Relative Stabilities of the Five Polymorphs of Sulfathiazole

Relative Stabilities of the Five Polymorphs of SulfathiazoleAine Munroe, Åke C. Rasmuson, B. Kieran Hodnett, and Denise M. Croker*

Solid State Pharmaceuticals Cluster, Materials and Surface Science Institute, Department of Chemical and Environmental Sciences,University of Limerick, Ireland

ABSTRACT: The relative stabilities of the five polymorphs of sul-fathiazole have been investigated using solution-based and solid-statemethods. In the lower temperature range, the stability order is pro-posed to be FI < FV < FIV < FII < FIII. FI and FV were identified asthe least stable polymorphs below 50 °C using a combination of solu-bility measurements and isothermal suspension equilibration, withFII, FIII, and FIV displaying very similar stabilities. Between 30 and50 °C, the stability order was established as FIV < FII < FIII. At10 °C, FII is still more stable than FIV, but it was not possible toplace FIII in relation to these two forms. Above 100 °C, the resultsfrom DSC and high-temperature XRD measurements suggest that thestability order changes completely as a result of several enantiotropictransitions. In this upper temperature range, FII and FIII are the leaststable forms, with FII being less stable than FIII. The stability order among the remaining three forms is FI < FV < FIV initially,but this reverses with increasing temperature, and as the transition into a melt is approached, a stability order of FII < FIII < FIV <FV < FI is suggested.

■ INTRODUCTIONKnowledge of the polymorphic stability of a drug substance isvital, so that conditions can be defined to control the isola-tion of the desired polymorph: If a metastable polymorph isrequired from a monotropic system, precautions must be takenduring crystallization and storage to avoid transformation tothe more stable form, whereas if the system is enantiotropic,detailed knowledge of the transition point is necessary to main-tain the desired polymorph. Polymorph stability is deter-mined by the free energies of different polymorphic forms. Thelower the free energy of a given polymorph, the more stable theform is, and hence, a spontaneous change from one form toanother is accompanied by a decrease in free energy. The solu-bility of different polymorphs of the same compound decreaseswith increasing stability, that is, with decreasing free energy.Therefore, comparing the solubilities of polymorphs is a reliablemethod for assessing their relative stabilities. It should be clearthat the stability order between polymorphs is independent ofthe solvent; that is, it is entirely governed by the solid phases.However, the rate by which equilibrium is reached in the deter-mination of solubility can depend significantly on the solvent.Another useful technique for assessing the order of stability ofrespective polymorphs is to perform so-called “suspensionequilibration” experiments. In this method, a mixture of twopolymorphs is added in solid form to a solvent and agitated,and sufficient time is allowed for the suspension to reachequilibrium. Polymorphic transformations are facilitated by thesolvent, and thermodynamically, the more stable polymorphwill prevail if the process is given sufficient time. It is alsopossible to recover an alternative polymorph that is more stablethan either of the starting materials. Again, the solvent will not

influence on the equilibrium form remaining in the solvent but cansubstantially influence the time it takes to reach equilibrium. In thesolid state, high-temperature powder X-ray diffraction (HTPXRD),differential scanning calorimetry (DSC), and hyperdifferential scan-ning calorimetry (HyperDSC) can give information on polymorphstability by investigating solid-state polymorphic transformations.Sulfathiazole (STZ) (Figure 1) is a well-known sulfonamide

antibiotic agent whose crystallographic properties have beenstudied extensively throughout the past 40 years.1−6

The five polymorphs of sulfathiazole are widely reported inthe literature,7,8 but confusion arises over the naming of thepolymorphs and their preparation methods. Recent work byBakar et al.27 presents a comprehensive review of the reportedpreparation methods for the five polymorphs of sulfathiazole,along with an account of the preparation of each form in a purestate using a selected method. In this work the polymorphs arelabeled FI−FV in accordance with CCDC reference codes asper the works of Blagden et al.,9 Davey et al.,10 and Chan et al.4

(Table 1), in good agreement with the aforementioned review.

Received: December 12, 2011Revised: April 24, 2012

Figure 1. Sulfathiazole molecule.

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© XXXX American Chemical Society A dx.doi.org/10.1021/cg201641g | Cryst. Growth Des. XXXX, XXX, XXX−XXX

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A number of solvates have also been reported forsulfathiazole11,12 but are not considered in this work.The solid-state transformation of sulfathiazole polymorphs

has been reported. When the structures of FII and FIII wereinitially reported by Kruger and Gafner,1,2 it was noted that themelting point of FIII was 174−175 °C, but sometimes atransition occurred at 174−175 °C followed by melting at200−202 °C. FII showed similar melting and transition points.The authors identified this as the transition to FI. Anwar et al.5

thoroughly characterized the four known polymorphs of sul-fathiazole in 1989 and noted that DSC showed mixed behavior,with transformations occurring between 150 and 170 °C beforemelting at 201 °C. Lagas and Lerk13 reported the meltingpoints of FI, FV, and FIII as 201, 196.5, and 173.6 °C, respec-tively. For the next 25 years, the solid-state transformation ofsulfathiazole did not appear in literature until 2006, whenZeitler et al.14 characterized the transitions of the five poly-morphic forms of sulfathiazole by terahertz pulsed spectroscopyand DSC. Zeitler et al. noted that FII, FIII, and FIV convert toFI at varying temperatures between 147 and 177 °C throughsolid-state transformations. They noted that FV melted at196 °C. They also noted it was not possible to differentiate theforms based on DSC alone, and the work also includedHyperDSC, which resulted in partial inhibition of therecrystallization of the lower melting form.Since the discovery of the fifth polymorph,7,14−25 the thermo-

dynamic stability order of all five forms of sulfathiazole has notbeen determined. It has been suggested, based on the packingcoefficients and the calculated densities, that the stabilities ofthe sulfathiazole polymorphs are in the order FI < FII < FIII <FIV (Blagden et al.9). In an earlier work based on solubilitydeterminations, Khoshkhoo and Anwar26 reported that thestability order is FI < FV < FIV < FIII, whereas Lagas andLerk13 reported that the order is FV < FI < FIII. It is clear thatthere are inconsistencies that need to be addressed, as sul-fathiazole continues to be used extensively as a model com-pound for polymorphism studies.In the present study, the stabilities of all five polymorphs of

sulfathiazole were assessed using a combination of solution-based and solid-state analyses. A critical part of being able toperform this work was the reliable production of pure poly-morphic forms.

■ EXPERIMENTAL SECTIONMethods as described in Bakar et al.27 were used for the production ofFII (Table 3, method 527), FIII (Table 4, method 227), FIV (Table 5,method 227), and FV (Table 6, method 127). FI was produced usingthe method described by Blagden et al.9 and Anwar et al.:5

Commercial sulfathiazole (a mixture of FIII and FIV) was placed ona dish and heated in an oven to 180 °C for 15 min. The crystals wereremoved from the oven and placed in a sealed container in adesiccator. The crystals were sometimes observed to have a pink tinge,but this did not affect the quality of the FI polymorph obtained.

For all of the preparation methods mentioned above, the poly-morphs remained stable during storage in sealed containers in adesiccator for up to 2 months.

Solubility Measurements. A thermostatic water bath (GrantGR150 with S38 stainless steel water bath; volume, 38 L; 690 × 300 ×200 mm; stability, ±0.005 °C; uniformity, ±0.02 at 37 °C) with aserial magnetic stirrer plate placed on the base was used. Twenty-fivemilliliter test tubes (150 × 25 mm) with a Teflon-coated magneticstirrer were charged with solvent and monitored until the temperatureof the solvent had reached the temperature of the water bath. Excesssolid of the different pure polymorphs was added to each of the testtubes. The solutions were agitated at 500 rpm and allowed toequilibrate for 48 h in the temperature range of 5−50 °C in incrementsof 5 °C. The high stirring rate was required to maintain the solids insuspension. After equilibration, agitation was stopped, and the solidswere allowed settle for 2 h. Samples of the clear saturated solution(approximately 4 mL) were transferred from each of the test tubes intriplicate to clean dry weighed vials (mass of dry vial = mempty) usingpreheated syringes. A 0.2-μm, 15-mm-membrane-diameter syringefilter was attached to the head of the syringe before the saturatedsolution was passed into the vials to further ensure that no suspendedsolid was present. The amount of liquid sample in each vial wasdetermined by weighing the vial with liquid (mass = mliq) andsubtracting the weight of the dry vial. Samples were then dried at roomtemperature, and the mass was monitored until no further changeoccurred. Finally, the vials were placed in an oven (Lenton ThermalDesigns oven) at 45 °C to ensure complete dryness. The mass of drysolids was recorded (mass = mdry). All weighing was carried out using aMettler Toledo AX054 balance with a weighing capacity of up to 520 gand a readability of 0.1 mg. The solubility of the polymorphs in thesolution, Cs (g of solute/g of solution), was calculated as

=−−

Cm m

m msdry empty

liq empty (1)

At all temperatures, a portion of the solid in contact with the solutionprior to the removal of the fixed volume was also collected, filtered,and dried, and the polymorphic form verified by PXRD to ensure thatthe original phase had not transformed.

Isothermal Suspension Equilibration Experiments. A mixtureof two pure sulfathiazole polymorphs in powder form was dispersed inpresaturated (with respect to FIII sulfathiazole) ethanol, 1-propanol,or water at 10, 30, or 50 °C for 3 or 7 days with agitation. Thesaturated solutions of sulfathiazole were prepared at each respectivetemperature by adding the amount of FIII sulfathiazole required forsaturation to the pure solvent, heating to 5 °C above the saturationtemperature for 1 h, cooling to the desired temperature, and holdingfor a further 30 min prior to addition of the solid forms, with agitationprovided throughout. A saturated solution was used to preventcomplete dissolution of either polymorph.

Approximately 0.02 g of each pure polymorph was added to 5 mL ofthe prepared solution in an 8 mL glass vial pre-equilibrated at theappropriate temperature in a Grant GR150 thermostatic water bath.Agitation was provided by means of a 10-mm magnetic flea, and theagitation rate was held at 230 rpm. After 3 days, the excess solids werefiltered using 25-mm poly(vinylidene difluoride) (PVDF) filter paperfrom Millipore and allowed to air-dry. PXRD analysis was undertakenon the recovered solids to determine the phases present. Theprocedure was repeated with a 7-day equilibration period to allow fortransformations with very slow kinetics.

Table 1. Lattice and Crystallographic Data for the Five Polymorphs of Sulfathiazole

polymorph FI FII FIII FIV FV

a (Å) 10.554 8.235 17.57 10.867 14.33b (Å) 13.22 8.55 8.57 8.543 15.273c (Å) 17.05 15.58 15.583 11.456 10.443β (deg) 108.06 93.67 112.93 88.131063 91.05CCDC ref code SUTHAZ01 SUTHAZ SUTHAZ02 SUTHAZ04 SUTHAZ06

Crystal Growth & Design Article

dx.doi.org/10.1021/cg201641g | Cryst. Growth Des. XXXX, XXX, XXX−XXXB

X-ray Diffraction (XRD). Powder XRD was performed using aPhilips X’Pert-MPD PRO diffractometer with nickel-filtered Cu Kαradiation (λ = 1.542 Å) as the X-ray source. The Cu Kα diffractometeranode was run under a tension of 40 kV and a current of 35 mA. AnX’Celerator strip detector was used to collect the diffracted data. Driedground samples were placed on a zero-background sample holder, andthe samples were scanned over a range of 5−55° 2θ or 5−35° 2θ usinga step size of 0.02° 2θ and a scan speed of 0.02° 2θ/s.High-temperature XRD was performed using an Anton Parr

HTK1200 stage in conjunction with the above diffractometer. Beforemeasurement, the chamber was calibrated with an indium standard tonote the temperature lag between the chamber and the controller. Thetemperature difference was found to be 13 °C (i.e., the chamber was13 °C higher than the temperature indicated on the controller), andthis was taken into account in the analysis. Samples were measuredunder nitrogen at a heating rate of 20 °C/min from room temperatureto 220 °C, using scan parameters similar to those listed above. Sampleswere placed on aluminum foil that had been pretreated with 1 MNaOH for 3 min to remove any coating, resulting in an aluminumoxide background with a peak at 25° 2θ.Differential Scanning Calorimetry (DSC). DSC was performed

on a Perkin-Elmer Pyris 1 instrument, which was calibrated usingindium (mp 156.6 °C; ΔH = 28.45 J/g). Calibration was performedfor each heating rate and applied for each analysis to account for anychanges in the thermal profiles and the thermal lag resulting from theincreased heating rates. For each experiment, 2−5 mg of sample wasaccurately weighed into a hermetically sealed aluminum pan. An emptyaluminum sample pan was placed in the reference holder, and bothholders were covered with platinum lids. The sample and referencewere heated to 240 °C at 20, 100, and 300 °C/min using nitrogen as apurge gas. The heat flow (milliwatts) was measured as a function oftemperature.Raman Spectroscopy. Sulfathiazole samples were analyzed using

a Renishaw Raman microscope system. The samples were placed,and areas of analysis located, on the stage of a Leica microscope, with10×, 20×, and 50× objective lens. Measurements were made atroom temperature using a 514-nm argon laser at 10% power, and thelaser spot size was less than 5 μm. Samples were scanned from 150 to3310 cm−1 with an exposure time of 50 s. Multiple (five) acquisitionswere made to ensure that a representative spectrum was obtained.

■ RESULTSCharacterization of the Pure Polymorphs. Raman

spectra were collected for polymorphs FII, FIII, FIV, and FV(Figure 2); a satisfactory spectrum of FI could not be collected

because of its powder optical properties, which caused thesample to fluoresce. Although it was possible to differentiate

between the forms with this technique, identification of mix-tures of polymorphic forms proved difficult.Each of the pure polymorphs exhibited a unique DSC profile

at 20 °C min−1 heating rate (Figure 3). The DSC traces of

forms FII, FIII, and FIV showed a broad endotherm in the130−170 °C region, indicative of a solid-state polymorphictransformation, and a second endotherm at 201 °C indicative ofthe melting point of FI. FV exhibited an initial endotherm at195 °C followed directly by an exotherm that is indicative of amelt recrystallization. FII exhibited a small endotherm at 195 °C,which indicated that a portion of FII transformed to FV as well,or that there was a slight impurity of FV in the prepared FII.In general, the DSC traces were in good agreement with thefindings of Bakar et al., with the exception of FII and FIII. Inthis work, FII was observed to transform to FI at a lower onsettemperature than that at which FIII transformed, whereas Bakaret al. reported the opposite. This could be a function of thedifferent heating rate employed: 20 °C/min was used here asopposed to 10 °C/min in the earlier study. The repeatability ofthe DSC data showed that onset times were within 1° whenmultiple samples of the same polymorph were analyzed. It wasnoted in a previous study14 that it is not possible to distinguishthe different polymorphic forms by thermal analysis alone.However, under the conditions of this study (in the absence ofdiluents), the pure forms were distinguished from one anotherusing DSC. When mixtures of polymorphs were present, theDSC endotherms could not be used to differentiate individualpolymorphs present, as the mixtures caused the endotherms toshift and merge. Therefore, DSC alone could not be used toanalyze the polymorphic purity of samples of sulfathiazole.PXRD patterns of each of the sulfathiazole polymorphs

showed significant similarities, especially for FII, FIII, and FIV,but distinguishing peaks were identified for each form (Figure 4and Table 2). It was difficult to obtain a pure sample of FIVwithout a trace of the FII XRD peak at 21.6° 2θ. Once the FIIpeak was less than 1% of the sample, the FIV material wasconsidered to be as pure as possible.Theoretical diffraction patterns for each polymorph were

generated using Mercury 2.2. There was good agreementbetween the experimental patterns and these theoreticalpatterns (Figure 4), indicating that the polymorph preparationmethods were successful. There was some difference in theintensity profiles of the peaks compared to the theoreticalpatterns; this was due to preferred orientation effects, whichpersisted even when samples were ground prior to analysis.

Figure 2. Raman spectra of the FII, FIII, FIV, and FV polymorphs ofsulfathiazole using laser excitation of 532 nm.

Figure 3. DSC profiles of FI, FII, FIII, FIV, and FV sulfathiazolemeasured at a heating rate of 20 °C min−1.


dx.doi.org/10.1021/cg201641g | Cryst. Growth Des. XXXX, XXX, XXX−XXXC

The slight shift observed between the theoretical and experimentalpatterns is thought to be due to temperature differencesbetween the original single-crystal data used for calculatingthe theoretical patterns and the powder obtained taken in thepresent work, especially with respect to the high-temperaturePXRD data presented later. At higher temperature, the latticespacing (d value) increases as a result of thermal expansion, and inthe context of Bragg’s equation, an increase in d value corresponds

to a shift to lower 2θ value. Accordingly, we would expect thetheoretical pattern to present the peaks at somewhat higher 2θpositions.

Solubility Measurements. Solubilities were successfullydetermined for FIII in propanol, ethanol, and water; for FIV inethanol and propanol; and for FII in ethanol only. Theremaining measurements were not successful because ofpolymorphic transformation during the equilibration time or,in the case of water, because the differences in measured valuesbetween FII, FIII, and FIV were within experimental uncer-tainty. As illustrated in Figure 5, the solubility of sulfathiazole isquite low in all solvents, with the greatest solubility observed inethanol, followed by propanol and then water. Commercialsulfathiazole (a mixture of FIII, FIV, and an amorphous phase)was reported by Bakar et al.27 to be soluble in acetonitrile,isopropanol, sec-butanol, and water, and good agreement wasobserved with our results for FIII in water and propanol. FI,FIII, and FIV sulfathiazole were described by Khoshkhoo andAnwar26 to be soluble in water, n-propanol, and acetone. Inabsolute terms, both our solubility values for FIII and FIV inwater at 30 °C agree well with those reported by Khoshkhoo

Figure 4. PXRD patterns for FI−FV sulfathiazole as labeled. The dashed traces represent the theoretical patterns calculated from CCDC filesSUTHAZ01, SUTHAZ, SUTHAZ02, SUTHAZ04, and SUTHAZ06 for FI−FV, respectively, using Mercury 2.2. Prominent hkl planes are indicated.The solid traces represent the experimental patterns of sulfathiazole solids prepared as described above.

Table 2. Distinguishing PXRD Peaks for the FivePolymorphs of Sulfathiazole

polymorphdistinguishing PXRD peaks 2θ (deg), λ =

1.54 Å

FI peaks at 17.7° 2θ and 20.9° 2θFII major peak at 21.6° 2θ, peak at 25.18° 2θ,

and triplet at 15° 2θFIII major peak triplet at 21.7° 2θ, peak at

22.9° 2θ, and doublet at 20−20.4° 2θFIV major peak at 22.22° 2θ and peak at

25.57° 2θFV peak at 23.3° 2θ and doublet at

15.9−16.2° 2θ


dx.doi.org/10.1021/cg201641g | Cryst. Growth Des. XXXX, XXX, XXX−XXXD

and Anwar, whereas our result in n-propanol is somewhathigher than theirs.The solubilities of the three polymorphs were very similar

between 10 and 35 °C in ethanol. Above 35 °C, FIV appearedto have a slightly higher solubility than FII or FIII. The data onsolubility in propanol indicate that FIII and FIV exhibit anenantiotropic relationship with a crossover in stability at 20−21 °C;FIII is more stable than FIV above this temperature, and vice versabelow this temperature.Accurate solubilities could not be determined for FI and

FV. FI transformed quickly upon contact with solvent, and itwas not possible to generate the quantity of FV needed forthe solubility study. Improvised experiments were attemptedwhereby known quantities of FI and FV were independentlydissolved in pure ethanol. A greater amount of FI was observedto dissolve in these experiments, suggesting that FI is less stablethan FV, but it was not possible to further confirm this findingexperimentally. Solubility data were determined as accurately aspossible. However, within the experimental error, the solubilitycurves for the polymorphs within each solvent system lie tooclose together to differentiate accurately, especially at lowertemperatures.Isothermal Suspension Equilibration. The solid forms

recovered following 3- and 7-day equilibration times were char-acterized with PXRD, and the results are summarized in Tables 3and 4, respectively.

Binary Mixture FI + FII. Mixtures of forms FII and FInormally underwent a transformation to FII. This indicates thatFI is less stable than FII. In one instance (ethanol at 50 °C),a polymorph that was not originally presentFIIIwasidentified. This illustrates that a new more stable polymorph,namely, FIII, nucleated and that the existing solids underwent acomplete transformation to this form. This nucleation of FIIIwas seen only in ethanol at 50 °C, which can be considered arange more favorable to polymorphic transformations in thesulfathiazole system given the relatively larger differences insolubilites observed in this temperature range for polymorphsFII, FIII, and FIV of sulfathiazole. It can be summarized that,over the entire temperature range, FI is less stable than FII, andat 50 °C, the order of stability is F1 < FII < FIII.

Binary Mixture FI + FIII. Pure FIII was recovered in allinstances of this mixture, establishing that FI is less stable thanFIII across the entire temperature range.

Binary Mixture FI + FIV. Depending on the experimentalconditions, this polymorphic mixture underwent transforma-tions to FIV, FIII, a mixture of FIV and FIII, and a mixture ofFII and FIV. However, at all three temperatures, there werecases in which only FIV remained, clearly showing that FIV ismore stable than FI, and especially in ethanol, the conversionwas promoted. The other forms that appeared under variousconditions, namely, FII and FIII, are all similar in stability toFIV. Clearly, under the conditions used, FII and FIII cannucleate, and FI can transform into these forms through theintermediary of FIV or directly. At 50 °C in ethanol, only FIIIwas observed in the final solids; this indicates that, under theseconditions, FIII is more stable than FIV and FI.

Binary Mixture FI + FV. This polymorphic mixture under-went transformations to FII, FIII, and FIV. The most commonnew polymorph present at the end was FIV. FI and FV werenever observed in the final solids obtained at the end ofthe experiment, and therefore, the stability order between FIand FV cannot be safely established from these experiments.However, given the facts that neither FI nor FV remained in thefinal mixture and that, in every case, at least one newpolymorph nucleated, this experiment verifies that these formsare less stable than FII, FIII, and FIV.

Binary Mixture FII + FIII. In most instances of this mixture,the slurry remained as a mixture of FII and FIII at the com-pletion of the equilibration time. This was the case in all experi-ments at 10 °C. However, at 30 and 50 °C, several experimentsresulted in pure FIII, and the fraction of such experi-ments clearly increased with increasing equilibration time.This establishes FIII as more stable than FII at 30 and 50 °C,

Figure 5. Solubilities of FII, FIII, and FIV sulfathiazole as determinedgravimetrically after 2 days of equilibration in ethanol, propanol, andwater as a function of temperature. The polymorph form was verifiedupon completion of the equilibration time using PXRD.

Table 3. Polymorphic Compositions of Solids Recovered after 3 Days of Equilibration of Binary Polymorphic Mixtures inPresaturated Solvents at 10, 30, and 50 °C as Identified by PXRD

starting binary polymorph mixture

solvent,temperature FI + FII

FI +FIII FI + FIV FI + FV FII + FIII FII + FIV

FII +FV FIII + FIV

FIII +FV FIV + FV

ethanol, 10 °C FII FIII FIV FIV FII + FIII FII FII FIII + FIV FIII FII + FVpropanol, 10 °C FII FIII FIV FIV FII + FIII FII FII FIII + FIV FIII FII + FIVwater, 10 °C FII FIII FIV + FII FIII + FIV FII + FIII FII + FIV FII FIII+ FIV FIII FII + FIVethanol, 30 °C FII FIII FIV FII + FIV FIII FII FII FIII + FIV FIII FII + FVpropanol, 30 °C FII FIII FIV + FII FII + FIV FIII FII FII FIII + FIV FIII FIVwater, 30 °C FII FIII FII + FIV FIV FII + FIII FII + FIV FII FIII + FIV FIII FIII + FIVethanol, 50 °C FIII FIII FIV FIII... FIII FIII FII FIII FIII FIIIpropanol, 50 °C FII FIII FIV FII + FIII FII FII FIII + FIV FIII FIII + FIVwater, 50 °C FII FIII FIV FII FII + FIII FII + FIV FII FIII + FIV FIII FIII + FIV


dx.doi.org/10.1021/cg201641g | Cryst. Growth Des. XXXX, XXX, XXX−XXXE

but at 10 °C, the results do not establish the stability order. Thedata suggest that the transformation from FII to FIII is fastestin ethanol and slowest in water, as pure FIII is obtained in thismedium only at the highest temperature, 50 °C, and the longesttime, 7 days. This is due to the fact that the solubility is lower inwater than in the alcohols.Binary Mixture FII -FIV. In most instances of these

experiments, the remaining solid was identified as pure FII. Acomplete transformation to FII was observed at 10 and 30 °Cin ethanol and at all three temperatures in propanol. Thisclearly establishes that FII is more stable than FIV at all threetemperatures. However, at 50 °C in ethanol, the remainingsolid phase was pure FIII, suggesting that FIII is more stablethan FII and FIV, at least at 50 °C. In all water experiments, amixture of FII and FIV remained at the end. The transforma-tion is much slower in water, because of the overall lowersolubility of sulfathiazole in water.Binary Mixture FII + FV. Pure FII was recovered in all

instances of this mixture, establishing that FV is less stable thanFII across the entire temperature range. In addition, the datasuggest that the conversion from FV to FII is quite rapid.Binary Mixture FIII + FIV. This polymorphic mixture

remained as FIII and FIV at the end of the equilibration time inalmost all instances. However, at 50 °C, only FIII was detectedat the end, indicating that FIV transformed into FIII in ethanoland water. This confirms that, at 50 °C, FIII is more stable thanFIV, but at lower temperatures, the stability order is unclear.The data indicate that the transformation from FIV to FIII ismost rapid in ethanol, followed by water and then propanol.Binary Mixture FIII + FV. Pure FIII was recovered in all

instances of this mixture, establishing that FV is less stable thanFIII across the entire temperature range.Binary Mixture FIV + FV. Results from this mixture were

quite complex. At 10 °C, in all cases but one, the final materialwas a mixture of FII and FIV. This indicates that, at 10 °C, FVis less stable than FII, as the FV has disappeared, FIV remains,and FII has nucleated. However, after 3 days in ethanol at10 °C, the final product was a mixture of FII and FV, suggestingthat FIV has transformed into FII. The same situation wasobserved after 3 days at 30 °C in ethanol; however, FV wasnever found in any of the other experiments on this mixture.After 7 days in ethanol at 10 and 30 °C, FV was replaced by

FIV. All experiments at 50 °C led to either pure FIII or amixture of FIII and FIV. In addition to the ethanol experimentat 30 °C discussed in the preceding paragraph, the material atthe end contained FIV, sometimes in pure form, sometimestogether with FII, and sometimes together with FIII. These

experiments suggest that FIV is more stable than FV. This wasconclusively confirmed for 30 °C by the propanol experiments,and it is a reasonable interpretation of the results for the othertemperatures.

Solid-State Stability. PXRD patterns recorded during theheating of FII sulfathiazole from 20 to 202 °C demonstrate thesolid-state transformation of FII to FI above 144 °C (Figure 6).At 163 °C, the transformation is complete, with all peakspresent characteristic of FI sulfathiazole. The DSC trace for FII(Figure 3) showed a small endotherm at 195 °C, suggestingthat a small amount of FV was present. Peaks associated withFV were not observed in any PXRD patterns recorded in thisexperiment, but the amount of FV generated could be belowthe detection limit of this method. The PXRD patterns exhibita slight shift in the location of the peaks, but the sequence ofpeaks is correct. This is explained by the expansion of thecrystal lattice at higher temperatures. DSC indicated that themelt of pure FI had an onset at 201 °C. PXRD patternscollected at 197 and 199 °C were characteristic of FI, whereasat 202 °C, no peaks were observed, indicating that the FI crys-tals had melted.This experiment was carried out also for FIII and FIV

sulfathiazole, and in each case, a solid-state polymorphic trans-formation to FI was observed, in good correspondence with therecorded DSC data (Figure 6). For FV, no polymorphictransformation could be detected before the sample melted.The pure polymorphs of sulfathiazole were analyzed using

HyperDSC conditions to investigate whether the solid-state transformation from FII, FIII, FIV, and FV to FI couldbe surpassed and a characteristic melting point for each of thepure polymorphs determined. In addition, HyperDSC providesincreased capability to observe low-energy transitions, becausethe same amount of energy is released or absorbed over ashorter period of time (milliwatts), resulting in increased signalheight (greater sensitivity). HyperDSC was performed at and300 °C/min and is compared to the standard 20 °C/min tracein Figure 7.FI returned the same DSC profile at all heating rates (Figure 7).

As the heating rate increased, the peak onset moved to lowertemperatures, but only one characteristic peak was observed. Themovement to a lower onset can be attributed to the heat transferlag observed when using high heating rates.The thermal profiles of FII, FIII, and FIV obtained at higher

heating rates showed an exaggeration of the initial trans-formation endotherm (Figure 7). The onset temperature of thisendotherm increased with increasing heating rate. At 300 °C/min, the transformation of FII, FIII, and FIV to FI was still

Table 4. Polymorphic Compositions of Solids Recovered after 7 Days of Equilibration of Binary Polymorphic Mixtures inPresaturated Solvents at 10, 30, and 50 °C as Identified by PXRD

starting binary polymorph mixture

solvent,temperature FI + FII

FI +FIII FI + FIV FI + FV FII + FIII FII + FIV

FII +FV FIII + FIV

FIII +FV FIV + FV

ethanol, 10 °C FII FIII FIV FIV FII + FIII FII FII FIII + FIV FIII FII + FIVpropanol, 10 °C FII FIII FII + FIV FIV FII + FIII FII + FIII FII FIII + FIV FIII FII + FIVwater, 10 °C FII FIII FIV + FII FIV FII + FIII FII + FIV FII FIII + FIV FIII FII + FIVethanol, 30 °C FII FIII FIV FIV FIII FII FII FIII + FIV FIII FII + FIVpropanol, 30 °C FII FIII FIV FIV FIII FII FII FIII + FIV FIII FIVwater, 30 °C FII FIII FIV + FII FIII + FIV FII + FIII FII + FIV FII FIII + FIV FIII FIII + FIVethanol, 50 °C FIII FIII FIII FIII FIII FIII FII FIII FIII FIIIpropanol, 50 °C FII FIII FIV + FIII FIV FIII FII FII FIII + FIV FIII FIII + FIVwater, 50 °C FII FIII FIV FII + FIII + FIV FIII FII + FIV FII FIII FIII FIII + FIV


dx.doi.org/10.1021/cg201641g | Cryst. Growth Des. XXXX, XXX, XXX−XXXF

kinetically favorable and observed. Under the conditions used,it was not possible to surpass the transformation of thesepolymorphs to FI.However, when FV was heated at 100 and 300 °C/min, it

showed a single endotherm, indicating the melting of FV(Figure 7). There is a possibility that the two endothermsobserved at lower heating rates merged because of the lagassociated with HyperDSC. This might be the case at 100 °C/min, where a shoulder in the endotherm is observed, indicatingthe merger of two endotherms. At the higher heating rates, theinitial endotherm corresponding to the melting of the poly-morph is larger because of the increased sensitivity at higherheating rates.

■ DISCUSSION

In this work, solubility measurements could not conclusivelyestablish the stability order among the five forms of sul-fathiazole, partly because the solubilities in the three solvents usedwere quite low, which impacts the accuracy of the measure-ments; partly because metastable forms have a tendency toconvert into more stable forms during the equilibration period;

and partly because the solubilities of FII, FIII, and FIV are quitesimilar. However, the results do establish that FII, FIII, and FIVare very close from a stability point of view in the temperaturerange from 10 to 50 °C and that FI and FV are clearly lessstable in that temperature range. Solubility data further indicatethat FIII is more stable than FIV at 50 °C and that this order ispossibly altered at lower temperature (i.e., that the pair isenantiotropically related). Finally, solubility data demonstratethat the solubilities of FII, FIII, and FIV of sulfathiazole aregreatest in ethanol, followed by propanol and then water, butoverall, sulfathiazole is poorly soluble in all solvents. Earliersolubility measurements reported by Khoshkhoo and Anwar26

demonstrated the solubilities of FIII and FIV to be similar inn-propanol, water, and acetone and indicated an enantiotropicrelationship between FIII and FIV in n-propanol, albeit in thereverse order from that which we propose. This work clearlyestablishes that FII, FIII, and FIV are close in terms of stability,and we note that it has been shown that FII and FIV havesignificant structural similarities.28 The results presented hereprovide a foundation for investigating possible polymorphictransformations in the sulfathiazole system.

Figure 6. In situ PXRD patterns recorded at 25−202 °C during heating of the designated pure polymorphic forms at 20 °C/min under flowingnitrogen. Characteristic peaks for each of the forms are indicated with corresponding hkl values.


dx.doi.org/10.1021/cg201641g | Cryst. Growth Des. XXXX, XXX, XXX−XXXG

The isothermal suspension equilibration experiments con-firmed the highly metastable nature of FI and FV and providedfurther information with respect to the relative stabilities of FII,FIII, and FIV. However, complete clarity with respect to thestability order could not be reached. There are several reasonsfor this. The first reason is that FI and FV were never found atthe end of a suspension experiment where these two formswere added simultaneously from the beginning. The secondreason is that the rate of conversion is very low when thedriving force is very low, that is, when the forms are very closein stability, or at low temperatures. The isothermal suspensionequilibration experiments do reveal that FII is more stable thanFIV in the temperature range of 10−50 °C, that FIII is morestable than FIV at 50 °C, and that FIII is more stable than FII at30 and 50 °C. Combined, these results imply a stability order ofFIV < FII < FIII in the range 30−50 °C. At 10 °C, FII is morestable than FIV, but in all solvents, a mixture of FIII and FIVand a mixture of FIII and FII persisted after 3 and 7 days ofequilibration, which provides no information on where FIII isplaced at 10 °C (other than that FIII is clearly more stable thanFI and FV). This could be due to a lower “solubility-difference”driving force for conversion at 10 °C, coupled with a lower rateof conversion at the lower temperature. Hence, the stabilityorder at 10 °C remains somewhat unclear, and the possibleenantiotropic transition temperature between FIII and FIV at21−23 °C, as indicated by the solubility measurements, cannotbe verified. Overall, a stability order of FI < FV < FIV < FII <FIII is proposed from the isothermal suspension equilibrationexperiments at 30−50 °C, whereas at 10 °C, the position ofFIII is unclear. The result is in good agreement with thestability order reported by Khoshkhoo and Anwar,26 namely,FI < FV < FIV < FIII, and supplements the relative stabilityof FII to that finding. The stability order proposed by Lagasand Lerk13 (FV < FI < FIII) is also in general agreement withour findings, but with FV and FI interchanged. The stabilityorder predicted by Blagden et al.9 from density measurements

(FI < FII < FIII < FIV) gives a reasonably correct trend in thatFI is placed as the least stable form, but it is not able to resolvethe small differences in stability among FII, FIII, and FIV.The results of the equilibration at 30 °C for FII + FIV and

FIII + FIV suggest that the transformation of FIV to FII is morekinetically favorable than that of FIV to FIII, because the con-version to FII goes to completion whereas a mixture remainsfor FIII + FIV. This could be due to FII and FIV havingmutually identical structural features, which might facilitate thetransformation.28

The influence of the solvent on the rate of conversion wasobserved in several ways. Complete conversion to one purepolymorph was most common in ethanol and rarely observedin water, in good agreement with the solubility order observedfrom the solubility measurements. A higher rate of trans-formation is expected in a solvent in which the compound has ahigh solubility. The solvent can also interact with solutemolecules, and this molecular interaction might have someinfluence on stabilizing a metastable form and slowing, orpreventing, the onward transformation to a more stable form.In this work, this is evident in propanol at 50 °C, where amixture of FIII and FIV persists after an equilibration time of7 days. The equivalent experiment in ethanol and waterresulted in complete conversion to FIII within 3 and 7 days,respectively. This suggests an interaction between FIV andpropanol that slows the onward transformation to FIII.Complete conversion was also most likely at 50 °C, illustrat-

ing the effect of temperature on the rate of transformation.Experiments at 10 °C tended to remain as a mixture after7 days of equilibration. This is most likely due to a combinationof a reduced driving force and slower conversion kinetics atlower temperature.In the solid state, all of the polymorphs transformed to FI

before melting, suggesting that FI is, in fact, the most thermo-dynamically stable form at temperatures above 130 °C. At a20 °C/min heating rate, FII, FIII, and FIV showed one initial

Figure 7. HyperDSC of the pure polymorphs of sulfathiazole, as designated, at 20, 100, and 300 °C/min under flowing nitrogen.


dx.doi.org/10.1021/cg201641g | Cryst. Growth Des. XXXX, XXX, XXX−XXXH

characteristic endotherm, indicative of a solid-state trans-formation, before melting as FI. According to Burger’s heatof transition rule, an endothermic enthalpy of transition isindicative of an enantiotropic polymorph pair, with the thermo-dynamic transition point lying somewhere below the onset ofthat endothermic peak.29 Thus, FII, FIII, and FIV are allenantiotropically related to FI, with thermodynamic transitionpoints lying below 139, 153, and 156 °C, respectively. Thethermodynamic transition point of FIII to FI has been experi-mentally determined as 94.530 and 95.5 °C31 in the publishedliterature. The delay in observation of the endothermictransition peak is most likely due to the relatively high heatingrate used in this study. The relative stabilities of these threeforms in the temperature range of 130−200 °C are not as clear.It might be reasonable to assume that the polymorph thattransforms at the lowest temperature is least stable at highertemperatures, as it requires the least amount of energy to trans-form to FI. FV displays a melt recrystallization to FI at 198 °Cbefore melting as FI at 201 °C. This behavior does not dis-tinguish whether FV is enantiotropically or monotropicallyrelated to FI,31 but it does show that FV is less stable than FI at200 °C. Combined, these data propose a stability order of FII <FIII < FIV < FV < FI in the upper end of the range 130−201 °C.The molecular packing of the molecules in FI sulfathiazole is

different from the packing in the other forms.20 Blagden andDavey20 used graph set analysis to investigate the intermo-lecular interactions in FI, FII, FIII, and FIV polymorphs, all ofwhich are monoclinic. This showed that the FI structure is

based on a unique dimer growth unit packed into chains,referred to as α, consisting of two molecules that are hydrogen-bonded through two imine nitrogen and amino hydrogencontacts N2−H3. These dimers are linked in eight-memberedchains through H1−O2 hydrogen bonding. FII, FIII, and FIVall are based on a dimer growth unit referred to as β, con-structed from sulfato oxygen to aniline hydrogen (O2−H1)and aniline nitrogen to amino hydrogen (N1−H3) contacts,that is assembled into sheets, and the variation of assemblygives rise to the difference between the forms. FV is also uniqueand based on a tetrameric growth unit with a dimer chainstructure assembled into sheets. The transformations of FII,FIII, and FIV can be considered in terms of the β sheetsrearranging themselves into α chains, which are energeticallymore stable at higher temperatures (Figure 8).The stabilities of the five polymorphs inferred from the above

experimental measurements are represented in Figure 9,illustrating a relative stability order at specific temperatures.The solubility determinations in conjunction with the outcomeof the isothermal suspension equilibration were used to deter-mine the stability order below 50 °C. At higher temperatures,the onset temperature of the transformation endotherms obser-ved for each polymorph with DSC was used to propose theorder of stability. One polymorph was considered less stablethan another polymorph if it transformed to FI at a lowertemperature than that polymorph; however, we are aware thatthis approach can be used only as an indication of the order.Post-transformation, the polymorph is represented by a

Figure 8. Mercury 2.2 representations of the unit cells of (left) FII, FIII, and FIV and (right) FI.


dx.doi.org/10.1021/cg201641g | Cryst. Growth Des. XXXX, XXX, XXX−XXXI

transparent colored block. The stability of polymorphs prior totransformation to FI was approximated as the order observed atlower temperatures. FI itself is represented with a transparentcolor block post-melting.From the stability information, a schematic free energy dia-

gram for the system was constructed across the entire tempera-ture range (Figure 10). Here, polymorph stability is correlated

with free energy, with the most stable polymorph at anygiven temperature having the lowest free energy. Aschematic liquidus curve is included. In the lower temper-ature range, we excluded an enantiotropic transition betweenFIII and FIV, a transition that was indicated in the solubilitydata. As shown in Figure 10, the DSC data combined withsuspension equilibration data at 30 and 50 °C suggest thatthere is an enantiotropic transition point between these twoforms in the upper temperature range (or at least above50 °C). If FIV is more stable than FIII at 10 °C, it wouldsuggest that there are two enantiotropic transitions betweenFIII and FIV, which should be a violation of the phase rule.The relation between FII and FIII at 10 °C is not clear, butfor simplicity, we have kept FIII as the most stable phase at10 °C because we do not have any results pointing to anenantiotropic transition between these two forms. Eventhough not fully proved, we believe that FI is less stable than

FV in the low temperature range, as FI dissolves much morerapidly than FV. Polymorph behavior above 50 °C is indicated ina qualitative fashion only with the melting point (m.p.) of FIpresented at 201 °C.

■ CONCLUSIONSAs is evident in the numerous published works dedicated to it,the sulfathiazole system is challenging. In this work, the fivepolymorphs of sulfathiazole were prepared, and the purity ofeach polymorph was assessed using DSC, Raman spectroscopy,and PXRD. Based on a combination of solubility measure-ments and isothermal suspension equilibration experiments, itis clearly shown that, in the temperature range of 10−50 °C, FIand FV are less stable than FII, FIII, and FIV and there are onlysmall differences in stability among the latter three forms.However, it is established that, in the range of 30−50 °C, FIII ismore stable than FII, which, in turn, is more stable than FIV. At10 °C, we cannot experimentally clarify where FIII is positionedin relation to FIV and FII, only that FII is more stable than FIV.Based on the various experimental results, it is proposed that, inthe lower temperature range of 10−50 °C, the stability order isFI < FV < FIV < FII < FIII.At temperatures above 100 °C, the order of stability between

the polymorphs changes completely, as deduced from thetransformation behavior suggested by DSC and HTPXRD. FIIappears to be the least stable phase, followed by FIII. At first,the stability order among the three more stable forms is FI <FV < FIV, but with increasing temperature, this alters into thecomplete opposite. Accordingly, when approaching the finalmelting temperature, the stability order appears to be FII < FIII <FIV < FV < FI.In the lower temperature range, slurry experiments demon-

strated that the choice of solvent can have an impact on the rateof conversion from a metastable to a more stable polymorph.The transformation will be fastest in a solvent in which thecompound has a high solubility, but specific molecular inter-actions between the solvent and the molecule can also have aneffect.

■ AUTHOR INFORMATIONCorresponding Author*E-mail: [email protected].

NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTSThe authors gratefully acknowledge the generous support ofthis research under the Embark Initiative of the Irish ResearchCouncil for Science, Engineering and Technology (IRCSET).This material is based on works supported by the Solid StatePharmaceutical Cluster and by Science Foundation Irelandunder Grant 07/SRC/B1158

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Figure 10. Schematic representation of the free energy phase diagramfor the five polymorphs of sulfathiazole.


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Relative Stabilities of the Five Polymorphs of Sulfathiazole