Molecular Understanding of the Compaction Behavior of Indomethacin

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Molecular Understanding of the Compaction Behaviour of Indomethacin Polymorphs Kailas S Khomane, Parth K More, Guru Raghavendra, and Arvind K. Bansal Mol. Pharmaceutics, Just Accepted Manuscript • DOI: 10.1021/mp300390m • Publication Date (Web): 09 Jan 2013 Downloaded from http://pubs.acs.org on January 22, 2013

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Molecular Pharmaceutics

Molecular Understanding of the Compaction Behaviour

Molecular Understanding of the Compaction Behaviour of Indomethacin Polymorphs Kailas S. Khomanea, Parth K. Morea, Guru Raghavendraa, Arvind K. Bansala* a

Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S. A. S Nagar, Mohali, Punjab, India;

*

Corresponding author:

Arvind K. Bansal Professor, Department of Pharmaceutics National Institute of Pharmaceutical Education and Research (NIPER) S.A.S. Nagar, Mohali, Punjab- 160 062, India Tel.: -91-172-2214682-2126; fax: +91-172-2214692 Email address: [email protected]

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ACS Paragon Plus Environment


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Graphical Abstract

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Abstract Polymorphs enable us to gain molecular insights into the compaction behaviour of pharmaceutical powders. Two polymorphs (α and γ) of indomethacin (IMC) were investigated for in-die and out-of-die compaction behavior using compressibility, tabletability and compactibility (CTC) profile, stress-strain relationship, Heckel, Kawakita and Walker equations. Compaction studies were performed on a fully instrumented rotary tabletting machine. CTC analysis revealed that γ-form has increased compressibility while α-form showed greater compactibility. The α-form also showed increased tabletibility over γ-form at all the compaction pressures. Lower values of Py (Heckel parameter) and 1/b (Kawakita parameter) indicated increased deformation behaviour of γ-form. Stress-strain analysis also supports the increased compressibility of γ-form. In addition, Walker analysis showed higher compressibility coefficient (W) for α-form, consistent with its greater tabletability. Thus, tabletability of IMC polymorphs was governed by the compactibility of the material. Detailed examination of crystallographic data revealed that presence of slip plane system in γ-form offered it increased compressibility and deformation behaviour. However, α-form showed greater compactibility by virtue of closer molecular packing (higher true density). Hence, although direct correlation between tabletability and presence of slip planes in the crystals has been reported, prediction solely based on this crystallographic feature must be avoided. Present work reiterates the influence of the crystal packing on the tabletability of the pharmaceutical polymorphs.

Keywords: Indomethacin polymorphs, Compaction, Bonding strength, Slip planes, Molecular packing, Heckel equation, Stress-strain relationship

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Introduction An understating of the structure property relationship is imperative to improve pharmaceutical processing and performance. Compaction is not an exception to this, however, link between structure and property is not fully understood and requires systematic evaluation. Few attempts correlating crystal structure to the tabletting performance, have been reported.1-4 Molecular level parameters such as slip plane system1, thermodynamic properties (heat of fusion)2 and molecular packing (true density)5, have been correlated with tabletability of the pharmaceutical powders. Robert et al correlated compaction properties with thermodynamic stability (heat of fusion) of the polymorph. Stable polymorphs showed higher yield strength, mean yield pressure and resist densification under compaction pressure, but also showed better tabletability.2 In a previous report from our lab5, we studied compaction behaviour of clopidogrel bisulfate (CLP) polymorphs. Being density violator (stable polymorph with higher heat of fusion and lower true density), CLP polymorphic system allowed us to study individually, the impact of molecular packing and heat of fusion on bonding strength. It was revealed that true density and not heat of fusion, governed the bonding strength of the pharmaceutical powders.5 Closer cluster packing of the molecules offered rigid structure to the form I (meta-stable polymorph) that resists densification under compaction pressure and showed higher yield strength and mean yield pressure. However, it also showed greater tabletability by virtue of its greater compactibility. Another crystallographic feature that directly influences the compaction properties is the slip plane system. Presence of slip plane system in the crystal lattice has been reported to allow easier inter-planar slip motion under compaction pressure that offers greater compressibility and deformation (increased plasticity) to the material.1,

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Thus, slip plane system affects the

compressibility while molecular packing governs the compactibility of the material. However, 4


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both compressibility (represents bonding area) and compactibility (represents bonding strength) contribute to tabletability. Hence it would be interesting to investigate the contribution of individual features like slip plane system and molecular packing to the compaction behaviour. Present study involves investigation of compaction behaviour of α and γ polymorphic forms of Indomethacin (IMC). The α-form has higher true density while γ-form shows presence of slip planes in its crystals. Thus, crystallographic features of the IMC polymorphic system enable us to study individually the impact of molecular packing and slip plane system on the compaction behaviour. Being density violator, IMC polymorphic system also allows us to investigate the contribution of heat of fusion and true density to bonding strength of the material. These two polymorphs of IMC were investigated for in-die and out-of-die compaction behavior using CTC profile, stress-strain relationship, Heckel, Kawakita and Walker equations. Compaction studies have been performed at different pressures using a fully instrumented rotary tablet press.

Experimental Section IMC Polymorphs. IMC (γ-form) was kindly gifted by Mylan Lab Ltd, Hyderabad (India). It was recrystallized from diethyl ether at room temperature and dried using a silica gel desiccator. The α-form was generated by a modification of a method reported by Kaneniwa et al7, 8. Supersaturated solution was obtained by dissolving 100 g of IMC bulk powder in the 200 ml ethanol at 80 °C. This supersaturated solution of the drug (at 80 °C) was directly filtered into 400 ml of double distilled water at room temperature. The precipitated crystals were filtered and dried overnight under vacuum at room temperature using a P2O5 desiccator. Both forms were characterized for their solid form, to confirm the purity.7

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Powder X-ray Diffraction (PXRD). PXRD of both polymorphs was recorded at room temperature 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 performed in a continuous mode with a step size of 0.01° and step time of 1 s over an angular range of 3-40° 2θ. Obtained 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, Model Q2000 (TA Instruments, New Castle, DE, USA) operating with Universal Analysis® software, version 4.5A (TA Instruments, New Castle, DE, USA). About 2.5-3.5 mg of each form was accurately weighed in crimped aluminium pans and subjected to the thermal scan from ambient to 200 °C at the heating rate of 20.0 °C min-1. Dry nitrogen purge was maintained at 50 mL min1

. Prior to analysis, instrument was calibrated using high purity standards of zinc (Zn) and

indium (In). Moisture Content. Moisture content of both samples (300 mg) was determined by Karl Fischer (KF) titration (Metrohm 794 Basic Titrino, Herisau, Switzerland) before performing compaction studies. Instrument was calibrated with disodium tartrate dihydrate for the accuracy of moisture determination. Particle Size Distribution. Similar particle size fraction of each form was obtained by sieving. D90 and D50 of each fraction were determined by optical microscopy by measuring diameter along the longest axis, for at least 150 particles (DMLP microscope, Leica Microsystems, Wetzlar, Germany). 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 6


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voltage of 15 kV. Powders were mounted onto steel stage using double sided adhesive tape and coated with gold using ion sputter (E-1010, Hitachi Ltd., Japan). Bulk and True Density. Bulk density was calculated by carefully adding accurately weighed powder to 250 ml measuring cylinder. The true density of both polymorphs was determined in triplicate by helium pycnometry (Pycno 30, Smart Instruments, Mumbai, India) at 25±2 °C/40±5 % RH. Tableting and Data Acquisition. Rotary tablet press (Mini II, Rimek, Ahmedabad, India) was equipped at one of the 8 stations with 8 mm D-tooling with flat punch tip. Feed frame was used for uniform die filling and blind dies were used at all other positions. Pre-compression rollers were set out of function. Tablets of each material were compressed at constant volume. Humidity (40 ± 2 % RH) and temperature (25 ± 2 °C) conditions were monitored throughout the study. Tablet weight was kept at 200 ± 5 mg and applied force was leveled by moving the pressure roller with a hand wheel. Each powder was compacted at different compaction pressures on an instrumented rotary tablet press ranging from around 25 to 300 MPa. The tableting speed was kept constant at 14.0 rpm. Data was acquired by Portable Press Analyzer TM (PPA) version 1.2, revision D (Data Acquisition and Analyzing System, PuuMan Oy, Kuopio, Finland), through an infrared (IR) telemetric device with 16-bit analog-to-digital converter (6 kHZ). Force was measured by strain gauges at upper and lower punches (350 X, full Wheatstone bridge; I. Holland Tableting Science, Nottingham, UK), which were coupled with displacement transducers (linear potentiometer, 1000 X). Upper and lower punch data were recorded and transmitted on separate channels by individual amplifiers (“Boomerangs”). The amplifiers truncated the raw data from 16 bit to 12 bit after measuring to check IR transmission (data transmission rate-50 kbaud; 7



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internal data buffer–1024 measurement points). Analysis of compaction data was carried out by PPA Analyse software (version 1.2, revision D). Accuracy of force and displacement transducers was 1% and 0.02%, respectively. The suitability of the data acquisition system has been reported in the literature.5, 9 Calculation of Tablet Tensile Strength and Porosity. Breaking force of the tablets was measured using a tablet hardness tester (Tablet hardness tester, Erweka, USA). Tablet dimensions were measured using a digital caliper (Digimatic Mitutoyo Corporation, Japan). Tensile strength was calculated using equation 1 to eliminate the undesirable effect of variable tablet thickness on measured breaking force.

σ = 2 F πdt

Equation 1

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 by the equation 2,

ε = 1 − ρc ρ t

Equation 2

where ρc is the density of the tablet calculated from the weight and volume of the resulting tablet.

ρt is the true density of powder. Statistical Analysis. Statistical significance for values of various compaction parameters were compared using a two-tailed paired t-test (SigmaStat version 3.5, San Jose, California, USA) and the test was considered to be statistically significant if P < 0.05. Molecular Modeling. The crystal structures of two polymorphs of IMC, γ (reference code: INDMET) and α (reference code: INDMET02) were downloaded from the Cambridge Structural 8


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Database. The structure property relationship was established by studying the relative arrangements of atoms/molecules and the variation in hydrogen bonding, using Mercury software V2.3 CCDC. The observed structural features were then correlated to the compaction behaviour of the corresponding polymorphs.

Results Solid State Characterization of IMC Polymorphs. Figure 1 shows PXRD overlay for polymorph α and γ, and these compared well with the patterns reported in literature.10-12 2400 2300 2200 2100 2000 1900 1800 1700 1600 1500

Lin(Counts)

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1400 1300 1200 1100 1000 900 800

IMC-A

700 600 500

IMC-G

400 300 200 100 0 4

10

20

30

2-Theta - Scale

Figure 1. PXRD overlay of IMC polymorphs Table 1. Melting point, heat of fusion and true density of IMC polymorphs Polymorph

Melting point (°C)

Heat of fusion (J/g)

True density* (g/ml)

α-form

154.70

92.47

1.427 (0.012)

γ-form

160.26

102.7

1.377 (0.007)

*Standard Deviations in Parentheses

DSC trace of α-form showed a single melting endotherm with a peak at 154.70 °C. The γ-form showed similar behaviour with a sharp melting endotherm at 161.26 °C (Table 1). Both values 9



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were in close agreement to the earlier reports.11, 12 Higher melting polymorph, γ-form showed higher heat of fusion while α-form showed lower heat of fusion (Table 1). Thus, according to heat-of-fusion rule13, polymorphic system has monotropic relationship. Both forms of IMC were found to be non-hygroscopic and showed moisture content lower than 0.1% w/w. True density of both forms, determined using helium pycnometry, was comparable with values calculated from single crystal structure of respective form10, coworkers.15,

16

14

and experimental values reported by other

The stable form of IMC (γ-form) showed lower true density thus violating

density rule13 (Table 1). Physical characterization revealed that both samples had similar D50 and D90 values (Table 2). As shown in figure 2, bulk solids of the both polymorphs observed as nearly spherical agglomerates under scanning electron microscopy. It is essential to keep the particle shape and size similar to understand the impact of molecular level properties on compaction behaviour.

Figure 2. Photomicrographs of IMC polymorphs (a) agglomerates of α-form (b) agglomerates of γ -form (c) single particle of α-form (c) single particle of γ –form

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Table 2. Physical characterization of IMC polymorphs Particle size (µm) Polymorph

Bulk density (g/ml) D90

D50

α-form

180-300

280

200

0.303 (0.0017)

γ-form

180-300

280

200

0.167 (0.0006)

*Standard Deviations in Parentheses Compaction Behaviour of IMC Polymorphs. Preliminary experiments at very high compaction pressure (800 MPa) were performed to rule out the possibility of polymorphic transformation during study. Both forms were found stable and no polymorphic transformation was observed. CTC Profile of IMC Polymorphs. Tabletability is defined as the capacity of the powder material to be transformed into a tablet of specified strength under the effect of compaction pressure.4 Figure 3 shows tabletability plot for IMC polymorphs. Tensile strength of the both forms increased with compaction pressure; however, α-form showed higher tensile strength over γ-form at all compaction pressures. Thus α-form showed increased tabletability as compared to γ-form.

Tensile strength (MPa)

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2.0

α

γ

1.6 1.2 0.8 0.4 0.0 0

50

100 150 Compaction pressure (MPa)

200

250

Figure 3. Tabletibility plot for IMC polymorphs. The α-form shows increased tabletibility over γ-form at all compaction pressures. 11




The compressibility of the material is its ability to be reduced in volume as a result of an applied pressure and is represented by a plot of tablet porosity against pressure.4 Compressibility plot has been reported to represents the interparticulate bonding area.1 The compressibility plot (Figure 4) indicates greater compressibility of γ-form as compared to α-form at a given compaction pressure. As shown in figure 5, in-die compressibility plot17 also supports the out-ofdie observation by compressibility plot . 0.5

α

γ

Porosity

0.4 0.3 0.2 0.1 0.0 0

50

100 150 200 Compaction pressure (MPa)

250

Figure 4. Plot showing greater compressibility of γ-form over α-form at all compaction pressures 0.7 In-die tablet porosity

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α

γ

0.6 0.5 0.4 0.3 0.2 0.1 0 0

50 100 Compaction pressure (MPa)

150

Figure 5. In-die compressibility plot of IMC polymorphs 12


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Compactibility is the ability of the material to produce tablets with sufficient strength under the effect of densification and is represented by a plot of tensile strength against tablet porosity.4 Thus it shows the tensile strength of tablets normalized by tablet porosity. The α-form of IMC has significantly higher compactibility indicating its increased tensile strength over γ-form at a given porosity (Figure 6). 1.6 Tensile strength (MPa)

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IMC A

1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 0.0

0.1

0.2 0.3 Porosity

0.4

0.5

Figure 6. Compactibility plot showing greater bonding strength of α-form over γ-form Heckel Analysis. The Heckel equation transforms force and displacement data to a linear relationship for the materials undergoing compaction.18,

19

The basis for the equation is that

densification of the bulk powder under pressure follows first-order kinetics. It presents compaction data in term of its relative density under applied pressure.20 The Heckel equation is expressed as equation 3. ln [1 / 1 - D] = KP + A,

Equation 3

where, D is the relative density of the tablet at applied pressure P and K is the slope of straight line portion of the Heckel plot. Reciprocal transformation of the slope (K) gives mean yield pressure, Py which can be related to the yield strength of the material. Constant A gives

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densification of the powder due to initial particle rearrangement, (Da). Da is calculated from equation 4. Da = 1 – e-A

Equation 4

Densification behaviour of IMC powders was studied using Heckel analysis. Apparent mean yield pressure (Py) was calculated from the linear portions of the Heckel plot (R2 > 0.99 in all cases) The in-die parameters obtained from Heckel analysis of the two polymorphs each at different compression forces are summarized in table 3. As shown by figure 7, γ-form showed higher densification and hence lower Py value at all compaction pressures. Densification due to initial particle rearrangement (Da) is also higher for γ-form as compared to α-form at all compaction pressure (Table 3). 1.4

α

γ

1.2 1.0 In (1/1-D)

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0.8 0.6 0.4 0.2 0.0 0

20

40

60

80

100

120

Compaction pressure (MPa)

Figure 7. In-die Heckel plot of IMC polymorphs at the compression pressure of 5.25 kN

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1 2 Molecular Understanding of the Compaction Behaviour 3 4 Table 3. Heckel, Kawakita and Walker parameters for IMC polymorphs 5 6 Heckel parameter Kawakita parameter Walker parameter 7 Compaction Polymorph pressure (MPa) Py (MPa) Da 1/b a W L 8 9 α 866.58 (3.1) 0.5418 (0.011) 4.47 (0.21) 0.4379 (0.0041) 26.28 (2.12) 3.23 (0.14) 104.4 (0.40) 10 γ 657.27 (6.8) 0.5957 (0.009) 2.88 (1.01) 0.4865 (0.0011) 19.05 (1.48) 5.24 (0.62) 11 α 1296.48 (8.2) 0.5431 (0.021) 4.71 (0.42) 0.4372 (0.0024) 27.16 (1.58) 3.60 (0.49) 157.1 (6.38) 12 γ 766.99 (9.4) 0.6178 (0.019) 2.97 (0.87) 0.5986 (0.0063) 16.37 (0.98) 5.90 (0.68) 13 α 1559.08 (3.6) 0.5490 (0.006) 6.26 (0.92) 0.4420 (0.0084) 32.09 (1.30) 3.02 (0.09) 187.4 (1.59) 14 γ 1089.10 (6.6) 0.6240 (0.016) 4.31 (0.12) 0.4976 (0.0099) 25.57 (1.19) 3.86 (0.06) 15 α 1938.24 (11.12) 0.5535 (0.024) 7.97 (1.12) 0.4260 (0.021) 19.71 (0.91) 4.86 (0.81) 275.5 (4.97) 16 γ 1204.29 (13.12) 0.6702 (0.029) 4.65 (0.85) 0.5492 (0.011) 16.67 (0.61) 7.49 (0.72) 17 Each value represents an average of at least four tablet measurements with their standard deviations in parenthesis. Statistically 18 significant difference was observed between values of each abovementioned parameter for α and γ-forms (P value < 0.05) 19 20 Stress-strain Analysis. Stress-strain analysis is a basic representation of the compaction data 21 22 for the material. Engineering strain also called as degree of compression (C) is plotted against the 23 24 25 applied compaction pressure. Engineering strain was calculated using equation 5. 26 27 C= [(V0 – V)/V0], Equation 5 28 29 where, V is volume of compact at pressure P, and V0 is the initial apparent volume of powder. 30 31 32 As depicted in figure 8, high initial compression at low compaction pressures followed by 33 34 plateau (Cmax) was obtained for both the powders. However, γ-form showed higher Cmax as 35 36 compared to α-form indicating its increased compressibility. C-values of the powder bed were 37 38 39 also calculated by using an initial volume (V0) transformed from the bulk density (BD) of the 40 41 powder. Stress-strain profile obtained using these values (CBD) for both powders follow the same 42 43 44 trend. Thus stress-strain profiles for both powders support the out-of-die and in-die 45 46 compressibility plot. 47 48 49 50 51 52 53 54 55 56 57 58 15 59 60 ACS Paragon Plus Environment


Molecular Understanding of the Compaction Behaviour 0.7

α

γ

20

40

0.6 0.5 0.4 C

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0.3 0.2 0.1 0 0

60

80

100

120

140

160


Figure 8. Stress-strain profile for the IMC polymorphs (0-140 MPa) Kawakita Analysis. Kawakita equation is commonly used expression to linearize compaction data and is based on the assumption that the particles subjected to compressive load are in equilibrium at all stages of compression, so that the product of pressure term and volume term is constant21, 22. The Kawakita equation is: P/C= [P/a + 1/ab],

Equation 6

where, P is the applied axial pressure, C is the engineering strain and a is the value of initial porosity and mathematically, it represents the engineering strain or degree of compression at infinite pressure. It also corresponds to the total portion of reducible volume at maximum pressure. The inverted b parameter (1/b) represents the pressure needed to compress the powder to one half of the total volume reduction estimated as a term. The parameter b is proposed to be inversely related to the yield strength and plasticity of the material.23, 24 Kawakita parameter a and 1/b for IMC polymorphs were obtained from linear regression (R2 > 0.999) of P/C versus P. In-die parameters of the Kawakita equation obtained for IMC 16


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polymorphs at different compaction pressures are described in table 3. Comparatively, α-form showed higher values of parameter 1/b at all compaction pressures. Like Py, the parameter 1/b which also describes the yield strength of the material, showed pressure dependency and its value increases with an increase in compression pressure. Values of parameter a are higher for γform at all compaction pressures (Table 3). Thus, γ-form showed higher values of Kawakita parameter a and the lower values of Kawakita parameter 1/b, which is consistent with its higher Cmax.24 Plastic Energy Determination. The plastic energies (PE) were determined for each polymorph at different compaction pressures from the force–displacement compaction profiles.25-27 The data of PE from figure 9 indicates that as the compression pressure was raised, tablets made from both powders showed increased tendency to undergo plastic deformation. However, γ-form showed higher values of PE as compared to α-form at all compaction pressures. This indicates that γ-form underwent higher degree of plastic deformation as compared α-form, thus supporting the observations from Heckel and Kawakita analysis. 8 7 6 PE (J)

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


5 4 3 2 1 0 0

50

100

150

200

250

300


Figure 9. Plastic energy plot for IMC polymorphs

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Walker Analysis. The Walker equation28 (Equation. 5) is based on the assumption that the rate of change of pressure with respect to volume, is proportional to the applied pressure. Log P = -L (V’/V0) + C1,

Equation 7

where, V0 is the volume at zero porosity and V’ is the volume at pressure P. The coefficient L is referred to as the pressing modulus and C1 is a constant. Walker also proposed another equation (Eq. 9) in terms of the percentage relative volume as the dependent variable.5, 29 100(V′/V0) = -W Log P + C2

Equation 8

100V = -W Log P + C2

Equation 9

where, W is compressibility coefficient that expresses the percent change in volume of the material undergoing compaction and C2 is a constant. It was found to be well correlated with tabletability of the material.

5, 30

Material with higher compressibility coefficient showed

increased tabletability.5 Values of Walker parameters, W and L at different compaction pressures for both forms were obtained from the linear regression analysis of 100V versus Log P and Log P versus V (R2 > 0.99 in all cases) respectively and represented in the table 3. As compared to γform, α-form showed higher coefficient of compressibility at all four compaction pressures (Table 3). Thus α-form possesses better tabletibility over γ-form. These results are consistent with observation from the tabletibility plot (Figure 3). Values of pressing modulus follow similar trend as shown by parameter a and hence can be correlate with the compressibility of the material. This observation is consistent with previous reports.29

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Discussion Solid state characterization of IMC polymorphs revealed that γ-form possesses higher heat of fusion as compared to α-form and hence it is thermodynamically stable. However, it shows lower true density and violates the density rule.13 This allows us to study individually the contribution of molecular packing (true density) and thermodynamic properties (heat of fusion) to the compactibility of the IMC polymorphs. Compaction behaviour of the pharmaceutical powders is mainly governed by the compressibility and compactibility of the material undergoing compaction.31 Tabletability, the ability of the material to convert to a tablet of adequate mechanical strength, is governed by both compressibility and compactibility. In case of IMC polymorphs, CTC profile revealed greater compactibility of α-form (Figure 6) while γ-form possesses higher compressibility (Figure 4 & 5). Despite its poorer compressibility, α-form showed increased tabletability over γ-form (Figure 3 & 4). Higher value of W, a Walker parameter, at all four compaction pressures also supports increased tabletability of α-form (Table 3). Thus, compaction behaviour of IMC was governed by compactibility of the material and not the compressibility. At a given pressure, α-form forms tablets with greater tensile strength as compared to γ-form, by virtue of its greater compactibility. Thus, results of this study are in accordance with our previous conclusion that true density and not heat of fusion governs the compactibility of the pharmaceutical powders.5 The α-form having higher true density, showed greater compactibility. As discussed previously, the presence of slip planes in the crystal structure influences the tabletability of the pharmaceutical powders.6, 32-35 The crystallographic data of γ-form indicates presence of slip planes in its crystal structure [Figure 10 (b)]. Hence it was expected to have 19



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greater compressibility and plasticity as compared to α-form. Out-of-die and in-die compressibility plots (Figure 4 & 5), and stress-strain profile (Figure 8) confirmed the increased compressibility of γ-form over α-form. Heckel analysis also showed lower Py value for γ-form at all compaction pressures (Table 3). Kawakita analysis supports Heckel plot, as lower values were obtained for parameter 1/b at all four compaction pressures. Parameter 1/b is inversely related to the plasticity of the material.24,

36

Thus compaction data was consistent with the

previous reports6, 32-35 that presence of slip planes in the crystals offer greater compressibility and greater plasticity to the material. Thus, IMC polymorphic system showed two crystallographic features i.e. slip plane system and differential molecular packing, which influence the overall compaction behaviour of the material. Molecular packing governs the compactibility while slip plane system governs the compressibility. Detailed examination of crystallographic data of IMC polymorphs revealed that α-form has closer molecular packing (higher true density) while γ-form shows slip planes system. Crystal structure of both forms was studied further to gain molecular insight into the compaction behaviour. Crystal Structure of IMC Polymorphs. Crystal structure of the meta-stable α-form has been reported by Chen et al. in 2002.14 The crystallographic data of α-form revealed the noncentrosymmetric monoclinic space group (P21) containing six molecules in its unit cell (Z=6). Molecules exist as a trimer, each having a different conformation. Three intermolecular hydrogen bonds are present between the molecules of the trimer. As depicted in figure 10 (a), two molecules form mutually hydrogen-bonded carboxylic acid dimers and the third molecule forms a hydrogen bond between the carboxylic acid and an amide carbonyl in the dimer.14

20


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Figure 10. Intermolecular hydrogen bonding present in α-trimer (a) and γ-dimer (b) Crystal structure of γ-form has been determined by Kistenmacher et al.37 Unlike α-form, crystals of γ-form are in the centrosymmetric triclinic space group (P1) and its unit cell consists of two molecules (Z=2) that exist as mutually hydrogen-bonded carboxylic acid dimers.37 Thus only two intermolecular hydrogen bonds are present between the molecules of the dimer [Figure 10 (b)].

21



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Figure 11. Crystal structures of IMC polymorphs viewed in a-direction (a) closer molecular packing in the α-form (b) presence of slip plane system in the γ-form In depth examination of crystal structures of both forms revealed that molecular arrangement differs significantly (Figure 11). As reported by Burger and Ramberger, hydrogen bonding and molecular conformations play significant role in the molecular packing of the density violator.13 There is difference between number and strength of hydrogen bonding present in the two forms. The α-form has an additional hydrogen bonding present between a carboxylic acid hydroxyl group and the carbonyl oxygen of an amide group [Figure 10 (a)]. IMC molecules adopt three different molecular conformations in α-form, as compared to single conformation in γ-form. These additional hydrogen bonding and conformations afford it a closer crystal packing which 22


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confers a dense crystalline structure.14 Closer packing of the molecules in α-form offered a rigid structure and hence it showed poor compressibility and resists deformation under compaction pressure. As a result, α-form showed lower densification, higher yield strength and yield pressure at a given pressure as compared to γ-form. Slip planes are crystallographic planes in the crystals that exhibit weakest interactions between the adjacent planes and are characterized by the highest molecule density and largest d-spacing, as compared to other planes in the same crystal.38 The γ-form of IMC also possesses this crystallographic feature [Figure 11 (b)]. In previous reports6,

32-35

crystals having slip planes

showed increased tabletability by virtue of greater compressibility offered by sliding of slip planes under compaction pressure. However, tabletability may not be affected significantly, if compaction behaviour is governed by compactibility of the material. In other words, if material possesses very weak bonding strength, high bonding area provided by sliding of slip planes may not result into stronger tablets. Hence, despite greater deformation behaviour, γ-form produced tablets of poor tensile strength. Stronger hydrogen bonding present between carboxylic acid dimers in γ-form offers it greater thermodynamic stability. However, crystal analysis revealed that the hydrophobic phenyl and indol rings are prevalent on the peripheral faces of γ-crystals and the polar mutually hydrogen-bonded carboxylic acid dimers are caged inside a hydrophobic shield.14 The shielding of the polar hydrogen bonded dimer, may be responsible for weaker interparticulate bonding of γ-form.

Conclusion Crystallographic feature of IMC polymorphic system allowed us to study impact of molecular packing, heat of fusion and slip plane system, on the compaction behaviour of pharmaceutical powders. Meta-stable α-form (having lower heat of fusion) showed greater compactibility by 23



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virtue of its closer crystal packing (higher true density). Thus, true density and not heat of fusion, governed the compactibility of the IMC polymorphs. This is in agreement with our previous work, wherein meta-stable polymorph (form I) of clopidogrel bisulphate showed increased tabletability, by virtue of its greater bonding strength.5 The γ-form exhibited poor tabletability, despite its increased compressibility and deformation behavior. This is in contrast to previous reports6,

32-35

, wherein presence of slip planes in the

crystals correlated to the increased tabletability of the materials. As revealed by CTC profile and supported by various in-die parameters (Py, 1/b, W), compaction behaviour of IMC polymorphic system is governed by compactibility and not by compressibility. Hence, although direct correlation between tabletability and presence of slip planes in the crystals has been reported, prediction

solely

based

on

this

crystallographic

feature

must

be

avoided.

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Molecular Understanding of the Compaction Behavior of Indomethacin

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