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Texturing the spherical granular system influence of the spheronisation stage
Powder Technology 157 (2005) 156 – 162 www.elsevier.com/locate/powtec
Texturing the spherical granular system influence of the spheronisation stage Sophie Galland a,T, Thierry Ruiz a, Miche`le Delalonde a, Anna Krupa b, Bernard Bataille a a
Laboratoire de Ge´nie des Proce´de´s d_Elaboration de Bioproduits- UMR CIRAD 016 site Universite´ Montpellier I, 15 avenue Charles Flahault, B.P.14491, 34093 Montpellier cedex 5, France b Laboratoire de Pharmacie Gale´nique et Biopharmacie, CM UJ, Cracovie, Pologne, France Accepted 4 May 2005 Available online 11 July 2005
Abstract The extrusion/spheronisaton technique has made a notable contribution to the existing range of pharmaceutical forms, especially in the area of modified-release products. The present work helps to establish guidelines for a rationalised approach to engineering medicinal pellets. This study proposes an approach to monitoring the hydro-textural and morpho-granular characteristics of the product up to its final form. The hydrotextural states, produced by the different unit operations, resulting from the joint influence of the properties of the material and the action of the process, are located on a porosity/water content diagram. The spheronisation stage is studied more closely through the process parameters of spheronisation speed, load and time. What emerges from this study is that the spheronisation stage conserves the saturated state of the extrudates, its role being restricted to that of a shaping process. Moreover, a solid/liquid ratio is established independently of the three operating variables leading to constant particle size distribution. These results orient research toward finding optimum quality by working on formulation/process adjustment. D 2005 Elsevier B.V. All rights reserved. Keywords: Extrusion; Spheronisation; Pellets; Texture; Morpho-granulometry; Product engineering
1. Introduction Spherical or pellet-shaped minigranules have been processed in the pharmaceutical industry for several years. Processes have evolved within this context and extrusion/ spheronisation [1] is still developing in the pharmaceutical field. The process provides an alternative means of obtaining these forms, which are particularly important in the area of modified-release drugs. Pellets are regular in shape, of homogeneous size, with surface and porosity characteristics. The quality of pellets depends on the properties of the raw materials, but it also relies on the efficiency of the processing used. Pellet quality control means taking into account the influence of material properties and processes parameters.
T Corresponding author. E-mail address: [email protected] (S. Galland). 0032-5910/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.powtec.2005.05.037
The extrusion/spheronisation process takes place in four successive stages (Fig. 1), wetting the powders (carried out by kneading), extruding the wet mass, spheronisation and drying the pellets. Each of these operations contributes to the final texturing of the product depending on a wide range of apparatus (different types of blenders, extruders, driers. . .), operating modes and conditions. The numerous studies observing this process vary considerably as to the influence of the different operating parameters on the quality of pellets. The results presented in the literature [2 – 9] showed different opinions on the predominant influence of an operating parameter, a type of apparatus or formulation variable for a chosen quality criterion. There is no simple way to determine the influence of parameters on the quality of pellets. The aim of the present study is to set up a methodology integrating both the properties of the material and the influences of the process by monitoring a certain number of
S. Galland et al. / Powder Technology 157 (2005) 156 – 162
157
Flow of process Powders and water
Extrudates
Wet mass
Wetting
Extrusion
Mixer
Extruder
Wet pellets
Spheronisation
Spheroniser
Dry pellets
Dryin Dr ing
Ventilated oven
Fig. 1. Diagram of the process used in producing pellets by extrusion/spheronisation.
responses describing the resulting states. This involves a twin product/process approach to propose engineering tools that notably provide rationalised optimisation. The first part suggests a representational framework for the various states of the product in the course of elaboration. As the influence of wetting and extrusion was the subject of a former study [10], the second part will focus on the results of spheronisation. The spheronisation operation is monitored according to three operating parameters i.e., speed, load, and time. One raw material is used, adapted to this type of processing: microcrystalline cellulose formulated with different degrees of water content. Finally, the different results are discussed.
2. Product engineering approach Shaping by extrusion/spheronisation produces dry granular media from a powder which is first wetted to create the desired form. A fluid is added to impart the properties of flow, cohesion and malleability that are necessary for shaping. After shaping, pellets are obtained after extracting the water by drying. The extrusion and spheronisation stages are mechanical processes that distort the material thus changing the organisation of this heterogeneous medium through the different phases. Drying, which involves mass and energy transfers, also induces distorsions and changes in structural properties. The morphological (dimensions, shape) and textural (intergranular porosity, saturation) characteristics must be identified at the various stages of processing to produce the defined size, shape and porosity. A coherent ‘‘representational framework’’ is needed to understand and model the different phenomena involved in each operation. It then becomes possible to integrate each aspect, whether linked to the material or to the process. Having determined which variables to monitor during the production process, a representational framework is defined on the product scale using a hydro-textural diagram [10] and the morpho-granulometric characteristics.
2.1. ‘‘Hydro-textural aspects’’ through porosity –water content diagrams Two extensive variables are required to describe the mass and volume states of an elementary volume of a three-phase porous medium (solid – liquid – gas) [11]. Mass water content (w) and intergranular porosity (n) was chosen. The hydro-textural diagram is established by representing mass and volume states on the porosity/water content graph [12]. The first stage in constructing the hydro-textural diagram is to define the hydric zone of extrusion/spheronisation feasibility. The limits imposed by the material, and the narrower limits within which engineering is realistic, are both taken into account. The hydric zone fixed by the physico-chemical and rheological properties of the material is defined by a lower boundary, the hygroscopic limit (noted as w hyg) and an upper boundary, the fluidity limit (noted as w f). The hygroscopic limit corresponds to the quantity of water adsorbed and is evaluated using sorption isotherms at 30 -C. The fluidity limit marks the transition beyond which the rheological behaviour of the plastic mass will tend toward that of a suspension. This is obtained by the cone penetrometer technique. Within the hydric limits previously established, the second stage consists in strictly defining the surface combining all the hydro-textural states that can be reached at the different stages of product engineering. The saturation curve represents the value of porosity for which the interstitial fluid saturates all the pores for a given wetting and constitutes the lower limit of the diagram (Fig. 2). This curve corresponds to relationship: nsat ¼
dsT wsat dwT þ dsT wsat
ð1Þ
where d *s is the true density of the solid phase. The wetting curve ! (Fig. 2) described in an earlier study [12], demonstrates a phenomenon linking the porosity
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S. Galland et al. / Powder Technology 157 (2005) 156 – 162
1
Intergranular porosity (/)
➀
0,8
Wet mass Wetting curve
➁a
Extrudates
0,6
Wet pellets
0,4
➁b ➂
Saturation curve
➀ ➁ ➂ ➃
➃
Dry pellets
wetting extrusion spheronisation drying
0,2 Shrinkage limit
0 0
whyg
50
Texturation limit by extrusion
100
150
wf
200
250
Mass water content (%) Fig. 2. Typical hydro-textural diagram – definition of processing paths.
of the material to its water content for a given mixing. This curve is composed of the different hydro-textural states of the wet mass after kneading, and expresses the adjustment of the intergranular poral volume to the water content during the mixing operation. It fixes the upper limit of the hydro-textural diagram, for the given mixing operation conditions. The area between these wetting and saturation curves provides a definition of the texturation aptitude of the wet mass, for the range of water contents previously defined between hygroscopicity and fluidity. Moreover, the processes have a texturation capacity depending on the operating conditions and technological parameters used. These limits are constrained by the process in terms of lubrication, stress transmission, and cohesion. For wettings too low (< 60%) extrusion becomes impossible, whereas high wettings lead, during spheronisation, to an agglomeration of the whole mass impeding the formation of individual pellets. The product’s potential texturation aptitude is thus bounded by a wetting range within a minimal (w min) and a maximal (w max) feasible water content. When all these conditions and parameters are fixed, the material is textured and the different states in the engineering process follow a particular processing path. This path is graphically represented as the trajectory of the hydrotextural state of the product. If the twin influences of operating conditions and the characteristics of the material allow for different processing paths, the results of study show that this approach will distinguish these influences, helping to define an optimal path in relation to the qualities required for pellets. Each material and operating condition imposed corresponds to a particular processing path. A
typical processing path begins with initial wetting, in the sense that the kneading operation places the wet mass on a point on the wetting curve (Fig. 2). The extrusion of this wet mass produces compaction and may in some cases induce drainage. The resulting extrudates are then in a different hydro-textural state which corresponds, depending on the operating conditions used, to diminished porosity and water content "a. In the absence of liquid drainage, only porosity diminishes and processing is represented by a straight section "b. This may extend as far as the saturation curve if compaction takes place with the total drainage of interstitial air. However texturation capacity by extrusion is only possible for mixtures whose water content is inferior to a value corresponding to the intersection of the wetting and saturation curves (Fig. 2). Above this water content, extrusion is merely a shaping operation as it does not affect the relative hydro-textural state. The spheronisation stage is represented by # and may, like extrusion, lead to a reduction in porosity and possibly in water content. Following these two shaping operations, in all the trials, the hydro-textural state was systematically at saturation. Drying in a ventilated oven couples a mechanical shrinkage as the water departs. When the wet pellets are at saturation, the contraction of the material is equally compensated by the volume of evaporated water. We note that this ideal shrinkage is isotropic thus conserving the spherical shape of the particles produced. The processing path follows the saturation curve corresponding to consolidation up to the shrinkage limit marking the rigidification of the material, and at which desaturation of the porous network start [11]. This shrinkage limit is a thermo– hydro – mechanical characteristic of the mass that can be accurately defined by a standard trial [13]. Depending on the mechanical behaviour of the material, shrinkage can either totally block at this point or not. Processing will show different trajectories depending on the intensity of the operating modes. When a processing path reaches the saturation curve, this indicates that subsequent processes will have no influence on the texture of the material. The process merely intervenes in terms of the time and energy required for shaping. 2.2. Morpho-granulometric aspects From a morphological point of view, the resulting granular arrangements change shape during extrusion/ spheronisation (Fig. 3). These changes, resulting from the
Fig. 3. Morphological evolution of the material.
S. Galland et al. / Powder Technology 157 (2005) 156 – 162
different modes of shaping and the various mechanical stresses imposed during the process, depends on the mechanical behaviour of the material, which itself evolves and changes texture at the different stages of engineering. Rheological studies conducted on a wet granular mass show shear-thinning behaviour suggesting that the particles tend to reorient in the direction of the flow [14,15,16]. Each form (extrudates and pellets) can be studied with a mean elongation ratio ER. This corresponds to an elongation factor for cylindrical extrudates and a sphericity index for pellets, respectively defined as: ; ; D ERextrudates ¼ ð2Þ L ; ERpellets
¼
; D min Dmax
ð3Þ
with D and L as the diameter and length of an extrudate and D min and D max the smallest and largest diameter of a pellet. Sphericity is considered to be good at 0.8 ERpellet 0.9 and perfect beyond that. The distribution of these dimensions in relation to the mean value will not be considered here, but will be subject to a separate study. In terms of particle size, pharmaceutical powders are agglomerated into pellets of calibrated size essentially through the diameter of the extrusion grid holes, which may be 10 to 50 times bigger than the initial size of the particles. The mean size is described by the median diameter d 50 with the following centred distribution criterion (noted as DC) but usually called the ‘‘span’’: DC ¼
d25 d75 d50
ð4Þ
where d 75, d 50 and d 25 designate the sieve diameters beneath which 75%, 50% and 25% of the population mass are found, respectively. These factors may be defined for the various intermediary products. They are used here to compare the dry pellets obtained for the different operating conditions.
3. Materials and methods 3.1. Materials Microcrystalline cellulose powder (Celpac50\-Penwest), currently used in pellet formulation, as an excipient, was chosen for this study. It takes a form of baton-like particles that are more or less broken or agglomerated. True density, d *s = 1.55 g cm 3, is evaluated by Multivolum Pycnometer 1305-Micromeretics helium pycnometer. Mean size of the microcrystalline cellulose particles is approximately 60 Am and evaluated using a Malvern Instrument Southboutough-MA laser. The span (DC = 0.98) was calculated (Eq. 4). Wetted in different
159
proportions with distilled water, mass water content (w) is defined as the ratio of mass water and dry mass in the mixture. The hygroscopic limit (noted w hyg) and fluidity limit (noted w f) are 35% and 190%, respectively. Technologically, this zone is limited by minimal (w min) and maximal (w max) feasible water content 65% and 165%, respectively [10]. Wetting is carried out in a planetary mixer (Kenwood major) at a fixed speed of 65 rpm. The water was added to 200 g of powders steadily for 3 min and the wetted mass was homogeneised for a further 3 min. The mass is immediately extruded using a single Archimede screw axial extruder (Gabler Machinenbau Pharmex 35T) through a 1 mm diameter screen at the extruder screw rotation speed of 55 rpm. The extrudates are then spheronised (Gabler Machinenbau Sphaeromat SPH 250 MA spheroniser). The influence of spheronisation load (50 g, 100 g or 200 g), speed (X = 620, 760, 1180 or 1600 rpm) and spheronisation time (1, 2 or 4 min) was studied. The pellets obtained are then dried in a ventilated oven at 60 -C for 24 h (Prolabo). 3.2. Methods The hydro-textural characteristics, mass water content (w) and mean intergranular porosity (n), are selected to characterise the material at the various stages of the shaping process. Mass water content is determined by drying at 105 -C in an oven. Porosity is calculated by measuring the apparent volume of a known dry mass. Apparent volume is evaluated, in the case of wet mass, by taking a core sample of the agglomerate using a cylindrical metal ring. In the case of extrudates and pellets, the displaced volume is measured immediately after placing them in graduated test tubes containing paraffin oil. This measurement is based on the fact that the paraffin oil does not wet the hydrophilic formulation (CMC/ water). Porosity and saturation degree are calculated on the basis of these variables according to the following relationships: V Vs ms ¼1 V V ds4
ð5Þ
mw Vw dw4 Sw ¼ ¼ ms V Vs V 4 ds
ð6Þ
n¼
where d w* is the true density of water and equal to 1 g cm 3, and where V s and V w are the volumes of solid and water fractions, respectively. All the results presented are the average of three measures. Morphologic analysis of the extrudates and pellets before and after drying is determined using an optical microscope. The elongation ration ER (Eqs. 2 and 3), calculated for each extrudate and pellet batch by measuring the minimal and maximal diameters for 30 pellets. Parallel to this, the median diameter (d 50) and
S. Galland et al. / Powder Technology 157 (2005) 156 – 162
particle size distribution of the pellets DC (Eq. 4) is determined by sieving (Retsch-agitation amplitude 1.5) using a nest of standard sieves: 2.0 mm, 1.6 mm, 1.0 mm, 0.710 mm, 0.5 mm, 0.355 mm, 0.250 mm, 0.180 mm, 0.125 mm and 0.090 mm agitated for 5 min on a sieve shaker.
3,5
Dmax
3 Pellet size (mm)
160
Dmin
2,5 2 1,5 1
Ωc
0,5
4. Results of the twin product/process approach
E.R
0 0
400
4.1. Hydro-textural aspects
800
1200
1600
Spheronisation speed (rpm)
For all the experiments conducted, the mass water content before and after each operation remains below 5%, showing the absence of significant drainage or evaporation of the interstitial water in the tested range of water contents. The hydro-textural diagram for microcrystalline cellulose is given in Fig. 4. The hydric feasibility zone of microcrystalline cellulose is explored for the following five water contents: 95%, 105%, 115%, 125% and 135%. It emerges from this study that the extrusion stage systematically densifies the material to a porous state ensuring its saturation, locating the characteristic extrudate porosity point on the saturation curve. This result was confirmed for different extrusion speeds [10]. The lower the wetting, the more marked the compaction by extrusion. Furthermore, beyond 160%, the material is saturated at the end of kneading, and extrusion merely becomes a shaping operation. This value corresponds to the upper feasibility limit giving it a physical sense. The spheronisation stage does not modify the hydro-textural state of extrudates. Indeed, in all the trials conducted, wet pellet porosity is identical to that of extrudates. This aspect remains valid after varying the three chosen operating parameters linked to the spheronisation stage: speed, load and time of spheronisation. Whatever the value of these three parameters, the influence of the spheronisation phase is not expressed as hydro-textural characteristics, at least for the ranges tested. Thus, the role of spheronisation is only that of a shaping operation, when the product has already been brought to saturation by extrusion. Before drying, the wet
Fig. 5. Dimensional variations depending on spheronisation speed (w= 115%).
pellets are at the same relative hydro-textural state, regardless of wetting. However, porosity and water content, considered here as averaged variables, also intervene through their local distribution between the core and the outer surface. It is highly likely that the different wettings yield disparities in local water content distribution which may affect processing. 4.2. Morpho-granulometric aspects The influence of spheronisation speed on the morphological characteristics of wet extrudates and pellets is shown in Fig. 5 for a wetting of 115%. The results obtained for extrudates are positioned on the y-axis (spheronisation speed equal to zero). Increasing the speed always results in a reduction of the greatest dimension. When the pellets are produced by extrudate breaking, this tends to occur transversally. The minimum diameter of the pellets is directly dependent on the diameter of the holes in the extrusion screen, which in this case is 1 mm. The elongation ratio (Fig. 5) thus approaches 1 for high spheronisation speeds. This result is verified throughout the tested range of water contents. Fig. 6 highlights this result by presenting the variation in pellet elongation ratio depending on spheronisation speed and for different wettings. 1
Elongation ratio (/)
0,9 0,75 extrusion
Intergranular porosity (/)
0,85
0,65
0,8 0,7 95% 115% 135%
0,6
spheronisation
105% 125%
Ωc
0,5
0,55 65
80
95
110
125
140
155
Mass water content (%) Fig. 4. Variation in the hydro-textural state of the material.
0
400
800
1200
1600
Spheronisation speed (rpm) Fig. 6. ER variations depending on spheronisation speed.
S. Galland et al. / Powder Technology 157 (2005) 156 – 162
1,7 620rpm 760rpm 1180rpm 1600rpm
d50 (mm)
1,5 1,3
0,7
95% 115% 135%
0,6 DC (/)
This study shows that for all wettings, sphericity increases with spheronisation speed. Two types of behaviour are identified on each side of a particular speed. With no precise evaluation yet available of this critical speed, we would put its value at around, 1180 rpm (Fig. 6). For lower speeds, both the formulation variable (water content) and the process variable (spheronisation speed) influence sphericity. An increase of either of these variables increases sphericity (Fig. 6). For higher speeds, sphericity becomes less and less controlled by water content and the effect of the process is reduced. The tendency is toward a maximal elongation ratio obtained asymptotically (Fig. 6). The studies carried out on spheronisation load and time reveal their lack of influence on elongation ratio irrespective of speed. This suggests a transversal rupture due to the initial contact with the spheroniser plate that appears to be sufficient to cut the extrudates into small segments. Determining the mean diameter of the dry pellets shows the prevailing influence of water content on the size of pellets in relation to spheronisation speed (Fig. 7). The smaller size was obtained with small water content. Moreover at a fixed water content, an increase in spheronisation speed will tend to reduce the size of the pellets, and the higher the wetting the more this will be the case. The effect of spheronisation speed on fractioning is more marked for stronger wettings. For instance, for a low wetting (95%), a speed of 620 rpm is sufficient to ensure fractioning whereas for a high wetting (135%), the greater the speed, the smaller the d 50. The influence of load is significant for 50 g and for all wettings produces smaller pellets than in the case of a load of 100 g or 200 g, in which pellet size is still essentially controlled by wetting. The fractioning modes (breaking) in the spheroniser result from friction between the particles and impacts against the side of the spheroniser bowl. A weak load (50 g) appears to favour the direct impact of particles against the spheroniser, mainly responsible for the initial fractioning. For higher loads, these impacts are limited by more frequent interparticle friction, and fractioning is limited. The time variation range for this study has no significant influence on the size of pellets.
161
105% 125%
0,5 0,4 0,3 Ωc 0,2 0
400
800
1200
1600
Spheronisation speed (rpm) Fig. 8. Variations in DC depending on spheronisation speed.
As regards pellet population distribution, Fig. 8 shows DC variation according to spheronisation speed by water content. Spheronisation speed has no influence on this criterion for wettings of 105% and 115%. The absence of influence produced by the spheronisation speed for these particular wettings coincides with the results of Galland et al. [10]. The results also showed that extrusion speed had no influence for the same wettings using the same distribution criterion. Conversely, spheronisation speed affects DC for wettings on either side of this range. In the case of strong wettings, DC increases with speed. For low wettings, the opposite occurs, with an increase in spheronisation speed improving distribution. In both cases, beyond the previously defined critical speed (X c), it does not seem to be possible to vary distribution by speed (Fig. 8). Wettings of 105% and 115% for which the process has no influence on the distribution criterion may fit the ‘‘material optimum’’ already demonstrated by the study on extrusion step parameters [10]. Moreover, the same observation may be extended to all the operating conditions studied, (spheronisation load and time). The material thus dictates the DC value for these two wettings irrespective of the operating parameters specific to the stages of extrusion and spheronisation. The distribution criterion corresponding to these wettings shows no minimum value characteristic of better homogeneity. The minimum criterion is obtained for a stronger wetting, (130%) and the weakest spheronisation speed (620 rpm). The properties resulting from a nonoptimal formulation may thus be improved by the operating parameters of the process.
1,1 0,9
5. Conclusion
0,7 0,5 80
90
100
110
120
130
140
Mass water content (%) Fig. 7. Variations in mean diameter of dry pellets depending on water content.
The quality of products produced by extrusion/spheronisation results from the twin action of the properties of the material and the process. To quantify their effects, a representational framework is proposed in which the twin influences are analysed according to hydro-textural and morpho-granulometric representations.
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S. Galland et al. / Powder Technology 157 (2005) 156 – 162
In the case where extrusion yields compaction allowing for the saturation of extrudates, spheronisation merely becomes a shaping operation, as the hydro-textural properties are conserved. This result is confirmed whatever the operating conditions tested. Water contents of between 105% and 115% define a hydric zone for which the extrusion and spheronisation processes have no effect on the particle size quality criterion chosen (DC), this being true for any of the three process parameters chosen. This finding may be interpreted in terms of a ‘‘material optimum’’ and is extended here to the extrusion/spheronisation stage. For wettings outside this optimal range, two groups can be distinguished to either side of a critical spheronisation speed (Xc). Beyond the Xc varying spheronisation speed has no effect on distribution criterion (DC) values and elongation ratio (ER). DC values are thus dictated by the formulation, whereas ER tends asymptotically toward a value that is independent of this. In all these cases the values attained are satisfactory. For speeds below Xc, an increase in speed will improve the distribution criterion and elongation ratio when water contents are below the ‘‘material optimum’’. For higher wettings, DC tends to increase with speed. This result shows that the quality of a non-optimal wetting can be modified by an action process: for lower wettings, an increase in speed will improve distribution and sphericity, for higher wettings, ER will also improve, whereas DC evolves inversely. The sum of the findings shows that the adopted approach enables engineering conditions to be adjusted to produce a given quality, by favouring a processing path according to the constraints linked to the material or the process.
References [1] J.M. Newton, Extrusion-spheronisation, Powder Technology and Pharmaceutical Processes, vol. 9, Elsevier, 1998, pp. 391 – 401. [2] H.J. Malinowski, W.E. Smith, Use of factorial design to evaluate granulations prepared by spheronization, J. Pharm. Sci. 64 (1975) 1688 – 1692.
[3] S.R. Chapman, R.C. Rowe, P.J. Harrison, J.M. Newton, The influence of process variables on the density of granules produced by extrusion/spheronisation, Proc. 4th. Cong. Int. Trch. Pharm., vol. III, 1986, pp. 9 – 14. [4] M. Chariot, J. France`s, G.A. Lewis, D. Mathieu, R. Phan Tan Luu, H.N.E. Stevens, A factorial design approach to process variables of extrusion-spheronisation of wet powder masses, Drug Dev. Ind. Pharm. 13 (9-11) (1987) 1639 – 1649. [5] R.E. O’Connor, J. Holonej, J.B. Schwartz, Spheronization: I. Processing and evaluation of spheres prepared from commercially available excipients, Am. J. Pharm. 156 (1984) 80 – 87. [6] L.S.C. Wan, P.W.S. Heng, C.V. Liew, Spheronization conditions on spheroid shape and size, Int. J. Pharm. 96 (1993) 59 – 65. [7] B. Bataille, K. Ligarski, M. Jacob, Etude des parame`tres mouillage et vitesse de sphe´ronisation sur la granulome´trie et la durete´ de minigranules obtenus par extrusion – sphe´ronisation, Pharm. Acta Helv. 65 (1990) 334 – 337. [8] K. Ligarski, B. Bataille, M. Jacob, G. Cassanas, Influence des parame`tres technologiques sur la durete´ de minigranules fabrique´s par extrusion-sphe´ronisation, STP Pharma 1 (1991) 256 – 261. [9] S. Boutell, J.M. Newton, J.R. Bloor, G. Hayes, The influence of liquid binder on the liquid mobility and preparation of spherical granules by the process of extrusion/spheronization, Int. J. Pharm. 238 (2002) 61 – 76. [10] S. Galland, B. Bataille, M. Delalonde, T. Ruiz, N. Bennacer, C. Dupuy, Preparation of granular systems by extrusion/spheronization: a twin product/process approach, Trans IchemE, vol. 81, 2003, pp. 1237 – 1242 (Part A). [11] J.P. Magnan, Description, identification and classification des sols, Traite´ construction C208, Tech. Ling (1997) 2. [12] T. Ruiz, M. Delalonde, B. Bataille, G. Baylac, C. Dupuy, D. Crescendo, Texturing unsaturated granular media submitted to compaction and kneading processes, Powder Technol. 154 (2005) 43 – 53. [13] XP P94-060-2, Essai de dessiccation, partie 2 De´termination conventionnelle de la limite de retrait sur un pre´le`vement non remanie´, AFNOR (1997). [14] M. Delalonde, B. Bataille, G. Baylac, M. Jacob, Rheological study of wet powder masses: application to a pharmaceutical grade of microcrystalline cellulose, S.T.P. Pharma Sciences 10 (3) (2000) 205 – 209. [15] R.D. Shah, M. Kabadi, D.G. Pope, L.L. Augsburger, Physicomechanical characterization of the extrusion-spheronization process: Part II. Rheological determinants for successful extrusion and spheronisation, Pharm. Res. 12 (1995) 496 – 507. [16] M. Delalonde, B. Bataille, G. Baylac, M. Jacob, R. Sabatier, Definition of indices for mechanical design of wet powders: application to the study of a natural polymer, microcrystalline cellulose, Int. J. Pharm. 146 (1997) 159 – 165.
Texturing the spherical granular system influence of the spheronisation stage Sophie Galland a,T, Thierry Ruiz a, Miche`le Delalonde a, Anna Krupa b, Bernard Bataille a a
Laboratoire de Ge´nie des Proce´de´s d_Elaboration de Bioproduits- UMR CIRAD 016 site Universite´ Montpellier I, 15 avenue Charles Flahault, B.P.14491, 34093 Montpellier cedex 5, France b Laboratoire de Pharmacie Gale´nique et Biopharmacie, CM UJ, Cracovie, Pologne, France Accepted 4 May 2005 Available online 11 July 2005
Abstract The extrusion/spheronisaton technique has made a notable contribution to the existing range of pharmaceutical forms, especially in the area of modified-release products. The present work helps to establish guidelines for a rationalised approach to engineering medicinal pellets. This study proposes an approach to monitoring the hydro-textural and morpho-granular characteristics of the product up to its final form. The hydrotextural states, produced by the different unit operations, resulting from the joint influence of the properties of the material and the action of the process, are located on a porosity/water content diagram. The spheronisation stage is studied more closely through the process parameters of spheronisation speed, load and time. What emerges from this study is that the spheronisation stage conserves the saturated state of the extrudates, its role being restricted to that of a shaping process. Moreover, a solid/liquid ratio is established independently of the three operating variables leading to constant particle size distribution. These results orient research toward finding optimum quality by working on formulation/process adjustment. D 2005 Elsevier B.V. All rights reserved. Keywords: Extrusion; Spheronisation; Pellets; Texture; Morpho-granulometry; Product engineering
1. Introduction Spherical or pellet-shaped minigranules have been processed in the pharmaceutical industry for several years. Processes have evolved within this context and extrusion/ spheronisation [1] is still developing in the pharmaceutical field. The process provides an alternative means of obtaining these forms, which are particularly important in the area of modified-release drugs. Pellets are regular in shape, of homogeneous size, with surface and porosity characteristics. The quality of pellets depends on the properties of the raw materials, but it also relies on the efficiency of the processing used. Pellet quality control means taking into account the influence of material properties and processes parameters.
T Corresponding author. E-mail address: [email protected] (S. Galland). 0032-5910/$ - see front matter D 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.powtec.2005.05.037
The extrusion/spheronisation process takes place in four successive stages (Fig. 1), wetting the powders (carried out by kneading), extruding the wet mass, spheronisation and drying the pellets. Each of these operations contributes to the final texturing of the product depending on a wide range of apparatus (different types of blenders, extruders, driers. . .), operating modes and conditions. The numerous studies observing this process vary considerably as to the influence of the different operating parameters on the quality of pellets. The results presented in the literature [2 – 9] showed different opinions on the predominant influence of an operating parameter, a type of apparatus or formulation variable for a chosen quality criterion. There is no simple way to determine the influence of parameters on the quality of pellets. The aim of the present study is to set up a methodology integrating both the properties of the material and the influences of the process by monitoring a certain number of
S. Galland et al. / Powder Technology 157 (2005) 156 – 162
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Flow of process Powders and water
Extrudates
Wet mass
Wetting
Extrusion
Mixer
Extruder
Wet pellets
Spheronisation
Spheroniser
Dry pellets
Dryin Dr ing
Ventilated oven
Fig. 1. Diagram of the process used in producing pellets by extrusion/spheronisation.
responses describing the resulting states. This involves a twin product/process approach to propose engineering tools that notably provide rationalised optimisation. The first part suggests a representational framework for the various states of the product in the course of elaboration. As the influence of wetting and extrusion was the subject of a former study [10], the second part will focus on the results of spheronisation. The spheronisation operation is monitored according to three operating parameters i.e., speed, load, and time. One raw material is used, adapted to this type of processing: microcrystalline cellulose formulated with different degrees of water content. Finally, the different results are discussed.
2. Product engineering approach Shaping by extrusion/spheronisation produces dry granular media from a powder which is first wetted to create the desired form. A fluid is added to impart the properties of flow, cohesion and malleability that are necessary for shaping. After shaping, pellets are obtained after extracting the water by drying. The extrusion and spheronisation stages are mechanical processes that distort the material thus changing the organisation of this heterogeneous medium through the different phases. Drying, which involves mass and energy transfers, also induces distorsions and changes in structural properties. The morphological (dimensions, shape) and textural (intergranular porosity, saturation) characteristics must be identified at the various stages of processing to produce the defined size, shape and porosity. A coherent ‘‘representational framework’’ is needed to understand and model the different phenomena involved in each operation. It then becomes possible to integrate each aspect, whether linked to the material or to the process. Having determined which variables to monitor during the production process, a representational framework is defined on the product scale using a hydro-textural diagram [10] and the morpho-granulometric characteristics.
2.1. ‘‘Hydro-textural aspects’’ through porosity –water content diagrams Two extensive variables are required to describe the mass and volume states of an elementary volume of a three-phase porous medium (solid – liquid – gas) [11]. Mass water content (w) and intergranular porosity (n) was chosen. The hydro-textural diagram is established by representing mass and volume states on the porosity/water content graph [12]. The first stage in constructing the hydro-textural diagram is to define the hydric zone of extrusion/spheronisation feasibility. The limits imposed by the material, and the narrower limits within which engineering is realistic, are both taken into account. The hydric zone fixed by the physico-chemical and rheological properties of the material is defined by a lower boundary, the hygroscopic limit (noted as w hyg) and an upper boundary, the fluidity limit (noted as w f). The hygroscopic limit corresponds to the quantity of water adsorbed and is evaluated using sorption isotherms at 30 -C. The fluidity limit marks the transition beyond which the rheological behaviour of the plastic mass will tend toward that of a suspension. This is obtained by the cone penetrometer technique. Within the hydric limits previously established, the second stage consists in strictly defining the surface combining all the hydro-textural states that can be reached at the different stages of product engineering. The saturation curve represents the value of porosity for which the interstitial fluid saturates all the pores for a given wetting and constitutes the lower limit of the diagram (Fig. 2). This curve corresponds to relationship: nsat ¼
dsT wsat dwT þ dsT wsat
ð1Þ
where d *s is the true density of the solid phase. The wetting curve ! (Fig. 2) described in an earlier study [12], demonstrates a phenomenon linking the porosity
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1
Intergranular porosity (/)
➀
0,8
Wet mass Wetting curve
➁a
Extrudates
0,6
Wet pellets
0,4
➁b ➂
Saturation curve
➀ ➁ ➂ ➃
➃
Dry pellets
wetting extrusion spheronisation drying
0,2 Shrinkage limit
0 0
whyg
50
Texturation limit by extrusion
100
150
wf
200
250
Mass water content (%) Fig. 2. Typical hydro-textural diagram – definition of processing paths.
of the material to its water content for a given mixing. This curve is composed of the different hydro-textural states of the wet mass after kneading, and expresses the adjustment of the intergranular poral volume to the water content during the mixing operation. It fixes the upper limit of the hydro-textural diagram, for the given mixing operation conditions. The area between these wetting and saturation curves provides a definition of the texturation aptitude of the wet mass, for the range of water contents previously defined between hygroscopicity and fluidity. Moreover, the processes have a texturation capacity depending on the operating conditions and technological parameters used. These limits are constrained by the process in terms of lubrication, stress transmission, and cohesion. For wettings too low (< 60%) extrusion becomes impossible, whereas high wettings lead, during spheronisation, to an agglomeration of the whole mass impeding the formation of individual pellets. The product’s potential texturation aptitude is thus bounded by a wetting range within a minimal (w min) and a maximal (w max) feasible water content. When all these conditions and parameters are fixed, the material is textured and the different states in the engineering process follow a particular processing path. This path is graphically represented as the trajectory of the hydrotextural state of the product. If the twin influences of operating conditions and the characteristics of the material allow for different processing paths, the results of study show that this approach will distinguish these influences, helping to define an optimal path in relation to the qualities required for pellets. Each material and operating condition imposed corresponds to a particular processing path. A
typical processing path begins with initial wetting, in the sense that the kneading operation places the wet mass on a point on the wetting curve (Fig. 2). The extrusion of this wet mass produces compaction and may in some cases induce drainage. The resulting extrudates are then in a different hydro-textural state which corresponds, depending on the operating conditions used, to diminished porosity and water content "a. In the absence of liquid drainage, only porosity diminishes and processing is represented by a straight section "b. This may extend as far as the saturation curve if compaction takes place with the total drainage of interstitial air. However texturation capacity by extrusion is only possible for mixtures whose water content is inferior to a value corresponding to the intersection of the wetting and saturation curves (Fig. 2). Above this water content, extrusion is merely a shaping operation as it does not affect the relative hydro-textural state. The spheronisation stage is represented by # and may, like extrusion, lead to a reduction in porosity and possibly in water content. Following these two shaping operations, in all the trials, the hydro-textural state was systematically at saturation. Drying in a ventilated oven couples a mechanical shrinkage as the water departs. When the wet pellets are at saturation, the contraction of the material is equally compensated by the volume of evaporated water. We note that this ideal shrinkage is isotropic thus conserving the spherical shape of the particles produced. The processing path follows the saturation curve corresponding to consolidation up to the shrinkage limit marking the rigidification of the material, and at which desaturation of the porous network start [11]. This shrinkage limit is a thermo– hydro – mechanical characteristic of the mass that can be accurately defined by a standard trial [13]. Depending on the mechanical behaviour of the material, shrinkage can either totally block at this point or not. Processing will show different trajectories depending on the intensity of the operating modes. When a processing path reaches the saturation curve, this indicates that subsequent processes will have no influence on the texture of the material. The process merely intervenes in terms of the time and energy required for shaping. 2.2. Morpho-granulometric aspects From a morphological point of view, the resulting granular arrangements change shape during extrusion/ spheronisation (Fig. 3). These changes, resulting from the
Fig. 3. Morphological evolution of the material.
S. Galland et al. / Powder Technology 157 (2005) 156 – 162
different modes of shaping and the various mechanical stresses imposed during the process, depends on the mechanical behaviour of the material, which itself evolves and changes texture at the different stages of engineering. Rheological studies conducted on a wet granular mass show shear-thinning behaviour suggesting that the particles tend to reorient in the direction of the flow [14,15,16]. Each form (extrudates and pellets) can be studied with a mean elongation ratio ER. This corresponds to an elongation factor for cylindrical extrudates and a sphericity index for pellets, respectively defined as: ; ; D ERextrudates ¼ ð2Þ L ; ERpellets
¼
; D min Dmax
ð3Þ
with D and L as the diameter and length of an extrudate and D min and D max the smallest and largest diameter of a pellet. Sphericity is considered to be good at 0.8 ERpellet 0.9 and perfect beyond that. The distribution of these dimensions in relation to the mean value will not be considered here, but will be subject to a separate study. In terms of particle size, pharmaceutical powders are agglomerated into pellets of calibrated size essentially through the diameter of the extrusion grid holes, which may be 10 to 50 times bigger than the initial size of the particles. The mean size is described by the median diameter d 50 with the following centred distribution criterion (noted as DC) but usually called the ‘‘span’’: DC ¼
d25 d75 d50
ð4Þ
where d 75, d 50 and d 25 designate the sieve diameters beneath which 75%, 50% and 25% of the population mass are found, respectively. These factors may be defined for the various intermediary products. They are used here to compare the dry pellets obtained for the different operating conditions.
3. Materials and methods 3.1. Materials Microcrystalline cellulose powder (Celpac50\-Penwest), currently used in pellet formulation, as an excipient, was chosen for this study. It takes a form of baton-like particles that are more or less broken or agglomerated. True density, d *s = 1.55 g cm 3, is evaluated by Multivolum Pycnometer 1305-Micromeretics helium pycnometer. Mean size of the microcrystalline cellulose particles is approximately 60 Am and evaluated using a Malvern Instrument Southboutough-MA laser. The span (DC = 0.98) was calculated (Eq. 4). Wetted in different
159
proportions with distilled water, mass water content (w) is defined as the ratio of mass water and dry mass in the mixture. The hygroscopic limit (noted w hyg) and fluidity limit (noted w f) are 35% and 190%, respectively. Technologically, this zone is limited by minimal (w min) and maximal (w max) feasible water content 65% and 165%, respectively [10]. Wetting is carried out in a planetary mixer (Kenwood major) at a fixed speed of 65 rpm. The water was added to 200 g of powders steadily for 3 min and the wetted mass was homogeneised for a further 3 min. The mass is immediately extruded using a single Archimede screw axial extruder (Gabler Machinenbau Pharmex 35T) through a 1 mm diameter screen at the extruder screw rotation speed of 55 rpm. The extrudates are then spheronised (Gabler Machinenbau Sphaeromat SPH 250 MA spheroniser). The influence of spheronisation load (50 g, 100 g or 200 g), speed (X = 620, 760, 1180 or 1600 rpm) and spheronisation time (1, 2 or 4 min) was studied. The pellets obtained are then dried in a ventilated oven at 60 -C for 24 h (Prolabo). 3.2. Methods The hydro-textural characteristics, mass water content (w) and mean intergranular porosity (n), are selected to characterise the material at the various stages of the shaping process. Mass water content is determined by drying at 105 -C in an oven. Porosity is calculated by measuring the apparent volume of a known dry mass. Apparent volume is evaluated, in the case of wet mass, by taking a core sample of the agglomerate using a cylindrical metal ring. In the case of extrudates and pellets, the displaced volume is measured immediately after placing them in graduated test tubes containing paraffin oil. This measurement is based on the fact that the paraffin oil does not wet the hydrophilic formulation (CMC/ water). Porosity and saturation degree are calculated on the basis of these variables according to the following relationships: V Vs ms ¼1 V V ds4
ð5Þ
mw Vw dw4 Sw ¼ ¼ ms V Vs V 4 ds
ð6Þ
n¼
where d w* is the true density of water and equal to 1 g cm 3, and where V s and V w are the volumes of solid and water fractions, respectively. All the results presented are the average of three measures. Morphologic analysis of the extrudates and pellets before and after drying is determined using an optical microscope. The elongation ration ER (Eqs. 2 and 3), calculated for each extrudate and pellet batch by measuring the minimal and maximal diameters for 30 pellets. Parallel to this, the median diameter (d 50) and
S. Galland et al. / Powder Technology 157 (2005) 156 – 162
particle size distribution of the pellets DC (Eq. 4) is determined by sieving (Retsch-agitation amplitude 1.5) using a nest of standard sieves: 2.0 mm, 1.6 mm, 1.0 mm, 0.710 mm, 0.5 mm, 0.355 mm, 0.250 mm, 0.180 mm, 0.125 mm and 0.090 mm agitated for 5 min on a sieve shaker.
3,5
Dmax
3 Pellet size (mm)
160
Dmin
2,5 2 1,5 1
Ωc
0,5
4. Results of the twin product/process approach
E.R
0 0
400
4.1. Hydro-textural aspects
800
1200
1600
Spheronisation speed (rpm)
For all the experiments conducted, the mass water content before and after each operation remains below 5%, showing the absence of significant drainage or evaporation of the interstitial water in the tested range of water contents. The hydro-textural diagram for microcrystalline cellulose is given in Fig. 4. The hydric feasibility zone of microcrystalline cellulose is explored for the following five water contents: 95%, 105%, 115%, 125% and 135%. It emerges from this study that the extrusion stage systematically densifies the material to a porous state ensuring its saturation, locating the characteristic extrudate porosity point on the saturation curve. This result was confirmed for different extrusion speeds [10]. The lower the wetting, the more marked the compaction by extrusion. Furthermore, beyond 160%, the material is saturated at the end of kneading, and extrusion merely becomes a shaping operation. This value corresponds to the upper feasibility limit giving it a physical sense. The spheronisation stage does not modify the hydro-textural state of extrudates. Indeed, in all the trials conducted, wet pellet porosity is identical to that of extrudates. This aspect remains valid after varying the three chosen operating parameters linked to the spheronisation stage: speed, load and time of spheronisation. Whatever the value of these three parameters, the influence of the spheronisation phase is not expressed as hydro-textural characteristics, at least for the ranges tested. Thus, the role of spheronisation is only that of a shaping operation, when the product has already been brought to saturation by extrusion. Before drying, the wet
Fig. 5. Dimensional variations depending on spheronisation speed (w= 115%).
pellets are at the same relative hydro-textural state, regardless of wetting. However, porosity and water content, considered here as averaged variables, also intervene through their local distribution between the core and the outer surface. It is highly likely that the different wettings yield disparities in local water content distribution which may affect processing. 4.2. Morpho-granulometric aspects The influence of spheronisation speed on the morphological characteristics of wet extrudates and pellets is shown in Fig. 5 for a wetting of 115%. The results obtained for extrudates are positioned on the y-axis (spheronisation speed equal to zero). Increasing the speed always results in a reduction of the greatest dimension. When the pellets are produced by extrudate breaking, this tends to occur transversally. The minimum diameter of the pellets is directly dependent on the diameter of the holes in the extrusion screen, which in this case is 1 mm. The elongation ratio (Fig. 5) thus approaches 1 for high spheronisation speeds. This result is verified throughout the tested range of water contents. Fig. 6 highlights this result by presenting the variation in pellet elongation ratio depending on spheronisation speed and for different wettings. 1
Elongation ratio (/)
0,9 0,75 extrusion
Intergranular porosity (/)
0,85
0,65
0,8 0,7 95% 115% 135%
0,6
spheronisation
105% 125%
Ωc
0,5
0,55 65
80
95
110
125
140
155
Mass water content (%) Fig. 4. Variation in the hydro-textural state of the material.
0
400
800
1200
1600
Spheronisation speed (rpm) Fig. 6. ER variations depending on spheronisation speed.
S. Galland et al. / Powder Technology 157 (2005) 156 – 162
1,7 620rpm 760rpm 1180rpm 1600rpm
d50 (mm)
1,5 1,3
0,7
95% 115% 135%
0,6 DC (/)
This study shows that for all wettings, sphericity increases with spheronisation speed. Two types of behaviour are identified on each side of a particular speed. With no precise evaluation yet available of this critical speed, we would put its value at around, 1180 rpm (Fig. 6). For lower speeds, both the formulation variable (water content) and the process variable (spheronisation speed) influence sphericity. An increase of either of these variables increases sphericity (Fig. 6). For higher speeds, sphericity becomes less and less controlled by water content and the effect of the process is reduced. The tendency is toward a maximal elongation ratio obtained asymptotically (Fig. 6). The studies carried out on spheronisation load and time reveal their lack of influence on elongation ratio irrespective of speed. This suggests a transversal rupture due to the initial contact with the spheroniser plate that appears to be sufficient to cut the extrudates into small segments. Determining the mean diameter of the dry pellets shows the prevailing influence of water content on the size of pellets in relation to spheronisation speed (Fig. 7). The smaller size was obtained with small water content. Moreover at a fixed water content, an increase in spheronisation speed will tend to reduce the size of the pellets, and the higher the wetting the more this will be the case. The effect of spheronisation speed on fractioning is more marked for stronger wettings. For instance, for a low wetting (95%), a speed of 620 rpm is sufficient to ensure fractioning whereas for a high wetting (135%), the greater the speed, the smaller the d 50. The influence of load is significant for 50 g and for all wettings produces smaller pellets than in the case of a load of 100 g or 200 g, in which pellet size is still essentially controlled by wetting. The fractioning modes (breaking) in the spheroniser result from friction between the particles and impacts against the side of the spheroniser bowl. A weak load (50 g) appears to favour the direct impact of particles against the spheroniser, mainly responsible for the initial fractioning. For higher loads, these impacts are limited by more frequent interparticle friction, and fractioning is limited. The time variation range for this study has no significant influence on the size of pellets.
161
105% 125%
0,5 0,4 0,3 Ωc 0,2 0
400
800
1200
1600
Spheronisation speed (rpm) Fig. 8. Variations in DC depending on spheronisation speed.
As regards pellet population distribution, Fig. 8 shows DC variation according to spheronisation speed by water content. Spheronisation speed has no influence on this criterion for wettings of 105% and 115%. The absence of influence produced by the spheronisation speed for these particular wettings coincides with the results of Galland et al. [10]. The results also showed that extrusion speed had no influence for the same wettings using the same distribution criterion. Conversely, spheronisation speed affects DC for wettings on either side of this range. In the case of strong wettings, DC increases with speed. For low wettings, the opposite occurs, with an increase in spheronisation speed improving distribution. In both cases, beyond the previously defined critical speed (X c), it does not seem to be possible to vary distribution by speed (Fig. 8). Wettings of 105% and 115% for which the process has no influence on the distribution criterion may fit the ‘‘material optimum’’ already demonstrated by the study on extrusion step parameters [10]. Moreover, the same observation may be extended to all the operating conditions studied, (spheronisation load and time). The material thus dictates the DC value for these two wettings irrespective of the operating parameters specific to the stages of extrusion and spheronisation. The distribution criterion corresponding to these wettings shows no minimum value characteristic of better homogeneity. The minimum criterion is obtained for a stronger wetting, (130%) and the weakest spheronisation speed (620 rpm). The properties resulting from a nonoptimal formulation may thus be improved by the operating parameters of the process.
1,1 0,9
5. Conclusion
0,7 0,5 80
90
100
110
120
130
140
Mass water content (%) Fig. 7. Variations in mean diameter of dry pellets depending on water content.
The quality of products produced by extrusion/spheronisation results from the twin action of the properties of the material and the process. To quantify their effects, a representational framework is proposed in which the twin influences are analysed according to hydro-textural and morpho-granulometric representations.
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In the case where extrusion yields compaction allowing for the saturation of extrudates, spheronisation merely becomes a shaping operation, as the hydro-textural properties are conserved. This result is confirmed whatever the operating conditions tested. Water contents of between 105% and 115% define a hydric zone for which the extrusion and spheronisation processes have no effect on the particle size quality criterion chosen (DC), this being true for any of the three process parameters chosen. This finding may be interpreted in terms of a ‘‘material optimum’’ and is extended here to the extrusion/spheronisation stage. For wettings outside this optimal range, two groups can be distinguished to either side of a critical spheronisation speed (Xc). Beyond the Xc varying spheronisation speed has no effect on distribution criterion (DC) values and elongation ratio (ER). DC values are thus dictated by the formulation, whereas ER tends asymptotically toward a value that is independent of this. In all these cases the values attained are satisfactory. For speeds below Xc, an increase in speed will improve the distribution criterion and elongation ratio when water contents are below the ‘‘material optimum’’. For higher wettings, DC tends to increase with speed. This result shows that the quality of a non-optimal wetting can be modified by an action process: for lower wettings, an increase in speed will improve distribution and sphericity, for higher wettings, ER will also improve, whereas DC evolves inversely. The sum of the findings shows that the adopted approach enables engineering conditions to be adjusted to produce a given quality, by favouring a processing path according to the constraints linked to the material or the process.
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