S1

The Supporting Information for the paper:

Comprehensive spectroscopic characterization of finasteride

polymorphic forms. Does the form X exist?

Jadwiga Frelek,a Marcin Górecki,

a Alicja Dziedzic,

a Ewa Jabłońska,

b Bohdan Kamieński,

a,c

Ryszard K. Wojcieszczyk,b Roman Luboradzki,

c and Wojciech J. Szczepek*

d

a Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, Warsaw,

Poland

b University of Technology and Humanities in Radom, Chrobrego 27, 26-600 Radom, Poland

c Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, Warsaw,

Poland

d Pharmaceutical Research Institute, Rydygiera 8, 01-793 Warsaw, Poland

Contents:

page

EXPERIMENTAL PROCEDURES S3

PREPARATION OF FINASTERIDE POLYMORPHS S5

FT-IR SPECTROSCOPY

S8

Table S1. FT-IR (KBr) after final drying.

Table S2. FT-IR (nujol) after final drying.

Table S3. FT-IR (ATR) after final drying.

Table S4. FT-IR (KBr [cm-1

]) data for samples of form I.

Table S5. FT-IR (KBr [cm-1

]) data for samples of form II.

Table S6. FT-IR (KBr [cm-1

]) data for samples of form III.

DIFFERENTIAL SCANNING CALORYMETRY (DSC) S12

Table S7. DSC data for samples of form I.

Table S8. DSC data for samples of form II.

Table S9. DSC data for samples of form III.

X-RAY POWDER DIFFRACTION (XRPD) S13

Fig. S1. XRPD of the sample S1 (form I).

Table S10. XRPD data for samples of form I.

Fig. S2. XRPD of the sample S4 (form II).

Table S11. XRPD data for samples containing forms II and III.

Fig. S3. XRPD of the sample S6 (form III).

Fig. S4. XRPD of the sample S7 (a mixture of forms II and III).

13

C CP-MAS NMR SPECTROSCOPY S16

Table S12. Carbon-13 chemical shifts (δC/ppm) for finasteride forms I.

Table S13. Carbon-13 chemical shifts (δC/ppm) for finasteride forms II.

Fig. S5. 13

C CP-MAS NMR of the sample S0 (form I).

Fig. S6. 13

C CP-MAS NMR of the sample S1 (form I).

S2

Fig. S7. 13

C CP-MAS NMR of the sample S4 (form II).

Fig. S8. 13

C CP-MAS NMR of the sample S6 (form III).

Fig. S9. 13

C CP-MAS NMR of the sample S7 (a mixture of forms II and III).

SOLUTION 1H AND

15N NMR DATA S20

Fig. S10. 1H NMR spectrum of finasteride sample S6 (600 MHz, CDCl3).

Fig. S11. 15

N NMR spectrum of finasteride sample S6 (60.8 MHz, CDCl3).

Fig. S12. 1H-

15N gHMBC NMR spectrum of finasteride sample S6.

Fig. S13. 1H-

15N HSQC NMR spectrum of finasteride sample S6.

SOLID 15

N CP-MAS NMR DATA S23

Fig. S14. 15

N CP-MAS NMR of the form I, sample S0.

Fig. S15. 15

N CP-MAS NMR of the form I, sample S1.

Fig. S16. 15

N CP-MAS NMR of the form II, sample S4.

Fig. S17. 15

N CP-MAS NMR of the form III, sample S6.

Fig. S18. 15

N CP-MAS NMR of a mixture of forms II and III, sample S7.

CONFORMATIONS OF FINASTERIDE AND RELATED MOLECULES IN

THE CRYSTALLINE FORMS (POLYMORPHS AND SOLVATOMORPHS)

AND FINASTERIDE IN SOLUTION

S26

Table S14. Conformations of ,-unsaturated lactam (en-lactam) and amide

chromophores in finasteride and its analogs (unsolvated and solvated forms).

COMPUTED ECD SPECTRUM OF FINASTERIDE POLYMORPHIC

FORM I

S27

Figure S19. Solid-state ECD spectrum recorded in KCl pellet of Form I (S1)

compared with the TDDFT calculations based on X-ray data at CAM-B3LYP/TZVP

level of theory.

SOLID-STATE VCD SPECTRA

S28

Fig. S20. Reproducibility of solid-state VCD spectra of forms I-III.

SOLUTION VCD AND IR CALCULATIONS

S28

Fig. S21. Structures of conformers within a 5 kcal/mol–1

energy window of

finasteride.

Fig. S22. Experimental VCD and IR spectra recorded in CDCl3 compared to

simulated.

Table S15. Vibrational analysis of selected bands for the lowest energy conformer

(Conf. 1) of finasteride in CDCl3 solution.

Table S16. Rotational strengths for selected bands of conformers 1-3 of finasteride in

chloroform solution.

REFERENCES

S30

S3

EXPERIMENTAL PROCEDURES

Commercially available, pure solvents such as hexane, heptane, cyclohexane,

dichloromethane (methylene chloride), ethyl acetate, diethyl carbonate, ethanol,

tetrahydrofuran, propan-2-ol (isopropanol), and acetic acid were used without additional

purification in preparation of finasteride polymorphs.

Finasteride was synthesized in Pharmaceutical Research Institute from commercially

available 3-oxoandrost-4-ene-17-carboxylic acid (Chart 1A). Thus, the absolute

configurations at C(10), C(9), C(8), C(14), C(13) and C(17) remained unchanged and are the

same as in the substrate, i.e. can be described as 10-CH3, 9-H, 8-H, 14-H, 13-CH3 and

17-H, respectively. The absolute configuration of the newly formed stereogenic center at

C(5) resulted from 1H NMR spectrum of finasteride, described in Supporting Information on

page S20 and can be described as 5-H (Chart 1B). The obtained finasteride shows specific

optical rotation +13.3 (c=1, methanol; temperature: 23 ºC) and meets requirement of

European Pharmacopoeia 5.0 (+12.0 to +14.0).

Chart 1. A: 3-oxoandrost-4-ene-17-carboxylic acid; B: finasteride with its systematic name;

C: finasteride and its IUPAC name with the proper numbering of its skeleton and R/S

stereodescriptors at the chiral centers.

FT-IR Spectroscopy FT-IR spectra were recorded using JASCO FTIR-6200 spectrometer equipped with

DLATGS detector and temperature regulator. The spectra were obtained using KBr pellet

technique (~1 mg per 300 mg KBr) and Nujol mull technique (qualitatively) in the range of

4000-400 cm1

with 4 cm1

resolution, as well as by reflectance method using single

reflection ATR attachment (ZnSe crystal) in the range of 4000-550 cm1

with 4 cm1

resolution.

Differential Scanning Calorimetry (DSC) DSC was carried out using Universal V4.3A TA Instruments. All samples were run

from 30 to 300 °C. Argon was used as purge gas in ambient mode. The heating rate was kept

constant at 5 or 10 °C min1

. Aluminum sample pans were used for all samples. A single point

calibration was carried out using indium as a standard sample.

X-ray Powder Diffraction (XRPD)

Diffraction data for all samples were collected using Bruker D8 ADVANCE (Cu K

1.5418 Å) diffractometer, in Bragg-Brentano geometry. Diffractograms were measured for 2

S4

values ranging from 5 to 40 °, with step size 0.01 ° and time per step equal 20 s, at room

temperature.

Nuclear Magnetic Resonance (1H NMR,

13C NMR,

15N NMR)

The NMR measurements in solution were performed using Varian VNMRS 600 MHz

spectrometer operating at 600 MHz and 60.8 MHz for proton and nitrogen, respectively. 5

mm Inverse, variable temperature, PFG, probe was used. Internal TMS was used as a

reference for proton spectra. The nitrogen spectra were referenced to external nitromethane.

The assignment of the chemical shifts for nitrogen in solution was made by gHMBC and

HSQC methods. The standard Varian procedures were used for acquisition and processing of

data.

The solid-state CP-MAS spectra were measured at 298 K using Bruker 500 Avance II

spectrometer equipped with MAS 4 BL CP TRIPLE probe-head. 4 mm Zirconia rotors were

used. The CPMAS technique, performed by Bruker cp.av pulse program, was applied.

CPMAS experimental conditions for 15

N measurements were the following: spectral width

25kHz, acquisition time 50 ms, contact time 4 ms, rotation rate 6 kHz, relaxation delay 10 s.

2k Scans were collected to obtain good quality spectra. For carbon CPMAS experiments the

following conditions were applied: spectral width 31.25 kHz, acquisition time 50 ms, contact

time 2 ms, rotation rate 10 kHz, relaxation delay 10 s. 512 Scans were collected. For short

contact time CH spectra the contact time 40 μs was applied.

Solution ECD measurements The experimental solution ECD and UV spectra were recorded using Jasco J-815

spectrometer at room temperature in spectroscopic grade CH3CN. Solutions with

concentration 6.2×104

M were measured in a quartz cell with a path length of 1–0.1 cm. All

spectra were recorded using scanning speed of 100 nm/min, step size of 0.2 nm, bandwidth of

1 nm, response time of 0.5 s, and an accumulation of 5 scans. The spectra were background-

corrected using spectrum of CH3CN collected under the same conditions.

Solid-state ECD measurements The diffused transmission circular dichroism (DTCD) spectra were recorded between

400-200 nm at room temperature using Jasco J-815 ECD spectropolarimeter equipped with

the powder ECD attachment (i.e. the integrating sphere compartment coating with barium

sulphate). All spectra were obtained using 100 nm/min scanning speed, step size of 0.2 nm,

bandwidth of 5 nm, response time of 0.5 sec, and an accumulation of 5 scans. The spectra

were background corrected.

Samples were prepared with the KCl pellet technique (0.06-0.1 mg of finasteride per

100 mg KCl). In each case, the compound was mixed with dried KCl, finely ground in Specac

Mill for 10 min and pressed at 10 ton under vacuum for 5 min to make a 13 mm diameter

transparent and spotless disk. The pellet was mounted on a rotatable holder in

spectropolarimeter. For each sample, several ECD spectra were measured upon rotation of the

disk around the incident axis direction at various rotation angles. These spectra were almost

identical, demonstrating the absence of detectable spectral artifacts.

Solid-state ECD calculations The calculations were performed using as an input structure the X-ray data for the form

I (WOLXOK02) of finasteride.1 After optimization of hydrogen atoms at B3LYP/6-31G(d)

level of theory, ECD/UV spectra were simulated in vacuum using the CAM-B3LYP

functional and TZVP basis set. Moreover, TDDFT calculations were repeated using

S5

B3LYP/TZVP level of approximations. In all cases the agreement with experimental data was

good, therefore we focused herein only on results obtained from CAM-B3LYP functional.

Solution VCD measurements The VCD and IR solution spectra were recorded using ChiralIR-2X VCD spectrometer

at a resolution of 4 cm–1

in the range of 2000–850 cm1

at room temperature using

spectroscopic grade CDCl3. The spectrometer was equipped with dual sources and dual ZnSe

photoelastic modulators (PEMs) optimized at 1400 cm–1

. Solutions with a concentration of

~0.22 M for 1650-850 cm-1

and ~0.03 M for 2000-1650 cm1

range were measured in a BaF2

cell (d=102 μm) assembled in a rotating holder. To improve the signal-to-noise ratio, the

spectra were measured for 5 h. Baseline correction was achieved by subtracting the spectrum

of a CHCl3 obtained under the same conditions.

Solution VCD calculations The conformational analysis was done using CONFLEX 7

2-4 program within 10 kcal

mol-1

energy window. Next, all structures were submitted to the Gaussian09 program5 for

DFT optimization at B3LYP/TZVP level with the implicit polarizable continuum model

(PCM) for CHCl3. All conformers were confirmed to contain no imaginary frequencies. As a

result three conformers were found which were further used for simulating VCD and IR

spectra. The final spectra were obtained by Boltzmann averaging (T=298 K) according to the

population percentages of individual conformers based on the relative Gibbs free energy. All

calculated spectra were simulated using Lorentzian line shapes with 8 cm−1

half width at half

height and were further rescaled by a constant scaling factor of 0.977, which gave the best

agreement between computation results and experimental values.

Solid-state VCD measurements VCD spectra were measured using ChiralIR-2X spectrometer (BioTools, Inc) equipped

with a dual PEM accessory at a resolution of 4 cm1

using Synchrocell (2.75 sec/cycle). The

ZnSe photoelastic modulators of the instrument were set to 1400 cm1

. To improve the S/N

ratio, the spectra were measured for 6 h. Solid-phase samples were prepared with the KBr

pellet technique (using 0.8-0.9 mg of finasteride per 300 mg of KBr in the range 2000-1600

cm1

, and ~3 mg per 300 mg of KBr in the range 1600-850 cm1

). Baseline correction was

achieved by subtracting the spectrum of a reference KBr pellet obtained under the same

conditions. For each polymorphic form at least two sample pellets were prepared and

measured.

PREPARATION OF FINASTERIDE POLYMORPHS

A nine-year-old sample of the form I (sample S0) was obtained in Pharmaceutical

Research Institute. The remaining samples S1-S7 were prepared in Institute of Organic

Chemistry (Polish Academy of Sciences in Warszawa) and, to confirm the results, at Faculty

of Material Science and Design of Technical University of Radom (now University of

Technology and Humanities in Radom).

Form I, sample S0 (nine-year-old sample of form I stored at room temperature)

Finasteride (10.08 g) was dissolved in a mixture of dichloromethane (50 mL) and ethyl

acetate (100 mL) at reflux. Then 125 mL of solvents were distilled off under normal pressure.

The resulting suspension was stirred and cooled slowly to r.t. The crystals were filtered off

and washed with ethyl acetate (18 mL). The product was dried at r.t. for 2 days and then under

reduced pressure at 50 C for 6 hours to give form I, sample S0.

S6

Form I, sample S1

Finasteride (8.0 g) was dissolved in hot ethanol (40 mL). The stirred solution was cooled to

r.t. and then water (120 mL) was slowly added. The obtained suspension was stirred at r.t. for

20 hours. The crystals were filtered off and dried at r.t. for 2 days and then under reduced

pressure at 75 C for 6 hours to give form I, sample S1.

Form I, sample S2

A solution of finasteride (3.0 g) in dichloromethane (10 mL) was added dropwise to the

vigorously stirred boiling and distilling under normal pressure heptane (55 mL). About 50 mL

of solvents were distilled off. The resulting suspension was stirred and cooled slowly to r.t.

The crystals were filtered off and dried at r.t. for 2 days, under reduced pressure at 75 C for 6

hours and finally under reduced pressure at 135 C for 6 hours to give form I, sample S2.

Form I, sample S3

Finasteride (2.0 g) was dissolved in a minimal amount of diethyl carbonate at reflux. The

resulting solution was stirred and cooled slowly to r.t. The crystals were filtered off and dried

at r.t. for 2 days and then under reduced pressure at 75 C for 6 hours to give form I, sample

S3.

Form II, sample S4

Finasteride (5.0 g) was dissolved in a hot mixture acetic acid-water (4:6; 35 mL) and kept at

70-80 C for 30 min. The resulting solution was stirred and cooled slowly to r.t., and then

stirred at r.t. overnight. The crystals were filtered off and washed with water. The crystals of

so-called “form V”,6 i.e. finasteride acetic acid solvate,

7-9 were dried at r.t. for 2 days [FT-IR

(KBr): 3440, 3407, 3223, 3109, 1679, 1664, 1596, 1502, 1452, 1394, 1364, 1255, 1219, 1128

and 819 cm1

], then under reduced pressure at 75 C for 6 hours and finally under reduced

pressure at 135 C for 6 hours to give form II, sample S4.

Impure form II, sample S5

Finasteride (2.0 g) was dissolved in the minimal amount of propan-2-ol at reflux. The

resulting solution was stirred and cooled slowly to r.t. The crystals of so-called “form H1”,10

i.e. [bis(finasteride) monohydrate mono(isopropanol) solvate]7,8

were filtered off and dried at

r.t. for 2 days [FT-IR (KBr): 3439, 3385, 3293, 3187, 3099, 1681, 1650, 1599, 1514, 1451,

1365, 1252, 1222, 1126, 952, 816 and 809 cm1

], then under reduced pressure at 75 C for 6

hours and finally under reduced pressure at 135 C for 6 hours to give impure form II, sample

S5.

Form III, sample S6

A solution of finasteride (3.1 g) in dichloromethane (10 mL) was added dropwise to the

vigorously stirred boiling and distilling under normal pressure cyclohexane (60 mL). About

50 mL of solvents were distilled off. The resulting suspension was stirred and cooled slowly

to r.t. The crystals were filtered off and dried at r.t. for 2 days, then under reduced pressure at

75 C for 6 hours and finally under reduced pressure at 135 C for 6 hours to give form III,

sample S6.

S7

Impure form III, sample S7

Finasteride (8.0 g) was dissolved in dichloromethane (24 mL) and then 15 mL of

dichloromethane were distilled off. The resulting solution was saturated with hexane (80 mL)

and then 10 mL of solvents were distilled off under atmospheric pressure. The obtained

suspension was stirred and cooled slowly to r.t. The crystals were filtered off and dried at r.t.

for 2 days, then under reduced pressure at 75 C for 6 hours and finally under reduced

pressure at 135 C for 6 hours to give mixed crystals of form III and form II, sample S7.

S8

FT-IR SPECTROSCOPY FT-IR spectra of all obtained samples were recorded in KBr pellets (Table S1), in nujol

(Table S2) and by ATR method (Table S3).

Table S1. FT-IR (KBr) after final drying.

F I F II F III F (III+II)

S0 S1 S2 S3 S4 S5 S6 S7

•3429

3348

••3236

3114

1687

1668

1600

1505

1449

1384

1364

1331

1257

1218

1125

815

688

•3429

3352

••3237

3114

1690

1667

1600

1505

1449

1384

1364

1331

1258

1218

1125

815

688

•3429

3348

••3233

3114

1687

1667

1600

1504

1444

1384

1364

1331

1257

1218

1125

815

688

•3429

3347

••3233

3114

1687

1669

1600

1505

1444

1384

1363

1330

1257

1217

1125

814

687

•3438

3337

••3213

3110

3047

1688

1679

1658

1598

1500

1451

1415

1389

1365

1251

1219

1200

1126

820

•3438

3384

3289

••3201

3106

3047

1680

1658

1597

1500

1451

1415

1390

1364

1251

1220

1200

1126

819

•3426

3328

••3229

3104

3040

1679

1601

1499

1449

1384

1365

1357

1332

1254

1219

1201

1126

820

691

*•3426

3327

••3229

3105

3043

1679

1600

1498

1448

1385

1365

1331

1254

1219

1200

1125

820

691 * – this band is overlapped by a weaker band at higher frequency; • – sharp, intensive band over 3040 cm

-1;

•• – broad, the most intensive band over 3040 cm-1

S9

Table S2. FT-IR (nujol) after final drying.

F I F II F III F (III+II)

S0 S1 S2 S3 S4 S5 S6 S7

3427

3347

•3231

3114

1688

1668

1599

1504

1254

1219

1124

814

685

3428

•3223

3114

1688

1667

1600

1505

1444

1384

1364

1331

1258

1218

1126

815

688

3428

3348

•3222

3113

1687

1667

1600

1504

1473

1442

1383

1364

1331

1257

1224

1125

815

721

688

3428

3347

•3229

3113

1687

1668

1600

1505

1442

1385

1363

1331

1257

1218

1125

815

688

3437

3337

•3199

3106

3042

1689

1677

1655

1596

1498

1479

1433

1415

1389

1361

1251

1219

1200

1125

820

722

3437

3383

3288

•3188

3099

3045

1678

1651

1597

1498

1475

1439

1416

1389

1362

1251

1220

1200

1126

818

741

722

3425

3327

•3220

3102

1680

1600

1497

1473

1445

1383

1365

1332

1254

1219

1200

1126

819

722

691

*3425

3327

•3217

3104

1679

1600

1498

1447

1390

1365

1332

1254

1219

1200

1126

819

692 * – this band is overlapped by a weaker band at higher frequency; • – the most intensive band over 3040 cm

-1

S10

Table S3. FT-IR (ATR) after final drying.

F I F II F III F (III+II)

S0 S1 S2 S3 S4 S5 S6 S7

3427

•3233

3114

1685

1667

1600

1504

1453

1389

1362

1255

1221

1124

813

685

3429

•3234

3114

1686

1667

1600

1505

1448

1384

1364

1331

1257

1224

1125

815

688

3429

•3237

3115

1687

1667

1601

1505

1449

1384

1364

1331

1257

1225

1125

815

688

3429

•3237

3115

1687

1667

1601

1505

1449

1384

1364

1331

1257

1225

1125

815

688

3437

•3206

3110

1686

1678

1656

1597

1498

1451

1415

1389

1365

1251

1220

1200

1126

819

3438

•3208

3110

1686

1678

1657

1597

1499

1451

1416

1389

1364

1251

1220

1200

1126

819

3426

•3232

3103

1679

1601

1497

1448

1384

1366

1357

1333

1254

1220

1201

1126

819

692

3426

•3230

3104

1679

1601

1497

1448

1385

1366

1333

1254

1220

1200

1126

819

692 • – the most intensive band over 3040 cm

-1

All samples containing form I, i.e. freshly prepared samples S1, S2 and S3, as well as

nine-year-old sample S0 show FT-IR data in KBr well-matched with that reported in the

literature (shown in Table S4). The identity of these samples confirm the complete IR data in

KBr (Table S1), in nujol (Table S2) and ATR (Table S3).

Table S4. FT-IR (KBr [cm-1

]) data for samples of form I.

Literature data Current work 11

9

1

12

13 S0 S1 S2 S3

3431

3237

1692

1666

1602

688

3429

3348

3238

3115

1689

1669

1601

3430

3349

3236

3114

1690

1668

3429

3241

1689

1669

3426

3240

1687

1666

1599

1504

814

688

3429

3348

•3236

3114

1687

1668

1600

1505

815

688

3429

3352

•3237

3114

1690

1667

1600

1505

815

688

3429

3348

•3233

3114

1687

1667

1600

1504

815

688

3429

3347

•3233

3114

1687

1669

1600

1505

814

687 in italics - values calculated from figure included in the literature; • – the most intensive band above 3040 cm

1

Sample S4, containing form II, has FT-IR data in KBr consistent with that reported in

the literature, while sample S5 clearly shows presence of additional absorption bands at 3384

and 3289 cm1

(Table S5, underlined values), which belong to the not completely

decomposed bis(finasteride) monohydrate mono(isopropanol) solvate.7,8

The latter sample

S11

(i.e., S5) does not have a well-shaped absorption band at 1688 cm-1

. Samples S4 and S5 show

also differences in IR data in KBr (Table S1) and nujol (Table S2), although the data in ATR

are similar (Table S3).

Table S5. FT-IR (KBr [cm-1

]) data for samples of form II.

Literature data Current work 11

9

1

12 S4 S5

3441

3215

1678

1654

1597

1476

752

3439

3336

3213

1680

1657

1599

3440

3342

3213

3115

3048

1677

1655

3439

3221

1689

1678

3438

3337

•3213

3110

3047

1688

1679

1658

1598

1451

3438

3384

3289

•3201

3106

3047

1680

1658

1597

1451

in italics - values calculated from figure included in the literature; • – the most intensive band above 3040 cm

-1

Finally, samples S6 and S7 (form III) exhibited FT-IR data in KBr well-matched with

that reported in literature as it is shown in Table S6. However, in the case of sample S7 a

weaker band at higher frequency is superimposed on the absorption band at 3426 cm1

. At

this point, the origin of this weak band was not yet clear. However, it might be expected that

in this case the form III is contaminated by the form II. The IR data in KBr (Table S1) and

nujol (Table S2) show small differences between samples S6 and S7, although ATR spectra

(Table S3) are similar.

Table S6. FT-IR (KBr [cm-1

]) data for samples of form III.

Literature data Current work 6 S6 S7

3427

3233

1679

1600

1501

1451

1387

1365

1332

1254

1222

1125

820

693

3426

3328

•3229

3104

3040

1679

1601

1499

1449

1384

1365

1332

1254

1219

1126

820

691

*3426

•3230

3104

1679

1601

1497

1448

1385

1366

1333

1254

1220

1126

819

692

* this band is overlapped by a weaker band at higher frequency; • – the most intensive band above 3040 cm-1

S12

DIFFERENTIAL SCANNING CALORYMETRY (DSC) After detailed analysis of the FT-IR spectra, the differential scanning calorimetry (DSC)

measurements for samples S1, S2, S4, S6 and S7 were carried out. DSC curves of the samples

S1and S2 (polymorphic form I), at heating rates of 5 C min1

and 10 C min1

, respectively,

exhibit a minor endotherm with a peak temperature of about 230-240 C, and a major melting

endotherm with a peak temperature of about 260 C. The obtained results agree with the

majority of those presented in the literature for polymorphic form I (see Table S7).

Table S7. DSC data for samples of form I.

DSC

parameters

Literature data Current work 11,14

1

13

7

15

16

17 S1 S2

Heating rate

[°C min1]

20 10 10 1 10 10 ? 5 10

Endotherm

onset [°C]

peak [°C]

heat [J g-1

]

223

232

11

230

11

222

236

12

211.8

217.0

6.44

237

226.4

11.41

~230

236.6

240.1

10.08

224.3

230.3

11.50

Endotherm

onset [°C]

peak [°C]

heat [J g1]

258

261

89

257

89

253.2

71

257.7

257.9

56.09

258

258.7

81.53

257

257.7

260.0

81.58

258.0

259.4

80.91

DSC curve of the sample S4 (polymorphic form II), at heating rate of 5 C min1

,

exhibits only a single melting endotherm with a peak temperature of about 260 C. In this

case, our results are consistent with the literature data for polymorph II (see Table S8).

Table S8. DSC data for samples of form II.

DSC parameters Literature data Current

work 11

1

7 S4

Heating rate [°C min-1

] 20 10 1 5

Endotherm Onset [°C]

Peak [°C]

Heat [J g-1

]

258

261

89

257

88

257.6

257.8

46.41

258.1

260.3

77.34

Similarly, the DSC results for samples S6 and S7 (form III) are consistent with the

literature reports (see Table S9).

Table S9. DSC data for samples of form III.

DSC parameters Literature data Current work 6

14 S6 S7

a

Heating rate [°C/min] ? 10 10 10

Endotherm Onset [oC]

Peak [°C]

Heat [J g-1

]

262.7

257

259

86.5

257.9

259.4

76.77

258.0

259.4

80.21 a – form III probably contaminated by form II

S13

X-RAY POWDER DIFFRACTION (XRPD) X-ray powder diffraction (XRPD) measurements were done for samples S1 (form I), S4

(form II), S6 (form III) and S7 (form III probably contaminated by form II).

The XRPD pattern of sample S1 (form I, Figure S1), is characterized by major peaks at

2Θ values of 13.9, 14.3, 15.4, 15.8, 16.9, 17.3, 18.5, 19.9, 21.7, 25.1, 27.2 and 28.7 (Table

S10). As it is evident from the Table S10, our results agree well with literature reports.11,13-15

Fig. S1. XRPD of the sample S1 (form I).

Table S10. XRPD data for samples of form I.

Literature data Current work 11

13

14

15

S1

d *2Θ d *2Θ 2Θ 2Θ 2Θ

6.44

5.69

5.36

4.89

4.55

4.31

3.85

3.59

3.14

13.8

15.6

16.5

18.1

19.5

20.6

23.1

24.8

28.4

6.39

5.64

5.28

5.13

4.81

4.47

4.30

3.83

3.57

3.12

13.9

15.7

16.8

17.3

18.4

19.9

20.7

23.2

24.9

28.6

13.8

15.6

16.7

18.3

19.3

20.3

22.9

24.7

28.4

13.9

14.3

15.3

15.8

16.9

17.3

18.5

19.6

19.9

20.7

21.7

23.1

25.0

26.1

28.5

etc.

13.9

14.3

15.4

15.8

16.9

17.3

18.5

19.9

21.7

25.1

27.2

28.7

* - recalculated for Cu K 1.5418 Å

S14

The major peaks at 2Θ values of 6.4, 8.7, 11.3, 12.8, 14.1, 15.1, 15.9, 19.1, 19.7 and

27.6 recorded for our form II, sample S4 (Figure S2 and Table S11) could not be compared

directly with the literature data given as d values. However, our results agree with the reported

values recalculated for Cu K 1.5418 Å.

Fig. S2. XRPD of the sample S4 (form II).

Table S11. XRPD data for samples containing forms II and III.

F II F II + F

III

F III F IIIa „F X”

a

Literature

data

Current

work

Current

work

Current

work

Literature

data

Literature

data

Literature

data 11

S4 S7 S6 6

14

7,8

7

d *2Θ 2Θ 2Θ 2Θ 2Θ 2Θ 2Θ 2Θ

14.09

10.36

7.92

7.18

6.40

5.93

5.66

5.31

4.68

3.90

3.60

3.25

6.3

8.5

11.2

12.3

13.8

14.9

15.7

16.7

19.0

22.8

24.7

27.4

6.4

8.7

11.3

12.8

14.1

15.1

15.9

19.1

19.7

27.6

c5.4

b6.4

b8.7

10.1

c10.8

b11.3

b12.8

c13.7

b14.1

b,c15.1

b,c15.9

c16.2

c18.3

b19.2

b19.7

c23.1

5.4

10.8

13.8

15.1

16.0

16.2

18.3

23.2

28.5

5.32

10.70

13.64

14.96

15.86

16.12

16.56

17.20

18.22

19.60

23.04

5.2

10.6

13.5

14.8

15.8

16.0

16.4

17.1

18.1

19.4

5.4

10.7

13.7

16.2

18.3

5.4

10.7

16.2

17.3

18.3

23.1

a – extracted signals; * - recalculated for Cu K 1.5418 Å;

b - signals corresponding to form II;

c – signals

corresponding to form III The XRPD pattern of form III, sample S6 (Figure S3 and Table S11) is characterized by

major peaks at 2Θ values of 5.4, 10.8, 13.8, 15.1, 16.0, 16.2, 18.3, 23.2 and 28.5. Comparison

S15

of these values with those cited in the literature (see Table S11) showed that sample S6 is a

pure crystalline form III. However, the crystals of the sample S7, exhibiting FT-IR and DSC

data compatible with the literature data of form III, show in its XRPD peaks characteristic for

both form II (at 2Θ: 6.4, 8.7, 11.3, 12.8, 14.1, 15.1, 15.9, 19.2 and 19.7) and form III (at 2Θ:

5.4, 10.8, 13.7, 15.1, 15.9, 16.2, 18.3 and 23.1) (see Figure S4 and Table S11).

It should be noted at this point that the extracted data presented for form III and the

extracted data for the so-called “form X” are highly consistent with values cited in the patent

literature as well as with our data of form III (see Table S11).

Fig. S3. XRPD of the sample S6 (form III).

Fig. S4. XRPD of the sample S7 (a mixture of forms II and III).

S16

13C CP-MAS NMR SPECTROSCOPY

The polymorphic purity of our samples of form I (S0 and S1), II (S4) and III (S6) was

also confirmed by 13

C CP-MAS NMR measurements. The same methodology was used to

demonstrate that the sample S7 is a mixture of polymorphic forms II and III.

Comparison of the 13

C data for samples S0 or S1 (Table S12) and sample S4 (Table

S13) with the data cited in the literature showed that within an experimental error their

chemical shifts are the same as those measured for the polymorphs I and II, respectively.

These results strongly support conclusion that samples S0 and S1 are pure samples of form I,

and S4 is pure sample of form II, despite the fact that sample S0 was crystallized from

solvents different than those used in the literature.1,7,9,11-15

The 13

C CP-MAS NMR spectra of

samples S0, S1 and S4 are shown at Figures S5, S6 and S7, respectively.

S17

Table S12. Carbon-13 chemical shifts (δC/ppm) for finasteride forms I.

C No C type Literature data Current work 1

12

7,8 S1 ΔδI S0

1 CH 146.9 146.7 146.9 147.0 –0.1 147.0 2 CH 126.6 126.4 126.9 126.6 +0.3 126.6 3 CN 163.3 163.5 164.3 163.6 +0.7 163.6 5 CHN 60.1 59.9 60.6 60.4 +0.2 60.4 6 CH2 26.5 25.9 26.8 26.5 +0.3 26.6 7 CH2 30.6 30.5 30.6 30.6 0.0 30.7 8 CH 36.5 36.2 36.8 36.5 +0.3 36.5 9 CH 47.6 47.4 48.0 47.6 +0.4 47.7 10 C 39.0 39.6 40.2 39.9 +0.3 39.9 11 CH2 21.5 21.5 21.9 21.5 +0.4 21.6 12 CH2 38.4 38.3 38.8 38.5 +0.3 38.5 13 C 43.9 43.7 44.3 44.0 +0.3 44.0 14 CH 55.7 55.5 56.1 55.7 +0.4 55.7 15 CH2 25.6 25.5 26.0 25.7 +0.3 25.7 16 CH2 24.0 23.8 24.3 24.0 +0.3 24.0 17 CH 57.3 57.1 57.6 57.3 +0.3 57.3 18 CH3 14.9 14.6 15.2 14.9 +0.3 14.9 19 CH3 14.3 14.1 14.7 14.3 +0.4 14.3 20 CN 168.8 168.8 169.3 169.0 +0.3 169.0 22 CN 51.5 51.5 51.9 51.7 +0.2 51.7

23,24,25 CH3 28.9 28.6 29.3 28.9 +0.4 28.9 ΔδI = F I

7,8 – F I(S1)

Table S13. Carbon-13 chemical shifts (δC/ppm) for finasteride forms II.

C No C type Literature data Current work 1

12

7,8 S4 ΔδII

1 CH 150.1/151.6 149.9/151.4 150.4/151.9 150.2/151.7 +0.2/+0.2 2 CH 123.0 122.8 123.3 123.1 +0.2 3 CN 164.4/165.1 164.8 164.9/165.7 164.7/165.5 +0.2/+0.2 5 CHN 59.2/60.4 59.8 59.6/60.9 59.4/60.6 +0.2/+0.3 6 CH2 25.9 25.3 26.6 26.0 +0.6 7 CH2 30.8/31.4 30.8 31.1/31.7 30.8/31.5 +0.3/+0.2 8 CH 35.3 35.0 35.6 35.3 +0.3 9 CH 48.5/48.8 48.6 48.9/49.2 48.6/48.9 +0.3/+0.3

10 C 39.9/40.3 39.7/40.0 40.3/40.6 40.0/40.3 +0.3/+0.3 11 CH2 21.0/21.5 22.6 21.3/21.9 21.1/21.6 +0.2/+0.3 12 CH2 37.4/38.4 38.3 37.7/38.7 37.5/38.5 +0.2/+0.2 13 C 44.0 43.8 44.3 44.1 +0.2 14 CH 56.7/57.8 56.5 57.1/58.1 56.8/57.9 +0.3/+0.2 15 CH2 24.8 25.0 25.6 25.3 +0.3 16 CH2 23.6 24.0 24.0/25.2 23.7/25.0 +0.3/+0.2 17 CH 58.0/58.5 57.9 58.3/58.8 58.1/58.6 +0.2/+0.2 18 CH3 13.1/13.6 12.9/13.3 13.5/13.9 13.2/13.6 +0.3/+0.3 19 CH3 12.1/12.5 11.9/12.3 12.5/12.9 12.2/12.6 +0.3/+0.3 20 CN 169.4 169.2 169.7 169.4 +0.3 22 CN 50.8 50.7 50.9 50.9 0.0

23,24,25 CH3 27.9/28.2 27.7/28.1 28.3/28.7 28.0/28.4 +0.3/+0.3 ΔδII = F II

7,8 – F II(S4)

S18

Fig. S5.

13C CP-MAS NMR of the sample S0 (form I).

Fig. S6.

13C CP-MAS NMR of the sample S1 (form I).

S19

Fig. S7.

13C CP-MAS NMR of the sample S4 (form II).

Fig. S8.

13C CP-MAS NMR of the sample S6 (form III).

S20

Fig. S9.

13C CP-MAS NMR of the sample S7 (a mixture of forms II and III).

SOLUTION 1H AND

15N NMR DATA

1H NMR spectrum (600 MHz) of finasteride sample S6 in CDCl3 solution (Figure S10) shows

the following well-defined signals at : 0.67 (3H, s, 18-H), 0.95 (3H, s, 19-H), 1.32 (9H, s,

tert-Bu), 3.30 (1H, dd, J = 11.0 and 5.3 Hz, 5-H), 5.07 (1H, s, 21-NH), 5.78 (1H, dd, J =

9.95 and 2.3 Hz, 2-H), 5.82 (1H, br s, 4-NH) and 6.76 (1H, d, J = 9.94 Hz, 1-H) [lit.18

1H-

NMR (400 MHz, CDCl3, δ): 0.70 (s, 3H, 18-CH3), 0.98 (s, 3H, 19-CH3), 1.36 (s, 9H, (CH3)3),

3.34 (m, 1H, H5), 5.07 (br s, 1H, NH), 5.15 (br s, 1H, NH), 5.82 (dd, 10.0, 1H, H2), and 6.79

(d, 10.0, 1H, H1); lit.19

1H-NMR (300 MHz, CDCl3, δ): 0.71 (s, 3H), 0.98 (s, 3H), 1.34 (s,

9H), 3.34 (dd, 1H), 5.10 (brs, 1H), 5.49 (brs, 1H), 5.81 (d, 1H), 6.82 (d, 1H)].

S21

Fig. S10.

1H NMR spectrum of finasteride sample S6 (600 MHz, CDCl3).

Fig. S11.

15N NMR spectrum of finasteride sample S6 (60.8 MHz, CDCl3).

S22

Fig. S12.

1H-

15N gHMBC NMR spectrum of finasteride sample S6.

Fig. S13.

1H-

15N HSQC NMR spectrum of finasteride sample S6.

S23

SOLID 15

N CP-MAS NMR DATA

Fig. S14.

15N CP-MAS NMR of the form I, sample S0.

Fig. S15.

15N CP-MAS NMR of the form I, sample S1.

S24

Fig. S16.

15N CP-MAS NMR of the form II, sample S4.

Fig. S17.

15N CP-MAS NMR of the form III, sample S6.

S25

Fig. S18.

15N CP-MAS NMR of a mixture of forms II and III, sample S7.

S26

CONFORMATIONS OF FINASTERIDE AND RELATED MOLECULES IN THE

CRYSTALLINE FORMS (POLYMORPHS AND SOLVATOMORPHS) AND

FINASTERIDE IN SOLUTION

Table S14. Conformations of ,-unsaturated lactam (en-lactam) and amide chromophores in

finasteride and its analogs (unsolvated and solvated forms).

Note: For some structures, in the databases, are shown their enantiomers. Therefore, we changed them the signs

of the torsion angles to the opposite and marked them red.

Ring A

Side chain

Torsion angles:

a – C(5)-C(10)-C(1)-C(2)

b – C(10)-C(1)-C(2)-C(3)

c – C(1)-C(2)-C(3)-C(4)

d – C(2)-C(3)-C(4)-C(5)

e – C(3)-C(4)-C(5)-C(10)

f – C(4)-C(5)-C(10)-C(1)

g – C(16)-C(17)-C(20)-N(21)

h – C(17)-C(20)-N(21)-C(22)

i – C(20)-N(21)-C(22)-C(23)

amide – O=C(3)-N(4)-C(5) or O=C(20)-N(21)-C(22)

Comp.

[lit.]

CSD code

or

CCDC code

Ring A

En-lactam chromophore

Side chain

Amide chromophore

torsion angles

a b c d e f amide g h i amide mono(finasteride) type structures

A9 WOLXOK01 +33.4 +1.7 –15.9 –10.5 +47.3 –54.5 +172.1 +155.6 +172.6 –59.1 –5.5 A1 WOLXOK02 +34.6 +0.6 –15.3 –10.6 +47.5 –55.1 +171.4 +156.2 +173.0 –59.3 –3.8 B9 WOLXEA +30.3 +2.0 –13.8 –11.8 +45.8 –51.0 +169.3 +153.0 +174.4 –57.4 –3.2 C20 701192 +154.8 +177.5 –62.2 –0.5 D21 BEQKEN +157.6 +178.8 –56.0 +1.8 E22 +156.8 +172.6 –58.5 –4.2

bis(finasteride) structures

F1 WOLXOK03 +31.9 +3.0 –16.3 –9.8 +46.6 –54.0 +167.6 +151.9 +176.1 –54.6 –3.1 +35.1 –1.0 –13.2 –12.3 +48.4 –55.7 +168.3 +155.2 +177.0 –57.3 +1.8

G9 WOLXIE +30.7 +5.1 –17.4 –11.2 +47.6 –52.7 +169.4 +153.7 +170.3 –49.3 –9.7 +31.0 +0.2 –10.4 –15.1 +49.3 –53.0 +172.9 +162.0 +176.7 –61.1 –0.3

H8 638162 +32.0 +1.2 –13.6 –12.5 +47.5 –53.4 +170.0 +156.8 +175.8 –58.8 –0.1 +33.5 –0.8 –12.4 –12.6 +47.4 –53.9 +171.0 +162.8 +172.3 –54.3 –7.0

I8 638163 +31.7 +1.7 –14.2 –12.0 +47.3 –53.4 +169.9 +155.5 +173.4 –56.5 –3.9 +34.2 –0.3 –13.9 –11.0 +47.0 –54.4 +172.6 +161.8 +173.6 –57.0 –3.2

K8 638164 +32.2 +1.4 –15.1 –10.4 +46.2 –53.1 +172.3 +156.5 +174.3 –58.7 –1.9 +32.4 +1.3 –14.7 –10.7 +46.1 –53.0 +172.5 +164.0 +173.8 –55.6 –4.8

L16 749582 +29.2 +4.0 –14.8 –12.6 +48.0 –52.1 +169.0 +151.9 +173.0 –58.7 –5.8 +30.5 +2.7 –11.7 –14.5 +45.9 –51.5 +172.5 +162.1 +176.3 –61.4 –1.0

calculations data for finasteride solution

M Conf. 1 +30.7 +1.1 –10.9 –16.3 +49.8 –52.5 +165.8 +149.6 +179.2 –60.9 +0.1 Conf. 2 +30.6 +1.2 –11.0 –16.2 +49.7 –52.4 +165.9 +6.1 +176.3 –61.0 –1.7 Conf. 3 +30.7 +1.1 –11.1 –16.1 +49.7 –52.5 +166.0 –4.5 +178.5 –61.1 –0.7

A – finasteride form I; B – finasteride acetic acid solvate; C – 1,2-dihydrofinasteride; D – 1,2-dihydro-5-

finasteride methanol solvate; E – N-tert-butyl-5-androstane-17-carboxamide, F – finasteride form II; G –

bis(finasteride) monohydrate mono(ethyl acetate) solvate; H – bis(finasteride) monohydrate mono(1,4-dioxane)

solvate; I – bis(finasteride) monohydrate mono(propan-2-ol) solvate; K – bis(finasteride) monohydrate

mono(tetrahydrofuran) solvate; L – bis(finasteride) monohydrate mono(toluene) solvate; M – solution of

finasteride in chloroform.

S27

COMPUTED ECD SPECTRUM OF FINASTERIDE POLYMORPHIC FORM I

Figure S19. Solid-state ECD spectrum recorded in KCl pellet of Form I (S1) compared with

the TDDFT calculations based on X-ray data at CAM-B3LYP/TZVP level of theory.

Simulated curve generated with = 0.5 eV. For better comparison with experiment the

TDDFT curve was divided by 2 and red-shifted by 25 nm (UV shift correction).23,24

Vertical

blue bars represent rotational strength values (divided by 8).

98 100 101

102 (HOMO) 103 (LUMO) 107

Rotatory Strengths (R) in cgs (10-40

erg-esu-cm/Gauss)

Excited State 1: Singlet-A 4.7116 eV 263.15 nm f=0.0013 R(velocity) = −10.7137

98 ->103 0.11667

100 ->103 0.37456

101 ->103 -0.16584

102 ->103 0.52465 55% nC=O (lactam) → 1* (en-lactam)

Excited State 2: Singlet-A 5.6586 eV 219.11 nm f=0.0198 R(velocity) = −30.8683

98 ->103 -0.22778

S28

100 ->103 0.56886 65% O=C-N (lactam) → 1* (en-lactam)

102 ->103 -0.32932

Excited State 3: Singlet-A 5.6958 eV 217.68 nm f=0.0020 R(velocity) = +9.4006

101 ->104 0.19670

101 ->105 0.36421

101 ->107 0.43890 39% nC=O (amide) → 2* (amide)

101 ->108 0.10602

101 ->110 0.17642

102 ->105 0.10245

102 ->107 0.12257

Excited State 4: Singlet-A 6.3490 eV 195.28 nm f=0.4226 R(velocity) = +26.2307

98 ->103 0.64184 82% C=C-C=O (lactam) → 1* (en-lactam)

100 ->103 0.12818

102 ->103 -0.22014

SOLID-STATE VCD SPECTRA

in black – spectra recorded in 2012; in red – spectra recorded in 2013/14

Fig. S20. Reproducibility of solid-state VCD spectra of forms I-III.

SOLUTION VCD AND IR CALCULATIONS

Conf. 1

0.00 kcal/mol

80.73%

Conf. 2

0.96 kcal/mol

16.04%

Conf. 3

1.91 kcal/mol

3.23%

Fig. S21. Structures of conformers within a 5 kcal/mol–1

energy window of finasteride

calculated at the B3LYP/TZVP/PCM(CHCl3) level of theory.

S29

Fig. S22. Experimental VCD (top) and IR (bottom) spectra recorded in CDCl3, compared to

simulated spectra at the B3LYP/TZVP/PCM(CHCl3) level of theory, obtained as a

population-weighted sum of the calculated spectra of individual conformers. The simulated

spectra were scaled by 0.977.

Table S15. Vibrational analysis of selected bands for the lowest energy conformer (Conf. 1)

of finasteride in chloroform solution.

Band [cm-1

]

theor. / exp.

Mode assignment

1539 / ~1493 bending H-N(21)-C(20) within amide moiety (57%)

stretching N(21)-C(20) within amide moiety (16%)

1510 / ~1466 bending H-C-H within C(6)H2 and C(19)H3 moieties (70%)

bending H-C(19)-C(10) and C(19)-C(10)-C(5) within moiety (11%)

1489 / ~1448 bending H-C-H within tert-butyl moiety (59%)

bending H-C-C and C-C-C within tert-butyl moiety (17%)

Table S16. Rotational strengths for selected bands of conformers 1-3 of finasteride in

chloroform solution.

Conf. Torsion angle [deg]

C(16)-C(17)-C(20)-N(21)

R at ca.

1539/~1493 cm-1

R at ca.

1510/~1466 cm-1

R at ca.

1489/~1448 cm-1

1 +149.6 +15.93 −7.43 −8.65

2 +6.1 −18.39 −9.90 −16.21

3 −4.5 −21.71 −8.37 −19.45

S30

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