Revealing the role of structural features in bulk mechanical

Subscriber access provided by UNIVERSITY OF TOLEDO LIBRARIES

Article

Revealing the role of structural features in bulk mechanical performance of ternary molecular solids of Isoniazid Jay Prakash A. Yadav, Bharat Yadav, Navin Kumar, Arvind K Bansal, and Sanyog Jain Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.8b00759 • Publication Date (Web): 28 Sep 2018 Downloaded from http://pubs.acs.org on September 30, 2018

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

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

Page 1 of 24 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

Molecular Pharmaceutics

Revealing the role of structural features in bulk mechanical performance of ternary molecular solids of Isoniazid Jay Prakash A. Yadav1, Bharat Yadav2, Navin Kumar2, Arvind K. Bansal1*, Sanyog Jain1*

1

National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar - 160 062, Punjab,

India. 2

Department of Mechanical Engineering, Centre of Materials Science and Energy Engineering, Indian Institute of Technology (IIT) Ropar, Rupnagar - 140 001, Punjab, India

*Corresponding Authors Dr. Sanyog Jain Associate Professor, Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar - 160 062, Punjab, India. Email: [email protected], Contact No: +91-172-2292055, Fax No.: +91-172-2214692 Prof. Arvind K. Bansal Head, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar - 160 062, Punjab, India. E-mail address: [email protected], Contact No. +91-172- 2214682, Fax No.: +91-172-2214692

1

ACS Paragon Plus Environment

Molecular Pharmaceutics 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

Graphical abstract

[Solid-state structural chemistry engineering in tableting process]

2


Page 2 of 24

Page 3 of 24 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


Abstract Mechanical performance in ternary (3n) molecular solids has been rarely studied and hence it is an interesting topic of investigation in direct compression method of tableting. The structural features of 3n-eutectic (3n-Eu: INZ-ADP-NIC) and 3n-cocrystal (3n-Co: INZ:SUC:NIC) were explored to understand the bonding area-bonding strength (BA-BS) interplay. Higher compressibility and lower values of Heckel parameter of 3n-Co as compared 3n-Eu suggested its better deformation behavior with BA being predominant factor. Higher tensile strength and Walker analysis indicated higher compressibility coefficient (W) and lower pressing modulus (L) for 3n-Eu, which was consistent with its better tabletability over 3n-Co. Higher compressibility and plastic energy, and higher value of L of 3n-Co was attributed from facile propagation (< -1ʹ 0ʹ 5ʹ >) of shearing molecular slip (-1 0 5) when subjected to the external mechanical stress. Thus, overall higher tableting performance of 3n-Eu over 3n-Co was found due to predominant BS and limited contribution of BA. Later was the dominant factor in 3nCo. Cohesive interactions like 3D mechanically interlocked structure of conglomerates of 3n-Eu contributed towards higher BS. Moreover, prediction of better tabletability solely based on crystallographic feature slip planes (0D/1D/2D H-bonded layer (h k l) Ʇ vdW interactions) is warranted in pharmaceutical molecular solids. Eutectics with varying microstructural variants (nLα+ nLβ + nLγ) may open up opportunity to manipulate the physico-mechanical performance.

Keywords:

Ternary molecular solids, Tensile strength, Plastic deformation, Active slip system, Eutectic

solids, Fracture mechanics

3



Page 4 of 24

Introduction Eutectic solids exhibit microstructure level periodicity;3, 4 which can modify physicochemical properties such as solubility,5, 6 dissolution rate,5, 7, 8 hygroscopicity,3 stability,5, 6 and mechanical behavior9, 10 (tensile strength, yield strength and plasticity). The smallest structural elements of eutectics can be viewed at microscopic level.9 These unit microstructures from the individual components are proposed to co-solidify based on their non-dimensional entropy of fusion difference11 (ΔS ) during the solidification kinetics.10,

12

ΔS controls formation of

microstructure which provides different physicochemical properties than parent components. However, specific rules concerning this ΔS have been rarely reported in literature for pharmaceutical (organic) eutectic systems.6 Sometimes, major value of ΔS dictated other observed underlying microstructures.5, 13, 14 Hence, it is expected

that if the system has been formed wherein third component is being incorporated, with unit structural variant4, then solidification kinetics may demonstrate the overall microstructural outcomes with respect to the entropy of fusion difference12 of the all partner components. Apparently microstructure is a consequences of the balanced ΔS during the faceted or non-faceted (lamellar) growth of microstructure.4, 11 The lamellar microstructures in

eutectics demonstrated better tableting performance as compared to simple or non-reacted physical mixture.9 However, bonding strength remained relatively unaltered and further proposed to be responsible for the similar extrinsic chemical nature9 (non bonding interactions; NBIs) inherited from the same components in two crystalline systems. On the same line, the microstructure’s influence was eliminated by forming two binary drugdrug eutectics with similar microstructures.10 Henceforth, it was found that overall bulk deformation behavior of eutectics was primarily governed by the differing intrinsic deformational of crystal structure and chemical nature of the second components with common shearing solid.10 This further strengthened the fact that if microstructures play important role in tableting,9 and so equally does its components10 and composition. Moreover, the reports on mechanical behavior of pharmaceutical eutectics have been uncommon; hence, it further seeks our understanding in tableting process. In tableting, the plasticity15, 16 and tensile strength17, 18 have been prime focus in order to achieve excellent tabletability. The crystal structure of molecular solids has been responsible for plasticity (increase in bonding area, BA) in single component (1n) polymorphs,

16, 17, 19, 20

and

multi-component (≥2n) cocrystals21-23 and few solvates15, 24. However, bonding strength has been contributed

4


Page 5 of 24 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


variably from layered crystallographic planes.17, 20, 23

Furthermore, hitherto it still remains to be explored the

potential of crystal structure of homogeneous solid like cocrystal against microstructural variants of eutectic, a heterogeneous system. Thus, in an attempt we reveal the comparison of two structural features in bulk mechanical behavior of ternary cocrystal and ternary eutectics. Moreover, eutectics and cocrystals are mutually exclusive outcomes of cocrystallization experiments.25 For example, Isoniazid forms ternary cocrystal with Niacinamide and Succinic acid, but the same molecules does not form ternary eutectic. Hence for two or more given molecules, if one system is definite then other remains elusive.25 We report that Adipic acid can provide exact ternary eutectic composition which was screened using thermal method. Hence different component, Adipic acid, of 3n eutectic (3n-Eu) has been selected to be structurally homologous and chemically equivalent to the supramolecular linker of 3n cocrystal (3n-Co) in order to maintain the similar NBIs.

Experimental section Materials Isoniazid (INZ) was purchased from Wockhardt Ltd., Aurangabad, Maharastra, India. Niacinamide (NIC), Succinic acid (SUC) and Adipic acid (ADP) (Loba Chemi Pvt. Ltd., Mumbai, India), and Isoniacinamide 5 (Alfa Aesar, Heysham, England) were of LR grade. Methanol (J. T. Bakers, Gliwice, Poland) was of HPLC grade.

Methods Differential scanning calorimetry (DSC) Thermal analysis was performed using DSC (Q2000, TA Instruments, New Castle, DE, USA) operating with Universal Analysis® software, version 4.5A. 3-4 mg of each sample was weighed accurately in aluminum pans and subjected to the thermal scan from 25 to 200°C at the heating rate (β) of 10°C min−1. During analysis, dry nitrogen (N2) purge was maintained at 50 mL min−1. The instrument was calibrated using high purity standard of indium (In) before analysis.

Generation of 3n eutectics (3n-Eu) and 3n cocrystal (3n-Co) Exact eutectic composition was screened by DSC and compositions were prepared by solvent-drop grinding (SDG). Bulk generation was further carried out by solvent evaporation method followed by SDG (for detail see ESI, SM 1). 3n cocrystal (INZ:SUC:NIC) was synthesized as per the reported method2 (ESI, SM 2).

5



Page 6 of 24

Particle size distribution (PSD) Comparable particle size distribution was obtained by BSS sieve passing the sample through 100# and retaining on 120#. D50 and D90 of eutectics and cocrystal were determined by optical microscope (Leica DMLP microscope, Leica Microsystems, Wetzlar, Germany) equipped with camera (JVS color video) and analytical software (Lynksys32) by measuring diameter along the longest axis, for 300 particles.

Moisture content (MC) MC of all samples (accurately weighed about 500 mg) was estimated by Karl Fischer (KF) titration (Metrohm 794 Basic Titrino, Herisau, Switzerland). The instrument was calibrated with disodium tartrate dehydrate for the accurate MC determination (n=3).

Bulk and true density determination Bulk density (ρb) was determined by adding accurately weighed powder to a 50 mL measuring cylinder. The true density (ρt) of all samples was determined in triplicate by helium pycnometry (Pycno 30, Smart Instruments, Mumbai, India) at 25±2 °C/40±5 %RH.

Specific surface area analysis Specific surface area (Asp) of all samples was determined using N2 gas sorption (SMART SORB 91 Surface Area Analyzer, Smart instruments, Mumbai, India). The instrument was calibrated by injecting a known quantity of N2. The measured parameters were further used to calculate Asp of all solids by employing BET equation. 500 mg of sample was placed into the glass loop of the instrument and submerged into liquid N2. The amount of the adsorbed N2 was quantified using thermal conductivity detector and further integrated by electronic circuit. The reported values are average of the three measurements (n=3).

Powder X-ray diffraction (PXRD) PXRD patterns of all solids were recorded at room temperature (25±2 °C) on Bruker’s D8 Advance Diffractometer (Bruker, AXS, Karlsruhe, Germany) with Cu Kα radiation (1.54 Å), at 40 kV, 40 mA passing through Nickel filter. Analysis was carried out in a continuous mode with a step size of 0.01° and step time of 1s

6


Page 7 of 24 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


over an angular range of 4 to 40° 2θ. Further, the obtained PXRD patterns were analyzed using DIFFRAC plus EVA, version 9.0 (Bruker, AXS, Karlsruhe, Germany) diffraction software.

“Out-of-die” bulk deformation profile Hydraulic press (Type KP, Sr. No. 1125, Kimaya Engineers, Maharastra, India) was used to investigate the compaction properties of solids. Compacts were prepared by compacting 400 mg of crystalline material applying up to 300 MPa compaction pressure in a hydraulic press with a dwell time of 1 min using 13 mm flat punch-die set. The applied hydraulic load (L) was converted into pressure (P) using the cross-sectional area (A) of flat punch-die set. The tablets were further analyzed accurately for weight, thickness and required breaking force (F) after 24 h of elastic recovery.

Calculation of tensile strength (τ) and porosity (ε) Breaking force of compact was measured by hardness tester (Erweka, TBH 20, USA) after 24 h of elastic relaxation. Tablet dimensions were measured using a digital caliper (CD-6 CS, Digimatic Mitutoyo Corporation, Japan). Tensile strength (τ, MPa) was calculated by employing the following equation to eliminate the undesirable effect of variable compact thickness on measured F.

=

Equation 1.0

Where, F is the breaking force (N), d is the diameter 1, and t is the thickness of the compact 1. The porosity, ε, of the compacts was calculated as ―

= 1 −

Equation 2.0

Where, ρc is the density of the compact calculated from the weight and volume of the resulting tablet, and ρt is the true density of the solid.

Dynamic hydraulic compression analysis In order to generate the load-displacement profile, samples were tested on “in-die” compressive set-up using closed-loop hydraulic dynamic testing machine (Servo-Pulser, 4830, Shimadzu) with a capacity of maximum achievable load. The loading platens and compressive set-up are made of hard steel and have polished surfaces. Accurately weighed 400 mg of powder sample was compressed for each solid using a maximum of 5.290 kN compressive load with a single loading method in a load control mode (TD1) with a accurate strain rate ( ) of 0.5

7



Page 8 of 24

kN s-1 and data sampling interval was kept at 0.1 second (where, = / , speed, where is the axial flat punchto-platen displacement in the die cavity, and is the initial distance between the top flat punch and bottom platen surfaces over the height (or volume) of powder sample). Two accurately calibrated linear variable differential transformers (LVDTs) were used to measure axial displacement. The load, F and the axial displacement ( ) were continually monitored and recorded.

Statistical analysis Statistical significance for values of various bulk deformation parameters was compared using two tailed paired t-test (SigmaStat version 3.5, San Jose, CA, USA), and the test was considered to be statistically significant if P < 0.05.

Molecular modeling The crystal structure of 3n-Co, INZ, INC, and ADP were investigated using CSD-Enterprise’s module Mercury software (Version 3.9 CCDC, Reg. No. 800579, UK).

Results and Discussion The molecular structure of components of the ternary molecular solids, 3n-Eu and 3n-Co are shown in scheme 1. Figure 1 shows DSC heating curves for screening of exact composition (ϕ) of 3n-Eu which is composed of three

(iii)

(i)

(ii)

(iv)

Scheme 1. Molecular structure of components of 3n-Eu (eutectics) and 3n-Co (cocrystal): (i) Isoniazid (INZ; n1), (ii) Niacinamide (NIC; n2), (iii) Succinic acid (SUC; n3), and (iv) Adipic acid (ADP; n3ʹ). ADP (n3ʹ ∈ 3n-Eu) is structurally homologous and chemically equivalent to the SUC (n3 ∈ 3n-Co).

components, INZ, NIC and ADP. A single solidus endotherm (heating curve ‘h’) devoid of any other minor liquidus events confirmed the formation of 3n-Eu (exact eutectic composition, ϕ = 40:26.66:33.33). The ternary

8


Page 9 of 24

phase-diagram shown in Figure 2 demonstrates the region of eutectic reaction wherein thermal events like major invariant solidus and minor variant liquidus take place. Table S1 (Supporting information) shows experimental

30

a b c

15

d e

Heat Flow (mW: ∆Hf)

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


0

f g h i j k l m

-15

-30

-45

-60 15

55

95

135

175

205

Temperature (ºC)

Figure 1. Endothermic heat flow (mW) on melting of components of eutectic (a‒c) and varying (% w/w; NIC:ADP:INZ) proportion (d‒m) screened for exact eutectic point: (a) 0:0:100, (b) 0:100:0, (c) 100:0:0, (d) 53.33:13.33:33.33, (e) 50.00:16.33:33.33, (f) 46.66:20.00:33.33, (g) 33.33:33.33:33.33, (h) 40.00:26.66:33.33, (i) 36.36:30.00:33.33, (j) 30.00:36.66:33.33, (k) 26.66:40.00:33.33, (l) 46.66:20.00:33.33, (m) 20.00:46.66:33.33. A melting endotherm ‘h’ (single solidus) gives exact eutectic composition (ϕ = 40:26.66:33.33 % w/w) with eu = 112.79 ºC (∆Hf = 204.7 J g‒1)

values such as melting temperature and other excess thermodynamic parameters (enthalpy of fusion (∆Hf) and entropy of fusion (∆Sf)) of the individual components and ternary eutectic system. The ΔS between INZ and

NIC is < 2 (1.32), the difference between INZ and ADP is > 2 (3.93), and the difference between NIC and ADP is > 2 (5.26), hence, only INZ and NIC can form non-faceted or regular growth, whereas NIC and ADP or INZ and ADP can be responsible for faceted or irregular growth as a microstructural outcome.11, 12 As the current system is ternary, specific rule concerning the co-solidification of multiple components (i.e. n > 2) based on ΔS

has not been documented in the literature. However, the microstructure can be the consequence of the balance of overall non-dimensional ∆Sf during the kinetics of co-solidification.

9



1 165 INZ(S)α + NIC (L)β +

Mole Fraction of Isoniazid (INZ)

ADP(L)γ

150

0.6 135

INZ(S)α + NIC (L)β + ADP(S)γ 0.4

120

INZ(S)α + NIC (S)β + ADP(S)γ

Temperature (ºC)

0.8

eu1

0.2

105

INZ(S)α + NIC(S)β + ADP(S)γ 0

90 0

0.2

0.4

0.6

0.8

1

Mole Fraction of NIC Mole Fraction

ER-INZ

ER-NIC

ER-ADP

Figure 2. Phase diagram of a ternary mixture of components (INZ, NIC and ADP) depicting the temperature of the system as a function of mole fraction of the components. Xn=1 suggests pure (100 %) component: XINZ = 1 (Tm = 172.18 ºC), XNIC = 1 (Tm = 128.71 ºC), XADP = 1 (Tm = 152.17 ºC). A trajectory formed showing variant liquidus and invariant solidus is encircled which gives region of eutectic reaction and eutectic point (eu = 112.78 ºC). B a

300000

b

5

c 4

d -15

Lin (Counts)

Heat Flow (mW: ∆Hf)

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

Page 10 of 24

200000

e

4ʹ 5 3 3ʹ

100000

-35

2 2ʹ 1

A -55 15

1ʹ

0

65

115

165

215

5

10

Temperature (ºC)

20

30

40

2-Theta - Scale

Figure 3. A. Overlay of endothermic heat flow (mW) on melting of components of 3n-Eu and melting endotherm of 3nCo: (a) INZ (∆Hf = 217.70 J g‒1, (b) ADP (∆Hf = 290.20 J g‒1, (c) NIC (∆Hf = 128.70 J g‒1, (d) 3n-Eu (∆Hf = 204.70 J g‒1, and (e) 3n-Co (Tm = 136.93 ºC, ∆Hf = 192.40 J g‒1). B. Overlay of X-ray diffractograms: 1ʹ (Ref. Code: INICAC02), 2ʹ (Ref. Code: NICOAM01), 3ʹ (Ref. Code: ADIPAC12) and 4ʹ (Ref. Code: BICQAH) simulated X-ray diffractograms of INZ, NIC, ADP and 3n-CO, respectively. 1, 2, 3, 4 and 5 experimentally recorded powder X-ray diffraction patterns of INZ, NIC, ADP, 3n-Eu and 3n-Co, respectively.

10


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


Figure 4. “Out-of-die” bulk deformation behavior obtained as a function of applied mechanical pressure (P, MPa): (i) compressibility (↑ BA) plot, (ii) compactibility (↑ BS) plot, (iii) tabletability (BA + BS) and (iv) Heckel analysis [ln (1/ε) = KP + A], where ε = (1 ‒ solid fraction (SF)).

“Out-of-die” bulk mechanical behavior: From molecular perspective In an attempt to correlate molecular level structural features, particle level parameters were kept comparable to eliminate their variation on their bulk level deformation behavior for both materials. Figure 3-B shows overlay of powder X-ray diffraction pattern of 3n-Eu and 3n-Co wherein experimentally recorded powder X-ray patterns are compared with simulated X-ray diffractograms. Figure 3-A represents endothermic heat flow on the melting behavior of the molecular solids. Figure 4 (i) shows compressibility plot which assesses the increase in interparticulate bonding area (↑ BA). Compactibility signifies the increase in interparticulate bonding strength (↑ BS), whereas tabletability involves both BA + BS. Heckel analysis is a kinetic model which represents the degree of densification as a function of applied pressure.26, 27 The porosity (ε) of both solids decreased as a function of applied pressure as expected (Figure 4 (i)), however, the relative volume reduction of 3n-Eu is lower as compared to 3n-Co. At highest pressure (~296 MPa), lowest ε values were found to be 0.042 and 0.009 for 3n-

11



Page 12 of 24

Eu and 3n-Co, respectively. On the other hand, compactibility (BS) is significantly higher for 3n-Eu than cocrystal (Figure 4(ii)). Compactibility is measurement of the ability of materials to form a compact of sufficient tensile strength under the effect of densification. At maximum porosity (ε > 0.12) 3n-Eu demonstrated 2.88 MPa tensile strength (τ), while at minimum achieved porosity (ε ≈ 0.0095), 3n-Co possessed 2.10 MPa τ. At ε = 0.00, 3n-Co was predicted to possess maximum of 2.50 MPa τ by performing Ryshkewitch-Duckworth analysis. This finding implied that slip planes invariably enhances the BA, however contribution of BS towards tabletability should also be evaluated in both, single and multi-component system. It is equally noteworthy that these both system possess quite comparable measured true density values (3n-Eu: ρt1 = 1.438 ± 0.006 g cm-3, 3n-Co: ρt2 = 1.442 ± 0.005 g cm-3), hence in this case, the relationship of higher true density value related with higher BS is ruled out as it has been reported in case of polymorphic pairs.10, 17, 19 However, this relationship has not been investigated in case of multi-component co-crystal polymorphs and/or co-crystals. Tabletability has been considered as a summation of both BA and BS (BA-BS interplay). Hence, τ has been frequently used as a performance criterion to quantify the bulk mechanical performance of pharmaceutical materials. τ was increased for both systems at applied range of compaction pressure, but it is quite higher for 3n-Eu as compared 3n-Co (Figure 4 (iii)). This further suggested that better tabletability of 3n-Eu over 3n-Co attributed from the significant ↑ BS (dominant factor), while ↑ BA has limited role in BA-BS interplay. In tableting behavior of 3n-Co, increase in compressibility implied facile increment of BA (dominant factor), but BS remained limiting factor in BA-BS interplay. In other words, shearing type of molecular plane under applied stress ↑ BA, however, the same did not enhance the BS as compared to ↑ BS of 3n-Eu in BA-BS interplay. It is noteworthy that physical mixture of these two solids exhibited different tableting and the formation of coherent compact was unsatisfactory as compared to their reacted counterparts. In order to eliminate ambiguity related with physical mixture and differentiate them from 3n-Eu + 3n-Co, τ was also measured for the physical mixture. At 148 MPa pressure (P), physical mixture of 3n-Co (Pm-Co) demonstrated τ = 2.19 MPa. It is higher as compared to 1.68 MPa for 3n-Co. At higher P (>148 MPa), Pm-Co showed capping which was not observed in plastically deforming 3n-Co. On the other hand, at the same P, Pm-Eu demonstrated τ = 2.36 MPa, and 3n-Eu possessed quite higher 3.65 MPa τ. There was negligible compact defect found to be associated with Pm-Eu. Thus, rank ordering of plasticity at 148

12


Page 13 of 24 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


MPa can be given as 3n-Co > 3n-Eu > Pm-Eu > Pm-Co. On the other hand, at pressure of 148 MPa according to the quantitative tensile strength, the order is: 3n-Eu > Pm-Eu > Pm-Co > 3n-Co. Heckel analysis is widely used mathematical model to characterize pharmaceutical materials. It expresses linearism of compaction data and considers densification behavior as function of a range of applied compaction pressure.26 Its linear region (with R2=0.988 in both cases) was used to determine the yield pressure (Py) for both solids. “Out-die” Heckel analysis gives true mean Py calculated from reciprocal transformation of slope. Py for 3n-Eu was found to be higher (256.41 MPa) as compared to lower value of 3n-Co (130.33 MPa). This indicated that yield strength of 3n-Eu is higher as compared to plastically deforming 3n-Co. Further, the densification behavior due to initial particle rearrangement (Da) is higher for 3n-Co (0.82) than 3n-Eu (0.66). On the other hand, Walker analysis assumes that the rate of change of pressure with respect to volume is directly proportional to the applied pressure.28 The values of Walker parameters (i.e. W and L) for both solids were obtained from the liner regression analysis (R2= 0.978) of 100V versus Log P and Log P versus V, respectively. 3n-Eu showed higher coefficient of compressibility (W=73.16) than 3n-Co (W=54.86). Hence, higher compressibility coefficient W is consistent with higher tabletability of 3n-Eu over 3n-Co (Figure 4(iii)).17 The value of pressing modulus (L) is higher for 3n-Co (3.91) as compared to 3n-Eu (1.95), and hence it is correlated with higher compressibility and lower yield strength of 3n-Co than 3n-Eu (lower BA and higher Py).17 Furthermore, 3n-Eu and 3n-Co, Pm-Eu and Pm-Co solids were subjected for hydraulic dynamic compressive analysis in order to generate stress-strain profile. Further the obtained axial displacement (Figure 5(i)) at the same dynamic compressive load (0 to 5.290 kN) follows the order: 3n-Co > 3n-Eu > Pm-Eu > Pm-Co. This rank order suggested their compressive ability or compressive strength. Figure 5(ii) and 5(iii) shows stress-strain curves and plastic energy (ηe) plots, respectively. The stress-strain relationship is the basic representation of deformation behavior of material. As shown in Figure 5(ii), initially higher compression recorded at lower stress followed by plateau phase at higher compressive stress. An ultimate strain recorded (u) was obtained at maximum stress (ultimate stress recorded, u) and the obtained results are enumerated in Table 1. Apparent yield pressure was calculated from the slope of linear region (R2=0.998) of – curve. The apparent yield pressure suggests higher compressive strength of material and reveals its resistance towards plastic deformation. Hence apparent yield pressure from lower to higher, followed the order as: 3n-Co < 3n-Eu < Pm-Co < Pm-Eu. It is

13



1.8 Axial displacement (mm)

Axial displacement (mm)

3.5 3 2.5 2 1.5

1.5

1.2

0.9

0.6

1 0.3

0.5 Pm-Co

Pm-Eu

3n-Eu

Pm-Co

3n-Co

Pm-Eu

3n-Eu

0

0 0

1.1

2.2

3.3

4.4

3n-Eu

45

3n-Co

Pm-Co

0

5.5

1.1

(i)

Dynamic axial compressive load (kN)

3n-Eu

3.5

Pm-Eu

2.2

3.3

4.4

5.5


3n-Co

Pm-Co

Pm-Eu

3 Plastic Energy (ηe, J)

36

Stress (Š, MPa)

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

Page 14 of 24

27

18

2.5 2 1.5 1

9

(ii)

0.5

(iii)

0

0 0

0.13

0.26

0.39

0.52

0.65

0

Strain (Ŝ)

7

14

21

28

35

42

Stress (Š, MPa)

‒ ) curves, and (iii) Plastic Energy (ηe, Joule) versus Figure 5. (i) Load-displacement (P–h) profile, (ii) Stress-strain ( stress (MPa) plots of reacted (3n-Eu and 3n-Co) and un-reacted (Pm-Eu and Pm-Co) solids obtained from hydraulic dynamic compression analysis.

shown in the – curve that the shearing stain recorded among the conglomerates of 3n-Eu is higher than the shearing strain recorded among the particles of Pm-Eu. Moreover, at the comparable u, ultimate strain recorded (u) followed the trend from higher to lower as 3n-Co > 3n-Eu > Pm-Co > Pm-Eu. In other words, 3n-Co demonstrated almost ~60% deformation while 3n-Eu experienced 40% deformation. The apparent yield pressure can be conversely related with plastic energy (ηe) of the system. Plastic or plastic-elastic strain energy is the energy absorbed or stored by a system undergoing deformation. As shown, ηe is linearly increased with increase in applied stress; however it is quite higher and rapidly increased for easily deforming 3n-Co (supporting the lower value Py). And henceforth, other solids can be ordered as 3n-Eu > Pm-Eu > Pm-Co. The magnitude of apparent yield pressure confers the resistance to the material towards its storage of plastic or elastic deformation.

14


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


Table 1. Mechanical parameters and plastic energy calculated from stress-strain relationship

Solid

Apparent yield pressure (MPa)

u (ultimate Stress, MPa)

u (ultimate Strain)

Maximum Plastic energy (ηe, J)

3n-Eu

256.03 (± 3.11)

39.25 (± 0.10)

0.401 (± 0.05)

2.72 (± 0.06)

3n-Co

228.37 (± 5.17)

39.25 (± 0.13)

0.598 (± 0.03)

3.31 (± 0.03)

Pm-Eu

317.28 (± 3.14)

39.32 (± 0.16)

0.321 (± 0.03)

2.45 (± 0.08)

Pm-Co 279.36 (± 4.22) 39.27 (± 0.18) (Standard deviations are shown in parenthesis)

0.347 (± 0.02)

2.33 (± 0.07)

The bulk mechanical behavior can be understood from bottom-up molecular level by visualizing the molecular packing and/or relative intermolecular interaction and arrangement of molecules in the crystal lattice. 3n-Co is considered to be a homogeneous solid having predominant bonding interactions (BIs), whereas 3n-Eu system has been perceived as a heterogeneous solid, having both bonding and non-bonding interactions29 (NBIs). Eutectic solid retains their structural domains inherited from parent components,3 and hence they show combination of diffraction peaks of their parent components in XRPD (Figure 3-B). This molecular level structural integrity is evidence of their dominant BIs (cohesive interactions). NBIs (adhesive interactions) are also formed lead to melting point depression. These NBIs are also responsible for overall compromised thermodynamic parameters as compared to their parent components. The crystal structure of 3n-Co is responsible for excellent compressibility, higher L (pressing modulus) and lower Py. The detail organization of crystal structure of 3n-Co is depicted in Figure 6 and 7. It has been claimed that presence of crystallographic slip planes (Figure 7 A) enhances the effective bonding area under applied mechanical stress.10, 17, 20, 21, 23 Crystallographic plane (-1 0 5) was identified as active slip planes (Figure 7 B) and, < -1ʹ 0ʹ 5ʹ > can be considered as the slip direction30. Thus, (-1 0 5) and < -1ʹ 0ʹ 5ʹ > together constitute slip system.30 Facile plastic deformation has been attributed from crystallographic feature slip planes in polymorphs17, 19, 20 and few multi-component cocrystals21-23. Slip planes are generally identified by visualizing crystal structures, and are based on highest molecular packing density of layers and hydrogen bonding dimensionalities.31 0D/1D/2D H-bonded stacking flat layers are perpendicular to the numerous vdW interactions containing smooth surfaces that interact weakly with adjacent crystallographic layers.1, 31 Molecular crystals with such feature were responsible for good compressibility and tabletability. However, tableting is an interplay between BA and BS,27 and compressibility has been observed consistently in

15



Page 16 of 24

Figure 6. Supramolecular organization of 3n-Co (INZ:SUC:NIC): (i) unit structural H-bonded motif (USHbM) showing three types of synthons, 1 and 1ʹ: C(4) (acid···pyridine)1 between (acid···pyridine)2 between SUC(―COOH) and NIC(―Pr), and 3:

SUC(―COOH) and INZ(―Pr), 2 and 2ʹ: C(4)

(8)

(amide···amide)3 between two NIC(―CONH2)

molecules. (ii) Co-planar USHbM present in the crystallographic layer (-1 0 5). (iii) and 2 Visualization of close-packing of USHbM along crystallographic a‒axis in the plane (-2 0 0). No H-bonds are present among adjacent USHbMs subsequently forming 0D H-bonded layered structure.

polymorphs containing slip planes.19-21 However, it seems that increase in BS has not been guaranteed from such

16


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


Figure 7. A and B: Identification of crystallographic feature slip planes (-1 0 5) (0D H-bonded highest molecular density layer perpendicular (Ʇ) to the van der Waals (vdW) interactions) in the crystal lattice of 3n-Co (INZ:SUC:NIC) when projecting along b-axis.

slip system in multi-component systems23. Lower compressibility and higher Py of 3n-Eu indicated that it resists deformation as compared to 3n-Co, but it possesses quite higher BS. Close look at crystal structure of individual components of 3n-Eu could give better insight to understand BA-BS interplay. All components of 3n-Eu exhibit two kind of common molecular packing and H-bonding dimensionalities. Both INZ and NIC possess 3D H-bonded mechanically interlocked structure (Figure 8, a1 and a2 and b1 and b2), hence they can be referred as isotropic molecular solids.30 On the other hand, ADP shows quite distinct 1D H-bonded extended chains formed from

(8)

acid···acid homosynthons (Figure 8, c1 and c2). This

makes ADP layered and anisotropic molecular solid as compared to NIC and INZ. Directional H-bonding and non-directional vdW interactions can have major influence in directing molecular slip when solids are subjected to the external stress.30 The molecular slip < -1ʹ 0ʹ 0ʹ > in ADP takes place along 1D H-bonded extended

(8)

acid···acid chains of ADP. This is perpendicular to the weakly interacting hydrophobic aliphatic backbone (– (CH2)4 –) of ADP molecules along the plane (-1 0 0). This slip system is energetically favorable. Such slip system is absent in both NIC and INZ. It involves a breaking of strong directional 3D H-bonded network in INZ and NIC, which is energetically unfavorable. It is obvious that zig-zag or herringbone molecular packing of brittle INZ (33.33 % w/w) cannot significantly contribute towards BA. Instead it can resist deformation and it also holds

17



Figure 8. Molecular packing and H-bonding D of components of 3n-Eu when projecting along b-axis in all cases: (a1), (b1) and (c1): USHbMs of INZ, NIC and ADP. (a2) Zig-zag or corrugated arrangement: each INZ interacts with 3 adjacent INZ with Pr···H-NH– and two azide···azide functionalities having –HN···H2N– interactions, (b2) parallel and orthogonal Hbonding framework formed by four (two of each perpendicular to one another) (Pr···HNH–)2 and (–CO···H2N–)2 interactions among each relatively tilted NIC molecule, (c2) 1D H-bonded chains extended by acid···acid dimer (8) homosynthons. 1.5

45

1.3

37.5

1.0

30

Stress (Š, MPa)

Axial displacement (mm)

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

Page 18 of 24

0.8

0.5

0.3 INZ

NIC

NIC

ADP

22.5

15

7.5

( i)

ADP

INZ

0.0

( ii)

0 0

1.1

2.2

3.3

4.4

5.5

0.00


0.08

0.15

0.23

0.30

0.38

0.45

Strain (Ŝ)

‒ ) curves of unit components of 3n-Eu (INZ, NIC and Figure 9. (i) Load-displacement (P–h) profile, (ii) Stress-strain ( ADP).

18


Page 19 of 24 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


true for relatively orthogonal H-bonded framework of almost elastic NIC (40 % w/w). The molecular packing of NIC is near isotropic (no 0D/1D/2D H-bonds) and its H-bond type is mutually orthogonal 3D H-bonded framework of Pr···azide and azide···azide chemical functionalities. Therefore direct compression of NIC into coherent compact remains practically impossible. Strong intermolecular interactions govern inter-particulate BS provided that intermolecular interactions are dominating bonding mechanism.17, 20, 27, 32 These both structures of INZ and NIC would have resulted in lower compressibility and higher Py. However, the same contributed towards higher BS. The molecular packing of ADP (26.33 % w/w) is roughly recognized as plastic but not plastic like 3n-Co. Thus ↑ BA are anticipated from loosely bound weak vdW interactions quite orthogonal to the extended and stacked molecular chains of ADP (Figure 6, c). As per the exact composition of 3n-Eu, 3D mechanically interlocked H-bonded structure of both INZ + NIC (73.33 % w/w) conferred relatively higher BS than 3n-Co, but the same lead to lower BA.

Figure 10. Schematic presentation or set-up of hardness measurement during application of diametric breaking force and

observing fracture behavior in compacts: A) stationary support, C) compact placement, D) movable displacement plunger, #####$ + ! #####$ ), E) Crack initiation site and further F, formation of fracture (E → F), % #$: proposed F) Force: (where F= !" accommodation/management of strain based on fracture mechanics, (i) for shearing solid; 3n-Co, (ii) 3n-Eu, and (iii) physical mixtures (i.e. Pm-Eu and Pm-Co).

19



Page 20 of 24

This assumption is further supported by bulk mechanical response performed by dynamic compressive analysis. It involves measurement of relative axial displacement as a function of applied compressive load. Figure 9 (i) demonstrates that relative displacement is higher for ADP as compared to NIC and INZ. INZ shows least displacement at the same applied compressive load. The relative magnitude of axial displacement is inversely proportional to the resistance offered by molecular solids towards its deformation. Figure 9 (ii) shows – curves of individual component of 3n-Eu. Apparent yield pressure was calculated from slope of the curve (R2 = 0.998). The value of apparent yield pressure is higher for INZ (336.97 MPa) as compared to NIC (283.92 MPa) and ADP (248.81 MPa). Thus, the rank order of relative degree of deformation can be given as: ADP (1D)H-bond > NIC (3D)H-bond > INZ (3D)H-bond. Hence, this supported that intrinsic deformational nature of crystal structure can be close approximation of single crystal and bulk mechanical behavior of multi-component system like 3n-Eu.8 Although such solids are considered to be complex crystalline solid dispersions (CSDs), whose molecular level structural integrity has only been partially characterized. Furthermore, the fracture behavior of compacts was visualized during the application of diametric crushing force (Fc) for measurement of tensile strength. Generally, fracture is the stress-induced separation of an object or materials into two or multiple pieces.30 Figure 10 depicts schematic representation of general set-up for Fc application and observed nature of fracture behavior. The analysis on carefully preserved compacts after fracture further helps to understand the intrinsic deformational nature due to cohesive interactions: BIs. It also helps to understand the relative degree of consolidation due to adhesive interactions: NBIs. Figure 11: 1st row supports the claim that 3n-Eu having maximum tensile strength and highest degree of consolidation demonstrated uniform and comparatively smooth fracture along the direction of crack initiation and fracture propagation (A → B, for all compact from 1 to 7). This behavior is different from un-reacted solids (physical mixture, Figure 11: 3rd row, 1 and 2). The BIs are almost same for 3n-Eu and Pm-Eu, but they are quite different in their NBIs. NBIs are responsible for improvement of BA-BS interplay of 3n-Eu as compared to their physical mixtures. Because of significant NBIs, after a yield point the shear strength between conglomerates of 3n-Eu remains consistently less than the shear strength among particles of Pm-Eu. Compact defects and non-uniform fracture mechanism are associated with physical mixture, and they collapsed with inhomogeneous brittle fracture (Figure 11: 3rd row, both 1 and 2). Conversely, 3n-Co is homogeneous solids wherein BIs are dominant, and NBIs can be negligible.

20


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


Figure 11. Analysis of nature of fracture in compacts of ternary solids: moving from 1 to 7 shows ascending order of increased compaction pressure of compacted solids, From A → B: Crack initiation along the direction of fracture propagation (same is applied to the direction from D to/(– C –) A in Figure 9). 1st row: 3n-Eu, 2nd row: 3n-Co, and 3rd row: 1. Pm-Co 2. Pm-Eu. C: crack and fracture occurs at relatively high pressure and with maximal tensile strength in 3n-Co.

Shearing molecular solid (3n-Co) exhibited extensive plastic deformation prior to occurrence of fracture. It demonstrated viscous flow at macroscopic level when shear strength is lower than maximum tensile strength (Figure 11: 2nd row, 6C and 7C). Such material is categorized as ductile solid (3n-Co). Hence, based on compressive strength , fair plasticity and consolidation, τ and from a fracture mechanics standpoint, the overall mechanical performance can be assigned as, 3n-Co: ductile, 3n-Eu: plasto-elastic, Pm-Eu: plasto-brittle, and PmCo: elasto-brittle.

Conclusion Eutectics are known class of multi-component (Nn, where N = 2, 3, …) solids, however, in comparison to other multi-component systems such as salts, cocrystals, solid solutions and molecular complexes. They are less explored in terms of their molecular level structural organization. The present study explored the qualitative aspect of bulk mechanical performance at molecular level structural in 3n-Eu and 3n-Co. It was also found that their macroscopic level deformation is different than non-reacted physical mixture. Hence, effort can be made to understand the mechanical behavior from supramolecular assembly of unit components. However, quantitative behavior of such bottom-up molecular approach becomes relatively more difficult in the bulk mechanical behavior of heterogeneous multi-component solids like 3n-Eu or 3n-Pm as compared to 3n-Co. Moreover,

21



Page 22 of 24

crystallographic slip planes can be qualitatively informative for plasticity in molecular solids, but further claim on tensile strength and better tableting behavior needs to be systematically investigated. On the other hand, while it is not always possible to form supramolecular layered architecture for two or more given pharmaceutical molecules, eutectics with varied underlying microstructural variants (nLα + nLβ + nLγ) may confer an opportunity to modulate the physico-mechanical performance using anti-supramolecular approach.

Supplementary Information The method of eutectic preparation, particle and bulk level characterization of ternary solids, Walker equations, and the information on melting and thermodynamic function of eutectic solid and its unit components have been as enclosed as supporting information of this work.

References 1.

Shariare, M. H.; Leusen, F. J. J.; de Matas, M.; York, P.; Anwar, J., Prediction of the mechanical behaviour of crystalline solids. Pharmaceutical research 2012, 29, (1), 319-331.

2.

Aitipamula, S.; Wong, A. B. H.; Chow, P. S.; Tan, R. B. H., Novel solid forms of the anti-tuberculosis drug, Isoniazid: ternary and polymorphic cocrystals. CrystEngComm 2013, 15, (29), 5877-5887.

3.

Cherukuvada, S.; Nangia, A., Eutectics as improved pharmaceutical materials: design, properties and characterization. Chemical Communications 50, (8), 906-923.

4.

De Rosa, C.; Park, C.; Thomas, E. L.; Lotz, B., Microdomain patterns from directional eutectic solidification and epitaxy. Nature 2000, 405, (6785), 433.

5.

Law, D.; Wang, W.; Schmitt, E. A.; Qiu, Y.; Krill, S. L.; Fort, J. J., Properties of rapidly dissolving eutectic mixtures of poly (ethylene glycol) and fenofibrate: the eutectic microstructure. Journal of pharmaceutical sciences 2003, 92, (3), 505-515.

6.

Moore, M. D.; Wildfong, P. L. D., Aqueous solubility enhancement through engineering of binary solid composites: pharmaceutical applications. Journal of Pharmaceutical Innovation 2009, 4, (1), 36-49.

7.

Cherukuvada, S.; Nangia, A., Fast dissolving eutectic compositions of two anti-tubercular drugs. CrystEngComm 2012, 14, (7), 2579-2588.

8.

Yong, C. S.; Oh, Y.-K.; Jung, S. H.; Rhee, J.-D.; Kim, H.-D.; Kim, C.-K.; Choi, H.-G., Preparation of ibuprofen-loaded liquid suppository using eutectic mixture system with menthol. European journal of pharmaceutical sciences 2004, 23, (4-5), 347-353.

9.

Jain, H.; Khomane, K. S.; Bansal, A. K., Implication of microstructure on the mechanical behaviour of an aspirinâ€“paracetamol eutectic mixture. CrystEngComm 2014, 16, (36), 8471-8478.

22


Page 23 of 24 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


10. Yadav JPA, B. A., Jain S., Molecular Understanding and Implication of Structural Integrity in the Deformation Behavior of Binary Drug-Drug Eutectic Systems. Mol Pharm. 2018. 11. Hunt, J. D.; Jackson, K. A., Binary eutectic solidification. Transactions of the Metallurgical Society of AIME 1966, 236, (6), 843-&. 12. Meng, G.; Lin, X.; Huang, W., The relationship between effective entropy change and volume fraction of the eutectic phases in eutectic microstructures. Materials Letters 2008, 62, (6-7), 984-987. 13. Das, S. S.; Singh, N. P.; Agrawal, T.; Gupta, P.; Tiwari, S. N.; Singh, N. B., Studies of Solidification Behavior and Molecular Interaction in Benzoic Acidâ€“o-Chloro Benzoic Acid Eutectic System. Molecular Crystals and Liquid Crystals 2009, 501, (1), 107-124. 14. Smith, P.; Pennings, A. J., Eutectic solidification of the pseudo binary system of polyethylene and 1, 2, 4, 5tetrachlorobenzene. Journal of Materials Science 1976, 11, (8), 1450-1458. 15. Chang, S.-Y.; Sun, C. C., Superior plasticity and tabletability of theophylline monohydrate. Molecular pharmaceutics 2017, 14, (6), 2047-2055. 16. Joiris, E.; Di Martino, P.; Berneron, C.; Guyot-Hermann, A.-M.; Guyot, J.-C., Compression behavior of orthorhombic paracetamol. Pharmaceutical research 1998, 15, (7), 1122-1130. 17. Khomane, K. S.; More, P. K.; Raghavendra, G.; Bansal, A. K., Molecular understanding of the compaction behavior of indomethacin polymorphs. Molecular pharmaceutics 2013, 10, (2), 631-639. 18. Pedersen, S.; Kristensen, H. G., Compaction behaviour of 4-hydroxybenzoic acid and two esters compared to their mechanical properties. European journal of pharmaceutics and biopharmaceutics 1995, 41, (5), 323-328. 19. Yadav, J. A.; Khomane, K. S.; Modi, S. R.; Ugale, B.; Yadav, R. N.; Nagaraja, C. M.; Kumar, N.; Bansal, A. K., Correlating single crystal structure, nanomechanical, and bulk compaction behavior of febuxostat polymorphs. Molecular pharmaceutics 2017, 14, (3), 866-874. 20. Sun, C.; Grant, D. J. W., Influence of crystal structure on the tableting properties of sulfamerazine polymorphs. Pharmaceutical research 2001, 18, (3), 274-280. 21. Sun, C. C.; Hou, H., Improving mechanical properties of caffeine and methyl gallate crystals by cocrystallization. Crystal Growth and Design 2008, 8, (5), 1575-1579. 22. Karki, S.; FriÅ¡Ä iÄ‡, T.; Fabian, L.; Laity, P. R.; Day, G. M.; Jones, W., Improving mechanical properties of crystalline solids by cocrystal formation: new compressible forms of paracetamol. Advanced materials 2009, 21, (38â€ 39), 3905-3909. 23. Krishna, G. R.; Shi, L.; Bag, P. P.; Sun, C. C.; Reddy, C. M., Correlation among crystal structure, mechanical behavior, and tabletability in the co-crystals of vanillin isomers. Crystal Growth & Design 2015, 15, (4), 1827-1832. 24. Sun, C. C.; Grant, D. J. W., Improved tableting properties of p-hydroxybenzoic acid by water of crystallization: a molecular insight. Pharmaceutical research 2004, 21, (2), 382-386.

23



Page 24 of 24

25. Cherukuvada, S., On the issues of resolving a low melting combination as a definite eutectic or an elusive cocrystal: A critical evaluation. Journal of Chemical Sciences 2016, 128, (4), 487-499. 26. Heckel, R. W., Density-pressure relationships in powder compaction. Trans Metall Soc AIME 1961, 221, (4), 671-675. 27. Sun, C. C., Decoding powder tabletability: roles of particle adhesion and plasticity. Journal of Adhesion Science and Technology 2011, 25, (4-5), 483-499. 28. Walker, E. E., The properties of powders. Part VI. The compressibility of powders. Transactions of the Faraday Society 1923, 19, (7), 73-82. 29. Janssens, S.; Van den Mooter, G., Physical chemistry of solid dispersions. Journal of Pharmacy and Pharmacology 2009, 61, (12), 1571-1586. 30. Varughese, S.; Kiran, M.; Ramamurty, U.; Desiraju, G. R., Nanoindentation in crystal engineering: Quantifying mechanical properties of molecular crystals. Angewandte Chemie International Edition 2013, 52, (10), 2701-2712. 31. Zolotarev, P. N.; Moret, M.; Rizzato, S.; Proserpio, D. M., Searching new crystalline substrates for OMBE: topological and energetic aspects of cleavable organic crystals. Crystal Growth & Design 2016, 16, (3), 1572-1582. 32. Upadhyay, P.; Khomane, K. S.; Kumar, L.; Bansal, A. K., Relationship between crystal structure and mechanical properties of ranitidine hydrochloride polymorphs. CrystEngComm 2013, 15, (19), 3959-3964.

24


Revealing the role of structural features in bulk mechanical

Recommend Documents