Mechanochemical Reaction of Sulfathiazole with Carboxylic Acids

Article pubs.acs.org/crystal

Mechanochemical Reaction of Sulfathiazole with Carboxylic Acids: Formation of a Cocrystal, a Salt, and Coamorphous Solids Yun Hu, Katarzyna Gniado, Andrea Erxleben,* and Patrick McArdle* School of Chemistry, National University of Ireland, Galway, University Road, Galway, Ireland S Supporting Information *

ABSTRACT: The anhydrous solvent-free mechanochemical reaction of sulfathiazole, STZ, polymorphs I, III, and V with 10 carboxylic acids was monitored by powder X-ray diffraction (PXRD), attenuated total reflectance infrared (ATR-IR), and near-infrared (NIR) spectroscopy. A 1:1 cocrystal was observed with glutaric acid and the strongest acid, oxalic acid, gave a 1:1 salt. A principal components analysis of the glutaric acid NIR data showed that forms I and V proceeded to the cocrystal, but that form III transformed to form IV before cocrystal formation. The oxalic acid salt was formed via complete amorphization. The crystal structures of the cocrystal and the salt were determined. Sulfathiazole comilled with L-tartaric and citric acids gave coamorphous systems that were stable at 10% RH for up to 28 days. Comilling sulfathiazole with DL-malic acid gave mixtures of form V and the amorphous form. lization, and solvate formation.6 As an alternative, solid-state milling methods, including neat milling and solvent drop milling, have been explored as a more efficient means of cocrystal synthesis.5,10−15 Comilling with additives also has been employed in an attempt to control solid-state phase transformation and to both stabilize and suppress the generation of amorphous forms.8,9,16−19 Sulfathiazole (STZ) (Figure 1) is a model drug which is known to have at least five polymorphs, forms over 100 solvates and numerous adducts, and has more than 6000 STZ references in SciFinder.20−22 STZ was also part of the first pharmaceutical application of a cocrystal when the 1:1 cocrystal of sulfathiazole and proflavine, branded as flavazole, was used as an antibacterial agent during the Second World War.23 Thus, it has been extensively investigated as a model system in polymorphism research and as a model cocrystal former.20,21,24−26 There are some inconsistencies in the nomenclature of sulfathiazole forms in the literature, and in this study the numbering of the polymorphic forms FI−FV is in accordance with that used by the Cambridge Crystallographic Data Centre (CCDC).27 In this study, we extend our previous research on the mechanochemistry of STZ with an investigation of the reaction of STZ with a series of carboxylic acids, half of which are on the GRAS list, in an effort to understand the factors that control cocrystal, salt, and coamorphous formation. The molecular structures of STZ and the carboxylic acids are given in Figure 1.

1. INTRODUCTION Solubility and dissolution rates are important factors in determining the efficacy as well as activity of pharmaceutical solids.1,2 Thus, the discovery of methods that will improve the solubility and dissolution rate of active pharmaceutical ingredients (APIs) is an important challenge in the pharmaceutical industry. Some of the methods currently being examined include the discovery of new polymorphs, amorphous forms, solid dispersions, cocrystals, salt forms, and inclusion complexes.1 Cocrystals and salt forms in particular have recently attracted significant interest in the pharmaceutical industry because of their potential to improve the physicochemical properties of APIs. The wide range of Generally Recognized as Safe (GRAS)3 coformer properties and the multiple possible interactions in the solid state provide many strategies for the control of cocrystal and salt properties, including enhanced dissolution rates, thermal stability, and improved mechanical properties.4−6 Alternatively, transferring a crystalline drug into an amorphous form can also increase dissolution rate and apparent solubility. However, the physical stability of amorphous forms during manufacture or storage is a problem, and it is necessary to find ways to stabilize the amorphous state. Recently, the concept of coamorphous systems has been introduced as a potential solution to this problem.7−9 In coamorphous systems, a combination of two complementary drugs or a drug and a suitable GRAS small molecule is used instead of drug−polymer combinations. Many methods and technologies have been described for the preparation of cocrystals. Preparation from solution may be the only suitable method where large single crystals are required for structure determination. However, this approach is not efficient for cocrystal screening due to the time-consuming solvent selection process, the potential for multi component crystal© 2013 American Chemical Society

Received: November 8, 2013 Revised: December 19, 2013 Published: December 20, 2013 803

dx.doi.org/10.1021/cg401673z | Cryst. Growth Des. 2014, 14, 803−813

Crystal Growth & Design

Article

Figure 1. Chemical structures of sulfathiazole and the carboxylic acids used. GRAS acids are denoted by a *. °C) under different relative humidity (RH) conditions ranging from 10 to 75% RH. RH values of 10, 43, and 75% were achieved in desiccators sealed using silica gel and using solutions of the salts K2CO3, NaCl, and KCl.28 Repeated measurements suggest that RH values were maintained at ±3% of the stated values. Stored samples were analyzed after 7 and 28 days, and two months by NIR spectroscopy and PXRD. 2.3. Analytical Techniques. 2.3.1. Single Crystal X-ray Diffraction. An Oxford Diffraction Xcalibur system was used to collect X-ray diffraction data at 150 K. The crystal structures were solved by direct methods (SHELXS-97) and refined by full matrix least-squares using SHELXL-97 within the Oscail package.29,30 2.3.2. X-ray Powder Diffraction (XRPD). X-ray powder diffraction data were collected on a Siemens D500 powder diffractometer which was fitted with a diffracted beam monochromator. Diffraction patterns were recorded between 5 and 40° (2θ) using Cu Kα radiation with steps of 0.05° with a 2 s counting time per step. The Oscail software package was used to generate theoretical PXRD patterns of the STZ forms.31 2.3.3. Thermal Analysis. Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) were performed on a STA625 thermal analyzer from Rheometric Scientific. The samples were scanned at 10 °C/min from 20 to 300 oC under a nitrogen purge of 50 mL/min in open aluminum crucibles. The system was calibrated using an indium standard. 2.3.4. Attenuated Total Reflectance-Infrared Spectroscopy. ATRIR spectra were recorded from 4000 to 650 cm−1 using a PerkinElmer Spectrum 400 (FT-IR/FT-NIR spectrometer) with 32 accumulations at a resolution of 4 cm−1. This instrument was equipped with a DATR 1 bounce Diamond/ZnSe Universal ATR sampling accessory. 2.3.5. Near-Infrared Spectroscopy. NIR spectra were collected in glass vials (15 mm × 45 mm) on a PerkinElmer Spectrum One fitted with an NIR reflectance attachment. Spectra were collected using interleaved scans in the 10000 to 4000 cm−1 range with a resolution of 8 cm−1, using 32 coadded scans. 2.3.6. Data Analysis. Data analysis was carried out using the multivariate data analysis software The Unscrambler v.9.8 (Camo, Norway). Principal components analysis (PCA) was used to investigate

2. EXPERIMENTAL SECTION 2.1. Materials. Sulfathiazole was purchased from Sigma-Aldrich with a purity of 98%. HPLC-grade dichloromethane and spectrophotometric grade acetone were also obtained from Sigma-Aldrich. Oxalic acid, oxalic acid dihydrate, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, DL-malic acid, L-tartaric acid, anhydrous citric acid, and fumaric acid were purchased from Sigma-Aldrich. 2.2. Methods. 2.2.1. Preparation of Sulfathiazole Polymorphs and Physical Mixtures. Commercial sulfathiazole was determined to be FIII, and it was used as received.21 Sulfathiazole FI was prepared by heating commercial sulfathiazole samples in an oven for 30 min at 180 °C as described in a previous study.21 Crystals of FV were obtained by evaporating a boiling aqueous solution of sulfathiazole to dryness, followed by drying at 105 °C.20 A physical mixture of sulfathiazole and each carboxylic acid was prepared by gentle mixing of both at a molar ratio of 1:1 in an agate mortar with pestle. 2.2.2. Milling Experiments. Milling experiments were performed using an oscillatory ball mill (Mixer Mill MM400, Retsch GmbH & Co., Germany) using a 25 mL stainless steel milling jar containing one 15 mm diameter stainless steel ball at 25 Hz. Each experiment was carried out with a fresh 0.5 g sample. Sulfathiazole samples were comilled with the carboxylic acids in a 1:1 molar ratio for 7.5, 15, 17, 20, 25, 30, 45, 60, and 90 min. The resulting milled powder samples were analyzed immediately by powder X-ray diffraction (PXRD), infrared (IR), and near infrared (NIR) spectroscopy. In order to avoid overheating the samples, pause periods of 5 min were made after every 30 min of milling. The maximum temperature recorded on the outside of the milling jars, during milling, using a digital thermometer was 37 °C. 2.2.3. Preparation of Sulfathiazole Cocrystal and Salt. The cocrystal and salt powders were prepared by grinding stoichiometric amounts of solid STZ with glutaric and oxalic acids for 60 min. Single crystals were grown by slow evaporation of solutions of these powders from dichloromethane and acetone respectively. 2.2.4. Storage Conditions. The stability of the coamorphous and cocrystal and salt samples was studied at ambient temperature (22 ± 2 804



Article

the spectral variation during the comilling process and stability of comilled samples under various RH conditions. Standard normal variate (SNV) and second derivative preprocessing methods were sequentially applied to NIR data for PCA analysis. Savitzki−Golay second derivative calculations were performed with a window size of 11 points and a second-order polynomial. 2.3.7. Hydrogen Bonded Adduct Modeling. The molecules were docked using the molecular modeling functionality, Moilin, within the Oscail software package.32 DFT calculations were carried out using the Firefly quantum chemistry package,33 which is partially based on the GAMESS (US) source code.34

melting point of any of the acids used and is the least likely to act like a solvent. Succinic acid with the second highest melting point gave results closest to those of fumaric acid, the only difference being that samples that started with form V (FV) contained FV. Of the other transformations observed, DL-malic acid is perhaps the most interesting as milling all three forms led to no change when starting from FV or to FV/FA mixtures in the other two cases. The only reported preparative methods for STZ FV involve crystallization either from boiling water at 100 or from npropanol at 95 °C.24 The temperature of the outside of the milling jars reached a maximum of 37 °C during milling, and it is possible that a combination of temperature and the extra hydroxyl group provide hydroxylic solvent-like conditions which promote the generation of FV. Malonic acid gives results that are closest to those of DL-malic acid, but here some FI was observed in samples which started with FI and FIII. Adipic and pimelic acids have closely related structures, and the results differ only in the amount of FIII which remained in samples which started with FIII. 3.2. Sulfathiazole Glutaric Acid Cocrystal. When STZ and GA (β-polymorph) were comilled, a new diffraction pattern was observed, Figure 2a. It was possible to grow the tabloidshaped crystals of this STZ−GA cocrystal from DCM solution that are shown in Figure 2b. The crystal structure of the cocrystal was determined, and the crystal data are given in Table 2. The hydrogen bonding in the crystal structure is shown in Figure 3, and hydrogen bonding distances and angles are in Table 3. In the crystal structure both the STZ and GA molecules form dimers via R22(8) rings.38 The GA dimers are linked via a bifurcated hydrogen bond to N3 and O2 of two adjacent STZ molecules, and there is also a hydrogen bond between N3−H3B and the O1 of an adjacent STZ molecule. The experimental PXRD pattern was an excellent match to the pattern calculated using the atom coordinates, Figure 2a. Figure 4a shows the DSC curves of STZ FI, β-glutaric acid, and the cocrystal. The melting point of FI is around 202 °C. There are two endothermic peaks in the curve for pure glutaric acid: the first and shallower one at 75 °C is the transition peak of β form to α form, and the second and deeper one at 97 °C is due to melting of α-glutaric acid.39 The endothermic peak at 120 °C in the cocrystal curve indicates a decomposition of the cocrystal. The IR spectra of sulfathiazole FI, glutaric acid, and the cocrystal are compared in Figure 4b. Particular differences between the spectra of the cocrystal and of pure sulfathiazole are found in the range 3500−3300 cm−1, corresponding to the N−H stretching vibrations. Four bands at 3481, 3399, 3385, and 3326 cm−1 are observed in IR spectra of the cocrystal compared two IR bands for STZ FI at 3464 and 3358 cm−1. In a similar way, the largest spectral difference in the NIR is in the 6980−6400 cm−1 range (Figure 4c). PCA was used to give a better insight into the solid-state STZ− GA transformation and to visualize the different rates of cocrystal formation. The PCA scores and the corresponding loadings plots for the NIR spectra of the milled samples in the regions 6980− 5800 and 5130−4000 cm−1 are shown in Figure 5. In Figure 5a PM is used to indicate a physical mixture before milling started. A three-component PCA model was used to explain 96.6% of the variance observed in the NIR data. Overall, the differences in the solid-state behavior during comilling of the three STZ forms with GA were seen in the score plot. PC1 explained 57.4% of the total variance because the NIR spectra of the cocrystal exhibits unique features that are not present in the NIR spectra of pure STZ forms or GA and vice versa. This is illustrated by the positive

3. RESULTS AND DISCUSSION 3.1. Comilling Experiments. The main differences between the STZ polymorphs lie in hydrogen bonding and packing of the molecules in the crystal lattice.35 In an analysis of the crystal structures of the five forms using the XPac program, Gelbricht et al.36 have shown that the low density forms FI and FV have different structures that are unrelated to those of FII, FIII, and FIV. The latter three forms have structures based on the same monolayer, and forms II and IV have bilayers which differ in a slip of the monolayers, while FIII is more complex in that it consists of the bilayers of both FII and FIV. Consequently, these three polymorphs are very similar in their spectral and physicochemical behavior, and the properties of FIII are to a large extent the average of the superposition of the properties of FII and FIV.21 Therefore, to maximize the effectiveness of monitoring the milling of STZ polymorphs in the presence of a range of carboxylic acids forms I, III, and V were used, and the experimental results are summarized in Table 1. Table 1. Results of Milling Sulfathiazole with Different Carboxylic Acids for 60 min starting material carboxylic acids

m.p.

FIII

FI

FV

glutaric acid oxalic acid L-tartaric acid citric acid adipic acid pimelic acid malonic acid DL-malic acid succinic acid fumaric acid

95 189 171 156 152 103 135 130 184 287

cocrystal salt coamorphous coamorphous FI+FAa FIII+FI+FA FV+FI+FAa,b FV+FAa FI+FA FI+FA

cocrystal salt coamorphous coamorphous FI+FA FI+FA FV+FI+FA FV+FA FI+FA FI+FA

cocrystal salt coamorphous coamorphous FV+FA FV+FA FV FV FV+FI+FA FI+FA

a

A small amount of FIII can be detected by IR spectra. b90 min milling time.

As is clear from Table 1, four different results have been observed: cocrystal formation with glutaric acid (GA); salt formation with oxalic acid (OA); stable coamorphous generation with citric (CA) and L-tartaric (TA) acids and STZ polymorph transformations with the six other acids. It was also observed that cocrystal, salt, and coamorphous formation were dependent on the carboxylic acid used but not on the starting STZ polymorph, whereas the polymorph transformations did show some variation with the starting polymorph. 3.1.1. Polymorph Transformations. The simplest result was observed in the presence of fumaric acid where all three starting forms gave mixtures of FI and the amorphous form (FA). This result is identical to that observed for neat milling of these three forms.37 This may be because fumaric acid has by far the highest 805



Article

Figure 2. (a) PXRD patterns for glutaric acid, STZ FI, STZ−GA cocrystal experimental, and STA−GA cocrystal calculated, (b) morphology of the STZ−GA cocrystals.

Table 2. Crystallographic Data for STZ−GA Cocrystal and STZ−OA Salt sample name empirical formula formula weight temperature, K wavelength, Å crystal system space group unit cell dimensions Å and °

volume, Å3 Z density (calculated), Mg/m3 absorption coefficient, mm−1 F(000) crystal size, mm theta range for data collection, ° reflections collected independent reflections completeness to theta = 25.242° data/restraints/parameters goodness-of-fit on F2 final R indices [I > 2σ(I)] largest diff. peak and hole, e·Å−3

STZ−GA

STZ−OA

C14H17N3O6S2 387.42 150.1(1) 0.71073 monoclinic P21/n a = 8.8854(5) b = 13.3231(5) c = 14.7403(7) β = 101.159(5) 1711.98(14) 4 1.503 0.348 808 0.40 × 0.10 × 0.10 2.917−25.347 10819 3131 [R(int) = 0.0406] 99.8% 3131/0/289 1.013 R1 = 0.0356 wR2 = 0.0848 0.270 and −0.380

C11H11N3O6S2 345.35 150.1(1) 0.71073 monoclinic P21/c a = 8.0392(6) b = 19.9339(10) c = 8.6360(3) β = 97.715(4) 1371.41(13) 4 1.673 0.423 712 0.22 × 0.10 × 0.08 3.137−25.346 4727 2510 [R(int) = 0.0249] 99.8% 2510/0/200 1.211 R1 = 0.0399 wR2 = 0.1043 0.426 and −0.537

Figure 3. Hydrogen bonding in the STZ−GA cocrystal structure. H atoms not involved in hydrogen bonding have been omitted for clarity.

unlike FI and FV, transforms to STZ FIV before it forms the cocrystal. The possibility of an intermediate polymorphic conversion, or amorphous phase formation, prior to the cocrystal formation was further tested by using a combination of PXRD, NIR, and IR spectra. It is known that the shift or appearance/disappearance of new IR and NIR bands can suggest the occurrence of a polymorphic transformation or the formation of an amorphous phase.40 In the STZ FI−GA mixture, the NIR bands shift and become broader, which indicate the formation of small amounts of amorphous content prior to cocrystal formation. However, the cocrystal formation seems direct in the STZ FV−GA mixture during milling as detected by IR spectra. The STZ FIII−GA mixture is more complicated, Figure 6. First, there is an increase in the intensity of the NIR band at 6126 cm−1, which suggests an STZ FIII to FIV conversion. This result is in agreement with our previous study.37 The appearance of new NIR bands around 6880 and 5080 cm−1 also suggested that the formation of some STZ FI and FA prior to cocrystal formation. The physical stability of the STZ−GA cocrystal samples obtained from the three starting STZ polymorphs was

bands in the PC 1 loadings. PC2 accounted for 25.0% of the total variance, and it describes the variation between the STZ FIII− GA PM and STZ FV−GA PM, the positive bands in the loadings at 6138 and 5046 cm−1, and the negative bands at 6126 and 4896 cm−1 could be from STZ FV−GA PM and STZ FIII−GA PM, respectively. PC3 explained 14.2% of the variation, and differentiated samples containing STZ FI−GA PM from the other two, as indicated by the bands at 6150, 5082, and 4184 cm−1 in the corresponding loadings plot. Figure 5a illustrates the overall process of cocrystal formation in a single plot. The rate at which the scores travel toward the STZ−GA cocrystal region depends on the sulfathiazole starting material. It can be seen that the STZ FIII−GA PM move toward the cocrystal region takes the longest time (30 min).15 Also initially STZ FIII−GA PM moves along PC3 before heading in the cocrystal direction. This is because STZ FIII, 806



Article

Table 3. Hydrogen Bonds for STZ−GA and STZ−OA [Å and °]a STZ−GA

STZ−OA

D−H···A

d(D−H)

d(H···A)

d(D···A)

∠(DHA)

N(1)−H(1N1)···N(2)#2 N(3)−H(3A)···O(2)#3 N(3)−H(3B)···O(1)#4 O(3)−H(3)···N(3)#5 O(3)−H(3)···O(2) O(5)−H(5A)···O(6)#6 N(3)−H(3)···O(6) N(1)−H(2N1)···O(4)#2 N(1)−H(3N1)···O(4)#3 N(1)−H(1N1)···N(2)#2 O(3)−H(1O3)···O(5)#4

0.86 0.86 0.86 0.82 0.82 0.82 0.86 0.89 0.89 0.89 0.82

2.05 2.13 2.36 2.09 2.64 1.77 1.85 1.98 2.24 2.14 2.04

2.905(3) 2.986(3) 3.154(3) 2.743(4) 3.289(4) 2.580(13) 2.697(3) 2.847(3) 2.953(3) 3.025(3) 2.745(3)

170.9 171.5 153.4 136.8 137.5 170.2 170.5 165.4 137.3 174.1 143.4

a Symmetry transformations used to generate equivalent atoms STZ−GA: #2 −x + 1, −y + 2, −z. #3 x − 1, y, z. #4 −x + 1/2, y + 1/2, −z + 1/2. #5 x + 1, y, z. #6 −x + 1, −y + 3, −z + 1. STZ−OA: #2 x − 1, y, z. #3 x − 1, −y + 3/2, z + 1/2. #4 −x + 1, −y + 1, −z − 1.

Figure 4. (a) DSC graphs, (b) IR spectra, and (c) NIR spectra of (1) STZ FI, (2) GA, and (3) the STZ−GA cocrystal.

Figure 5. PCA scores plots (a) and loading plots (b) of the NIR spectra of STZ−GA cocrystal formation prepared by comilling. The arrows represent the direction of cocrystal formation, and PM denotes physical mixtures.

investigated, and the results showed that they were stable under RH in the 10−75% range at room temperature at least for 2 months. 3.3. Sulfathiaole Oxalic Acid Salt. Milling STZ with oxalic acid also gave a new crystalline solid, as evidenced by a PXRD

pattern that did not contain any reflections belonging to the starting materials (Figure 7). Crystals of this new solid were grown from acetone solution, and the crystal structure was determined. Crystal data are given in Table 2, and the hydrogen bonding network is shown in Figure 8, and hydrogen bond 807



Article

which bridge adjacent STZ molecules. The experimental PXRD pattern corresponds to the pattern calculated from the atom coordinates Figure 7. Figure 9a shows the DSC curves of STZ FI, OA, and the salt. It can be seen that the STZ−OA salt has a melting point around 190 °C. The IR spectra are given in Figure 9b with the spectrum of STZ FI−OA PM milled for 15 min for comparison. Two IR bands at 3464 and 3364 cm−1 were ascribed to amorphous sulfathiazole, and they disappeared when the salt formed. It is suggested that there is no molecular interaction between amorphous sulfathiazole and oxalic acid in this coamophous system. Furthermore, there is a new sharper IR band at 3121 cm−1 which appears on salt formation. Figure 10 shows NIR monitoring of the formation of the STZ−OA salt with milling time. It is clear that the salt forms from each of the starting polymorphs, but unlike the STZ−GA cocrystal formation a complete coamorphous STZ−OA system is first formed, as evidenced by the PXRD patterns shown in the figure insets (Figure 10). The salt formed with extended milling after the system was amorphous. Milling STZ FIII−OA required the longest time (60 min). The physical stability of the STZ−OA salt was also investigated, and the results showed that it was stable at 10% RH and room temperature at least for 28 days. When RH value is above 43%, NIR spectra clearly indicated that the salt took up water. The formation of a salt by proton transfer as opposed to a cocrystal of the same stoichiometry has been studied by several researchers. In general it has been suggested that a minimum pKa difference of 3 units is required for salt formation.41 However, while pKa values measured in solution may not be directly relevant to transformations which take place under anhydrous solvent-free conditions the pKa difference for STA−OA is close to 6 units. In general it does appear, probably due to the charge separation involved, that salt formation is a more difficult process than cocrystal formation. For example, it has been reported that mortar and pestle ground physical mixtures of pimelic acid and a ferrocene base did not react until they were exposed to solvent vapor and that nonhydroxylic solvents gave a cocrystal, whereas

Figure 6. NIR spectra of STZ FIII comilled with GA for various times. The plots from bottom to top: STZ FIII−GA PM, milled for 7.5, 15, 20, and 25 min, STZ FI, and STZ FA (amorphous sulfathiazole obtained from cryomilling).

Figure 7. Calculated and experimental PXRD patterns of STZ−OA salt.

lengths and angles are given in Table 3. This compound is a salt. Proton transfer from OA to the STZ NH2 has taken place. The oxalate anions form hydrogen bonded dimers via R22(10) rings

Figure 8. Hydrogen bonding in the STZ−OA salt. H atoms not involved in H-bonding have been omitted for clarity. 808



Article

Figure 9. (a) DSC graphs and (b) IR spectra of (1) STZ FI, (2) OA, and (3) STZ−OA salt, (4) IR spectrum of STZ FI−OA PM milled for 15 min.

Figure 10. NIR spectra of sulfathiazole polymorphs (a) STZ FI, (b) STZ FIII, and (c) STZ FV comilled with OA, respectively, at various milling times. The inset figure represents the PXRD patterns of STZ polymorphs comilled with OA for 15 min; PM denotes physical mixtures.

hydroxylic solvents gave a salt.42 There is a report that milling of the bases trimethoprim and pyrimethamine with carboxylic acids, without PXRD monitoring, gave salts under anhydrous solventfree conditions in 40% of the cases studied.43 However in every one of the cases that gave a salt, in the absence of solvent, the melting point of the carboxylic acid was less than 100 °C. It is possible that actual temperature inside the mill could have given these acids sufficient mobility to allow them to act in a solventlike manner. Interestingly, it was found that when the milling of benzyladenine with maleic acid was monitored by PXRD that system went amorphous before the diffraction pattern of a salt appeared just as described here.44 It has also been reported that milling glycine/anhydrous oxalic acid mixtures gave no reaction but that milling glycine/oxalic acid dihydrate mixtures gave a salt.45 We have found that milling STZ with OA dihydrate gives a new PXRD pattern, Figure 11, which is different from that of either of the starting materials or the STZ−OA salt. It was not possible to obtain single crystals of this compound, and its composition or structure has not been established. In summary, it appears that solid state anhydrous salt formation by proton transfer is a higher energy process than cocrystal formation and that in the absence of a hydroxylic catalyst in the form of a solvent or a relatively low melting acid salt formation is difficult.

Figure 11. PXRD pattern observed when sulfathiazole was milled with oxalic acid dihydrate.

3.4. Milling Sulfathiazole with L-Tartaric and Citric Acids. 3.4.1. Stability of Comilled Amorphous Samples. It has been mentioned above that a combination of two drugs or a drug and a small molecule could form a single phase amorphous system of enhanced stability. In this study, comilling STZ with Ltartaric acid (TA) and citric acid (CA) in a 1:1 mol ratio for 60 and 90 min was found to give samples which were noncrystalline as determined by PXRD. The importance and nature of the effect 809



Article

Figure 12. PCA scores plots of the NIR spectra of the 60 and 90 min comilled STZ samples with (a) TA and (b) CA stored at different humidity; (c) NIR spectra of STZ FI−TA milled for 60 min stored at 10% RH for 28 days and (2) at 43% RH for 7 days; (3) STZ FIII−TA milled for 60 min and (4) for 90 min at 43% RH for 7days; (5) STZ FV−TA milled for 60 min at 43% RH for 7 days; (6) STZ FI−TA milled for 60 min at 75% RH for 7 days; (d) NIR spectra of STZ FI−CA milled for 60 min stored (1) at 10% RH for 28 days and (2) at 43% RH for 7 days; (3) STZ FIII−CA milled for 60 min and (4) for 90 min at 43% RH for 7days; (5) STZ FV−CA milled for 60 min at 43% RH for 7 days; (6) STZ FI−CA milled for 60 min at 75% RH for 7 days.

of moisture on amorphous materials are especially important when formulating amorphous products. Water can act as a plasticizer which increases molecular mobility and recrystallization rate.46 The samples were stored at 10% RH for 28 days and at 43 and 75% RH for 7 days. NIR spectra were used to monitor the samples using PCA analysis. To reduce the interference due to the NIR bands of water, a combination of the 6980−5800 and 5130−4000 cm−1 regions was chosen for PCA analysis. Figure 12 shows the PCA scores scatter plots obtained using the first and second PCs of the amorphous samples stored under different humidity conditions. Overall, the PCA model showed clustering of the samples based on relative humidity. For STZ−TA systems (Figure 12a), the first two principal components summarized 83.6% of the variation in the spectral information. The differences arose from FA with other polymorphic forms (FII, FIII, and FIV) along PC1, and the second component, PC2, accounted for variability of amorphous and FI and FV. At 10% RH, the amorphous samples remain amorphous up to 28 days irrespective of the starting sulfathiazole polymorph used (Figure 12c (1)). Similarly, at 75% RH, the FA recrystallized mostly to FIV with a small amount of FII and FIII within 7 days irrespective of the starting STZ polymorph used (Figure 12c (6)). However, at 43% RH, the STZ polymorphs which recrystallized were not only dependent on the starting sulfathiazole polymorph used but also on milling time. When the starting polymorphs are FI and FV, the amorphous samples

recrystallized to FI and FV (with a small amount of FI), respectively, without correlation to milling time (Figure 12c (2) and (5)). If FIII was used as the starting material, the amorphous samples crystallized to the mixture of FIV with FII and FIII when the milling time was 60 min (Figure 12c (3)), and only FI formed when the milling time was extended to 90 min, as indicated by the NIR band at 6876 cm−1, Figure 12c (4). Apart from STZ, amorphous tartaric acid also recrystallized detected by the bands at 5146 cm−1 at 43 and 75% RH. In the STZ−CA systems, the first two principal components summarized 84.3% of the variation in the spectral information. In contrast to the STZ−TA system, PC1 can differentiate the variability of FA, FI and FV, PC2 shows spectral differences arising from the FA with other polymorphic forms (FII, FIII, and FIV) along PC1. The FA samples remain amorphous for up to 28 days at 10% RH but recrystallize to a mixture of FII, FIII, and IV within 7 days at 75% RH irrespective of the starting sulfathiazole polymorph used (Figure 12d (6)). At 43% RH, when the starting polymorphs are FI and FV, the amorphous samples recrystallized to FI and FV (with a small amount of FI), respectively (Figure 12c (2) and (5)). If FIII was used as the starting material, the amorphous samples crystallized to a mixture of FIV, FII, and FIII when the milling time was 60 min (Figure 12c (3)), and FI was formed when the milling time was extended to 90 min, as indicated by the NIR band at 6876 cm−1, shown in Figure 12c (4). Amorphous citric acid easily absorbed water (see NIR bands 810



Article

Figure 13. IR spectra of STZ FIII comilled with (a) tartaric acid (TA) and (b) citric acid (CA) at various times. Figure insets represent the PXRD patterns of STZ comilled with TA and CA for 60 min. The IR spectra from top to bottom: physical mixture (PM), mixtures milled for 15, 30, 60, and 90 min, and amorphous sulfathiazole obtained from cryomilling.

caused by water) and recrystallized at 43 and 75% RH as indicated by the band at 6800 cm−1. The above results strongly suggested that the stability of these two coamorphous systems is very strongly influenced by relative humidity. 3.4.2. Characterization of Coamorphous Systems. FTIR spectra were used to monitor amorphization and to detect any intermolecular interactions. Figure 13 shows the evolution of these two coamorphous systems with time. As can be seen from the figure, the IR bands due to crystalline STZ, TA, and CA disappeared after 60 min milling. The PXRD patterns of both mixtures milled for 60 min also confirmed that the products were coamorphous. The IR results also showed that when the milling time was extended to 90 min the samples remained amorphous. When the IR spectra of amorphous STZ was compared to that of the coamorphous systems, no band shifts were observed. For example, there was no shift in the band at 3364 cm−1 of amorphous STZ. This suggests that the coamorphous system contains small particles of the components which are stabilized by particle to particle hydrogen bonding. The observed FTIR spectra arise from the bulk of the particles and not from the surface molecules which are involved in the interparticle interactions. DSC results for the coamorphous samples at two scan rates are given in the Supporting Information. At the scan rates used, the TA samples showed a single crystallization exotherm, while the CA samples showed a double exotherm at the slower scan rate. Double exotherms are not characteristic of coamorphous systems as they have been observed even for amorphous systems generated from a single phase and have been ascribed to surface and bulk crystallization phenomena.47,48 However, in the present case the quality of the DSC results is not great, and it is difficult to draw definite conclusions from them. 3.4.3. Modeling STZ TA/CA Interactions. It is interesting to consider why TA and CA are the only acids that stabilize coamorphous systems. A likely possibility is that these are the only acids rhat not just equal but exceed STZ in hydrogen bonding ability. STZ has three hydrogen bond donors and four hydrogen bond acceptors, while TA and CA have four and six and four and seven hydrogen bond donors and acceptors, respectively. Thus small particles of STZ, TA, and CA will have surface molecules that will have spare hydrogen bonding capacity for binding to other particles. In an attempt to demonstrate this, we have modeled gas phase adducts of STZ with TA and CA using DFT calculations with B3LYP functionals and 6-31G* basis sets. The molecules were docked so that the acids spanned

the SO2 and either the -NH2 or the thiazole ring. The results are shown in Figure 14.

Figure 14. Calculated adduct structures for STZ−CA (a) and (b) and STZ−TA (c) and (d).

Citric acid with three carbons between its −COOH groups was better able to span the STZ molecules than TA. In each case, spare hydrogen bonding capacity remains in both molecules. The adducts in Figure 14 were more stable than their components by 52.79, 70.45, 51.68, and 53.49 kJ/mol, respectively.

4. CONCLUSIONS Milling sulfathiazole with carboxylic acids led to the formation of a 1:1 cocrystal with glutaric acid a 1:1 salt with oxalic acid and stable coamorphous systems with L-tartaric and citric acids. While it is not possible to rationalize either the cocrystal or salt formation, nevertheless the formation of a salt by proton transfer under anhydrous and solvent-free conditions is a higher energy process than cocrystal formation. The stable coamorphous systems were formed by acids that have hydrogen bonding capacities which exceed those of sulfathiazole. Polymorphic transformation to FV in the presence of DL-malic acid has been attributed to its hydroxylic solvent-like behavior. Relative humidity up to 75% did not transform either the cocrystal or the salt. However, the coamorphous systems were more sensitive to relative humidity. At 10% RH, the coamorphous systems remained amorphous for up to 28 days. At higher RH coamorphous sulfathiazole crystallized to different polymorphs, 811



Article

(13) Yamamoto, K.; Tsutsumi, S.; Ikeda, Y. Establishment of cocrystal cocktail grinding method for rational screening of pharmaceutical cocrystals. Int. J. Pharm. 2012, 437 (1−2), 162−171. (14) Lin, H.-L.; Zhang, G.-C.; Hsu, P.-C.; Lin, S.-Y. A portable fiberoptic Raman analyzer for fast real-time screening and identifying cocrystal formation of drug-coformer via grinding process. Microchem. J. 2013, 110 (0), 15−20. (15) Chieng, N.; Hubert, M.; Saville, D.; Rades, T.; Aaltonen, J. Formation Kinetics and Stability of Carbamazepine−Nicotinamide Cocrystals Prepared by Mechanical Activation. Cryst. Growth Des. 2009, 9 (5), 2377−2386. (16) Lin, S.-Y.; Hsu, C.-H.; Ke, W.-T. Solid-state transformation of different gabapentin polymorphs upon milling and co-milling. Int. J. Pharm. 2010, 396 (1−2), 83−90. (17) Balani, P. N.; Ng, W. K.; Tan, R. B. H.; Chan, S. Y. Influence of excipients in comilling on mitigating milling-induced amorphization or structural disorder of crystalline pharmaceutical actives. J. Pharm. Sci. 2010, 99 (5), 2462−2474. (18) Curtin, V.; Amharar, Y.; Hu, Y.; Erxleben, A.; McArdle, P.; Caron, V.; Tajber, L.; Corrigan, O. I.; Healy, A. M. Investigation of the Capacity of Low Glass Transition Temperature Excipients to Minimize Amorphization of Sulfadimidine on Comilling. Mol. Pharmaceutics 2012, 10 (1), 386−396. (19) Brittain, H. G. Polymorphism and solvatomorphism 2010. J. Pharm. Sci. 2012, 101 (2), 464−484. (20) Anwar, J.; Tarling, S. E.; Barnes, P. Polymorphism of sulfathiazole. J. Pharm. Sci. 1989, 78 (4), 337−342. (21) Apperley, D. C.; Fletton, R. A.; Harris, R. K.; Lancaster, R. W.; Tavener, S.; Threlfall, T. L. Sulfathiazole polymorphism studied by magic-angle spinning NMR. J. Pharm. Sci. 1999, 88 (12), 1275−1280. (22) Bingham, A. L.; Hughes, D. S.; Hursthouse, M. B.; Lancaster, R. W.; Tavener, S.; Threlfall, T. L. Over one hundred solvates of sulfathiazole. Chem. Commun. 2001, 0 (7), 603−604. (23) McIntosh, J.; Robinson, R. H. M.; Selbie, F. R. AcridineSulphonamide Compounds As Wound Antiseptics Clinical Trials of Flavazole. Lancet 1945, 246 (6361), 97−99. (24) Abu Bakar, M. R.; Nagy, Z. K.; Rielly, C. D.; Dann, S. E. Investigation of the riddle of sulfathiazole polymorphism. Int. J. Pharm. 2011, 414 (1−2), 86−103. (25) Munroe, Á .; Rasmuson, Å. C.; Hodnett, B. K.; Croker, D. M. Relative Stabilities of the Five Polymorphs of Sulfathiazole. Cryst. Growth Des. 2012, 12 (6), 2825−2835. (26) Caira, M. R. Sulfa Drugs as Model Cocrystal Formers. Mol. Pharmaceutics 2007, 4 (3), 310−316. (27) Allen, F. The Cambridge Structural Database: a quarter of a million crystal structures and rising. Acta Crystallogr., Sect. B 2002, 58 (3 Part 1), 380−388. (28) Lu, T.; Chen, C. Uncertainty evaluation of humidity sensors calibrated by saturated salt solutions. Measurement 2007, 40 (6), 591− 599. (29) Sheldrick, G. A short history of SHELX. Acta Crystallogr., Sect. A 2008, 64 (1), 112−122. (30) McArdle, P.; Gilligan, K.; Cunningham, D.; Dark, R.; Mahon, M. A method for the prediction of the crystal structure of ionic organic compounds-the crystal structures of o-toluidinium chloride and bromide and polymorphism of bicifadine hydrochloride. CrystEngComm 2004, 6 (53), 303−309. (31) McArdle, P.; Hu, Y.; Lyons, A.; Dark, R. Predicting and understanding crystal morphology: the morphology of benzoic acid and the polymorphs of sulfathiazole. CrystEngComm 2010, 12 (10), 3119− 3125. (32) McArdle, P. J. Appl. Crystallogr. 1995, 28, 65. (33) Granovsky, A. A. Firefly (previously PC GAMESS). http:// classic.chem.msu.su/gran/firefly/index.html. (34) Schmidt, M. W.; Baldridge, K. K.; J.A.Boatz, J. A.; Elbert, S. T.; Gordon, M. S.; Jensen, J. H.; Koseki, S.; atsunaga, N.; Nguyen, K. A.; Su, S.; Windus, T. L.; Dupuis, M.; Montgomery, J. A. J. Comput. Chem. 1993, 14, 1347−1363.

the ratio of which depended both on RH and on the starting sulfathiazole polymorph used.

■

ASSOCIATED CONTENT

S Supporting Information *

DSC plots and crystallographic cif files and tables are available free of charge via the Internet at http://pubs.acs.org.

■

AUTHOR INFORMATION

Corresponding Authors

*(P.M.) Tel.: +353 91 49 2487; fax: +353 91 525700; e-mail: p. [email protected]. *(A.E.) E-mail: [email protected]. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This work was supported by Science Foundation Ireland under Grant No. [07/SRC/B1158] as part of the Solid State Pharmaceutical Cluster (SSPC). Mr. Dermot McGrath and Dr. Gerard Wall are thanked for DSC and microscope measurements.

■

REFERENCES

(1) Masuda, T.; Yoshihashi, Y.; Yonemochi, E.; Fujii, K.; Uekusa, H.; Terada, K. Cocrystallization and amorphization induced by drug− excipient interaction improves the physical properties of acyclovir. Int. J. Pharm. 2012, 422 (1−2), 160−169. (2) Thakuria, R.; Delori, A.; Jones, W.; Lipert, M. P.; Roy, L.; Rodríguez-Hornedo, N. Pharmaceutical cocrystals and poorly soluble drugs. Int. J. Pharm. 2013, 453 (1), 101−125. (3) See US FDA GRAS List. http://www.fda.gov/food/ ingredientspackaginglabeling/gras/default.htm. (4) Brittain, H. G. Pharmaceutical cocrystals: The coming wave of new drug substances. J. Pharm. Sci. 2013, 102 (2), 311−317. (5) Qiao, N.; Li, M.; Schlindwein, W.; Malek, N.; Davies, A.; Trappitt, G. Pharmaceutical cocrystals: An overview. Int. J. Pharm. 2011, 419 (1− 2), 1−11. (6) Lu, E.; Rodriguez-Hornedo, N.; Suryanarayanan, R. A rapid thermal method for cocrystal screening. CrystEngComm 2008, 10 (6), 665−668. (7) Löbmann, K.; Laitinen, R.; Grohganz, H.; Gordon, K. C.; Strachan, C.; Rades, T. Coamorphous Drug Systems: Enhanced Physical Stability and Dissolution Rate of Indomethacin and Naproxen. Mol. Pharmaceutics 2011, 8 (5), 1919−1928. (8) Löbmann, K.; Strachan, C.; Grohganz, H.; Rades, T.; Korhonen, O.; Laitinen, R. Co-amorphous simvastatin and glipizide combinations show improved physical stability without evidence of intermolecular interactions. Eur. J. Pharm. Biopharm. 2012, 81 (1), 159−169. (9) Chieng, N.; Aaltonen, J.; Saville, D.; Rades, T. Physical characterization and stability of amorphous indomethacin and ranitidine hydrochloride binary systems prepared by mechanical activation. Eur. J. Pharm. Biopharm. 2009, 71 (1), 47−54. (10) Braga, D.; Giaffreda, S. L.; Grepioni, F.; Pettersen, A.; Maini, L.; Curzi, M.; Polito, M. Mechanochemical preparation of molecular and supramolecular organometallic materials and coordination networks. Dalton Trans. 2006, 10, 1249−1263. (11) Trask, A.; Jones, W. Crystal Engineering of Organic Cocrystals by the Solid-State Grinding Approach. In Organic Solid State Reactions; Toda, F., Ed.; Springer: Berlin Heidelberg: 2005; Vol. 254, pp 41−70. (12) Trask, A. V.; van de Streek, J.; Motherwell, W. D. S.; Jones, W. Achieving Polymorphic and Stoichiometric Diversity in Cocrystal Formation: Importance of Solid-State Grinding, Powder X-ray Structure Determination, and Seeding. Cryst. Growth Des. 2005, 5 (6), 2233− 2241. 812



Article

(35) Blagden, N.; J. Davey, R.; F. Lieberman, H.; Williams, L.; Payne, R.; Roberts, R.; Rowe, R.; Docherty, R. Crystal chemistry and solvent effects in polymorphic systems Sulfathiazole. J. Chem. Soc., Faraday Trans. 1998, 94 (8), 1035−1044. (36) Gelbrich, T.; Hughes, D. S.; Hursthouse, M. B.; Threlfall, T. L. Packing similarity in polymorphs of sulfathiazole. CrystEngComm 2008, 10 (10), 1328−1334. (37) Hu, Y.; Erxleben, A.; Hodnett, B. K.; Li, B.; McArdle, P.; Rasmuson, Å. C.; Ryder, A. G. Solid-state Transformations of Sulfathiazole Polymorphs: the Effects of Milling and Humidity. Cryst. Growth Des. 2013, 13, 3404−3413. (38) Etter, M. C. Encoding and decoding hydrogen-bond patterns of organic compounds. Acc. Chem. Res. 1990, 23 (4), 120−126. (39) Zhang, S.; Rasmuson, Å. C. Thermodynamics and Crystallization of the Theophylline−Glutaric Acid Cocrystal. Cryst. Growth Des. 2013, 13 (3), 1153−1161. (40) Van Eerdenbrugh, B.; Taylor, L. S. Application of mid-IR spectroscopy for the characterization of pharmaceutical systems. Int. J. Pharm. 2011, 417 (1−2), 3−16. (41) Childs, S. L.; Stahly, G. P.; Park, A. The Salt−Cocrystal Continuum: The Influence of Crystal Structure on Ionization State. Mol. Pharmaceutics 2007, 4 (3), 323−338. (42) Braga, D.; Giaffreda, S. L.; Grepioni, F.; Chierotti, M. R.; Gobetto, R.; Palladino, G.; Polito, M. Solvent effect in a “solvent free” reaction. CrystEngComm 2007, 9 (10), 879−881. (43) Trask, A. V.; Haynes, D. A.; Motherwell, W. D. S.; Jones, W. Screening for crystalline salts via mechanochemistry. Chem. Commun. 2006, 1, 51−53. (44) McHugh, C.; Erxleben, A. Supramolecular Structures and Tautomerism of Carboxylate Salts of Adenine and Pharmaceutically Relevant N6-Substituted Adenine. Cryst. Growth Des. 2011, 11 (11), 5096−5104. (45) Losev, E. A.; Mikhailenko, M. A.; Achkasov, A. F.; Boldyreva, E. V. The effect of carboxylic acids on glycine polymorphism, salt and cocrystal formation. A comparison of different crystallisation techniques. New J. Chem. 2013, 37 (7), 1973−1981. (46) Grisedale, L. C.; Belton, P. S.; Jamieson, M. J.; Barker, S. A.; Craig, D. Q. M. An investigation into water interactions with amorphous and milled salbutamol sulphate: The development of predictive models for uptake and recrystallization. Int. J. Pharm. 2012, 422 (1−2), 220−228. (47) Chattoraj, S.; Bhugra, C.; Telang, C.; Zhong, L.; Wang, Z.; Sun, C. Origin of Two Modes of Non-isothermal Crystallization of Glasses Produced by Milling. Pharm. Res. 2012, 29 (4), 1020−1032. (48) Trasi, N.; Byrn, S. Mechanically Induced Amorphization of Drugs: A Study of the Thermal Behavior of Cryomilled Compounds. AAPS PharmSciTech 2012, 13 (3), 772−784.

813


Mechanochemical Reaction of Sulfathiazole with Carboxylic Acids

Recommend Documents