Polymorphism and Phase Transformation Behavior of Solid Forms of 4

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Polymorphism and Phase Transformation Behavior of Solid Forms of 4-Amino-3,5-Dinitrobenzamide J. Prakasha Reddy, Diptikanta Swain, and V. R. Pedireddi Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/cg500673a • Publication Date (Web): 13 Aug 2014 Downloaded from http://pubs.acs.org on August 21, 2014

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Crystal Growth & Design

Polymorphism and Phase Transformation Behavior of Solid Forms of 4-Amino-3,5-Dinitrobenzamide J. Prakasha Reddy,*a Diptikanta Swain,b and Venkateswara Rao Pedireddi c a

Department of Chemistry, MS 015, Brandeis University, P.O. Box 549110, Waltham,

Massachusetts 02454-9110, USA b

Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore 560 012, India

c

School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Toshali Bhavan,

Bhubaneswar 751 013 India KEYWORDS: Polymorphism • Hydrogen bonding • X-ray crystallography • single-crystal-tosingle-crystal transformations ABSTRACT We report the preparation, analysis and phase transformation behavior of polymorphs and the hydrate of 4-amino-3,5-dinitrobenzamide. The compound crystallizes in four different polymorphic forms, Form I (monoclinic, P21/n), Form II (orthorhombic, Pbca), Form III (monoclinic, P21/c), and Form IV (monoclinic, P21/c). Interestingly, a hydrate (triclinic, Pī) of the compound is also discovered during the systematic identification of the polymorphs. Analysis of the polymorphs has been investigated using hot stage microscopy, differential

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scanning calorimetry, in situ variable temperature powder X-ray diffraction, and single crystal Xray diffraction. On heating, all of the solid forms convert into Form I irreversibly and on further heating, melting is observed. In situ single crystal X-ray diffraction studies revealed that Form II transforms to Form I above 175 oC via single-crystal-to-single-crystal transformation. The hydrate, on heating, undergoes a double phase transition; first to Form III upon losing water in a single-crystal-to-single-crystal fashion and then to a more stable polymorph Form I on further heating. Thermal analysis lead to the conclusion that Form II appears to be the most stable phase at ambient conditions while Form I is more stable at higher temperature.

Introduction Crystal polymorphism, the ability of a compound to exist in different crystalline forms that have different arrangements and/or conformations of molecules in the solid state, is a widespread phenomenon which has gained much interest in both academic and industrial research.1 Polymorphic forms display different physicochemical properties;2-5 and are important in connection with bioavailability and ease of manufacturing of active pharmaceutical ingredients (APIs) resulting in patenting and financial profits of pharmaceutical companies.6,7 The area of polymorphism, both in terms of experimental and theoretical studies, has advanced significantly in the past two decades and developments in this area continue to look promising.8,9 We have initiated our investigations on amide class of compounds, as the amide group is an important functionality found in both natural and synthetic compounds, such as peptides, proteins, synthetic polymers, APIs, etc. Our endeavor was started with 3,5-dinitrobenzamide,10 and we were unable to obtain new forms of it. But, upon extending the study to its derivatives, we were successful with 4-amino-3,5-dinitrobenzamide (ADNBA). In this paper, we report preparation


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and analysis of four polymorphs and the hydrate of ADNBA which form different types of hydrogen bonding networks found in the amides.11 In addition, phase transformation behavior of all the forms is also reported.

Results and Discussion Crystal and Molecular Structure Description of Polymorphs and the Hydrate The crystallization of ADNBA, depending on the conditions employed and solvents used (see supporting information Table S1-S4), lead to the formation of five different solid forms; four polymorphs and a hydrate. ADNBA has six proton donors and five oxygen acceptors that can take part in hydrogen bonding interactions. At the outset, it is worth mentioning that, in all the forms, intramolecular N-H···O hydrogen bonding is present between the -NH2 and -NO2 groups. However, arrangement of the molecules in three-dimensions in the crystal lattice is quite distinct in each form. While Forms I, II, III and the hydrate adopt different types of sheet structures (Form I, corrugated; Form II, crinkled; Form III & hydrate, planar), Form IV adopts a herringbone packing arrangement (Figure S1-S5 in supporting information). Further analysis of the arrangement of molecules in two-dimensions reveals various salient features of these structures, as described below.


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(b)

(a)

(d)

(c)

Figure 1. Interactions between the molecules in the two-dimensional arrangement in the crystal structure of (a) Form I, (b) Form II, (c) Form III, and (d) Form IV. Intermolecular interactions are shown by dashed lines. Co-crystallization of 3,5-dinitrobenzamide and ADNBA in a 1:1 ratio from methanol resulted in the formation of Form I along with Form II as concomitant polymorphs12 with fewer crystals of Form I (see supporting information Figure S6). The single crystal X-ray structure revealed that Form I crystallizes in space group P21/n with Z = 4. Crystallographic parameters


4

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are given in Table 1. The molecular arrangement in the crystal lattice is shown in Figure 1(a). The molecules are linked through catemeric N-H···O (N···O 2.819(3) Å, N-Ĥ···O 171.5o) hydrogen bonds forming a tape like structure in one-dimension. Such tapes are connected through N-H···O hydrogen bonding in two-dimensions. Furthermore, the oxygen atom of the amide group forms a C-H···O hydrogen bond13 with an aromatic hydrogen atom (Table S5). Crystallization of ADNBA from methanol and many other solvents gave Form II (see supporting information Table S1-S4). The arrangement of molecules in the crystal lattice is shown in Figure 1(b). Molecules recognize each other through the formation of catemeric N-H···O (N···O 2.886(4) Å, N-Ĥ···O 162.6o) hydrogen bonds. The characteristics of hydrogen bonds are listed in Table S5. Crystal structure determination of the single crystals of Form III, obtained by hydrothermal reaction, reveals that the asymmetric unit consists of two molecules of ADNBA unlike Forms I and II which contain only one molecule in the asymmetric units. In Form III, in contrast to Forms I and II, the adjacent molecules are held together by a dimeric N-H···O hydrogen bonded R(8) motif,14 a well-known recognition pattern between amide groups. The dimers are formed between symmetry independent molecules, through a non-centrosymmetric N-H···O (N···O 2.873(2), 2.903(8) Å and N-Ĥ···O 173.2, 171.6o respectively) hydrogen bonded coupling. Adjacent dimers interact through N-H···O hydrogen bonds formed as a result of the interactions between -NH2 and -NO2 groups resulting in a one-dimensional zig-zag tape as shown in Figure 1(c). Such adjacent tapes interact with each other through C-H···O hydrogen bonds (see Table S5). The molecular ensemble forms a planar sheet structure and stacks in threedimensions, stabilized by π-π interactions with the distance between adjacent sheets being 3.3 Å (see Figure S3 supporting information).


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Form IV is obtained by the crystallization of ADNBA from a benzene solution by slow evaporation method. Structural analysis reveals that Form IV has a quite distinct feature in terms of packing with the incorporation of both the types of hydrogen bonding patterns observed in the amide compounds, i.e., catemer and dimer formation. Arrangement of molecules is shown in Figure 1(d). The adjacent molecules, related by inversion symmetry, form dimers through R(8) pattern consisting of N-H···O (N···O 2.822(7) Å, N-Ĥ···O 170.1o) hydrogen bonds, formed by syn H atoms of amide group. These dimers further interact with each other through catemeric C(4) chain pattern involving the anti H atom of the amide group forming N-H···O (N···O 3.033(4) Å, N-Ĥ···O 165o) hydrogen bonds. As a result, both cyclic as well as acyclic hydrogen bonds, as in 3,5-dinitrobenzamide,10 are observed in the structure. In a systematic study of exploring hydrothermal technique for the discovery of new solid forms, a hydrate of ADNBA was obtained by keeping the reaction mixture at 130/140 oC for 24 hours (see supporting information Table S3 and S4). Crystal structure analysis reveals that the water molecule is disordered over two positions. The basic recognition pattern is the same in both Form III and the hydrate with significant changes within these patterns. In the hydrate, unlike Form III, the symmetry dependent molecules interact with each other involving –CONH2 groups forming a centrosymmetric R(8) motif through N-H···O (N···O 2.899(5), 2.930(2) Å and NĤ···O 178.3, 173o respectively) hydrogen bonds. These dimeric units interact each other through N-H···O hydrogen bonding between –NH2 and –NO2 groups forming one-dimensional zig-zag tapes as observed in Form III. Such adjacent tapes interact with water molecules through hydrogen bonding (see Figure 2).The molecules form a planar sheet structure and these sheets stack

in

three-dimensions

held

together

by

water


molecules

through

O-H···O

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Table 1. Crystallographic Data for ADNBA Polymorphs I- IV and the Hydrate.

empirical formula formula weight crystal habit crystal color crystal system space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å 3) Z Dcalc (g cm-3) T (K) µ (mm-1) 2θ range (deg) F(000) No. parameters GOF on F2 R1[I>2σ(I)] wR2 ∆ρmin/ ∆ρmax (e Å-3)

Form I C7H6N4O5

Form II C7H6N4O5

Form I' C7H6N4O5

Form III C7H6N4O5

Form IV C7H6N4O5

226.15

226.15

226.15

226.15

226.15

irregular blocks

rectangular blocks yellow orthorhombic Pbca 9.986(4) 10.756(5) 15.973(6) 90 90 90 1715.63(12) 8 1.751 120 0.152 2.5-29.9 928 169 0.9618 0.0348 0.0894 -0.29, 0.43

irregular blocks yellow monoclinic P21/n 7.756(18) 12.275(3) 9.512(2) 90 111.05(15) 90 845.2(3) 4 1.777 451 0.154 2.8-31.1 464 145 1.0374 0.0590 0.1623 -0.59, 0.74

Needles/ blocks/plates yellow monoclinic P21/c 8.340(8) 8.860(9) 23.686(2) 90 96.59(6) 90 1738.7(3) 8 1.728 120 0.150 2.4-30.1 928 337 0.9996 0.0411 0.0962 -0.39, 0.47

small blocks

yellow monoclinic P21/n 7.750(7) 12.301(11) 9.511(8) 90 111.09(4) 90 846.00(13) 4 1.775 120 0.154 2.8-30.0 464 169 1.0919 0.0375 0.0859 -0.27, 0.53


yellow monoclinic P21/c 13.968(4) 7.608(2) 8.663(2) 90 94.19(1) 90 918.1(4) 4 1.636 298 0.142 1.4-23.3 464 169 0.765 0.0439 0.0783 -0.19, 0.18

Hydrate C7H6N4O5. ¼ H2O 230.15

Form III' C7H6N4O5

Needles/ blocks/plates yellow triclinic Pī 4.992(1) 7.305(2) 25.341(7) 96.41(1) 95.61(1) 90.04(1) 913.9(4) 4 1.673 298 0.146 2.4-27.8 472 339 1.027 0.0535 0.1486 -0.42, 0.37

Needles/ blocks/plates yellow monoclinic P21/c 8.350(4) 8.858(3) 23.695(10) 90 96.71(3) 90 1740.50(13) 8 1.726 422 0.149 2.4-28.1 928 289 1.201 0.0676 0.1404 -0.65, 0.72

226.15

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(O···O 2.773(5) Å) hydrogen bonding and π-π interactions (Figure S5 supporting information). The stacking distance between the planar sheets, in three-dimensions, in both Form III and the hydrate is same (3.3 Å) though there is inclusion of water molecules in the hydrate.

Figure 2. Hydrogen bonding interactions observed in the hydrate. Investigation of the Stability and Transformation Behaviour of the Forms Thermal behavior and the stability relationship between all the forms were investigated using hot stage microscopy (HSM), differential scanning calorimetry (DSC) and in situ variable temperature powder X-ray diffraction (PXRD). Moreover, only a few single crystals of Form I could be obtained from the method discussed above, leading to question regarding the large-scale preparation of this polymorph, as a pure phase. The visual changes, such as in morphology,


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colour, transparency/opaqueness, etc., observed in the crystals during heating were recorded and are shown in Figure 3.

30

250

253

255

210

30

176

253

255

210

30

225

253

255

209

253

254

30

185

209

Figure 3. Hot stage microscopy pictures at different temperatures (oC) during the heating of Forms I-IV (top to bottom). Heat progress is from left to right and last picture in each row is recrystallization temperature of melt during cooling. Crystals of Form I did not show any changes during heating and melting occurred at 255 o

C which upon cooling recrystallized at 210 oC. In the case of crystals of Form II, however,

around 174-176 oC, quite remarkable changes were observed in colour (Figure 3) and eventually melted at 255 oC (m. p. of Form I) which subsequently recrystallized at 210 oC just like Form I.15 Similarly, Forms III and IV crystals showed changes in crystal characteristics before melting, but at different temperatures. In Form III, the changes were observed at 225 oC, while, Form IV showed changes at 185 oC. However, both Forms III and IV melted and recrystallized


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approximately the same temperature as observed in Form I and II. Crystals of the hydrate transformed to Form III and then to Form I on further heating, melting at 254 oC (Figure S7 supporting information).16 The HSM analyses suggests a possible phase transition in Forms II, III, IV and the hydrate to Form I. To explore furthermore the nature of phase transition, differential scanning calorimetry (DSC) measurements were carried out. It is evident from Figure 4 that no changes were observed in the energy profile for Form I, except a sharp endothermic peak at 256 oC, which is due to the melting of Form I. However, for Form II (Figure 4(a)) two endothermic peaks were observed (174 and 256 oC). Since the latter peak corresponds to the melting point of Form I, it suggests that a phase transition of Form II → I might have occurred at 174 oC and subsequently melted at 256 oC. Similarly, for Forms III and IV, two endothermic peaks corresponding to phase transitions were observed at 227 and 184 oC respectively and eventually melting was observed at 256 oC as shown in Figure 4(a).

(a)

(b)

Figure 4. DSC traces of Forms I-IV, a) heating up to melting point and b) cooling.


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It was further noted that all forms recrystallized approximately the same temperature upon cooling as shown in Figure 4(b) demonstrating that Forms IV, III and II transformed into I within the solid state, during heating. In the case of the hydrate, three endothermic peaks were observed at 135, 220 and 256 oC (Figure S8(a) supporting information). The last peak at 256 oC corresponds to the melting point of Form I while the first peak at 135 oC indicates a phase transition to Form III from the hydrate. The second peak at 220 oC suggests that a transformation occurred from Form III to I and recrystallized upon cooling at 208 oC as observed in other forms (Figure S8(b) supporting information). However, reheating of all polymorphs and the hydrate, in DSC in the second ramp after cooling, showed only one melting endotherm corresponding to Form I. Furthermore, unambiguous evidence for the phase transition of II, III, IV and the hydrate into Form I was obtained from in situ variable temperature powder diffraction experiments. It is evident from Figure 5(a) that Form I did not show any phase transitions as the position and intensity of the peaks remain intact throughout the process, irrespective of the temperature variations. However, phase transitions of Forms II, III and IV to Form I are evident from the appearance of new peaks during heating. The transformations are shown in blue in Figure 5. The patterns in blue are identical with that of the patterns shown in Figure 5(a) for Form I. This unequivocally confirms the transition of Forms II, III and IV into I before the melting of forms. In Form II, the transition is observed between 170-180 oC (with the appearance of the new peaks at 2θ 12, 18, 27o and disappearance of peaks at 16, 18, 32o) (Figure 5(b)), while similar transformation is observed for Form III in between 220-230 oC with a clear observation of the characteristic peaks of Form I in the above mentioned 2θ positions shown in Figure 5(c). However, in Form IV, such a transformation was found in between 180-190 oC (Figure 5(d)). In the case of the hydrate, a double phase transition was observed clearly during heating further


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substantiating the results observed in the HSM and DSC measurements. The first phase transition occurred in the temperature range 130-140 oC which corresponds to phase transformation of the hydrate to Form III and the second phase transition from Form III to I occurred in between 220230 oC (Figure S9 supporting information).

(a)

(b)

(d)

(c)

Figure 5. In situ variable temperature powder X-ray diffraction patterns for the polymorphs a) Form I, b) conversion of Form II → Form I, c) conversion of Form III → Form I , d) conversion of Form IV → Form I. Patterns during cooling are prefixed with ‘c’.


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In solution, however, quite interesting and noteworthy results were obtained which were different from those observed in the solid-state upon heating different forms. A schematic representation of the transformations (involving melting and/or dissolution and recrystallization) of forms both in solid and solution state is shown in Scheme 1. Form I, stable at elevated temperatures, can be converted to Form III by hydrothermal technique. Furthermore, Form II can be prepared from Form III when crystallized from methanol at ambient conditions which is again not observed in the solid-state (vide supra). On the other hand, Form I remained intact when crystallized at ambient conditions (irrespective of the solvent used for crystallization) which shows that hydrothermal conditions playing a crucial role in the dissolution and recrystallization of Form I to III in solution (Figure S10 supporting information). It is worth mentioning that in the solid-state, Form I could not be converted to any other form which is possible in the solution crystallization. Thus, phase transformations were well characterized with a high degree of correlation of transition temperature from different experiments as tabulated in Table S6 (supporting information). Taking into account the observations made in the solid state, phase transformations in the single crystals has been carried out. It is observed that Form II and the hydrate transformed to Form I and III respectively via crystal-to-crystal transformation, while, Forms III and IV did not retain crystallinity during the in situ heating. Detailed methodology and observations are discussed below.


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Scheme 1. Schematic representation showing interconversion between the forms. The red, green and purple colored arrows denote solution, solid-state and crystal-to-crystal transformation behavior respectively. Single-Crystal-to-Single-Crystal Transformation Crystal-to-crystal transformation, occurring due to cooperative movement of atoms in the solid state, is an interesting and challenging phenomenon in terms of obtaining good-quality single crystals even after phase transformations which gives more insights about the mechanism of transformation from one solid form to another.17 Single crystals of Form I did not show any changes in the unit cell dimensions during in situ heating even up to 200 oC demonstrating the stability of Form I and no unit cell parameters could be obtained above this temperature. However, single crystals of Form II showed a change in the unit cell parameters and the phase transition occurred in the temperature range 174-176 oC which corresponds to Form II to I transformation. The overlay diagram of the arrangement of the molecules in two-dimensions, in both Forms I and II, is shown in Figure S11 (see supporting information). The centroid distance between the molecules of adjacent tapes is less in Form II (~10 Å) when compared to Form I (~12 Å). The SCSC phase transformation from Form II to I occurring without loss of crystallinity (Figure S12(a) supporting information) is attributed to the fact that the cooperative


14

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moment of atoms from one form to another is easier. This is because the basic recognition pattern (N-H···O hydrogen bonded catemer) and structural arrangement of molecules is similar in both forms. The crystal system, however, changed from orthorhombic (Form II) to monoclinic (Form I). Furthermore, without any complications, the structure was refined and solved to a Rfactor of 5.9% with the intensity data collected at 176 oC. In a similar way, SCSC reactivity was observed in the case of ADNBA hydrate. When a crystal of the hydrate was subjected to in situ heating, irreversible transformation occurred from triclinic (the hydrate) to monoclinic (Form III) system in the temperature range 135-140 oC with loss of the water molecule. This may be due to the fact that the two solid forms are iso-structural in terms of the arrangement of molecules in both two- and three-dimensions making easier movement of atoms in the solid-state. As in the case of Form II to I transformation, single crystals of the hydrate retained crystallinity throughout in situ heating on the diffractometer and data collection process at high temperature (Figure S12(b) supporting information) and the structure solved to a R factor of 6.7%. In contrast, Forms III and IV, however, remain intact without any changes up to 180 oC but above this the single crystals lost their crystallinity and as a result the diffraction pattern failed to converge to yield a unit cell. A plausible explanation for the loss of crystallinity above 180 oC may be due to the fact that Forms III and IV show a large structural deviation from that of Form I, for example, transformation of cyclic R(8) dimeric hydrogen bonding between amides into a C(4) chain catemeric hydrogen bonding. In fact, the higher phase transition temperature for Form III is also indicative of lattice relaxation before transformation occurs.

Conclusion To summarize, preparation and rational analysis of four polymorphs and the hydrate of 4-amino3,5-dinitrobenzamide (ADNBA) have been reported and thoroughly characterized. Crystal


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structure analysis reveals that all the forms are clearly distinguishable in terms of the intermolecular interactions. In all the forms, the -NH2 group present between the -NO2 groups forms intramolecular N-H···O hydrogen bonding. In Forms I and II, however, molecules interact through N-H···O catemer hydrogen bond formation while N-H···O dimeric pattern is observed in the case of Form III and the hydrate. In Form IV, molecules interact through N-H···O hydrogen bonded R(8) dimer as well as C(4) catemer formation. ADNBA hydrate, obtained by hydrothermal process, could not be obtained at ambient conditions even in the presence of water as solvent for crystallization. This shows the important conditions (hydrothermal process) required for the preparation of the hydrate. The DSC and HSM results are in good agreement with the crystallographic studies and complete analysis assured us that the ADNBA samples were homogeneous with regard to phase composition. Furthermore, solid-state reactivity has been reported and, in particular, in situ single-crystal-to-single-crystal transformation of Form II to I and the hydrate to Form III have also been demonstrated. Form II is the most stable phase at ambient conditions while Form I is stable at higher temperatures. The noteworthy and interesting observation is that Form I (which does not transform to any other form in the solid state) can be converted to Form III and then to Form II (not directly from Form I to II) in the solution crystallization (dissolution and recrystallization) while reverse is observed in the solid-state i.e., Form II to I transformation. We believe that this kind of systematic study involving preparation and solid state reactivity would be of immense utility in understanding drug-polymorphism.

Experimental Section Chemicals and Crystal Growth: ADNBA was purchased from Sigma-Aldrich. HPLC grade solvents were used for crystallization. From PXRD, it is confirmed that the commercially


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available material (ADNBA) is found to be Form II. Crystallization was carried out from a wide variety of solvents, solvent mixtures and other crystallization methods (see supplementary information) which resulted in five different solid forms labelled as Forms I, II, III, IV and the hydrate. Crystals of Form I (space group P21/n, Z = 4), as yellow hexagonal blocks, were obtained by crystallization of equimolar ratio of 3,5-dinitrobenzamide and ADNBA from methanol along with Form II as concomitant polymorphs. Form II (space group Pbca, Z = 8) consisted of rectangular blocks and was obtained in many cases; the measured crystal being obtained by crystallization from methanol. Form III (space group P21/c, Z = 8) was obtained by hydrothermal technique. A Teflon flask containing an aqueous solution of 20 mL of ADNBA (40 mg), placed in a stainless steel autoclave. It was kept in a hot-air oven and heated at 170 oC for 24 hrs. Single crystals of different morphologies (needles/plates/irregular blocks) were obtained upon cooling the apparatus to the laboratory temperature over a period of 7-8 hours. All crystal morphologies are of the same phase as confirmed by PXRD and single crystal XRD. The experiment was repeated at every 10 oC decrease in oven temperature i.e., at 160, 150, 140, 130, 120, 110, 100, 90, 80 oC. Similarly, experiment was repeated by employing mixture of other solvents such as methanol, acetone and ethanol with water (solvothermal method) by varying time (36 and 48 h). Form IV (space group P21/c, Z = 4) can be obtained by crystallization of ADNBA from benzene by slow evaporation method. ADNBA hydrate (space group Pī, Z = 4) is also obtained by hydrothermal technique which is similar to Form III preparation but by lowering temperature i.e., keeping the reaction mixture at 130/140 oC for 24 hours and cooling to room temperature over a period of 7-8 hours. Single-crystal X-ray Diffraction. Details of the single crystal X-ray diffraction intensity measurements and refinements are given in Table 1. All operations for Forms I, II, III, I' and III'


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were performed on a Bruker-Nonius Kappa Apex2 diffractometer, using graphitemonochromated MoKα radiation (λ=0.7107 Å). All diffractometer manipulations, including data collection, integration, scaling, and absorption corrections for these forms were carried out using the Bruker Apex2 software.18 Preliminary cell constants were obtained from three sets of 12 frames. Data collection for Forms I, II and III was carried out at 120K, using a frame time of 20 sec and a detector distance of 60 mm. The optimized strategy used for data collection consisted of four phi and six omega scan sets, with 0.5° steps in phi or omega. Data collection for Form IV and the hydrate was performed on a Bruker Apex diffractometer. The intensity data were processed by using the Bruker SAINT suite of programs.19 The structures were solved by using SHELXS and refined by least-square methods using SHELXL.20 From the systematic absences, the observed metric constants and intensity statistics, space groups P21/n, Pbca, P21/c and Pī were chosen for Forms I, II, III & IV and the hydrate respectively at the beginning; subsequent solution and refinement confirmed the correctness of the choice. The structures (Forms I, II, III, I' and III') were solved using SIR92 and subsequent electron-density difference syntheses21 and refined (full-matrix-least squares) using the Oxford University Crystals for Windows program.22,23 All non-hydrogen atoms were refined using anisotropic displacement parameters, while H atoms were refined using isotropic displacement parameters. Crystallographic data (excluding structural factors) for the structures reported in this paper have been deposited with the Cambridge Crystallographic Data Centre and allocated the deposition numbers CCDC 955506-955512. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EW, U.K. (E-mail:[email protected]). PXRD: Powder X-ray diffraction measurements were carried out with a Rigaku Dmax 2500 diffractometer using Cu Kα radiation (λ = 1.5418 Å). The sample holder was a copper block, and


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a very thin layer of powder sample was pressed on this block. The patterns were collected in the 2θ range of 4-40o with a step size of 0.02o and 1.0s counting per step. The copper block with the sample was heated at the rate of 10 °C/min. The diffraction pattern was collected while the sample temperature was held constant within 1 °C of the set temperature, and the data were acquired in 8 min. The diffraction data were collected at room temperature and subsequently after every 10 °C to monitor the change in structure during heating. The positions of the peaks were fixed by deconvoluting the peaks using Rigaku multipeak separation software available with the diffractometer system. Thermal Analysis. The DSC experiments were performed using a DSC 1 Star System with STARe Excellence Software from Mettler-Toledo AG. Samples in the range 3-4 mg were placed in Al crucibles after surface-drying on filter paper. The sample was heated from 30 oC to 280 oC at a rate of 10 oC/min and cooled at the same rate under a continuous flow of nitrogen. For hot stage microscopy (HSM) analysis, a stereomicroscope equipped with a hot stage apparatus was used. Photographs were recorded with an Olympus Digital color camera. Single crystal of a particular form was placed on a glass slide with a cover slip and the sample was heated at the rate of 10 oC/min. Temperatures at which phase transition occurred, melting started, completely melted and recrystallization occurred were determined by visual observation.

ASSOCIATED CONTENT Supporting Information. Crystallographic information files (CIF) and packing diagrams for all forms in 3D arrangement, DSC and PXRD for hydrate. This material is available free of charge via the Internet at http://pubs.acs.org.


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AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]

Notes Any additional relevant notes should be placed here.

ACKNOWLEDGMENT This work was supported by Department of Science and Technology, India and National Science Foundation, USA for support of this research. We thank Professors T. N. Guru Row and Bruce M. Foxman for their support in providing single crystal data. REFERENCES (1) (a) Hilfiker, R. Polymorphism in the Pharmaceutical Industry; Wiley-VCH: Weinheim, Germany, 2006. (b) Bernstein, J. Polymorphism in Molecular Crystals. Oxford University Press. New York. 2002. (c) Brittain, H. G. Polymorphism in Pharmaceutical Solids; Marcel Dekker Inc.: New York, 1999; Vol. 23. (d) Byrn, S. R. In Solid-State Chemistry of Drugs; SSCI, Inc.: West Lafayette, IN, 1999. (e) McCrone, W. C. Polymorphism. In Polymorphism in Physics and Chemistry of the Organic Solid State; Fox, D.; Labes, M. M.; Weissenberg, A. Eds. Interscience: New York, 1965; Vol. II, 725−767. (f) Singhal, D.; Curatolo, W. Adv. Drug Delivery Rev. 2004, 56, 335-347. (g)


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Using HSM, it was possible to observe change in the unit cell parameters from

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3572. (p) Supriya, S.; Das, S. K. J. Am. Chem. Soc. 2007, 129, 3464-3465. (q) Halasz, I. Cryst. Growth Des. 2010, 10, 2817-2823. (18)

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Graphical abstract

4-Amino-3,5-dinitrobenzamide exists in five different forms - 4 polymorphs and a hydrate. In the solid state, all forms transform to a high temperature stable form (Form I) while in the solution, all the forms convert to a room temperature stable form (Form II). This could be useful in understanding phase transformation behavior of organic compounds and active pharmaceutical ingredients (APIs).


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Polymorphism and Phase Transformation Behavior of Solid Forms of 4

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