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This journal is c The Royal Society of Chemistry 2011 Chem. Commun.
Cite this: DOI: 10.1039/c1cc16301a
Fast crystallization of organic glass formers
Tanja Gnutzmann,ab
Klaus Rademann*band Franziska Emmerling*
a
Received 10th October 2011, Accepted 4th November 2011
DOI: 10.1039/c1cc16301a
An unusually fast crystallization of the organic glass former
nifedipine has been observed. The crystallization process, starting
from an amorphous film to crystalline material, was investigated by
time resolved Raman microspectroscopy. The crystallization rates
of the initially crystallizing metastable b-form are four orders of
magnitude higher than those of previous studies.
In many different fields of materials science, the crystallization of
metallic, silicate, and organic glass formers is investigated to
understand the stability of materials and their various
polymorphs. This is particularly true for organic compounds.
Recently, the new phenomena of diffusionless and surface-
enhanced crystallization have been recognized, indicating that
crystallization processes can be much faster than processes driven
only by bulk diffusion.1–6 Furthermore, organic compounds are
commonly known for the phenomena of polymorphism and
polyamorphism.7–10 For pharmaceutical applications both aspects
are of fundamental importance, for features such as shelf life,
bioavailability and solubility.11,12 Knowledge of basic processes
and mechanisms behind polymorphic conversions of one form
into another is rather limited. A prominent example for this lack
of knowledge is the compound Ritonavir, which was intensively
studied due to the ‘disappearing’ of its polymorph form I.13
Herein, we report an even faster conversion with crystallization
rates three to four orders of magnitude higher than those reported
by Zhu et al. for the surface-enhanced crystallization.1 In a pilot
study, we investigated the crystallization of the organic compound
nifedipine by time resolved Raman spectroscopy. Nifedipine
(4-(2-nitrophenyl)-2,6-dimethyl-3,5-dicarbomethoxy-1,4-dihydro-
pyridine, see Fig. 1) is an antihypertensive and vasodilating drug
of dihydropyridine type.14 This calcium channel blocker has been
studied intensively as it forms one amorphous and at least three
crystalline modifications.1,15–20 Amongst these are the thermo-
dynamically most stable a- and the metastable b-modification.21,22
In a typical experiment, 10 mL of a freshly prepared 185 mM
solution of nifedipine (Z98%, Sigma Aldrich, CAS 21829-25-4)
in acetone were pipetted on a glass slide (1 mm, Menzel,
Braunschweig, Germany) and left for drying. The concentration
was chosen significantly below the saturation point, to avoid the
presence of any crystalline material in the starting solution. After
the solvent has evaporated completely, a thin glassy film of
Fig. 1 Structure of nifedipine (4-(2-nitrophenyl)-2,6-dimethyl-3,5-
dicarbomethoxy-1,4-dihydropyridine).
Fig. 2 Time resolved Raman spectra of a nifedipine sample measured
during the growth of the crystallites starting with the amorphous film
(bottom, 0 min) to the thermodynamically stable crystalline material
(top). The spectra show the rapid evolution of the b-modification (1 min)
and the subsequent conversion to the a-nifedipine (11.5 to 20 min).
a BAM Federal Institute for Materials Research and Testing,Richard-Willstaetter-Strasse 11, 12489 Berlin, Germany.E-mail: [email protected]; Fax: +49 30 8104 1137;Tel: +49 30 8104 1133
bDepartment of Chemistry, Humboldt Universitaet zu Berlin,Brook-Taylor-Strasse 2, 12489 Berlin, Germany.E-mail: [email protected];Fax: +49 30 2093 5559; Tel: +49 30 2093 5565
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Chem. Commun. This journal is c The Royal Society of Chemistry 2011
nifedipine remained on the surface which was identified as
amorphous nifedipine by Raman spectroscopy. The Raman
measurements were performed using a Ramanmicrospectroscopic
setup (LabRam, Horiba-Jobin-Yvon, Bensheim, Germany)
equipped with a BX41 microscope (Olympus, Hamburg, Germany)
and a nitrogen-cooled CCD detector (256 � 1024 pixels). To reject
the Rayleigh scattered light a Notch filter was used. A helium–neon
laser emitting at 633 nm was used for excitation. The spectra were
recorded every 30 seconds with an irradiance of 2.9 � 104 W cm�2
on the sample. An acquisition time of 5 � 5 s was chosen. After
several minutes the crystallization started statistically distributed over
the surface of the amorphous nifedipine film. The transformation of
the amorphous to the b-modification was followed in situ. The time
resolved Raman measurements were started on an amorphous part
of the film. The process was then monitored till no more changes
proceeded.
The Raman spectra displayed in Fig. 2 show the crystallization
process of an amorphous film leading to the thermodynamically
stable crystalline material measured on the same spot. The first two
spectra (until 0.5 minutes) display the Raman signals of the
amorphous (glassy) form, abbreviated as g-nifedipine.16 The spec-
tra collected between 1 minute and 11.5 minutes can be assigned to
the b-modification. No changes were detected during this interval
and therefore these spectra are omitted in Fig. 2. The spectrum
collected after 12 minutes exhibits contributions from both poly-
morphs, b- and a-nifedipine. After 12.5 minutes the spectra are
dominated by the signals of the pure a-modification and no further
changes were observed. The crystallization follows the Ostwald rule
of stages as the amorphous film crystallizes first to the metastable
b-polymorph which then transforms to the stable a-modification.
The conversion of the metastable b-modification to the
thermodynamically stable a-modification can also be observed
by light microscopy. Fig. 3 displays the microscopic images
taken sequentially during the Raman measurements in the
interval of 30 seconds. Within this time frame, the images
show the rapid propagation of a distinct crystallization front.
The b-modification (light yellow crystals) is converted to the
stable a-modification (dark crystals). The sharply defined
crystallization front propagates with 1.9 � 0.1 mm s�1.
The assignment of the different modifications (see Fig. 3) is
unambiguous by the characteristic C–C–O-vibration of the
ester groups at 1215 cm�1 (b) and 1225 cm�1 (a) as well as theCQC stretching vibration at 1652 cm�1 (b), respectively,
1648 cm�1 (a). Furthermore, the ester bond stretching modes
in the wave number region between 1660 and 1710 cm�1 can
be used for differentiation.16 The CQO stretching vibration at
1680 cm�1 with high relative intensity is characteristic for the
a-modification while the spectra of the b-form display signals
at 1663 cm�1, 1675 cm�1 and 1701 cm�1.
The growth rate of the initially formed b-polymorph was
investigated in detail using light microscopy (Leica MZ 12.5,
Leica Microsystems GmbH, Wetzlar, Germany, equipped
with a hot stage and a 2048 � 1536 pixel camera). At different
temperatures the crystal growth rate was determined. A heating
rate of 5 1C per minute was applied and images were taken every
5 s. In each experiment, a thin film of nifedipine was prepared on
a glass slide as described before. After the crystallization started,
the propagation of one crystallization front was monitored.
The deduced crystal growth rates are shown in Fig. 4 in
comparison to the crystal growth rates reported by Zhu et al.1
In their publication, the authors proved the existence of surface-
enhanced crystallization of nifedipine in comparison to the
crystallization of the bulk material and gold coated nifedipine
surfaces. Our investigations lead reproducibly to growth rates in
Fig. 3 Light microscope images of the crystal growth of nifedipine (A–F, total width and height of a single image: 770 mm � 550 mm) and Raman
spectra recorded before (top) and after (bottom) the crystallization front as indicated by the arrows. The assignment of the crystal phases and the
respective wave numbers are given in the spectra.
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This journal is c The Royal Society of Chemistry 2011 Chem. Commun.
the region of 10�6 m s�1 for the crystallization of the
b-modification from thin films of g-nifedipine around the glass
transition temperature (Tg = 315 K).
This rate is four orders of magnitude higher than those
reported by Zhu et al. Also the conversion of b-modification
to the final a-form is as large as 10�6 m s�1. Both observations
have implications for a long sought molecular level interpreta-
tion of diffusionless crystal growth processes observed for
organic glass formers.4–6
The two rapid conversions (g to b and b to a) are too fast by
many orders of magnitude for employing any physical move of
the entire molecular building blocks via classical diffusion. The
two high rates suggest instead the existence of a pre-ordered
physical arrangement of nifedipine entities even for the under-
cooled liquid (g-nifedipine). In this case, only an intra-
molecular rotation of a side chain would be required for
g-nifedipine to crystallize rapidly into a more stable inter-
molecular network. As a fact, theoretical calculations show
that such rotations of side chains have low barriers with
activation energies of a few kJ mol�1.23 Also a detailed
analysis of the molecular packing in the b-form as compared
to the a-form indicates directly that the densities and unit cell
volumes are nearly the same, as reported earlier, to within
1%.19 An overlay of the molecules in both crystalline forms,
a and b, strongly corroborates the point of view that the
intermolecular arrangements differ only by side chain inter
actions and the two fast processes are enabled by pre-ordering.
Summarizing, we report unexpected high crystallization
rates from an amorphous thin film nifedipine. This phenomenon
is of importance with respect to pharmaceutical applications
as poorly soluble active pharmaceutical ingredients are often
administered in their amorphous form. Therefore the stability
of the amorphous form against crystallization and the possibility
of competitive fast crystallization in solution, film, and bulk
material need to be characterized in detail. Further studies using
different solvents and pharmaceuticals are currently in process.
We gratefully acknowledge financial support by the Deutsche
Forschungsgemeinschaft through SPP 1415 (Crystalline non-
equilibrium phases and polymorphs): Ra 494/15-1, and
Em 198/4-1.
Notes and references
1 L. Zhu, L. Wong and L. Yu,Mol. Pharmaceutics, 2008, 5, 921–926.2 Y. Sun, L. Zhu, K. L. Kearns, M. D. Ediger and L. Yu, Proc. Natl.Acad. Sci. U. S. A., 2011, 108, 5990–5995.
3 L. Zhu, C. W. Brian, S. F. Swallen, P. T. Straus, M. D. Ediger andL. Yu, Phys. Rev. Lett., 2011, 106, 256103.
4 Y. Sun, H. Xi, M. D. Ediger and L. Yu, J. Phys. Chem. B, 2008,112, 661–664.
5 Y. Sun, H. M. Xi, S. Chen, M. D. Ediger and L. Yu, J. Phys.Chem. B, 2008, 112, 5594–5601.
6 Y. Sun, H. Xi, M. D. Ediger, R. Richert and L. Yu, J. Chem. Phys.,2009, 131, 074506.
7 T. L. Threlfall, Analyst, 1995, 120, 2435–2460.8 L. Yu, Acc. Chem. Res., 2010, 43, 1257–1266.9 J. Senker and E. A. Rossler, Chem. Geol., 2001, 174, 143–156.10 C. A. Angell, Proc. Natl. Acad. Sci. U. S. A., 1995, 92, 6675–6682.11 J. D. Dunitz and J. Bernstein, Acc. Chem. Res., 1995, 28, 193–200.12 R. Hilfiker, Polymorphism: in the Pharmaceutical Industry, Wiley,
2006.13 J. Bauer, S. Spanton, R. Henry, J. Quick, W. Dziki, W. Porter and
J. Morris, Pharm. Res., 2001, 18, 859–866.14 W. Vater, K. Schlossmann, K. Stoepel, F. Hoffmeister,
G. Kroneberg, W. Puls, H. Kaller, A. Oberdorf and K. Meng,Arzneim.-Forsch., 1972, 22, 1–14.
15 M. R. Caira, Y. Robbertse, J. J. Bergh, M. N. Song and M. M. DeVilliers, J. Pharm. Sci., 2003, 92, 2519–2533.
16 K. L. A. Chan, O. S. Fleming, S. G. Kazarian, D. Vassou,G. D. Chryssikos and V. Gionis, J. Raman Spectrosc., 2004, 35,353–359.
17 D. Grooff, M. M. De Villiers and W. Liebenberg, Thermochim.Acta, 2007, 454, 33–42.
18 H. Ishida, T. A. Wu and L. A. Yu, J. Pharm. Sci., 2007, 96,1131–1138.
19 M. Klimakow, J. Leiterer, J. Kneipp, E. Rossler, U. Panne,K. Rademann and F. Emmerling, Langmuir, 2010, 26,11233–11237.
20 M. Klimakow, K. Rademann and F. Emmerling, Cryst. GrowthDes., 2010, 10, 2693–2698.
21 A. M. Triggle, E. Shefter and D. J. Triggle, J. Med. Chem., 1980,23, 1442–1445.
22 M. Bortolotti, I. Lonardelli and G. Pepponi, Acta Crystallogr.,Sect. B: Struct. Sci., 2011, 67, 357–364.
23 A. Heidenreich, private communication.
Fig. 4 Growth rate of nifedipine crystals as a function of temperature.
The bluish colored data points denote conversion rates derived from
repeated experiments. The reddish data points have been reproduced
from ref. 1. These data points show the crystallization of bulk crystals,
crystals grown on the surface of bulk nifedipine, and crystals grown on
the gold coated surface of bulk nifedipine.
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