Pharmaceutical co-crystals of diflunisal and. diclofenac with theophylline

Transcription

1 SUPPORTING INFORMATION FOR PUBLICATION Pharmaceutical co-crystals of diflunisal and diclofenac with theophylline Artem O. Surov a, Alexander P. Voronin a, Alex N. Manin a, Nikolay. G. Manin a, Lyudmila G. Kuzmina b, Andrei V. Churakov b and German L. Perlovich a* a G.A. Krestov Institute of Solution Chemistry RAS, 15345, Ivanovo, Russia. b Institute of General and Inorganic Chemistry RAS, Leninskii Prosp. 31, Moscow, Russia * Corresponding Author glp@isc-ras.ru. Tel.: ; Fax.:

2 S1. X-ray diffraction experiments Figure S1. Experimental and calculated (SIKLIH7) PXRD patterns of diclofenac acid (form II). Figure S2. Experimental and calculated (FAFWIS1) PXRD patterns of diflunisal (form I). 2

3 Figure S3. Experimental and calculated (BAPLOT6) PXRD patterns of theophylline (form II). 3

4 (a) (b) (c) Figure S4. Molecular packing projections for (a) theophylline (form II), (b) diflunisal (form I) and (c) diclofenac acid (form II). Form II of THP crystallises in the orthorhombic spacegroup Pna2 1 and has the planar conformation, with the methyl substituents in plane with the purine ring (Figure S4a). In the crystal, the THP molecules connected by only one N H N hydrogen bond involving the NH group of the five-membered ring of one molecule as donor and the second nitrogen atom of the same purine ring as acceptor. In form I of DIF, the molecules are packed as dimers via the R (8) carboxylic acid motif (Figure S4b). The two aromatic rings of DIF are bent out of 2 2 plane, with the angle of 43.. However, the hydroxyl and carboxylic groups lie in plane with the benzene ring. The molecules of DIC form II also form centrosymmetric dimers linked by hydrogen bonds between the carboxylic groups (Figure S4c). In contrast to DIF, the carboxylic group of the molecule is out of plane of the aromatic ring forming the τ 1 torsion angle of ca (Figure 1). 4

5 Figure S5. Experimental PXRD patterns of diclofenac acid, theophylline and the [DIC+THP] co-crystals 5

6 Figure S6. Experimental PXRD patterns of diflunisal, theophylline and the [DIF+THP] cocrystal Figure S7. Experimental and calculated PXRD patterns of the [DIC+THP] co-crystal 6

7 Figure S8. Experimental and calculated PXRD patterns of the [DIF+THP] co-crystal 7

8 Table S1. Energy of interactions between the closest molecules in the co-crystals and THP (form IV) calculated using the PIXEL approach in kj mol -1. Distance (Å) a E coul E pol E disp E rep E tot Symmetry [DIС+THP] DIC-DIC interaction x, -y, -z x, -y, 1-z x, -y, 1-z x, y, z DIC-THP interaction x, y, z x, y, z THP-THP interaction x, 1-y, -z [DIF+THP] DIF-DIF interaction x, -y, -z x,.5-y,.5+z DIF-THP interaction x, y,1+z x, y, z x, y, z THP-THP interaction x, -y, -z THP form IV x, y, z x,1-y,1-z x,-y,1-z x,1-y,1-z a The distance between the centres of mass of the neighbouring molecules. Analysis of the strongest interactions between the neighbouring molecules (Table S1) indicate that for both co-crystals the interaction between the hydrogen bonded THP molecules is the largest one, namely kj mol 1 for [DIC+THP] and kj mol 1 for [DIF+THP]. It appears that the mentioned values are energetically comparable to that in the 8

9 thermodynamically stable form IV of pure THP (-84.5 kj mol 1 ). The second largest interaction energies correspond to O H N hydrogen bond in an acid-imidazole heterosynthon between the neighbouring API and THP molecules. The total energy of this contact is calculated to be kj mol 1 for [DIC+THP] and -5.5 kj mol 1 for [DIF+THP]. The other API-THP interaction energies are at the level of ca kj mol 1. Interestingly, in [DIF+THP], the π π interactions between the diflourbenzene rings of the DIF molecules (-17.4 kj mol 1 ) are more stabilizing than hydrogen bonded dimers of DIF (-12.9 kj mol 1 ). In [DIC+THP], the π π and С-H π interactions between APIs molecules are important for the stabilization of DIC layers in the crystal. 9

10 Table S2. The weight, g (mg), solution concentrations, m (mol kg -1 ), and solution enthalpies, (kj mol -1 ), of the co-crystals in methanol at 298 К. [DIC+THP] g m H sol [DIF+THP] g m 1-3 H 298 sol =46.3±.5 =47.1±.2 Table S3. The weight, g (mg), solution concentrations, m (mol kg -1 ), and solution enthalpies, (kj mol -1 ), of DIC and DIF in THP methanol solutions and THP in DIC and DIF methanol solutions at 298 К. DIC in m THP methanol solution THP in m DIC methanol solution g m 1 g m 1 H sol -3 H 298 sol =17.2±.2 =24.3±.2 DIF in m THP methanol solution THP in m DIF methanol solution g m 1 g m 1 H sol -3 H 298 sol =14.5±.3 =21.4±.2 1

11 Table S4. The intrinsic dissolution rates at 37 C and solubilities at 25 C of diclofenac acid, diflunisal and the co-crystals in ph 7.4 phosphate buffer. Intrinsic dissolution rate, Solubility, -2 mg min -1 cm mol l -1 DIC.189±.1 (5.2±.1) 1-3 [DIC+THP].255±.2 (8.3±.5) 1-3 DIF.539±.12 (15.5±.4) 1-3 [DIF+THP].56±.3 (35.3±1.4)