Correlating Single Crystal Structure, Nanomechanical, and Bulk

Febuxostat exhibits unprecedented solid forms with a total of 40 polymorphs and pseudopolymorphs reported. Polymorphs differ in molecular arrangement ...
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Correlating Single Crystal Structure, Nanomechanical, and Bulk Compaction Behavior of Febuxostat Polymorphs Jayprakash A. Yadav,† Kailas S. Khomane,† Sameer R. Modi,† Bharat Ugale,‡ Ram Naresh Yadav,§ C. M. Nagaraja,‡ Navin Kumar,§ and Arvind K. Bansal*,† †

Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar - 160 062, Punjab, India ‡ Department of Chemistry, and §Department of Mechanical Engineering and Centre of Materials and Energy Engineering, Indian Institute of Technology (IIT) Ropar, Rupnagar - 140 001, Punjab India S Supporting Information *

ABSTRACT: Febuxostat exhibits unprecedented solid forms with a total of 40 polymorphs and pseudopolymorphs reported. Polymorphs differ in molecular arrangement and conformation, intermolecular interactions, and various physicochemical properties, including mechanical properties. Febuxostat Form Q (FXT Q) and Form H1 (FXT H1) were investigated for crystal structure, nanomechanical parameters, and bulk deformation behavior. FXT Q showed greater compressibility, densification, and plastic deformation as compared to FXT H1 at a given compaction pressure. Lower mechanical hardness of FXT Q (0.214 GPa) as compared to FXT H1 (0.310 GPa) was found to be consistent with greater compressibility and lower mean yield pressure (38 MPa) of FXT Q. Superior compaction behavior of FXT Q was attributed to the presence of active slip systems in crystals which offered greater plastic deformation. By virtue of greater compressibility and densification, FXT Q showed higher tabletability over FXT H1. Significant correlation was found with anticipation that the preferred orientation of molecular planes into a crystal lattice translated nanomechanical parameters to a bulk compaction process. Moreover, prediction of compactibility of materials based on true density or molecular packing should be carefully evaluated, as slip-planes may cause deviation in the structure−property relationship. This study supported how molecular level crystal structure confers a bridge between particle level nanomechanical parameters and bulk level deformation behavior. KEYWORDS: febuxostat polymorphs, CTC profile, yield strength, slip plane system, true density, nanomechanical hardness, compactibility crystals with respect to their underlying crystal structure.17 The present study investigated the mechanical behavior of the Febuxostat (FXT) polymorphic pair designated as Form Q (FXT Q) and Form H1 (FXT H1). The crystal structure of Form Q shows the presence of an active slip plane system and hence enabled us to understand the contribution of the slip plane system toward nanomechanical and bulk compaction behavior. The bulk compaction behavior of polymorphs was investigated using out-of-die compressibility−tabletability− compactibility (CTC) profiling and Heckel analysis. Single particle nanomechanical properties were investigated by performing nanoindentation experiments. Subsequently, the crystal structure of these polymorphs was correlated to their nanomechanical and bulk compaction properties.

1. INTRODUCTION Mechanical properties of materials are best studied by measuring the tensile strength of the compact after compaction. Tabletability is described as the capacity of a powdered material to be transformed into a tablet of specified strength (tensile strength) under the effect of compaction pressure.1,2 Thus, tabletability can be used as a performance criterion to study the compaction behavior of pharmaceutical powders. Tensile strength is governed by the interparticulate bonding area and bonding strength.3 These two factors must be studied individually to gain mechanistic understanding of compaction behavior. The contribution of each factor can be understood by studying compressibility and compactibility, respectively. Recently the authors have reported compaction behavior of a few pharmaceutical polymorphic systems,2,4−9 including Clopidogrel bisulfate polymorphs2 (forms I and II) and Indomethacin polymorphs7 (α and γ forms). There have been reports on the importance of slip system or crystal structure to achieve superior tableting behavior.10−16 These studies emphasized the mechanical properties of molecular © 2017 American Chemical Society

Received: Revised: Accepted: Published: 866

November 29, 2016 January 25, 2017 February 2, 2017 February 2, 2017 DOI: 10.1021/acs.molpharmaceut.6b01075 Mol. Pharmaceutics 2017, 14, 866−874

Article

Molecular Pharmaceutics

2.4.2. 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 both polymorphs was determined in triplicate by helium pycnometry (Pycno 30, Smart Instruments, Mumbai, India) at 25.0 ± 2.0 °C/40.0 ± 5.0% RH. 2.4.3. Specific surface area analysis. The specific surface area of both the polymorphs 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 then used to calculate the surface area of both the polymorphs by employing the adsorption theories of Brunauer, Emmett, and Teller (BET). 500 mg of 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 a thermal conductivity detector and then integrated using an electronic circuit. The reported values are the average of three measurements. 2.5. Molecular level characterization. 2.5.1. Powder Xray diffraction (PXRD). Powder XRD patterns of both forms were recorded at room temperature (25.0 ± 2.0 °C) on a 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 a 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 Xray diffractograms were analyzed with DIFFRAC plus EVA, version 9.0 (Bruker, AXS, Karlsruhe, Germany) diffraction software. 2.5.2. Differential scanning calorimetry (DSC). DSC analysis was performed using DSC, model Q2000 (TA Instruments, New Castle, DE, USA) operating with Universal Analysis software, version 4.5A (TA Instruments, New Castle, DE, USA). About 3.00 mg of each polymorphic form was accurately weighed in aluminum pans and subjected to the thermal scan from 0 to 260.0 °C at the heating rate of 20.0 °C min−1. During the entire analysis, a dry nitrogen purge was maintained at 50.0 mL min−1. Prior to analysis, the instrument was calibrated using a high purity standard of indium (In). 2.5.3. Hot stage microscopy (HSM). HSM was carried out to observe thermal transitions using a Leica DMLP polarized microscope (Leica Microsystems Wetzlar GmbH, Wetzlar, Germany) equipped with a Linkam LTS 350 hot stage. Photomicrographs were captured using a JVS color video camera and analyzed using Linksys32 software. Form H1 was mounted in silicon oil and heated from 25 to 250 °C, at a heating rate of 20 °C/min. 2.6. Preparation of compact for bulk deformation profile. A hydraulic press (Hydraulic unit Model 3912, Carver Inc., Wabash, USA) was used to study the compaction properties of Febuxostat polymorphs. Tablets of the two forms were prepared by compacting 400 mg of crystalline materials up to 40.0 MPa compaction pressure in a hydraulic press with a dwell time of 2.0 min using a 13.0 mm punch die set. Different compression forces were applied manually, to achieve a range of compaction pressures (1−40 MPa). The compression force required to achieve particular compaction pressure is dependent on the tip area of the punch and is related by eq 1

2. EXPERIMENTAL SECTION 2.1. Materials. Febuxostat (molecular structure given in Scheme 1) was obtained from Precise Chemipharma Private Scheme 1. Molecular Structure of Febuxostat (FXT)

Limited, Navi Mumbai, India. Acetonitrile (Sigma-Aldrich, St. Louis, USA), ethyl acetate (J.T. Baker, Center Valley, PA, USA), and diiodomethane (Alfa Aesar, Johnson Matthew Company, UK) were of high performance liquid chromatography (HPLC) grade. Toluene (SDFC fine-chem Limited, Mumbai, India), ethylene glycol (Rankem, RFCL Limited, Haryana, India), and ethanol (Merck, India) were of analytical grade. 2.2. Crystallization of FXT Q and FXT H1. The procured sample contained FXT Form A (FXT A).18 For obtaining Form Q, about 20 g of this was dissolved in 834.0 mL of hot acetonitrile at the temperature 65.0 ± 3.0 °C.19 The resultant clear solution was left for slow evaporation at room temperature (26.0 ± 2.0 °C). Colorless needle to plate-shaped crystals were obtained after 7 to 8 days. Form H1 was obtained dissolving 20.0 g of Form A in 325.0 mL of ethyl acetate20 and heating to 60.0 ± 3.0 °C. 25.0 mL of rectified toluene was added to this. The resultant clear solution was left for slow evaporation at room temperature (26.0 ± 2.0 °C). Colorless plate-shaped crystals were obtained after 9 to 10 days. The crystals of both forms were dried for 16 h in a hot air oven at the temperature 40.0 ± 2.0 °C. 2.3. Microscopic analysis. 2.3.1. Optical and polarized light microscopy. Febuxostat crystals were subjected to microscopy to visualize their crystal habit, size, and crystalline nature using an optical and cross-polarized light microscope (DMLP microscope, Leica Microsystems, Wetzlar, Germany) equipped with a camera (JVS color video) and software (Lynksys32). 2.3.2. Particle size distribution (PSD). A similar particle size fraction of each form was obtained by using BSS sieve size 120# and 100#. D50 (FXT Q: 50.5 μm and FXT H1:49.8 μm) and D90 (FXT Q: 83.5 μm and FXT H1:82.6 μm) of each fraction were determined by optical microscopy by measuring the length along the longest axis, for at least 200 particles (DMLP microscope, Leica Microsystems, Wetzlar, Germany). 2.3.3. Scanning electron microscopy (SEM). Particle morphology of both forms was studied using a scanning electron microscope (S-3400, Hitachi Ltd., Tokyo, Japan) operated at an excitation voltage of 15 kV. Sample powders were mounted onto a steel stage using double-sided adhesive tape and coated with gold using ion sputtering (E-1010, Hitachi Ltd., Japan). 2.4. Bulk level characterization. 2.4.1. Moisture content. The moisture content of both polymorphic forms (accurately weighed about 500 mg) was determined by Karl Fischer (KF) titration (Metrohm 794 basic titrino, Herisau, Switzerland) before assessment of compaction behavior. The instrument was calibrated with disodium tartrate dehydrate for accurate moisture content determination (n = 3).

P (MPa) = 867

F (N ) A (mm 2)

(1) DOI: 10.1021/acs.molpharmaceut.6b01075 Mol. Pharmaceutics 2017, 14, 866−874

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Molecular Pharmaceutics

Figure 1. Optical and polarized light photomicrograph of FXT polymorphs, respectively: Form Q (A and B); Form H1 (C and D).

calibration, a series of indents with different contact depths were performed on a standard sample of known elastic modulus, and the contact area was calculated. A plot of the calculated area as a function of contact depth was created and fitted by the TriboScan software. For quasi static analysis of sample, 10 subsequent indents were performed along the length of sting (on the midline parallel to the length of crystal present on a dominant face) for both the forms at specified locations with user-specified parameters. Indentations with contact depths of an order of magnitude larger than the local surface roughness are thought to be sufficiently deep to avoid a strong effect of roughness on the measured properties. Hence, the peak load for these indentations was 1000 μN and the indent spacing was 45.0 μm. A load function consisting of a 5 s loading to peak force segment, followed by a 2 s hold segment and a 5 s unloading segment, was used. The mechanical hardness (H) and the elastic modulus (E) were computed using the Oliver and Pharr method.26,27 The reduced modulus Er is related to the Young’s modulus Es of the testing material through the following relationship:

In the present study, the actual compaction pressure was measured for both the polymorphs and was used for compaction data analysis. The tablets were further analyzed for weight, thickness, and breaking force. 2.7. Calculation of tablet tensile strength and porosity. The breaking force of the tablets 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. σ=

2F πdt

(2)

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 tablets was calculated as

ε=1−

ρc ρt

(3)

(1 − υi2) (1 − υs2) 1 = + Er Ei Es

where ρc is the density of the tablet calculated from the weight and volume of the resulting tablet. ρt is the true density of the powder. 2.8. Single crystal X-ray diffraction of Febuxostat form H1. Single crystal X-ray structural data of Form H1 was collected on a Bruker D8 Venture PHOTON 100 CMOS diffractometer equipped with a INCOATEC microfocus source and graphite monochromated Mo Kα radiation (λ = 0.71073 Å) operating at 50 kV and 30 mA. The SAINT program21 was used for integration of diffraction profiles, and absorption correction was made with the SADABS22 program. The structure was initially solved by SIR 9223 and refined by the full matrix least-square method using the SHELXL-201324 and WinGX system, Version 2013.3.25 The non-hydrogen atoms were located from the difference Fourier map and refined anisotropically. All the hydrogen atoms were fixed by HFIX and placed in ideal positions and included in the refinement process using a riding model with isotropic thermal parameters. 2.9. Nanoindentation experiment. Nanoindentation was performed on oriented single crystals of both the polymorphs using a Ti-950 TriboIndenter (Hysitron Inc., Minneapolis, MN) equipped with a Berkovich diamond tip. The tip area function calibration was done using fused silica and polycarbonate sample as standard to calibrate the machine and diamond indenter tip. The testing temperature was 22 ± 0.5 °C, and the relative humidity was 55 ± 5.0%. A three-sided pyramidal tip with an included angle of 142.3° and a tip radius of ∼150 nm was utilized. Regions for testing were identified using an optical microscope integrated into the nanoindentation system. The “tip to optics calibration” was done by performing 7 indents in “H Pattern”. For area function

(4)

where Ei, Es and vi, vs are the elastic modulus and Poisson’s ratio for the indenter and the substrate materials, respectively. The reduced modulus was calculated by taking the values of the elastic modulus and Poisson’s ratio to be 1140 GPa and 0.07, respectively, for the diamond indenter tip. The Young’s modulus of elasticity and mechanical hardness of both forms obtained, expressing the elastic and plastic properties at the single crystal level, correlated to out-of-die bulk compaction profiling, compactibility, and compressibility and Heckel analysis. 2.10. Statistical analysis. The 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. 2.11. Molecular modeling. The crystal structure of FXT Q was already reported in the literature.19 A Form H1 single crystal was generated using the modified slow solvent evaporation method.20,28 CCDC number 1404782 (for Form H1) has been included in the supplementary crystallographic information of this paper. This information can be obtained free of charge from The Cambridge Crystallographic Data Centre (CCDC) via www.ccdc.cam.ac.uk/data_request/cif. The structure property relationship was established by studying the relative arrangement of atoms/molecules and differences in intermolecular interactions using Mercury software V2.3 CCDC. 868

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Molecular Pharmaceutics Table 1. Physical Characterization of FXT Polymorphs Particle Size Distribution (μm)

a

Polymorph

Size Range

D50

D90

True Densitya (g/mL)

Bulk Densitya (g/mL)

Form Q Form H1

12.30−104.90 11.80−103.70

50.50 49.80

83.50 82.60

1.2997 (0.007) 1.1952 (0.009)

0.3720 (0.003) 0.2486 (0.002)

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

Figure 2. Scanning electron micrograph of FXT polymorphs: (A) Form Q (FXT Q); (B) Form H1 (FXT H1).

Figure 3. Powder X-ray diffraction overlays of both FXT polymorphs.

3.0. RESULTS

1). Similar particle shape (Figure 1 A and C) and size distribution (Table 1) allows better comparison of compaction behavior of the two polymorphs. 3.2.3. Scanning electron microscopy (SEM). Scanning electron microscopy also revealed a plate-like habit and comparatively similar size of both the forms. The surface of Form Q was smooth (Figure 2 A), while the Form H1 surface showed a slightly rough surface (Figure 2 B). 3.3. Bulk level characterization. 3.3.1. Moisture content. Both the forms of FXT had a moisture content of less than 0.1% w/w (i.e., Form Q: 0.0725% w/w; and Form H1: 0.0998% w/w).

3.1. Generation of febuxostat polymorphs. Form Q and H1 were successfully obtained from solvent crystallization experiments and were characterized further. 3.2. Microscopic analysis. 3.2.1. Optical and polarized light microscopy. Optical and cross-polarized light microscopic evaluation (lens magnification: 20×) showed a plate-like habit of both the forms (Figure 1A and C). Birefringence under the cross-polarized light confirmed the crystalline nature of both the forms (Figure 1 B and D). 3.2.2. Particle size distribution (PSD). Particle size analysis revealed that both forms had similar D50 and D90 values (Table 869

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Molecular Pharmaceutics 3.3.2. Bulk density, true density, and specific surface area analysis. The bulk density of Form Q was significantly higher as compared to Form H1 (Table 1). Form Q had higher true density (1.2997 ± 0.008 g/cm3) as compared to Form H1 (1.2240 ± 0.005 g/cm3). The specific surface areas of Form Q and Form H1 were comparable with values of 0.263 (±0.002) m2/g and 0.272 (±0.001) m2/g, respectively. 3.4. Molecular level characterization of FXT polymorphs. 3.4.1. Powder X-ray diffraction (PXRD). Figure 3 shows an overlay of the experimental and simulated powder Xray diffraction patterns for FXT Q (Form Q) and FXT H1 (Form H1), respectively, and they were found to be quite comparable, confirming solid phase purity of the desired polymorphic forms. 3.4.2. Thermal analysis: Differential scanning calorimetry and hot-stage microscopy. The DSC heating curve of Form Q showed a single melting endothermic peak at 205.2 °C (onset at 198.9 °C and endset at 208.2 °C) (Figure 4). FXT H1

plot represents the extent of increase in an interparticulate bonding area. The compressibility plot (Figure 6) indicates greater compressibility of the FXT Form Q over Form H1 at a given compaction pressure. Tabletability is defined as the capacity of the powder material to be transformed into a tablet of specified tensile strength under the effect of applied compaction pressure.2,3,6,7 The tensile strength of both polymorphic forms increased with increase in compaction pressure, and Form Q showed greater tensile strength as compared to Form H1 at all applied compaction pressures (Figure 6). Compactibility can be defined as the ability of the powder material to produce tablets of sufficient tensile strength under the effect of densification,2,3,6,7 and it is represented by a plot of tensile strength against tablet porosity. The compactibility curves of both forms crossed each other. At higher porosity values (>0.7), Form H1 showed higher tensile strength at a given porosity as compared to Form Q. On the other hand, Form Q showed greater tensile strength at lower porosity values ( 0.96 in case of both the polymorphs). Form Q showed higher densification and lower Py. The Py of Form H1 (50 MPa) is higher as compared to Form Q (38 MPa). Lower true mean yield pressure (Py) values obtained for both the polymorphs indicate their plastic deformation under the applied compaction pressure. This is further supported by the nanoindentation experiment. The loading curve for both the forms was smooth and without any “pop-in” phenomena, which suggests that both the forms deformed plastically under the applied indentation load (Figure 7B). 3.6. Nanoindentation experiment: Elastic modulus and mechanical hardness. The average values of elastic modulus and mechanical hardness of both the forms are shown in Table 2. Figure 7B captures the load−displacement curve,

Figure 4. Overlay of DSC heating curves of FXT polymorphs: FXT Q (Form Q); FXT H1 (Form H1).

shows a polymorphic transition (between 140.0 and 150.0 °C) as Form H1 is a metastable polymorph with respect to FXT Q and Febuxostat Form A. HSM was performed to observe this solid phase transition at 140.0 °C, and the same is shown in Figure 5 (A to D). Subsequently, Form H1 showed an endothermic peak around melting point of Form Q, and a major endotherm at 210.3 °C was observed. The latter can be attributed to melting of stable Form A at around 210.3 °C (Figure 4). 3.5. CTC profile and Heckel analysis of FXT polymorphs. The bulk deformation behavior of a material can be determined by performing CTC (compressibility, tabletability, compactibility) profiling.2,5,29−31 A compressibility

Figure 5. Hot stage photomicrographs of FXT Polymorph Form H1 representing the polymorphic transition: (A) 85.2 °C; (B) 130.0 °C; (C) 135.2 °C; and (D) 145.0 °C. 870

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Figure 6. Compressibility, tabletability, and compactibility; and Heckel plots for FXT polymorphs.

Figure 7. Graphical presentation of elastic modulus (A), load−displacement curve without “displacement burst”: (a) loading curve; (b) unloading curve (B), and mechanical hardness of FXT polymorphs (C).

wherein elastic modulus and mechanical hardness are determined from the slope of the unloading curve.

Table 3. Crystallographic Parameters of FXT Polymorphs

Table 2. Nanoindentation Data of FXT Polymorphs (mean values)

a

Polymorph

E (GPa) Averagea

H (GPa) Averagea

Form Q Form H1

2.473 (±0.160) 4.510 (±0.631)

0.214 (±0.009) 0.310 (±0.028)

Standard deviations are shown in parentheses (n = 10).

3.7. Single crystal X-ray diffraction (SCXRD) analysis. More than 35 Febuxostat polymorphs and pseudopolymorphs have been reported in different patent applications worldwide.18,20,28,36−47 A crystallographic information file was available for Form Q.19 We generated a single crystal of Form H1 and acquired crystal structure information using single crystal X-ray diffraction (CCDC 1404782). The guestfree form of FXT, i.e. Form Q has monoclinic space group P21/ c, while Form H1 possesses triclinic space group P1. Both the forms exhibit one molecule of febuxostat in the asymmetric unit. Other crystallographic and unit cell parameters for both the forms are captured in Table 3.

a

871

Parameters

Form Q

Form H1

Chemical formula Formula mass (Da) Crystal system Space group a axis (Å) b axis (Å) c axis (Å) α angle (deg) β angle (deg) γ angle (deg) V (Å3) Z Dc (g/cm−3) μ (mm−1) T (K) Total data Unique data Data [I > 2σ(I)] R1a wR2b GOF

C16H16N2O3S 316.37 Monoclinic P21/c 4.6756(4) 17.6317(1s) 19.4992(1s) 90 94.523 90 1602.5(2) 4 1.311 0.215 298 6299 2099 3268 0.0549 0.1043 0.982

C16H16N2O3S 316.37 Triclinic P1 7.216(5) 15.347(5) 15.682(5) 90.282 96.179 99.574 1702.1(14) 4 1.235 0.203 150 56211 8443 6869 0.0429 0.1205 1.03

R1 = ∑||Fo| − |Fc||/∑|Fo|, bwR2 = [∑w(Fo2 − Fc2)2/∑w(Fo2)2]1/2

DOI: 10.1021/acs.molpharmaceut.6b01075 Mol. Pharmaceutics 2017, 14, 866−874

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4. DISCUSSION 4.1. Bulk deformation behavior. Thermal characterization suggested that the higher melting polymorph, Form Q (Tm: 205.2 °C), is the stable form, while the lower melting polymorph, Form H1 (200.3 °C), is the metastable form (Figure 4). Particle level analysis confirmed similar particle size, similar particle size distribution, and similar crystal habit in order to eliminate the particle effect on different compaction behavior4,48,49 (Table 1). Thus, it was possible to correlate and consider the effect of crystal structure and bulk deformation behavior. It is also important to confirm the absence of a compaction-induced polymorphic transition to obtain meaningful data. Hence, both samples were compacted at the highest compaction pressure (50 MPa) and examined by PXRD. PXRD patterns before and after the compaction sample was powdered for PXRD were comparable (data not shown). Form Q exhibited both greater compressibility and tabletability (Figure 6); this can be attributed to the presence of an active slip system in the crystal lattice. Form Q had greater tabletability as compared to Form H1, but the compactibility plots for the forms crossed each other in the range of compaction pressure. Determination of the compactibility at zero porosity can be a true indicator of the compactibility of materials. Tensile strength at zero porosity (τ0) determined using Rhyskewitch analysis (R2 > 0.95) revealed a higher value for Form Q (2.8 MPa) as compared to Form H1 (2.1 MPa). The higher value of τ0, which represents interparticulate bonding strength, indicated greater bonding strength of Form Q over Form H1. 4.2. Nanomechanical parameters. Ten indents were performed in order to determine the elastic modulus and mechanical hardness of single crystals of both the forms. The elastic modulus of the material is the resistance of the material toward elastic deformation.50 The latter can be related to intermolecular interaction in the crystal lattice. The stronger the intermolecular interactions, the higher will be the elastic modulus. The elastic modulus of Form H1 is significantly higher (4.510 GPa) as compared to Form Q (2.473 GPa). Mechanical hardness is the resistance offered by the indented material toward plastic deformation.50 Form H1 had a higher value of mechanical hardness (0.310 GPa) as compared to Form Q (0.214 GPa). The loading curve for both the forms is smooth and without any “pop-in” or “displacement burst” phenomena (Figure 7), which suggests that both the forms deformed plastically under the applied indentation load. A smooth curve also denoted that indentation may be performed along the slip-planes.50 Displacement was comparatively higher in the case of Form Q at the same indentation load as compared to Form H1. This finding aligned with the presence of active slip-planes in Form Q, which allowed easier slippage of the molecular plane, while Form H1 demonstrated resistance against a similar kind of slippage. As an active slip plane is absent in Form H1, it does not allow easier slippage of the molecular plane as compared to Form Q. Activation of the slip plane under the mechanical load confers plasticity to the molecular crystal. 4.3. Single crystal structure analysis. Figure 8 captures the molecular arrangement in the crystal lattice of Form Q and Form H1. Form Q exhibits an active slip plane system in the crystal lattice, while the slip plane is absent in Form H1. The crystallographic information on Form Q exhibited the centrosymmetric monoclinic space group (P21/c), consisting of four molecules in its unit cell (Z = 4). The molecules exist as

Figure 8. Crystal structures of FXT polymorphs viewed in the bdirection: (A) (top) Slip plane system of Form Q; and (B) (bottom) intermolecular hydrogen bonding of Form H1.

a dimer, each having a different conformation in a common unit cell. Intermolecular hydrogen bonds are absent between the dimers; however, they are held together by numerous van der Waals interactions. The single crystal structure of Form H1 revealed a centrosymmetric triclinic space group (P1) consisting of four molecules in its unit cell (Z = 4). Like Form Q, they also exhibited dimer arrangement vis-à-vis a different conformation in the unit cell. Unlike Form Q, Form H1 exhibits intermolecular hydrogen bonding. The sulfonamide (―SO2NH2) group participates in intermolecular hydrogen bond formation. Hence, only one hydrogen bond is present between the dimers. Slip planes are crystallographic planes in the crystal structure which contain the weakest interaction between the adjacent planes and are accounted for by the highest molecular density and largest d-spacing, as compared to the other planes in the same crystal.1,14,51,52 Form Q exhibits active slip planes in its crystal structure. Form H1 does not have an active slip plane in its crystal structure. 4.4. Comparative assessment of deformation behavior. Tabletability of pharmaceutical compacts is governed by compressibility and compactibility.2,7,31 Overall tabletability is the result of the interplay between the compaction conditions (pressure and strain rate), mechanical properties, crystal structure, and chemical nature of the surfaces.3,16,17,31,49,52,53 In the present investigation, Form Q exhibited greater compressibility and tabletability whereas the compactibility of both the forms is not significantly different. This indicates the dominant role of compressibility in governing the tableting performance of the FXT polymorphic pair. However, the tensile strength at zero porosity (τ0) values indicated higher interparticulate bonding strength of Form Q over Form H1, which can also contribute to the higher tensile strength of Form Q. It has been reported that crystals having a slip system possess greater tabletability due to their greater compressibility conferred by the sliding motion of molecular planes. Form H1 possesses interplanar H-bonding along the “b” axis direction, which resists gliding of molecular planes. Thus, Form H1 does not have an active slip system in its crystal structure. This was 872

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further correlated by the higher mechanical hardness and elastic modulus of Form H1 as compared to Form Q (Table 2). Plastic deformation can be related to ease of gliding of active slip planes in the crystal structure, which confers both compressibility and tabletability to Form Q. Examination of the crystal lattice revealed the absence of active slip planes in Form H1. Interplanar H-bonding in Form H1 resists plastic deformation under applied mechanical stress. The higher Py value for Form H1 further supports this. This finding suggests that Form Q is a plastically deforming material as compared to Form H1. Form H1 possesses interplanar H-bonds in its crystal lattice while Form Q is equipped with active slip planes along the “b” axis direction. Interplanar H-bonds resisted gliding of crystal planes in Form H1. In line with these crystallographic features, Form H1 offers higher hardness and higher value of the elastic modulus. Thus, there was a significant correlation between single crystal nanomechanical parameters and bulk deformation behavior. A higher elastic modulus (E = 4.510 GPa) of Form H1 was expected to offer higher bonding strength by virtue of its stronger interactions. However, Form Q showed higher tensile strength at zero porosity (τ0 = 2.8 MPa) as compared to Form H1 (τ0 = 2.1 MPa), indicating its greater interparticulate bonding strength despite having lower elastic modulus (E = 2.473 GPa). Nevertheless, this unexpected behavior of Form Q is consistent with our earlier observation that a polymorph having higher true density possesses greater interparticulate bonding strength.

AUTHOR INFORMATION

Corresponding Author

*Phone: + 91 172 2214682; Fax: +91 172 2214692; E-mail address: [email protected]. ORCID

Arvind K. Bansal: 0000-0001-6051-6680 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS

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REFERENCES

We thank Indian Institute of Technology (IIT) Ropar, Rupnagar, Punjab, India, for providing single crystal X-ray diffraction and nanoindentation facilities and National Institute of Pharmaceutical Education and Research (NIPER), S.A.S Nagar, Punjab, India, for financial support to carry out this work.

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5.0. CONCLUSION In the present study, as compared to Form H1, Form Q, which has an active slip plane system in its crystal structure, showed lower crystal hardness, lower mean yield pressure, greater compressibility, and greater densification under applied pressure. Here, the active slip plane system governed the mechanical behavior of Form Q. The superior tabletability of Form Q is attributed to its greater plastic deformation under applied pressure, which offered greater interparticulate bonding area and hence higher tablet tensile strength. Thus, the lower hardness measured by nanoindentation is found to be consistent with the bulk compaction behavior of Form Q. As discussed earlier, interparticulate bonding strength also contributes to the tablet tensile strength and is governed by interparticulate interactions. The higher elastic modulus of Form H1 was anticipated to offer greater bonding strength to its compacts. However, the lower tensile strength at zero porosity (τ0) of Form H1 is not in agreement of this hypothesis. The higher elastic modulus of Form H1 could be largely attributed to anisotropic interactions, and random particle reorientation during compaction would have reduced the probability of these anisotropic interactions. However, this needs to be investigated further to establish the relationship.

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DOI: 10.1021/acs.molpharmaceut.6b01075 Mol. Pharmaceutics 2017, 14, 866−874

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DOI: 10.1021/acs.molpharmaceut.6b01075 Mol. Pharmaceutics 2017, 14, 866−874