Bringing new life into old drugs. A case study on nifuroxazide polymorphism

Ovidiu-Ilie Covaci, Raul-Augustin Mitran, Lucian Buhalteanu, Dan George Dumitrescu, Sergiu Shova, Corina-Mihaela Manta*

*corina.manta@sara-pharm.com

SUPPLEMENTARY MATERIALS

Figure S1. Nifuroxazide solubility over time measured by HPLC (37 oC, pH=7, ultrapure MilliQ water)

Figure S2. Hydrogen bonding propensity (H-bond pairing score) versus coordination score (H-bond co-ordination score) for possible crystal arrangements of nifuroxazide, the according to LHP model

Electronic Supplementary Material (ESI) for CrystEngComm.This journal is © The Royal Society of Chemistry 2017

Table S1. Bond distances (Å)

Form sVIICompound Form sIV FormsVI

Molecule A Molecule B

O1-C1 1.354(4) 1.343(4) 1.353(3) 1.352(3)

O2-C7 1.245(4) 1.206(4) 1.236(3) 1.226(3)

O3-C9 1.379(4) 1.356(4) 1.382(3) 1.377(3)

O3-C12 1.357(4) 1.342(4) 1.342(4) 1.352(4)

O4-N3 1.238(4) 1.224(4) 1.231(3) 1.227(3)

O5-N3 1.233(4) 1.228(3) 1.221(3) 1.232(3)

N1-N2 1.372(4) 1.356(4) 1.372(3) 1.361(3)

N1-C7 1.363(4) 1.379(4) 1.359(4) 1.368(4)

N2-C8 1.282(4) 1.285(4) 1.272(4) 1.276(4)

N3-C12 1.419(4) 1.410(4) 1.426(4) 1.412(4)

C1-C2 1.388(5) 1.390(4) 1.387(4) 1.383(4)

C1-C6 1.380(5) 1.374(5) 1.388(4) 1.388(4)

C2-C3 1.377(5) 1.365(4) 1.376(4) 1.377(4)

C3-C4 1.389(5) 1.378(4) 1.398(4) 1.394(4)

C4-C5 1.398(4) 1.389(4) 1.387(4) 1.393(4)

C4-C7 1.484(5) 1.474(4) 1.484(4) 1.478(4)

C5-C6 1.384(5) 1.361(4) 1.379(4) 1.374(4)

C8-C9 1.440(4) 1.421(5) 1.435(4) 1.434(4)

C9-C10 1.367(5) 1.357(4) 1.360(4) 1.356(4)

C10-C11 1.402(5) 1.400(5) 1.402(4) 1.404(4)

C11-C12 1.357(5) 1.339(5) 1.342(4) 1.341(4)

O6-C15 1.282(5) 1.230(4) - -

N4-C13 1.492(6) 1.331(4) - -

N4-C14 1.483(5) - - -

N4-C15 1.303(6) - - -

C15-C16 1.490(6) 1.505(5) - -

N4-C16 - 1.451(4) - -

N4-C17 - 1.439(4) - -

C13-C14 - 1.491(5) - -

C14-C15 - 1.519(5) - -

S1-O6 - - 1.515(2) 1.523(2)

S1-C13 - - 1.774(3) 1.774(3)

S1-C14 - - 1.780(3) 1.774(3)

O7-C18 - 1.233(4) - -

N5-C18 - 1.325(4) - -

N5-C21 - 1.418(5) - -

N5-C22 - 1.449(5) - -

C18-C19 - 1.484(5) - -

C19-C20 - 1.506(5) - -

C20-C21 - 1.508(6) - -

Figure S3. Packing along a, b and c of the DMA solvate Form sIV

Figure S4. Packing along a, b and c of the NMP solvate Form sVI

Figure S5. Packing along a, b and c of the DMSO solvate Form sVII

Sample Temperature (°C)35030025020015010050

TG (%

)100

80

60

40

20

0

Hea

tFlo

w (µ

V)

1,500

1,000

500

0

Δm (%) -35.601

Exo

Peak Maximum : 299.116 (°C) Onset : 290.27 (°C)

Figure S6. TGA/DTA analysis of Form I

Figure S7. TGA/DTA analysis of Form II

Figure S8. TGA/DTA analysis of Form III

Figure S9. TGA/DTA analysis of Form sIV

Figure S10. TGA/DTA analysis of Form sV

Figure S11. TGA/DTA analysis of Form sVI

Figure S12. TGA/DTA analysis of Form sVII

Figure S13. TGA/DTA analysis of Form sVIII

Figure S14. TGA/DTA analysis of Form sIX

Table S2. Overview of the new forms obtained and experimental conditions

Experimental conditions

Crystalline form

Method of crystallization Solvent

Dissolution Temperature

(oC)

Concentration (mg/mL) Antisolvent

Antisolvent temperature

(oC)

Solvent:antisolvent volumetric ratio

Short description of experimental method

DMSO 40-50 210-240 water 0-10 1:10

The concentrated DMSO solution was kept under stirring at 40-50°C for 1 hour; hot filtered DMSO solution was dropwise added in pre-cooled antisolvent; the precipitated solid was air dried on filter paper

Reverse antisolvent addition

DMA 40-50 210-240 water 0-10 1:10

The concentrated DMA solution was kept under stirring at 40-50°C for 1 hour; hot filtered DMA solution was dropwise added in pre-cooled antisolvent; the precipitated solid was air dried on filter paper

Form II

Crash cooling DMSO 60-70 210-240 N.A. N.A. N.A.

The concentrated DMSO solution was kept under stirring for 1 hour to dissolve at 60-70°C; hot filtered DMSO solution was crash-cooled at 0-10°C for 1 day; the precipitated solid was air dried on filter paper

NMP 25 50-60 N.A. N.A. N.A. Solution was evaporated at 120°C and 10 mbar

Form III Fast evaporation Cumene:DMSO

(1/1 v/v) 60-70 100-120 N.A. N.A. N.A.

The concentrated cumene:DMSO solution was kept under stirring for 1 hour to dissolve at 60-70°C; hot filtered solution was cooled at 25°C for 1 day; solution was quickly evaporated at 120C and 10 mbar

Reverse antisolvent addition

DMA 40-50 210-240 Toluene 0-10 1:10

The concentrated DMA solution was kept under stirring for 1 hour to dissolve at 40-50°C; filtered DMA solution was drop wise added in pre-cooled antisolvent; the precipitated solid was air dried on filter paper

Form sIV

Crash cooling DMA 40-50 210-240 N.A. N.A. N.A.

The concentrated DMA solution was kept under stirring for 1 hour to dissolve at 40-50°C; hot filtered DMA solution was crash-cooled at 0-10°C for 1 day; the precipitated solid was air dried on filter paper

Form sVAntisolvent diffusion into solutions

NMP 40 80-100Diethyl ether or acetone

25 1:25

Diffusion at 25°C for 4 days; a small vial containing the solution was placed in a larger vial containing the antisolvent and sealed for the duration of the experiment.

Reverse antisolvent addition

NMP 40-50 100-120Acetone or

1,4-Dioxane

0-10 1:10

The concentrated NMP solution was kept under stirring for 1 hour to dissolve at 40-50°C; hot filtered NMP solution was drop wise added in pre-cooled antisolvent; the precipitated solid was air dried on filter paper

Antisolvent diffusion into

solutionsNMP 40 80-100 Diethyl

ether 5 1:18 Diffusion at 5°C for 4 days

Form sVI

Reverse antisolvent addition

NMP 40-50 100-120 Ethyl acetate 5 1:10

The concentrated NMP solution was kept under stirring for 1 hour to dissolve at 40-50°C; hot filtered NMP solution was drop wise added in pre-cooled antisolvent; the precipitated solid was air dried on filter paper

Form sVIIReverse antisolvent addition

DMSO 40-50 210-240 toluene 0-10 1:10

The concentrated DMSO solution was kept under stirring for 1 hour to dissolve at 40-50°C; hot filtered DMSO solution was drop wise added in pre-cooled antisolvent; the precipitated solid was air dried on filter paper

Crash cooling DMSO 40-50 210-240 N.A. N.A. N.A.

The concentrated DMSO solution was kept under stirring for 1 hour to dissolve at 40-50°C; hot filtered DMSO solution was crash-cooled at 0-10°C for 5 days; the precipitated solid was air dried on filter paper

Crash cooling Pyridine 40-50 30-40 N.A. N.A. N.A.

The concentrated Pyridine solution was kept under stirring for 1 hour to dissolve at 40-50°C; hot filtered Pyridine solution was crash-cooled at 0-10°C for 5 days; the precipitated solid was air dried on filter paper

Form sVIII

Fast evaporation Pyridine 25 30-40 N.A. N.A. N.A. Solution was evaporated at room

temperature and 25 mbar

Form sIX Crash cooling Formamide 60-70 20-25 N.A. N.A. N.A.

The concentrated formamide solution was kept under stirring for 1 hour to dissolve at 60-70°C; hot filtered formamide solution was crash-cooled at 0-10°C for 1 day; the precipitated solid was air dried on filter paper

Table S3. Crystal habit of anhydrous Forms I, II and III

PLM imagesCrystalline form

Solvent/system solvent 10x magnification

Form I (commercially

available)N.A.

Form II DMSO

Form III Cumene:DMSO (1/1 v/v)

XRPD powder patterns indexing of Form II and Form III using Le Bail refinement procedure

XRPD analysis was carried out using a Bruker D8 Discover diffractometer with DAVINCI configuration, scanning the

samples between 1.5 and 45° 2θ angles in transmission mode. Approximately, 1-2 mg of each screening sample was used.

Calibration was performed prior to the analysis using a corundum sample (NIST SRM1976a) and in transmission mode using a

silicon powder standard (NIST SRM640e).

For pattern indexing, the extraction of the peak positions was carried out with the program WinPLOTR and the

indexation process was carried out using the DICVOL subroutine integrated in the Fullprof1 suite software. The lines of powder

pattern were completely indexed on the basis of monoclinic system. Le Bail fitting method2 with a constant scale factor and

using a Pearson pseudo-Voigt function profile for the refinement were used for whole powder diffraction pattern

decomposition.

The estimated space group in the monoclinic system was P 1 21/c 1 which was determined with the aid of the

program Check Group interfaced by WinPLOTR.

In the first round the zero point of detector and lattice constants were refined, then peak shape and full-width-at half-

minimum parameters (U, V, W and X) were refined, followed by refinement of asymmetry parameters (Asy1, Asy2, Asy3, Asy4).

The final refinement cycles were performed using instrumental or physical aberration corrections for sycos or sysyn

parameters.

Crystallographic data resulted after refinements for Form II and Form III are depicted in the table below, and in Figure S1 and

Figure S2. As a comparison Form I already known is presented in the second column.

Form I from LEQTAC Form II Form IIITemperature (K) 293 293 293 293

Wavelength (Å) 1.5406 1.5406 1.5406Crystal System Triclinic Monoclinic Monoclinic

Space group P-1 P 1 21/c 1 P 1 21/c 1 a (Å) 6.879(6) 13.143 22.324b (Å) 8.164(5) 20.463 12.945c (Å) 11.410(7) 6.453 20.040α (°) 78.87(5) 90.000 90.000β (°) 78.91(6) 91.144 94.185γ (°) 69.68(7) 90.000 90.000

Number of global refined parameters

- 2 2

Number of profile refined parameters

- 13 13

Rp 10.95 (%) 7.69 (%) 6.87 (%)Rwp 10.95 (%) 10.8 (%) 9.79 (%)Rexp - 6.32 (%) 5.67 (%)÷2 - 2.91 2.98

XRPD powder patterns for Form II and Form III indexed using Le Bail refinements are presented in Figure S15 and

Figure S16. Experimental XRPD patterns are presented in red, while the calculated patterns using Le Bail method are presented

in black. The fitting difference pattern (lower trace) is in blue, and the vertical bars in blue indicate the positions of Bragg peak.

Figure S15. XRPD powder patterns for Form II indexed using Le Bail refinements

Figure S16. XRPD powder patterns for Form III indexed using Le Bail refinements

LHP model for nifuroxazide solvates

A LHP model was constructed for quantifying the H-bond probabilities between nifuroxazide and the various solvents which were found to yield solvates (Table S4).

Table S4. LHP model results for nifuroxazide solvates, including observed hydrogen bonding in single crystal structures.

Donor Acceptor Propensity sIV sVI sVII

O (water) O (hydrazide) 0.87 √

OH (phenol) O (DMSO) 0.85 √

NH (hydrazide) O (DMSO) 0.81

OH (phenol) O (DMF) 0.78

OH (phenol) O (nitro) 0.74

NH (hydrazide) O (DMF) 0.72

OH (phenol) N (Py) 0.69

OH (phenol) O (NMP) 0.69 √

NH (hydrazide) O (nitro) 0.68

OH (phenol) O (hydrazide) 0.67

O (water) N (hydrazide) 0.64 √

NH (hydrazide) O (NMP) 0.62 √

NH (hydrazide) O (hydrazide) 0.60 √ √ √

OH (phenol) O (DMA) 0.51 √

NH (hydrazide) O (water) 0.30 √

NH (hydrazide) N (hydrazide) 0.29

1 Rodriguez-Carvajal, J. (2001). FULLPROF CEA/Saclay, France.2 A. LeBail, H. Duroy and J.L. Fourquet, Mat. Res. Bull. 1988, 23, 447.