Identifying Slip Planes in Organic Polymorphs by Combined Energy

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Identifying slip planes in organic polymorphs by combined energy framework calculations and topology analysis Chenguang Wang, and Changquan Calvin Sun Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.8b00202 • Publication Date (Web): 14 Feb 2018 Downloaded from http://pubs.acs.org on February 15, 2018

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Crystal Growth & Design

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Identifying slip planes in organic polymorphs by combined energy framework calculations and topology analysis

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Chenguang Wang and Changquan Calvin Sun*

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Pharmaceutical Materials Science and Engineering Laboratory, Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA

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*Corresponding author

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Changquan Calvin Sun, Ph.D.

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9-127B Weaver-Densford Hall

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308 Harvard Street S.E.

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Minneapolis, MN 55455

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Email: [email protected]

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Tel: 612-624-3722

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Fax: 612-626-2125

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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

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Abstract

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The relationship between crystal structure and mechanical properties is commonly studied by

29

identifying slip planes through inspecting crystal structures visually, with a focus on the hydrogen

30

bonding interactions. While useful, the visualization method lacks quantitative insight and the

31

identification of slip planes is sometimes subjective. Sometimes, crystal plasticity predicted from

32

structure visualization does not match experimental crystal plasticity and powder tabletability as

33

observed in three polymorphic systems, i.e., 6-chloro-2,4-dinitroaniline, indomethacin, and

34

febuxostat. Here, we explored the feasibility of more reliably identifying slip planes by the energy

35

framework approach, combined with the analysis of potential slip layer topology. In all three cases,

36

this new approach identified slip planes that are consistent with the observed mechanical plasticity

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and compaction behavior. Thus, it is superior to the visualization method for crystal structure

38

analysis aimed at identifying active slip planes in organic crystals.

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KEY WORDS：：structure – mechanical property, polymorph, slip plane, intermolecular interaction

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Introduction

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Polymorphism, the phenomenon of crystalline materials with identical molecular

44

composition but different internal crystal structures,1 plays an important role in the development

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and commercialization of fine chemicals, including pharmaceuticals, pigments, herbicides, foods,

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and explosives.2,

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distinct properties, such as solubility, dissolution rate, bioavailability, stability, and mechanical

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properties, which impact drug product development and manufacturing.2, 4 Polymorphs are also

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suitable for probing crystal structure-mechanical property relationship, which is an active area of

50

research for crystal engineers, chemists, and pharmaceutical scientists. 5-12

3

Polymorphs are of interest to pharmaceutical industry because they display

51

The bonding area and bonding strength (BABS) model suggests that higher crystal plasticity

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(i.e., lower hardness) favors larger bonding area and, therefore, stronger tablets during powder

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compaction.13, 14 Under an external compaction stress, crystals initially always undergo reversible

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elastic deformation but irreversible deformation, such as brittle fracture or plastic yield, takes place

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once the elastic limit is exceeded.15 High crystal plasticity, i.e., low hardness, corresponds to facile

56

plastic deformation.11, 16 The presence of slip planes is necessary for plastic deformation to occur in

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crystals, where the lower interaction energy and smoother surfaces of slip planes favor more facile

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slip.17

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hydrogen bonding patterns and molecular packing density of layers.18, 19 Stacking flat layers or

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parallel columns with smooth surfaces that interact weakly are crystal packing features that

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correspond to facile plastic deformation of crystals (Figure 1). Crystals with such structures were

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observed to exhibit good compressibility and tabletability, if bonding strength (collective interaction

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strength between two adjacent particles over unit bonding area) is comparable among crystals.6, 20-22

Slip planes are commonly identified by visualizing crystal structures, which relies on



(a)

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(b)

64 65 66 67

Figure 1. Crystal packing features that favor facile plastic deformation. a) hexachlorobenzene (refcode, HCLBNZ14) with parallel columns and 2) acetaminophen form II (refcode, HXACAN) with flat layered structure. Possible slip directions are indicated by arrows.

68 69

Crystal structure analysis based on visualization is qualitative and objective when obvious

70

layers cannot be unambiguously identified. Therefore, crystal structure visualization has led to

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some difficulties in explaining crystal mechanical properties and tabletability in several polymorph

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systems.7,

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dimensional (2D) layers without hydrogen bonds between them. However, the tabletability of Form

74

I is unexpectedly much lower than Form II.7 For indomethacin, crystal structure visualization

75

positively identified slip planes (0 1 1) in γ form but not in α form.

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to exhibit better tabletability than γ form, which is inconsistent with the expected behavior based on

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the BABS model if γ form were indeed more plastic.23 For febuxostat polymorphs, an active slip

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plane was identified in Form Q but absent in Form H1.24 This is inconsistent with the high

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plasticity of both crystals suggested by their low nanoindentation hardness (0.310 GPa for Form H1

23, 24

Both Forms I and II of 6-chloro-2,4-dinitroaniline (CDNA) exhibited flat two

23

However, α form was found


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and 0.214 GPa for Form Q).

The discrepancies between experimentally observed

81

plasticity/tabletability and that expected from structure visualization of these polymorphs were

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either not discussed7 or rationalized by considering factors that influence layer slip, e.g., presence of

83

weak hydrogen bonds,24, 25 or different bonding strength inferred from true density.23

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An alternative approach to address these discrepancies is to re-examine the accuracy of slip

85

plane identification by the visualization method. One main drawback in the visualization method is

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its reliance on sorting molecules based on the conventional hydrogen bonds.17 To identify slip

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planes by visualization, the following assumptions are made: 1) layers with the largest separation

88

distance exhibit weakest interlayer interactions, hence, easier molecular slip along the layer; 2) 2D

89

hydrogen bonded layers are rigid and slipping along them is energetically more favored than

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crossing them; 3) rough layer topology hinders facile interlayer slip, hence, lowers crystal plasticity.

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While the last assumption about layer topology is correct, the first two assumptions are questionable

92

because weak hydrogen bonds, such as C-H···O, are usually not considered during visualization.25

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In addition, because of geometrical sensitivity, the interaction strength cannot be accurately

94

assessed by visualization even when they are considered. Moreover, other important interactions,

95

e.g., halogen bonding, CH-π, and π-π interactions, are usually not graphically presented when

96

identifying slip planes by visualization. Consequently, visualization may not always accurately

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identify slip planes in a crystal, especially if molecular layers in some crystals cannot be easily

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visualized. Another common method for identifying slip planes is based on attachment energy, Eatt,

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which is defined as energy per mole of molecules released when one slice of thickness dhkl attaches

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onto a crystal face (hkl).26 The primary slip plane is assumed to be the crystallographic planes with

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the lowest Eatt, i.e., the interactions between slip planes are the weakest. The major drawback of

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this approach is that it does not consider layer topology. Therefore, planes with the lowest Eatt may

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not easily slip when they are corrugated due to physical hindrance by adjacent planes.11 Obviously, 5 ACS Paragon Plus Environment


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simultaneous consideration of Eatt along with structure visualization is better than either method

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alone. However, slip planes predicted by the two methods sometimes are at odds,18 which makes it

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difficult to finalize slip plane assignment in those cases. Crystal packing may also be described

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using “energy framework” based on pairwise intermolecular interaction energy by density

108

functional theory (DFT) calculation, which is graphically represented by cylinders connecting the

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centers of mass of the two molecules.27, 28 The calculated intermolecular interaction energy may be

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divided into the electrostatic, polarization, dispersion and exchange-repulsion components and

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properly scaled based on a large training set.29 It has been successfully utilized to rationalize the

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mechanical behavior of several molecular crystals, such as bending hexachlorobenzene and 3,4-

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dichlorophenol crystals, as well as the remarkably different tabletability of two paracetamol

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polymorphs.27 This method yields more accurate energy calculations than that based on force

115

fields, which is commonly used in calculating Eatt. A drawback of the DFT calculation is the longer

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calculation time, which can be compensated by using faster computers. Another useful method that

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also uses DFT calculation is Gavezzotti’s PIXEL method,30 which can also be graphically presented

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to characterize intermolecular interaction topology. 31

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Herein, we explored the potential application of the “energy framework” approach in

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identifying slip planes using CDNA, indomethacin, and febuxostat polymorphs (Figure 2). We

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assumed that slip planes are molecular layers exhibiting the lowest interlayer interaction energy and

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ease of sliding is allowed by layer topology. The correctness of the predicted slip planes was

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checked against the known mechanical properties and/or tableting behavior of those organic

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crystals.


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(a)

Form I

Form II

Form III

c

c

c

a

a a

Form α (b)

Form γ

b a

b c Form Q

(c)

Form H1

b

b

c

c

125 126

Figure 2. Crystal unit cell of a) CDNA, b) indomethacin, and c) febuxostat polymorphs.

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Method

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Crystal structure visualization

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CIFs of selected crystal structures were downloaded from Cambridge Crystallographic

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Structural Database using ConQuest (V. 1.19, CCDC, Cambridge, UK) and WebCSD. Crystal

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structures were visually examined to identify crystallographic planes using Mercury CSD (V. 3.9,



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CCDC, Cambridge, UK). This effort was aided by showing hydrogen bonds that meet the default

134

criteria given in the software.

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Attachment energy calculation

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Attachment energy was calculated using the Dreiding force field and Qeq charges at fine

137

quality available in the crystal growth module of the Materials Studio 7.0. (Accelrys Software Inc.,

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San Diego, CA, USA). The “Ewald” electrostatic summation method and “atom based” van der

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Waals summation was chosen. In addition, a minimum dhkl was set at 1.0 Å.18

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Energy framework

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The intermolecular interaction energy calculation was performed using dispersion-corrected

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DFT at the B3LYP-D2/6-31G(d,p) level of theory (CrystalExplorer V.17). During the calculation,

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hydrogen positions were normalized to standard neutron diffraction values.

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energies of a chosen molecule with all molecules having any atom within its 3.8 Å were calculated.

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Subsequently, all interaction energies within and between an identified layer or column were

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manually added to arrive at the total intra-layer, inter-layer, or inter-column interaction energies.

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For a crystal structure containing multiple molecules in the asymmetric unit, different total

148

interaction energies were obtained. In that case, an arithmetic mean value is used for ease of

149

comparison. The “energy framework” was constructed based on the crystal symmetry and total

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intermolecular interaction energy, which included electrostatic, polarization, dispersion, and

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exchange-repulsion components with scale factors of 1.057, 0.740, 0.871, and 0.618, respectively.29

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The interactions energies below a certain energy threshold are omitted for clarity and cylinder

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thickness is proportional to the intermolecular interaction energies. It should be pointed out that,

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although used to quantify intermolecular interaction energy in a periodic structure, the DFT

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calculations are not periodic structure calculations.

32

Then, the interaction

Where needed, interlayer or intralayer 8

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interaction energies were calculated by manually adding interaction energies between a given

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molecule in one layer and all interacting molecules in a neighboring layer or within the same layer,

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respectively (Figure S1).

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Results and discussion

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6-chloro-2,4-dinitroaniline (CDNA) polymorphs

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Three CDNA polymorphs exhibited distinctive shear (Form I, UCECAG01), bending (Form

163

II, UCECAG02), and brittle (Form III, UCECAG03) behavior.12 The slip planes predicted by

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visualization, attachment energy calculation, and energy framework approaches, as well as the

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mechanical behavior of three CDNA polymorphs are summarized in Table 1. The monoclinic Form

166

I CDNA consists of stacking flat (1 0 -1) planes (Figure 3a). Molecules in (1 0 -1) plane are

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hydrogen bonded (N-H···O=N, 3.032 Å; 3.054 Å), whereas no hydrogen bonds are present between

168

these planes. Therefore, (1 0 -1) plane is identified as the primary slip plane based on visualization.

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However, the (1 0 0) plane is found to have the lowest attachment energy and corresponded to the

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largest surface in the predicted crystal morphology (Table S2). For the (1 0 -1) plane, the energy

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framework analysis shows comparable intra- and interlayer intermolecular bonding energies

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(Table S1, Figure 3b). In fact, the total intralayer intermolecular bonding energies (-84.0 kJ/mol)

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are actually lower than that between layers (-106.4 kJ/mol). Therefore, sliding along (1 0 -1) plane

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is energetically unfavorable. In contrast, for (1 0 0) plane, the total interlayer interaction energy (-

175

84.8 kJ/mol) is significantly lower than the total intralayer interaction energies (-106.1 kJ/mol),

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implying the molecule slide along the (1 0 0) is energetically more favorable (Figure 3b).

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Molecules sliding along the (1 0 0) plane is also topologically feasible. Thus, (1 0 0) is the primary

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slip plane for CNDA Form I based on the energy framework approach. This is consistent with the 9 ACS Paragon Plus Environment


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experimental observation that the block morphology of Form I crystal is sheared along the

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dominating (1 0 0) facet instead of (1 0 -1) facet.

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The structure of monoclinic Form II CDNA consists of 2D thick layers parallel to the (0 0 1)

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plane (Figure 3c). Molecules within the layers are connected through two N-H···O=N (2.938 Å;

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3.066 Å) hydrogen bonds. Layers interact mainly through weaker Cl···Cl (3.996 Å) halogen

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bonding and C-H···O=N (3.382 Å) hydrogen bonds. The notably larger intralayer (-148.8 kJ/mol)

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interaction energy than the interlayer (-30.2 kJ/mol) interaction energy indicates that (0 0 1) is the

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active slip plane (Table S1), which is consistent with its lowest attachment energy (Tables S2).

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The structure of triclinic Form III CDNA consists of 2D interlocked layers (Figure 3e).

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Both visualization and attachment energy methods suggested (0 0 1) as the slip plane (Table S2).

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This was confirmed by the much larger total intralayer interaction energies (-148.6 kJ/mol) than

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interlayer total interaction energies (-69.6 kJ/mol) (Figure 3f, Table S1). However, the topological

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feature of (0 0 1) plane restricted the slip direction to be along the b direction only. This means that

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slip in Form III CDNA is not facile.

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The best tabletability of Form II among the three polymorphs is attributed to the ease of

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molecules sliding along the slip planes, which exhibit much weaker interlayer interaction energies

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compared with other polymorphs. Although flat slip planes are identified in both Forms I and II,

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the lower interlayer bonding energies of Form II, which corresponds to higher plasticity, explains its

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superior tabletability than Form I. The worst tabletability of Form III in this polymorph system is

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attributed to the restricted mobility of the primary slip planes due to unfavorable layer topology.7

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200


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(a)

(10-1)

(c) (001)

(e)

(100)

(b)

(d)

(f) (001)

201 202 203 204 205

Figure 3. Crystal packing patterns (left) and corresponding energy frameworks (right) for CDNA polymorphs, a, b) Form I, c, d) Form II, and e, f) Form III. A likely slip layer by visualization is shaded in blue and that by energy framework is shaded in pink. The thickness of each cylinder (in blue) represents the relative strength of interaction. The energy threshold for the energy framework is set at -15 kJ/mol.



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Table 1. Summary of mechanical behavior and slip planes predicted by visualization, attachment energy, and energy framework approaches of three CNDA polymorphs. Slip planes

Form I

CSD

Visualization

refcode

(ref. 32)

UCECAG01

(1 0 -1)

Energy

Crystal Mechanical

framework

behavior

(1 0 0)

sheared along the largest

(hkl)/Eatt (kCal/mol)

(1 0 0)/-71.44

facet Form II

UCECAG02

(0 0 1)

(0 0 1)/ -14.15

(0 0 1)

Bending

Form III

UCECAG03

(0 0 1)

(0 0 1)/-45.12

(0 0 1)

Brittle

209 210 211

Indomethacin polymorphs

212

Molecules in indomethacin monoclinic Form α (INDMET02) are connected through O-

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H···O (2.593 Å, 2.704 Å, and 2.735 Å) hydrogen bonds. Visualization suggests a lack of obvious

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crystallographic slip planes (Figure 4a).23 However, a column structure could be identified with the

215

aid of the energy framework (Figure 4b, Table S1). The inter-columnar molecular interaction

216

energies (-41.7 kJ/mol) is significantly lower than intra-columnar interaction energies (-254.7

217

kJ/mol). Therefore, in contrast to the lack of slip planes predicted based on visualization, multiple

218

active slip planes parallel to a axis are identified by the energy framework approach. Among those

219

potential slip planes, (0 0 1) has the lowest interlayer interaction energy, which makes it the most

220

energetically favorable plane for molecules to slide under an external shear stress. This is also

221

consistent with the lowest attachment energy of (0 0 1) (Table S2). 12 ACS Paragon Plus Environment

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For indomethacin triclinic Form γ (INDMET03), visualization suggested (0 1 1) as the

223

primary slip plane (Figure 4c).23 Within the (0 1 1) layer, indomethacin molecules formed dimers

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through O-H···O (2.651 Å) hydrogen bonds (Figure 4c).

225

interaction energy between adjacent (0 1 1) layers (-189.6 kJ/mol) is much higher than that within

226

the layers (-54.9 kJ/mol) (Figure 4d), suggesting that molecules slipping along the (0 1 1) plane is

227

energetically unfavorable. An inspection of the energy components revealed that C-H···O (3.397

228

Å), CH- π, and π-π interactions contributed significantly to the total interaction energy between (0 1

229

1). Such contributions are neglected when identifying slip planes by the visualization method.

230

Instead, the (0 0 1) plane is likely the primary slip plane because the total intralayer bonding energy

231

(-164.8 kJ/mol) is much higher than the interlayer bonding energy (-86.0 kJ/mol). This assignment

232

of slip plane is consistent with the lowest attachment energy of (0 0 1) planes (Table S2). However,

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molecular slip along (0 0 1) is difficult due to the rough topology of the (0 0 1) layers (Figure 4c).

234

Table 2 shows a summary of the slip planes predicted by visualization, attachment energy, and

235

energy framework approaches, as well as the tableting behavior of two indomethacin polymorphs.

236

Therefore, the analysis of crystal structures using energy framework combined with layer topology

237

consideration led to the conclusion that indomethacin Form α is more plastic than Form γ, a

238

prediction that is consistent with the superior tabletability of Form α.23

239 240

Table 2. Summary of tableting behavior and slip planes, predicted by visualization, attachment energy, and energy framework approaches, of two indomethacin polymorphs.

Surprisingly, strong intermolecular

Slip plane Visualization (ref. 23) (hkl)/Eatt (kCal/mol) Energy framework CSD refcode Tabletability Form α

None

(0 0 1)/-44.67

(0 0 1)

INDMET02

Higher

Form γ

(0 1 1)

(0 0 1)/-54.41

(0 0 1)

INDMET03

Lower

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(a)

(b)

(c)

(d)

(011)

(001)

243 244 245 246 247

Figure 4. Crystal packing patterns (left) and corresponding energy framework (right) for indomethacin polymorphs, a, b) α form, and c, d) γ form viewed along the a axis. Molecular layers based on visualization method are shaded in blue and those by energy framework are in pink. The green lines in (c) outline a molecular layer identified from the energy framework. The energy threshold for the energy framework is set at -25 kJ/mol.

248 249 250

Febuxostat polymorphs

251

Visualization suggested (-1 0 4) as slip plane in monoclinic febuxostate Form Q (HIQQAB).

252

Molecules within this layer are connected through C-H···N≡C (2.782 Å) hydrogen bonds while no

253

hydrogen bond is present between layers (Figure 5a).24 However, the energy framework suggests 14 ACS Paragon Plus Environment

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254

the molecules stacking cross (-1 0 4) exhibit stronger interaction energy (-180.4 kJ/mol) than the

255

bonding energy within the (-1 0 4) plane (-114.1 kJ/mol) (Figure 5b, Table S1). Therefore, sliding

256

along the (-1 0 4) plane is energetically unfavorable even (-1 0 4) planes are smooth. The energy

257

framework of Form Q revealed a columnar structure, instead of layer structure, where the intra-

258

columnar interaction energy (-155.4 kJ/mol) is higher than inter-columnar interaction energy (-

259

139.1 kJ/mol) (Figure 5c).

260

planes based on energy consideration.

Therefore, planes (0 1 1), (0 1 -1), (0 0 1) and (0 1 0) are likely slip

261

In triclinic febuxostat Form H1 (HIQQAB02), molecules formed dimers via O-H···O (2.624

262

Å) hydrogen bonds, which are further connected through C-H···N≡C (3.536 Å) and C-H···O (3.408

263

Å) hydrogen bonds along (2 0 1) (Figure 5d). In an effort to explain the inferior plasticity of Form

264

H1, it was suggested that the sulfonamide groups participate in the interlayer interaction, thus

265

immobilizing the layers.24 However, the energy framework results showed significant dispersive

266

energy due to π- π interaction stacked along the (2 0 1) planes (Table S1). Consequently, the

267

intralayer interaction energies (-115.4 kJ/mol) are weaker than the interlayer interaction energies (-

268

183.2 kJ/mol), suggesting the molecules slip along the (2 0 1) plane is energetically unfavorable

269

(Figure 5e). Instead, the (0 1 0) plane is energetically more favored slip plane (Figure 5f). This is

270

consistent with the lowest attachment energy of this crystal facet (Table S2). The intermolecular

271

bonding energies within (0 1 0) (-257.7 kJ/mol) are significantly higher than those between (0 1 0)

272

(-31.5 kJ/mol), which suggests that it is energetically much more favorable for molecules to slid

273

along (0 1 0). Thus, the Form H1 consists of stacking thick 2D (0 1 0) layers, which could serve as

274

slip planes. The slip planes predicted by visualization, attachment energy calculation, and energy

275

framework approaches, as well as the mechanical properties of the two febuxostat polymorphs are

276

summarized in Table 2. Therefore, both Forms Q and H1 are expected to be plastic owing to the

277

slip planes identified by the energy framework based approach. This is in accordance with the 15 ACS Paragon Plus Environment


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higher plasticity (i.e., low hardness) and excellent compressibility and tabletability of both forms.24

279

The higher plasticity of Form Q than Form H1 corresponds to its columnar structure, which leads to

280

multiple slip systems and more facile plastic deformation than Form H1 featured with 2D thick

281

layers.

282

283 284

Table 3. Summary of mechanical properties and slip planes, predicted by visualization, attachment energy, and energy framework approaches, of two febuxostat polymorphs Slip plane

Form Q

Form H1 285 286

a.

CSD

Visuali-

(hkl)/Eatt

refcode

zation

(kCal/mol)

HIQQAB

(-1 0 4)

(0 1 1)/-32.81

HIQQAB02

(2 0 1) a

(0 1 0)/-22.10

Energy framework

Mechanical properties

(0 1 1), (0 1 -1), (0 0 1),

Plastic crystal with lower H

(0 1 0)

and higher tabletability

(0 1 0)

Plastic crystal

No active slip plane was identified in Form H1 in ref. 24.

287


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(a)

(c)

(-104)

(001) (011)

(01-1)

(b) (010)

(d) (201)

(f)

(010)

(e)

288 289 290 291 292 293

Figure 5. Crystal packing patterns (a, d) and corresponding energy framework (b, c, e, f) for febuxostat polymorphs. a, b, c) Form Q, and d, e, f) Form H1. Molecular layers based on visualization are shaded in light blue and molecular columns and layers based on energy framework are shaded in pink. 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.

294 295

296 297

Conclusions Qualitative analysis of crystal structure based on hydrogen bond analysis faced difficulty in explaining the mechanical properties and tableting behavior of three polymorph systems.

In



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contrast, the quantitative crystal structure by the energy framework approach successfully explained

299

experimental observations in all cases.

300

The higher plasticity of indomethacin Form α than γ and febuxostat Form Q than H1 is

301

explained by multiple active slip planes corresponding to their parallel columnar structures. Slip

302

planes with smooth layer topology were identified in CDNA Forms I and II, febuxostat Forms Q

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and H1 forms. This is consistent with their low hardness and absence of tableting problem. The

304

relatively lower tabletability of CDNA Form I than Form II corresponds to its lower plasticity

305

because of the higher interlayer bonding energies between flat layers. The rough topology of

306

CDNA Form III and indomethacin Form γ hinders facile slip, which led to poor plasticity and

307

tabletability.

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The visualization method accounts for hydrogen bonding but overlooks the large variability

309

of hydrogen bonds strength and contributions by other types of intermolecular interactions, e.g.,

310

dispersive interactions. Consequently, slip planes can be erroneously identified by visualization

311

alone. This, in turn, leads to difficulty in explaining mechanical properties and tableting behavior

312

of crystals in the three model polymorph systems. In contrast, the energy framework approach led

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to correct identification of slip planes in all model crystals. Along with the consideration of slip

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plane topology, such information was successfully used to clearly explain experimentally observed

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mechanical behavior and tableting performance. The attachment energy approach could correctly

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identify slip planes but inherently incapable of revealing structural features that promote molecular

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slip, such as the slip columns, in certain crystals. Overall, the approach of combined energy

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framework and topological analysis led to more accurate identification of slip planes and more

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reliable predictions of crystal mechanical properties. If proven robust in a much larger set of

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crystals, this approach is expected to be an important tool for the future research aimed at

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establishing crystal structure – mechanical property - tabletability relationship. 18 ACS Paragon Plus Environment

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Supporting Information

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Intermolecular interaction energies, attachment energies and crystallographic parameters of CDNA,

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indomethacin, and febuxostat polymorphs.

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Acknowledgments

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We thank the Minnesota Supercomputing Institute (MSI) at the University of Minnesota for

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providing resources that contributed to the research results reported in this paper.

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References

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For Table of Contents Use Only

Synopsis Analysis of crystal structures using the energy framework approach correctly identified slip planes that reconciled inconsistency between observed mechanical properties and predicted plasticity based on slip plane predicted from crystal structure visualization.


Identifying Slip Planes in Organic Polymorphs by Combined Energy

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