Supporting Information Three Polymorphic Forms of Ciprofloxacin Maleate: Formation Pathways, Crystal Structures, Calculations and Thermodynamic Stability Aspects Artem O. Surov a, Andrei V. Churakov b, German L. Perlovich a,* a Institution of Russian Academy of Sciences, G.A. Krestov Institute of Solution Chemistry RAS, 153045, Ivanovo, Russia. E-mail: glp@isc-ras.ru b Institute of General and Inorganic Chemistry RAS, Leninskii Prosp. 31,119991, Moscow, Russia. *To whom correspondence should be addressed: Telephone: +7-4932-533784; Fax: +7-4932- 336237; E- mail glp@isc-ras.ru
Figure S1. Experimental PXRD patterns of ciprofloxacin maleate form I, form II, form III and ciprofloxacin maleate monohydrate obtained by solution crystallization
Figure S2. Experimental and calculated PXRD patterns of ciprofloxacin maleate polymorphs
Figure S3. DSC thermogram and TG analysis of ciprofloxacin maleate monohydrate
(a) (b) (c) (d) Figure S4. Hydrogen bonded supramolecular unit in the crystal structures of (a) ciprofloxacin maleate monohydrate and (b) norfloxacin maleate monohydrate. Packing arrangements of (c) ciprofloxacin maleate monohydrate and (d) norfloxacin maleate monohydrate. The maleate ions are colored red, water molecules are colored blue.
Figure S5. Selected intermolecular C H O (green), N O (light blue) and F C contacts in the crystal structure of form I derived from the Bader analysis of periodic electron density. The interaction energies are given in kj mol -1.
Figure S6. Selected hydrogen bonds (blue) and intermolecular C H O (green) contacts in the crystal structure of form II derived from the Bader analysis of periodic electron density. The interaction energies are given in kj mol -1.
Figure S7. Selected hydrogen bonds (blue), intermolecular C H O (green) and and F H contacts in the crystal structure of form III derived from the Bader analysis of periodic electron density. The interaction energies are given in kj mol -1.
Figure S8. DSC traces for the polymorphs of ciprofloxacin maleate and ciprofloxacin maleate monohydrate
Figure S9. DSC and TG analysis for ciprofloxacin maleate
Figure S10. PXRD analysis of residual materials after solubility of ciprofloxacin maleate form I, form II and form III in the ph 1.2 solution. Note that form III transforms to form II during solubility experiment.
Details of the DFT calculations DFT computations with periodic boundary conditions (solid-state DFT calculations) were performed using the CRYSTAL14. The B3LYP functional was employed with an all-electron Gaussian-type localized orbital 6-31G(d,p) basis set. According to previous results, S1-S5 the B3LYP/6-31G** level of approximation provides reliable and consistent results in studying the various intermolecular (noncovalent) interactions in molecular crystals. The default CRYSTAL14 computation options are used to achieve an appropriate level of accuracy in evaluating the Coulomb and Hartree-Fock exchange series and the exchange-correlation contribution. Tolerance on energy controlling the self-consistent field convergence for geometry optimizations and frequencies computations is set to 1 10-9 and 1 10-10 hartree, respectively. The shrinking factor, reflecting the density of the k-points grid in the reciprocal space, was set at least to 3. The space groups and unit cell parameters of the considered cocrystal obtained in the single-crystal X-ray studies are fixed and structural relaxations are limited to the positional parameters of atoms. The atomic positions from experiment are used as the starting point in the solid-state DFT computations. All the optimized structures correspond to the minimum point on the potential energy surface. References S1 Oddershede, J.; Larsen, S. Charge density study of naphthalene based on X-ray diffraction data at four different temperatures and theoretical calculations. J. Phys. Chem. A, 2004, 108, 1057-1063. S2 Munshi, P.; Guru Row, T. N. Exploring the Lower Limit in Hydrogen Bonds: Analysis of Weak CH O and CH π Interactions in Substituted Coumarins from Charge Density Analysis. J. Phys. Chem. A, 2005, 109, 659-672. S3 Munshi, P.; Thakur, T. S.; Guru Row, T. N.; Desiraju, G. R. Five varieties of hydrogen bond in 1-formyl-3-thiosemicarbazide: an electron density study. Acta Cryst. B, 2006, 62, 118-127. S4 Munshi, P.; Guru Row, T. N. Intra-and intermolecular interactions in small bioactive molecules: cooperative features from experimental and theoretical charge-density analysis. Acta Cryst. B, 2006, 62, 612-626. S5 Vener, M. V.; Manaev, A. V.; Egorova, A. N.; Tsirelson, V. G. QTAIM study of strong H-bonds with the OH A Fragment (A= O, N) in three-dimensional periodical crystals. J. Phys. Chem. A, 2007, 111, 1155-1162.
Table S1. Characteristics of the intermolecular (noncovalent) interactions in the ciprofloxacin maleate form I calculated by the solid-state DFT method coupled with the Bader analysis of the periodic wave-function* Interaction D(D A)/ Å ρ b / 2 ρ b / G b / (D(H A)/ Å) a.u. a.u. a.u. E int / kj mol -1 Hydrogen bonds N3-H32 O22 a 2.782 (1.940) 0.046 0.123 0.033 36.9 N3-H31 O22 b 2.791 (1.932) 0.034 0.107 0.026 29.8 C-H O(F) contacts C17-H171 O23 c 3.330 (2.378) 0.017 0.046 0.012 13.6 C15-H151 O23 d 3.162 (2.519) 0.013 0.043 0.010 11.2 C3-H3 F3 d 3.248 (2.401) 0.010 0.041 0.009 10.4 C22-H22 O3 e 3.221 (2.563) 0.011 0.039 0.009 9.8 C14-H142 O2 e 3.196 (2.544) 0.011 0.037 0.009 9.7 C17-H172 O2 f 3.413 (2.522) 0.011 0.036 0.008 9.2 C17-H171 O24 c 3.342 (2.672) 0.009 0.036 0.008 9.0 C7-H72 O23 g 3.420 (2.748) 0.010 0.035 0.008 8.7 C5-H5 O1 e 3.475 (2.656) 0.010 0.033 0.008 8.6 C23-H23 O3 e 3.283 (2.672) 0.008 0.031 0.007 7.4 C16-H162 O24 c 3.198 (2.840) 0.007 0.029 0.006 6.9 C6-H62 O22 h 3.602 (2.706) 0.007 0.023 0.005 5.5 C15-H152 O21 a 3.373 (2.891) 0.006 0.024 0.005 5.4 C6-H62 O23 g 3.486 (2.854) 0.005 0.021 0.004 4.8 C14-H141 O1 i 3.675 (2.953) 0.005 0.020 0.004 4.7 C16-H161 O3 j 3.639 (2.911) 0.006 0.020 0.004 4.7 Other interactions C6 F1 k 3.121 0.008 0.036 0.007 8.4 N1 O23 g 3.114 0.009 0.029 0.007 7.5 C9 F1 i 3.155 0.007 0.032 0.006 7.2 N3 O23 d 2.949 0.007 0.029 0.006 7.1 H72 H151 h 2.373 0.007 0.027 0.005 6.0 C6-H61 N2 d 3.855 (3.014) 0.008 0.022 0.005 5.5 C21 O24 c 3.277 0.006 0.023 0.005 5.2 C24 O21 c 3.221 0.006 0.023 0.005 5.1 C11 O2 l 3.296 0.006 0.019 0.004 4.6 C4 C12 l 3.318 0.006 0.020 0.004 4.4 H61 H152 k 2.504 0.005 0.020 0.004 4.1 H23 H72 m 2.535 0.005 0.019 0.004 4.1 H5 H152 k 2.401 0.005 0.019 0.004 4.0 C12 C23 g 3.570 0.006 0.017 0.003 3.8 C2 C13 l 3.477 0.006 0.016 0.003 3.7 H9 H141 i 2.550 0.004 0.017 0.003 3.5 C1 N1 l 3.521 0.004 0.014 0.003 3.3 C10 C22 g 3.601 0.004 0.011 0.002 2.6 E latt, kj mol -1 286.2 *The X A and H A distances, D(X A) and D(H A), where X, A = O, N and C; the X-H A angle, (D- H A); the electron density ρ b, the Laplacian of the electron density 2 ρ b and local electronic kinetic energy density G b at the bond critical point; the energy of the intermolecular noncovalent interaction E int. Symmetry codes: a (2-x, 1-y, 1-z); b (x, y, z); c (1-x, 1-y, 1-z); d (1+x, y, z); e (1-x, -y, 1-z); f (1.5-x, 0.5+y, 1.5-z); g (0.5+x, 0.5-y, 0.5+z); h (-0.5+x, 0.5-y, 0.5+z); i (2-x, -y, 1-z); j (1.5-x, -0.5+y, 1.5-z); k (-1+x, y, z); l (1-x, -y, 1-z); m (- 0.5+x, 0.5-y, -0.5+z);
Table S2. Characteristics of the intermolecular (noncovalent) interactions in the ciprofloxacin maleate form II calculated by the solid-state DFT method coupled with the Bader analysis of the periodic wave-function* Interaction D(D A)/ Å ρ b / 2 ρ b / G b / (D(H A)/ Å) a.u. a.u. a.u. E int / kj mol -1 Hydrogen bonds N3-H32 O22 a 2.750 (1.832) 0.052 0.138 0.038 42.3 N3-H31 O23 b 2.972 (2.277) 0.019 0.055 0.014 15.9 N3-H31 O24 b 3.011 (2.312) 0.013 0.049 0.011 12.9 N3-H31 O3 c 3.055 (2.409) 0.012 0.042 0.010 11.0 C-H O contacts C12-H12 O23 d 3.217 (2.475) 0.012 0.040 0.009 10.5 C17-H172 O3 e 3.391 (2.549) 0.012 0.037 0.009 9.9 C14-H142 O22 f 3.280 (2.699) 0.010 0.035 0.008 8.8 C22-H22 O2 g 3.314 (2.594) 0.009 0.032 0.007 8.1 C15-H151 O24 b 3.220 (2.741) 0.008 0.032 0.007 7.7 C5-H5 O23 d 3.258 (2.547) 0.008 0.031 0.007 7.4 C15-H152 O21 a 3.262 (2.743) 0.008 0.030 0.006 7.1 C5-H5 O1 h 3.429 (2.578) 0.008 0.027 0.006 6.8 C16-H161 O23 d 3.493 (2.633) 0.008 0.027 0.006 6.7 C17-H171 O3 c 3.272 (2.804) 0.006 0.026 0.005 6.0 C16-H162 O24 i 3.456 (2.829) 0.006 0.025 0.005 5.8 C17-H171 O21 i 3.416 (2.762) 0.006 0.025 0.005 5.6 C16-H162 O21 i 3.286 (2.852) 0.006 0.025 0.005 5.6 C16-H162 O1 e 3.682 (2.848) 0.006 0.023 0.005 5.5 C14-H141 O21 a 3.443 (2.787) 0.006 0.021 0.004 4.9 C7-H71 O22 i 3.802 (2.882) 0.006 0.021 0.004 4.7 C14-H141 O2 j 3.272 (2.833) 0.005 0.021 0.004 4.7 C23-H23 O2 g 3.458 (2.920) 0.004 0.018 0.004 3.9 C7-H72 O1 e 4.057 (3.182) 0.005 0.017 0.003 3.9 Other interactions O3 O23 k 3.309 0.009 0.039 0.008 9.4 C15 O22 f 2.972 0.009 0.037 0.008 8.7 H9 H72 e 2.320 0.008 0.029 0.006 6.4 C17 O24 i 3.142 0.006 0.027 0.005 6.1 H172 H172 l 2.442 0.007 0.026 0.005 5.6 H152 H161 f 2.397 0.007 0.025 0.005 5.5 C8 C8 e 3.588 0.006 0.018 0.004 4.3 C9 C13 e 3.486 0.006 0.018 0.004 4.2 C2 C10 e 3.604 0.006 0.017 0.003 3.9 H62 H62 m 2.855 0.005 0.019 0.003 3.9 C12 H23 d 3.142 0.004 0.012 0.002 2.7 E latt, kj mol -1 266.4 *The X A and H A distances, D(X A) and D(H A), where X, A = O, N and C; the electron density ρ b, the Laplacian of the electron density 2 ρ b and local electronic kinetic energy density G b at the bond critical point; the energy of the intermolecular noncovalent interaction E int. Symmetry codes: a (x, y, z); b (x, 1.5-y, 0.5+z); c (-1+x, y, z); d (1-x, 1-y, 1-z); e (2-x, 1-y, 2-z)j f (1-x, 0.5+y, 1.5-z); g (- 1+x, 0.5-y, -0.5+z); h (2-x, -0.5+y, 1.5-z); i (1-x, -0.5+y, 1.5-z); j (2-x, -0.5+y, 1.5-z); k (1+x, 1.5-y, 0.5+z); l (1-x, 1-y, 2-z); m (2-x, -y, 2-z).
Table S3. Characteristics of the intermolecular (noncovalent) interactions in the ciprofloxacin maleate form III calculated by the solid-state DFT method coupled with the Bader analysis of the periodic wave-function* Interaction D(D A)/ Å ρ b / 2 ρ b / G b / (D(H A)/ Å) a.u. a.u. a.u. E int / kj mol -1 Hydrogen bonds N3-H32 O22 a 2.791 (1.850) 0.047 0.123 0.033 37.2 N3-H31 O22 b 2.838 (2.022) 0.029 0.090 0.023 25.6 N3-H31 O23 c 3.116 (2.589) 0.009 0.035 0.008 8.6 C-H O(F, N) contacts C15-H151 O23 d 3.254 (2.411) 0.013 0.040 0.010 11.0 C17-H172 O23 c 3.201 (2.558) 0.012 0.040 0.009 10.3 C16-H162 O24 c 3.435 (2.532) 0.012 0.036 0.009 9.9 C9-H9 F1 e 3.180 (2.445) 0.009 0.037 0.008 9.2 C22-H22 O3 f 3.432 (2.536) 0.010 0.034 0.008 8.8 C5-H5 O1 g 3.392 (2.591) 0.010 0.032 0.007 8.3 C14-H141 O3 h 3.286 (2.600) 0.009 0.033 0.007 8.2 C6-H61 O2 i 3.086 (2.797) 0.009 0.035 0.007 8.2 C6-H62 F1 c 3.708 (2.753) 0.006 0.028 0.006 6.5 C6-H62 N2 c 3.402 (2.818) 0.008 0.025 0.005 6.1 C7-H71 O23 j 3.690 (2.809) 0.007 0.024 0.005 6.0 C14-H141 O22 b 3.454 (2.788) 0.007 0.025 0.005 6.0 C15-H152 O21 a 3.403 (2.920) 0.006 0.025 0.005 5.6 C16-H161 O3 g 3.711 (2.807) 0.007 0.023 0.005 5.6 C3-H3 O2 i 3.678 (2.760) 0.006 0.021 0.004 4.9 C7-H71 O21 c 3.365 (2.805) 0.005 0.020 0.004 4.6 C14-H142 O2 h 3.646 (2.988) 0.004 0.017 0.003 3.9 Other interactions C17-H172 C21 j 3.428 (2.730) 0.007 0.030 0.006 6.5 C16-H161 C22 j 3.428 (2.707) 0.009 0.028 0.006 6.4 F1 F1 e 3.009 0.004 0.027 0.005 5.9 O24 O24 k 3.252 0.006 0.024 0.005 5.8 C23 O21 d 3.222 0.007 0.022 0.005 5.4 C15-H152 C7 l 3.840 (2.928) 0.007 0.024 0.005 5.3 C22 O24 d 3.237 0.006 0.022 0.005 5.2 C3 C9 g 3.326 0.006 0.018 0.004 4.1 C1 C13 g 3.348 0.006 0.018 0.004 4.0 C11 O3 h 3.455 0.004 0.015 0.003 3.5 C17-H171 C6 l 3.716 (2.910) 0.004 0.016 0.003 3.4 H141 H22 b 2.703 0.004 0.015 0.003 3.1 C4 C10 g 3.685 0.004 0.014 0.003 3.0 C2 C9 g 3.679 0.004 0.012 0.003 2.9 E latt, kj mol -1 258.6 *The X A and H A distances, D(X A) and D(H A), where X, A = O, N and C; the X-H A angle, (D- H A); the electron density ρ b, the Laplacian of the electron density 2 ρ b and local electronic kinetic energy density G b at the bond critical point; the energy of the intermolecular noncovalent interaction E int. Symmetry codes: a (x, y, z); b (2-x, 1-y, 1-z); c (x, 1+y, z); d (2-x, -y, 1-z); e (2-x, 1-y, -z); f (x, -1+y, 1+z); g (1-x, 2-y, -z); h (2-x, 2-y, -z); i (1-x, 3-y, -z); j (1-x, 1-y, 1-z); k (1-x, -y, 1-z); l (x, -1+y, z)
Table S4. The weight, g (mg), solution concentrations, m (mol kg -1 ), and solution 0 enthalpies, H sol (kj mol -1 ), of ciprofloxacin maleate polymorphs in ph 1.2 media at 25.0 ºC. g m 10 Form I Form II Form III -3 298 H sol g m 10-3 298 H sol g m 10-3 H 298 sol 7.97 0.37 49.5 8.09 0.36 47.8 7.95 0.36 40.9 8.08 0.38 49.4 7.93 0.36 46.7 8.09 0.36 40.9 7.97 0.37 49.0 7.95 0.38 47.3 7.95 0.37 41.3 8.08 0.38 49.6 8.02 0.38 46.8 8.02 0.37 41.6 7.99 0.38 50.1 7.97 0.37 46.4 7.97 0.36 40.8 8.04 0.38 49.2 7.99 0.37 47.1 7.98 0.36 41.4 7.97 0.37 47.3 7.95 0.35 40.6 8.17 0.36 40.6 0 H sol =49.5±0.2 0 H sol =47.0±0.2 =41.0±0.3 0 H sol