64
RAYMONDN. CASTLEAND NORMAN P.W m
It is suggested that not quite all of the simple silicic a d d condenses to form the large polysilicic acids, but remains in equilibrium with the products of condensation. It is able to diffuse through the membrane, upsetting the equilibrium
Vol. 68
and forming more simple acid molecules. This probably explains the attack of sodium hydroxide solutionupon thegel. ~C~BNBCTADY. NBWYORS RBCEIVBD" APRIL9.1945 (17) hidneimanu-pt -ived
~~h~~ 15. 1843.
The Polymorphism of Sulfapyridine BY RAYMONDN.
CASTLE"^^ AND NORMAN F. W
In the course of the determination of the optical crystallographic properties of some of the sulfanilamide drugs and their derivatives, five polymorphic forms of sulfapyridine (2-sulfanilamidopyridine) were discovered.* The methods of preparation of these forms, their melting points and analyses (Table I), their optical crystallographic properties (Table 11). and their photomicrographs (Figs. 1-5) are presented. Experimental Reparation of ihe Forma of Sulfapyridine Sdfamdinc, Phase 1.-This form of sulfapyridine was
m
form. The solution wm d o w e d to cool slowly undisturbed to about 40°. thcn rapidly filtered, and the cryst& were w h e d with ether and air dried at room t e m m t u r e . Usually this method gave a preparation consisting of pure Phase 11. However. it was nccwary t o exercise great care with this procedure or the product was a mixture of P W I1 and IV. the latter predominating. W h e n dilliculty experieoced iu obtaining Phase I1 in puce fonn. a process of selective seeding was applied. A crop of crystals containing a mixture of Phases I1 and IVwas used to seed the bot n-propyl alcohol solution. The conditions described above w e followed and the crop of crystals filtered. dried and examined mimmapically. By repeating this process of selective seeding with crops of crystals successively richer in Phase 11, a pure prepration wa.. obtained.
obtained b y crystallization from hot water or methanol. and is the form occurring in commercial preparations of sulfapyridine. This form appears to he the stable modification at room temperature because all other forms (except Phase IV') have been observed to change into Phase I on standing at room temperature in the dry state. well protected from light and moistnrp.
Fig. Z.--Sulfapyridine,
Fig. I.--Sulfapyridine. I'haw I ( X W). Sdfepyridine, P W IL-In order to prepare this form of sulfapyridine. a slightly lcss than saturated solution of sulfapyridine in hot n-propyl alcohol was allowed to stand on the steam-bath at about 80". until crystals began to (In) Pmm L portion o( t h e Pb.D. thesis. Deprtrncnt of Chemir UT. wnircnity of colordo. (Ib) P-ot d d r e u . Bdtellc Uemori.1 Iaslitulc. Columbus 1. Ohio. (2) AIter this work cm sulfepfidime mmplcted. am sbstrnet of the mort 01 P. RC~.IICI. appc~rcd:C. A., a,2250 (1944). (3) Ph1V c h o z u into PhPv I . I t s meltimp: (l74-175+),
--
Phase I1 ( X 56).
When crystals of Phase 11 from n-propyl alcohol were allowed to stand in contact with the mother liquor, a mixture of Phase I and Phase I V was obtained. Phase I1 slowly changed into Phase I at room temperature. even when carefully dried arid stored in well-stoppered hottles protected from light. Sulfapyridine. Phase IIL-This form of sulfapvdioe was prepared by allowing a hot saturated solution of sulfapyridine in n-butyl. isobutyl. OT n-amyl alcohol to cool undistrubed to about 35". The solution was filtered rapidly, and the crystals were washed with ether. and air dried at room temperature. crystals of Pbare I11 h s e d completely into crystds of Phase I on standing in contact with the mother liquor for t w o days at room temperature. Crystals of Phase I11 changed into crystals of Phase I at a fairly rapid rpte even when perfectly dry. The crystals of Phase 111 were found t o he somewhat soluble in the immersion liquids used in studying the optical propenies. After crystals of Phaoe
POLYMORPHISM OF SULFAPYRIDINE
Jan., 1946
111 dissolved in the immersion liquids crystals of Phase I appeared.
-
that i t was sulfapyridine and that it did not contain solvent of crystallization. 5
.:.
-"
. . '
.
.
Fig. 3.-Sulfapyridine.
65
Phaw III ( X 56).
Sulfapyridine, Phase N.-This form of sulfapyridine was prepared from a hot saturated solution of sulfapyridine in n-propyl alcohol. T h e solution wascooled quiterapidly without shaking. The solution was atered rapidly, and the crystals were washed with ether and air dried at room temperature. This form also was obtained nearly pure from isopropyl alcohol under similar conditions. Preparations from ethyl alcohol contained appreciable quantities of this phase in addition to Phase I. At room temperature Phase IV appeared to have no tendency to change into Phase I either a t contact with n- or isopropyl alcohol solutions of sulfapyridine or when perfectly dry.
I
n
.
Fig. 5.-Sulfapyridine, Phase V ( X 56).
Melting Points and Analyses The melting points were determined on the Maquenne block apparatus which facilitated the placing of crystals on the block as the temperature was increased. All melting points are corrected. The melting points and analyses of the five polymorphic forms of sulfapyridine are summarized in Table I. TABLB I MELTINGPOINTSAND A".YSBS OF THE P o ~ u r r o w a r c Phase
FORMS OF SULPAPYRlDINB M. P. cor., 'C. Amdyxs.
95 nitrweo
Sulfapyridine Calcd.. 16.86 Phase I l91.&192. SI. dec. 16.75 16.74 Phsse I1 181-18Za 16.69 16.69 Phase 111 177 16.94 16.97 Phase IV 174.5-175' 16.91 16.95 Phase V a Part of the melt solidified on increasing the temperature. Part of the melt solidilied and remelted a t 1 8 6 190°. No melting point determinations or analyses were made.
Optical and Crystallographic Properties Leitz petroApparatus and Technique.-A graphic microscope Model No. 30CM was used in the present research. The light source was a fluorescent lamp equip+ with a 15-watt G. E. Fig. 4.-Sulfapyridine, Phase IV ( X 56). Mazda fluorescent tube, 350O0 white. The principal refractive indices a, i3 and y at Sulfappidinc,Phase V.-Attempts to prepare this phase io the pwe state wcre unsuccessful. I t frequently oc- 25 * 1". were determined by the immersion curred in moderate amonats in oreoarations from n- and method, using intederence figures as a guide in isopropyl alcohol solutions wh& ihey were allowed to selecting correctly oriented crystals. The immerstand undisturbed a few hours. Crystals of Phase V when sion liquids were those described by Winchell'P allowed to stand for long periods of time in contact with the mother liquor (n- or isopropyl solutions of sulfapyridine) disappear and crystals of Phases I and I V are found. AtternpL~t i o l h n a p&e preparation hy wlectivc stwling
failed. Preparations containing appreciable quantities of tlik phase have k n anallyred. aod the results indicated
(4) (d Winchell. "Blcmurt. of Optical M i n e d m , ' ' 5th ed.. John Wiley *ad Soas. he.. New York. N. Y.. 1937. p. 81. (b) Lnrren sod Bermen. "The M i p i e Dct.crrnioation of Nom~weMi~h,"2odnl..U S. .Depsnrncmtolthe 1nterior.Deologi-I S-cy Bulletim No. 848. Washington. D. C.. 1934. p. 12.
RAYMOND N. CASTLEAND N o w F. W m
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TABLEI1 O ~ C A CRYSTALLOGRAPHIC L PROPERTIES OF THE POLYMORPHIC FORMSOF SULFAPYRIDINE Habit 1 Tabular to equant I1 Lath shaped I11 Lamellar I V Tabular
Phase
V
Optic
Crystal system MonoclinicC
Extinction Yllb, Z h c 390d
Elongation
Mondic
Yllb, X h c
Parallel to b, 36'
- -- -
Orthorhombic X a, Y Yllb, Z h c Monoclinic
TriclMc(?) Calcd. for a,8, and y . Equant
?
a
38"s
b,Z
2V' 880
( -1
*
c
' 4
Parallel t o b,
Verylargc 74'
( -)
?
Verysmall
sign
+ + + -
Dispersion Verystrongaxia1,r Inclined, v
>r
Strongrhombic, v Axial,r> v Strong, r
-Refractive indicesba 8 . r > v' 1.670 1.736 1.8131
>d
1.585
>I
*
1.625
'
1.722
1.739
1.697 1.721 1.693 1.835' 1.745
* The values of the refractive indices are accurate to A0.002 unless otherwise noted.
1.761
Prien and Frondel, J . U r d , 46,756 (lSal), reported the following data: triclinic, pseudoorthorhombic; opticsign uncertain, 90'; a = c = 1.673. y = 1.770; crystals elongated laths; dispersion very strong. d Extincprobably negative; 2V tion position shows residual blue violet color. The dispersion is so strong that a purple fringe extends the entire length Keenan, J. Assw. OfiiOZ Agr. C k . ,27, 1.53 (1944),reported a = 1.680, 19 1.733, and y > 1.733. of the isogyre. Common orientation shows parallel extinction. Indeternunate due to +e extreme thinness of the plates. 6 Accuracy probably not greater than O.OO5. Anomalous dispersion. Indetermumble.
-
e
f
and Larsen and B e r m a ~ ~ . The * ~ optic axial angle 2V was calculated from the refractive indices a, 3, and 7 , using the more exact formula suggested by Larsen and B e r m a ~ ~ . ~ The opticall constants of the five phases of sulfapyridine are summarized in Table 11. Characteristic Details.-An inclined optic axis interference figure is obtained on the commonly observed orientation of crystals of Phase I. Thus the indices of refraction obtained on the common orientation are near j3 but are variable. The dispersion of the refractive indices is great, especially 8. An optic axis interference figure inclined toward the obtuse bisectrix is obtained on the commonly observed orientation of crystals of Phase 11. Thus 8 is the only principal index of refraction obtained on lhe common orientation. Crystals showing a centered acute bisectrix interference figure do not extinguish sharply and the interference colors are abnormal blue and yellow. The commonly observed orientation of crystals of Phase I11 yields a centered obtuse bisectrix interference figure. This orientation gives the principal indices of refraction j3 and y. The polarization colors are an abnormal shade of yellow. An abnormal shade of violet is occasionally observed. The commonly observed orientation of crystals of Phase IV yields an incline optic axis interference figure. 'This orientation gives B and a fairly constant value between j3 and y. The most commonly observed orientation of crystals of Phase V yields an interference figure ( 5 ) Ref. 4b, p. 6
in which one brush sweeps the field of view. From this orientation no principal indices of refraction are obtainable. The interference figure shows strong dispersion of an anomalous character. When the trace of the axial plane is in the three-nine o'clock position, the dispersion appears to be horizontal. However, in the 45' position, the dispersion appears to be inclined, showing a red fringe on the concave side of one isogyre and on the convex side of the other. It is signscant that the existence of more than one form of sulfapyridine was detected first by the different degree of dispersion, observed on the interference figures of crystals of Phase I and IV. A subsequent determination of the B indices of refraction showed the values to be widely different. In attempting to isolate the two forms, the other fonns were detected. The petrographic microscope proved to be a powerful tool with which to follow the degree of separation of the various forms. The determination of the melting points of the pure forms was possible only after careful microscopic study as a check against contamination of one form with another. S-arg 1. Five phases of sulfapyridine (2-sulfanilamidopyridine) have been discovered and methods of preparation of the pure phase described for four of them. 2. The optical crystallographic properties and melting points of these phases have been determined. BOULDER,COLORADO RECESVED MAY17,1945
