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Physicochemical and Structural Study of Sulfamethazine
Physicochemical and Structural Study of Sulfamethazine LUC AND
MAURY',JOELLERAMBAUD,BERNARD PAUVERT, MICHELAUDRAN
YVES
LASSERRE, GILBERTBERGE,
Received September 19, 1983, from the Groupe Polymorphisme et Biodisponibilite, Faculte de Pharmacie, 34060 Montpellier Cedex, Accepted for publication November 6, 1984. France. Abstract 0 We have shown by several physicochemical methods that the existence of different crystal habits for a given molecule does not necessarily imply polymorphism. For sulfamethazine, we found one polymorph, form I , whose crystalline structure is published herein, and a methanol solvate.
Unlike the two sulfonamides we studied previously,',2 sulfamethazine has been the object of numerous investigation^.'-^ In these published works. however, there is a major discrepancy concerning the number of sulfamethazine polymorphs. Consequently. we decided to carry out a detailed study on the polymorphism of this sulfamide. In the present paper, we show that sulfamethazinc gives only one polymorph, designated form I.
intensities were corrected for Lorentz and polarization factors, but not for absorption. The structure was resolved by direct methods using the MULTAN 80 ~ r o g r a m An . ~ E-map calculated from the set of phases with the highest figure of merit revealed the position of all nonhydrogen atoms. Full-matrix least-squares techniques were used to refine the structure with the SHELX 76 program.'" Two cycles of isotropic refinement converged at an r value of 0.090. Two cycles of anisotropic refinement reduced r to 0.058. A difference Fourier map then revealed the position of all the hydrogen atoms. The final refinement was performed holding the hydrogen atoms with a temperature factor of Bq = 0.67 nm2 and reduced r to 0.0474 and r, to 0.0465. The weighting sheme was: 1u = 1.5052/a2(F) + 0.000648F2. A stereoscopic view of the sulfamethazine molecule was generated using the PLUTO program."
Experimental Section P r e p a r a t i o n of Different C r y s t a l Habits of Sulfamethazine-To compare our results with those published by Abdel Hadi et a].," we used the same solvents to recrystallize sulfamethazine, i.e., methanol, ethanol, dichloromethane, ethyl acetate, and benzene:alcohol mixtures. Hot, saturated solutions were prepared and then cooled at room temperature. Cold, saturated solutions were also used. The crystals were collected and dried in a desiccator. Instrumentation-Differential thermal analysis-thermogravimetry analysis (DTA-TG) thermograms were recorded on a Setaram-IJgine Eyraud B 60 Thermal Analyzer equipped with a thermobalance. Samples of 30-50 mg were used. For differential calorimetric analysis, the Perkin-Elmer DSC 1B instrument was used for the quantitative measurements of transition; fusion was calibrated with indium, tin, lead, benzil, acetanilide, phenacetin, and acetamidosalol (salophen; Bayer) according to a literature procedure.' The samples were heated from room temperature to -10°C above their melting points a t a heating rate of 16"C/min. IR spectra of the crystals were taken on a Perkin-Elmer 457 IR Spect rophotometer as potassium bromide pellets. The sample-KBr ratio was 1:300 mg and a pressure of 10 tons was used. Spectra were recorded over a range of 4000-250 cm-'. Raman spectra were recorded on a ,Jobin and Yvon Raman Spectrometer model Ramanor HG 2s equipped with holographic gratings and an argon gas laser: laser line, 514.5 nm; laser power, 400 mW (when necessary,
1 Journal of Pharmaceutical Sciences Vol. 74,No. 4 , April
1985
Results and Discussion Microscopic Analysis of t h e C r y s t a l Habits-Microscopic examination showed that sulfamethazine crystals recrystallized from the various solvents had different habits. This general observation is in agreement with the results reported by Abdel Hadi et a1.6 However, except for the crystals from methanol where our results are similar (Fig. Id), crystals from the other solvents did not have the same morphological forms as those of Abdel Hadi et a1.6 Crystals from the benzene:ethanol mixtures and from ethyl acetate were identical and showed needle growth (Fig. l a ) . Crystals from ethanol were columnar shaped and asymmetrically truncated (Fig. Ib). These crystals were comparable with those obtained from ethyl acetate by the aforementioned authors. Crystal habits from dichloromethane (Fig. lc) were packed spiny plates; these were not observed by Abdel Hadi and co-workers. We conclude from our microscopic analysis that, in the case of sulfamethazine, it is not the solvent that induces the habits characteristic of the crystals but rather the operating conditions: temperature of saturation, rate of recrystallization, number of recrystallizations. T h e r m a l Analyses-The differential calorimetric curve (DSC) of the methanol solvate and of form I of sulfamethazine are shown in Fig. 2. Recrystallization from methanol was characterized by an endothermic peak at 80°C followed by a second peak at 197-198°C corresponding to the melting point. For the other recrystallizations, one peak only was recorded at 197-198"C, i.e., the melting point. The DTA-TG thermograms are shown in Fig. 2; the peak at 80°C was attributed to desolvation. X-ray Diffraction-The X-ray diffraction patterns (Fig. 3) of all the crystals, except for those obtained from methanol, gave a spectrum comparable to the one published by Abdel Hadi et aL6 The spectrum of the crystals obtained from methanol was quite different from not only the spectrum of the 0022-3549/85/0400-0422$01.OO/O
0 1985, American PharmaceuticalAssociation
Figure 1-Micrographs of sulfarnethazine crystals obtained in benzene: ethanol or ethyl acetate (a), ethanol (b), dichlorornethane (c), and methanol (d).
other crystals but also that published? This is shown in Table
I. The results of the X-ray diffraction study confirm the therma1 analysis findings. As far as the results on the crystallization from methanol are concerned, there is a major discrepancy between our work and that of Abdel Hadi and co-workers that cannot be attributed to errors in measurements. These authors did not mention the existence of a solvate. It seems reasonable
to conclude that the crystals studied by Abdel Hadi et al. were not similar to the ones which we studied as soon as they appeared in solution even though the habits were comparable. The loss of weight of -9.6% found by thermogravimetric analysis of the solvate corresponds to two water molecules or one methanol molecule. Infrared Spectroscopy-Whatever the solvent used, except for methanol, the IR spectra (Fig. 4) of all the crystals Journal of Pharmaceutical Sciences Vol. 74, No. 4, April 1985
1
423
were identical between 250 and 4000 cm-'. This finding correlates with the results obtained by the other methods. The spectrum of the crystals obtained from methanol was only slightly different from the spectra of the other crystals in the Table I-Comparison of dhrl and Intensity Values for Sulfamethazine Crvstals in Methanol dhkl,
x 10 nma
Intensity"
dhkl.
x 10 nm
Intensity ~
9.927 9.709
200
100
T"C
9.556 9.305
-
57 83
7.823 7.688 6.856 6.458 6.320 6.103
I
4.482 4.160
I
I
I
I
.
I
I
I
, , , , I
I
100
50
150
I
Figure 2-TG and DTA thermograms of methanol solvate of sulfamethazine and DSC thermograms of form Iand the solvate.
a
5
15
10
20
( 8")
Figure 3-X-ray (bl.
424
3.776
8
3.602
100
200
T'C
3.393
18
3.190 3.077 3.036 2.926
15 24 8 7
2.538 2.388 2.055
7 8 9
Vol. 74, No. 4, April 1985
4.791 4.726 4.548 4.502
27 54 66 56
4.148 3.880 3.860 3.830
25 29 29 29
3.750
80
3.572 3.490
39.5 44
3.287
29
2.837
44
Taken from ref. 6.
4Ooo
3ooo
m
1500
loo0
Wavelength u1 cm-'
powder diffraction patterns of form I (a) and the solvate
/ Journal of Pharmaceutical Sciences
54 16.5 16.5
86 9
I
I
5.063 4.951 4.896 41
4.806
I
73 42 19 80 35 100
30 9
5.845 5.212
form
14.5 27
Figure 4-Iff
spectra of the solvate (a) and form I(b).
500
500-1800 cm-' region investigated by the other authors. Comparison of the 1800-4000 cm-' regions, however, showed important differences at the level of the u NHz and u NH valence vibrations that distinguished the crystals obtained in methanol from the other crystals. The spectrum of form I exhibited
spectral bands at 3442, 3342, and 3240 cm-I, which were attributed to the uaS NHz, us NH2, and u NH modes, respectively. These modes appeared at frequencies lower than those expected in the case of free groups and indicated the presence of intermolecular hydrogen bonds. The last two bands were found again a t the same frequencies in the solvate, whereas three more spectral bands appeared at 3520, 3465, and 3445 cm-', indicating the existence of hydrogen bonds different from the ones observed in form I. R a m a n Scattering-Raman scattering spectrometry is used to study internal vibrations (vibrations specific to the molecule in question) and lattice vibrations or vibrations of the crystalline network. For the internal vibrations, in the 3500-3200 cm-' region, no changes were observed between the spectra for form I and for the solvate other than a displacement of vibrations characterTable Il-Wavenumber and Relative Intensities of Raman Lines of Lattice Vibrations for Form I and the Solvate of Sulfarnethazine
Form I
Solvate
~
A ~
A".
U,
crn-' ~ _ _ _ _ _ _ Intensity _
19 36 40 43 47 81 91 105 117 122 138
Crn'
Figure 5-Raman spectra in the 100-1800 cm-' region of the methanol solvate (a) and form I (b).
Table Ill-Bond Molecule
58 79 77 100 sh
A
U,
crn-'
23 28 37 47 52
66 12 8 13 10 11 12
77 81
-
117 120 -
Intensity
55 sh 16 sh 100 45 98 96
44 50
Distances and Angles of the Sulfamethazine Bond Distance, x 10 nrn
C(1b V 7 ) C(1F-42) C(1b C ( 6 ) C(+C(3) C(3P44) C(4kC(5) C(4kS(8) C(5bC(6) S(8t-0(9) S(W-O(l0)
150
50
100
rx",cm
'
Figure 6-Raman spectra of lattice vibrations of the sulfamethazine solvate with methanol (a) and sulfarnethazine form I (b).
O(lO)-S(8)-N(ll) 0(1O)--S(8)-0(9) S(8)-N(ll)-C(12) N(ll)-C(l2)-N(13) N(llkC(12)-N(17) N(17)-C(12)-N(13) C(12)--N(13tC(14) N(13bC(14bC(15) N(13+C(14)-C(18) C(15)--C(14)-C(18) C(14kC(15)-C(16) N(17tC(16)-C(15) N(17)-C(16)-C(19) a
S(8)-N(ll) 1.373 (6) 1.399 (6) N(llkC(12) C(12)-N(13) 1.392 (6) C(lZbN(17) 1.372(6) 1.397 (6) N(13)-C(14) 1.382 (5) C(14)-C(15) 1.738 (4) C(14)-C(18) 1.375 (6) C(15)-C(16) C(16)--N(17) 1.427 (3) 1.438 (3) C(16tC(19) Bond Angle, 109.1 (2) 119.0 (2) 127.9 (2) 113.5 (4) 117.6 (4) 128.9 (4) 115.5 (4) 120.3 (4) 117.0 (4) 122.7 (4) 119.0 (4) 121.7 (4) 116.7 (4)
C(15)-C(16)--C(19) N(7)-C(l)-C(2) N(7)-C(l)-C(6) C(6bC(l)-C(2) C(3)-C(2&C(1) C(4)-C(3)-C(2) C(5)-C(4tC(3) C(5)-C(4bS(8) C(3tC(4)-S(8) C(6)-C(5)-C(4) C(4tS(8)-N(ll) C(4)-S(8)-0(9) C(4)-S(8jO(lO) 0(9tS(8!-N(ll)
1.632 (4) 1.402 (5) 1.336 (5) 1.31915) 1.346 (5) 1.387 (6) 1.495 (7) 1.366 (6) 1.354 (5) 1.505 (7) 121.6 (4) 121.0 (4) 120.1 (4) 118.9 (4) 120.1 (4) 120.6 (4) 119.3 (4) 119.8 (3) 120.8 (3) 120.3 (4) 108.6 (2) 108.8 (2) 107.9 (2) 103.0 (2)
The standard deviations are given in parentheses
Journal of Pharmaceutical Sciences Vol. 74, No. 4, April 1985
425
istic of amino and amido groups and the existence of a 3090 cm-’ band in the spectrum of form I. In the 1700-150 cm-’ region (Fig. 5 ) there was a change in the intensity of the 870 and 438 cm-’ bands and the appearance of the two bands at 507 and 303 cm-’, absent in the spectrum of form I. For the lattice vibrations, a study of the low frequency region (Fig. 6) allows immediate identification of the different forms. Apart from the crystals obtained from methanol, the spectrum of form I was observed for all crystals. Characteristic frequencies of form I and the solvate are listed in Table 11. Form I is characterized by an intense pattern located between 30 and 60 cm-‘; in addition, bands at 19,91,105, and 138 cm-’ are specific to form I. The solvate was identified and characterized by intense bands a t 23, 52, 77, 81, and 120 cm-I, which were not observed for form I. S t r u c t u r e Determination-Sulfamethazine crystalline form I, C1,Hl4N4O2S(mol. wt. 262), obtained from absolute alcohol had the following unit cell dimensions and angles: a = 0.7426 (2) nm; b = 1.8874 (8) nm; c = 0.9317 (2) nm; p = 9.906 Mo-Ka ; (A = (2) nm; V = 129.6 nm3; 2 = 4; peal= 1.38 g . ~ m - ~ 0.071069 nm); space group = P2Ja. To complete the present study, we measured the crystalline parameters and determined the structure of form I. Our results are in good agreement with those reported by Basak et a1.12 Sulfamethazine exhibits .Ir-electron delocalization (Table 111) leading to intense conjugation at the level of the pyrimidyl radical and a marked quinonic effect on the aminobenzene group. This effect has been observed for one of the forms of and sulfabenzamide,’ for form I of sulfameth~xypyridazine,’~ for s~lfadimethoxine.’~ Apparently this effect facilitates the solubility of the compound and consequently increases its bioavailability. The crystalline structure is held together by three hydrogen bonds and by Van der Waals forces (Table IV). The molecular conformation is presented in Fig. 7.
Figure 7-A stereoscopic drawing of form I of the sulfamethazine molecule (PLUTO program, ref. 1 1).
426
1 Journal of Pharmaceutical Sciences Vol. 74, No. 4, April 1985
Table IV-Intermolecular Bonds: Hydrogen Bonds and Van der Waals Contacts for Sulfamethazine Form I’
Hydrogen Bonds
Code for symmetry 1, x, y, z
11.2-x,1 - y , 2 - z 111, -0.5 + X, 0.5 - y, z IV, 1.5 - X, -0.5 y. 2 - z 0.3097 nm N(7),-H(7). . . N(l7),1 N(ll),-H(ll). . ~0(10)111 0.2947 nm 0.3212 nm N(7),-H’(7). . . N(13),” Van der Waals Contacts N(7). . . ‘C(3) 0.3408 nm N(7). . . .C(18) O(9)’. . .C(3) 0.3393 nm O(9). . . -C(15) O(lO)-..C(S) 0.3415 nm O(9). . . -0(10) C(1). ’ ’ .C(2) 0.3395 nm
+
a
0.3456 nm 0.3321 nm 0.3481 nm
Does not include those bonds and contacts that are <0.35 nm.
It can be concluded from the results of the different physicochemical studies on sulfamethazine that whatever the solvent used, except for methanol, all the crystals corresponded to a single polymorph even though they had different habits. The structure of this polymorph (designated form I) has been characterized. The crystals we isolated from methanol were identical to those reported by Abdel Hadi et ale6excepted that we identified a methanol solvate of sulfamethazine. We noted, in fact, that if the crystals obtained from methanol were left in open air for some time before grinding, the solvate completely disappeared and the polymorph then corresponded to form I. The methanol solvate was shown to have a sulfamethazine:methanol composition of l : l . 1 5
References and Notes 1. Rambaud, J.; Maury, L.; Lefebvre, C.; Roques, R. Znt. J. Phurm. 1983.15.199-212. 2. Maury, L.; Rambaud, J.; Pauvert, B.; Audran, M.; Lasserre, Y.; Berg&,G. Pharm. Acta Helu. 1984,59,112-117. 3. Yang, S.S.; Guillory, J. K. J . Phurm. Sci. 1972.61,26-40. 4. Kurhnert-Brandstatter, M.; Wunch. W. Microchim. Acta fWied 1969,1297-1307. 5. Mesley, R. J.; Hougthon, E. E. J. Phurm. Phurmacol. 1967,295304. 6. Abdel Hadi, I.; Mezosi, J.; Kedvessy, G.; Morvay, J. Pharmazie 1977,32,791-793. 7. Perkin-Elmer Corp. Norwalk, CT, 1966. 8. Susa, K.; Steinfink, H. J. Solid State Chem. 1971,3,75-82. 9. Main, P.; Fiske, S. J.; Hull, S. E.; Lessinger, L.; Germain, G.; Declercq, J. P.; Woolfson, M. M. “MULTAN 80. A System of Computer Programs for the Automatic Solution of Crystal Structures from X-ray Diffraction Data”; University of York England and Louvain-la-Neuve, Belgium, 1980. 10. Sheldrick, G . M. “SHELX-76: Program for Crystal Structure Determination”; University of Cambridge: England, 1978. 11. Motherwell, S; Clegg, B. “PLUTO. Program for Plotting Molecular and Crystal Structures”; 1978. 12. Basak, A. K.; Mazumdar, S. K.; Chaudhuri, S. Acta Crystallogr. 1983.(239.492-494. 13. Rambaud, J.;. Roques, R.; Declercq, J. P.; Germain, G.; Sabon, F. Bull. SOC.Chzm. France 1981,2,153-157 14. Shefter, E.; Chmielewicz, Z. F.; Blount, J. F.; Brennan, T. F.; Sackman, L. F.; Sackman, P. J. Phurm. Sci. 1972,61,872-877 15. Rambaud, J.; Maury, L.; Pauvert, B.; Berg&, G.; Audran, M.; Lasserre, Y.; Declercq, J. P. Acta Crystallogi-., in press.
MAURY',JOELLERAMBAUD,BERNARD PAUVERT, MICHELAUDRAN
YVES
LASSERRE, GILBERTBERGE,
Received September 19, 1983, from the Groupe Polymorphisme et Biodisponibilite, Faculte de Pharmacie, 34060 Montpellier Cedex, Accepted for publication November 6, 1984. France. Abstract 0 We have shown by several physicochemical methods that the existence of different crystal habits for a given molecule does not necessarily imply polymorphism. For sulfamethazine, we found one polymorph, form I , whose crystalline structure is published herein, and a methanol solvate.
Unlike the two sulfonamides we studied previously,',2 sulfamethazine has been the object of numerous investigation^.'-^ In these published works. however, there is a major discrepancy concerning the number of sulfamethazine polymorphs. Consequently. we decided to carry out a detailed study on the polymorphism of this sulfamide. In the present paper, we show that sulfamethazinc gives only one polymorph, designated form I.
intensities were corrected for Lorentz and polarization factors, but not for absorption. The structure was resolved by direct methods using the MULTAN 80 ~ r o g r a m An . ~ E-map calculated from the set of phases with the highest figure of merit revealed the position of all nonhydrogen atoms. Full-matrix least-squares techniques were used to refine the structure with the SHELX 76 program.'" Two cycles of isotropic refinement converged at an r value of 0.090. Two cycles of anisotropic refinement reduced r to 0.058. A difference Fourier map then revealed the position of all the hydrogen atoms. The final refinement was performed holding the hydrogen atoms with a temperature factor of Bq = 0.67 nm2 and reduced r to 0.0474 and r, to 0.0465. The weighting sheme was: 1u = 1.5052/a2(F) + 0.000648F2. A stereoscopic view of the sulfamethazine molecule was generated using the PLUTO program."
Experimental Section P r e p a r a t i o n of Different C r y s t a l Habits of Sulfamethazine-To compare our results with those published by Abdel Hadi et a].," we used the same solvents to recrystallize sulfamethazine, i.e., methanol, ethanol, dichloromethane, ethyl acetate, and benzene:alcohol mixtures. Hot, saturated solutions were prepared and then cooled at room temperature. Cold, saturated solutions were also used. The crystals were collected and dried in a desiccator. Instrumentation-Differential thermal analysis-thermogravimetry analysis (DTA-TG) thermograms were recorded on a Setaram-IJgine Eyraud B 60 Thermal Analyzer equipped with a thermobalance. Samples of 30-50 mg were used. For differential calorimetric analysis, the Perkin-Elmer DSC 1B instrument was used for the quantitative measurements of transition; fusion was calibrated with indium, tin, lead, benzil, acetanilide, phenacetin, and acetamidosalol (salophen; Bayer) according to a literature procedure.' The samples were heated from room temperature to -10°C above their melting points a t a heating rate of 16"C/min. IR spectra of the crystals were taken on a Perkin-Elmer 457 IR Spect rophotometer as potassium bromide pellets. The sample-KBr ratio was 1:300 mg and a pressure of 10 tons was used. Spectra were recorded over a range of 4000-250 cm-'. Raman spectra were recorded on a ,Jobin and Yvon Raman Spectrometer model Ramanor HG 2s equipped with holographic gratings and an argon gas laser: laser line, 514.5 nm; laser power, 400 mW (when necessary,
1 Journal of Pharmaceutical Sciences Vol. 74,No. 4 , April
1985
Results and Discussion Microscopic Analysis of t h e C r y s t a l Habits-Microscopic examination showed that sulfamethazine crystals recrystallized from the various solvents had different habits. This general observation is in agreement with the results reported by Abdel Hadi et a1.6 However, except for the crystals from methanol where our results are similar (Fig. Id), crystals from the other solvents did not have the same morphological forms as those of Abdel Hadi et a1.6 Crystals from the benzene:ethanol mixtures and from ethyl acetate were identical and showed needle growth (Fig. l a ) . Crystals from ethanol were columnar shaped and asymmetrically truncated (Fig. Ib). These crystals were comparable with those obtained from ethyl acetate by the aforementioned authors. Crystal habits from dichloromethane (Fig. lc) were packed spiny plates; these were not observed by Abdel Hadi and co-workers. We conclude from our microscopic analysis that, in the case of sulfamethazine, it is not the solvent that induces the habits characteristic of the crystals but rather the operating conditions: temperature of saturation, rate of recrystallization, number of recrystallizations. T h e r m a l Analyses-The differential calorimetric curve (DSC) of the methanol solvate and of form I of sulfamethazine are shown in Fig. 2. Recrystallization from methanol was characterized by an endothermic peak at 80°C followed by a second peak at 197-198°C corresponding to the melting point. For the other recrystallizations, one peak only was recorded at 197-198"C, i.e., the melting point. The DTA-TG thermograms are shown in Fig. 2; the peak at 80°C was attributed to desolvation. X-ray Diffraction-The X-ray diffraction patterns (Fig. 3) of all the crystals, except for those obtained from methanol, gave a spectrum comparable to the one published by Abdel Hadi et aL6 The spectrum of the crystals obtained from methanol was quite different from not only the spectrum of the 0022-3549/85/0400-0422$01.OO/O
0 1985, American PharmaceuticalAssociation
Figure 1-Micrographs of sulfarnethazine crystals obtained in benzene: ethanol or ethyl acetate (a), ethanol (b), dichlorornethane (c), and methanol (d).
other crystals but also that published? This is shown in Table
I. The results of the X-ray diffraction study confirm the therma1 analysis findings. As far as the results on the crystallization from methanol are concerned, there is a major discrepancy between our work and that of Abdel Hadi and co-workers that cannot be attributed to errors in measurements. These authors did not mention the existence of a solvate. It seems reasonable
to conclude that the crystals studied by Abdel Hadi et al. were not similar to the ones which we studied as soon as they appeared in solution even though the habits were comparable. The loss of weight of -9.6% found by thermogravimetric analysis of the solvate corresponds to two water molecules or one methanol molecule. Infrared Spectroscopy-Whatever the solvent used, except for methanol, the IR spectra (Fig. 4) of all the crystals Journal of Pharmaceutical Sciences Vol. 74, No. 4, April 1985
1
423
were identical between 250 and 4000 cm-'. This finding correlates with the results obtained by the other methods. The spectrum of the crystals obtained from methanol was only slightly different from the spectra of the other crystals in the Table I-Comparison of dhrl and Intensity Values for Sulfamethazine Crvstals in Methanol dhkl,
x 10 nma
Intensity"
dhkl.
x 10 nm
Intensity ~
9.927 9.709
200
100
T"C
9.556 9.305
-
57 83
7.823 7.688 6.856 6.458 6.320 6.103
I
4.482 4.160
I
I
I
I
.
I
I
I
, , , , I
I
100
50
150
I
Figure 2-TG and DTA thermograms of methanol solvate of sulfamethazine and DSC thermograms of form Iand the solvate.
a
5
15
10
20
( 8")
Figure 3-X-ray (bl.
424
3.776
8
3.602
100
200
T'C
3.393
18
3.190 3.077 3.036 2.926
15 24 8 7
2.538 2.388 2.055
7 8 9
Vol. 74, No. 4, April 1985
4.791 4.726 4.548 4.502
27 54 66 56
4.148 3.880 3.860 3.830
25 29 29 29
3.750
80
3.572 3.490
39.5 44
3.287
29
2.837
44
Taken from ref. 6.
4Ooo
3ooo
m
1500
loo0
Wavelength u1 cm-'
powder diffraction patterns of form I (a) and the solvate
/ Journal of Pharmaceutical Sciences
54 16.5 16.5
86 9
I
I
5.063 4.951 4.896 41
4.806
I
73 42 19 80 35 100
30 9
5.845 5.212
form
14.5 27
Figure 4-Iff
spectra of the solvate (a) and form I(b).
500
500-1800 cm-' region investigated by the other authors. Comparison of the 1800-4000 cm-' regions, however, showed important differences at the level of the u NHz and u NH valence vibrations that distinguished the crystals obtained in methanol from the other crystals. The spectrum of form I exhibited
spectral bands at 3442, 3342, and 3240 cm-I, which were attributed to the uaS NHz, us NH2, and u NH modes, respectively. These modes appeared at frequencies lower than those expected in the case of free groups and indicated the presence of intermolecular hydrogen bonds. The last two bands were found again a t the same frequencies in the solvate, whereas three more spectral bands appeared at 3520, 3465, and 3445 cm-', indicating the existence of hydrogen bonds different from the ones observed in form I. R a m a n Scattering-Raman scattering spectrometry is used to study internal vibrations (vibrations specific to the molecule in question) and lattice vibrations or vibrations of the crystalline network. For the internal vibrations, in the 3500-3200 cm-' region, no changes were observed between the spectra for form I and for the solvate other than a displacement of vibrations characterTable Il-Wavenumber and Relative Intensities of Raman Lines of Lattice Vibrations for Form I and the Solvate of Sulfarnethazine
Form I
Solvate
~
A ~
A".
U,
crn-' ~ _ _ _ _ _ _ Intensity _
19 36 40 43 47 81 91 105 117 122 138
Crn'
Figure 5-Raman spectra in the 100-1800 cm-' region of the methanol solvate (a) and form I (b).
Table Ill-Bond Molecule
58 79 77 100 sh
A
U,
crn-'
23 28 37 47 52
66 12 8 13 10 11 12
77 81
-
117 120 -
Intensity
55 sh 16 sh 100 45 98 96
44 50
Distances and Angles of the Sulfamethazine Bond Distance, x 10 nrn
C(1b V 7 ) C(1F-42) C(1b C ( 6 ) C(+C(3) C(3P44) C(4kC(5) C(4kS(8) C(5bC(6) S(8t-0(9) S(W-O(l0)
150
50
100
rx",cm
'
Figure 6-Raman spectra of lattice vibrations of the sulfamethazine solvate with methanol (a) and sulfarnethazine form I (b).
O(lO)-S(8)-N(ll) 0(1O)--S(8)-0(9) S(8)-N(ll)-C(12) N(ll)-C(l2)-N(13) N(llkC(12)-N(17) N(17)-C(12)-N(13) C(12)--N(13tC(14) N(13bC(14bC(15) N(13+C(14)-C(18) C(15)--C(14)-C(18) C(14kC(15)-C(16) N(17tC(16)-C(15) N(17)-C(16)-C(19) a
S(8)-N(ll) 1.373 (6) 1.399 (6) N(llkC(12) C(12)-N(13) 1.392 (6) C(lZbN(17) 1.372(6) 1.397 (6) N(13)-C(14) 1.382 (5) C(14)-C(15) 1.738 (4) C(14)-C(18) 1.375 (6) C(15)-C(16) C(16)--N(17) 1.427 (3) 1.438 (3) C(16tC(19) Bond Angle, 109.1 (2) 119.0 (2) 127.9 (2) 113.5 (4) 117.6 (4) 128.9 (4) 115.5 (4) 120.3 (4) 117.0 (4) 122.7 (4) 119.0 (4) 121.7 (4) 116.7 (4)
C(15)-C(16)--C(19) N(7)-C(l)-C(2) N(7)-C(l)-C(6) C(6bC(l)-C(2) C(3)-C(2&C(1) C(4)-C(3)-C(2) C(5)-C(4tC(3) C(5)-C(4bS(8) C(3tC(4)-S(8) C(6)-C(5)-C(4) C(4tS(8)-N(ll) C(4)-S(8)-0(9) C(4)-S(8jO(lO) 0(9tS(8!-N(ll)
1.632 (4) 1.402 (5) 1.336 (5) 1.31915) 1.346 (5) 1.387 (6) 1.495 (7) 1.366 (6) 1.354 (5) 1.505 (7) 121.6 (4) 121.0 (4) 120.1 (4) 118.9 (4) 120.1 (4) 120.6 (4) 119.3 (4) 119.8 (3) 120.8 (3) 120.3 (4) 108.6 (2) 108.8 (2) 107.9 (2) 103.0 (2)
The standard deviations are given in parentheses
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istic of amino and amido groups and the existence of a 3090 cm-’ band in the spectrum of form I. In the 1700-150 cm-’ region (Fig. 5 ) there was a change in the intensity of the 870 and 438 cm-’ bands and the appearance of the two bands at 507 and 303 cm-’, absent in the spectrum of form I. For the lattice vibrations, a study of the low frequency region (Fig. 6) allows immediate identification of the different forms. Apart from the crystals obtained from methanol, the spectrum of form I was observed for all crystals. Characteristic frequencies of form I and the solvate are listed in Table 11. Form I is characterized by an intense pattern located between 30 and 60 cm-‘; in addition, bands at 19,91,105, and 138 cm-’ are specific to form I. The solvate was identified and characterized by intense bands a t 23, 52, 77, 81, and 120 cm-I, which were not observed for form I. S t r u c t u r e Determination-Sulfamethazine crystalline form I, C1,Hl4N4O2S(mol. wt. 262), obtained from absolute alcohol had the following unit cell dimensions and angles: a = 0.7426 (2) nm; b = 1.8874 (8) nm; c = 0.9317 (2) nm; p = 9.906 Mo-Ka ; (A = (2) nm; V = 129.6 nm3; 2 = 4; peal= 1.38 g . ~ m - ~ 0.071069 nm); space group = P2Ja. To complete the present study, we measured the crystalline parameters and determined the structure of form I. Our results are in good agreement with those reported by Basak et a1.12 Sulfamethazine exhibits .Ir-electron delocalization (Table 111) leading to intense conjugation at the level of the pyrimidyl radical and a marked quinonic effect on the aminobenzene group. This effect has been observed for one of the forms of and sulfabenzamide,’ for form I of sulfameth~xypyridazine,’~ for s~lfadimethoxine.’~ Apparently this effect facilitates the solubility of the compound and consequently increases its bioavailability. The crystalline structure is held together by three hydrogen bonds and by Van der Waals forces (Table IV). The molecular conformation is presented in Fig. 7.
Figure 7-A stereoscopic drawing of form I of the sulfamethazine molecule (PLUTO program, ref. 1 1).
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1 Journal of Pharmaceutical Sciences Vol. 74, No. 4, April 1985
Table IV-Intermolecular Bonds: Hydrogen Bonds and Van der Waals Contacts for Sulfamethazine Form I’
Hydrogen Bonds
Code for symmetry 1, x, y, z
11.2-x,1 - y , 2 - z 111, -0.5 + X, 0.5 - y, z IV, 1.5 - X, -0.5 y. 2 - z 0.3097 nm N(7),-H(7). . . N(l7),1 N(ll),-H(ll). . ~0(10)111 0.2947 nm 0.3212 nm N(7),-H’(7). . . N(13),” Van der Waals Contacts N(7). . . ‘C(3) 0.3408 nm N(7). . . .C(18) O(9)’. . .C(3) 0.3393 nm O(9). . . -C(15) O(lO)-..C(S) 0.3415 nm O(9). . . -0(10) C(1). ’ ’ .C(2) 0.3395 nm
+
a
0.3456 nm 0.3321 nm 0.3481 nm
Does not include those bonds and contacts that are <0.35 nm.
It can be concluded from the results of the different physicochemical studies on sulfamethazine that whatever the solvent used, except for methanol, all the crystals corresponded to a single polymorph even though they had different habits. The structure of this polymorph (designated form I) has been characterized. The crystals we isolated from methanol were identical to those reported by Abdel Hadi et ale6excepted that we identified a methanol solvate of sulfamethazine. We noted, in fact, that if the crystals obtained from methanol were left in open air for some time before grinding, the solvate completely disappeared and the polymorph then corresponded to form I. The methanol solvate was shown to have a sulfamethazine:methanol composition of l : l . 1 5
References and Notes 1. Rambaud, J.; Maury, L.; Lefebvre, C.; Roques, R. Znt. J. Phurm. 1983.15.199-212. 2. Maury, L.; Rambaud, J.; Pauvert, B.; Audran, M.; Lasserre, Y.; Berg&,G. Pharm. Acta Helu. 1984,59,112-117. 3. Yang, S.S.; Guillory, J. K. J . Phurm. Sci. 1972.61,26-40. 4. Kurhnert-Brandstatter, M.; Wunch. W. Microchim. Acta fWied 1969,1297-1307. 5. Mesley, R. J.; Hougthon, E. E. J. Phurm. Phurmacol. 1967,295304. 6. Abdel Hadi, I.; Mezosi, J.; Kedvessy, G.; Morvay, J. Pharmazie 1977,32,791-793. 7. Perkin-Elmer Corp. Norwalk, CT, 1966. 8. Susa, K.; Steinfink, H. J. Solid State Chem. 1971,3,75-82. 9. Main, P.; Fiske, S. J.; Hull, S. E.; Lessinger, L.; Germain, G.; Declercq, J. P.; Woolfson, M. M. “MULTAN 80. A System of Computer Programs for the Automatic Solution of Crystal Structures from X-ray Diffraction Data”; University of York England and Louvain-la-Neuve, Belgium, 1980. 10. Sheldrick, G . M. “SHELX-76: Program for Crystal Structure Determination”; University of Cambridge: England, 1978. 11. Motherwell, S; Clegg, B. “PLUTO. Program for Plotting Molecular and Crystal Structures”; 1978. 12. Basak, A. K.; Mazumdar, S. K.; Chaudhuri, S. Acta Crystallogr. 1983.(239.492-494. 13. Rambaud, J.;. Roques, R.; Declercq, J. P.; Germain, G.; Sabon, F. Bull. SOC.Chzm. France 1981,2,153-157 14. Shefter, E.; Chmielewicz, Z. F.; Blount, J. F.; Brennan, T. F.; Sackman, L. F.; Sackman, P. J. Phurm. Sci. 1972,61,872-877 15. Rambaud, J.; Maury, L.; Pauvert, B.; Berg&, G.; Audran, M.; Lasserre, Y.; Declercq, J. P. Acta Crystallogi-., in press.