SUPPLEMENTARY INFORMATION
On the issues of resolving a low melting combination as a definite eutectic or an elusive
cocrystal: A critical evaluation
SURYANARAYAN CHERUKUVADA*
Solid State and Structural Chemistry Unit, Indian Institute of Science, Bengaluru 560 012, India
Email: [email protected]; [email protected]
*For correspondence
Table of Contents:
Figure S1: Schematic representation of different solid forms
Page S2
Structural integrity of cocrystals, solid solutions and eutectics
Pages S2-S3
Table S1: Attributes of cocrystal and eutectic formation
Page S3
Preparation and Characterization of Cocrystal and Eutectic
Pages S3-S6
Figure S2: Heteromeric units in caffeine cocrystals
Page S7
Figure
S3:
Ornidazole–4-aminobenzoic
acid
cocrystal
and
putative Page S7
supramolecular unit for putative ornidazole–4-iodobenzoic acid cocrystal
Figure
S4:
Pyrazinoic
acid–isonicotinamide
cocrystal
and
putative Page S8
supramolecular unit for putative pyrazinoic acid–nicotinamide cocrystal
Figure S5: Glutarimide–3,5-dihydroxybenzoic acid cocrystal and putative Page S8
supramolecular unit for putative glutarimide–3-hydroxybenzoic acid cocrystal
Practicality of Indo-US group's definition on cocrystals
Page S9
References S1-S30
Pages S9-S11
S1
Figure S1. Schematic representation of different solid forms. In a cocrystallization experiment,
when adhesive (heteromeric) interactions between materials dominate over cohesive
(homomeric) interactions, a new adduct with a crystal structure different from that of the parent
materials forms (e.g. salt and cocrystal). Combination of materials having similar
size/shape/crystal structures results in 'continuous solid solutions' (which resemble one of the
parent crystal structures), and the ones with mismatch/misfit/domination of homomeric
interactions can give rise to a 'eutectic' (conglomerate/ensemble of solid solutions). Cocrystals
and solid solutions are homogenous (single phase) throughout the crystal lattice whereas
eutectics are heterogenous (multi-phasic). Extracted from Ref. S1.
Manifestation and structural integrity of cocrystals, solid solutions and eutectics
A cocrystal is formed between a combination of substances featuring high geometric (steric fit)
and supramolecular (heteromolecular interactions) compatibility such that the components
propagate hand-in-hand as continuous heteromolecular units in the crystal lattice in effect
making a distinct crystalline entity.S1,S2,S3 A solid solution is manifested between substances
having unlimited solubility (i.e. compatibility in terms of size/shape/crystal structures) such that
it can form a variable stoichiometry but homogeneous (single phase) crystalline combination (see
Figure S1).S1,S3b,S4 The crystal structure of a solid solution, in general, resembles/sustains the
crystal structure of one of the parent substances. A eutectic is formed between those having
limited solubility (not-so-supramolecularly compatible in terms of size, shape, heteromolecular
S2
interactions etc.) so that each of the substances combined make discontinuous (heterogeneous or
multi-phasic) solid solutions within the same crystal lattice upon incorporating minor amounts of
other substances of the combination.S1,S3 Since only discontinuous/finite/random heteromeric
units manifest among the homomeric units of the components in the crystal lattice, the crystalline
environment of a eutectic combination remains as a summation of its individual components
taking the form of discontinuous solid solutions (see Figure S1).S1,S3 It was proposed, by this
author and Nangia,S1 that a combination of materials where hetero-supramolecular interactions
between components can outcompete homo-supramolecular interactions of individual
components form cocrystals and those where homo-supramolecular interactions are too strong to
be outweighed can lead to eutectics. This concept has been strengthened by Guru Row et al.'s
workS3 with further improvements in the understanding of several chemical factors and attributes
that dictate cocrystal/eutectic formation as well as their mutual exclusivity (see Table TS1).
Given the unpredictability associated and moderate design control on the formation of cocrystals
with many failed cocrystallization reports, the studies by Guru Row et al.S3 are remarkable in that
they confer enhancement of success rate of cocrystallization, further making it a win-win
situation in terms of both cocrystal and eutectic formation. On the other hand, when a
combination is not-at-all compatible at supramolecular level, it just remains as a simple mixture
illustrated by succinamide–4,4-bipyridine combination.S3a
Table S1. Findings on the attributes of cocrystal/eutectic formation for a combination of
materials.S1,S3
S. No.
Aspect
1
heteromolecular units
2
3
4
5
Attribute
Resultant
continuous growth
cocrystal
finite or discrete
eutectic
supramolecular affinity or propensity of
high
cocrystal
hydrogen bond donor-acceptor groups
low
eutectic
geometric and steric compatibility of hydrogen
high
cocrystal
bond donor-acceptor groups
low
eutectic
induction strength complementarity of
high
cocrystal
hydrogen bond donor-acceptor groups
low
eutectic
'W' shape
cocrystal
'V' shape
eutectic
temperature vs. composition phase diagramS5,S6
S3
Methods for Preparation of Cocrystal and Eutectic and associated issues
Both cocrystals and eutectics are commonly prepared by thermal (e.g. co-melting),S6b,S7,S8
mechanochemical (e.g. co-grinding)S1,S3,S9,S10 and solution (evaporation/precipitation)S7,S11 based
methods. However, solution based methods suffer from the risk of precipitation of individual
components and thermal methods can have issues with temperature gradients (for mixing of
components and consequent crystallization upon cooling) and moreover are not suitable for heatlabile materials. Recently, Fucke et al.S12 showed that solvent-assisted grinding is more reliable
for making a cocrystal. But, unseeded caffeine–benzoic acid (CAF–BA) system proved that the
above methods, including the supposedly reliable grinding method, does not ensure the
formation of a putative/targeted cocrystal.S13 On the other hand, traditionally employed technique
of solvent-mediated co-precipitation and recent technique of co-grinding for making
eutecticsS1,S3,S7,S9,S11b have a basic flaw. The resultant material from these techniques is used to
be characterized as a eutectic when the material exhibits characteristic lower melting point than
that of the components i.e. it is not clear whether co-precipitation or co-grinding can really result
in eutectic formation, since a eutectic-forming physical mixture too upon heating results in a
eutectic.S1,S3,S6a,S8 Nevertheless, the analogy between heating and grinding and formation of
eutectics by compaction techniqueS14 supports grinding to be a technique to form eutectics as
follows. Grinding is well established to result in the formation of non-covalent adducts (e.g.
cocrystal, molecular salt etc.)S2d,S3,S10,S15 and even covalent adductsS16 for a combination of
materials. Grinding induces the development of reactant domains by facilitating molecular
agitation and mobility finally leading to reorganization of molecules into a new adduct phaseS17
in a manner heating facilitates. To a first approximation, when grinding results in the formation
of cocrystals having different interactions and lattice structure as compared to parent materials
through full-fledged molecular reorganization, it is not unusual that it can induce eutectic
formation,S18 on par with heating, which needs lesser reorganization as compared to cocrystal.
Second, Bi et al.S14 have shown that compaction, a similar physical stress technique like
grinding, can result in the formation of eutectics. They showed the difference between a eutecticforming physical mixture and preformed eutectic (obtained by melting and compaction force
independently) in terms of onset of eutectic endotherm and peak broadness. Eutectic-forming
physical mixture exhibited a broad eutectic endotherm with higher onset contrast to eutectic
material obtained by compaction which showed lower onset and sharp peak. Additionally, they
have demonstrated an increase in the intimate contact area and thermal conductivity between the
eutectic-forming components in the eutectic phase with increase of compaction force.S14 Thus,
S4
grinding and compaction assume to be new techniques that can make eutectics as well as
applicable to heat-labile materials. Atomic pair distribution function (PDF) analysis, small-angle
X-ray or neutron scattering (SAXS/SANS) measurements etc. are some of the future endeavors
to characterize organic eutecticsS1,S3a in general and to assess eutectic formation upon grinding in
specific.
Characterization of Cocrystal and Eutectic
Unlike a cocrystal, a eutectic is insensitive to conventional X-ray diffraction and spectroscopy
techniques.S1,S3 In case of the former, the replacement of homomolecular interactions by
heteromolecular ones takes place followed by change in crystal packing (as compared to parent
materials) such that it can be characterized by powder X-ray diffraction (PXRD) and
spectroscopy. But, in case of a eutectic, the components of the combination accommodate each
other in a substitutional or interstitial manner only partially forming an ensemble of
discontinuous solid solutions wherein the homomolecular interactions as well as the parent
component lattices are largely unaffected. As a result, no appreciable change can be observed in
the diffraction or spectroscopic pattern of a eutectic compared to its parent materials and it
manifests as the summation of parents.S1,S3 Traditionally, the only indicator of eutectic formation
for a combination is the depression of its melting point which is traced by constructing a
temperature vs. composition phase diagram.S1,S3,S5,S6,S19 A typical binary phase diagram of a
eutectic assumes a ‘V’ shape with the minimum representing the eutectic melting point and
maxima for individual melting of parent materials of the binary combination. For a eutecticforming combination, only one interface i.e. eutectic phase exists between the combination,
while a cocrystal-forming combination manifests at least three different interfaces viz. a
cocrystal and two eutectic (independent eutectics between cocrystal and individual parent
materials) phases.S3a,S6,S20 Hence, the binary phase diagram of a cocrystal-forming system
assumes 'W' shape; the two lower minima in ‘W’ represent eutectics between cocrystal and
individual parent materials in excess; the middle maximum pertains to cocrystal phase whose
melting point can be upper, median or lower compared to parent materials.S3a,S6,S20
Skepticism in establishing a combination as a cocrystal/eutectic-forming one and solution
With respect to establishing a combination as a cocrystal- or eutectic-forming one, caffeine–
benzoic acidS13 and benzoquinone–diphenylamineS21 systems formed the premise for the referees
to question our assertion in two articles of Guru Row's groupS3c,d that eutectic formation for a
S5
particular combination refrains it to form cocrystal. It should be noticed that benzoquinone–
diphenylamine system and several other systems manifest cocrystals past heating of their eutectic
melts (in thermal microscopy or differential scanning calorimetry (DSC)), respectively,
indicating that eutectic formation is a preceding step for cocrystal formation in those
cases.S6b,S8,S21 They typically exhibit at least two endotherms in DSC (initial one for eutectic and
latter for cocrystal melting) and 'W'-type phase diagrams characteristic of cocrystal-forming
systems. Lu et al.S8 have provided a rationale on the mechanism of cocrystal formation from
eutectic melt for such cases. But, pure CAF–BA system did not show any sign of cocrystal
formation from its eutectic melt as analyzed by DSC (only a single endotherm is observed) and
PXRD (no new or distinct peaks are observed) in this study (see Figure 1 of main article).
Further, it manifested 'V'-type pattern of a eutectic-forming system (Figure 1b). The system gave
cocrystal only upon seeding with cocrystals of caffeine and various fluorobenzoic acids.S13 Thus,
the combination behaved as a eutectic-forming one in pure state and as a cocrystal-forming one
when subjected to heteronuclear seeding. There seems to be an inherent nucleation issue, the
rate-limiting step of crystallization,S22 for CAF–BA combination such that the formation of
cocrystal happens only when the nucleation step is evaded by seeding. Heating or co-melting a
combination is known to result in adduct (cocrystal) formationS6b,S8,S21,S23 by facilitating higher
energy state/activation of the reactants so that they can reorganize into a new adduct phase.
Similarly, as discussed before, grinding method too can facilitate molecular agitation and
consequent reorganization to result in a new adduct. This tends to mean that heat/grinding
process is able to cross the kinetic barrier for nucleation to result in the growth of a cocrystal but
it actually did not happen in the case of CAF–BA. Therefore, a technique which evades or
crosses the activation barrier for cocrystal nucleation and sustains the growth of cocrystal nuclei
will be helpful to resolve cocrystal/eutectic formation for a particular combination.
Heteronuclear seedingS24 followed by slurry crystallization,S25 which resulted in the formation of
long elusive CAF–BA cocrystal,S13 has the potential to facilitate cocrystal formation. This is
because the technique synergizes the evasion of rate-limiting nucleation step through seed
effectS24 and conferment of supersaturation for cocrystal growth through solution-mediated phase
transformationS25b in slurry conditions to finally result in cocrystal formation. Therefore,
heteronuclear seeding can be affirmed as a validation technique to establish a combination as a
cocrystal- or eutectic-forming one.
S6
caffeine–2,3-difluorobenzoic
caffeine–benzoic acid
caffeine–salicylic acid
acid (CAF–23DFBA)
(CAF–BA)
(CAF–SA)
Figure S2. Heteromeric units in caffeine cocrystals. In CAF–23DFBA and CAF–SA cocrystals,
tetrameric motif formed by carboxylic acid–imidazole and C–H∙∙∙O=C(CAF) interactions extends
into other dimensions through methyl–fluoro/hydroxyl interactions. In CAF–BA cocrystal, the
same tetrameric motif is propagated through methyl–carbonyl(COOH) interactions in the absence
of additional acceptor groups on benzoic acid. CAF–BA cocrystal is isomorphous and
isostructural with CAF–23DFBA cocrystal but not with CAF–SA cocrystal.S13,S26
Supramolecular unit for putative
Ornidazole–4-aminobenzoic acid cocrystal
ornidazole–4-iodobenzoic acid cocrystal
(extracted from Ref. S3b)
(adapted from Ref. S3b)
Figure S3. Tetrameric unit consisting of acid–imidazole and nitro–amine dimers in 1:1
ornidazole–4-aminobenzoic acid cocrystal lends supports to the feasibility of 1:1 ornidazole–4iodobenzoic acid cocrystal formation based on the commonality in acid–imidazole interactions
and analogy of nitro–amine and nitro–iodo interactions.
S7
Pyrazinoic acid–isonicotinamide cocrystal (adapted
Supramolecular unit for putative pyrazinoic acid–
from Ref. S3c)
nicotinamide cocrystal (extracted from Ref. S3c)
Figure S4. In 1:1 pyrazinoic acid–isonicotinamide cocrystal, the para location of amide group
renders the anti NH donor to make linear supramolecular units to extend into a sheet structure.
For the putative 1:1 pyrazinoic acid–nicotinamide cocrystal to form, the amide group should go
out-of-plane so as to overcome steric hindrance and render the anti NH donor to make nonplanar supramolecular units of the cocrystal.
Supramolecular unit for putative
Glutarimide–3,5-dihydroxybenzoic acid
glutarimide–3-hydroxybenzoic acid cocrystal
cocrystal (extracted from Ref. S3d)
(adapted from Ref. S3d)
Figure S5. Tetrameric [(acid–imide)–(hydroxyl–imide)] units in 1:1 glutarimide–3,5dihydroxybenzoic acid cocrystal support the manifestation of putative 1:1 glutarimide–3hydroxybenzoic acid cocrystal based on the structural similarity between 35DHBA and 3HBA
and commonality of interactions.
S8
Indo-US group's definition of cocrystals and its practicality
According to an Indo-US group, cocrystals are "solids that are crystalline single phase materials
composed of two or more different molecular and/or ionic compounds generally in a
stoichiometric ratio".S27 This evolved definition in 2012 is so inclusive that it is quite handy in
categorizing some of the solid forms of drugs, which are otherwise difficult to classify. For
example, dapagliflozin propylene glycol monohydrate,S28 escitalopram oxalic acid oxalateS29 and
valproic acid sodium valproate,S30 which are the respective marketed solid forms of the drugs
namely dapagliflozin, escitalopram and valproic acid, readily come under the Indo-US group's
definition of cocrystals.
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