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Anion-switchable supramolecular gels for controlling pharmaceutical crystal growth

Jonathan A. Foster, Marc-Oliver M. Piepenbrock, Gareth O. Lloyd, Nigel Clarke, Judith A. K. Howard and Jonathan W. Steed* Supplementary Data Synthesis of 1 A solution of 1,3-bis(1-isocyanato-1-methylethyl)benzene (2.00 g, 8.2 mmol) in dry CHCl3 (40 mL) was heated to reflux and stirred under N2 atmosphere. A solution of (3-aminopropyl)triethoxysilane (3.65 g, 16.4 mmol) in dry CHCl3 (40 mL) was slowly added dropwise to the reaction mixture. After complete addition the reaction mixture was stirred at reflux for 24 h. After this period the clear solution was evaporated to dryness and the recovered crude product was washed with diethyl ether (370 mL) to obtain the clean product as a white powder. Yield 4.96 g , 7.2 mmol, 87.8 %. 1H NMR (400 MHz, DMSO) δ 7.32 (s, 1H, Ar-H), 7.14 (m, 3H, Ar-H), 6.11 (s, 2H, NH), 5.81 (t, J = 5.7 2H, NH), 3.73 (q, J = 7.0 12H, O-CH2-), 2.89 (dd, J = 6.6. 12.9, 4H, NH-CH2-) 1.50 (s, 12H, CH3), 1.37 (m, 4H, -CH2-), 1.13 (t, J = 7.0, 18H, CH3) 0.5 (m, 4H, -CH2-Si). IR max(cm-1): 3354 (NH), 1631 (C=O), 1560 (NH) 1074 + 953 (Si-O-C). ES+-MS m/z 709 ([M+Na]+, 68%), 1395 ([2M+Na]+, 100%). Anal. calc. for C32H62N4O8Si2: C 55.94, H 9.10, N 8.15 % Found: C 55.73, H 9.02, N 8.20 %. Synthesis of 3 Phenylalanine methyl ester dihydrochloride (1.30g, 6mmol) was dissolved in 150ml chloroform by the slow addition of a slight excess of triethylamine (0.62g, 6.1mmol). Following heating and sonication of the mixture a hot filtration was carried out to remove un-dissolved amino acid. 1,6 di-isocyanatohexane (0.50g, 3.0mmol) was dissolved in 50ml chloroform and slowly added over a period of 1 hour. The solution was refluxed at 70˚C for 24hrs. The chloroform was reduced under vacuum and the compound washed with warm water for 1hour. The suspension was filtered, washed with ethyl acetate and dried in a heat pistol for 30minutes. A white powder (1.26g, 2.4mmol, 80%) was obtained and identified as 3: 1H NMR (700MHz, DMSO) δ 7.28 (t, 4H, J = 7.6, Ar-H), 7.21 (t, J=7.6, 2H, Ar-H), 7.15 (d, J= 7.2, 4H, Ar-H), 6.12 (d, J=8.3, 2H, CH-NH), 6.06 ( t, J=5.8, 2H, NH-CH2), 4.36 (td, J= 5.5, 8.1,13.6, 2H,-CH-), 3.59 (s, 6H, -OCH3), 2.98-2.90 (m, 6H, Ar-CH2 + NH-CH2), 2.87 (dd, J=8.0, 13.8, 2H, Ar-CH2), 1.34-1.24 (m, 4H, -CH2-), 1.24-1.14 (m, 4H, -CH2). 13C NMR (700MHz, DMSO-d6, J/Hz): 173.8 (s, CO-OCH3), 158.0 (s, CO), 137.8 (s, C-Ar), 129.9 (s, C-Ar), 129.0 (s, C-Ar), 127.3 (s, C-Ar), 54.7 (s,CH), 52.4 (s,OCH3), 41.0-39.5 (m, DMSO + CH2), 38.3 (s, CH2-Ar), 30.6 (s, CH2), 26.8 (s,CH2). m/z (ES+-MS): 527.3 ([M+H]+, 78%), 549.4 ([M+Na]+, 88%), 1052.6 ([2M+H]+, 13%), 1074.8 ([2M+Na]+, 100%). Anal. Calcd for

C28H38N4O6: C, 63.86; H, 7.27; N, 10.64. Found: C, 63.58; H, 7.24; N, 10.77%.

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20.0 30.0 40.0 50.0 60.0 70.0 80.0temperature (°C)

1.000E-4

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Gelator 1Gelator 1 + CBZ (1 wt%)

Figure S1: Temperature sweep of Gelator 1 with and without CBZ.

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0.1000 1.000 10.00 100.0osc. stress (Pa)

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Gelator 1Gelator 1 + 0.1 equiv. TBAOAcGelator 1 + 0.5 equiv. TBAOAcGelator 1 + 0.7 equiv. TBAOAcGelator 1 + 1.0 equiv. TBAOAc

Figure S2. Stress sweep rheology of gelator 1 in toluene with 100 µL of MeCN with varying amounts of TBAOAc.

Figure S3. Result of crystallisation of 20mg of CBZ from solution or with 1 wt% gel of 3. (a)

crystallisation from ethyl acetate (left) and ethyl acetate gel (right) in (b) crystallisation from

1:9 CH3CN:toluene (left) and 1:9 CH3CN:toluene gel (right), (c) crystallisation from 1:9

CHCl3:toluene (left) and 1:9 CHCl3:toluene gel (right) (d) crystallisation from gels of 3 in 1:1

DMSO:H2O (20 or 40mg CBZ, left and right respectively) – no crystals form in solution.

(a) (b) (c) (d)

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0.01000 0.1000 1.000 10.00 100.0osc. stress (Pa)

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Gelator 3Gelator 3 + 0.5 equiv. TBAOAcGelator 3 + 1.0 equiv. TBAOAc

Figure S4. Stress sweep rheology of 1 wt% gelator 3 in toluene + 1ml of MeCN with and

without addition of varying amounts of TBAOAc.

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Figure S5. SEM images of xerogels of 3 (1 wt%) formed from stated solvents

0

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400

3 8 13 18 23 28 33 38

2θ

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nsity

Experimental pattern from DMSO:waterCalculated pattern for CBMZPN13

Figure S6. Comparison of the experimental XRPD pattern obtained by crystallisation of

40mg of CBZ from a 1 ml, 1:1 DMSO:water gel of 3 at 1 wt% (shown in blue) with the

calculated pattern for CSD entry CBMZPN13 (P. Fernandes, K. Shankland, A. J. Florence,

N. Shankland, A. Johnston, J. Pharm. Sci. 2007, 96, 1192) generated using Mercury

software (shown in pink).

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Figure S7 Photomicrograph of ASP crystals grown from a 0.3% gel by weight of 2 in

MeCN (x40 magnification). Note the visible gel fibres that have been broken by smearing

some of the gel that contains the crystals on a microscope.

Figure S8 Crystals of 2-hydroxybenzyl alcohol grown from a gel of 3 in toluene.

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Table S1 Results of comparative gel phase and solution studies on a range of drug

substances. Conditions were chosen such that solution crystallisation was expected.

Drug Substrate Solvent

CH3CN:Tol CHCl3:Tol EtOAc DMSO:H2O MeOH:H2O Sparfloxacin G C C G C C X - C G C C G C C Piroxicam G C C G C C G C C G C C G - C Theophylline G C C G C C G - C G - C G - C Caffeine G C C G - C G C - G C C G C C Ibuprofen G C C G C C G C C X - - X C - Acetaminophen (Paracetamol)

G C C G C C X - - X - - G - -

Sulindac G C C G C C G - - G - - X C - Indomethacin G - C G - - G - - X C C G C C Key – columns from left to right for each solvent: (1) G or X indicate gel or no gel formation (2) C indicates crystals observed in the gel (3) C indicates crystals observed in solution control in absence of gel. In both gel and solution experiments dashes represent no crystals formation. Entries in light blue indicate cases where no crystals form in the gel. Entries in light blue indicate cases where no crystals form in either the gel or solution. The green entry is a case where crystals failed to form in the solution control experiment but did form in the gel.

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Figure S9 Piroxicam crystallisation experiments in pairs with gel phase experiment on the

left (inverted) and solution control on the right. Close up views of the gels are shown in row

2 and the solution crystallisations in row 3. Conditions given in the table.

(a) CH3CN:Tol

(b) CHCl3:Tol

(c) EtOAc

(d) DMSO:H2O

(e) MeOH:H2O

Gelation partial gel partial gel gel

Crystal

from gel

Needles

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needles

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Crystal

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Block

Form I

Needle

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Long needles

Form II

Irregular blocks

Hydrate

Irregular blocks

Hydrate

(a) (b) (c) (d) (e)

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CBZ + 1 1wt% Tol 70oC

0.005 0.015 0.025concentration of Guest

4.54

4.58

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4.66

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Figure S10 NMR titration data and fit for binding of CBZ by gelator 1 in toluene at 70 oC;

above Tgel; log K11 = 0.87(27) CBZ + 1 1wt% CDCl3

0.00 0.02 0.04 0.06concentration of Guest

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Figure S11 NMR titration data and fit for binding of CBZ by gelator 1 in CDCl3 at 20 oC; log

K11 = 0.84(8)

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Figure S12 Variable temperature 1H NMR spectra 20 – 80oC for carbamazepine and

gelator 1 at 1 wt% 1 and 0.5 wt % CBZ. (a) CBZ, (b) mixture of 1 and CBZ and (c) gelator

1.