A small-angle X-ray scattering study of powder compaction

Powder Technology 188 (2008) 119–127

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Powder Technology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p ow t e c

A small-angle X-ray scattering study of powder compaction Peter R. Laity ⁎, Ruth E. Cameron Pfizer Institute for Pharmaceutical Materials Science, University of Cambridge Department of Materials Science and Metallurgy, New Museums Site, Pembroke St. Cambridge CB2 3QZ, UK

A R T I C L E

I N F O

Article history: Received 5 March 2007 Received in revised form 9 April 2008 Accepted 9 April 2008 Available online 16 April 2008 Keywords: Small-angle X-ray scattering (SAXS) Powder Compaction

A B S T R A C T This work demonstrated a novel and potentially important application of two-dimensional small-angle X-ray scattering (2D-SAXS) to investigate powder compaction. SAXS from powder compacts of three materials commonly used for pharmaceutical tabletting exhibited azimuthal variations, with stronger intensity in the direction of the applied compaction force, relative to the transverse direction. This implied that compaction of a (macroscopic) powder could also produce changes on the molecular (nanometre) scale, which can be probed by 2D-SAXS. Two possible explanations for this effect were suggested. A combination of anisometric (i.e. elongated or flattened) granules with anisotropic morphologies could result in azimuthal variation in Xray scattering due to granule orientation. It is expected that this mechanism would require relatively low packing density, so may operate during die filling. Granule re-orientation appeared less likely at higher packing densities and compaction pressures, however. Under these conditions, the changes in the 2D-SAXS patterns would be consistent with the powder granules becoming relatively flattened in the compression direction, with corresponding changes in their nano-scale morphology. The magnitude of this effect was found to vary between the materials used and increased with compaction pressure. This suggested that 2DSAXS studies could provide useful information on force-transmission within a compressed powder. Further analysis of the data also suggested differences in the compaction mechanisms (i.e. granule re-orientation, deformation or fragmentation) between the materials studied. © 2008 Elsevier B.V. All rights reserved.

1. Introduction Powder compaction is important and widely used in many manufacturing sectors. For example, compaction is widely used to produce moulded engineering parts, from metal, ceramic or polymer powders. Most notably, the pharmaceutical industry relies heavily on powder compaction to produce tablets for oral administration, which remains a very popular method for drug delivery [1–4]. In this application, issues such as tablet strength, propensity to fragmentation during manufacture or subsequent handling, porosity and disintegration when swallowed can have significant effects on the costs and the medical efficacy of the formulation. Hence, the compaction behaviour of various commonly used pharmaceutical excipient powders, such as microcrystalline cellulose (MCC), cellulose ethers and modified starches has been studied extensively. Powder compaction is a complex process, involving granule movement and re-orientation within the powder bed, together with deformation or fracture, resulting in increased contact area and intergranular bonding [2–4]. This can be affected by the material properties of the powder granules, such as modulus and strain behaviour (i.e. elastic, plastic deformation or brittle fracture), as well as geometric factors such as surface rugosity, shape and size distribution

⁎ Corresponding author. E-mail address: [email protected] (P.R. Laity). 0032-5910/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.powtec.2008.04.006

[2–9]. The compaction behaviour also depends on friction, both between granules and with the compaction die surfaces [3–5,10–12]. The combination of these factors generally results in variations of density and strength within compacted tablets, which may depend on their shape and can result in fragmentation faults (e.g. chipped edges, delamination or capping). Various experimental techniques have been used to investigate powder compaction, including: force–displacement measurements, helium pycnometry, mercury intrusion porosimetry, indentation measurements of hardness and various types of microscopy. Following recent advances in X-ray microtomography (XµT), several studies [13– 15] have used this method to observe the local density variations within tablets. Eiliazadeh et al. [16] used XµT to follow the movements of metal shot tracer beads, to investigate the effect of die geometry on the compaction behaviour of a pharmaceutical excipient powder. Djemai and Sinka [17] have also reported a new method using magnetic resonance imaging to observe density distributions within tablets of differing shapes and preparation conditions. In parallel with experimental investigations, there have also been considerable advances in the modelling of powder compaction [10–12,14,18–26]. Nevertheless, and notwithstanding the considerable research effort that has been motivated by the importance for pharmaceutical tablet manufacture, a complete understanding of compaction physics still eludes us [4]. For example, many variables such as the solid-state properties and inherent deformation behaviour of the material, granule size, granule shape, tooling geometry and process conditions

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can affect the attributes of the resulting tablets, in ways that may not be entirely predictable, given the present state of knowledge. Moreover, while it is generally accepted that granule rearrangement at low packing fraction is superseded by various relative amounts of deformation and fragmentation at higher compaction pressures, no direct evidence of densification mechanisms has yet been reported [14]. Small-angle X-ray scattering (SAXS) is a powerful and widely used method for investigating the structures of materials. The angular dependence of the scattered X-ray intensity is related to electron density variations associated with nano-scale morphological features (i.e. with characteristic lengths from 1 to 100 nm) within the illuminated region of the sample. This can encompass a plethora of diverse features, such as: mass-density fluctuations due to the size, orientation and distribution of crystallites within semi-crystalline polymers; composition variations due to microphase-separation in block or segmented copolymers; the presence of voids in microporous silica gels, rock or glass, soot and other granular aggregates; the distribution of hydroxyapatite crystals in bone; the sub-microscopic topology of surfaces or composition gradients at interfaces; crazing and fibrillation due to polymer deformation or (generally adverse) interactions with solvents; the morphology and mechanical response of muscle proteins; fibrillar structures in wood, cellulose or deformed polymers. This diversity of SAXS can be both advantageous and problematic; while it has led to numerous applications and extensive literature, interpretations of the origins of the scattering, in the absence of support from other techniques (e.g. electron or atomic force microscopy), may be ambiguous. For detailed discussions of the principles underlying SAXS and an overview of its uses, the reader is directed to the excellent textbooks, by Roe [27], Glatter and Kratky [28], Guinier [29,30] and others. The usefulness of SAXS is well demonstrated by countless applications in polymer science, biochemistry and materials science. In addition to numerous ‘static’ studies, SAXS has been used to investigate dynamic systems, in which morphological responses to chemical reaction, temperature changes and mechanical deformation can be observed. Nevertheless, there appears to be no previous application of SAXS to study powder compaction — even though it may be expected to provide quantitative information on granule deformation. The present paper examines the effects of compaction for three compacted polymer powders: hydroxypropyl-methyl-cellulose (HPMC), MCC and pre-gelatinised starch (PGS), which are commonly used as excipients in pharmaceutical tablet manufacture. Various explanations for the observed changes in 2D-SAXS patterns are explored and potential applications of the methods are discussed. This work represents the first part of a more extensive project using SAXS to investigate the compaction behaviour of various granular materials, which will be reported subsequently. 2. Experimental Commercial samples of HPMC (Methocel K4M premium EP, Colorcon Ltd. Kent, UK), PGS (1500, Colorcon Ltd. Kent, UK) and spheronised MCC (Celphere SCP100, Asahi-Kasei, Japan) were stored at room temperature and ambient humidity. All materials were used as received, without subsequent conditioning or purification.

the starting point. Compaction measurements were performed under ambient conditions, at 1 mm min− 1 to the desired maximum loading, which was maintained for 1 min before releasing, also at 1 mm min− 1. The die was promptly removed from the mechanical testing rig, separated from its base, inverted and the compact was gently ejected upwards (i.e. in the same direction as the initial compaction). The length (hT) and diameter (d) of the compact were measured to ±0.01 mm, using a micrometer gauge, within about 1 min of releasing the compaction force; its weight (m) was subsequently determined to ±0.0003 g using an electronic top-pan balance. The apparent distance travelled by the compaction head, xa(t), and the corresponding force on the upper punch, F(t), as measured by the load cell, were recorded during the experiment. By performing measurements on an empty die, the apparent displacement due to the apparatus bending under load (compliance) was found to follow an empirical relationship of the form: nfF ðt Þg ¼ kfF ðt Þga

where k and α were constants (evaluated respectively as 0.115 × 10− 3 and 0.8, for compliance in mm and force in N, over the load-range used). Hence, the true compaction displacement was obtained using: xðt Þ ¼ xa ðt Þ  nfF ðt Þg:

ð1bÞ

The initial length (h0) of the uncompacted powder sample was calculated from hT and the terminal compaction distance (xT), which included the effect of elastic ‘spring-back’ as the force was relaxed: h0 ¼ hT þ xT :

ð2Þ

It should be noted that, although the compaction force was returned to zero with the compact still in the die, a small amount of additional elastic recovery may be expected between ejection and measuring the final thickness. This would result in a slight overestimate of hT and a corresponding error in h0. However, a greater variation in h0 may be expected, due to the initial packing density of the uncompacted powder, which can be significantly affected by die filling conditions and granule shape. The bulk density of the ejected compact was calculated using: qB ¼

4m phT d2

ð3aÞ

where the diameter of the compact was found to be equal to the internal diameter of the die, within the accuracy of the present measurements, and presumed to remain constant throughout the compaction experiment (i.e. no distortion of the die). Similarly, the bulk density of the powder bed during the compaction experiment was calculated using: qB ðt Þ ¼

4m : pðh0  xðt ÞÞd2

ð3bÞ

Hence, the relative density of the powder during a compaction experiment could be calculated from: qR ðt Þ ¼ ¼

2.1. Sample preparation and compaction force measurements Flat-ended cylindrical compacts (5 mm diameter, ca. 0.08 g) were prepared by single-sided compaction in an unlubricated stainless steel die (Specac Ltd. Smiths Industries, Kent, UK), using a mechanical testing rig (Instron Ltd. High Wycombe, Buckinghamshire, UK). The lower pellet was inserted into the die, followed by the powder charge (weighed approximately); the upper pellet was inserted and the die assembly was gently tapped on the bench to achieve a loosely packed powder bed as

ð1aÞ

qB ðt Þ q0

4m q0 pðh0  xðt ÞÞd2

ð3cÞ

where ρ0 is the true density of the material. Given the uncertainty expected in h0, as noted above, it was decided to use relative density as a basis for comparing compaction behaviour. The average upper punch pressure during a compaction experiments was calculated from F(t) and d: P ðt Þ ¼

4F ðt Þ : pd2

ð4Þ

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2.2. SAXS measurements SAXS studies were performed using a Nanostar camera (Bruker AXS Inc. Madison, WI, USA), fitted with a sealed microbeam source, which was run at 40 kV, 35 mA and filtered to give CuKα radiation (wavelength, λX = 0.154 nm). The sample to detector distance was approximately 1.05 m and the entire optical path, including sample chamber, was evacuated. Two-dimensional scattering patterns (2DSAXS) were collected using a Hi-Star gas-filled wire grid area detector; a circular cross-section lead ‘beamstop’ was suspended ahead of the detector, on four thin, transparent polymeric threads, to absorb the undeviated X-ray beam. The scattering angle (2θ) was calibrated using a silver behenate powder sample and the modulus of the scattering vector was calculated using: q ¼ jqj ¼

4p  sin kX

h

ð5Þ

where q = (qx, qy, qz) is the scattering vector, which expresses the difference between the incident and scattered wave vectors. Acquisition times of 15 min were used for all samples. In order to correct for ‘parasitic scattering’, background subtractions were performed, after suitable normalisation based on absorbance measurements using a glassy carbon sample inserted into the optical path after the sample to spread the undeviated beam. Uncompacted powder samples were mounted in a sample holder between thin mica sheets. Diametric cross-sections from compacts (approximately 2 mm thick) were cut gently (shaved, rather than sliced) by hand, using a fresh scalpel blade and mounted in the SAXS camera with the compaction direction vertical. The sample was then positioned, using an adjustable sample stage, to locate the X-ray spot near the centre of the cross-section. SAXS intensity curves were extracted from the 2D-SAXS patterns using SAXS for Windows® NT software (Bruker AXS Inc. Madison, WI, USA). Unidirectional ‘q-scans’ were obtained by integrating over arcs spanning ± 5° of the desired direction, with increments in the scattering angle (2θ) of 0.01°. Scans of intensity against azimuthal angle (ϕ) were also performed, selecting a 2θ range that included all the observable SAXS, with increments in ϕ of 0.5°, measured from the compaction direction. Angular variations in the azimuthal scans were quantified using the Hermans orientation parameter [26]: H¼

3h cos 2 /i  1 2

121

Thin compacts were prepared by pressing small amounts of excipient (ca. 0.08 g) in a 13 mm diameter die, to a maximum loading of 1.0 kN, equivalent to an average punch pressure of 74 MPa. These specimens were mounted vertically, on specially prepared aluminium stubs, using adhesive carbon tape and carefully fractured by hand, to reveal the cross-section. All samples were gold-coated, using an Emitech K550 sputtercoater, at 20 mA for 3 min. The samples were then viewed using a JSM820 (Jeol) at 10 kV and 15 mm sample distance. 3. Results SAXS data for the three types of uncompacted polymeric powders are presented in Fig. 1. In each case, the 2D-SAXS patterns exhibited circular symmetry, indicating that the morphologies of the uncompacted powders were essentially isotropic. There appeared to be either no preferred orientation of the morphology within the powder granules or no preferred orientation of the powder granules within the uncompacted bed. The intensity curves appeared relatively featureless and decreased continuously from the lowest observable q limit (ca. q = 0.1 nm− 1, defined by the edge of the beamstop shadow) until they became

ð6aÞ

where: R 360 hcos 2 /i ¼

0

Iðq; /Þ cos 2 /  j sin /j  d/ : R 360 Iðq; /Þ  j sin /j  d/ 0

ð6bÞ

Values of H can range from 1.0 to −0.5. Hence, H = 1.0 would indicate that all scattering occurred parallel to the applied compaction force (i.e. vertical in the 2D-SAXS patterns, defined as the y-axis or meridian); a value of H = −0.5 would indicate that all scattering occurred perpendicular to the applied compaction force or parallel to the diameter of compacted samples (i.e. horizontal in the 2D-SAXS patterns, defined as the y-axis or meridian); H = 0 would indicate completely isotropic scattering. 2.3. Scanning electron microscopy The granule shapes of the uncompacted excipient powders were investigated by scanning electron microscopy (SEM). A small piece of conductive (carbon-impregnated) double-sided adhesive tape was placed on an aluminium stub and a small amount of the powder was sprinkled onto it. Excess was removed by gently blowing, prior to gold-coating.

Fig. 1. Radial SAXS data for uncompacted powders: (a) linear plots (insets show 2DSAXS patterns); (b) double-logarithmic plots.

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indistinguishable from the background. This suggested the absence of any regular or periodic nano-scale morphological features within these three materials. The data for HPMC and PGS appeared very similar (essentially identical, apart from intensity scaling), while the curve for MCC decreased somewhat more gradually. Plots of log{I(q)} vs. log(q) were approximately straight lines, with slopes between −2 and −4, as shown in Fig. 1b, indicating that the scattering followed power-law dependences: IðqÞ ¼ IA  qa

ð7Þ

where IA is a constant that depends on the beam intensity, the irradiated volume and scattering power of the sample. There was clearly insufficient data for detailed structural analyses of these materials. Nevertheless, deviations of the scattered intensities from q− 4 dependences (as predicted by Porod's law) suggested that the morphologies could be loosely described as ‘fractal’ — that is: random structures with some degree of self-similarity over the (roughly 1 to 60 nm) length scales probed by the scattering range used, which do not completely fill three-dimensional space, corresponding to fractional dimensions [27,31]. This morphological interpretation is consistent with the random copolymeric nature expected for HPMC [32,33] and the effects of the pre-gelatinisation process undergone by PGS [34–38]. In the case of MCC, the fractal structure may be related to the distribution of crystalline microfibrils and amorphous material or voids within the powder granules, as suggested previously by Lin et al. [39]. In line with this interpretation, the steeper gradient beyond ln(q)=−0.5 suggested a change in the morphology of MCC, becoming more densely space-filling over shorter length scales. 3.1. Effect of compaction on SAXS patterns Compaction curves for the three materials under similar experimental conditions are compared in Fig. 2. The relative densities were calculated using published values of the true densities [32,40]. In each case, the differences between materials were considerably greater than the relatively small variations observed between duplicate experiments using the same materials. The compaction curves followed roughly similar trends for each of the materials examined: the pressure increased progressively more rapidly during the loading stage, as granules became more densely packed; holding at constant (maximal) pressure caused a small increase in relative density, indicating a time-dependent relaxation process; unloading allowed a small decrease in strain (elastic recovery or ‘spring-back’), indicating an elastic component. While the pressure increase during loading appeared similar for MCC and PGS (essentially parallel curves, offset along the relative density axis), the pressure rise with HPMC was initially more gradual, but became steeper during the later stage.

Fig. 3. SAXS data for powders compacted at 255 MPa average upper punch pressure; the compaction direction was vertical.

Fig. 2. Comparison of compaction curves for HPMC, PGS and MCC.

After ejection from the die, the 2D-SAXS patterns were measured for specimens corresponding to the compaction experiments of Fig. 2; this data is shown in Fig. 3. In each case, the one-dimensional q-scans remained essentially featureless, as for the uncompacted powders. However, the 2D-SAXS patterns were distinctly anisotropic, with stronger scattering parallel to the compaction direction (defined as the y-axis or meridian) compared with the transverse direction

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(defined as the x-axis or equator). This was most clearly evident for HPMC, but was also observable to lesser extents with PGS and MCC, as demonstrated by the azimuthal scans in Fig. 4 and the (non-zero) values of the Hermans orientation parameters given in Table 1. More recent work (to be reported elsewhere) has also revealed similar azimuthal variation in 2D-SAXS patterns for a wider range of compacted polymeric materials. These observations demonstrated that the compaction of a macroscopic powder (i.e. with granules on the scale of tens of micrometres up to a significant fraction of a millimetre) may be accompanied by morphological changes on the scale of nanometres — i.e. the lengthscale probed by SAXS. Hence, it may be possible to infer the nature of the morphological changes that occurred during compaction, even though the actual morphologies present within the materials could not be deduced on the basis of the SAXS data alone.

123

Table 1 Comparison of bulk compaction behaviour, for HPMC, PGS and MCC compacted to 255 MPa average upper punch pressure

True density (kg m− 3) Relative density, ρR

SAXS analysis a b

Uncompacted At maximum pressure After ejection Hermans parameter

HPMC

PGS

MCC

1335a 0.39 ± 0.01 1.00 ± 0.01 0.92 ± 0.01 0.24 ± 0.01

1493b 0.49 ± 0.01 1.00 ± 0.01 0.94 ± 0.01 0.10 ± 0.01

1590b 0.46 ± 0.01 0.97 ± 0.01 0.92 ± 0.01 0.04 ± 0.01

Middle of range for HPMC K4M, reported by Gustafsson et al. [32]. Values for PGS 1500 and MCC, reported by Wu et al. [40].

In principle, the azimuthal variations observed in the 2D-SAXS may be explained by two types of morphological effects: re-orientation or deformation, both of which could occur during powder compaction. It was found that scaling the equatorial scattering intensity (vertically) gave a close match to the meridional scattering: Ieq ðqÞic  Ieq ðqÞuImer ðqÞ:

ð8aÞ

This is demonstrated in Fig. 5a, for a sample of HPMC compacted at 255 MPa (where c = 3.25, for this data). The small discrepancies observable at low and high q may be due to errors in background subtraction close to the beamstop and as the scattered intensity decreased towards the background level and electronic ‘noise’ on the detector. This scaling would be consistent with compaction causing a re-

Fig. 4. Azimuthal scans for uncompacted powders and after compaction at 255 MPa average upper punch pressure: (a) HPMC; (b) PGS; (c) MCC.

Fig. 5. Transforming the scattering intensity for HPMC compacted at 255 MPa average upper punch pressure, logarithmic intensity scales; (a) scaling the intensity; (b) scaling the scattering vector; arrows indicate the directions of the transforms.

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orientation of the morphological features responsible for the scattering, to favour the direction of the externally applied force. Alternatively, as demonstrated in Fig. 5b, an equally good match was obtained by a (horizontal) scaling of the scattering vector, according to: Ieq ðqÞiIeq

 q uImer ðqÞ b

ð8bÞ

where b is an arbitrary constant (b = 1.38, for the data shown). As a consequence of the Fourier-transform relationship between morphology and scattering [27–30], this would be equivalent to granule deformation, with the nano-scale morphology being compressed (b N 1) in the direction of the externally applied force, relative to the transverse direction. It can be shown that these transformations are mathematically equivalent, as a consequence of the rather featureless, power-law scattering dependences (Eq. (7)) for the materials investigated. Scaling

q (as in Eq. (8b), equivalent to stretching or compressing the morphology) gives: qa ba ¼ IA ba  qa

Idef ðqÞ ¼ IA

ð8cÞ

which is equivalent to an intensity scaling (with c = bα), as in Eq. (8a). Consequently, it was not possible to obtain a conclusive interpretation of the underlying morphological behaviour from the SAXS data alone — another example of the previously-noted ambiguity often encountered in SAXS analyses. 3.2. SEM observations of compaction SEM was used to observe the shapes of the uncompacted powder granules and to investigate the possibilities of the re-orientation or

Fig. 6. SEM images of powder granules: (a and b) HPMC; (c and d) PGS; (e and f) MCC. Compacted samples (b, d, f) prepared at 74 MPa average upper punch pressure. Arrow indicates compaction direction; circle (in f) marks apparent granule fragmentation.

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deformation hypotheses during compaction. Typical images of the three materials before compaction and cross-sections of compacts prepared at relatively low pressure (74 MPa) are shown in Fig. 6. Granules of the HPMC (Figs. 6a) exhibited highly irregular shapes. Closer examination (up to 1000 × magnification) failed to reveal any evidence of residual pulp fibre; these were presumed to be completely destroyed during etherification. Some HPMC granules appeared distinctly flattened or elongated, probably as a result of drying and milling processes during manufacture. While their geometric irregularities may impede granule rotation at higher packing fraction, the anisometry may favour a certain amount of concerted re-orientation during the early stages of compaction — especially during die filling, when considerable granule movement is expected. Examination of the compacted HPMC cross-section (Fig. 6b) suggested that the longer axes of the granules were orientated predominantly away from the compaction direction, which may be due to granule rotation. This was not conclusive with respect to the changes in 2D-SAXS, however, since: (i) the appearance of flattened granules and preferential alignment in the compacted cross-section could also arise from granule deformation, even though a relatively low compaction pressure was used; (ii) SEM did not demonstrate the existence of morphological anisotropy within the granules, which would also be required for an explanation of the changes in 2D-SAXS based on granule re-orientation. Moreover, re-orientation at low packing fraction did not preclude HPMC granule deformation at a later stage of the compaction process. Indeed, a combination of granule rotation and deformation could explain why HPMC exhibited the largest azimuthal variations in SAXS. Examination of the PGS (Fig. 6c) revealed irregular, angular but essentially isometric granules, with a broad size distribution. The MCC (Fig. 6e) appeared as roughly spherical aggregates of spherical or irregular granules. Again, there was little or no trace of the original pulp fibre structure, which is presumed to have been destroyed during the manufacture of this spheronised cellulose. In contrast to HPMC, neither PGS nor MCC exhibited any obvious reasons to expect concerted granule re-orientation during compaction. This was supported by the images of compacted cross-sections (Fig. 6d and f), which showed no evidence of preferred granule anisometry. Consequently, it is likely that the changes in 2D-SAXS observed with both PGS and MCC were due to granule deformation during compaction, even though this effect was too small to observe directly in these SEM images. SEM examination of the compacted MCC cross-section also appeared to indicate the onset of granule fragmentation (circled in Fig. 6f). This may have been promoted by the apparent agglomerate nature of the MCC used here. Similar observations with spheronised MCC have also been reported by Johansson et al. [9]. No evidence of granule cracking was observable with HPMC or PGS. Moreover, since fragmentation could provide an alternative to deformation during compaction, this could explain why the changes in 2D-SAXS were smaller for MCC than PGS. 3.3. Effect of compaction pressure Since the azimuthal variations in SAXS were relatively small for MCC, perhaps as a result of granule fragmentation, investigations into the effects of compaction pressure in the present work were restricted to HPMC and PGS (although further studies of MCC and other materials are in progress and will be reported elsewhere). Compaction data for experiments performed to different maximum loadings are compared in Fig. 7. For each material, the loading curves appeared to follow a similar path, within the accuracy of the present experiments. Relative densities in excess of 1.0 were calculated for both materials at the highest average punch pressures used here. This was marginal for PGS, and may be explained by small errors in the experimental measurements or the value of ρ0 used. In the case of HPMC, however, a relative density of 1.047 was estimated at 1028 MPa, which cannot be accounted for easily by

125

Fig. 7. Compaction curves to different maximum loadings (as indicated), for (a) HPMC and (b) PGS.

errors in the present measurements or ρ0. Instead, this may be indicative of an increase in the true density of HPMC, as the free volume between molecules was squeezed at high pressure. This type of behaviour is quite common; other examples have been reported by Wu et al. [14] using lactose and Gustafsson et al. [32] for some samples of HPMC. Van der Voort Maarschalk et al. [41] reported similar behaviour for PGS and also commented that ‘compression always leads to a certain extent of material compression, expressed as an increase in true density, which is fully reversible’. Clearly, this indicates a link between molecular-scale deformation processes within granules during compaction and elastic recovery during unloading. In the present work, some spring-back was always observed during unloading. This elastic recovery was relatively small for either material below about 5 kN maximum compaction force (equivalent to 255 MPa average upper punch pressure), but increased significantly for higher loadings, which may be associated with greater granule deformation and increases in true density. The effects of maximum average upper punch pressure on the 2DSAXS patterns for ejected HPMC and PGS specimens are compared in Fig. 8. The values of the Hermans orientation parameter obtained for PGS appeared to increase smoothly from zero for the uncompacted powder, up to a plateau at H = 0.12 for compaction with an average

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phology, as described by the electron density function ρe(r) [27]. This can be expressed as:  2 2 I ðqÞ ¼ jT fqe ðrÞgj ¼ jF qx ; qy ; qz j ¼ j

Z V

qe ðrÞeiqr drj2

ð9Þ

where the integral is performed over the irradiated sample volume and dr is a volume element (=dx dy dz, in Cartesian co-ordinates). Deforming the nano-scale morphology can be expressed as:  

T qe bx rx ; by ry ; bz rz



¼

 1 qx qy qz F ; ; jbx by bz j bx by bz

ð10Þ

where the scaling may vary with direction and b N 1 indicates compaction. Hence, the scattering from the deformed structure is:

Fig. 8. Effect of average upper punch pressure on Hermans' orientation parameter for compacted HPMC and PGS.

upper punch pressure above 500 MPa. The levelling off observed for H appeared to coincide with the increase in elastic recovery indicated in Fig. 7b, which would be consistent with a change from (predominantly) plastic deformation below 500 MPa to increases in true density at higher compaction pressures. By contrast, for HPMC, H was found to increase abruptly (shown as a dotted line in Fig. 8), between zero for the uncompacted powder and H = 0.15 at 25 MPa, the minimum pressure required to produce a compact that was sufficiently robust to permit sectioning for the SAXS measurements. This may be explained by granule re-orientation during die filling, as suggested previously, or by a very facile initial deformation at low pressures. However, it was not possible to explore this in more detail during the present work. Increasing the compaction pressure caused further increases in H, up to a plateau of H = 0.22 above 500 MPa. This subsequent increase in H appeared similar to the behaviour observed with PGS and implied a similar interpretation — plastic deformation at intermediate pressures, followed by an increase in true density above 500 MPa. 4. Discussion Small-angle X-ray scattering originates from electron density variations on the nano-scale [27–30]. Hence, the results presented here clearly demonstrate a link between the macroscopic behaviour of a compacted powder and its morphological responses at the molecular scale. Two possible mechanisms for this link were suggested. On the more trivial level, anisometric granules may become preferentially oriented, due to geometric and packing effects. Azimuthal variations in the 2D-SAXS could then arise if the nano-scale morphologies are also anisotropic and preferentially aligned within the granules. This mechanism is only expected to operate if the packing fractions are sufficiently low to permit granule rotation. Nevertheless, it may account for the abrupt increase in the Hermans orientation parameter observed for lightly compacted HPMC and could provide a useful method for studying granule behaviours during powder flows, such as during die filling. The second mechanism assumes that the nano-scale morphology within granules is deformed in response to changes in granule shape during compaction. This produces a compression of the characteristic length scales in the direction of the (externally applied) compaction force, relative to the transverse direction. The azimuthal variations in 2D-SAXS arise because of the ‘scaling property’ of the Fouriertransform relationship between the X-ray scattering and the mor-

  Idef qx ; qy ; qz ¼ 

1 bx by bz

  2 I0

qx qy qz ; ; bx by bz

ð11Þ

where the subscript ‘0’ indicates scattering that would be expected from the undeformed morphology. In other words, compressing the morphology in the direction of the applied force causes the SAXS pattern to become elongated in that direction. This mechanism is neither limited by the shape, a requirement for anisotropic internal structure nor low packing fraction of the powder granules. Several previous publications [9,42–44] have reported changes in granule shape during powder compaction that would be consistent with the deformation hypothesis. Hence, it appeared to be the more likely explanation for the changes in 2D-SAXS observed under most of the experimental conditions used in the present work — the only possible exception being for HPMC at low packing fractions. The inability to distinguish between the rotation and deformation hypotheses in the present work is largely due to the relatively featureless SAXS patterns obtained and a lack of information concerning the precise morphological origins of the scattering. Many polymers are semi-crystalline, forming lamellar crystals that give rise to well-understood scattering patterns [27]; however, that structural model was not consistent with any of the materials studied here. It is expected that crystallinity in HPMC would be prevented by its randomly substituted nature [32,33], while the semi-crystalline structure of native starch would be destroyed by ‘pre-gelatinisation’ [34–38]. Although MCC is expected to be semi-crystalline, this should be in the form of a fibrillar morphology [39,45,46], as a result of its biological origin. Scattering due to the contrast between cellulose fibrils and voids has previously been suggested by Lin et al. [39]; similarly, scattering due to voids within HPMC or PGS granules cannot be excluded at this stage. Moreover, uneven substitution of hydroxypropyl and methyl groups along the HPMC chains may be expected, due to the original morphology of the precursor dissolving pulp or inadequate mixing during manufacture, which could give rise to electron density variations and SAXS. Further powder compaction studies using materials with well-defined morphologies may lead to a better understanding of the effects reported here. To this effect, further 2D-SAXS measurements from other materials are underway, which will be reported subsequently. A good understanding of the various mechanisms that operate over different length scales, from the bulk powder bed to the molecular scale, is very important. In this respect, SAXS could provide a method for investigating the compaction mechanisms on a subgranule scale, as distinct from the bulk compaction of the powder bed. This would be very useful since, for example, several important faults shown by tablets (e.g. capping and delamination) are believed to be linked to mechanical energy stored elastically within the compacted excipients. Since azimuthal variations in 2D-SAXS patterns for both PGS and HPMC appeared to be related quantitatively to the applied compaction pressures between roughly 25 and 500 MPa, this offers

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the novel possibility to directly investigate local variations in forcetransmission through a compacted powder bed. Further investigations are underway and will be reported separately. 5. Conclusions This work demonstrated a novel and potentially useful application of SAXS to study the morphological responses of polymeric powders undergoing compaction. It was observed that 2D-SAXS patterns became elongated in the compaction direction, to an extent that depended on the magnitude of the applied pressure and the material used. Under certain circumstances, the changes in 2D-SAXS may be attributable to granule re-orientation. However, deformation with corresponding changes in the nano-scale morphology of the granules, appeared to provide a more plausible explanation for most of the situations studied here. Over a certain range, the applied compaction pressures appeared to correlate with changes in 2D-SAXS patterns for HPMC and PGS. This offers the novel possibility to observe directly the transmission of forces within compacted powder beds. Acknowledgements The authors are grateful for the thought-provoking comments of the referees during the peer-review process. The authors would also like to thank Pfizer Ltd. for their generous funding. References [1] R.C. Rowe, Hard to swallow, Drug Discov. Today 9 (2004) 733–735. [2] M.E. Aulton, Pharmaceutics: the Science of Dosage Form Design, 2nd ed.Churchill Livingstone, Edinburgh, 2002. [3] G. Alderborn, C. Nyström, Pharmaceutical Powder Compaction Technology, Marcel Dekker, Inc., New York, 1996. [4] S. Patel, A.M. Kaushal, A.K. Bansal, Compression physics in the formulation development of tablets, Crit. Rev. Ther. Drug. Carr. Syst. 23 (2006) 1–65. [5] N.A. Fleck, On the cold compaction of powders, J. Mech. Phys. Solids 43 (1995) 1409–1431. [6] O. Antikainen, J. Yliruusi, Determining the compression behaviour of pharmaceutical powders from the force–distance compression profile, Int. J. Pharm. 252 (2003) 253–261. [7] H.X. Guo, J. Heinämäki, J. Yliruusi, Characterisation of granule deformation during compression measured by confocal laser scanning microscopy, Int. J. Pharm. 186 (1999) 99–108. [8] P. Narayan, B.C. Hancock, The relationship between the granule properties, mechanical behaviour and surface roughness of some pharmaceutical excipient compacts, Mater. Sci. Eng. A355 (2003) 24–36. [9] B. Johansson, F. Nicklasson, G. Alderborn, Effect of pellet size on degree of deformation and densification during compression and on compactability of microcrystalline cellulose, Int. J. Pharm. 163 (1998) 35–48. [10] J.C. Cunningham, I.C. Sinka, A. Zavaliangos, Analysis of tablet compaction. I. Characterisation of mechanical behaviour of powder and powder/tooling friction, J. Pharm. Sci. 93 (2004) 2022–2039. [11] A. Michrafy, J.A. Dodds, M.S. Kadiri, Wall friction in the compaction of pharmaceutical powders; measurement and the effect on the density distribution, Powder Technol. 148 (2004) 53–55. [12] I.C. Sinka, J.C. Cunningham, A. Zavaliangos, The effect of wall friction in the compaction of pharmaceutical tablets with curved faces: a validation of the Drucker–Prager Cap model, Powder Technol. 133 (2003) 33–43. [13] V. Busignies, B. Leclerc, P. Porion, P. Evesque, G. Courraze, P. Tchoreloff, Quantitative measurements of localised density variations in cylindrical tablets using X-ray microtomography, Eur. J. Pharm. Biopharm. 64 (2006) 38–50. [14] C.-Y. Wu, O.M. Ruddy, A.C. Bentham, B.C. Hancock, S.M. Best, J.A. Elliott, Modelling the mechanical behaviour of pharmaceutical powders during compaction, Powder Technol. 152 (2005) 107–117. [15] I.C. Sinka, S.F. Burch, J.H. Tweed, J.C. Cunningham, Measurement of density variations in tablets using X-ray computed tomography, Int. J. Pharm. 271 (2004) 215–224. [16] B. Eiliazadeh, K. Pitt, B. Briscoe, Effects of punch geometry on powder movement during pharmaceutical tabletting processes, Int. J. Solid Struct. 41 (2004) 5967–5977.

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