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New News about an Old Drug Investigations on the Polymorphism of Triamcinolone Acetonide.

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Angewandte
Chemie
Drug Polymorphism
DOI: 10.1002/anie.200601468
New News about an Old Drug: Investigations on
the Polymorphism of Triamcinolone Acetonide**
Christian N
ther* and Inke Jeß
Polymorphism, defined as the ability of a compound to exist
in more than one crystalline modification, is a widespread
phenomenon and of extreme importance in a number of areas
like material science and pharmaceutical development.[1, 2]
For polymorphic drugs several aspects are of importance:[2]
Before a new drug is approved by the authorities for sale, it is
subjected to a battery of tests, also including investigations of
its polymorphism. In addition, information on the influence of
a particular corresponding phase on the chemical, biological,
and physical properties of a drug are needed, and under
certain circumstances different modifications can be patented
separately.
The glucocorticoid triamcinolone acetonide (1) is an
extremely versatile and effective drug and has been used, for
example, for treating autoimmune diseases for several years.[3]
the polymorphism of this drug, and the only crystal structure
available in the CSD is that of the methanol solvate.[4, 5]
We started our research by recording powder diffraction
data for several batches of commercially available triamcinolone acetonide prepared by sterile filtration.[6, 7] While most
batches were found to contain the form used in therapy
(modification I), one batch exhibited an additional reflection
indicating the presence of a second form. To determine the
thermodynamically most stable modification at room temperature, we stirred suspensions of the crystalline form of the
drug in several solvents, and the products were examined by
powder diffraction. In most solvents, for example, acetone,
modification I was obtained, whereas in ethanol a new and
hitherto unknown modification was discovered (form II).
Interestingly, this form corresponds to that observed as a
contamination in one of the batches investigated. Modification I crystallizes in different morphologies, whereas form II
crystallizes mostly as plates (Figure 1).
Figure 1. Microscopic images of crystals of modifications I (left) and II
(right).
In most cases it is administered as a suspension of a crystalline
form and hence marketed in glass ampules. In the preparation
of its dosage form the drug must be sterilized, and different
methods exist. Sterile filtration is a very interesting method in
which the compound is dissolved in a given solvent, filtered
off, recrystallized, and dried. After the drug has been ground
into a fine powder it must be guaranteed that the phase
formed is exactly that used in therapy or preferred by the
producer. Surprisingly there are very few investigations on
Differential scanning calorimetry (DSC) shows that
form II melts at about 288 8C without any further transformation, while the DSC curve of form I exhibits a very
broad signal only in a few cases before its melting point at
288 8C (Figure 2).[7] The powder pattern of the residue of
modification I obtained at 220 8C unambiguously shows the
formation of form II. Thermogravimetric (TG) measure-
[*] Dr. C. N+ther, I. Jeß
Institut f.r Anorganische Chemie
Christian-Albrechts-Universit+t zu Kiel
Olshausenstrasse 40, 24098 Kiel (Germany)
Fax: (+ 49) 431-880-1520
E-mail: cnaether@ac.uni-kiel.de
[**] This work was supported by the State of Schleswig-Holstein. We
thank Prof. Dr. Wolfgang Bensch for allowing us to use his
equipment and Dr. Michael Bolte, Institute of Inorganic Chemistry
Frankfurt, for collecting the data of modification II.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2006, 45, 6381 –6383
Figure 2. DSC curve of modification I (Tp = peak temperature,
Te = onset temperature).
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6381
Communications
ments of form I using small sample weights did not show
appreciable weight loss.
Crystal structure analysis of I shows that it crystallizes in
space group R3.[8] In the structure the molecules are
connected by O H···O hydrogen bonds into layers, which
are parallel to (001). This arrangement leads to the formation
of trigonal channels in the direction of [001], within which two
small residual electron density peaks were found after
refinement which were assigned to water (Figure 3). Form II
crystallizes in space group P41212 with the molecules connected by O H···O hydrogen bonds into layers parallel to
(001) (Figure 3).[8] In contrast to form I a dense structure is
observed.
As the structural results indicated that form I is a hydrate,
transformation of I into II in ethanol can be explained if one
assumes that the dry solvent dehydrates form I. To prove this,
a suspension of crystalline I was stirred in ethanol until
form II formed. Afterwards a few drops of water were added,
and the suspension was stirred for a few hours. As expected,
the powder diffraction pattern of the product thus obtained
corresponds to that of form I. In addition, I can also be
transformed to II by evacuation at room temperature or by
storage at about 100 8C. TG measurements of form I in
combination with mass spectrometry using large sample
weights show clearly that this form contains 1.7 % water
(Figure 4).[7] Further investigations using microgravimetry
under controlled humidity add credence to our findings.
Figure 4. DTG, TG and MS trend-scan curves of I (m/z 18 (water and
triamcinolone acetonide); m/z 43 (triamcinolone acetonide). MID:
multiple-ion detection.
Figure 3. Crystal structures of modifications I (left) and II (right) (ellipsoids at 50 % probability).
6382
www.angewandte.org
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 6381 –6383
Angewandte
Chemie
In summary, our investigations clearly show that the
modification of triamcinolone acetonide used in therapy is a
hydrate and contains a small amount of water, which is
responsible for the stability of this form. When the water is
removed, a transformation into the new and hitherto unkown
form II was observed. It is to be noted that the melting point
given in the patent of this drug does not correspond to that of
I; it actually corresponds to that of II. Based on our results the
entire process of sterile filtration was improved so as to yield
form I as a pure phase. Since this drug is mainly used as a
suspension of the crystalline form in water, our results
indicate that II can also be used as it will transform in water
into modification I. We note, however, that the stability of the
suspension depends, for example, on the particle size, which is
difficult to control if the hydrate is formed in situ by
transformation of modification II.
Received: April 13, 2006
Published online: August 29, 2006
.
Keywords: drugs · hydrates · polymorphism ·
structure elucidation · transition behavior
[1] a) “Crystal Engineering”: in Mater. Sci. Monogr. (Ed.: G. R.
Desiraju), Elsevier, Amsterdam, 198; b) J. Bernstein in Organic
Solid State Chemistry: Conformational Polymorphism (Ed.: G. R.
Desiraju), Elsevier, Amsterdam, 1987, p. 471; c) J. Bernstein, R.
Davey, O. Henck, Angew. Chem. 1999, 111, 3646 – 3669; Angew.
Chem. Int. Ed. 1999, 38, 3440 – 3461; d) J. Bernstein in X-Ray
Crystallography and Drug Action (Eds.: A. S. Horn, C. J.
De Ranter), Clarendon, Oxford, 1984, p. 23; e) J. D. Dunitz,
Acta Crystallogr. Sect. B 1995, 51, 619 – 631; f) J. D. Dunitz, J.
Bernstein, Acc. Chem. Res. 1995, 28, 193 – 200; g) C. NDther, I.
Jeß, Z. Havlas, N. Nagel, M. Bolte, S. Nick, Solid State Sci. 2002, 4,
859 – 871.
[2] a) Polymorphism in Pharmaceutical Solids (Ed.: H. G. Brittain),
Marcel Dekker, New York, 1999; b) S. R. Vippagunta, H. G.
Brittain, D. J. W. Grant, Adv. Drug Delivery Rev. 2001, 48, 3 – 26;
c) H. G. Brittain, Am. Pharm. Rev. 2000, 3, 67 – 68; d) K. R.
Morris, U. J. Griesser, C. J. Eckhardt, J. G. Stowell, Adv. Drug
Delivery Rev. 2001, 48, 91 – 114; e) B. Bechtlov, S. Nordhoff, J.
Ulrich, Cryst. Res. Technol. 2001, 36, 1315 – 1328.
[3] a) H. J. Hatz, Glucocorticoide, Wissenschaftliche Verlagsgesellschaft, Stuttgart, 2005; b) P. J. Barnes, Clin. Sci. 1998, 94, 557 –
572; c) F. Buttgereit, Z. Rheumatol. 2000, 59, 119 – 123; d) E.
Falkenstein, H. C. Tilmann, M. Christ, M. Feuring, M. Wehling,
Pharmacol. Rev. 2000, 52, 513 – 556.
[4] a) Analytical Profiles of Drug Substances, Vol. 11 (Ed.: K.
Florey), Academic Press, New York, 1982; b) J. Fried, A.
Borman, W. B. Kessler, P. Grabowich, E. F. Sabo, J. Am. Chem.
Soc. 1958, 80, 2338 – 2339; c) S. Bernstein, R. H. Lenhard, W. S.
Allen, M. Heller, R. Littel, S. M. Stolar, L. Feldman, R. H. Blank,
J. Am. Chem. Soc. 1959, 81, 1689 – 1696; d) M. Heller, S. Stolar, S.
Bernstein, J. Org. Chem. 1961, 26, 5044 – 5046.
[5] a) E. Surcouf, Acta Crystallogr. Sect. B 1979, 35, 2638 – 2642; b) C.
NDther, I. Jeß, Acta Crystallogr. Sect. E 2005, 62, 0960 – 0962.
[6] The sterilzed material was obtained from HPP Pharmaceutical
Products (Magdeburg, Germany).
[7] X-Ray powder diffraction experiments were performed using a
STOE STADI P transmission powder diffractometer (MoKa
radiation) equipped with a position-sensitive detector (scan
range: 5–458) from STOE & CIE. DSC experiments were
performed on a DSC 204/1/F instrument from Netzsch. DTAAngew. Chem. Int. Ed. 2006, 45, 6381 –6383
TG-MS measurements were performed using the STA-409CD
with Skimmer coupling from Netzsch, which is equipped with a
quadrupole mass spectrometer from Balzers. The MS measurements were performed in analog and trend-scan mode (Al2O3
crucibles, dynamic helium atmosphere, heating rate: 4 K min 1).
(Mw = 441.89),
a = b = 17.684(1),
c=
[8] I:
C24H31.82FO6.41
18.143(1) P, V = 4913.6(4) P3 (170 K), 1calcd = 1.344 g cm 3, trigonal, R3, Z = 9, STOE IPDS-1, MoKa radiation, m = 0.102 mm 1,
9159 measured (58 2 q 568) and 2628 independent reflections
(Rint = 0.0299 %), structure solution: SHELXS-97, structure
refinement: SHELXL-97, 295 parameters, R1 for 2491 reflections
with I > 2 s (I) = 0.0298, wR2 for all data = 0.0778, GOF = 1.055,
residual electron density: 0.22/ 0.20 e P 3. II: C24H31FO6 (Mw =
434.49), a = b = 9.1692(4) P, c = 49.946(4) P, V = 4199.1(4) P3
(170 K), 1calcd = 1.375 g cm 3, tetragonal, P41212, Z = 8, STOE
IPDS-2, MoKa radiation, m = 0.103 mm 1, 24 250 measured (58 2 q 518) and 2418 independent reflections (Rint = 0.1099 %),
structure solution: SHELXS-97, structure refinement:
SHELXL-97), 287 parameters, R1 for 1601 reflections with I >
2 s (I) = 0.0352, wR2 for all data = 0.0698, GOF = 0.834, residual
electron density: 0.15/ 0.15 e P 3. Non-hydrogen atoms were
refined anisotropic. C H and O H hydrogen atoms were
positioned with idealized geometry (the position was optimized
for OH) and refined using a riding model. The hydrogen atoms of
water in form I were not located. Friedel opposites were merged
in the refinement. CCDC 604474 (I) and CCDC 604475 (II)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
6383
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