SUPPORTING INFORMATION
Spectroscopic investigation of the formation and disruption of hydrogen bonds in pharmaceutical semi-crystalline dispersions Tu Van Duong,†,⊥ Gunter Reekmans,§ Akkaladevi Venkatesham,‡ Arthur Van Aerschot,‡ Peter Adriaensens,§ Jan Van Humbeeck,¶ and Guy Van den Mooter*,† †
Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological
Sciences, KU Leuven, Campus Gasthuisberg O&N2, Herestraat 49 b921, 3000 Leuven, Belgium ⊥
Department of Pharmaceutics, Hanoi University of Pharmacy, 13-15 Le Thanh Tong, Hoan
Kiem, Ha Noi, Vietnam §
Applied and Analytical Chemistry, Institute for Materials Research, Hasselt University,
Diepenbeek BE-3590, Belgium ‡
Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49
b1041, 3000 Leuven, Belgium ¶
Department of Materials Engineering, KU Leuven, Campus Arenberg, Kasteelpark Arenberg
44 b2450, 3001 Heverlee, Belgium
Corresponding Author *E-mail:
[email protected]. Tel.: +32 16 330 304. Fax: +32 16 330 305.
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Table of contents Section S1. Synthesis of methoxy and amide derivatives of indomethacin Section S2. Synthesis of methoxy and amide derivatives of ketoprofen Figure S1. DSC thermograms with heat flow signal vs. temperature for dispersions of PEG and ketoprofen and its methoxy/amide derivative containing different compositions. Section S3. Synthesis of fenofibric acid Figure S2. FTIR spectra of PEG, γ-IMC, α-IMC and amorphous IMC in the spectral region between 4000-400 cm-1 at room temperature. Figure S3. 13C MAS NMR spectra of PEG/IMC dispersions containing different molar ratios of IMC to PEG monomer units at 75°C.
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Section S1
Synthesis of methoxy and amide derivatives of indomethacin Synthesis of the desired compounds was straightforward. Indomethacin (1) was converted almost quantitatively at room temperature (rt.) into its acid chloride derivative 2 by stirring in DCM in presence of an excess of oxalyl chloride (at least 2 equivalents) and a few drops of dimethyl-formamide as catalyst (with the imidoyl chloride being the active chlorinating agent), followed by simple evaporation and washing with hexane (ref.: R. Adams, L. H. Ulich, J. Am. Chem. Soc. 1920, 42, 599 - 611). The acid chloride allowed conversion to the methyl ester 3 in 61% yield by reaction with MeOH or to the amide derivative 4 in 75% yield, following treatment with conc. aqueous ammonia. NMR and mass spectrometric analysis confirmed the correct structures with an additional methyl ester signal (δ 3.70 ppm and 52.3 ppm in 1H and 13C NMR, respectively) for 3, and a more upfield shift for the methylene signal of CH2CONH2 (δ at 3.47 ppm) and a CONH2 signal at δ 7.43 ppm for 4 in addition to the expected mass.
Scheme 1. Reagents and conditions: (a) oxalyl chloride, dry CH2Cl2, DMF (few drops), 25οC, 12 h (93%); (b) anhydrous MeOH, rt, 30 min (61%); (c) aq.NH3 (25% w/v), rt, 2 h (75%). 3
Experimental procedures 2-(1-(4-Chlorobenzoyl)-5-methoxy-1H-indol-3-yl)acetyl chloride (2) Oxalyl chloride (1.04 ml, 12 mmol) was added dropwise to a solution of 2-(1-(4chlorobenzoyl)-5-methoxy-1H-indol-3-yl)acetic acid (2.14 g, 6 mmol) in 50 mL of dry CH2Cl2 to which were added 3 drops of dry DMF under argon. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the crude product was washed with dry hexane (3 × 20 mL) and dried in vacuo to give 2.09 g (93%) of the title compound as a pale yellow solid. 1
H NMR (300 MHz, CDCl3) δ: 7.74 – 7.60 (m, 2H, benzoyl H-2 and H-6), 7.55 – 7.39 (m,
2H, benzoyl H-3 and H-5), 6.90 – 6.86 (m, 1H, indolyl H-4), 6.84 (s, 1H, indolyl H-7), 6.70 (dd, J = 9.0, 2.5 Hz, 1H, indolyl H-6), 4.17 (s, 2H, CH2COCl), 3.84 (s, 3H, OCH3), 2.41 (s, 3H, CH3);
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C NMR (75 MHz, CDCl3) δ: 171.1, 168.3, 156.27, 139.7, 137.2, 133.5, 131.3,
130.8, 129.8, 129.3, 115.1, 112.1, 110.0, 100.9, 55.8, 42.4, 13.4. Methyl 2-(1-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl)acetate (3) Compound 2 (0.800g, 2.13 mmol) was dissolved and stirred in dry MeOH (24 ml, 30 volumes) at rt. The reaction was monitored by TLC and shown to be complete after 30 min. The solvent was evaporated and the crude product was dissolved in a mixture of diethyl ether (5 ml) and DCM (1 ml) to which 50 ml of hexane was added. The precipitate formed was filtered to afford 0.482 g (61%) of the title compound as a pale white solid. 1
H NMR (300 MHz, CDCl3) δ: 7.70 – 7.62 (m, 2H, benzoyl H-2 and H-6), 7.51 – 7.43 (m,
2H, benzoyl H-3 and H-5), 6.96 (d, J = 2.5 Hz, 1H, indolyl H-4), 6.86 (d, J = 9.0 Hz, 1H, indolyl H-7), 6.67 (dd, J = 9.0, 2.5 Hz, 1H, indolyl H-6), 3.84 (s, 3H,OCH3), 3.70 (s, 3H, COOCH3), 3.67 (s, 2H, CH2COO), 2.39 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ: 171.4, 168.4, 156.2, 139.4, 136.1, 134.1, 131.3, 131.0, 130.8, 129.3, 115.1, 112.6, 111.8, 101.5, 55.9, 52.3, 30.3, 13.4; HRMS for C20H19ClNO4 ([M+H]+ ) calcd.: 372.0997; found 372.1000. 4
2-(1-(4-Chlorobenzoyl)-5-methoxy-1H-indol-3-yl)acetamide (4 ) To an ice-cooled solution of 2 (1 g, 2.66 mmol) in dry THF (50 mL) was added 25% aq. NH3 (2 ml, approximatively 10 eq.) and the mixture was stirred for 10 min. The reaction mixture was slowly allowed to reach rt. After 3 h at rt.,the solvent was evaporated and the residue was purified by column chromatography to give 0.712 g (75%) of the title compound as a pale yellow solid. 1
H NMR (300 MHz, DMSO-d6) δ: 7.76 – 7.59 (m, 4 H, benzoyl H-2, H-6, H-3 and H-5),7.43
(brs, 1H, NH2), 7.11 (d, J = 2.5 Hz, 1H, indolyl H-4 ), 7.02 – 6.87 (m, 2H,indolyl H-7, NH2), 6.71 (dd, J = 9.0, 2.5 Hz, 1H, indolyl H-6), 3.76 (s, 3H, OCH3), 3.46 (s, 2H, CH2CO), 2.23 (s, 3H, CH3); 13C NMR (75 MHz, DMSO-d6) δ: 171.5, 167.8, 155.5, 137.5, 135.1, 134.3, 131.1, 130.9, 130.3, 129.0, 114.5, 114.4, 111.1, 101.9, 55.4, 30.9, 13.3; HRMS for C19H18ClN2O3 ([M+H]+ ) calcd.: 357.1000; found 357.1000.
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Section S2
Synthesis of methoxy and amide derivatives of ketoprofen Synthesis of the ketoprofen methyl ester was carried out in one pot using thionyl chloride and methanol affording the colorless liquid 6 in almost quantitative yield. The amide analogue 8 was obtained from ketoprofen in 87% yield by in situ treatment with oxalyl chloride to obtain 7 followed by further treatment with aq. ammonia. Identification of 6 and 8 was carried out as for 2 and 4.
Scheme 2. Reagents and conditions: (a) SOCl2, dry MeOH, -30οC to 70οC , 8 h (98%); (b) oxalyl chloride, dry DCM, few drops DMF, rt, 2 h (93% crude); (c) aq. NH3 (25% w/v), rt., 1 h (overall for two steps 87%). Experimental procedures (R)-Methyl 2-(3-benzoylphenyl)propanoate (6) Thionyl chloride (1.7 mL, 23.9 mmol) was added dropwise to a solution of (R)-2-(3-benzoylphenyl) propanoic acid 5 (0.600 g, 2.39 mmol) in anhydrous methanol (40 mL) at -30οC under N2 atm. The reaction mixture was slowly heated to 70οC for 8 h and then the solvent was removed in vacuo, the residue was dissolved in ethyl acetate (3 x 50 mL) and washed with
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water (50 mL) and brine (50 mL) to give the (R)-methyl 2-(3-benzoylphenyl)propanoate 6 (0.622 g, 2.32 mmol, 98% yield) as a colorless liquid. 1
H NMR (300 MHz, CDCl3) δ: 7.86 – 7.38 (m, 9H, -Ar), 3.81 (q, J = 7.2 Hz, 1H, -CHCH3),
3.68 (s, 3H,-OMe), 1.54 (d, J = 7.2 Hz, 3H, -CHCH3); 13C NMR(75 MHz, CDCl3) δ: 196.5, 174.5, 140.8, 137.9, 137.5, 132.5, 131.5, 130.1, 129.2, 129.0, 128.6, 128.3, 52.1, 45.3, 18.5; HRMS for C17H17O3 ([M+H]+) calcd.: 269.1172; found: 269.1173. (R)-2-(3-Benzoylphenyl)propanoyl chloride (7) Oxalyl chloride (0.472 mL, 5.51 mmol) was added dropwise to a solution of (R)-2-(3benzoyl44.6, 18.4; HRMS for C16H16NO2 ([M+H]+ ) calcd.: 254.1175; found: 254.1181. phenyl)propanoic acid 5 (0.700 g, 2.75 mmol) in 15 mL of dry CH2Cl2 to which were added 2 drops of dry DMF under argon. The reaction mixture was stirred for 2 h at rt. The solution was washed with water (10 mL) and sat aq. NaHCO3 (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude acid chloride 7 (0.697 g, 93% crude), which was used for the next step without further purification. (R)-2-(3-Benzoylphenyl)propanamide (8 ) To an ice-cooled solution of 7 (0.697 g, 2.56 mmol) in dry THF (35 mL, 50 vol) was added 25% aq. NH3 (0.5 mL, about 10 eq.) and the mixture was stirred for 10 min. The reaction mixture was slowly allowed to reach rt. After 1h at rt., the solvent was evaporated and the residue was purified by silica gel column chromatography to give 8 (0.611 g, 2.41 mmol, 87% overall for two steps) as a white solid. 1
H NMR (300 MHz, DMSO-d6) δ: 7.86 – 7.40 (m, 9H, Ar), 6.88 (brs, 1H, NH), 5.75 (brs, 1H,
NH), 3.69 (q, J = 7.0 Hz, 1H, -CHCH3), 1.34 (d, J = 7.0 Hz, 3H, CH3); 13C NMR (75 MHz, DMSO-d6) δ: 195.7, 174.8, 142.8, 137.0, 136.8, 132.6, 131.6, 129.6, 128.5, 128.4, 128.0, 54.9, 44.6, 18.4; HRMS for C16H16NO2 ([M+H]+ ) calcd.: 254.1175; found: 254.1181. 7
Figure S1. DSC thermograms with heat flow signal vs. temperature for dispersions of PEG and ketoprofen and its methoxy/amide derivative containing different compositions.
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Section S3
Synthesis of fenofibric acid Fenofibric acid (10) was prepared in 94% yield from fenofibrate (9) by basic hydrolysis in aqueous NaOH – isopropanol, followed by acidification of the mixture to pH 2-3 and extraction with ethyl acetate.
Scheme 3. Reagents and conditions: (a) aq. NaOH, IPA, 80-90οC, 3h Experimental procedures 2-(4-(4-Chlorobenzoyl)phenoxy)-2-methylpropanoic acid (10) To an ice-cooled solution of 9 (0.700 g, 1.94 mmol) in isopropanol (35 mL, 50 vol) was added aq.NaOH (0.770 mL, 9.72 mmol) (50%w/v). After warming up to rt, the reaction mixture was heated to 70–80οC for 3 h. After completion of the reaction the mixture was acidified to pH 23 with conc. HCl. The organic solvent was concentrated under reduced pressure and the residue was partitioned between DCM (3 X 50 mL) and water (2 X 50 mL). The organic layer was separated and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 10 (0.581 g, 1.82 mmol, 94%) as a pale yellow pure solid without further purification. 1
H NMR (300 MHz, DMSO-d6) δ: 13.26 (brs, 1H, -COOH), 7.72 (d, J = 9.2 Hz, 4 H, -Ar),
7.60 (d, J = 8.3 Hz, 2H), 6.93 ( J = 9.2 Hz, 2 H, -Ar), 1.59 (s, 6H, 2CH3); 13C NMR (75 MHz, DMSO-d6) δ: 193.2, 174.4, 159.5, 137.0, 136.3, 131.8, 131.1, 129.3, 128.6, 117.0, 78.9, 25.1; HRMS for C17H14ClO4 ([M-H]- ) calcd.: 317.0586; found: 317.0574.
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Figure S2. FTIR spectra of PEG, γ-IMC, α-IMC and amorphous IMC in the spectral region between 4000-400 cm-1 at room temperature.
Figure S3. 13C MAS NMR spectra of PEG/IMC dispersions containing different molar ratios of IMC to PEG monomer units at 75°C.
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