Energetics of Glycine Cocrystal or Salt Formation with Two

Subscriber access provided by BUFFALO STATE

Article

Energetics of Glycine Co-crystal or Salt Formation with Two Regioisomers: Fumaric acid and Maleic acid António O. L. Évora, Carlos E. S. Bernardes, M. Fátima M. da Piedade, António C. L. Conceição, and Manuel E. Minas da Piedade Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.9b00379 • Publication Date (Web): 29 Jul 2019 Downloaded from pubs.acs.org on July 31, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Crystal Growth & Design

Energetics

of

Glycine

Co-crystal

or

Salt

Formation with Two Regioisomers: Fumaric acid and Maleic acid António O. L. Évora,a Carlos E. S. Bernardes,a M. Fátima M. Piedade,a,b António C. L. Conceição,b Manuel E. Minas da Piedadea,* a

Centro de Química e Bioquímica e Centro de Química Estrutural, Faculdade de Ciências

Universidade de Lisboa, Campo Grande, 1749-016 Lisboa, Portugal; E-mail: [email protected]. b

Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa,1049-

001 Lisboa, Portugal.

*Corresponding author. Tel. +351-21-7500866; Fax +351-21-7500088. E-mail address: [email protected] (M. E. Minas da Piedade)

RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the journal that you are submitting your paper to)

1 ACS Paragon Plus Environment

Crystal Growth & Design 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 44

Abstract

Multicomponent crystals have received significant attention in recent years, given their considerable potential to develop new products or improve the properties of known ones. Many studies have examined the synthesis and structure of multicomponent (mostly binary) crystals. The thermodynamic aspects related with the driving force for their formation and stability are, however, still relatively unexplored. This work describes a structure-energetics study of binary crystals consisting of glycine (Gly) and fumaric acid (FA) or maleic acid (MA), two regioisomers with different proton transfer ability. Single crystal X-ray diffraction experiments showed that the mechanochemically synthesized materials corresponded to a new FA:Gly2 co-crystal and a MA:Gly salt that had been previously prepared by crystallization from solution. A packing analysis further suggested that the stoichiometry difference (1:2 vs 1:1) is possibly related with differences in hydrogen bonding ability between FA and MA. Calorimetric and solubility measurements indicated that: (i) The two binary crystals are stable relative to decomposition into their precursors under ambient conditions (298.15 K; 1 bar), since the process is endergonic (  r Gmo > 0 ) in both cases. (ii) The stability is of enthalpic nature because  r H mo > 0 and  r H mo  T  r S mo . (iii) The formation of a salt, rather than a co-crystal, does not bring any notable stability advantage, since the obtained  r Gmo for MA:Gly exceeds that found for FA:Gly2 by 1.0 kJmol-1 only. (iv) The similarity appears to be originated by an enthalpy-entropy compensation effect: the  r H mo contribution (reflecting lattice enthalpy differences between the binary crystals and their components), is approximately twice as large for MA:Gly than for FA:Gly2, but the difference is balanced, to a considerable extent, by a larger and opposing T  r S mo contribution. (v) The number 2 ACS Paragon Plus Environment

Page 3 of 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


of classical hydrogen bonds established by a FA or MA molecule with Gly does not seem to be a reliable predictor of stability, as six of these bonds are present in FA:Gly2 and only four in MA:Gly. (vi) Finally, the results here obtained show that the formation of a binary crystal is not necessarily advantageous in terms of solubility enhancement. Indeed, while the solubility of FA from FA:Gly2 was found to be 4 times larger than that of pure FA, no analogous benefit was observed for the MA:Gly salt, which exhibited a 3 times lower MA solubility when compared with pure MA.

KEYWORDS: multicomponent crystal, co-crystal; organic salt, X-ray diffraction thermodynamics, calorimetry, solubility, DSC, TG.

BRIEFS (WORD Style “BH_Briefs”).



Page 4 of 44

Introduction

Multicomponent crystals, have attracted considerable interest in recent years as a means to tune the properties of crystalline products without changing the molecule of interest. This strategy has been particularly useful, for example, to improve the solubility of active pharmaceutical ingredients (APIs) or food additives.1,2 Another relevant aspect is the number of opportunities created in terms of possible new patents and patent “evergreening”.3 Two prevalent types of multicomponent organic crystals are binary salts and binary cocrystals, which differ by the fact that two counterions or two neutral molecules are present in the crystal lattice, respectively. They can be prepared by a variety of methods, including crystallization from melt or from solution, and solid state grinding.4 Different preparation methods can, however, lead to different products, even if starting materials from identical batches are used. This happens because the non-equilibrium pathways associated with the synthetic processes depend on a complex interplay of kinetic and thermodynamic factors that can vary with the experimental conditions, and are difficult to control in practice. It is also possible that, in some cases, the obtained products are metastable relative to their precursors. The assessment of the thermodynamic stability of a specific binary crystal system, therefore, becomes a significant issue if applications are in view (e.g. use as an active pharmaceutical ingredient). The subject has been theoretically investigated for large sets of binary (and also some ternary) co-crystals with different stoichiometries, and the results suggest that, based on lattice energy considerations alone, multicomponent forms are normally stabilized relative to their individual components, i.e. their lattice energy exceeds the combined lattice energies of the precursors.5-7 A higher lattice energy does not, however, necessarily imply higher stability. Indeed, based on an analogy with the “bond


Page 5 of 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


energy concept”,8 the thermodynamic stability of a AxBy(cr) species relative to the A(cr) and B(cr) precursors can be quantified by considering the energetics of the process:

AaBb(cr)  aA(cr) + bB(cr)

(1)

According to classical thermodynamics,9 for reaction 1 to be unfavorable the corresponding o standard molar Gibbs energy,  r Gm , should be positive,  r Gm > 0. The stability of AaBb(cr)

o

o o relative to reaction 1 will, therefore, increase as  r Gm becomes more positive. The value of  r Gm

includes, however, enthalpic (  r H m ) and entropic (  r Sm ) contributions: o

o

 r Gmo =  r H mo  T  r Smo

(2)

and only the enthalpic part reflects lattice energy changes. The discussion of stability is, therefore, incomplete without considering the entropy contribution which, in some cases, can be the determinant factor, as showcased by a recent work on a celecoxib:nicotinamide co-crystal.10 Few experimental studies have been reported on the energetics of organic co-crystals or salts, and even fewer exist where stability issues have been discussed in terms of Gibbs energy and/or both its enthalpic and entropic contributions. Besides the already mentioned celecoxib:nicotinamide

system,10

hydroquinone:quinhydrone,11 theophylline:salicylic

acid,14

representative

examples

carbamazepine:saccharin,12 theophylline:glutaric

include

the

theophylline:oxalic

acid,15

co-crystals acid,13

bicalutamide:benzamide,16



bicalutamide:salicylamide,16

and

the

salts

Page 6 of 44

arbidol+:benzoate,17

arbidol+:salicylate,17

salinazid+:oxalate,18 and salinazid+:acesulfame.18 The present work describes a structure-energetics study of binary crystals consisting of glycine (Gly) and two regioisomers with different proton transfer ability (Figure 1): fumaric acid (FA) and maleic acid (MA). Both these acids have been widely used in the pharmaceutical industry either as co-formers in the preparation of pharmaceutical salts and co-crystals1 or, in the case of fumaric acid and some of its derivatives, as APIs themselves for treatment of human conditions such as psoriasis19

20

and multiple sclerosis.19,21,22 Natural α-amino acids have also received

considerable attention as pharmaceutical co-formers since they are relatively cheap and belong to the FDA generally recognized as safe (GRAS) category of substances. A number of binary crystals of MA and FA with aminoacids have been prepared, mainly driven by questions such as of how biomolecular homochirality evolved from a prebiotic environment,23 the preparation of new materials for second-order nonlinear optical (NLO) applications,24-26 the importance of non-covalent interactions in the aggregation and interaction patterns of biological molecules,27-30 or the ionization states and main connectivities of the supramolecular synthons that, from a crystal engineering perspective, sustain the crystal

O HO

OH

HO

O O

OH O

(MA)

(FA)

Figure 1. Molecular structures of maleic acid, MA, (2Z)-but-2-enedioic acid, CAS: 110-16-7 and fumaric acid, FA, (2E)-but-2-enedioic acid, CAS: 110-17-8. 6 ACS Paragon Plus Environment

Page 7 of 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


structures.31-39 The available data, which by large refers to materials obtained through crystallization from water, indicates that amino acids show a strong tendency to give salts with MA and co-crystals with FA, where they adopt a zwitterionic form. This tendency seems to be difficult to predict from commonly used pKa rules,40-42 a feature that was confirmed here. The combination of structural, calorimetric, and solubility measurements performed in this work also allowed to examine questions such as: Are the obtained binary crystals of FA and MA with glycine stable relative to decomposition into their precursors? Is the stability of enthalpic nature, entropic nature, or both? How important is the crystal lattice “strength” (as measured by the lattice enthalpy) to that stability? Is there a clear thermodynamic stability advantage in the formation of a salt rather than a co-crystal, when proton transfer between the two co-formers is possible? Is the number of classical hydrogen bonds established by the co-formers a reliable predictor of stability? Finally, the present results highlighted the fact that the formation of a binary crystal is not necessarily an advantageous strategy to enhance solubility.

Materials and Methods

Materials. Maleic acid (Acros, 99%) was used as received. Elemental analysis for C4H4O4: expected C 41.39%, H 3.47%; found C 41.230.30%, H 3.420.10%. The powder pattern was indexed as monoclinic, space group P21/c, a = 7.131±0.013 Å, b = 10.110±0.005 Å, c = 7.628±0.014 Å, β = 119.25±0.14º. This indicated that the sample corresponded to form I maleic acid (Refcode: MALIAC14, monoclinic, P21/c, a = 7.15110.0008 Å, b = 10.11070.0011 Å, c = 7.6400.0010 Å, β = 119.4050.008º).43,44 The fumaric acid starting material was obtained by 7 ACS Paragon Plus Environment


Page 8 of 44

recrystallization of a commercial sample (Acros, 99%) from water. PXRD showed that prior to recrystallization a mixture of phases consisting of the -form and a small amount of -form was present. After recrystallization only the -form could be detected. Elemental analysis for C4H4O4: expected C 41.39%, H 3.47%; found C 41.260.30%, H 3.470.10%. Indexation of the corresponding PXRD pattern (monoclinic, P21/c, a = 7.5830.0173 Å, b = 15.0200.007 Å, c = 6.6500.153 Å, β = 111.32±1.91º) confirmed that the recrystallized sample corresponded to polymorph α (Refcode: FUMAAC, monoclinic, P21/c, a = 7.619 Å, b = 15.014 Å, c = 6.686 Å, β = 112.0º).44,45 -Glycine was prepared by slurring a sample consisting of the  and  forms (Amaresco, 99%), in water, at 296 K, during 48 h. Elemental analysis for C2H5NO2: expected C 32.00%, H 6.71%, N 18.66%; found C 32.11%, H 6.74%, N 18.33%. The powder pattern was indexed as monoclinic, P21/n, a = 5.100.01 Å, b = 11.940.01 Å, c = 5.460.01 Å, β = 111.67025º, in agreement with the single crystal X-ray diffraction (SCXRD) results reported for

-glycine (Refcode: GLYCIN02, P21/n, a = 5.10200.0008 Å, b = 11.97090.0017 Å, c = 5.45750.0015 Å, β = 111.700.02º).44,46 -Glycine was prepared in a similar way from a sample containing the  and γ forms (Acros, 99%). Elemental analysis for C2H5NO2: expected C 32.00%, H 6.71%, N 18.66%; found C 32.010.30%, H 6.670.10%, N 18.340.30%. The indexation of the powder pattern led to space group P31, a = b = 7.0250.011 Å, c = 5.4770.010 Å, γ = 120.0º, in good agreement with previously reported SCXRD results for -glycine (Refcode GLYCIN18, P31, a = b = 7.0370.0017 Å, c = 5.4780.0015 Å, γ = 120.00.02º).44,47 The NaOH (0.1 moldm-3) and HCl (0.1 moldm-3) solutions used in the solubility measurements for quantification of dissolved FA, MA, and Gly by acid-base titration, were prepared by dilution of certified concentrates from Fisher Chemical (1 moldm-3) and Panreac (1


Page 9 of 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


moldm-3), respectively. The dilutions were made with water from a Milli-Q® Type 1 Ultrapure Water system. Synthesis of FA:Gly2. The 1:2 co-crystal of fumaric acid and glycine was obtained by mechanochemistry, using a Retsch MM400 mill. Typically, FA (203 mg, 1.75 mmol) and Gly (262 mg, 3.5 mmol) were ground for 45 min, at 30 Hz frequency, inside a 10 cm3 stainless steel jar containing two 7 mm diameter stainless steel balls. The experiments were carried out with the addition of 10 μL of water. The co-crystal could be obtained from either - or -glycine. Elemental analysis for C8H14N2O8: expected C 36.10%, H 5.30%, N 10.52%; found C 36.140.30%, H 5.310.10%, N 10.250.30% (starting from -Gly); C 36.180.30%, H 5.290.10%, N 10.300.30% (starting from -Gly). The indexation of the powder patterns led to: orthorhombic, space group Pbca, a = 9.495±0.008 Å, b = 8.061±0.004 Å, c = 14.938±0.006 Å (-Gly as reactant) and a = 9.506±0.006 Å, b = 8.073±0.003 Å, c = 14.939±0.007 Å (-Gly as reactant). Both results are in agreement with the corresponding SCXRD data obtained in this work (see below): orthorhombic, Pbca, a = 9.4914±0.0009 Å,

b = 8.0554±0.0008 Å, c = 14.9145±0.0015 Å. Attempts to prepare a fumaric acid:glycine co-crystal of 1:1 stoichiometry were unsuccessful, as mixtures of FA and FA:Gly2 were always obtained, irrespective of milling time, frequency and presence or absence of water during grinding. FA:Gly2 crystals suitable for SCXRD analysis were obtained as follows. An aqueous suspension of Gly (2.5028 g) and FA (0.6302 g) in water (10 cm-3) was prepared inside a closed 9 ACS Paragon Plus Environment


Page 10 of 44

vial and heated to approximately 343 K, under magnetic stirring, until complete dissolution was achieved. The flask was placed in a thermostated bath at 298 K, for 48 hours, to yield a precipitate from which well-formed FA:Gly2 crystals could be separated. Synthesis of MA:Gly. The glycinium maleate salt, MA:Gly, was obtained by milling equimolar quantities (0.4 mmol) of maleic acid (46.44 mg) and -glycine (30.5 mg) using the same apparatus and conditions described for the FA:Gly2 synthesis. Elemental analysis for C6H9NO6: expected C 37.70%, H 4.75%, N 7.33%; found C 37.700.30%, H 4.460.10%, N 7.120.30%. The powder pattern was indexed as monoclinic, space group C2/c, a = 17.908±0.045 Å, b = 5.687±0.004 Å, c = 17.429±0.042 Å, β = 112.77±0.13º. These values are in agreement with analogous SCXRD data published for MA:Gly (Refcode RENBAN):

C2/c, a = 17.689±0.004 Å, b = 5.6610±0.0011 Å, c = 17.328±0.004 Å, β = 112.30±0.03º.29,44 Attempts to prepare a MA:Gly2 binary crystal by milling MA+Gly mixtures in 1:2 molar proportion (with or without H2O assistance) always led to the formation of the MA:Gly salt with an excess of Gly. Elemental Analysis. C, H, N elemental analyses were made on a Fisons Instruments EA1108 apparatus, with typical maximum accuracy errors of 0.3% for carbon, 0.3% for nitrogen, and 0.1% for hydrogen.


Page 11 of 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Powder X-Ray Diffraction (PXRD). PXRD patterns were collected at 295±2 K, on D8 Advance Bruker or Philips X’Pert PRO X-ray diffractometers operating in the θ-2θ mode. In the first case a LinxEye detector, and a Ni-filtered Cu-Kα (λ = 1.5406 Å) radiation source operated at 40 kV and 40 mA were used. The samples were mounted on a glass sample holder and studied in the 2θ range 7-35º, in 0.02º steps, and with an overall scan time of approximately 15 min. The second apparatus had a PW 3050/60 vertical goniometer, a X’Celerator detector and a Cu Kα radiation source with tube amperage and voltage set to 30 mA and 40 kV, respectively. The diffractograms were recorded in the 2θ range 5-35º, in the continuous mode, with a step size of 0.017 º(2θ) and an acquisition time of 20 s/step. The samples were mounted on an aluminum sample holder. The indexation of the powder patterns was performed using the Checkcell program.48 Mercury 3.10.1 (Build 168220)49 was used to simulate diffraction patterns from published single crystal X-ray diffraction data. Single-crystal X-ray diffraction (SCXRD). Single crystal X-ray diffraction analysis of the FA:Gly2 co-crystal was carried out at 2962 K, on a Bruker AXS-KAPPA APEX II area detector diffractometer, using graphite-monochromated MoK ( = 0.71073 Å) radiation. The crystals were coated with Paratone-N oil and mounted on a Kaptan loop. The temperature scale of the apparatus had been previously calibrated against a standard platinum resistance thermometer (calibrated at an accredited facility in accordance to the International Temperature Scale ITS-90) placed at the same position 11 ACS Paragon Plus Environment


Page 12 of 44

as the crystal. The X-ray generator was operated at 50 kV and 30 mA and the X-ray data collection was monitored with the APEX2 program.50 All data were corrected for Lorentzian, polarization and absorption effects using the SAINT50 and SADABS50 programs. The structures were solved by direct methods with SHELXS-97,51 and refined by full-matrix least-squares on F2 with SHELXLv.2017,52 included in WINGX-Version 1.80.05.53 Non-hydrogen atoms were refined with anisotropic thermal parameters. All hydrogen atoms were located in a Fourier map and their positions and isotropic displacement parameters, Uiso(H), were refined freely. A summary of the crystal data, structure solution, and refinement parameters is given in Table 1. The corresponding crystallographic information (cif) file (see Supporting. Information) was deposited at the Cambridge Crystallographic Data Center (CCDC) with reference number CCDC 1942439. Graphical representations were prepared using Mercury 3.10.1 (Build 168220).49 PLATON54 was used for hydrogen bond interactions.


Page 13 of 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 1 Crystal data and structure refinement parameters for FA:Gly2.a FA:Gly2 1942439 CCDC number 2962 T/K 0.30  0.30  0.25 Crystal size/mm Monoclinic Crystal system Pbca Space group 9.4914(9) a/Å 8.0554(8) b/Å 14.9145(15) c/Å 3 1140.32(19) V/Å 4 Z 1 Z’ -3 1.5510(3) dcalcd/gcm -1 0.140 /mm 560 F(000) 2.731 to 25.968  limits/deg −10  h  11 −9  k  9 Limiting indices −18  l  18 10479 / 1108 (Rint = 0.0511) Reflections collected/unique 99.8% Completeness to ºθ 1108 / 0 / 110 Data / restraints / parameters 2 1.110 GOF on F R1 = 0.0357; wR2 = 0.0862 Final R indices [I > 2(I)] R1 = 0.0417; wR2 = 0.0900 R indices (all data) 6 -3 0.116 and −0.200 Largest diff. peak and hole10 /epm aThe uncertainties given in parenthesis for the unit cell parameters and density correspond to standard deviations for 0.95 confidence level, estimated as described in reference 55.

Thermogravimetry (TG). TG experiments were carried out on a Perkin Elmer TGA7 apparatus. The samples with an initial mass of 6-13 mg were placed in an open platinum crucible and subject to a temperature ramp at 5 Kmin-1, in the range 298-773 K.



Page 14 of 44

The balance chamber was kept under a nitrogen flow (Praxair 5.0) of 38 cm3min-1. The sample purge gas was nitrogen (Praxair 5.0) at a flow rate of 22.5 cm3min-1. The mass scale of the instrument was calibrated with a standard 100 mg weight and the temperature calibration was based on the measurement of the Curie points ( TC ) of alumel alloy (Perkin-Elmer, TC = 427.35 K) and nickel (Perkin-Elmer, 99.99%, TC = 628.45 K) standard reference materials. Differential

Scanning

Calorimetry

(DSC).

Differential

scanning

calorimetry

experiments were performed in the range 298-573 K, on a DSC 7 from Perkin Elmer. The Pyris V. 7.0.0.0110 software package was used for instrument control and data acquisition. The samples with a mass of 2-3 mg were sealed in aluminum pans and weighed in a Mettler XS205 balance (precision of ±10 µg). All experiments were carried out at a heating rate of 5 Kmin-1, under a dynamic nitrogen (Air Liquide N45) atmosphere (30 cm3min-1 flow rate). The temperature and enthalpy scale of the apparatus were calibrated at the same heating rate by using indium (Perkin Elmer, 99.999%, Tfus = 429.75 K,  fus ho = 28.45 J·g-1) and zinc (Perkin-Elmer, 99.999%, Tfus = 692.65 K,  fus ho = 107.5 J·g-1). Solution Calorimetry. Enthalpies of solution in water, at 298.15 K, were measured with a LKB 2277 Thermal Activity Monitor (TAM). A in-house designed 15.0 cm3 stainless steel cell equipped with stirring, dissolution and electrical calibration systems was used.56 Instrument control and data acquisition were performed with the CBCAL 3.0 program.57 In a typical experiment, 4-13 mg of sample, contained in an alumina crucible, was weighted in a Mettler XP2U 14 ACS Paragon Plus Environment

Page 15 of 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


ultra-microbalance (0.1 µg precision) and placed in the sample holder of the calorimetric cell. Approximately 12 g of water or an appropriate aqueous solution were introduced in the cell body and weighed using a Mettler XS 205 balance (10 µg precision). The cell was assembled and transferred to the thermostat unit. The dissolution process was started by dropping the crucible into the solvent after recording a suitable baseline. The corresponding enthalpy change was calculated from:  sol H mo 



M  ( A  Ab ) m

Q Ac

(3) (4)

where m and M represent the mass and molar mass of sample, respectively; A is the area of the curve corresponding to the dissolution process; Ab is the contribution to the measured area due to crucible drop; and  is the energy equivalent of the calorimeter. An average value of Ab was determined by performing several blank experiments where an empty crucible was dropped into the solvent. The energy equivalent of the calorimeter,  , was obtained from a series of electrical calibrations where a potential difference V was applied to a 22  manganin resistance immersed in the calorimetric liquid, causing a current of intensity I to flow during a pre-selected time t. This process led to the dissipation of an amount of heat Q = VIt inside the calorimetric cell, reflected by a measured curve of area Ac . The accuracy of the electrical calibration was found to be better than 0.5% by determining the enthalpy of solution of KCl in water.56 Solubility Measurements. The solubilities of fumaric acid, maleic acid, -glycine, glycine and the binary crystals were obtained as follows. A suspension of FA, MA, -Gly, -



Page 16 of 44

Gly, FA:Gly2 or MA:Gly in 5 cm3 of water was prepared inside a 10 cm3 glass vial closed by a screw cap. The vial, which also contained a magnetic stirring bar, was transferred to a thermostatic bath, whose temperature was controlled at 298.15±0.01 K by a Julabo MB unit and a HAAKE EK20 immersion cooler. After 1 week, stirring was stopped and a sample of the saturated solution (3 cm3) was extracted using a preheated syringe adapted to a Tecnocroma micro filter (hydrophilic;  = 25 mm; pore size = 0.22 m) and a Hamilton 7748-06 stainless steel needle. This aliquot was transferred to a 10 cm3 glass vial, and analyzed for the total concentration of FA or MA and Gly by acid-base titration with 0.1 moldm-3 NaOH. The FA or MA content was further determined by UV-vis spectrophotometry at 210 nm and 206 nm, respectively. The titrations were carried out with a Radiometer Analytical pHC3001-9 combined pH electrode and a previously described set-up and procedure.58 Spectrophotometric measurements were performed on a Shimadzu UV-1800 apparatus equipped with a TCC-240A cell holder connected to a TCC temperature controller. Quartz cells with 1 cm optical path, closed by Teflon lids, were used. Powder X-ray diffraction analysis of the solid materials in contact with solution at the end of the equilibration time showed that MA:Gly dissolved congruently, FA:Gly2 16 ACS Paragon Plus Environment

Page 17 of 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


incongruently (co-crystal and pure α-fumaric acid were present) and that the pure precursors maintained their original phases, namely form I MA, α-FA, α-Gly, and γ-Gly (see Supporting Information).

Results and Discussion

Structure. Single crystal X-ray diffraction experiments carried out at 296±2 K showed that the FA:Gly2 binary crystal obtained in this work corresponds to a co-crystal of 1:2 stoichiometry (Table 1). As illustrated in Figure 2, the FA molecule is non-ionized and the amino acid is in zwitterionic form.

Figure 2. Mercury 3.10.1 (Build 168220)49 diagram of the FA:Gly2 co-crystal. Ellipsoids of the C, N, and O atoms are drawn at 50% probability level.



Page 18 of 44

A packing analysis revealed that the FA molecules do not establish hydrogen-bonds (Hbond) among themselves (Figure 3). They act as H-bond bridges between amino acid (AA) zwitterions, forming (AA)(FA)(AA) motifs within an infinite C22 (12) helicoidal chain (Figure3a). These motifs are sustained by two types of H-bonds: (i) one involving the FA carboxylic OH group (donor) and the Gly COO group (acceptor) corresponding to a distance,

d OHL O = 1.48 Å; (ii) another between the FA carboxylic C=O group (acceptor) and the Gly

 NH3 group (donor), with d NHL O = 1.996 Å. Unlike fumaric acid, the glycine molecules directly interact through H3N+O=C hydrogen bonds ( d NHL O = 1.845 Å), forming C11 (5) chains (Figure 3b).


Page 19 of 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(a)

(b) Figure 3. The two main packing motifs of the FA:Gly2 co-crystal: (a) C22 (12) helicoidal chain sustained by H-bond interactions between alternating non-ionized fumaric acid and zwitterionic glycine molecules; (b) C11 (5) chain sustained by H-bond interactions between glycine molecules.

The main structural features observed for FA:Gly2 are also exhibited in the three published examples of binary crystals composed of FA and amino acids, namely with valine (FA:Val2),23,59 phenylalanine (FA:Phe),23,27 and proline (FA:Pro2).31 Regardless of 19 ACS Paragon Plus Environment


Page 20 of 44

the stoichiometry being 1:1 or 1:2: (i) they all correspond to co-crystals, where FA and AA are in neutral and zwitterionic forms, respectively; (ii) the FA molecules are intercalated between amino acid molecules forming (AA)(FA)(AA) motifs within C22 (12) chains; (iii) the amino acids define C11 (5) chains through mutual H-bond interactions. The reported structure of MA:Gly,29,44 at 293 K, shows that the compound is better described as a [Gly+][MA] salt formed by proton transfer from MA to Gly (Figure 4). The maleic acid molecules exist in mono-anionic form stabilized by an intramolecular C(O)OHOOC hydrogen bond. The amino acid is positively charged with the amino group present as  NH3 and the carboxylic acid unionized as COOH. Analogously to the fumaric acid case, in MA:Gly: (i) the maleic acid molecules are intercalated between amino acid molecules forming (AA)···(MA)···(AA) motifs within C22 (12) chains (Figure 5a) and (ii) the glycine molecules interact with each other forming C11 (5) chains (Figure 5b). The nature of the interactions sustaining both types of chains is, however, different: (i) in the C22 (12) chains MA acts only as H-bond acceptor, interacting with the  NH3 (donor) and COOH (donor) groups of glycine through the


Page 21 of 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Figure 4. Mercury 3.10.1 (Build 168220)49 diagram of the MA:Gly salt.29,44

(a)



Page 22 of 44

(b)

Figure 5. The two main packing motifs of the MA:Gly salt: (a) C22 (12) helicoidal chain sustained by H-bond interactions between alternating maleic acid anion and cationic glycine molecules; (b) C11 (5) chain sustained by H-bond interactions between glycine molecules only.

C=O group (acceptor) of the ionized COO ( d NHL O = 1.992 Å) and unionized COOH ( d OHL O = 1.773 Å) carboxylic groups, respectively. (ii) The C11 (5) chains, consisting of glycine only, are supported by H3N+O=C(OH) hydrogen bonds ( d NHL O = 2.147 Å) involving the protonated Nend and the unionized carboxylic-end of glycine. Furthermore, while in the FA:Gly2 co-crystal each fumaric acid molecule is engaged in six H-bonds to Gly close neighbours, only four of those interactions are established by MA in the MA:Gly salt (Figure 6). It should, nevertheless, be noted that the main features and differences observed in the packings of FA:Gly2 and MA:Gly are in accord with Etter’s rules,60 namely, the preference for firstly the formation of six membered-ring intramolecular rather than intermolecular H-bonds (in MA:Gly) and secondly the establishment of intermolecular H-bonds between the best proton donors and acceptors remaining after intramolecular H-bonds have been established. As observed for FA:Gly2, the main structural features of MA:Gly are also present in known binary crystals of MA with other aminoacids namely:44 alanine (MA:Ala),24,25,28 valine (MA:Val39,43 and MA:Val2),26 leucine (MA:Leu),33 methionine (MA:Met),34 phenylalanine, (MA:Phe),35,36,61,62 serine (MA:Ser),37 threonine (MA:Thr),38 lysine (MA:Lys),30 and histidine 22 ACS Paragon Plus Environment

Page 23 of 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(MA:His,30 and MA2:His).32 Regardless of the stoichiometry: (i) they are all salts. (ii) The MA molecules are intercalated between amino acid molecules forming (AA)(MA)(AA) motifs of

C22 type, most of them corresponding to C22 (12) chains. (iii) In the large majority of cases the amino acids establish mutual H-bond interactions sustaining C11 (5) chains, exceptions being lysine30 and valine,39,43 where C11 (9) and R22 (10) motifs are present, respectively.

(a)

(b)

Figure 6. (a) FAGly hydrogen bonding patterns in FA:Gly2. (b) The analogous pattern and for MA:Gly.

The preference of FA to form co-crystals and of MA to form salts with amino acids seems to be of general scope, since it has been observed in all published cases mentioned above.23-26,28,3039,43,59,61,62

42

This tendency cannot be unequivocally predicted from commonly used pKa rules,40-

albeit a larger proton transfer ability of MA compared to FA might be anticipated given that

pKa1 (MA ) < pKa1 (FA ) . Thus, in the case of the FA+Gly and MA+Gly systems studied here, based on pKa1 (Gly ) = 2.35, pKa1 (FA ) = 3.02, and pKa1 (MA ) = 1.92, at 298 K,63 it can be 23 ACS Paragon Plus Environment


Page 24 of 44

concluded that pKa (FA ) = 0.67 and pKa (MA ) = 0.43. These values approximately fall in the range pKa = 0-2 where there seems to be little correlation between pKa and the tendency for proton transfer between the precursors of a binary crystal.40-42 One of these pKa rules,40 derived from an extensive analysis of CSD structures (but excluding zwitterionic species such as Gly), predicts, for example, that the associations FA+Gly and MA+Gly should both lead to co-crystals with 83% probability and 65% probability, respectively. The prediction is, nevertheless, consistent with the observation that the FA+AA combination is more prone to co-crystal formation than the MA+AA one. Thermal analysis. The results of the TG and DSC experiments on FA:Gly2, MA:Gly, FA, MA, and -Gly are illustrated in Figure 7. The onset temperatures of the mass loss processes detected by TG (Figure 7a) were: 472.90.6 K (FA:Gly2), 432.04.8 K (MA:Gly), 527.81.2 K (FA), 427.82.6 K (MA), and 534.22.0 K (-Gly). Note that the quoted uncertainties correspond to twice the mean deviation of the results of two replicates. The TG behavior observed for -Gly was similar to that of -Gly, both in terms of mass loss onset (530.70.2 K) and curve profile (see Supporting Information). Two steps can be noted in the TG patterns of the binary crystals. Comparison with the curves of the precursors suggests that the first one is due to acid loss and the second one to glycine loss. The main features of the TG results were also captured by the DSC experiments. As can be concluded from Figure 7b, for all materials except maleic acid, fusion is accompanied by thermal decomposition. This was evidenced by the presence of black residues inside the crucibles at the end of the DSC and TG runs. The fusion onset temperatures approximately follow the same order observed in the TG experiments (uncertainties correspond to twice the standard error of n runs ): 24 ACS Paragon Plus Environment

Page 25 of 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


463.11.1 K (FA:Gly2, n = 4), 417.61.3 K (MA:Gly, n = 4), 571.20.7 K (FA, n = 5), 411.30.4 K (MA, n = 5), and 525.00.6 K (-Gly, n = 5). The DSC pattern of -Gly shows a peak with onset at 484.30.9 K (n = 6) corresponding to the well known    transition, followed by fusion of

-Gly at 524.31.6 K (n = 6).

(a)



Page 26 of 44

(b)

Figure 7. Overlay of (a) the TG curves for FA:Gly2, MA:Gly, FA, MA, and -Gly obtained at

β = 5 Kmin-1. (b) The corresponding DSC curves for the same heating rate. Both the TG and DSC experiments show that the decomposition of FA:Gly2 starts 40 K above that of MA:Gly. This correlates well with the fact that the lattice enthalpy of FA:Gly2 obtained in this work is 160 kJmol-1 higher than that of MA:Gly (see section on lattice enthalpy). Indeed, the temperature onset for thermal decomposition is expected to be determined by kinetic rather than thermodynamic aspects, in particular, by the activation energy of the process. The latter should bear a strong relationship with the lattice enthalpy of the binary crystals, which reflects the energetic cost associated with the disruption of their crystal lattices. It should be stressed at this point that, such “kinetic stability” is not necessary related with the thermodynamic stability discussed below.8 Finally, the TG observation that the FA mass loss is initiated before that of Gly, albeit the former undergoes fusion ~50 K above the latter, is not unexpected, given that the vapor pressure of solid FA in the range 490-580 K is considerably higher than that of solid glycine (490 K: 1.3 kPa for FA and 0.12 kPa for Gly; 580 K: 141 kPa for FA and 21 kPa for Gly).64,65 Energetics of MA:Gly and FA:Gly2. Based on the rationale presented in the Introduction, the thermodynamic stability of MA:Gly and FA:Gly2 relative to the corresponding precursors was analyzed by determining the standard molar Gibbs energy (  r Gmo ), enthalpy (  r H mo ), and entropy (  r S mo ) of the reaction:


Page 27 of 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


A:Glyb(cr)  A(cr) + bGly(cr)

(5)

where A represents FA (polymorph  in the product) or MA (polymorph I in the product), Gly refers to  or  -glycine, and b = 1 when A = MA and b = 2 for A = FA. The A:Glyb(cr) species will be stable relative to their precursors if  r Gmo > 0 for reaction 5. According to eq 2 this tendency will be favored by positive  r H mo (endothermic process) and negative T  r Smo contributions. The determination of  r H mo and  r Gmo for reaction 5 relied on calorimetric and solubility measurements, respectively. The corresponding entropy term, T  r Smo , was subsequently derived from eq 2. Note that the calculation of all molar thermodynamic quantities was based on the molar masses M(MA:Gly) = 191.139 gmol-1, M(FA:Gly2) = 266.206 gmol-1, M(FA) = M(MA) = 116.072 gmol-1, and M(Gly) = 75.067 gmol-1, obtained from the 2013 standard atomic masses recommended by the IUPAC Commission.66 The assignment of uncertainties according to literature procedures67 is detailed in the Supporting Information. Solution calorimetry. The determination of the enthalpy of reaction 5 will be first discussed for the case where -glycine is formed,  r H mo (5, -Gly). As mentioned above the acid products are either FA(cr, ) or MA(cr, I). The procedure relied on solution calorimetry studies of the following processes:

A:Glyb(cr) + nH2O(l)  (A + bGly + nH2O)(sln)

(6)

A(cr) + nH2O(l)  (A+ nH2O)(sln)

(7a)

Gly(cr, ) +

1 1 n (A+ nH2O)(sln)  ( A + Gly + H2O)(sln) b b b

(7b) 27

ACS Paragon Plus Environment


Gly(cr, ) +

Page 28 of 44

n n H2O(l)  (Gly + H2O)(sln) b b

(8a)

A(cr) + (bGly + nH2O)(sln)  (A + bGly + nH2O)(sln)

(8b)

where n is the amount of substance of water used in the experiments per 1 mol of dissolved solid compound (n  19000 and n  9500 for the FA and MA systems, respectively). From eqs 6, 7a and 7b or 6, 8a and 8b it is possible to conclude that:

 r H mo (5) =  sol H mo (6)   sol H mo (7a)  b  sol H mo (7b)

(9a)

 r H mo (5) =  sol H mo (6)  b  sol H mo (8a)   sol H mo (8b)

(9b)

The obtained enthalpies of the solution processes in eqs 6-8 are summarized in Table 2 (see Supporting Information for details) along with the corresponding enthalpies of reaction 5 calculated from eqs 9a and 9b, which refer to two distinct thermodynamic pathways. The fact that the values of  r H mo (5,  -Gly) obtained for FA:Gly2 and MA:Gly from these two equations are in

Table 2.

Enthalpies of solution and reaction at 298.15 K.a FA:Gly2

MA:Gly

 sol H mo (6)

59.000.20 (5)

42.661.06 (5)

 sol H mo (7a)

26.960.50 (5)

19.470.52 (5)

 sol H mo (7b)

13.210.18 (5)

12.610.54 (5)

 sol H mo (8a)

12.880.36 (11)

12.880.36 (11)


Page 29 of 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


 sol H mo (8b)

26.810.54 (5)

18.170.54 (6)

 sol H mo (11)

14.430.24 (5)

14.430.24 (5)

 r H mo (5, -Gly)

5.60.6b; 6.40.9c;

10.61.3b; 11.61.2c;

5.80.5d

11.10.9d

2.71.0e

9.61.0e

 r H mo (5, -Gly) a

Data in kJ∙mol-1; number of determinations given in parenthesis. b From eq 9a. c From eq 9b. d Weighted mean of results from eqs 9a and 9b. e Calculated from eq 10, by using the  H o (5, r m Gly) values indicated in bold type font. agreement within their combined uncertainty intervals, gives a strong indication that the calorimetric determinations have good internal consistency. The weighted mean68 of both  r H mo (5,  -Gly) values (in bold in Table 2) was, therefore, selected in this work. The enthalpy of

reaction 5 with -Gly as product,  r H mo (5,  -Gly) , was subsequently calculated from (b = 2 for FA and b = 1 for MA):

 r H mo (5, -Gly) =  r H mo (5, -Gly) + b[  sol H mo (8a)   sol H mo (11)]

(10)

where  sol H mo (11) refers to the enthalpy of solution of -Gly in water to give a solution of identical concentration as that for -Gly in process 8a:

Gly(cr, ) +

n n H2O(l)  (Gly + H2O)(sln) b b

(11)

The obtained  r H mo (5,  -Gly) and  sol H mo (11) results are also listed in Table 2. Table 2 shows that reaction 5 is endothermic for MA:Gly and FA:Gly2 regardless of 29 ACS Paragon Plus Environment


Page 30 of 44

glycine being formed as the - or -polymorph. This was also observed when a MA:Gly sample prepared by recrystallization from solution was used in the calorimetric measurements (eqn 6), namely:  r H mo (5, -Gly) = 11.90.8 kJ∙mol-1 and  r H mo (5, -Gly) = 10.40.9 kJ∙mol-1 (see Supporting Information). The fact that these values are slightly more endothermic than those for the mechanochemically produced material (11.10.9 kJ∙mol-1 and 9.61.0 kJ∙mol-1, Table 2) may reflect a slight stability advantage of the MA:Gly salt crystallized from solution. This is consistent with what should be expected, given that the high mechanical impact associated with mecanochemical synthesis tends to yield less crystalline products than crystallization from solution. Such conclusion is, however, impossible to ascertain because the enthalpic difference between the two samples is covered by the uncertainties of the results. Overall, the calorimetric results indicate that from an enthalpic point of view MA:Gly and FA:Gly2 are stable towards decomposition into their precursors and that this conclusion is unlikely to be changed if samples obtained by mechanochemistry or crystallization from solution are considered. The formation of -Gly as product makes, nevertheless, the FA:Gly2 and MA:Gly decompositions less endothermic. This is not unexpected given that the enthalpy of the Gly(cr )  Gly(cr ) transition is endothermic,  trs H mo (   ) =  sol H mo (11)   sol H mo (8a) = 1.550.43 kJ∙mol-1, indicating that on enthalpic grounds -Gly is more stable than -Gly at 298.15 K. The enthalpy of    transition has been reported to significantly vary with the size/morphology and thermal/mechanical histories of the crystals.69 The result here obtained,  trs H mo (   ) = 1.550.43 kJ∙mol-1 is within the 0.2-1.8 kJ∙mol-1 range of published values.69,70 It may finally be noted that, a simpler thermodynamic scheme, based on the determination of enthalpies of solution of stoichiometric FA+2Gly or MA+Gly physical mixtures, instead of the


Page 31 of 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


processes described by eqns 7a-8b, could, in principle, have been used. There are, however, reasons to prefer the more laborious methodology followed here: (i) Firstly, given the very small amounts of sample used in the calorimetric runs (4-13 mg), it is virtually impossible to accurately weight into the crucible the appropriate amounts of FA, MA or Gly, to warrant that physical mixtures of FA+ 2Gly or MA+Gly stoichiometries were indeed dissolved in each experiment. (ii) Even if stock mixtures were prepared, it would be very difficult to ensure that they were sufficiently homogeneous to avoid stoichiometry fluctuations between the samples used in individual calorimetric runs. (iii) Finally, and perhaps most importantly, the scheme based on physical mixtures would not allow the check to the internal consistency of the results (see above) provided by the method followed in the present work. Solubility measurements. The Gibbs energies of reaction 5,  r Gmo (5,  -Gly) or  r Gmo (5,  -Gly) , at 298.150.10 K, were obtained by studying the following solubility equilibria:

FA:Gly2(cr) ƒ

(1-a)FA(sln) + 2Gly(sln) + aFA(cr, )

(12a)

MA:Gly(cr) ƒ

MA(sln) + Gly(sln)

(12b)

FA(cr, ) ƒ

FA(sln)

(13a)

MA(cr, I) ƒ

MA(sln)

(13b)

Gly(cr, ) ƒ

Gly(sln)

(14a)

Gly(cr, γ) ƒ

Gly(sln)

(14b)

A mass balance based on the masses of solid compounds and water used in the experiments, and on the FA, MA and Gly solution contents determined by potentiometric titration and



spectrophotometry,

showed

that

MA:Gly(cr)

dissolved

Page 32 of 44

congruently

and

FA:Gly2(cr)

incongruently. As mentioned in Materials and Methods (Solubility) section, this was further confirmed by PXRD analysis which showed that, in the latter case, the solid material in equilibrium with the solution contained both the co-crystal and pure α-fumaric acid while only MA:Gly(cr) was present in the case of the maleic acid system (see Supporting Information). The stoichiometric coefficient of the undissolved FA(cr, α) present in the equilibrium 12a was obtained as a  (nGly  2nFA ) / nGly , where nGly and nFA are the amounts of substance of Gly and FA,

respectively, present in solution. The values of  r Gmo (5,  -Gly) or  r Gmo (5,  -Gly) are given in Table 3. They were obtained from eq 15 whose derivation and underlying approximations are detailed in the Supporting Information:  x  r G (5) =  RTln  Gly   xGly  o m

b

1 a

  xA       xA 

   

(15)

Here xA and xGly represent the molar fractions of FA or MA and Gly, respectively, in equilibrium  are the corresponding molar fractions for the analogous with the binary crystal, and xA and xGly

equilibria with the individual solid compounds. By using the  r Gmo (5,  -Gly) and  r Gmo (5,  -Gly)

Table 3. Results of the solubility measurements on FA:Gly2, MA:Gly, and their a components. FA:Gly2

MA:Gly


Page 33 of 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


xA

(3.380.04)10-3 (5)

(2.250.12)10-2 (4)

xGly

(1.850.02)10-2 (5)

(2.150.06)10-2 (4)

xA

(9.140.64)10-4 (5)

(7.440.41)10-2 (5)

 (-form) xGly

(5.710.04)10-2 (4)

(5.710.04)10-2 (4)

 (-form) xGly

(4.730.12)10-2 (6)

(4.730.12)10-2 (6)

a

0.6350.006

0b

b

2

1

 r Gmo (5, -Gly)/kJ∙mol-1

4.40.3

5.40.4

 r Gmo (5, -Gly)/kJ∙mol-1

3.50.4

4.90.4

a

The number of determinations is given in parenthesis. b The PXRD analysis of the solid in equilibrium with the solution showed no evidence of pure MA(cr) or Gly(cr) and the mean a value given by the analysis of the solution was a = (0.050.06). results in Table 3, and the corresponding  r H mo (5, -Gly) and  r H mo (5, -Gly) in Table 2 it is possible to conclude from eq 2 that T  r S mo (5, -Gly) = 1.40.6 kJ∙mol-1, T  r S mo (5, Gly) = 0.81.1 kJ∙mol-1 for FA:Gly2, and T  r S mo (5) = 5.71.0 kJ∙mol-1, T  r S mo (6) = 4.71.1 kJ∙mol-1 for MA:Gly. Figure 8 summarizes the overall thermodynamic results obtained from the solubility and calorimetric measurements. The illustration clearly indicates that the dissociation of the FA:Gly2 and MA:Gly binary crystals, at 298.15 K, is always endergonic (  r Gmo > 0). It can therefore be concluded that, on thermodynamic grounds, these two binary crystals are stable relative to



Page 34 of 44

Figure 8. Comparison of the Gibbs energies, enthalpies and entropies of reaction 5 for FA:Gly2 and MA:Gly (blue solid lines -Gly as product; red dash lines, -Gly as product). decomposition into their individual precursors, regardless of glycine being formed as the - or polymorph. It can also be concluded that the stabilization effect is, in both cases, of enthalpic nature since the dissociation processes are both endothermic (  r H mo >0) and  r H mo  T  r S mo . As expected the process becomes less unfavorable (less endergonic and endothermic) if the more stable -Gly polymorph is produced instead of the -Gly form. Lattice enthalpies. The stability of crystalline materials is often discussed based on the lattice enthalpy (or energy) concept, with the lattice enthalpy corresponding to the standard molar enthalpy change,  Lat H mo , associated with the disruption of the crystal lattice to originate the molecular components in the ideal gas state at a given temperature (normally 0 K or 298.15 K).8


Page 35 of 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


The thermodynamic cycle in Scheme I shows that the lattice enthalpies of FA:Gly2 and MA:Gly,  Lat H mo , at 298 K, can be calculated from:

 Lat H mo (A:Glyb) =  r H mo (5) +  sub H mo (A) + b  sub H mo (Gly)

(16)

where A refers to FA or MA,  r H mo (5) is the enthalpy of reaction 5,  sub H mo denotes enthalpy of sublimation, b = 1 when A = MA and b = 2 for A = FA. It should be pointed out that the  sub H mo data available in the literature for FA, MA and Gly have no reference to specific polymorphs. The present analysis will, therefore, arbitrarily assume that glycine corresponds to the -polymorph since it is the phase most often produced in routine crystallization processes and the essential conclusions would be the same if γ-Gly was considered. Thus, based on  r H mo (5, -Gly) = 5.80.5 kJ∙mol-1 for FA:Gly2,  r H mo (5, -Gly) = 11.10.9 kJ∙mol-1 for MA:Gly (Table 2),

A(g) + bGly(g) o LatHm

A:Glyb(cr)

o (5) rHm

o o (Gly) (A) bsubHm subHm

A(cr) + bGly(cr)

Scheme I



Page 36 of 44

 sub H mo (FA) =135.96.3 kJ∙mol-1,71  sub H mo (MA) = 110.02.5 kJ∙mol-1,71 and  sub H mo (Gly) =

136.40.4 kJ∙mol-1,71 it is possible to conclude that  Lat H mo (FA:Gly 2 ) = 414.56.4 kJ∙mol-1 and  Lat H mo (MA:Gly) = 257.52.7 kJ∙mol-1. These results and the  r H mo (5) and  r Gmo (5) data in

Tables 2 and 3 stress the fact that a larger lattice enthalpy does not necessarily imply a larger stability of a binary crystal relative to its decomposition into the precursors. Indeed, when measured in terms of both  r H mo (5) and  r Gmo (5) FA:Gly2 is less stable than MA:Gly, even if the lattice enthalpy of the former is larger by 1577 kJ∙mol-1 than that of the latter. This stresses the fact that the stability of a binary crystal relative to a given decomposition process does not only depend on the energetics of the binary crystal itself but also on those of the products formed. One further point is that any conclusion drawn on the relative stabilities of binary crystals is only valid for a given set of experimental conditions. In the present case, an estimation of  r Gmo (5) in the range 250-500 K, using eq 2 and assuming constant  r H mo (5) and  r S mo (5) contributions, suggests that above 420 K, an inversion in the relative stabilities of FA:Gly2 and MA:Gly occurs i.e. reaction 5 becomes more endergonic for FA:Gly2 than for MA:Gly (see Supporting. Information). Note finally that this does not contradict the statement in the “Thermal analysis” section that the larger


Page 37 of 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


thermal robustness of FA:Gly2 relative to MA:Gly observed in the TG and DSC experiments is most likely of kinetic origin. Indeed, reaction 5 is always predicted to be endergonic for both binary crystals in the temperature domain mentioned above (250-500 K), which encompasses the 432-473 K range where the decomposition onsets of FA:Gly2 and MA:Gly are observed by TG and DSC.

Conclusions

The structural information obtained from single crystal X-ray diffraction indicates that FA:Gly2 is better described as a co-crystal and MA:Gly as a salt. This difference is not unequivocally predictable from commonly used pKa rules.40-42 It seems, however, to be generally valid, since it is consistently observed for all FAa(AA)b and MAa(AA)b (AA = amino acid) structures available in the CSD,44 regardless of the stoichiometry being 1:1, 1:2, or 2:1. Despite some exceptions, there seems also to be a tendency of the FA+AA and MA+AA systems to adopt 1:2 and 1:1 stoichiometries, respectively. These preferences are probably related with the fact that the FA molecule (trans conformation) packs with the two carboxylic ends available for H-bonding with amino acid molecules, while in the case of MA (cis conformation), in accord with Etter’s rules, one of these ends is engaged in intramolecular H-bonding.



Page 38 of 44

The analysis of the energetics FA:Gly2 and MA:Gly indicated that: (i) the two binary crystals are stable relative to decomposition into their precursors, at 298.15 K, irrespective of glycine being formed as the - or -polymorph, i.e.  r Gmo (5) > 0. (ii) The stability is of enthalpic nature since in both cases reaction 5 is endothermic i.e.  r H mo (5) > 0, and  r H mo (5)  T  r S mo (5) . This finding supports the conclusion from a recent theoretical study, that

the stability of binary crystals relative to their precursors is most often controlled by differences in lattice energy.7 (iii) The number of classical hydrogen bonds per FA or MA molecule does not seem to be a reliable predictor of stability because six of these bonds are present in FA:Gly2 and only four in MA:Gly. This is not unexpected given that the contribution from ionic and van der Waals interactions and the presence of the FA, MA and Gly products cannot be ignored when analyzing the energetics of reaction 5. (iv) In the particular case investigated here, the formation of a salt, rather than a co-crystal, does not seem to bring any notable thermodynamic stability advantage since  r Gmo (5) is very similar for MA:Gly and FA:Gly2, particularly when uncertainty intervals are considered (Table 3 and Figure 8). (v) This is not true, however, for the corresponding  r H mo (5) contribution, which is approximately two times larger for MA:Gly than for FA:Gly2 (Table 2 and Figure 8). The larger enthalpic stability of MA:Gly relative to FA:Gly2, that perhaps results from the enhanced 38 ACS Paragon Plus Environment

Page 39 of 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


ionic nature of its crystal lattice relative to those of the precursors is, however, compensated by a larger and opposing T  r S mo contribution, leading to very similar  r Gmo (5) values. This stresses the fact that entropy effects can also play a decisive role in the stabilization of multicomponent crystals, as illustrated by the already mentioned celecoxib:nicotinamide case.10 Finally, the results here obtained also show that the formation of a binary crystal is not necessarily a method of choice to enhance the solubility of a given species. Indeed, while the mole fraction of FA(aq) in equilibrium with FA:Gly2(cr) was found to be 3.7 times larger than that for pure FA(cr), no analogous increase was observed for the MA:Gly salt, which exhibited a 3.3 times lower MA(aq) mole fraction solubility when compared with pure MA(cr).

Acknowledgements. This work was supported by Fundação para a Ciência e a Tecnologia (FCT), Portugal thorough projects PTDC/QUI-OUT/28401/2017 (LISBOA-01-0145FEDER-028401) and PEst-OE/QUI/UI0100/2013, and grants awarded to A. O. Évora (SFRH/BPD/115697/2016) and C. E. S. Bernardes (SFRH/BPD/101505/2014). We also acknowledge COST Action CM1402.

Supporting Information Available: Tables S1-S7 with the indexation of the powder patterns corresponding to various samples mentioned in the text. Figure S1 with a comparison of the DSC and TG patterns obtained for - and -glycine. Detailed results of the solution calorimetry experiments (Tables S8). Description of the thermodynamic framework and results of solubility measurements (Table S9 and Figures S2-S7). Details of the assignment of uncertainties. Temperature dependency of the Gibbs energy of reaction 5 (Table S10 and Figure S8). Details of 39 ACS Paragon Plus Environment


Page 40 of 44

the synthesis, characterization and calorimetric measurements on the MA:Gly salt prepared by crystallization from solution (Tables S11, S12). CIF file with single crystal X-ray diffraction structure of FA:Gly2 at 296 K, deposited at the Cambridge Crystallographic Data Center (CCDC) with reference number 1942439.

References

1. Wouters, J.; Quéré, L. Pharmaceutical Salts and Co-crystals; The Royal Society of Chemistry: Cambridge, 2012. 2. Berry, D. J.; Steed, J. W. Pharmaceutical Cocrystals, Salts and Multicomponent Systems; Intermolecular Interactions and Property Based Design. Adv. Drug Deliver. Rev. 2017, 117, 3-24. 3. Gadade, D. D.; Pekamwar, S. S. Pharmaceutical Cocrystals: Regulatory and Strategic Aspects, Design and Development. Adv. Pharm. Bull. 2016, 6, 479-494. 4. Karimi-Jafari, M.; Padrela, L.; Walker, G. M.; Croker, D. M. Creating Cocrystals: A Review of Pharmaceutical Cocrystal Preparation Routes and Applications. Cryst. Growth Des. 2018, 18, 6370-6387. 5. Issa, N.; Karamertzanis, P. G.; Welch, G. W. A.; Price, S. L. Can the Formation of Pharmaceutical Cocrystals Be Computationally Predicted? I. Comparison of Lattice Energies. Cryst. Growth Des. 2009, 9, 442-453. 6. Gavezzotti, A.; Colombo, V.; Lo Presti, L. Facts and Factors in the Formation and Stability of Binary Crystals. Cryst. Growth Des. 2016, 16, 6095-6104. 7. Taylor, C. R.; Day, G. M. Evaluating the Energetic Driving Force for Cocrystal Formation. Cryst Growth Des. 2018, 18, 892-904. 8. Martinho Simões, J. A.; Minas da Piedade, M. E. Molecular energetics: Condensed Phase Thermochemical Techniques; Oxford University Press: New York, 2008; 182-183. 9. Atkins, P. W.; de Paula, J. Physical Chemistry; 9th ed.; Oxford University Press: Oxford, 2010. 10. Zhang, S. W.; Brunskill, A. P. J.; Schwartz, E.; Sun, S. W. Celecoxib-Nicotinamide Cocrystal Revisited: Can Entropy Control Cocrystal Formation? Cryst. Growth Des. 2017, 17, 2836-2843. 11. Suzuki, K.; Seki, S. Physicochemical Studies of Molecular Compounds .IV. Heats of Solution of Crystalline Quinone, Hydroquinone and Quinidrone into Acetone and Heat of Formation of Crystalline Quinhydrone. Bull. Chem. Soc. Jp. 1953, 26, 372-380. 12. Oliveira, M. A.; Peterson, M. L.; Davey, R. J. Relative Enthalpy of Formation for Co-Crystals of Small Organic Molecules. Cryst. Growth Des. 2011, 11, 449-457. 13. Zhang, S.; Rasmuson, A. C. The Theophylline-Oxalic Acid Co-crystal System: Solid phases, Thermodynamics and Crystallisation. CrystEngComm 2012, 14, 4644-4655. 14. Zhang, S.; Chen, H.; Rasmuson, A. C. Thermodynamics and Crystallization of a TheophyllineSalicylic Acid Cocrystal. CrystEngComm 2015, 17, 4125-4135.


Page 41 of 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


15. Zhang, S.; Rasmuson, A. C. Thermodynamics and Crystallization of the Theophylline-Glutaric Acid Cocrystal. Cryst. Growth Des. 2013, 13, 1153-1161. 16. Surov, A. O.; Solanko, K. A.; Bond, A. D.; Bauer-Brandl, A.; Perlovich, G. L. Cocrystals of the Antiandrogenic Drug Bicalutamide: Screening, Crystal structures, Formation Thermodynamics and Lattice Energies. CrystEngComm 2016, 18, 4818-4829. 17. Surov, A. O.; Manin, A. N.; Churakov, A. V.; Perlovich, G. L. New Solid Forms of the Antiviral Drug Arbidol: Crystal Structures, Thermodynamic Stability, and Solubility. Mol. Pharmaceut. 2015, 12, 4154-4165. 18. Surov, A. O.; Voronin, A. P.; Simagina, A. A.; Churakov, A. V.; Perlovich, G. L. Pharmaceutical Salts of Biologically Active Hydrazone Compound Salinazid: Crystallographic, Solubility, and Thermodynamic Aspects. Cryst. Growth Des. 2016, 16, 2605-2617. 19. Das, R. K.; Brar, S. K.; Verma, M. Recent Advances in the Biomedical Applications of Fumaric Acid and its Ester Derivatives: The Multifaceted Alternative Therapeutics. Pharmacol. Rep. 2016, 68, 404-414. 20. Gottlieb, A. B. Psoriasis: Emerging Therapeutic Strategies. Nat. Rev. Drug Discov. 2005, 4, 1934. 21. Gold, R.; Linker, R. A.; Stangel, M. Fumaric Acid and its Esters: An Emerging Treatment for Multiple Sclerosis with Antioxidative Mechanism of Action. Clin. Immunol. 2012, 142, 44-48. 22. Haghikia, A.; Linker, R.; Gold, R. Fumaric Acid as Therapeutic Agent for Multiple Sclerosis. Nervenarzt 2014, 85, 720-726. 23. Klussmann, M.; Izumi, T.; White, A. J. P.; Armstrong, A.; Blackmond, D. G. Emergence of Solution-Phase Homochirality via Crystal Engineering of Amino Acids. J. Am. Chem. Soc. 2007, 129, 7657-7660. 24. Natarajan, S.; Britto, S. A. M.; Ramachandran, E. Growth, Thermal, Spectroscopic, and Optical Studies of L-Alaninium Maleate, A New Organic Nonlinear Optical Material. Cryst. Growth Des. 2006, 6, 137-140. 25. Dhas, S. A. M. B.; Ramachandran, K.; Natarajan, S. Photoacoustic Studies on the Thermal Properties of the NLO Compound: L-Alaninium maleate. Open Crystallogr. J. 2008, 1, 42-45. 26. Adhikari, S.; Kar, T.; Seth, S. K. Synthesis, Crystal Growth and Characterization of Di-Valine Maleic - A New Nonlinear Optical Material. RSC Adv. 2016, 6, 99139-99148. 27. Alagar, M.; Krishnakumar, R. V.; Rajagopal, K.; Nandhini, M. S.; Natarajan, S. L-Phenylalanine Fumaric Acid. Acta Crystallogr. 2003, E59, o952-o954. 28. Alagar, M.; Krishnakumar, R. V.; Nandhini, M. S.; Natarajan, S. L-Alaninium Maleate. Acta Crystallogr. 2001, E57, o855-o857. 29. Rajagopal, K.; Krishnakumar, R. V.; Mostad, A.; Natarajan, S. Glycinium Maleate. Acta Crystallogr. 2001, E57, o751-o753. 30. Pratap, J. V.; Ravishankar, R.; Vijayan, M. X-Ray Studies on Crystalline Complexes Involving Amino Acids and Peptides. XXXV. Invariance and Variability in Amino Acid Aggregation in the Complexes of Maleic Acid with L-Histidine and L-Lysine. Acta Crystallogr. 2000, B56, 690-696. 31. Tilborg, A.; Leyssens, T.; Norberg, B.; Wouters, J. Structural Study of Prolinium/Fumaric Acid Zwitterionic Cocrystals: Focus on Hydrogen-Bonding Pattern Involving Zwitterionic (Ionic) Heterosynthons. Cryst. Growth Des. 2013, 13, 2373-2389. 32. Fleck, M.; Ghazaryan, V. V.; Bezhanova, L. S.; Atanesyan, A. K.; Petrosyan, A. M. New Crystals of L-Histidine Maleates. J. Mol. Struct. 2013, 1035, 407-415. 33. Arkhipov, S. G.; Rychkov, D. A.; Pugachev, A. M.; Boldyreva, E. V. New Hydrophobic LAmino Acid Salts: Maleates of L-Leucine, L-Isoleucine and L-Norvaline. Acta Crystallogr. 2015, C71, 584-592. 34. Alagar, M.; Nandhini, M. S.; Krishnakumar, R. V.; Natarajan, S. DL-Methioninium Maleate. Acta Crystallogr. 2002, E58, o396-o398. 35. Alagar, M.; Krishnakumar, R. V.; Natarajan, S. L-Phenylalaninium Maleate. Acta Crystallogr. 2001, E57, o968-o970.



Page 42 of 44

36. Alagar, M.; Nandhini, M. S.; Krishnakumar, R. V.; Mostad, A.; Natarajan, S. DLPhenylalaninium Maleate at 123 K. Acta Crystallogr. 2003, E59, o209-o211. 37. Arkhipov, S. G.; Zakharov, B. A.; Boldyreva, E. V. Semi-Maleate Salts of L- and DL-Serinium: The First Example of Chiral and Racemic Serinium Salts with the Same Composition and Stoichiometry. Acta Crystallogr. 2013, C69, 517-521. 38. Rajagopal, K.; Ramachandran, E.; Mostad, A.; Natarajan, S. DL-Threoninium Maleate at 150 K. Acta Crystallogr. 2004, E60, O386-O388. 39. Alagar, M.; Krishnakumar, R. V.; Mostad, A.; Natarajan, S. DL-Valinium Maleate at 150 K. Acta Crystallogr. 2001, E57, o1102-o1104. 40. Cruz-Cabeza, A. J. Acid-Base Crystalline Complexes and the pKa Rule. CrystEngComm 2012, 14, 6362-6365. 41. Childs, S. L.; Stahly, G. P.; Park, A. The Salt-Cocrystal Continuum: The Influence of Crystal Structure on Ionization State. Mol. Pharmaceutics 2007, 4, 323-338. 42. Bhogala, B. R.; Basavoju, S.; Nangia, A. Tape and Layer Structures in Cocrystals of Some Diand Tricarboxylic Acids with 4,4 '-Bipyridines and Isonicotinamide. From Binary to Ternary Cocrystals. CrystEngComm 2005, 7, 551-562. 43. Rychkov, D.; Arkhipov, S.; Boldyreva, E. Structure-Forming Units of Amino Acid Maleates. Case Study of L-Valinium Hydrogen Mmaleate. Acta Crystallogr. 2016, B72, 160-163. 44. Groom, C. R.; Bruno, I. J.; Lightfoot, M. P.; Ward, S. C. The Cambridge Structural Database. Acta Crystallogr. 2016, B72, 171-179. 45. Brown, C. J. Crystal Structure of Fumaric Acid. Acta Crystallogr. 1966, 21, 1-&. 46. Marsh, R. E. A Refinement of the Crystal Structure of Glycine. Acta Crystallogr. 1958, 11, 654663. 47. Shimon, L. J. W.; Lahav, M.; Leiserowitz, L. Stereoselective Etchants for Molecular-Crystals Resolution of Enantiomorphs and Assignment of Absolute Structure of Chiral Molecules and Polar Crystals. New J. Chem. 1986, 10, 723-737. 48. Laugier, J.; Bochu, B. Checkcell; http://www.ccp14.ac.uk/tutorial/Imgp. 49. Macrae, C. F.; Bruno, I. J.; Chisholm, J. A.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Rodriguez-Monge, L.; Taylor, R.; van de Streek, J.; Wood, P. A. Mercury CSD 2.0 - New Features for the Visualization and Investigation of Crystal Structures. J. Appl. Crystallogr. 2008, 41, 466-470. 50. APEX2; Bruker Analytical Systems: Madison, 2005. 51. Sheldrick, G. M. A Short History of SHELX. Acta Crystallogr. 2008, A64, 112-122. 52. Sheldrick, G. M. Crystal Structure Refinement with SHELXL. Acta Crystallogr. 2015, C71, 3-8. 53. Farrugia, L. J. WinGX Suite for Small-Molecule Single-Crystal Crystallography. J. Appl. Cryst. 1999, 32, 837–838. 54. Spek, A. L. Structure Validation in Chemical Crystallography. Acta Crystallogr. 2009, D65, 148155. 55. Sheldrick, G. M. SHELXL-97: Program for the Refinement of Crystal Structure (http://shelx.uniac.gwdg.de/SHELX/); University of Göttingen: Germany, 1997. 56. Bento, R. N.; Rendas, M. A.; Semedo, V. A. R.; Bernardes, C. E. S.; Santos, M. S. C. S.; Diogo, H. P.; Antunes, F.; Minas da Piedade, M. E. The Standard Molar Enthalpy of the Base Catalysed Hydrolysis of Methyl Paraben Revisited. J. Chem. Thermodyn. 2016, 103, 176-180. 57. Bernardes, C. E. S. CBCAL 3.0 - A Program for Calorimeter Control and Data Acquisition; FCUL: Lisbon, 2016. 58. Gonçalves, E. M.; Joseph, A.; Conceição, A. C. L.; Minas da Piedade, M. E. Potentiometric Titration Study of the Temperature and Ionic Strength Dependence of the Acidity Constants of Nicotinic Acid (Niacin). J. Chem. Eng. Data 2011, 56, 2964-2970. 59. Alagar, M.; Krishnakumar, R. V.; Nandhini, M. S.; Natarajan, S. DL-Valine-Fumaric Acid (2/1). Acta Crystallogr. 2003, E59, o857-o859. 60. Etter, M. C. Encoding and Decoding Hydrogen-Bond Patterns of Organic-Compounds. Acc. Chem. Res. 1990, 23, 120-126.


Page 43 of 44 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


61. Woinska, M.; Jayatilaka, D.; Spackman, M. A.; Edwards, A. J.; Dominiak, P. M.; Wozniak, K.; Nishibori, E.; Sugimoto, K.; Grabowsky, S. Hirshfeld Atom Refinement for Modelling Strong Hydrogen Bonds. Acta Crystallogr. 2014, A70, 483-498. 62. Woinska, M.; Grabowsky, S.; Dominiak, P. M.; Wozniak, K.; Jayatilaka, D. Hydrogen Atoms Can Be Located Accurately and Precisely by X-ray Crystallography. Sci. Adv. 2016, 2. 63. Haynes, W. M. Handbook of Chemistry and Physics; 97th ed.; CRC Press: Boca Raton, 2017. 64. de Kruif, C. G.; Vanginkel, C. H. D. Torsion-Weighing Effusion Vapor-Pressure Measurements on Organic-Compounds. J. Chem. Thermodyn. 1977, 9, 725-730. 65. de Kruif, C. G.; Voogd, J.; Offringa, J. C. A. Enthalpies of Sublimation and Vapor-Pressures of 14 Amino-Acids and Peptides. J. Chem. Thermodyn. 1979, 11, 651-656. 66. Meija, J.; Coplen, T. B.; Berglund, M.; Brand, W. A.; De Bievre, P.; Groning, M.; Holden, N. E.; Irrgeher, J.; Loss, R. D.; Walczyk, T., et al. Atomic Weights of the Elements 2013 (IUPAC Technical Report). Pure Appl. Chem. 2016, 88, 265-291. 67. Taylor, B. N.; Kuyatt, C. E. Guidelines for Evaluating and Expressing the Uncertainty of NIST Measurements (NIST Technical Note 1297); NIST: Gaithersburg, 1994. 68. Computational Chemistry Comparison and Benchmark DataBase. In NIST Standard Reference Database 101 (Release 12); National Institute of Standards and Technology: Gaithersburg, 2005. 69. Perlovich, G. L.; Hansen, L. K.; Bauer-Brandl, A. The Polymorphism of Glycine Thermochemical and Structural aspects. J. Therm. Anal. Calorim. 2001, 66, 699-715. 70. Drebushchak, V. A.; Kovalevskaya, Y. A.; Paukov, I. E.; Boldyreva, E. V. Low-Temperature Heat Capacity of Alpha and Gamma Polymorphs of Glycine. J. Therm. Anal .Calorim. 2003, 74, 109-120. 71. Pedley, J. B. Thermochemical data and structures of organic compounds; Thermodynamics Research Center: College Station, 1994.

For Table of Contents Use Only

Energetics of Glycine Co-crystal or Salt Formation with Two Regioisomers: Fumaric acid and Maleic acid António O. L. Évora, Carlos E. S. Bernardes, M. Fátima M. Piedade, António C. L. Conceição, Manuel E. Minas da Piedade*



Page 44 of 44

Graphic TOC

Synopsis: Binary crystals consisting of glycine and fumaric or maleic acids (two regioisomers with different proton transfer ability) were prepared and investigated from structural and energetic points of view. It was found that their formation is enthalpically driven, and that the adoption of a salt rather than co-crystal character does not necessarily bring a notable thermodynamic stability or solubility advantage relative to the precursors.


Energetics of Glycine Cocrystal or Salt Formation with Two

Recommend Documents