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: franziska.emmerling@bam.de; 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: klaus.rademann@chemie.hu-berlin.de;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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