Molecular Understanding and Implication of Structural Integrity in the

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Molecular Understanding and Implication of Structural Integrity in Deformation Behavior of Binary Drug-drug Eutectic Systems Jay Prakash A. Yadav, Arvind K Bansal, and Sanyog Jain Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/acs.molpharmaceut.8b00077 • Publication Date (Web): 05 Apr 2018 Downloaded from http://pubs.acs.org on April 7, 2018

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Molecular Pharmaceutics

Molecular Understanding and Implication of Structural Integrity in Deformation Behavior of Binary Drug-drug Eutectic Systems Authors: Jay Prakash A. Yadav, Arvind K. Bansal*, Sanyog Jain*

*Corresponding Authors 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 Dr. Sanyog Jain Associate Professor, Centre for Pharmaceutical Nanotechnology (CPN), 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

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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

An implication of bonding and non-bonding interactions (NBIs) in eutectic’s deformation [Solid-state (structural chemistry) engineering in tableting process]


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Abstract In eutectic, a lamellar microstructure offers better tableting as compared to non-reacted physical mixture. However, bulk deformation remains elusive in two binary eutectics. We hypothesized that binary eutectic of a drug with different component having different H-bonding dimensionalities and crystal structure shall allow the understanding of structural integrity in bulk deformation behavior. Shearing molecular solid (FXT Q) shared common composition with viscoelastic crystal (ASP I) and brittle (PCM I) forming EM-1 (φ1 = 41.27:58.73 % w/w) and EM-2 (φ2 = 41.10:58.90 % w/w), respectively. Excess thermodynamic functions were contributed by high energy microstructures (non-bonding interactions) along incoherent phase boundaries (visualized under CLSM). Energy dispersive analysis enabled recognition of relative distribution of higher atoms over heterogeneous surface. EM-1 (FXT Q-ASP I) demonstrated higher compressibility, tensile strength and compactibility (CTC profile) compared to EM-2 (FXT QPCM I) over range of applied compaction pressure. Lower true yield strength (σ0(EM-1) = 138.66 MPa) of EM-1 as compared to EM-2 (σ0(EM-2) = 166.66 MPa) suggested better deformation performance and incipient plasticity quantified from “out-of-die” Heckel analysis. From Ryshkewitch analysis, tensile strength at zero porosity (τ01 = 3.83 MPa) was predicted to be higher for EM-1 than EM-2 (τ02 = 2.54 MPa). The higher bonding strength of EM-1 was contributed from additional influence of true density and isotropic van der Waals interactions of ASP I (0D). In contrast, EM-2 demonstrated lower compressibility and compactibility having herringbone molecular packing of PCM I (1D) with common shearing component (FXT Q (1D)). This study confirmed that intrinsic deformational and chemical nature of second component defined compressibility and compactibility tendency to a greater extent in tableting performance of conglomerates of crystalline solid dispersion (CSD).

Keywords: Eutectics point, Micro-structural elements, Thermodynamic functions, Deformation, Tensile strength, Yield pressure, Crystal structure, Shearing solid

Introduction 3 ACS Paragon Plus Environment


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Binary eutectics (organic, drug-polymer, or drug-drug) can be model systems to investigate and alter solidification kinetics1, hygroscopicity2, stability, interactions at phase boundaries3, and kinetic solubility advantage4 of parent components. The enthalpy of fusion influences the solidification behavior and controls formation of eutectic microstructure5, which can influence the material’s physicochemical properties including mechanical behavior. Eutectic systems have not been well characterized at molecular level2 and investigation on mechanical performance of binary organic eutectics has been done rarely. Bulk mechanical properties of any system can be best assessed from tensile strength of solid compacts as a result of bulk deformation.6 A gradual increase in tensile strength of materials with increase in mechanical stress implies material’s ability towards plastic deformation.7 Compressibility is the ability of materials to undergo a significant volume reduction under the applied mechanical stress.8 On the other hand, compactibility is the tendency of powder material to transform into a compact of sufficient tensile strength as a function of applied mechanical pressure. Thus, tabletability can be a summation of former two mechanical properties.8 Henceforth, tabletability has been used as a performance criterion to investigate bulk deformation behavior of pharmaceutical materials. Tensile strength is governed by interparticulate bonding area (BA) and interparticulate bonding strength.9,10 These two parameters must be investigated individually in order to gain mechanistic insight into the given system. Reports on polymorphic pairs have concluded that true density by virtue of intermolecular interactions govern interparticulate BS in tablet formation.7,

8, 11-14

Overall tableting behavior is

influence by both BA and BS. In general, increase in BA dominated in polymorphic pairs having slip mechanism, while true density (ρo) did not demonstrate correlation with BS. On the other hand, in polymorphic pair(s), devoid of slip system, true density (ρo) invariably governed BS and overall tableting behavior. In eutectics, a lamellar microstructure offered better tableting due to greater compressibility as compared to simple or non-reacted physical mixture.15 However, there was no influence on material’s BS over range of applied mechanical stress.15 Hence, compactibility

9

still remains poorly understood in binary drug-drug eutectic systems wherein

cohesive (homomolecular) interactions still dominate over adhesive (heteromolecular) interactions.

Moreover,

intermolecular interactions have been claimed to dictate interparticulate bonding strength;7,

Thus, we

10, 16

hypothesize two binary eutectic systems (conglomerates of solid solution) having common shearing solid (FXT Q) which can assist tableting of brittle component (PCM I) and another with viscoelastic (ASP I) to understand the implication of structural integrity on overall bulk deformation behavior. 4 ACS Paragon Plus Environment

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Experimental Section Materials Febuxostat (FXT) was obtained from Precise Chemipharma Private Limited, Navi Mumbai, India. Aspirin (ASP) and Paracetamol (PCM) was purchased from Alfa Aesar, Heysham, England and Coral Laboratories Ltd., Navi Daman, India, respectively. Acetonitrile (Sigma-Aldrich, St. Louis, USA) and Ethanol (Changshu Yangyuan Chemicals, China) were of high performance liquid chromatography (HPLC) grade and analytical grade, respectively.

Methods Crystallization and solvent-drop grinding (SDG) FXT Q and ASP form I (ASP I) was crystallized from acetonitrile (ACN) as per the reported method.17 PCM form I (PCM I) was recrystallized from ethanol. Eutectic mixtures were generated using solvent drop grinding with ACN and bulk quantity was scaled-up to 20 g (for detail, see Supporting Information (SI), SM 1), for studying bulk deformation behavior.

Microscopic analysis Optical and hot-stage microscopy (HSM) Both eutectic systems were visualized for their crystal habit, size and crystalline nature. Samples were mounted on glass slide with silicon oil for HSM. The resultant thermal events were captured by an optical and cross-polarized light microscope (DMLP microscope, Leica Microsystems, Wetzlar, Germany) equipped with camera (JVS color video) and analytical software (Lynksys32). Both samples were heated from 25.0 ± 2.0 to 250 °C, at a heating rate of 20 °C/min.

Particle size distribution (PSD) Similar particle size fraction of each form was obtained by using BSS sieve size 100 and 120#. D10, D50 and D90 of both eutectics were determined by optical microscope by measuring length along the longest axis, for at least 300 particles.

Scanning electron microscopy (SEM) Particle morphology of all samples were analyzed using a SEM (S-3400, Hitachi Ltd., Tokyo, Japan) operated at an excitation voltage of 15 kV. Sample powders were mounted onto steel stage using double-sided adhesive tape and coated with gold using ion sputter (E-1010, Hitachi Ltd., Japan). 5 ACS Paragon Plus Environment


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

Bulk and true density determination Bulk density was calculated by carefully adding accurately weighed powder to a 50 mL measuring cylinder. The true density of all samples was determined in triplicate by helium pycnometry (Pycno 30, Smart Instruments, Mumbai, India) at 25.0 ± 2.0 °C/40.0 ± 5.0 % RH.

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

Powder X-ray diffraction (PXRD) PXRD patterns of both eutectics were recorded at room temperature (25.0 ± 2.0 °C) on Bruker’s D8 Advance Diffractometer (Bruker, AXS, Karlsruhe, Germany) with Cu Kα radiation (1.54 Å), at 40.0 kV, 40.0 mA passing through Nickel filter. Analysis was performed in a continuous mode with a step size of 0.01° and step time of 1.0 s over an angular range of 3.0 to 40.0° 2θ. Obtained powder X-ray diffractograms were analyzed with DIFFRAC plus EVA, version 9.0 (Bruker, AXS, Karlsruhe, Germany) diffraction software.

Differential scanning calorimetry (DSC) DSC analysis was performed using DSC, Mettler Toledo, model 821e module, CH-8603, Schwerzenbach, Switzerland, operating with Stare software system, version 9.0, Schwerzenbach, Switzerland. About 3.00 mg of each sample was accurately weighed in aluminum pans and subjected to the thermal scan from 0 to 250.0 °C at the heating 6 ACS Paragon Plus Environment

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rate of 20.0 °C min−1. During entire analysis, dry nitrogen purge was maintained at 50.0 ml min−1. Prior to analysis, the instrument was calibrated using high purity standard of indium (In).

Energy-dispersive X-ray spectroscopy (EDS) Both samples were analyzed for surface nature to identify the higher atoms at Kα elemental line over the heterogeneous surface. X-ray intensities in counts per second were set at 200 and the accelerating voltage at 20 kV integrated with SEM (S-3400, Hitachi Ltd., Tokyo, Japan).

Confocal laser scanning microscopy (CLSM) Microstructure formation upon SDG experiments of both eutectics were visualized under CLSM (Olympus FV 1000 USA) by mounting them on glass slide and observed under microscope.

Preparation of compacts for bulk deformation Hydraulic pellet press (Type KP, Sr. No. 1125, Kimaya Engineers, Maharastra, India) was used to investigate bulk compaction properties of both solids. Compacts were prepared by compacting 400 mg of crystalline powder using up to 300.0 MPa compaction pressure in a hydraulic press with a dwell time of 1.0 minute using 13.0 mm punch die set. Different compression forces were applied manually, to achieve range of compaction pressures. The applied hydraulic load was converted into actual compaction pressure applying the Equation 1.0. Where, F is applied hydraulic load, and A is area of flat punch-die set. The compacts were further analyzed for weight, thickness and required breaking force. =

Equation 1.0

Calculation of tensile strength and porosity Breaking force of all the compacts was measured using a tablet hardness tester (Erweka, TBH 20, USA). Tablet dimensions were measured using a digital caliper (CD-6 CS, Digimatic Mitutoyo Corporation, Japan). Tensile strength was calculated using the following equation to eliminate the undesirable effect of variable tablet thickness on measured breaking force. =

Equation 2.0

Where, σ is the tensile strength (MPa), F is the observed breaking force (N), d is the diameter (mm), and t is the thickness of the compact (mm). The porosity, ε, of the compacts was calculated as ― 7 ACS Paragon Plus Environment


= 1

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Equation 3.0

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

Statistical analysis Statistical significance for values of various compaction parameters was compared using a 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 FXT Q, ASP I and PCM I were investigated by studying the relative arrangement of atoms/molecules and differences in their inter-molecular interactions and H-bonding dimensionalities using CSDEnterprise’s module Mercury software (Version 3.9 CCDC, Reg. No. 800579, UK).

Results

Figure 1. Molecular structure of Febuxostat (FXT) (a), Aspirin (ASP) (b), and Paracetamol (PCM) (c).

Screening and Characterization of Binary Eutectics Eutectics are usually binary systems in which two components are miscible in their liquid state, but physically separate (do not react chemically) in solid phase, and each component has the property of lowering the melting point of the other component.2 DSC can be a good screening technique to determine the eutectic point (eu) and composition (φeu). A 1:2.5 FXT Q-ASP I and 1:3 FXT Q-PCM I molar ratio gives eutectic mixture, a single melting endotherm devoid of any other variant liquidus curve (Figure 2 (d) and (e) shown by arrows). Above this composition, either variant liquidus peak(s) appear(s) or melting shifts towards higher temperature away from invariant single solidus endotherm.


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These broad (or sharp) variant liquidus endotherms are attributed to excess component or non-eutectic phase of eutectic system.2 These non-eutectic phases can also appear in diffraction analysis with their characteristic diffraction peaks, because in X-ray diffraction eutectic composition shows combination peaks of both the parent components like physical mixture (Figure 4). Thus, DSC can be a confirmatory tool to determine eutectic point (eutectic temperature and exact composition), while X-ray diffraction is confirmatory tool for successful co-crystallization. Moreover, the binary phase diagrams are also presented in Figure 3. Though in case of both the eutectic systems, the molar ratios of second components (ASP I and PCM I) are different, their % w/w proportion remains nearly the same, i.e. 41.27:58.73 %w/w (φ1) and 41.10:58.90 %w/w (φ2) proportion gives FXT Q-ASP I and FXT Q-PCM I eutectic system, respectively. This result indicates that, there eutectic formation is exclusively affected by proportion of individual components rather than stoichiometric interactions. In other words, same amount of two different components was required to form eutectics EM-1 and EM-2 with common solid form (FXT Q), irrespective of their molecular weight, true density, molecular size, shape and chemical functionalities (Figure 1, a, b and c).

Figure 2. DSC heating curves; A: FXT Q-ASP I eutectic (molar) composition screening: (a) 1:0, (b) 1:1, (c) 1:2, (d) 1:2.5, (e) 1:3, (f) 1:3.5, (g) 2:1, (h) 0:1. 1:2.5 stoichiometric composition (φ1) gives Eutectic point (eu); a single solidus endothermic peak at Tm: 130.80°C without any variant liquidus peaks as seen in other heating curves (presented by arrows). B: FXT Q-PCM I eutectic (molar) composition screening: (a) 1:0, (b) 1:1, (c) 1:2, (d) 1:2.5, (e) 1:3, (f) 1:3.5, (g) 2:1, (h) 0:1. 1: 3 stoichiometric composition (φ2) gives Eutectic point (eu); a single solidus endotherm at Tm: 158.52 °C without any variant liquidus peaks as they appear in other neighborhood

heating curves.



220

225

Melting Temperature (Tm)

200

Melting Temperature (Tm)

210

Liquid FXT Q +

Temperature (ºC)

Temperature (ºC)

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

Liquid ASP I

180

160

Liquid FXT Q + Solid ASP I

Liquid FXT Q + Liquid PCM I

195

180

Liquid FXT Q +

Solid FXT Q +

140

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Solid PCM I

Solid FXT Q +

165

Liquid ASP I

Liquid PCM I

Solid FXT Q + Solid ASP I

Solid FXT Q + Solid PCM I

150

120 0

0.2

0.4

0.6

0.8

1

Mole Fraction of ASP (X1)

0

0.2

0.4

0.6

0.8

1

Mole Fraction of PCM (X2)

Figure 3. Binary phase diagram of eutectic solids: (A) EM-1 (FXT Q-ASP I), (B) EM-2 (FXT Q-PCM I). In both diagram, x-axis presents mole fraction (X1 and X2) of second component, (ASP I and PCM I).

Figure 4. Powder X-ray diffractograms. A: (a) FXT Q, (b) Aspirin Form I (ASP I) and (c) FXT Q-ASP (1:2.5) Eutectic mixture (EM 1). B: (a) FXT Q, (b) Paracetamol Form I (PCM I), and (c) FXT Q-PCM I (1:3) Eutectic mixture (EM 2). EM-1 and EM-2, both show combination of diffraction peaks of individual components.

Figure 5 and 5-1 show thermal photomicrographs of EM 1 and EM 2 (i.e. FXT Q-ASP I and FXT-Q-PCM I). At melting temperature, both components melt and form a single miscible liquid phase which is consistent with melting temperature obtained from DSC (Table 1). The resultant molten mixture was kept on isothermal hold for 5 minutes and then slowly cooled to normal room temperature to visualize solidification. The nondimensional entropy of fusion (∆Sf0 = ∆Sf/R, where R is gas constant) is used to differentiate faceted and non-faced (regular) solidification of eutectics.18 As the ∆Sf0 difference between FXT Q and ASP I, and also the difference between FXT Q and PCM are similar but greater than 2 (i.e. ∆Sf0 > 2) (Table 1), both EM-1 and EM-2 co-solidifies with irregular microstructure 10 ACS Paragon Plus Environment

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with nodular or globular morphology of EM-1 (Figure 5 (g) and (h)), while EM-2 shows clustered growth with acicular or rods embedded in one another (Figure 5-1 (f), (g) and (h)). Interestingly, ∆Sf0 difference between ASP I and PCM I is < 2, thus, they formed regular or lamellar microstructure.15 However, care must be taken when characterizing microstructure, because the rate of cooling and thermal environment affects solidification or crystallization kinetics from molten phase and lack of 3-dimensional viewing techniques impose limitations in assignment of eutectic morphology. Table 1. Experimental values of thermodynamic functions: Enthalpy and entropy of fusion and melting temperature

Melting temperature

Nondimensional

Sr.

Drug/API and

Enthalpy of fusion

No.

eutectics

∆Hf (J/g)

Tm (°C)

Tm (K)

∆Sf (J/mol K)

1

FXT Q

166.78

205.30

478.45

110.28

13.26

2

ASP I

140.53

143.22

416.22

60.83

7.32

3

PCM I

178.94

170.89

444.04

61.01

7.33

4

FXT Q-ASP I

152.69

130.79

403.94

289.83

34.86

5

FXT Q-PCM I

129.56

158.62

431.77

231.02

27.79

Entropy of fusion

∆Sf0, (∆Sf/R)

Mol. wt. of API components; FXT: 316.374 Da, ASP: 180.157 Da, PCM: 151.163 Da, and R is gas constant.

Physical Chemistry of Surfaces of Eutectics Molecular level structural integrity of eutectics has not been fully characterized. However, efforts have been made to explore how two mechanically separated solids surfaced in their intact solid-phase. Initially, EDS was expected to characterize the nature of micro-structural elements in the solid state. Interestingly, Energy dispersive analysis revealed that EM-2 counter-intuitively exhibits comparatively higher intensity counts of Oxygen (O) atom than EM1 with Sulfur (S) containing component FXT Q (SI Figure S1 A and B). Though, it may seem obvious that 2-fold higher ‘O’ atoms are contributed from ASP than PCM in EM-1 (Figure 1). Relatively same % of elemental distribution was detected in



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Figure 5. Thermal photomicrographs of FXT Q-ASP I (EM-1) eutectic system. From (a) to (d) melting phenomenon; (a) 25.7 °C, (b) Figure 4. 110.35 °C, (c) 119.30 °C, (d) 125.09 °C and (e) 131.50 °C, complete melting. An (f) to (h) shows solidification from melt during cooling to room temperature.

Figure 5 - 1. Thermal photomicrographs of FXT Q-PCM I (EM-2) eutectic system. From (a) to (e) melting phenomenon; (a) 25.91 Figure 5. °C, (b) 145.60 °C, (c) 155.30 °C, (d) 159.09 °C and (e) 160.47 °C, complete melting. An (f) shows solidification from melt during cooling to room temperature and (g) and (h) shows clustered microstructure of eutectic.

both eutectics, which is in accordance with homogeneous distribution of higher atoms (‘O’, ‘S’) on their surface. However, it remains equally mysterious and surprising how % w/w proportion of an individual element (i.e. ‘O’ and ‘S’) coincidently dictates nearly similar % w/w content of an individual component in eutectic phase (i.e. 59.95 % w/w of ‘O’ for 58.73 % w/w ASP-I and 58.90 % w/w PCM-I; 40.05 % w/w of ‘S’ for % w/w FXT Q (SI, Table S1 and S2). It cannot be assumed that ‘S’ containing molecular species dominate ‘S’ over ‘O’ containing


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Figure 6. Energy dispersive mapping of eutectic solids for higher elements ‘O’ and ‘S’ at Kα line. EM-1 and EM-2 (A. and D. Grey scale, B. and E. Distribution of ‘O’, yellow dots, C. and F. Distribution of ‘S’, red dots). The regions where ‘S’ dominates over ‘O’ are marked with arrows in EM-1 (B and C). The relative and inhomogeneous distribution of ‘O’ is significant in EM-2 (E) due to relatively lack ‘O’ species are contributed from ASP as compared to PCM.

molecular species though possession of similar kind of elements in their molecular structure. This assumption was further assessed in localization and relative distribution of ‘O’ and ‘S’ in both the eutectic systems. Figure 6 supports that ‘S’ rich regions are distributed over entire surface in both EM-1 and EM-2, and where ‘S’ dominates; ‘O’ may be detected or remains undetected irrespective of ‘O’ and ‘S’ containing molecular species. ‘S’ containing molecular entity also harbors ‘O’ in its molecular structure (FXT Q), however, it is clear that ‘O’ rich regions in EM-1 also show ‘S’, but substantial difference surfaced in EM-2, wherein comparatively less ‘O’ is attributed from PCM. It is noteworthy that elemental dominance at molecular level is difficult to explain as all the atoms are integrated part of complex covalent structure. However, preferred orientation of chemical functional groups exposed on a solid surfaces might explain this energy dispersive mapping comprehensively. PCM I exposed higher ‘O’ containing chemical functional groups (–OH), such polar functional groups get relatively lower exposure in ASP I as they are buried in the bulk of material, rather than the surface.

Particle and Bulk Level Attributes 13 ACS Paragon Plus Environment


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The influence of variation in particle level was minimized by keeping similar particle size distribution, shape and specific surface area (SI Figure S2 A and B, and Table 2). Moreover, the nature of microstructure formed upon SDG was visualized under CLSM. Figure 7 shows deposition of mechanically activated components of both eutectics. A similar kind of microstructure was obtained due to interspersing of two components. For both eutectics, the morphology seems relatively irregular with smooth appearance, and clustered. Table 2. Particle and bulk level analysis of both eutectic mixtures (EM-1 and EM-2)

Solid

Bulk density

Particle size distribution (µm)

True density

Specific surface 2

Moisture content

(g/cc)

(g/cc)

D10

D50

D90

area (m /g)

(% w/w)

EM-1

0.411 (± 0.04)

1.368 (± 0.003)

9.8

22.8

40.1

0.615 (± 0.09)

0.098

EM-2

0.402 (± 0.05)

1.313 (± 0.004)

10.4

24.9

44.6

0.672 (± 0.08)

0.103

Standard deviations are shown in parenthesis (n=3).

Figure 7. Visualization of irregular microstructure using CLSM in conglomerate of both eutectics formed upon mechanical grinding. (A) and (B); EM-1, (C) and (D); EM-2.

Bulk Deformation Behavior of Eutectics Figure 8 shows graphical presentation for compressibility, tabletability, compactibility (CTC) profile and Heckel analysis of both eutectics. Compressibility is an ability of materials to undergo significant volume reduction under the effect of applied compaction pressure. The compressibility of EM-1 is significantly higher as compared to EM-2 (Figure 8 A), though the true density of EM-1 is higher (1.368 g/cc) over EM-2 (1.313 g/cc). Hence true density


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contribution did not resist deformation of EM-1 as compared to EM-2. Tabletability is the tendency of materials to EM-1

EM-2

3

EM-1

Tensile Strength (MPa)

Porosity

0.2

0.16

0.12

0.08

0.04

EM-2

2.5 2 1.5 1 0.5 0

0

60

120

180

240

300

0

60

Compaction Pressure (MPa)

A

EM-1

2.8

EM-2

120

180

240

300

240

300


B

3.75

EM-2

EM-1 2.4

3 2.25

ln (1/ε)

Tensile Strength (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


1.5

2

1.6 0.75 1.2

0 0.03

C

0.07

0.11 Porosity

0.15

0.19

0.23

0

D

60

120

180


Figure 8. Compressibility (A), Tabletability (B), Compactibility (C) plot and “Out-of-die” Heckel analysis (D) of eutectic solids. Compactibility plot (C) is extrapolated to y-axis in an attempt to determine tensile strength at zero porosity (τ0) for both EM-1 and EM-2.

form a compact with enough tensile strength under the effect of applied compaction pressure. EM-1 shows considerably good tableting property as compared to EM-2 at the range of studied compaction pressure (Figure 8 B). At 184.63 MPa, tensile strength reached at 2.0 MPa for EM-1, but EM-2 demonstrated approximately 2-fold lower tensile strength (0.95 MPa) at the same compaction pressure. 2.0 MPa is the minimum acceptable tensile strength to ensure robustness of compact. Compactibility is ability of materials to produce compact of sufficient tensile strength under the effect of densification8 (at similar porosity). Interestingly, compactibility is also higher in case of EM-1 than EM-2 (at low porosity, ε < 0.12). As the compactibility plots were not comparable, Ryshkewitch analysis was carried out (with R2 ≥ 0.986 for both eutectics) and tensile strength predicted at zero porosity (τ0). τ0 can be true indicator of interparticulate BS and used to predict compactibility, because both eutectics possess similar particle size, size distribution, and specific surface area19, 20 (Table 2), and thus, would result same BA at same porosity. τ0 15 ACS Paragon Plus Environment


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was predicted to be higher in case of EM-1 (τ01 = 3.83 MPa) as compared to lower value of EM-2 (τ02 = 2.54 MPa). At 0.02 porosity (ε0.02), EM-1 and EM-2 are predicted to possess tensile strength 3.39 MPa and 2.32 MPa, respectively. Further, at 0.05 porosity (ε0.06), EM-1 and EM-2 demonstrated tensile strength 2.5 MPa and 1.75 MPa, respectively. This was quite expected due to higher true density8, 21 of EM-1 and anticipated to be contributed from ASP I (1.43 Mg m-3). At lower porosity (ε 0.14), EM-1 demonstrated lower tensile strength because lower BS of EM-2 dominated limited BA-BS interplay10 of EM-1 at lower mechanical stress.22 This is further supported by Heckel analysis. Heckel analysis is most widely used kinetic model in order to determine yield strength of materials.23 It is based on the assumption that materials undergoing deformation due to densification follows 1st order kinetics.23,

24

For Heckel analysis, pressures required for

densification of materials can be estimated from “in-die” (i.e. “at pressure”) and “out-of-die” (i.e. “zero of pressure”) parameters. “In-die” measurement does not account for elastic deformation. Thus, “out-of-die” measures the true yield strength of materials. Yield strength of both eutectics was determined form the linear potion of Heckel curve (R2 ≥ 0.94 in both the cases). Yield strength of EM-1 is lower (σ01 = 138.66 MPa) as compared to higher yield strength (σ02 = 166.66 MPa) of EM-2. This confirmed that EM-1 deforms easily (more plastic) as compared to EM-2. Here it is noteworthy that true density did not resist densification of EM-1 as compared to EM-2, wherein composition of both eutectic systems is nearly same. Molecular basis behind deformation behavior has been explained in the later section of this manuscript.

Discussion Thermodynamic Functions and Thermo-chemistry Eutectics possess a microstructure-level periodicity that is different from either of the pure crystalline components.25 Microstructural elements can help to accurately classify a eutectic system.26 During solidification from melt, the effective entropy change and the volume fraction of the eutectic phase are interrelated and this relationship may be used to characterize the microstructure.5 The difference in nondimensional entropy of fusion (∆Sf0) between the individual components controls the resulting eutectic microstructure formation.18 When two materials possess equivalent or very similar ∆Sf0 values, both phases grow simultaneously, side-by-side and forms non-faceted 16 ACS Paragon Plus Environment

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microstucture.18 This planar solid–liquid interface results in a normal eutectic microstructure that appears as alternating lamellae or rods of one phase embedded in the other. On the other hand, large differences in ∆Sf result in faceted growth producing an anomalous structure, which may manifest as one of many internal structures or structural variants.27 Table 1 shows experimental values of melting point, enthalpy and entropy of fusion for individual components and eutectic system. Moreover, entropy of fusion for both the binary eutectics is higher (Table 1) which supports the fact that eutectic possesses higher thermodynamic state than either of the pure crystalline materials. This was expected because these higher thermodynamic functions are manifestation of the incoherent phase boundaries formed upon excessive micronization. All three components (i.e. FXT Q, ASP I and PCM I) represent nondimensional entropy of fusion (∆Sf0) is > 2. Hence, a faceted microstructure was obtained for both eutectic systems.18 The enthalpy of fusion of EM-1 is significantly higher than EM-2 (Table 1). This enthalpy or heat of fusion is function of energy of intermolecular interactions,28 crystallinity29 of materials and linearly proportional to true density.30 It is not always possible to explain the contribution of individual factors thoroughly, unless supported with enough experimental evidences. True density of FXT Q (1.31 g/cc)17 and PCM I (1.32 g/cc)15 are marginally similar, while ASP I possesses significantly higher true density (1.43 g/cc)15. Contribution of true density of ASP I in EM-1 can significantly increase the ∆Sf as compared to EM-2 of PCM-1, provided that true density (crystal density) is additive and true material property. On the other hand, the entropy of fusion of EM-1 is higher (289.83 J/K mol) than EM-2 (231.02 J/K mol), this can be explained based on the chemical nature31 (Figure 1) and hetero-molecular interactions (NBIs) between two components in a molten phase.31 Both FXT and ASP are weak acids with pKa of 3.4232 and 3.50, respectively, whereas PCM is weak base with pKa of 9.50. Thus, weak acid-acid interactions are expected to be repulsive in molten state which creates comparatively more disorderliness (higher ∆Sf) for EM-1 as compared to weak acid-base attractive interactions with comparatively less disorderliness (low ∆Sf) in EM-2.

Structural Interpretation of Bulk Deformation Behavior: A Molecular Approach Eutectics are binary systems in which both components retain their structural domains and integrity inherited from parent components, thus PXRD analysis contains a combination of peaks of both the components (Figure 4). Schematic presentation of these two dispersion systems is given in Figure 9. It depicts interspersing of crystalline domains and their random distribution, thus making the system discontinuous (heterogeneous). This was recorded by 17 ACS Paragon Plus Environment


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Figure 9. Schematic presentation for structural integrity of two eutectic solids (EM). Heterogeneity or irregularities increases moving from domain α, α´, αʺ and likewise among β, β´ and βʺ. A neighborhood domains αβ, α´β´, αʺβʺ retains regularities as compared to their proximity dispersion system.

CLSM images as well. Incoherent phase boundaries (green boarders in Figure 9) and microstructures formed upon mechanical activation are responsible for compromised and higher ∆Sf (Table 1) as compared to their pure component(s). Before discussing deformation behavior, it is important to understand the crystal structure of individual components of both eutectics. FXT Q is shearing solid with clear indication of slip plane in its crystal structure (as visualized along crystallographic b-axis) (Figure 10 A). Such solids confer excellent plasticity17, 33 over applied mechanical stress (Figure 11 A). FXT Q possesses intraplaner H-bonds and interplaner weak van der Waals (vdW) interactions, thus making FXT Q 2D H-bonding anisotropic crystal. PCM I, on the other hand, possess Hbonded extended chains (head to tail condensation of molecules) forming dense or close-molecular packing (1D Hbonding; isotropic but brittle crystal34). These kinds of structures resist deformation and are poorly compressible 18 ACS Paragon Plus Environment

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(Figure 11 E).6 In contrary, ASP I comes in between former two molecular solids (neither purely plastic like FXT Q nor brittle like PCM I), i.e. viscoelastic (Figure 11 D). This nature lies within its crystal structure as inter- and intra molecular H-bonds form (acid···acid (8)) dimers or discrete aggregates of ASP molecule (0D H-bonding, isotropic

crystal). This structure flows on one crystallographic plane and slightly resists on the other plane.35

Figure 10. Crystal structure analysis of an individual component of both eutectic solids. A. Shearing molecular planes of FXT Q observed along crystallographic b-axis, B. H-bonded discrete aggregates (acid···acid (8) dimers) of ASP I molecules along baxis, C. Close molecular packing or zigzag (herringbone) arrangement of PCM I molecules along crystallographic a-axis.

FXT Q is common for both eutectic systems, and hence can be exempted from the discussion. ASP I surrounds and exposes isotropic and weak vdW interactions upon excessive micronization in EM-1, thus conferring more compatible towards better overall tableting performance (CTC profile). Higher true density (1.43 Mg m-3), viscoelastic nature and isotropic H-bonding dimensionalities (0D) of ASP I crystal structure contributed better tableting behavior in EM-1. Moreover, random orientations of particles during bulk deformation cannot reduce significant contribution of (isotropic) vdW interactions; hence it showed higher compactibility9 over PCM I in EM-2. This notion can be further evaluated by Ryshkewitch analysis, wherein tensile strength (at zero porosity) was

Figure 10. 11. Photographs of compact prepared at 184.63 MPa pressure (dwell time 1.0 minute). A. FXT Q, B. EM-1, C. EM-2, D. ASP I, E. PCM I. Compact of PCM I is poorly formed (practically unlikely to compact).

predicted to be higher of EM-1 (τ01 = 3.83 MPa) as compared to EM-2 (τ02 = 2.54 MPa). True density also 19 ACS Paragon Plus Environment


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contributed towards higher compactibilty instead of resisting compressibility of EM-1 (increase in bonding area). The hydrophobic functional groups (aryl and methyl)36 are present in case of EM-1 from ASP, thus it showed lower ‘O’ counts (Figure 6 and S1 A (SI)). PCM I is a brittle solid6 and its lower true density (1.32 Mg m-3) and polar 1D H-bonded chains did not increase compactibility in EM-2 over EM-1. On the other hand, close-molecular packing (interlocked structure) of PCM I resisted deformation towards lower compressibility (BA) and subsequently limited compactibility9, thus provided higher true yield strength (σ01 = 166.66 MPa) as compared to relatively more plastic solid EM-1 (σ01 = 166.66 MPa). Thus, PCM I contributed towards poor tableting performance in EM-2 as compared to EM-1. However, tableting performance of EM-2 is better as compared to poorly compressible marketed monoclinic form PCM I. The order of tableting performance from better to poor based on their plasticity and tensile strength can be given as, FXT Q > EM-1 > EM-2 > ASP I > PCM I (Figure 11). Lower true density and brittle nature of PCM I (exposes polar and anisotropic ‒OH groups) which reduced its overall contribution towards compactibility. Thus, higher intensity counts for ‘O’ are recorded in energy dispersive analysis of EM-2 (Figure 6 and S1 B (SI)). Polar H-bonds requires appropriate juxtaposition in order to increase inter-particulate BS, which is unlikely during bulk deformation of EM-2. However, Ryshkewitch analysis helps in order to eliminate measurement bias on tensile strength assuming that τ0 is true indicator of materials compactibility tendency (inter-particulate BS). Weak isotropic vdW interactions in crystal structure(s) are crucial in order to accommodate and impart plasticity under the applied mechanical stress.33, 37, 38 This study implied that eutectic solids wherein nature of microstructure is similar, crystal structure and phase boundaries (non-bonding interactions (NBIs)) of individual component(s) impact the overall tableting performance. Better tableting of EM-1 was contributed from both, increase in BA and BS of ASP I. In contrast, EM-2 demonstrated poor tableting behavior over EM-1 due to limitations in both, increase in BA and BS of PCM I. Hence, these two systems suggested that intrinsic mechanical behavior of individual components (ASP I and PCM I) governed the overall tableting performance of eutectic with a common component (FXT Q). Moreover, eutectics wherein better tableting behavior attributed from only high energy lamellar microstructure, system became dominant and only contributing towards BA, but not BS.15 On the other hand, two eutectics wherein BA and BS, both are attributed differently from two different components provided both components build nearly same system in terms of their percent weight proportionality (% w/w), their intrinsic deformational behavior (i.e. crystal structure) and 20 ACS Paragon Plus Environment

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chemical nature implies compressibility and compactibility tendency to a substantial extent even imbibed within high energy (thermodynamic) boundaries of non-bonding interactions (NBIs).

Conclusion Binary drug-drug eutectics or simply eutectics have not been well explored at molecular level as compared to their multi-component counterpart co-crystals. The reason can be lack of techniques available for understanding their molecular level structural integrity as eutectics are complex and heterogeneous systems or crystalline solid dispersions (CSDs). Based on chemical nature and entropy of fusion participating components, they are likely to provide intermediate and structural variants to manipulate their solid state properties (physicochemical properties) including mechanical behavior (i.e. physicotechnical properties). Present study involved two eutectics having common solid form (FXT Q) by normalization of microstructure established that overall tableting behavior was influenced by intrinsic deformational nature of second component (ASP I and PCM I). This study further opens up the opportunity for modulating bulk deformation of pharmaceutical solids. It was also found that the physical chemistry of surface of eutectics detected by supramolecular attributes of the individual components not by the molecular structure. Finally, however, an anticipation of better mechanical performance based on solely molecular packing still remains to be evaluated in both single- and multi-component crystalline systems.

Acknowledgement We thank National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar for providing financial support to carry out this work.

Supplementary Information Solvent drop grinding (SDG) method, Energy dispersive X-ray spectrum (EDS) analysis (at Kα elemental line) and SEM

images of eutectic mixtures are enclosed as supporting information of this manuscript.

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35. Varughese, S.; Kiran, M.; Solanko, K. A.; Bond, A. D.; Ramamurty, U.; Desiraju, G. R., Interaction anisotropy and shear instability of aspirin polymorphs established by nanoindentation. Chemical Science 2011, 2, (11), 22362242. 36. Jain, T.; Sheokand, S.; Modi, S. R.; Ugale, B.; Yadav, R. N.; Kumar, N.; Nagaraja, C. M.; Bansal, A. K., Effect of differential surface anisotropy on performance of two plate shaped crystals of aspirin form I. European Journal of Pharmaceutical Sciences 2017, 99, 318-327. 37. 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), 27012712. 38. Krishna, G. R.; Devarapalli, R.; Lal, G.; Reddy, C. M., Mechanically flexible organic crystals achieved by introducing weak interactions in structure: supramolecular shape synthons. Journal of the American Chemical Society 2016, 138, (41), 13561-13567.

Table of Contents Graphic Title: Molecular Understanding and Implication of Structural Integrity in Deformation Behavior of Binary Drugdrug Eutectic Systems Authors: Jayprakash A. Yadav, Arvind K. Bansal, Sanyog Jain


Molecular Understanding and Implication of Structural Integrity in the

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