/ground reference
Table 3. KJMA Analysis of Isothermal Crystallization Data Measured at 308C and 0% RH for 60 Min Ground
Amorphous IMC and Quenched/Ground IMC References (6 and 60 Min Grinding). Speci®c Surface Area Data for
Amorphous Samples are Also Shown
Material
Quenched/6 min
ground
Quenched/60 min
ground
GA-g
GA-a
GA-d
GDA-MeOH
Crystallized
Phase
KJMA k
KJMA n
KJMA R2
Surface Area
Postgrinding [m2/g]
g
0.033
1.7
0.990
1.74
g
0.031
2.0
0.996
2.02
g
a and g
g
a and g
0.162
n.a.
0.100
n.a.
1.0
n.a.
2.7
n.a.
0.971
n.a.
0.993
n.a.
6.69
12.36
1.71
5.23
n.a., not applicable due to g and a cocrystallization.
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 2, FEBRUARY 2002
504
CROWLEY AND ZOGRAFI
samples reported in this work are in agreement
with the earlier studies, with further reduction in
particle size causing further increase in k. These
results are to be expected as IMC crystallization
at 308C and 0% RH is known to occur via surface
nucleation.16 Different grinding times of 6 and 60
min have little effect on KJMA k for quenched/
ground reference samples, demonstrating that
the lengthy grinding process does not introduce
chemical impurities or create high energy surfaces that affect the site or rate of nucleation in
ground amorphous IMC.
Differences in speci®c surface area failed to
explain the differences in crystallization rates
between ground amorphous and quenched/
ground reference samples. There is a threefold
difference in KJMA k between GA-d and both
reference samples despite comparable speci®c
surface areas (1.71 vs. 1.74±2.02 m2/g). One
possible explanation is that small quantities of
crystal phase are present in the ground amorphous samples below the limit of detection of
PXRD. Such residual crystal phase can provide
secondary nuclei for the growth of the same
polymorphic form or heterogeneous nuclei for
the growth of a different polymorph. We hypothesize that formation of g IMC on isothermal crystallization of GA-g occurs via secondary nucleation of
undetected g phase. In the case of GA-d, residual d
IMC acts as an heterogeneous nucleating agent of
g. Alternatively, residual d IMC undergoes a
polymorphic change to g and thus also affects
crystallization by secondary nucleation. It was not
possible to prove the presence of such residual
crystal phase as we know of no technique capable
of identifying less than 2% w/w crystal phase in
amorphous phase. Microscopic examination using
cross-polarized light failed to identify crystal phase
although this method was limited by the small
particle size and agglomerated nature of ground
amorphous samples, which reduced the intensity
of transmitted light.
KJMA k values were not calculated for GA-a or
GDA-MeOH as these samples form a mixture of
polymorphs on crystallization and so neither
polymorph approaches x & 1. Visual inspection
of Figure 5a±c suggests that GA-a has the slowest
overall rate of crystallization among the samples
studied despite possessing the largest speci®c
surface area. The formation of a IMC at early time
points followed by g crystallization can again be
explained by the presence of undetected crystal
phase. In this instance, residual a IMC in GA-a
appears to cause secondary nucleation of a to
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 2, FEBRUARY 2002
detectable levels. The formation of a delays the
onset of g crystallization and also reduces its rate
of crystallization, suggesting that the mechanism
of g crystallization has changed. Bulk nucleation
of g has been observed below Tg in quenched
amorphous IMC but at lower rates compared to
surface nucleation.16 It is possible that a formation reduces or prevents surface nucleation and so
crystallization of g can only occur via the slower
bulk mechanism. If true, we have an interesting
scenario whereby the seeded system exhibits
greater stability than the nonseeded system due
to redirection of the route of crystallization.
Isothermal crystallization of GA-a does not
form a completely crystalline sample even following 2 month storage at 308C and 0% RH. The fact
that a portion of amorphous phase fails to
crystallize in this sample is con®rmed by DSC
analysis after 2 months aging, recording a Tg of
51.68C. The increase in Tg from 41.0 to 51.68C (a
trend also apparent in Figure 6) represents
enthalpic relaxation of amorphous IMC to a lower
energy state. The decreased energy difference
between amorphous and crystalline states that
drives crystallization would be expected to reduce
the crystallization rate but not to the extent that
remaining amorphous phase is stabilized. It is
known that amorphous IMC contains a wide
distribution of relaxation times30 that are thought
to arise from heterogeneous dynamic behavior.
Such dynamics imply the presence of nanoscale
domains exhibiting different levels of molecular
motion.31 Crystallization from a heterogeneous
amorphous IMC phase could be favored in regions
where molecular mobility is greater, leaving
uncrystallized phase with lower molecular mobility and so greater physical stability. The longer
relaxation times of the remaining amorphous
phase would produce a higher Tg. An alternative
explanation for the stabilization of residual
amorphous phase in GA-a is that the cocrystallized mixture of g and a generates elastic
strains at amorphous/crystal interfaces that alter
the interfacial energies and impede further
crystallization.32
DSC analysis of amorphous materials provides
important information regarding glass structure
(via glass transition behavior) and glass stability
(via nonisothermal crystallization behavior). Tp
represents the temperature at which a known
percentage of transformation has taken place
(approximately 63%)33,34 and so can be used to
assess nonisothermal stability provided a constant heating rate is used. DSC data for ground
CRYOGENIC GRINDING OF IMC POLYMORPHS AND SOLVATES
amorphous IMC samples given in Table 2 show
variation in Tp that directly correlates with
speci®c surface area. Samples with a larger
speci®c surface area have a lower Tp so they
are less stable. This relationship is the same as
that seen for quenched amorphous IMC under
isothermal conditions but not for ground amorphous samples. The factor that overrides the
effect of speci®c surface area on isothermal
crystallization of ground amorphous samples
(thought to be residual crystal phase) has no
effect on the rate of nonisothermal crystallization.
One reason for this could be that different IMC
polymorphs crystallize above and below Tg
(g < Tg > a).13±16 Crystallization of g, which has
been shown to occur via both surface and bulk
nucleation below Tg, may be more readily in¯uenced by residual crystal phase than a crystallization above Tg (for which only surface
nucleation has been observed).16 It was not possible to identify the polymorphic form that crystallizes under nonisothermal conditions from single
DSC heating analyses because further phase
transformations took place between Tp and Tm
resulting in mixtures of a and g detected in the
melting region. Changes in heating rate do not
overcome this problem so it is not possible to
interpret nonisothermal crystallization behavior
from nonisothermal melting behavior. Additional
DSC experiments were performed using open
pans with the intention of isolating the crystallized phase, adjusting the temperature program
so that the heating ramp was terminated at a
temperature between 5 and 108C above Tp (close
to the crystallization offset temperature) followed
by rapid cooling to room temperature at 408C/min.
The solid product of nonisothermal crystallization
was shown to be a IMC for each ground amorphous and quenched/ground reference sample.
Therefore, the polymorph formed under nonisothermal conditions also appears to be insensitive to the property of ground amorphous IMC
that affects isothermal crystallization.
DSC measurements presented in Figure 6 were
carried out at different time points during the
isothermal crystallization of GA-a, so they comprise mixtures of amorphous and crystalline
phase. Both Tp and the shape of crystallization
exotherms were unaffected by increasing isothermal aging time, a variable that increases the
quantity of crystalline phase in the starting sample. It is interesting to compare this ®nding to the
DSC data obtained at different grinding times as
these samples are also mixtures of crystal and
505
amorphous phase but are generated by a different
route, namely, generating amorphous phase in a
crystalline sample. Increasing grinding time
causes a rise in Tp despite the fact that speci®c
surface area is also increasing on grinding
(Figure 4a±c). These data indicate that partially
crystalline mixtures formed by grinding have
reduced nonisothermal stability compared to
partially crystalline samples formed on aging.
The possible explanations for the reduced nonisothermal stability of partially crystalline samples generated by grinding are numerous,
including differences in crystal size, shape, and
surface properties, or lattice defect concentration
that promotes seeding effects or varying degrees
of relaxation of the amorphous component. Traditionally, prediction of the behavior of low levels
of amorphous phase in intimate contact with
crystal phase is based upon the properties of
an X-ray amorphous material often prepared by a
method other than grinding. DSC data presented in this work demonstrate that such approaches may be inappropriate as the behavior of
small quantities of amorphous phase created by
grinding differs from the behavior of X-ray
amorphous phase prepared by grinding or other
methods.
CONCLUSIONS
We have demonstrated that three polymorphs of
IMC and IMC methanolate can be made X-ray
amorphous by cryogenic grinding. Solvent
removal under vacuum was required to stabilize
GDA-MeOH, probably by increasing the Tg of
amorphous IMC plasticized by residual methanol.
The solvate structure of IMC tBA remained intact
on grinding and also on grinding followed by
vacuum drying, demonstrating that crystal-amorphous transition on grinding does not readily
occur for all crystal forms of a drug molecule.
Properties of both the solvate lattice and solvent
are likely to determine solvate susceptibility to
amorphous phase formation on grinding. Comparison of X-ray amorphous IMC samples prepared by crystal grinding and quenched/ground
references demonstrated comparable Tg values
and thus comparable amorphous phase structure.
Undetected crystal structure was thought to determine the isothermal crystallization behavior of
ground amorphous samples below Tg, in most
cases enhancing crystallization rates compared to
quenched/ground reference samples via a seeding
JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 91, NO. 2, FEBRUARY 2002
506
CROWLEY AND ZOGRAFI
effect. Such an effect was not evident under
nonisothermal conditions, with peak nonisothermal crystallization temperature correlating with
speci®c surface area. It is concluded that variation
in the physical stability of amorphous IMC generated by grinding and by quench melting is not
indicative of different amorphous phase structure
but instead re¯ects the sensitivity of the nucleation step to other factors, primarily residual
crystal structure and speci®c surface area.
ACKNOWLEDGMENTS
The Purdue-Wisconsin Program on the Physical
and Chemical Stability of Pharmaceutical Solids
is gratefully acknowledged for ®nancial support.
Professor Juan DePablo, Department of Chemical
Engineering, UW-Madison, and group members
are thanked for access to PXRD equipment.
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