Investigations on the polymorphism and pseudopolymorphism of clobetasone butyrate

Article abstract of DOI:10.1135/cccc2011027

Clobetasone butyrate was investigated for polymorphism and pseudopolymorphism. Solvent mediated conversion experiments reveal that the commercially available form I represent the thermodynamically most stable form at room temperature and DSC measurements shows that it should also be the most stable form until melting. Form I crystallizes in space group P2 ₁2₁2₁ with three crystallographically independent molecules of similar conformation. From methanol an additional pseudo polymorphic form was discovered. In the crystal structure (space group P2₁2₁2₁) the solvent molecules are connected to the clobetasone butyrate molecules by O-H···O hydrogen bonding. Investigations of the solvate using thermogravimetry, differential thermoanalysis as well as differential scanning calorimetry proves, that on solvent removal an amorphous form is obtained that crystallizes into form I on further heating.

Full text of DOI:10.1135/cccc2011027

Investigations on the Polymorphism
553
INVESTIGATIONS ON THE POLYMORPHISM AND
PSEUDOPOLYMORPHISM OF CLOBETASONE BUTYRATE
1,
2
Christian NÄTHER * and Inke JEß
Institut für Anorganische Chemie der Christian-Albrechts-Universität zu Kiel,
1
2
Max.-Eyth.-Str. 2, 24118 Kiel, Germany; e-mail: cnaether@ac.uni-kiel.de, ijess@ac.uni-kiel.de
Received January 31, 2011
Accepted March 18,2011
Published online April 29, 2011
Dedicated to Dr. Zdeněk Havlas on the occasion of his 60th birthday.
Clobetasone butyrate was investigated for polymorphism and pseudopolymorphism. Solvent
mediated conversion experiments reveal that the commercially available form I represent
the thermodynamically most stable form at room temperature and DSC measurements
shows that it should also be the most stable form until melting. Form I crystallizes in space
group P212121 with three crystallographically independent molecules of similar conforma-
tion. From methanol an additional pseudo polymorphic form was discovered. In the crystal
structure (space group P212121) the solvent molecules are connected to the clobetasone bu-
tyrate molecules by O–H···O hydrogen bonding. Investigations of the solvate using
thermogravimetry, differential thermoanalysis as well as differential scanning calorimetry
proves, that on solvent removal an amorphous form is obtained that crystallizes into form I
on further heating.
Keywords: Clobetasone butyrate; Polymorphism; Pseudopolymorphism; Crystal structures;
Thermoanalytical methods; Crystal growth; Calorimetry; X-ray diffraction.
Polymorphism, which is defined as the ability of a compound to exist in
more than one crystalline modification is a widespread phenomenon and
of particular importance in a number of areas like e.g. pharmaceutical de-
velopment or material science1–16. In pharmaceutical sciences several as-
pects are of importance. This includes requests by the authority responsible
for approval of a new drug, for which also investigations on the polymor-
phism of the active ingredient are needed, information on the influence of
the corresponding phase onto the chemical, biological or physical proper-
ties of a drug and aspects of the patent law2–4. Moreover, this phenomenon
is also of importance in academic research like e.g. for investigations on the
structure properties relationships of a new compound because all differ-
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 5, pp. 553–566
© 2011 Institute of Organic Chemistry and Biochemistry
doi:10.1135/cccc2011027

554
Näther, Jeß:
ences in physical properties can directly be traced back to their differences
in crystal structures1,5. In this context also pseudo polymorphic forms,
better be described as co-crystals are of importance, which includes com-
pounds that contain additional solvent10–11. If pseudo polymorphic forms
are identified, it has to be investigated in detail which solvent free modifi-
cation is formed on the solvent removal10. Finally, during processing of a
drug also amorphous forms can be generated, which in some cases can have
advantages over crystalline forms because of their better solubility and
faster dissolution rates2,3
.
One of the most versatile and effective drugs are still glucocorticoids,
widely used in therapy because of their anti-allergic, anti-rheumatic, anti-
inflammatory and immune repressive properties12–18. Although they are
commercially available for several years, their polymorphism has not been
investigated in detail but recently has become of increasing interest again.
During the preparation of the dosage form a drug must be sterilized for
which different methods exist. An elegant method is the sterile filtration,
which is often used for the preparation of glucocorticoids as well as other
drugs. In this procedure the drug is dissolved in a suitable solvent, filtered
under pressure and afterwards the solvent is vaporized, the drug is dried
and finally micronized. Different polymorphic modifications can be ob-
tained directly or by decomposition of solvates formed by this procedure.
Finally it must be guaranteed that the process provides only the form pre-
ferred by the manufacturer. This was one of our starting points for our
investigations on glucocorticoids, in which we have discovered a large
number of new forms, that were structurally characterized and investigated
for their thermodynamic properties and transition behaviour19–25. In this
contribution, we report on our investigations on clobetasone butyrate
(Chart 1), which is frequently used in combination with clobetasone for
the treatment of skin diseases, allergies and asthma26–28. For this drug, no
polymorphic modifications have been described and no single crystal struc-
ture is available in the Cambridge Structure Database29–31
.
CHART 1
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 5, pp. 553–566

Investigations on the Polymorphism
555
RESULTS AND DISCUSSION
Solvent Mediated Conversion Experiments
In the beginning of our investigations, solvent mediated conversion experi-
ments were performed at room temperature in order to investigate if the
commercially available form I of clobetasone butyrate represents the ther-
modynamically most stable form at room temperature or if other modifica-
tions or solvates exist. In these experiments an excess of crystalline powders
of form I were stirred in saturated solutions of different solvents and the
precipitates were investigated by X-ray powder diffraction after 14 days. In
all solvents except methanol the X-ray powder patterns correspond to that
of form I, which unambiguously shows that this form should be the ther-
modynamic most stable form at room temperature (Table I). Only in meth-
anol a different powder pattern is obtained, which corresponds to that of a
solvate (Table I).
TABLE I
Results of the solvent mediated conversion experiments
Solvent
Form
Solvent
Form
1-Butanol
I
I
I
I
I
I
I
I
I
I
I
I
I
I
Acetone
I
1-Propanol
Methyl acetate
Methanol
I
2-Butanol
solvate
Isopropanol
Acetonitrile
Chloroform
Ether
Water
I
I
I
I
I
I
I
I
I
I
I
HCl (0.1 M)
NaCl 150 mM, isotonic)
Methyl isobutyl ketone
Toluene
DMF
Ethyl acetate
Ethyl methyl ketone
Isoamyl alcohol
Methylene chloride
Pentanol
Heptane
Tetrahydrofuran
Acetone/Water
Ethanol/Water
Acetonitrile/Water
Cyclohexane
Carbon tetrachloride
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 5, pp. 553–566

556
Single Crystal Structures
Näther, Jeß:
In order to characterize the different forms by X-ray structure analysis sin-
gle crystals of form I were grown as irregular polyhedral from ethyl acetate
and crystals of the methanol solvate were obtained as needles from metha-
nol (see Experimental).
Form I crystallizes orthorhombic in space group P212121 with Z = 12
molecules in the unit cell (Table II). There are three crystallographically
independent molecules in the asymmetric unit, which exhibit a similar
conformation (Fig. 1). Only minor conformational differences are found
in the side chains around the oxygen atoms O3 (O33, O63) and O5 (O35,
O65) and around the carbon atoms C21 (C51, C81) and C22 (C52, C82)
(Fig. 2).
In contrast to the structure of most other glucocorticoids, which are
determined predominantly by intermolecular O–H···O hydrogen bonding
interactions, in this compound no hydroxyl groups are present and
FIG. 1
Crystal structures of the three crystallographically independent molecules of form I with label-
ing and displacement ellipsoids drawn at the 50% probability level and all three molecular
structures fitted onto each other (light grey, oxygen; mid grey, carbon; dark grey, chlorine;
black, fluorine)
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 5, pp. 553–566

Investigations on the Polymorphism
557
TABLE II
Selected crystal data and results of the structure refinement for form I and for the methanol
solvate of clobetasone butyrate
Parameter
Form I
Methanol solvate
Empirical formula
MW, g/mol
Crystal color
Crystal system
space group
a, Å
C26H32FClO5
478.97
C26H32FClO5·CH3OH
511.01
colorless
orthorhombic
P212121
14.2345
18.8570
27.7142
7439.04
–103
colorless
orthorhombic
P212121
7.4563
b, Å
14.4312
23.7464
2555.19
–103
c, Å
V, Å3
Temperature, °C
Z
12
4
Dcalc, mg/cm3
1.283
1.328
F(000)
3048.0
1088.0
2θ-range, °
h/k/l ranges
3.88 to 51.88
–17 ≤ h ≤ 17
–17 ≤ k ≤ 23
–33 ≤ l ≤ 33
0.20
5.88 to 56.16
–8 ≤ h ≤ 9
–19 ≤ k ≤ 18
–31 ≤ l ≤ 27
0.20
µ(MoKα), mm–1
Reflection collection
Rint
35239
13091
0.0361
0.0394
Independent refl.
Refl. with Fo > 4σ(Fo)
Refined parameters
R1[Fo > 4σ(Fo)]
wR2 [all data]
14312
6027
12171
5028
893
319
0.0437
0.0400
0.1083
0.0986
Flack-x-parameter
–0.06 (4)
1.016
0.00 (6)
1.018
GOOF
Min./max. res., e/Å3
0.880/–0.950
0.350/–0.350
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 5, pp. 553–566

558
Näther, Jeß:
therefore, its structure is determined predominantly by isotropic interac-
tions. Consequently a complicated packing of the three crystallographically
independent molecules is observed.
The methanol solvate of clobetasone butyrate crystallizes in the ortho-
rhombic space group P212121 with four molecules in the unit cell (Table II
and Fig. 2). In this structure significant conformational changes in the side
chains are found compared to those of the three crystallographically inde-
pendent in form I (Fig. 2).
In the crystal structure the molecules are stacked in the direction of the
crystallographic c-axis (Fig. 3, top). Between four adjacent stacks small
channels are formed in which the methanol molecules are located (Fig. 3).
The solvent molecules are connected to the clobetasone butyrate molecules
via O–H···O hydrogen bonding between the hydroxyl group of the metha-
nol molecule and the carbonyl oxygen atom of the clobetasone butyrate
molecule (d(H···O3) = 2.223 Å, ∠O6HO3 = 159.55° and d(O6···O3) = 3.024 Å).
Within the a/b plane, the molecules are arranged in layers in which the clo-
betasone butyrate molecules show a herringbone-like arrangement (Fig. 3,
bottom).
FIG. 2
Crystal structures of the methanol solvate with labeling and displacement ellipsoids drawn at
the 50% probability level
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 5, pp. 553–566

Investigations on the Polymorphism
559
FIG. 3
Crystal structure of the methanol solvate of clobetasone butyrate with view along the a-axis
(top) and the b-axis (bottom). O–H···O hydrogen bonding is shown as dashed lines
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 5, pp. 553–566

560
Näther, Jeß:
It must be noted, that this structure is very similar to that of the solvates
from triamcinolone diacetate, in which different molecules like alcohols or
ketones are embedded19. All of these solvates are isotypic crystallizing in
space group P212121 and exhibit similar cell parameters like the methanol
solvate of clobetasone butyrate. Surprisingly our experiments clearly show
that no solvates are formed if clobetasone butyrate is treated with other sol-
vents. The void volume in the methanol solvate (Z = 4) was calculated us-
ing Platon to 238.2 Å3 which is 9.3% of the complete unit cell volume32. In
contrast, in triamcinolone diacetate ethanol solvate (Z = 4) the void volume
is calculated to be 578.2 Å3 which corresponds to 21.3% of the unit cell vol-
ume. This clearly shows that in clobetasone butyrate the voids are smaller
and therefore, no larger guest molecules like e.g. ethanol can be incorpo-
rated.
However, based on the crystal structure of form I and the methanol
solvate X-ray powder patterns can be calculated. If these powder pattern are
compared with those measured, it is proven that both modifications are
formed as phase pure materials.
Differential Thermoanalysis and Thermogravimetry (DTA-TG)
In order to investigate which modification is formed on solvent removal,
the methanol solvate was investigated by simultaneous DTA-TG experi-
ments. On heating, the mass of the sample decreases practically from room
temperature and this mass step is finished at about 90 °C (Fig. 4). The ex-
perimental mass loss of this step of about –6.1%, corresponds to that calcu-
lated (∆mcalc = –6.3%) for the complete removal of the methanol molecules.
On further heating there is an additional mass loss at about 200 °C, which
corresponds to the vaporization or decomposition of the solvent free form.
The DTA curve shows a more complicated behavior. During desolvation
two endothermic events at Tp = 75 and 90 °C, and one exothermic event
are observed at Tp = 107 °C. The last peak at Tp = 180 °C corresponds to the
melting of the form obtained by desolvation (Fig. 4).
In further DTA-TG experiments heating was stopped at 150 °C and the re-
sidue was investigated by X-ray powder diffraction. The experimental pat-
tern of this residue is in perfect agreement with that calculated for form I,
which clearly shows that this modification has formed after complete re-
moval of the solvent (Fig. 5).
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 5, pp. 553–566

Investigations on the Polymorphism
561
Differential Scanning Calorimetry (DSC)
In order to investigate the thermal behavior of form I and the methanol
solvate in more detail additional measurements using differential scanning
calorimetry were performed (Fig. 6).
On heating form I melts at To = 177 °C without any further transforma-
tion (Fig. 6, top). If the sample is cooled down with different cooling rates
directly after melting a residue is obtained that is amorphous to X-rays.
There are no hints for the formation of additional crystalline modifications.
The DSC curve of the methanol solvate is more complex. On heating a
broad endothermic signal is observed at Tp = 55 °C that corresponds to the
removal of the solvent (Fig. 6, bottom). On further heating one additional
endothermic event at Tp = 89 °C and one exothermic event at Tp = 106 °C
is observed. In a second DSC run heating was stopped after desolvation and
DTG
T
= 70
p
∆m = –6.1
TG
endo
T
= 180
p
T
= 75
p
T
= 90
p
DTA
T
= 107
p
50
75 100 125 150 175 200
Temperature, °C
FIG. 4
DTA, TG and DTG curve for the methanol solvate (Al2O3 crucibles, nitrogen atmosphere, heat-
ing rate 4 °C/min, peak temperatures (Tp) given in °C and mass loss in %)
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 5, pp. 553–566

562
Näther, Jeß:
5
10
15
20
25
30
2θ, °
35
40
45
50
FIG. 5
Experimental X-ray powder pattern of the residue isolated after the removal of the solvent at
150 °C (top) and the calculated X-ray powder pattern for the commercially available form I
(bottom). For clarity only the range between 5° ≤ 2θ ≥ 35° is shown
T
= 180
p
endo
T
= 177
o
T
= 180
p
T
= 89
T
= 55
p
p
T
= 176
o
T
= 82
o
T
= 106
p
50
100
150
200
Temperature, °C
250
300
FIG. 6
DSC curves of form I (top) and the methanol solvate (bottom). (Al pans, nitrogen atmosphere,
heating rate 3 °C/min, extrapolated onset (To) and peak (Tp) temperatures given in °C)
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 5, pp. 553–566

Investigations on the Polymorphism
563
the residue was investigated by X-ray powder diffraction. This clearly shows
that this residue is amorphous to X-rays. An amorphous residue is also ob-
tained if heating is stopped after the second endothermic DSC signal at
about 93 °C. In contrast, if the residue is isolated directly after the exo-
thermic event at about 110 °C and investigated by X-ray powder diffraction
it is clearly proven that modification I is formed. Moreover, if the crystal-
line form I and both amorphous forms obtained after the first and second
DSC peak are investigated by IR and Raman-spectroscopy no differences are
found in their spectra.
The results of these experiments clearly shows that the first thermal event
correspond to the desolvation of the methanol solvate leading to the
formation of an amorphous form. On further heating there is a second
endothermic event that cannot unambiguously assigned to some definite
reaction. The transformation of one amorphous form into a second in an
endothermic reaction is unlikely. However, it might be that solvent re-
moval takes place in two different steps which cannot be resolved using
thermogravimetry. In any case the exothermic event at about 106 °C cor-
responds to the crystallization of the amorphous modification leading the
formation of the thermodynamic most stable form I.
In this context, it is noted that the amorphous form is relatively stable. If
this form is stored at 50 °C, no changes are observed for about three weeks.
Afterwards a very slow transformation into form I is observed, which is
even not completed after several weeks.
CONCLUSION
In this work, clobetasone butyrate was investigated for polymorphism. Sol-
vent mediated conversion experiments clearly show that the commercial
available form I should represents the thermodynamically most stable form
at room temperature and the DSC measurements prove that this form
might also be the most stable form until its melting point. From all of our
investigations there are no hints for further crystalline forms. However, in
methanol a pseudo polymorphic form is obtained, which transforms on
solvent removal into a new amorphous modification that is stable over sev-
eral weeks. If the amorphous form is heated to about 100 °C it transforms
immediately into the most stable crystalline form I.
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 5, pp. 553–566

564
Näther, Jeß:
EXPERIMENTAL
Chemicals
Clobetasone butyrate is commercially available and was received from Symbiotec Pharmalab
LTD, India. All solvents used for the crystallization experiments were of analytical grade.
Preparation of Single Crystals
Single crystals of form I were prepared by slow evaporation of the solvent from a solution of
clobetasone butyrate in ethyl acetate. Single crystals of the methanol solvate were prepared
by slow evaporation of the solvent from a solution of clobetasone butyrate in methanol.
Differential Thermal Analysis and Thermogravimetry
DTA-TG measurements were performed in Al2O3 crucibles using a STA-409CD thermo bal-
ance from Netzsch. Several measurements under nitrogen atmosphere (purity 5.0) and air
with different heating rates (1, 2, 4, 8 and 16 °C/min) were performed. All measurements
were performed with a flow rate of 75 ml/min and were corrected for buoyancy and current
effects. The instrument was calibrated using standard reference materials from Netzsch.
Differential Scanning Calorimetry
DSC investigations were performed on the DSC 204/1/F device from Netzsch. The measure-
ments were performed in Al pans with heating rates of 3, 10 and 20 °C/min. The instrument
was calibrated using standard reference materials.
X-ray Powder Diffraction
X-Ray powder diffraction experiments were performed with a STOE STADI P transmission
powder diffractometer using CuKα radiation (λ = 1.540598 Å) that is equipped with a 2° to
130° IP-PSD (image plate position sensitive detector) and a 4° position sensitive detector.
X-ray Single Crystal Structure Analysis
All data were measured at using an Imaging Plate Diffraction system (IPDS-1) from STOE.
Structure solutions were performed with direct methods using SHELXS97 and structure re-
finements were performed against F2 using SHELXL97 33. All non-hydrogen atoms were re-
fined using anisotropic displacement parameters. The C–H hydrogen atoms were positioned
with idealized geometry (some of the methyl H atoms were allowed to rotate but not to tip)
and refined with isotropic displacement parameters (Uiso(C) = 1.2 × Ueq(Cmethin/methylene) =
1.5 × Ueq(Cmethyl) using a riding model with C–Hmethine = 0.95 Å, C–Hmethylene = 0.99 Å,
C–Hmethyl = 0.98 Å. The O–H hydrogen atoms were located in difference map but positioned
with idealized geometry allowed to rotate but not to tip and were refined isotropic using a
riding model with O–H = 0.84 Å. The absolute structure was determined and is in agreement
with the selected setting. Selected crystal data and details of the structure determinations
can be found in Table II.
CCDC 681992 (form I of clobetasone butyrate) and 681993 (clobetasone butyrate
methanol solvate) contain the supplementary crystallographic data for this paper. These
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 5, pp. 553–566

Investigations on the Polymorphism
565
data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from
the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge, CB2 1EZ, UK;
fax: +44 1223 336033; or deposit@ccdc.cam.ac.uk).
This work was supported by the State of Schleswig-Holstein, Germany. We thank Prof. Dr.
W. Bensch for access to his experimental equipment.
REFERENCES
1. Bernstein J. L: Polymorphism in Molecular Crystals. Clarendon Press, Oxford 2002.
2. Brittain H. G.: Polymorphism in Pharmaceutical Solids, Vol. 23. Marcel Dekker, New York
1999.
3. Hilfiker R.: Polymorphism. Wiley-VCH, Weinheim 2006.
4. Brittain H. G.: Am. Pharm. Rev. 2000, 3, 67.
5. a) Bernstein J., Davey R., Henck O.: Angew. Chem. 1999, 111, 3646; b) Bernstein J.,
Davey R., Henck O.: Angew. Chem., Int. Ed. 1999, 38, 3440.
6. Dunitz J. D., Bernstein J.: Acc. Chem. Res. 1995, 28, 193.
7. Näther C., Jeß I., Havlas Z., Nagel N., Bolte M., Nick S.: Solid State Sci. 2002, 4, 859.
8. Morris K. R., Griesser U. J., Eckhardt C. J., Stowell J. G.: Adv. Drug Delivery Rev. 2001, 48,
91.
9. Vippagunta S. R., Brittain H. G., Grant D. J. W.: Adv. Drug Delivery Rev. 2001, 48, 3.
10. Bechtloff B., Nordhoff S., Ulrich J.: Cryst. Res. Technol. 2001, 36, 1315.
11. Aakeröy C. B., Samon D. J.: Cryst. Eng. Commun. 2005, 7, 439.
12. Hatz H. J.: Glucocorticoide. Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart 2005.
13. Neeck G.: Neuroendocrine Immune Basis of the Rheumatic Diseases, Vol. II, Chap. 1, p. 28.
Acad. Sciences, New York 2002.
14. McEwen B. S., De Kloet E. R., Rostene W.: Physiol. Rev. 1986, 66, 1121.
15. Parrillo J. E., Fauci A. S.: Annu. Rev. Pharmacol. Toxicol. 1979, 19 179.
16. Schleimer R. P., Claman H. N., Oronsky A. L.: Anti-inflammatory Steroid Action: Basic and
Clinical Aspects, p. 353. Academic Press, San Diego 1989.
17. Buttgereit F., Scheffold A.: Steroids 2002, 67, 529.
18. Pfeilschifter J., Steinhilber D.: Pharmazie in unserer Zeit (Glucocorticoide special edition)
2003, 4, 296.
19. Suitchmezian V., Jeß I., Näther C.: Int. J. Pharm. 2006, 323, 101.
20. a) Näther C., Jeß I.: Angew. Chem. 2006, 118, 6529; b) Näther C., Jeß I.: Angew. Chem.
Int. Ed. 2006, 45, 6381.
21. Suitchmezian V., Jeß I., Näther C.: Solid State Sci. 2006, 8, 1373.
22. Suitchmezian V., Jeß I., Näther C.: Cryst. Growth Des. 2007, 7, 69.
23. Suitchmezian V., Jeß I., Sehnert J., Seyfarth L., Senker J., Näther C.: Cryst. Growth Des.
2007, 8, 98.
24. Suitchmezian V., Näther C., Jeß I.: J. Pharm. Sci. 2008, 97, 4516.
25. Suitchmezian V., Jeß I., Näther C.: Cryst. Growth Des. 2009, 9, 772.
26. Mourits M. J., De Bock H. G.: Int. J. Gynecol. Cancer 2006, 16, 494.
27. Katelaris C. H., Peake J. E.: Med. J. Aust. 2006, 185, 517.
28. Sadowska A. M., Klebe B., Germonpre P., De Backer W. A.: Steroids 2006, 72, 1.
29. Allen F. H., Motherwell W. D. S.: Acta Crystallogr., Sect. B: Struct. Sci. 2002, 58, 407.
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 5, pp. 553–566

566
Näther, Jeß:
30. Allen H. H.: Acta Crystallogr., Sect. B: Struct. Sci. 2002, 58, 380.
31. Cambridge Structural Database V.5.29 (2010). Cambridge (UK) 2010.
32. Spek A. L.: J. Appl. Crystallogr. 2003, 36, 7.
33. Sheldrick G. M.: Acta Crystallogr., Sect A: Fundam. Crystallogr. 2008, 64, 112.
Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 5, pp. 553–566

Copyright of Collection of Czechoslovak Chemical Communications is the property of Institute of Organic
Chemistry & Biochemistry, Academy of Sciences of the Czech Republic, v.v.i. and its content may not be
copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.