close

Вход

Забыли?

вход по аккаунту

?

Polymorphism of Sulfaproxiline.

код для вставкиСкачать
57
Polymorphism of Sulfaproxiline
Polymorphism of Sulfaproxiline
Zur Polymorphie des Sulfaproxilin
Davide Pitri? and Riccardo Stradi'
Istituto di Chimica Farmaceutica
-
Istituto di Chimica Organica - Facolta di Farmacia, Universitk degli Studi di Milano, Viale Abruzzi, 42 Milano 2013 I , Italy
Received March 30,1990
The sulfonamides often demonstrate polymorphism ').
Many studies are found regarding the identification and
characterization of polymorphs of sulfonamides used therapeutically '). This note presents evidence that sulfaproxiline
(I), previously described 3, as monomorphic, is in fact polymorphic.
Preparation of the Polymorphic Forms
Form I1
Industrially produced sulfaproxiline was crystallized from
methanol, ethanol, acetone, methyl ethyl ketone; in addition, a sample was prepared by dissolution in 10% NaOH
and reprecipitation with HC1. In all cases the crystals obtained had identical XRD and IR-spectra. Twelve additional
lots of industrial production were examined without further
purification: all XRD spectra (Table 1) and IR spectra
(Table 2) could be superimposed on the preceding ones.
Table 1: XRD spectra of sulfaproxiline
The study was initiated after it was found that samples of
industrial-scale lots (all with HPLC purity ~ 9 9 % showed
)
differing and poorly-defined melting points. In fact literature values also show large variations: 187-8'C 4), 1857°C '), 173°C@198°C
,
').
This study has permitted the individuation of two polymorphic forms which have been characterized by X-ray diffraction and IR-spectroscopy. The dynamic correlation between the two polymorphs has been demonstrated using
DSC and HSM.
Experimental Part
I X-Ray DiffractionAnalysis (XRD)
X-ray powder diffraction patterns wer obtained with a Philips P.W. 1710
diffractometer in the e range between 3' and 50' using Cu-Ni radiation (40
kv; 40A) and 1' midl scanning rate.
2 Infrared Spectra (IR)
Infrared spectra were recorded in Nujol mull with a Perkin-Elmer 1210
instrument.
3 Differential Scanning Calorimetry (DSC)
FORM I 1
ze
I I I max'
28
9.52
98.73
9.16
66.49
12.95
61.27
10.50
31.36
13.01
54.47
13.77
32.05
13.99
11.47
13.97
18.82
15.71
22.06
15.47
21 .87
17.20
100.00
17.9'
12.52
17.68
52.60
18.94
100.00
IIImax
19.15
90.04
19.01
93.35
20.09
63.80
19.37
75.29
20.73
34.93
19.42
5'.29
21.08
82.33
19.68
11.46
22.44
18.88
21.36
52.73
22.04
12.80
22.66
25.46
22.57
87.63
23.16
65.49
22.63
63.80
24.83
76.36
23.55
24.84
24.89
66.49
26.14
29.50
25.18
15.51
26.42
11.47
25.33
13.63
28.88
48.07
27.75
18.03
30.26
11.47
29.13
14.32
Only the values 2 10 are reported.
Analyses were performed with a Perkin-Elmer DSC7 instrument, using a
pure sample of indium as calibration standard. Heating rate: 2-4O'C mid'.
4 Hot-Stage Microscopy (HSM)
The measurements have been done with a Koffler Hot-Stage apparatus
(Reichert- Wien)
Arch. Pharm. (Weinheim)324.57-58 (1991)
FORMI
Table 2: IR spectra (NH stretching) of sulfaproxiline
FORM
v a s NH2
vs NH2
v NH
I
I1
3500
3400
3290
3460
3360
3080
QVCH Verlagsgesellschaft mbH. D-6940 Weinheim. 1991
0365-6233/91/0101-0057 $3.50 + .25/0
58
PitrS! and Stradi
Form I
A sample of sulfaproxiline, crystallized from methanol,
was dipped in an oil bath at 187-188'C for a few seconds
and then quickly cooled.
The XRD spectrum and IR spectrum are different to those
of 11. Form I is a metastable form; this form in fact transforms spohtaneously, even a room temp. giving after 13
days a mixture of Form I and Form I1 (5050 by XRD
measurement).
A sample kept at 110°C for 48 h is transformed into a
mixture of I and I1 containing 72% of 11.
The DSC thermogram of the lower-melting Form 11, at a
heating rate of 2'C min", shows an endotherm at 186-8°Cin
dynamic equilibrium with an exotherm followed by a new
endotherm at 203S"C(fig. la).
The height of the two endotherms depends upon the heating rate and the lot examined. When the crystallization occurs from methanol with very slow cooling, only the endotherm at 186-8°Cwas observed (fig. lb). Higher-melting
Form I shows only the endotherm at 203-5'C (fig. lc).
V
1
bL
1
160
190
180
170
200
Temp. O C
210
Fig. 1 - DSC thermograms of sulfaproxiline recorded at 2'C mid'
a) - Typical DSC thennogram of Form I1 (industrial samples)
b) - DSC thennogram of Form I1 slowly recrystallized from methanol
c) - DSC thennogram of Form I
We thank Dr. V. Maruranza (Fermtec - Prochim, Varese, Italy) and Prof.
B. Trirnboli (Alchymars, Milano, Italy) for the samples of sulfaproxiline
and Prof. G. Liborio, Dipartimento di Scienza della Terra dell' Universith
di Milano, for helpful discussion of XRD.
References
Results and Discussion
1
Table 3: Thermal characteristics of the two forms
MP ("C)
Form I1 represents the stable form at room temp. The higher
melting Form I obtainable when Form I1 is heated at 187188"C,reverts to Form I1 at room temp. This transformation
is distinctive of an enantiotropic system. The enantiotropy is
confirmed by the thermal characteristics of the two forms
which are reported in table 3; it is found that the AH of
Form I (higher melting) is lower than that of Form I1 (heat
of fusion rule 7)>.
The IR-spectra are also consistent with this conclusion: in
fact it is clearly seen that in the N-H stretching region Form
I1 has lower frequency bands with respect to the corresponding bands of Form I (infrared rule 7)).
In light of these results the ambiguity regarding the melting point (as measured in a capillary) of various samples of
sulfaproxiline (all in the Form 11 as shown by XRD and IR)
can be explained as follows:
When the melting point 186-7°Cis observed the crystallization rate of the Form I from the melt is so slow as not to
be observable.
A double melting point at 186-772and 203-4°Cis observed, when Form I crystallizes from the melt and subsequently melts again.
Finally, when the observed melting point is 203-4'C,
probably the presence of a few seed crystals of I which are
present in the Form 11, facilitate the solid-solid transition
( 1 1 4 ) ; one observes only the melting of the higher melting
form.
In conclusion, all the bulck samples of sulfaproxiline
examined exist in Form 11, which is the more stable one at
room temp. It has been demonstrated, however, that an enantiotropic rearrangement of this crystal form is possible
and such a rearrangement may or may not be observed during the determination of melting point by the capillary
method.
We therefore considered it correct to state that sulfaproxiline, being a dimorphic substance, can show two melting points (1 86-188'C and / or 203-205°C)
even though this
product usually exists in Form 11.
hH
2
(KJ
-
mol-1)
203.5
29.46 t 0.32 (n8)
186.7
37.20 2 0.20 (n6)
The experimental results of DSC, in agreement with
HSM, XRD and IR data, demonstrate that the lower melting
3
M. Kuhnert-Brandstatter, Pure App. Chem. 10,133, (1965).
S.R. Bym, Solid State Chemistry of Drugs, p. 103, Academic Press,
New York, 1982.
L. Maury. J. Rambaud, B. Pauvert, Y. Lasserre, M. Audran, and G.
Berge, Pharm. Acta Helv. 62, 126 (1987).
4
5
J.R.GeigyA.G.,SwissP.265.717;C.A.45,3419b(1951).
M. Kuhnert-Brandstittter, A. Kofler, and H.-C. Rhi, Sci. Pharm. 32.
6
308 (1964).
Merck Index, 11. ed, Merck and Co., Inc., Rahway, N.J., U.S.A.,
(1990).
7
A. Burger and R. Bamberger, Mikrochim. Acta (Wien). 11, 273
(1979).
[KPh535]
Arch. Pharm. (Weinheini) 324.5748 (1991)
Документ
Категория
Без категории
Просмотров
0
Размер файла
170 Кб
Теги
polymorphism, sulfaproxiline
1/--страниц
Пожаловаться на содержимое документа