S1

Electronic Supplementary Information (ESI)

Amine-carboxylate Supramolecular Synthon in

Pharmaceutical Cocrystals

Duanxiu Li,ab Minmin Kong,ab Jiong Li,b Zongwu Deng,ab and Hailu Zhangab*

a Laboratory of Magnetic Resonance Spectroscopy and Imaging, Suzhou Institute of Nano-

Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, P. R. China. Tel:

+86-512-62872713; Fax: +86-512-62603079; E-mail: hlzhang2008@sinano.ac.cn.

b CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-

Bionics, Chinese Academy of Sciences, Suzhou 215123, P. R. China.

Electronic Supplementary Material (ESI) for CrystEngComm.This journal is © The Royal Society of Chemistry 2018

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Contents

S1. Virtual cocrystal screening.................................................................................................S3

Table S1 Chemical structures and abbreviation of APIs.........................................................S4

Table S2 Calculated change in interaction site pairing energies (−ΔE in kJ mol-1) for the

reported pharmaceutical cocrystals of L-pro and their CSD refcodes......................................S6

Table S3 Results of virtual cocrystals screening.....................................................................S7

S2. Cocrystal preparation..........................................................................................................S8

Table S4 Crystallographic data for new obtained cocrystals of L-pro..................................S10

Table S5 Hydrogen bonds for new obtained cocrystals of L-pro..........................................S11

Fig. S1 The PXRD patterns of CNX-L-pro and starting materials........................................S12

Fig. S2 The PXRD patterns of FC-L-pro and starting materials............................................S13

Fig. S3 The PXRD patterns of CLX-L-pro and starting materials.........................................S13

Fig. S4 The PXRD patterns of SMZ-L-pro and starting materials.........................................S14

Table S6 CSD refcodes of cocrystals with N—H···–OOC synthon......................................S14

Fig. S5 Electrostatic potential surfaces (in kJ mol−1) of CNX molecules using different

starting conformations (extracted from structures of Form I-IV, respectively).....................S15

Table S7 The MEPmax values (in kJ mol−1) of COOH, Ph-OH, and NH, NH2 functional groups

in cocrystals of L-pro..............................................................................................................S16

References .............................................................................................................................S17

S3

S1. Virtual cocrystal screening

Gaussian 09 program[1] was used to optimize the geometry and calculate the MEPS using

DFT and a B3LYP/6-31G* basis set. Multiwfn_3.4.1 program[2] was used to extract local

maxima and minima from the MEP mapped onto the 0.002 Bohr Å−3 electron density

isosurface. The MEPS were then converted into αi and βj H-bond parameters using eqn (3)

and (4) and calculation of the energies of the pure and cocrystal solids, E, were performed

using Excel spreadsheets. Such mapped electrostatic potential surface has been plotted using

the GaussView 5.0 software. The stability of cocrystals compared to pure components was

estimated for all combinations based on the difference in the interaction site pairing energies,

ΔE, calculated using eqn (1) and (2).

E=−Σαiβj (1)

Comparison of the total SSIP of two pure components with cocrystals of various

stoichiometries gives an energy difference, i.e.

ΔE=Ecc−nE1−mE2 (2)

where E1 is the interaction site pairing energy of the pure form of component 1, E2 is the

interaction site pairing energy of the pure form of component 2, Ecc is the interaction site

pairing energy of the cocrystal of stoichiometry 1n2m, which is a measure of the probability of

forming a cocrystal.

α = 0.0000162MEPmax2 + 0.00962MEPmax (3)

β = 0.000146MEPmin2 − 0.00930MEPmin (4)

where MEPmin and MEPmax are local minima and maxima on the MEPS in kJ mol−1.

S4

Table S1 Chemical structures and abbreviation of APIs.

API Name Chemical structure Abbreviation Reference

L-proline NH2

COO L-pro

IpragliflozinO

HOS

FHO

OH

HO

Ipr [3]

C-aryl Glucoside Derivatives

OHO

HOOH

OH

R3R2

R1

R4 R5R6OA - [4]

NaproxenO

COOH Nap [5]

AprepitantF3C

CF3

ON

O

NH

NHN

F

O

Apr [6]

Ezetimibe F N

OH

O

F

OH

Eze [7]

(1S)-1-[4-chloro-3-(4-ethoxybenzyl)phenyl]-1,6-

dideoxy-D-glucose

O

HOOH

OH

Cl OEt

Ptt [8]

HelicidO O

HOOH

OHO

HO

Hel [9]

(1S)-1, 5-dehydrogenation-1-C-[3-[[5-(4-fluorophenyl)-2-

thienyl]methyl]-4-methylphenyl]-D-glucitol

O

HOS

HO

HO

F

Ptc [10]

BaicaleinOHO

OH OHO

Bai [11]

ChrysinOHO

OH O

Chr [11]

GenisteinOHO

OH OOH

Gen [11]

kaempferol OHO

OHOH

OH

O

Kae [11]

Luteolin OHO

OH

OH

OH

O

Lut [11]

Quercetin OHO

OHOH

OH

OH

O

Que [11]

Myricetin OHO

OHOH

OHOH

OH

O

Myr [12]

Nitrofurantoin OO2N N

N

NHO

O

Nft [13]

S5

ResveratrolOH

HO

OH

Rsv [14]

FlurbiprofenF

COOH Flu [15]

Reluzole S

NH2N

OCF3 Rlz [16]

Diclofenac acidHN

Cl

Cl

COOH

Dfa [17]

ClonixinHN

N

ClCH3 COOH

CNX √

Nitazoxanide O

O

NH

O S

N NO2

NTZ

SulfamerazineH2N

SHN

O O N

NSMR

SulfadiazineH2N

SHN

O O N

N SDZ

Celecoxib N N

S

H3C

CF3

H2N O

O

CLX √

Acyclovir NHN

N

N

OHO

O

NH2

ACV

Sulfathiazole NH

S NS

O

O

NH2

STZ

Sulfamethizole NNH

SN

SO O

NH2

SMZ √

5-Fluorouracil HN

HNO

FO

FU

Flucytosine N

HNO

FNH2

FC √

S6

Table S2 Calculated change in interaction site pairing energies (ΔE in kJ mol−1) for the

reported pharmaceutical cocrystals of L-proline and their CSD refcodes.

API Stoichiometry −ΔE Reference

Nap 1:1 4.5 FEVZUD [5]

Apr 1:1:1(MeOH) 3.9 [6]

Chr 1:1 5.6 EJEQAN [11]

Gen 1:2 9.2 EJEQER [11]

Kae 1:2 17.5 EJEPOA [11]

Lut 1:1 11.6 EJEPUG [11]

Que 1:2 19.1 EJERAO [11]

1:1 21.2 PEBZOO [14]Rsv

1:2 32.5 PEBZUU [14]

2:1 7.6 VEVKOZ [15]

1:1 6.0

VEVKEP, VEVKEP01,

VEVMUH, VEVMUH01,

VEVLEQ, VEVLEQ01,

VEVLOA [15]

1:2 6.3 VEVLAM [15]

Flu

1:3 6.4 VEVKUF [15]

Rlz 1:1 10.9 YEPJEL [16]

Dfa 1:1 8.1 RETNEM [17]

S7

Table S3 Results of virtual cocrystal screening. Experimentally observed cocrystals are denoted by ‘‘√’’.

API Stoichiometry −ΔE (kJ mol−1) Experimental results

NTZ 2:1, 1:1, 1:2 1.3, 1.3, 2.3

SMR 2:1, 1:1, 1:2 1.9, 1.5, 2.3

SDZ 2:1, 1:1, 1:2 3.1, 2.3, 3.1

CLX 2:1, 1:1, 1:2 2.4, 2.3, 4.1 √(1:2)

ACV 2:1, 1:1, 1:2 3.9, 3.3, 3.3

STZ 2:1, 1:1, 1:2 4.5, 4.0, 5.1

SMZ 2:1, 1:1, 1:2 5.7, 4.9, 5.2 √(1:1)

FU 2:1, 1:1, 1:2 6.1, 5.8, 6.5

FC 2:1, 1:1, 1:2 14.6, 11.7, 17.8 √(1:1)

CNX-I 2:1, 1:1, 1:2 5.2, 4.6, 4.8

CNX-II 2:1, 1:1, 1:2 0.5, 0.3, 0.4

CNX-III 2:1, 1:1, 1:2 18.4, 13.3, 13.8

CNX-IV 2:1, 1:1, 1:2 18.4, 13.3, 13.8

√(1:1)

S8

S2. Experimental Screening of cocrystals

Materials

L-proline (>98%) was purchased from Aladdin. Clonixin (CNX, form I, >98%) and

Sulfamethizole (SMZ, >98.5%) were purchased from TCI. Celecoxib (CLX, ≥99%) was

purchased from Dalian Meilun Biotech Co., Ltd. Flucytosine (FC, ≥97%) and solvents of

analytical grade were purchased from Sinopharm Chemical Reagent Co., Ltd. All chemicals

were used without further purification.

Preparation of CNX-L-pro cocrystal (1:1)

CNX (66 mg, 0.25 mmol) and L-pro (57 mg, 0.5 mmol) were mixed and dissolved in

anhydrous CH3OH (5 mL) and filtered through a 0.22 μm PTFE syringe filter. The resulting

solution was left to slowly evaporate at room temperature. Colorless crystals of CNX-L-pro

were harvested after 2-3 days. Large-scale crystallization of CNX-L-pro can be realized

through CH3OH-assisted grinding of a mixture of a 1:1 molar ratio of CNX and L-pro.

Preparation of FC-L-pro cocrystal (1:1)

FC (65 mg, 0.25 mmol) and L-pro (115 mg, 1.0 mmol) were mixed and dissolved in

anhydrous CH3OH (5 mL) and filtered through a 0.22 μm PTFE syringe filter. The resulting

solution was left to slowly evaporate at room temperature. Colorless crystals of FC-L-pro

were harvested after 2-3 days. Large-scale crystallization of FC-L-pro can be realized through

CH3OH-assisted grinding of a mixture of a 1:1 molar ratio of FC and L-pro.

Preparation of CLX-L-pro cocrystal (1:2)

CLX (95 mg, 0.25 mmol) and L-pro (57 mg, 0.5 mmol) were mixed and dissolved in

anhydrous CH3OH (5 mL) and then filtered through a 0.22 mm PTFE syringe filter. The

resulting solution was left to slowly evaporate at room temperature. Colorless crystals CLX-

L-pro can be harvested after 2-3 days. Large-scale crystallization of CLX-L-pro can be

realized through CH3OH-assisted grinding of a mixture of a 1:2 molar ratio of CLX and L-pro.

Preparation of SMZ-L-pro cocrystal (1:1)

Eqivmolar mounts of SMZ (54 mg, 0.2 mmol) and L-pro (23 mg, 0.2 mmol) were mixed and

dissolved in anhydrous CH3OH (5 mL). The resulting solution was filtered through a 0.22 μm

PTFE syringe filter and left to slowly evaporate at room temperature. Colorless crystals of

SMZ-L-pro were harvested after 2-3 days. Large-scale crystallization of SMZ-L-pro can be

realized through CH3OH-assisted grinding of a mixture of a 1:1 molar ratio of SMZ and L-pro.

S9

X-ray crystallographic analysis

Single crystal X-ray diffraction data of CNX-L-pro was collected on a Bruker Apex-II CCD

diffractometer using a graphite monochrome Mo-Kα (λ = 0.71073 Å) at 120 K. The collected

data was subjected to absorption corrections using the multi-scan method. The diffraction data

reduction was performed using the Bruker SAINT software. Single crystal X-ray diffraction

data of CLX-L-pro and SMZ-L-pro were collected on an Agilent Xcalibur diffractometer

CCD using a graphite monochrome Mo-Kα (λ = 0.71073 Å) at 293 K for CLX-L-pro and

193K for SMZ-L-pro. FC-L-pro was measured on an Agilent Xcalibur diffractometer CCD

using a graphite monochrome Cu-Kα (λ = 1.54184 Å) at 293 K. The collected data was

subjected to absorption corrections using the multi-scan method. The diffraction data

reduction was performed using the CrysAlisPro software (CrysAlis171. NET, Version

1.71.36.32).

The structures of the four cocrystals were solved by direct methods and refined on F2 by

full-matrix least squares using SHELXTL-2014.[18] All non-hydrogen atoms were refined with

anisotropic thermal parameters. The positions of hydrogen atoms associated with carbon

atoms were placed geometrically. The active hydrogen atoms on the O/N−H groups of all

structures were located from the difference Fourier maps with the O/N−H distance restrained

to 0.82/0.86 Å and thermal parameters constrained to Uiso(H) = 1.2Ueq(O/N). For form

CLX-L-pro, the CF3 functional group displayed the positional disorder with the relative ratio

of 0.65/0.35, two proline rings displayed positional disorder with the relative ratio of

0.80/0.20 and 0.63/0.37 refined for the two disordered components. Crystallographic data and

structural refinements for CNX-L-pro, FC-L-pro, CLX-L-pro, and SMZ-L-pro are

summarized in Table S4. Hydrogen bonding distances and angles for CNX-L-pro, FC-L-pro,

CLX-L-pro, and SMZ-L-pro are summarized in Table S5.

Powder X-ray diffraction (powder XRD)

Powder XRD of all the samples were recorded on a Bruker D8 Advance X-ray powder

diffractometer (Bruker AXS, Karlsruhe, Germany) equipped with a LynxEye detector (Cu Kα

radiation). The tube current and voltage of the generator were set to 40 mA and 40 kV,

respectively. The data were recorded over the 2θ range from 3° to 40° scanning with a step

size of 0.0194° at ambient temperature. For CNX-L-pro, CLX-L-pro, SMZ-L-pro and FC-L-

pro, comparisons of the experimental and simulated PXRD patterns are given in the Fig.

S1−S4.

S10

Table S4. Crystallographic data for new obtained cocrystals of L-pro.

Crystal data CNX-L-pro (1:1) FC-L-pro (1:1) CLX-L-pro (1:2) SMZ-L-pro (1:1)

Formula C18H20ClN3O4 C9H13FN4O3 C27H32F3N5O6S C14H19N5O4S2

Formula weight 377.82 244.23 611.63 385.46

Temperature/K 120(2) 293(2) 293(2) 193(2)

Crystal system Orthorhombic Triclinic Orthorhombic Monoclinic

Space group P212121 P1 P212121 P21

a/Å 5.7789(3) 5.5932(3) 9.5641(7) 11.1850(9)

b/Å 12.3293(7) 6.0945(4) 20.0364(10) 8.9191(9)

c/Å 24.9401(14) 16.8563(8) 30.4887(17) 17.2838(15)

α/° 90 97.308(4) 90 90

β/° 90 94.713(4) 90 96.393(9)

γ/° 90 107.291(5) 90 90

V/Å3 1776.98(17) 539.79(5) 5842.6(6) 1713.5(3)

Z 4 2 8 4

ρcalc/(g·cm−3) 1.412 1.503 1.391 1.494

μ (Mo−Kα)/mm−1 0.245 1.082 0.179 0.342

F (000) 792 256 2560 808

total reflections 42221 5933 28262 8982

unique reflections 4100(Rint = 0.0712)

3167(Rint = 0.0215)

10336(Rint = 0.0734)

5096(Rint = 0.0524)

no. observations 3404 3080 6707 3522

no. parameters 236 339 796 456

R1[I > 2σ(I)]/R1a 0.0361/0.1040 0.0417/0.0426 0.0657/0.1115 0.0405/0.0541

wR2[I > 2σ(I)]/wR2b 0.0559/0.1268 0.1117/0.1136 0.1271/0.1437 0.1099/0.1206

cGOF 0.933 1.047 1.009 1.025

Δρmax/Δρmin (e Å−3) 0.180/-0.271 0.356/-0.302 0.412/-0.317 0.416/-0.371

Flack parameter −0.01(3) 0.02(11) −0.07(13) −0.05(17)

CCDC 1850498 1850499 1850500 1850501aR1 =Σ||Fo| − |Fc||/Σ|Fo|. bwR2= [Σw(Fo

2−Fc2)2/ ΣwFo

2]1/2. cGOF = [Σw((Fo2 − Fc

2)2)/(n − p)]1/2, where n = number of reflections and p = total number of parameters refined.

S11

Table S5 Hydrogen bonds for new obtained cocrystals of L-pro.

D—H···A D—H/Å H···A/Å D···A/Å D—H···A/º Symmetry code

CNX-L-pro O1—H1···O3 0.84 1.74 2.568(3) 170.4

N2—H2A···O2 0.88 1.94 2.676(3) 140.4

N3—H3···O4 0.91 2.00 2.800(3) 145.4 x−1/2, −y+1/2, −z

N3—H3A···O3 0.91 1.82 2.719(3) 167.8 x−1, y, z

FC-L-pro N3—H3B···F1 0.77(5) 2.46(4) 2.762(3) 105(4)

N6—H6B···F2 0.94(5) 2.45(4) 2.767(4) 100(3)

N7—H7A···O4 0.91(4) 2.21(4) 2.650(3) 109(3)

N8—H8B···O6 0.82(5) 2.20(4) 2.657(4) 115(4)

N1—H1A···N5 0.88 1.89 2.762(3) 172.5 x, y+1, z

N3—H3A···O2 0.93(4) 2.05(4) 2.978(3) 173(3) x+1, y, z

N3—H3B···O3 0.77(5) 2.18(5) 2.936(4) 171(4) x, y, z−1

N4—H4A···N2 0.79 1.98 2.759(3) 164.8 x−1, y, z

N6—H6A···O1 0.86(4) 2.10(5) 2.962(4) 176(4) x, y−1, z

N6—H6B···O5 0.94(5) 2.23(5) 3.070(4) 149(4) x+1, y, z

N7—H7A···O6 0.91(4) 2.02(4) 2.862(4) 154(3)

N7—H7B···O3 0.88(5) 1.91(4) 2.753(3) 160(4) x−1, y, z

N7—H7B···O4 0.88(4) 2.45(4) 3.173(4) 139(3) x−1, y, z

N8—H8A···O5 0.78(6) 1.99(6) 2.749(3) 164(5) x+1, y, z

N8—H8B···O4 0.82(5) 2.06(4) 2.755(4) 142(4) x, y, z-1

CLX-L-pro N1—H1B···O12 0.86(5) 2.17(6) 3.024(8) 173(4)

N4—H4A···O1 0.86 2.34 2.841(7) 117.4

N4—H4B···O8 0.86 2.02 2.838(7) 158.4

N7—H7B···O5 0.84 2.07 2.664(6) 128.1

N7—H7C···O7 0.86 1.91 2.746(6) 163.1

N8—H8B···O7 0.86 2.28 2.725(6) 112.1

N9—H9B··· O8 0.83 2.17 2.859(6) 140.6

N9—H9B···O10 0.83 2.13 2.644(6) 119.8

N10—H10B···O9 0.92 2.39 3.005(7) 124.6

N10—H10B···O10 0.92 1.9 2.811(6) 174.1

N10—H10C···O12 0.93 2.25 2.716(6) 110.4

N1—H1A···O4 1.01(7) 1.94(7) 2.937(8) 168(5) x−1, y, z

N7—H7B···O6 0.84 2.28 2.868(6) 127.1 x−1/2, −y+1/2, −z+1

N9—H9C···O6 0.93 1.75 2.683(6) 173.7 x−1/2, −y+1/2, −z+1

N8—H8B···O9 0.86 2.02 2.702(7) 135 x+1, y, z

N8—H8C···O11 0.85 1.89 2.727(6) 171.6 x+1/2, −y+3/2, −z+1

S12

N10—H10C···O11 0.93 2.08 2.833(6) 137.3 x−1/2, −y+3/2, −z+1

SMZ-L-pro N1—H1A···O5 0.84 2.01 2.847(10) 171.5

N1—H1B···O2 0.96 2.04 2.987(9) 166.1 −x+1, y+1/2, −z+2

N3—H3A···O8 0.88(3) 1.88(3) 2.749(9) 166(8)

N5—H5A···O7 0.81 2.14 2.938(9) 169.3

N5—H5B···O4 0.81 2.23 2.996(9) 156.8 −x+2, y−1/2, −z+1

N7—H7A···O6 0.76 2.02 2.729(9) 156.7

N9—H9D···O6 0.91 2.06 2.893(10) 152.2 −x+2, y−1/2, −z+2

N9—H9E···O3 0.91 2.17 2.987(8) 148.9 −x+2, y−1/2, −z+2

N9—H9E···N6 0.91 2.41 3.058(9) 128.5 −x+2, y−1/2, −z+2

N10—H10A···O8 0.91 1.86 2.767(9) 179.5 −x+1, y+1/2, −z+1

N10—H10B···O1 0.91 2.43 3.161(8) 137.2 −x+1, y+1/2, −z+1

N10—H10B···N2 0.91 2.56 3.055(9) 115.2 −x+1, y+1/2, −z+1

5 10 15 20 25 30 35 402 (degree)

CNX-L-pro simulated CNX-L-pro L-pro CNX form I

Fig. S1 The PXRD patterns of CNX-L-pro and starting materials.

S13

5 10 15 20 25 30 35 40

FC-L-pro simulated FC-L-pro L-pro FC

2 (degree)

Fig. S2 The PXRD patterns of FC-L-pro and starting materials.

5 10 15 20 25 30 35 40

2 (degree)

CLX-L-pro simulated CLX-L-pro L-Pro CLX

Fig. S3 The PXRD patterns of CLX-L-pro and starting materials.

S14

5 10 15 20 25 30 35 40

2 (degree)

SMZ-L-pro simulated SMZ-L-pro L-pro SMZ

Fig. S4 The PXRD patterns of SMZ-L-pro and starting materials.

Table S6 CSD-refcodes of cocrystals with N—H···–OOC synthon.a

Search motif Refcodes of hits

NH2···–OOC(n=19)

BEJNAI, CIDBOH, PAVXIV, COKTEC,b WECXAF, WECXEJ, UFOQEN, DADMIH, WETHOV,

YEPJEL, VETVUM, PIRXOF,cNAQPON, DAYREA03/DAYREA06, DUMJEA10,c

HUZVUT, REGKUK, PAQMECacyclic-NH···–OOC

(n=7)WUSTAH, DUCMAQ, HACKII, HACKOO,

HACKUU, DUKJUP, CUKPUUc

cyclic-NH···–OOC (n=8)

ALIWEZ, UPIGOR, NOBYAE, WETJEN, WUYROX, CUKPUU,c DUMJEA10,c PIRXOFc

a. Interaction between two electroneutral molecules and NH group is not charged.b. This structure was not used in Fig. 6 for the hydrogen bond angle < 120º.c. Structures holding two kinds of NH···–OOC interactions.

S15

Fig. S5 Electrostatic potential surfaces (in kJ mol-1) of CNX molecules using different

starting conformations (extracted from structures of Form I-IV, respectively).

S16

Table S7 The MEPmax values (in kJ mol-1) of COOH, Ph-OH, and NH, NH2 functional groups

in cocrystals of L-pro.

API H-bond donor MEPmax (kJ mol-1)

Chr 2 Ph-OH 290.8, 63.3

Gen 3 Ph-OH 300.8, 280.3, 71.2

Kae 4 Ph-OH 304.4, 295.7, 172.8, 91.0

Lut 4 Ph-OH 304.6, 299.4, 299.3, 57.2

Que 5 Ph-OH 319.8, 303.2, 221.8, 168.1, 90.2

Rsv 3 Ph-OH 275.7, 275.5, 275.1

Nap COOH 250.9

Flu COOH 261.6

Dfa COOH; NH 273.6; 68.5

CNX COOH; NH 286.2; 54.0

Apr NH 211.7

Rlz NH2 251.4, 225.4

CLX NH2 242.6, 240.5

SMZ NH2; NH 220.3, 219.5; 246.6

FC NH2; NH 238.9, 216.7; 235.1

The values in bold font indicate the corresponding H-bond donor in supramolecular synthon O—H···–OOC or N—H···–OOC of cocrystals.

S17

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