A Journal of

Accepted Article

Title: Molecular Basis for the Mechanical Response of Sulfa Drug

Crystals

Authors: SEETHA L SUNIL, Mangalampalli S. R. N. Kiran, Upadrasta

Ramamurty, and Sunil Varughese

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To be cited as: Chem. Eur. J. 10.1002/chem.201803987

Link to VoR: http://dx.doi.org/10.1002/chem.201803987

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Molecular Basis for the Mechanical Response of Sulfa Drug Crystals
Sunil SeethaLekshmi,[a] Mangalampalli S. R. N. Kiran, [c] Upadrasta Ramamurty*[d]
and Sunil Varughese*[a,b]
Abstract: Appreciating the nanomechanical response in crystalline
materials demands one to comprehend on the elastic and plastic
deformation mechanisms occurring in the vicinity of the nanoindenter
tip, in terms of the underlying crystal structures. We combined the
nanoindentation data with structural and computational inputs to
derive a molecular-level understanding of the nanomechanical
response in eight prototypical sulfa drug molecular crystals. The
magnitude of the modulus, E, is strongly connected to the non-
covalent bond features―the bond strength, the relative orientation
with the measured crystal facet as well as their disposition in the
crystal lattice. Additional features deciphered from the current studies
are: i) robust synthons well-isolated by weak and dispersive
interactions reduce the material stiffness; in contrast, interweaving of
interactions with diverse energetics fortifies the crystal packing; ii)
mere observation of layered structures with orthogonal distribution of
strong and weak interactions is a prerequisite but inadequate to attain
higher plasticity, and iii) interlocked molecular arrangements prevent
long-range sliding of molecular planes and hence lead to enhanced E.
Within a broader perspective, the observations are remarkable in
deriving a molecular basis of the mechanical properties of crystalline
solids, which can be exploited through crystal engineering for the
purposeful design of materials with specific properties.
Introduction
The mechanical properties of molecular crystals are dependent
on the constituent building blocks, their spatial arrangements and
the cementing non-covalent interactions holding them
organized.[1,2] Even subtle variations in the crystal packing can
have a profound effect on the bulk properties of the solid to impact
the end applications.[3] Because mechanical properties are critical
in the applications of organic crystals, such as in pharmaceutical
manufacturing, it is vital to draw the interrelations between the
properties and the underlying crystal structures of molecular
materials.[4] The hitherto derived knowledge is critical in designing
materials with precisely targeted properties―the third phase of
crystal engineering.[1a,1b] Nanoindentation offers a state-of-the-art
[a] Dr. S. Seetha Lekshmi, Dr. S. Varughese
Chemical Science and Technology Division
CSIR-National Institute for Interdisciplinary Science and Technology
Trivandrum 695 019, India
[b] Academy of Scientific and Innovative Research, CSIR-NIIST
Campus, Trivandrum 695 019, India
E-mail: s.varughese@niist.res.in
[c] Dr. M. S. R. N. Kiran
Department of Physics and Nanotechnology, SRM Institute of
Science and Technology, Chennai 603203, India
[d] Prof. U. Ramamurty
Department of Materials Engineering, Indian Institute of Science,
Bangalore 560 012, India
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/chem.201803987
technique to probe many of the intrinsic characteristics of crystals,
inclusive of the anisotropic nature, and to correlate the
mechanical response in terms of crystal packing and the
supramolecular bonding.[5,6] The interpretations from many of the
studies form part of the standard arsenal of strategies that are
applied to engineer mechanically responsive materials.[7,8]
Accepted Manuscript
Accordingly, anisotropic packing with the availability of slip
systems induces plastic deformation in molecular crystals, while
isotropic crystal packing with multi-directional weak dispersive
bonds and corrugated packing induce large flexural elasticity.[9]
In crystalline solids, crystal engineering[10] principles may be
gainfully employed to vary the nature and number of
intermolecular interactions to derive mechanical response in a
predictable manner.[11,12] However, this exercise solely depends
on our comprehension of the structural factors and features that
determine the elastic and plastic responses of organic
crystals.[13,14] In fact, assessing the generality of the design
principles that lead to a specific property is a challenging task; one
need to study a large library of related sets of molecules with
distinct crystal packing to reach a converging conclusion. The
usually adopted strategy is to systematically vary a set of
substitution, keeping the rest of the molecular backbone intact.
The prompted chemical perturbations could lead to distinct
packing modes and synthon hierarchy in the crystal structure,
enabling one to probe their role adequately. In this report, we
applied this strategy to derive structure-mechanical property
correlations in eight sulfa drug crystals. Sulfa drugs belong to a
group of synthetic antibiotics that contain sulfonamide moiety. [15]
Because of their multiple hydrogen bond donor and acceptor
abilities, sulfonamides make a diverse range of stable
supramolecular motifs and are inherently inclined to exist in
multiple crystal forms.[16,17] Further to their therapeutic worth, the
synthon preferences of the sulfonamide moieties are pertinent to
structural or crystal engineering studies. [18]
In the present work, we wish to pursue on deriving structure-
mechanical property relations by (i) correlating the synthon
energy, and their relative disposition with respect to the
indentation direction to the nanomechanical response in sulfa
drug crystals, (ii) analyzing the contributing structural descriptors
that determine the observed trends in the hardness (H) and
modulus (E), and (iii) highlighting the exceptions or deviations
observed from the general notions posited to yield a specific
mechanical property. To attain molecular-level understanding of
the nanomechanical response in eight prototypical sulfa drug
molecular crystals: Sulfapyridine (SPR), Sulfachloropyridazine
(SCP), Sulfadiazine (SDZ), Sulfamerazine (SMR), Sulfameter
(STR), Sulfadoxine (SDX), Sulfamethoxazole (SMX), and
Sulfathiazole (STZ) (Scheme 1), we combined nanoindentation
data with structural and computational inputs. The selected
compounds all have the same sulfanilamide functionality, yet their
packing arrangements offer diversity, directionality, and rich
hydrogen-bonding scenarios, conditional to the various moieties
attached to the opposite terminal of the sulfonamide group. Here,
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it is worth re-stating the view espoused by Desiraju that ‘‘a
detailed understanding of crystal packing and crystal design
depends very substantially on viewing the molecule as an organic
whole...”.[19] Hence, rather than counting the individual factors, the
materials property is the holistic outcome of several structural
descriptors.[10d] Keeping this in view, we investigate and
rationalize the observed mechanical properties in terms of the
molecular-level structural elements, opening the door further to
the design of molecular solids with desired mechanical properties.
SPR SCP SDZ
SMR STR SDX
SMX STZ
Scheme 1. The chemical structure of the sulfa drugs selected for the present
study.
Results and Discussion
Structure and Energy Framework Analysis
The CIFs of all the sulfa drugs, but two, were retrieved from the
Cambridge Structural Database (CSD).[20] The crystal forms of the
sulfa drugs were identified based on the crystal screening using
single crystal X-ray diffraction. The data for two of the compounds
(SDX and STR), however, were re-collected since the quality of
the data needed to be enhanced. Only the most relevant structural
descriptors are highlighted. All the compounds have the same
sulfanilamide functionality yet with distinct packing modes and
noncovalent interactions depending on the moieties attached to
the other end of the sulfonamide group (Scheme 1). The
indentation experiments were performed on the major faces of
their respective stable crystal forms at ambient laboratory
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10.1002/chem.201803987
conditions (30 °C / 35% RH). The structural features―packing
modes, interaction types, relative orientations of interactions with
the indentation direction―in combination with the Hirshfeld
surface,[21] energy frameworks,[22] and electrostatic potential
surface analyses cumulatively provide insights to the structure-
mechanical property profile. Supplementary to the interactions,
the mode of molecular arrangement, possible stress-
compensating mechanisms and the occurrence of the slip
systems[23] imbued substantial effect on the mechanical response.
By discussing the structural descriptors ranging from packing
modes to layer orientations, the work aims to show how subtle
variations in the interaction types and their distributions relative to
the indentation directions can lead to considerable changes in the
Accepted Manuscript
crystals’ mechanical properties.
Figure 1. Crystal packing of SPR and its schematic. The interaction patterns A
and B are highlighted. The slip plane (200) is denoted as the purple line, and
the indention direction is represented by a red arrowhead. The red and green
highlighted section shows the segregated distribution of strong and weak
interactions.
SPR: The compound is an N-heteroaromatic sulphonamide
antibacterial drug that exists as the imido tautomer in the
crystalline state. Projected down the [010], the molecules in the
V-configuration adopt a dual stacking mode―the phenyl rings
stack along [100] and the pyridine ring along [001] direction
(Figure 1). Down the [010], the molecules are bound by centric
𝑅44 (12) N–H(–NH2)···O(–SO2–) and N–H(–NH2)···N(imido) (Pattern A)
hydrogen bonds connecting four molecular units. The resultant
tetramer further extends through distinct 𝑅22 (12) cyclic pattern
(Pattern B). The primary cyclic patterns are augmented invariably
by C–H···O hydrogen bonds, further strengthening the
intermolecular bonding. The structural analysis implies strong
coulombic and weak dispersive stacking interactions arranged
alternately, making the packing anisotropic. The computed
energy frameworks further corroborate the distinct anisotropy in
the distribution of the non-covalent bonds. The stacking
interactions, both phenyl (–37.5 kJ/mol) and pyridyl (–31.4 kJ/mol)
are dispersive, while the patterns A (–93.8 kJ/mol) and B (–168.8
kJ/mol cumulative) are dominantly coulombic. The phenyl
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stacking and the cyclic synthons remain aligned with the indenter
direction, while the pyridyl moieties stack orthogonal to the
penetration direction (Table S4).
Figure 2. The close-packing mode adopted in SCP. The centric dimer and the
𝑅33(10) cyclic synthon observed in the crystal are shown.
SCP: Sulfachloropyridazine is used to treat chronic
genitourinary infections.[24] The crystal packing is described by a
cooperative set of Cl∙∙∙π(phenyl) (3.43 Å) and π∙∙∙π (~3.64 Å)
interactions (Figure 2), in the {011} plane, constituting a centric
dimer. The Cl∙∙∙π halogen interaction has a Ring1/Ring2 angle of
82.86º and is shorter than the average distance of Cl∙∙∙π
interactions known in CSD (Table S5). The dimers stack down
[100]; within a stack, three molecular units make acentric cyclic
N–H∙∙∙O pattern (𝑅33 (10)) involving the sulfonamide (–SO2NH–)
and amino (–NH2) moieties, along with bifurcated N–H∙∙∙O/C–
H∙∙∙O interactions that augment the primary synthon. An intralayer
non-centric C–H(phenyl)∙∙∙N(pyridazine) dimer (𝑅22 (6)) formed between
translationally related molecules further support the layer integrity.
The 𝑅33 (10) cyclic N–H∙∙∙O synthon (–64.7 kJ/mol) is dominantly
coulombic (with an electrostatic component of –42.2 kJ/mol). The
non-centric C–H(phenyl)∙∙∙N(pyridazine) (𝑅22 (6)) dimer and the Cl∙∙∙π and
π∙∙∙π dimers (–36.2 kJ/mol) formed between the inversely related
molecular units, however, possess substantial dispersive
characteristics. The tightly packed molecules with an interwoven
network of strong and weak interactions make the structure
significantly isotropic. With respect to the major face (011), the
𝑅33 (10) synthon and the constituent individual interactions remain
oblique to the indentation direction; the N–H(Ph–NH–)∙∙∙O(–S=O) and
N–H(–NH2)∙∙∙O(–S=O) with their corresponding computed energy of –
39.2 and –25.5 kJ/mol make 13 and 47º, respectively. Set of
interactions associated with the Cl moiety, with a combined
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10.1002/chem.201803987
energy value of –36.2 kJ/mol, the Cl∙∙∙π interaction remains near
parallel to the indentation direction (7º).
SDZ: Sulfadiazine (used for bacterial and extra-luminal
urinary-tract infections) structure is described as a layered
arrangement[25]; Figure 3 shows the overall crystal packing of SDZ,
stacked down [010]. Along [001], the molecules make a dimer
through robust four-point recognition unit, consisting of centric N–
H···N and C–H···O hydrogen bonds. The dimer, however,
extends in multiple directions through significantly weak and
dispersive interactions: along [010] pyrimidines stack through
π···π/C–H···π interactions, whereas the phenyl π···π stacking is
dominant along [100]. The energy framework analysis validates
that the dominantly coulombic four-point interactions (–74.2
Accepted Manuscript
kJ/mol) are isolated islands in the midst of weak dispersive
contacts. The pyrimidine π···π (–42.2 kJ/mol) and C–H···π (–23.0
kJ/mol) interactions and the non-directional π···π stacking of the
phenyl moieties (–36.7 kJ/mol) constitute the dispersive contacts
(Figure 10; Table S2).
Figure 3. The crystal packing in SDZ and its schematic. The four-point
recognition unit (showed in red dots) and its further propagation through
dispersive contacts (blue dots) are shown. The red highlighted region in the
schematic shows the area having the coulombic interactions, while the blue
region is populated by non-directional phenyl π···π stacking, making the slip
energetically viable.
SMR: SMR is the higher homolog of SDZ, and is administered
for bacterial infections in combination with other antibiotics. The
occurrence of a limited variety of interactions marks the
characteristic SMR structure. The crystal has zig-zag molecular
sheets stacked along [010] (Figure 4). A unique sheet consists of
a centric N–H(sulfamide)∙∙∙N(pyrimidine) (R(8)) pattern, augmented by
two C–H(pyrimidine)∙∙∙O(–SO–)―a four-point recognition unit. Energy
framework analysis hints at anisotropy in the distribution of
interactions. The four-point recognition remains as significant
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interaction with a considerable electrostatic contribution (–99.6
kJ/mol), but held at the corners by weak and dispersive forces.
Figure 4. SMR crystals have (002) as the active slip plane. The dimer formed
through four-point recognition unit is held at the corners by weak interactions.
Figure 5. The crystal packing in STR. The distribution of the interactions is
anisotropic―the strong synthons consisting of three-point recognition and the
weak multifurcated interactions are orthogonal to each other. The projection
perpendicular (down x-axis) to the plane of the paper is shown as a black spot
in A.
STR: The molecules with V-configuration assemble through
well-segregated strong and weak interactions. In the crystal, the
molecules make a dimer through C–H(–OCH3)∙∙∙π(pyrimidine)
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10.1002/chem.201803987
interactions formed between inversely related molecules. The
adjacent dimers along [001] make a triple hydrogen-bonded unit
through a combination of C–H(pyrimidine)···N(pyrimidine), N–H(–
SO2NH–)···N(pyrimidine), N–H(–SO2NH–)∙∙∙O(–SO2–) hydrogen bonds. The
centric dimers stack along [100] while the adjacent stacks, in [010],
are held by multifurcated interactions making the linking rather
weak (Figure 5). The plane consisting of these meeting points
through weak multifurcated interactions constitute the slip plane.
The centric dimers through C–H(–OCH3)∙∙∙π(pyrimidine) interactions (–
39.8 kJ/mol) and its stacking in [100] (–48.6 kJ/mol) are dispersive.
The triple hydrogen bonded interactions are dominantly
electrostatic with an associated energy contribution of –57.0
kJ/mol. The energy frameworks demonstrate the segregated
Accepted Manuscript
distribution of the strong and weak interactions (Figure 10).
Figure 6. SDX crystal structure with the active slip plane as (002). The relative
distribution of the four distinct patterns is highlighted. The patterns A and B stack
along [100] while C and D patterns remain in the (101) plane. The acentric cyclic
pattern E acts as a bridge between A/B and C/D patterns.
SDX: Four centric dimers describe the structure of SDX. Of
the four, two cyclic dimers are of notable dispersive
characteristics, though a whole host of these interactions make
them energetically robust (Figure 6). Inverse related molecules
interact through the C–H(–OMe)···π interactions (Pattern A), which
stack along [100] to make a dimer through multiple cross-stitched
C–H(–OMe)···O(–SO2–) and C–H(–OMe)··· π interactions (Pattern B).
The dimers A and B stack alternately along [100]. Adjacent
columns bond to the adjacent counterparts, along [010], through
N–H(–NH2)···O(–SO2–) / C–H(phenyl)···O(–SO2–) (Pattern C) and N–H(–
NH2)···O(–OMe) (Pattern D) interactions. Along [001], the stacked
columns interact through 𝑅22 (10) acentric N–H(–NH2)···O(–SO2–) / C–
H(phenyl)···N(pyrimidine) interactions (Pattern E). The patterns A (–43.3
kJ/mol) and B (–69.0 kJ/mol) are dominantly dispersive, while C
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and D have comparable energy profile (–46.4 and –45.7 kJ/mol,
respectively) but with coulombic characteristics. In accordance
with the synthon distribution across the lattice, the computed
energy framework shows a honeycomb-like distribution (Figure
10). Because of the comparable energy profile of the interactions
and their even distribution across the lattice, one could expect an
enhanced elastic modulus for such systems.
SMX: The SMX has a bilayer arrangement stacked along
[100]. Within a unique bilayer the centric 𝑅22 (8) N–H(–
SO2NH–)∙∙∙N(oxazole) interaction exist at the core and is augmented by
a host of dispersive C–H(–CH3)∙∙∙π(oxazole) interactions. An extended
N–H∙∙∙O/C–H∙∙∙O hydrogen bond formed between the phenyl, –
NH2 and –SO2– moieties stabilize the bilayer arrangement at the
periphery (Figure 7). The inter-bilayer region is populated by non-
directional π∙∙∙π interactions. The arrangement in the SMX leads
to an anisotropic distribution of interactions and hence a distinct
dispersal of the energy framework (Figure S2). Within an
individual bilayer, centric 𝑅22 (8) N–H(–NH2)∙∙∙N(methoxazole) dimer (–
59.9 kJ/mol) remain as the robust synthon, with substantial
electrostatic attribute (Table S2). Further, sets of interactions
such as non-centric N–H(–NH2)∙∙∙O(–SO2–)/C–H(phenyl)∙∙∙O(–SO2–), C–
H∙∙∙π and oxazole stacking strengthens the bilayer arrangement.
The inter-bilayer region possesses non-directional stacking
interactions (edge-edge π∙∙∙π stacking with the collective
contribution of energy –55.4 kJ/mol) with the dominant dispersive
trait.
Figure 7. The bilayer molecular packing in SMX. A: robust centric N–H∙∙∙N and
acentric N–H∙∙∙O/C–H∙∙∙O, C–H∙∙∙π and oxazole stacking observed within a
bilayer. B: represents the non-directional π∙∙∙π stacking existing in the inter-
bilayer region.
STZ: Stacked along [100], STZ has a bilayer
arrangement.[4b,26] The periphery of an individual bilayer, down
[010], is stabilized by an infinite lineup of cyclic N–H∙∙∙O/C–
H∙∙∙O/N–H∙∙∙N hydrogen bond network (𝑅33 (9)) comprising of the –
This article is protected by copyright. All rights reserved.
10.1002/chem.201803987
SO2–, thiazole and the –NH2 moieties (Figure 8). Cyclic N–
H∙∙∙O/N–H∙∙∙N ( 𝑅43 (12)) patterns, along [100], connect the
adjacent bilayer units. A significant range of π∙∙∙π interactions
exists in the interlayer and intralayer region, with an average
stacking distance of 3.47 and 3.89Å, respectively. Strong cyclic
N–H(–NH2)∙∙∙O(–SO2–)/ N–H(thiazole)∙∙∙N(–NH2) and C–H(thiazole)∙∙∙O(–SO2–)
hydrogen bonds (–95.9 kJ/mol), with dominant electrostatic
characteristics secure the bilayer arrangement. Thus, the
structure contains a sufficient blend of coulombic interactions with
weak/dispersive bonds, such as C–H∙∙∙π, and π∙∙∙π. The inter-
bilayer region, in fact, is enriched with the concurrent existence of
N–H(–NH2)∙∙∙O(–SO2–) / N–H(thiazole)∙∙∙N(–NH2) (–27.1 kJ/mol) and
thiazole stacking (3.48 Å; –41.7 kJ/mol) interactions.
Accepted Manuscript
Figure 8. The STZ crystal structure. The structure has a bilayer arrangement
stacked along [001]. The interactions, as shown in A, constitute the bilayer,
while the interactions between the bilayers are represented in B. Thiazole
stacking runs along the indentation direction.
Nanoindentation
Nanoindentation experiments provide quantitative insights
into the nanomechanical response from individual crystals. The
major faces, on which the indentation experiments performed, are
in agreement with the SXRD, the BFDH morphology obtained
from Mercury software and the growth morphology computed
from Materials Studio (Figure S1). The load, P, versus
displacement, h, curves and the corresponding residual indent
impressions on the crystal faces of the sulfa drugs are provided
in Figure 9. The P–h curves show significant residual depths upon
unloading, indicative of the significant elastoplastic deformation
that the crystals undergo upon nanoindentation. We employed the
standard Olive-Pharr (O–P) method to evaluate the elastic
modulus, E, and hardness, H, from the nanoindentation
experiments.[27]
SPR: Differential distribution of interactions―the robust and
coulombic interactions placed orthogonal to the dispersive
interactions―defines the structure of SPR. The SPR crystals
exhibit significant H (956 ± 51 MPa) and E (15.69 ± 0.726 GPa)
values. In fact, the stacking of phenyl (–37.5 kJ/mol) along [100]
and pyridyl (–31.4 kJ/mol) along [001] remains orthogonal to the
dominantly coulombic N–H···O and N–H···N hydrogen bonds.
The orthogonal distribution of strong and weak interactions is
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known to enhance the plasticity in molecular crystals. However,
the observed H and E highlights that the orthogonal distribution of
the strong and weak interactions alone is not enough to determine
the deformability of a molecular crystal. In the crystal, the
molecules in the V-configuration make an interdigitated
arrangement; the interlocking of the molecules leads to an
enhanced stiffness. The primary slip plane in a molecular material
is assumed to be the weakest bound plane in that the attachment
energy is the least, and in directions that are closest packed (so
that the slip vector is the smallest). Accordingly, the slip is
preferred along this plane. In SPR, (200) (d200 = 6.39 Å)
corresponds to the slip plane with the associated attachment
energy (Eatt) of –54.5 kJ/mol, and the potential slip system is
(200)[002]. To corroborate with the structural inputs, the P–h
curve shows significant pop-in events indicating that the
deformation mechanism adopted in the system is inhomogeneous.
Figure 9. The load-displacement (P-h) curves obtained for different sulfa
drugs. The arrowhead on the loading curves corresponds to pop-in events.
SCP: The loading curve of SCP on (011) is smooth with
scarcely located pop-ins having minor dimensions (Figure 9). The
average values of hardness, H, and elastic modulus, E are 550 ±
30 MPa and 15.5 ± 1.1 GPa, respectively. The measured values
of pop-in width (hpop-in) are ~4.1 and 5.2 nm for the first two pop-
ins on the loading curve and correspond to integer multiples of the
interplanar d-spacing (d011 = 10.14 Å). From the computed Eatt,
dhkl and structural correlations, the identified potential slip system
is (011)[10-1]. The close-packed molecular arrangement with
interwoven strong and weak interactions and evenly distributed
energy framework are contributing factors to the observed H and
E. Both the energetically demanding synthons and the dispersive
stacking interactions are aligned along the indentation direction,
contributing their inherent strength to the observed mechanical
response. The AFM scan images of the indenter impressions
show no evidence for materials pile-up.
SDZ: The indentation experiments performed on the major
face (100) of the crystals coincide with the slip plane, as computed
from structural, energy frameworks and Eatt inputs―the identified
slip system is (100)[011]. The P–h curve shows significant
penetration depth; the loading profile has a notable extent of pop-
ins, the manifestation of an intermittent plastic deformation
mechanism. In the crystal, the strong and dominantly coulombic
quadruple synthon is further connected through a network of
dispersive interactions (π···π and C–H···π). Additionally, the
constituent interactions within the quadruple synthons make ~68°
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10.1002/chem.201803987
with the indenter, diminishing its effective contributions. Hence it
is reasonable to correlate the observed plasticity to the structural
anisotropy consequent to the differential distribution of the
interactions; the computed average values of H and E are 395 ±
40 MPa and 7.69 ± 0.5 GPa, respectively.
SMR: The load-displacement curves obtained on the (002) of
SMR crystals display significant penetration depth and have a
smooth loading profile. The calculated slip system for SMR is
(002)[020]; the (002) corresponds to the active slip plane with the
lowest Eatt (–58.34 kJ/mol). The lower magnitude of H (Table 1)
could be a possible outcome of a viable molecular layer
movement under the influence of indenter. Unlike the slipping of
the planar layers, zig-zag tapes in SMR could face restriction in
Accepted Manuscript
their relative motion. Hence, alternate mechanisms are adopted
to reduce the strain developed within. The average plane of the
most prominent and the robust quadruple interaction, with the
computed energy of –75.8 kJ/mol, lies near normal (72º) to the
indenter direction. Further, the quadruple interactions are isolated
by several dispersive interactions making the structure
susceptible to plastic deformation under shear stress.
STR: The proposed slip system is (020)[10-1]. Significant
penetration depth marked in the P–h curve with smooth loading
profile is reminiscent of an eventless plastic deformation
mechanism. The apparent low values of H (355 ± 20 MPa) and E
(5.71 ± 0.18 GPa) obtained from the indentation experiments are
indicative of the soft nature of the crystals. The weak multifurcated
interactions make the contacts between the stacks (comprising of
strongly bound molecules) susceptible to slip under external
shear stress. The triply bound pattern, consisting of the N–H···N,
N–H∙∙∙O, C–H···N hydrogen bonds (–57.0 kJ/mol), remains
angular (29°) to the indentation direction, making its effect only
partially felt by the indenter. The AFM scan images of the indents
remain plain with no materials pile-up and are suggestive of the
ability of the materials to absorb the excess pressure applied on
the crystal surface.
Figure 10. The total energy framework representation for eight sulfa drugs. The
thickness of each cylinder (in blue) represents the relative strength of interaction.
The energy threshold for the energy framework is set at -20 kJ/mol. The
anisotropic distribution of the interactions, as evident from the energy
frameworks, allows us to identify the slip planes effectively in 5/8 systems
studied. Because of the even or intertwined distribution strong and weak
interactions in SCP, SDX and STZ, we combined the structural inputs, energy
framework and Eatt calculations to determine the slip systems. The indentation
direction is represented as arrowheads.
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SDX: The crystal has an intermediate H (544 ± 18 MPa) and
E (14.74 ± 0.168 GPa), with the P–h curve showing a moderate
penetration depth and a smooth loading profile. The comparable
energy profile of the interactions and their mosaic distribution
across the lattice makes the system hard and stiff. The dominantly
dispersive patterns A (–43.3 kJ/mol) and B (–69.0 kJ/mol) in
tandem with coulombic C and D having a comparable energy
profile (–46.4 and –45.7 kJ/mol, respectively) shows a
honeycomb-like distribution. The proposed slip system for SDX is
(002)[200].[28] The near normal and angular (~60°) orientation of
the robust synthons, with respect to the indentation direction,
lessens their effective contribution to the mechanical response.
The AFM scan images of the indenter impression show cracks on
the (002) plane along the corners of the indenter; the brittle nature
is resultant to the isotropic deployment of interactions, as
indicated by the energy frameworks.
SMX: Upon indenting (200) face, the tip penetrates along the
stacking direction of the bilayers, and the indent impressions
show substantial materials pile-up (Figure 12). Based on the
structural, energy framework and the calculated Eatt, the proposed
slip system is (200)[002]. The material exhibits moderate values
of H (489 ± 34 MPa) and E (13.74 ±0.498 GPa). The synthons
with significant strength and the demanding ones in the structure
formation remain near normal to the penetration direction. The N–
H(–SO2NH–)∙∙∙N(oxazole) interactions (–59.9 kJ/mol) remains oblique
(71º), while the N–H(–NH2)∙∙∙O(SO2)/ C–H(phenyl)∙∙∙O(SO2) cyclic
interaction (–29 kJ/mol) is near normal (86º) to the indentation
direction. The π∙∙∙π stacking interactions with dominant dispersive
characteristics (–26.4 kJ/mol), but are aligned along the
indentation direction. The anisotropic distribution of the
interactions, the bilayer molecular arrangement, and the
computed energy framework hints at an enhanced plastic
characteristic for the crystals; hence, the observed values for H
and E, as well as the material pile-up on the crystal surface is a
deviation from the normal observed mechanical response in
molecular crystals.
STZ: The proposed slip system is (100)[011].[4b] The
interwoven strong and weak interactions in STZ restrict the layer
migration, making the crystal harder and stiffer (H = 1080 ± 15
MPa and E = 20.44 ± 0.25 GPa). The strain generated within is
nullified by transfer of materials from the interior to the surface,
reflected as materials pile-up on the crystal facet (Figure 12). With
respect to the tip penetration, the average plane of the cyclic
(𝑅33 (9)) synthon lies near normal (~82°). While the inter-bilayer N–
H∙∙∙O/N–H∙∙∙N interactions (–27.1 kJ/mol) are angular (50°) to the
indenter, the thiazole stacking interactions (–41.7 kJ/mol) are
quite along the penetration direction.
Hirshfeld Surface Analysis
The Hirshfeld surface (HS) analysis allow to visualize the
intermolecular interactions and to provide quantitative data for
their relative contributions in structure formation. The percentage
contribution of various intermolecular interactions present in the
sulfa drugs is given in Figure 11; Table S3. All the systems have
a comparable input from electrostatic interactions (O···H and
N···H). However, SCP and STZ show a blend of coulombic and
dispersive interactions. In fact, STZ with highest values of H and
This article is protected by copyright. All rights reserved.
10.1002/chem.201803987
E in the series is dominated by weak interactions. The softer
systems (SMR, SDZ, and SPR) have a considerable contribution
from H···H contacts. Except for SCP, the C···H contacts is a
significant force to reckon. Hence, further to the nature and
strength of interactions, their relative disposition in the crystal
lattice is a significant design element to enhance the mechanical
property of the crystals.
Accepted Manuscript
Figure 11. Percentage contribution of various types of non-covalent bonds the
sulfa drugs.
Structure-mechanical property correlations
Analyzing the nanomechanical response of crystals requires
the comprehension of the elastic and plastic deformation
mechanisms underneath the nanoindenter tip. The hardness of a
material indicates its resistance to plastic deformation; the
measured hardness is indicative of the complex dislocation
activities occurring in the plastic zone, in response to the applied
pressure.[4c] In fact, an efficient plastic deformation mechanism is
quintessential in lowering the hardness of molecular crystals.
When accorded shear stress by indentation the layers get
compressed initially in an elastic regime and later plastically. [5a,5f]
However, the incompressible nature of a crystal beyond an
absolute limit generates enormous strain within. In molecular
crystals, the availability of slip systems, which are the
crystallographic planes on which the molecular layers to
migrate/slip along the most energetically viable directions, is the
key for accommodating plastic strain.[23a] All the sulfa drugs
analyzed in the present series have at least one active slip system
each, which enables the crystals to deform plastically.
The experimentally obtained E of the crystals can be
rationalized based on the molecular packing inputs, interaction
energy frameworks and their relative orientations with respect to
the indentation direction.[14a] A close-packed structure with evenly
distributed diverse non-covalent interactions of average strength
is the salient feature of SCP, with two of the prominent synthons
aligned to the indentation direction. Their cumulative effect makes
the crystal stiff. The similarity in the crystal structure of SMX and
STZ is limited to the overall topology of the bilayer arrangement
stacked down the indentation direction. The coulombic
Chemistry - A European Journal
FULL PAPER
interactions are confined within the bilayer with dispersive
stacking interactions dominating the inter-bilayer region; this
makes the structure anisotropic for SMX. In STZ, however, the
evenly distributed interactions both within and between the
bilayers strengthen the crystal packing. The intercalation of the
strong and weak interactions indeed enhances the magnitude of
E. Even distribution of interactions with comparable energies, and
the interweaving of coulombic and dispersive bonds make the
systems stiff, as in the case of SDX. Both STR and SPR have
anisotropic crystal structures with well-segregated strong and
weak interactions. Accordingly, STR shows a diminished
magnitude of E and remains as the softest of the systems studied
in the present contribution. SPR, however, exhibits a higher
modulus making a deviation from the universality of the aforesaid
design condition applied in enhancing the deformability in
molecular crystals. The observed modulus is consequent to the
interlocking of the V-shaped molecules in the crystal. The
structural homologs SDZ and SMR have comparable structural
descriptors―availability of a limited choice of interactions and the
oblique orientation of the robust four-point recognition units with
respect to the indentation direction―are causative elements to
lower the E. Moreover, in both the systems the strong synthons
are well-isolated by a network of weak dispersive interactions; this
discontinuity in the chemical space make them softer.
Scheme 2. The schematic of the various crystal packing modes observed in
the series. A: close-packing; B: interlocked; C: accordion-type and D: layered.
The hindered molecular movements in A and B enhance the hardness of the
materials. The accordion-type has strong bonds held at the corners by weak,
flexible interactions, allowing for the compression and relaxation of the layers
under stress. The layered topology allows for energetically viable routes to
molecular movements. Accordingly, C and D structures are softer..
The plastic deformation mechanisms observed in sulfa drugs
are broadly classified and is depicted in Scheme 2. The crystals
of SPR, SCP, STZ, SDX, and SMX, are characterized either by a
mosaic of interactions with varying strengths and directionalities
or by interlocked architecture attained through interdigitated
molecular arrangements. In contrast SMR, STR and SDZ
structures have limited variants of interactions and also weakly
bound planes, enabling viable routes to attain slip; this makes
This article is protected by copyright. All rights reserved.
10.1002/chem.201803987
them softer than the counterparts studied along. Anisotropic
distribution of strong and weak interactions is one of the primary
design elements in attaining plasticity in molecular crystals. While
layer migration is the adopted mechanisms in STR and SDZ, the
zig-zag stacking in SMR offers a practically different means for
compensating the strain developed within. In the structure, the
stacking is analogous to the bellows of an accordion, wherein
weak, flexible interactions with dominant dispersive
characteristics hold the strongly bound dimer units, at the corners
(Scheme 2). The specific packing offers an intrinsic and efficient
pathway for the molecules to adapt themselves to the application
of pressure and to annul the developed strain. Interestingly,
crystal forms (2 and 3) of Curcumin also exhibit a similar layer
Accepted Manuscript
compression mechanism; both the forms have substantially lower
H (~20%) and E (~50%) values than its close-packed crystal
counterpart (Form 1).[4b] Molecular crystals can be plastic, elastic
or brittle. High crystal plasticity, that is, low hardness, corresponds
to facile plastic deformation. Among the sulfa drugs studied, SMR,
STR and SDZ have low hardness and are closely associated with
the facile long-range sliding possible for the molecular planes.
Based on the bonding area and bonding strength (BABS) model,
the systems with higher crystal plasticity (i.e., lower hardness)
favors a larger bonding area and, hence, stronger tablets during
powder compaction.[29]
The AFM scan images of the indenter images depict distinct
post-indentation crystal surface profiles (Figure 12). The crystals
of SMX, STZ, SDX, and SPR show materials pile-up; interestingly,
only SMX exhibited materials piled up on all the three sides of the
indenter. The surface pile-up is observed when the materials
within reaches a point beyond which it cannot afford to absorb the
induced strain. In general, initial yield stress and work-hardening
exponents are known to be major contributors in determining the
piling-up or sinking-in behavior of materials in response to
indentation forces.[5f] Soft, easily hardened materials sink-in
whereas harder, work-hardened materials pile-up. In molecular
crystals, usually, close-packed structures with an enhanced H
(when the deformation mechanism is ineffective) are known to
show materials pile-up. All the four crystals possess a higher
magnitude of H. Extensive crack, along the corner of the indenter,
seen on the crystal surface of SDX may be the manifestation of
the close-packed structure formed through a mosaic of different
interaction patterns. Stronger, harder and energetically more
demanding hydrogen bonding network accumulate considerable
strain at shorter distances, which would contribute to the
enhanced stiffness of the crystal and further cause cracking. [9c] In
contrast, the crystals of SCP, SDZ, SMR, and STR showed no
evidence for materials pile up. The mechanical parameters show
all of the crystals, but SCP, is soft with a smaller magnitude of H.
Apart from the close-packed structure and hence with a higher
hardness, the SCP structure is rich in dispersive Cl···H (9.6%),
Cl···π (9.9%), π···π (4.7%) and H···H (22.5%) contacts; the
softness of these weak interactions provides the system with the
required flexibility to effectively absorb the induced strain.
How one can assess the stiffness of a crystal with the
hindsight of knowledge on intermolecular forces? For developing
a qualitative understanding, it is instructive to view the chemical
bond as a linear spring.[30] In a classic indentation experiment, the
Chemistry - A European Journal 10.1002/chem.201803987

FULL PAPER
indenter traverses normal to the crystal face; the interactions that
are normal to that crystal facet, hence, will remain aligned to the
indentation direction. The bond-spring analogy is an elementary,
but qualitative and relatively old model wherein a bond is
analogous to a spring.[30] The strength of the spring is ideally
determined when compressed or elongated along its length
(Scheme 3). The stress applied at an oblique orientation will only
invoke a partial response while at normal to the length the spring
will merely yield or breaks. With this analogy, the maximal
modulus values are obtained when pressure is applied along the
overall direction of the bonds. When the applied stress is not
directly along the interaction directions (at an oblique or
orthogonal direction), the effective response due to the bond gets
 Isolated strong bonds in the midst of weak dispersive
interactions bring about a discontinuity in the chemical
space and will lead to lowering of H and E.
 The interweaving of strong and weak interactions is a
principal element to enhancing the mechanical property
of crystals.
 The E of molecular crystals is anisotropic, and depend
on the relative orientation of the hydrogen bond network
with respect to the crystal facet.

Accepted Manuscript
significantly diminished. In the present study, we analysed the
orientations of the hydrogen bond networks with respect to the
indentation direction. The observed trend in the modulus shows
that the concept of bond-spring analogy is valid in the analysis of
nanomechanical response in molecular crystals. In most of the
crystals with a higher modulus, the robust synthons remain either
aligned or near parallel to the indenter direction. The observations
are in agreement with a recent report on Young’s modulus of a
few amino acids, which highlighted the importance of the
orientation of the hydrogen bond networks with respect to the
crystal facet of interest.[14a] In STZ, an exception, has most of the
interaction aligned along the propagation of the bilayer units,
making them near normal to the indenter direction. The sheer
number and the intertwining of strong and weak interactions
Scheme 3. Representation of a bond-spring analogy applied to a hydrogen
across the lattice make them stiff. bond. The mechanical response from a spring is reflected indeed when
deformed along the linear direction, rather than in an oblique or normal
orientation, i.e., the effect is linear > oblique > normal.

Table 1. The quantified mechanical response in terms of the hardness and

modulus of the studied sulfa drug crystals. The major face selected for
indentation and the proposed slip system are provided.

Sulfa Hardness Elastic Indented Slip system

Drugs (H) modulus face
(MPa)[a] (E) (GPa) [a]

SPR 956 ± 51 15.69 ± 0.726 (200) (200) [002]

SCP 550 ± 30 15.5 ± 1.1 (011) (011) [10-1]

Figure 12. The AFM scan images of the indent impressions. The crystals with
and without materials pile-up is represented. The crystals of SDX shows
extensive crack along the corners of the indenter. SDZ 395 ± 40 7.69 ± 0.50 (100) (100) [011]

SMR 313 ± 50 9.54 ± 0.86 (002) (002) [020]

From the present study of the mechanical properties of the
sulfa drugs, a few observations stand out: STR 355 ± 20 5.71 ± 0.18 (020) (020) [10-1]
 Close-packing of molecules leads to enhanced H and E
SDX 544 ± 18 14.74 ± 0.168 (002) (002) [200]
values.
 Mere observation of layered molecular arrangement SMX (200) (200) [002]
489 ± 34 13.74 ± 0.498
does not mandate a deformable molecular crystal.
 Orthogonal distribution of strong and weak interaction is STZ 1080 ± 15 20.44 ± 0.25 (100) (100) [011]
a prerequisite to attaining higher plasticity, but
[a] The error bars correspond to the standard deviations obtained from 20
insufficient to accomplish deformability in molecular
measurements.
crystals.
 Interlocked molecular arrangements prevent long-range
sliding of molecular planes; ergo lead to enhanced E.

This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
FULL PAPER
Conclusions
The above results provide us with a unique opportunity to analyze
the structural factors that contribute to the nanomechanical
response in a series of anisotropic crystalline molecular systems,
using eight prototypical sulfa drug crystals. We highlight the
critical role of the molecular arrangements in the crystal, the
nature, and strength of the hydrogen bond networks, their
disposition in the crystal lattice and their orientations with respect
to the crystal facets of interest, in determining the mechanical
properties. Stronger, harder and energetically more demanding
synthons accumulate considerable strain at shorter distances,
contributing to the added stiffness of the crystal; however, weaker,
flexible and dispersive forces provide the buffer mechanisms to
accommodate and annul the excess strain developed, making the
systems more pliable to external mechanical stimuli. An
orthogonal distribution of strong and weak interactions could lead
to plastic deformation, but the intertwined occurrence of strong
and weak bonds indeed leads to an enhanced E. Further, the
spatial arrangement of the molecular building units in the crystal
lattice is vital in determining the deformability of the crystals.
Accordingly, a layered system offers energetically viable routes
for the long-range sliding of the molecular planes, compared to a
close-packed system. The crystal packing that leads to the
interlocking of the molecular layer hinders the long-range
molecular movements. Additionally, the robust synthons held at
the corners of a zig-zag layer offer a distinct mode of mechanism
to effectively cancel out the strain developed within―an
accordion-like movement as an efficient option. Taking the cue of
the bond-spring analogy, we studied the effect of the orientation
of the hydrogen bond networks with respect to the crystal facet of
interest. In fact, the observed trend in the modulus shows that the
concept of bond-spring analogy is valid in the analysis of
nanomechanical response in molecular crystals. We expect that
the observed nanomechanical response is not limited to sulfa
drugs, but gives a more comprehensive picture and parallels with
other anisotropic molecular crystals.
Acknowledgements
SLS is thankful to SERB for a National Postdoctoral Fellowship
(PDF/2017/000798). MSRNK DST-SERB, New Delhi for an Early
Career Researcher Award (ECR/2016/000827). SV thanks the
DST-SERB, New Delhi for an Extra Mural Research Fund
(EMR/2016/005064).
Keywords: crystal engineering • structure-property correlation •
nanoindentation • molecular crystals • bond-spring analogy
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Chemistry - A European Journal 10.1002/chem.201803987

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Nanomechanical response in S.SeethaLekshmi, M. S. R. N. Kiran, U.
molecular crystals: Combined inputs Ramamurty* and S. Varughese*
from the nanoindentation, structural
and computational data aid in Page No. – Page No.
comprehending on the molecular-level

Accepted Manuscript
factors determining the mechanical
properties of sulfa drug crystals. Molecular Basis for the Mechanical
Response of Sulfa Drug Crystals

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