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Determination of the mechanical properties of pellets and film coated pellets using Dynamic Mechanical Analysis (DMA)
European Journal of Pharmaceutical Sciences 16 (2002) 209–214 www.elsevier.nl / locate / ejps
Determination of the mechanical properties of pellets and film coated pellets using Dynamic Mechanical Analysis (DMA) Fridrun Podczeck*, Susana M. Almeida The School of Pharmacy, University of London, 29 /39 Brunswick Square, London WC1 N 1 AX, UK Received 24 October 2001; received in revised form 16 May 2002; accepted 29 May 2002
Abstract The elastic and viscoelastic properties of pellets and film coatings applied to pellets were studied using Dynamic Mechanical Analysis (DMA). Four batches of spherical pellets produced with different methods were compared without film coating and after application of a plasticised ethylcellulose film of average thickness of 25 mm. The modulus of elasticity of the uncoated pellets was found to be related to the porosity of the pellets, as was the slope of the linear portion of the storage modulus–dynamic force curves. None of the other parameters obtained from DMA of the uncoated pellets appeared to be related to the macroscopic properties of these pellets. After application of the film coating the dynamic force at the onset of the linear portion of the storage modulus–dynamic force curve and the maximum storage modulus obtained at a dynamic force of 600 mN were found to be significantly different from the values of the uncoated pellets, but similar for all four coated pellet batches. Hence these parameters represented the viscoelastic behaviour of the film coatings. 2002 Elsevier Science B.V. All rights reserved. Keywords: Dynamic Mechanical Analysis (DMA); Film coating; Pellets; Tensile strength
1. Introduction Pellets are used as multiple-unit dosage form for controlled-release preparations. For this the pellets are coated with a controlled-release film and then either filled into hard shell capsules or compressed into tablets. The latter process requires the addition of special cushioning excipi´ ents in powder (Bechard and Leroux, 1992) or pellet form (Lundqvist et al., 1998) in order to avoid damage to the film coat due to the pressure applied and the close interparticulate contact. The advantage of using ‘soft’ pellets as cushioning material is that the particles of the mixture are all of similar size and shape, and hence segregation of the drug-containing pellets is less likely. To test how ‘soft’ or ‘hard’ pellets are, however, is rather difficult. The tensile strength of pellets can be determined by diametral compression (Salako et al., 1998). Such results can also provide, additionally to the physical strength, an assess*Corresponding author. Tel.: 144-20-7753-5857; fax: 144-20-77535857. E-mail address: [email protected] (F. Podczeck).
ment of brittleness but it is obtained by final destruction of the individual pellet. To determine truly elastic or ductile properties of pellets requires the evaluation of stress–strain curves. Although these can be obtained from some strength testers, due to the normally larger load cell capacity (5 kg or above), such assessments are never very accurate (the breaking load of individual 1 mm pellets is often below 1 kg, depending on the composition and manufacturing process). The success of the tabletting process to form single doses from pellets depends not only on the properties of the drug-containing pellets and the cushioning material, but also on the properties of the film. Mechanical properties of films are usually assessed on so-called ‘free’ or ‘cast films.’ However, it is questionable how well such films will represent the properties of coatings when applied to the surface of pellets or tablets. It would hence be helpful if a method of testing was developed, which could describe the mechanical properties of film coatings in situ, for example, on pellets. The aim of this work was to determine the elastic and viscoelastic properties of pellets using a non-destructive technique with high sensitivity, i.e. Dynamic Mechanical
0928-0987 / 02 / $ – see front matter 2002 Elsevier Science B.V. All rights reserved. PII: S0928-0987( 02 )00104-5
210
F. Podczeck, S.M. Almeida / European Journal of Pharmaceutical Sciences 16 (2002) 209 – 214
Analysis (DMA). A further goal was to develop a screening process for the in-situ testing of film coatings applied to pellets in order to estimate the mechanical properties of such films.
2. Materials and methods
2.1. Materials The materials used were all of Ph. Eur. quality and were used as supplied. The model drug included was paracetamol, fine powder (Bechpharm, Harlow, UK). The basic material used to ensure successful extrusion / spheronisation was microcrystalline cellulose (Avicel PH101 , FMC Corp., Cork, Ireland). A further aid to extrusion was the inclusion of glyceryl monostearate supplied as Imwitor 940 ¨ Milton Keynes, UK). The filler included as a water (Huls, insoluble material was barium sulphate (Chemische Werke GmbH, Sachtleben, Germany). The water used as an essential fluid for processing was purified by reverse osmosis. For one set of pellets this was replaced with a 70 v / v% solution of ethanol (Merck, Poole, UK) in water. The basic formulation was paracetamol 10%, glyceryl monostearate 16%, microcrystalline cellulose 50%, barium sulphate 24% and liquid q.s.
2.2. Pellet manufacture Pellets of different shape were prepared as described by Chopra et al. (2001). The object was here to produce spherical pellets with different mechanical properties. To this end the wet mass was either subjected to a standard process of extrusion and spheronisation, or the wet mass was passed through an oscillating granulator (ERWEKA type FGS, Heusenstamm, Germany) fitted with a 1 mm square aperture mesh, set at an oscillation speed of 4. In a further experiment the wet mass was processed directly from the planetary mixer. The wet mass was produced by dry mixing the powders for 5 min in a planetary mixer (Hobart, London, UK). The necessary quantity of fluid was gradually added and mixing was continued for 10 min, scraping the sides of the bowl at regular intervals. Samples to be extruded were processed with a capillary extrusion rheometer (ACER 2000, Rheometric Scientific, Loughborough, UK), fitted with a die of 1 mm diameter and 4 mm length with a 608 entry angle. The ram speed employed was 200 mm min 21 . The extrusion process was repeated until there was sufficient extrudate, at least 500 g, to process for 10 min unless otherwise stated on a 22.5 cm diameter radial geometry plate fitted to a spheroniser (GB Caleva, Stourminster Newton, UK) rotating at 1000 rpm. The wet mass from both the granulation and planetary mixing were subjected to the same spheronisation conditions. The pellets were dried for 24 h at 45 8C in an oven (Hotbox size 1,
Gallenkamp, London, UK). Each batch of pellets was sieved (Endecotts, London, UK) to obtain a 1–1.4 mm size fraction. The residual moisture content of the pellets was evaluated as loss on drying (Sartorius Thermo Control ¨ moisture balance YTC 01L, Sartorius GmbH, Gottingen, Germany) prior to testing. The values are the mean and standard deviation of three replicates (Table 1). All pellets (uncoated and coated) were stored and tested at ambient temperature (20–22 8C) and relative humidity (43–47%). The four pellet batches produced can be described as follows: • batch SP (extrusion / spheronisation) • batch AL (extrusion / spheronisation using 70% ethanol as binder liquid) • batch GR (granulation / spheronisation) • batch DS (direct spheronisation)
2.3. Film coating procedure A desirable film coating thickness of about 25 mm was chosen. The amount of coating material required per gram of pellets was estimated taking into account the mean diameter and surface area of the pellets and the calculated volume of the coating layer and its density. Preliminary experiments established that a 3% solution of ethylcellulose (Ethocel , Dow Chemical Company, Midland, MI, USA) in ethanol (Finsprit 95 v / v%, Kemetyl, Stockholm, Sweden) containing 17.5% of povidone (PVP; Kollidon K90, BASF, Ludwigshafen, Germany) provided a film coat with pores which would allow controlled release of the model drug (paracetamol). The film coating was carried out using the ‘Gandalf 0’ ¨ ¨ fluidised bed coater (Astra Hassle, Molndal, Sweden), which had a 10 cm diameter perforated bottom plate and a 5 cm diameter Wurster cylinder and was fitted with a bottom spray pneumatic nozzle (Schlich 970, Germany). Preliminary studies established that the optimum conditions, i.e. even coating with no pellet agglomeration, were batch size 400 g, inlet temperature 50 8C, outlet temperature 31 8C, atomising air flow 1.33 m 3 h 21 , fluidising air flow 34 m 3 h 21 , atomising air pressure 169 kPa, pump speed 46 min 21 and coating solution 1202 g. Under these conditions of operation without spraying fluid less than 5 g of weight loss of pellets was observed in any of Table 1 Pellet batch
sf (s) (MPa)
m
Eo (MPa)
RMC (%)
SP AL GR DS
0.35660.010 0.27160.005 0.39060.009 0.36260.011
4.974 6.360 5.757 4.131
18.564.8 15.264.2 15.462.8 16.563.5
0.2360.04 0.2560.03 0.2660.03 0.2360.03
¯ Surface tensile strength sf (s) (36s, n520), Weibull modulus m, ¯ modulus of elasticity Eo (36s, n520), and residual moisture content ¯ RMC (36s, n53) of uncoated pellets.
F. Podczeck, S.M. Almeida / European Journal of Pharmaceutical Sciences 16 (2002) 209 – 214
the formulations. Thus, pellets were not subjected to gross size changes caused by their friable nature. The equipment was set up and the pellets placed into the coating chamber. After the optimum conditions were achieved the coating cycle lasted 115 min.
lands) after gold sputter coating for 2 min (K550, Emitech, Ashford, Kent, UK).
3. Results and discussion
3.1. Tensile strength of uncoated pellets
2.4. Tensile strength measurements The tensile strength of the uncoated pellets was determined using a mechanical testing machine (CT–5, Engineering Systems, Nottingham, UK), equipped with a 5 kg load cell. Pellets were checked for true tensile failure to have occurred. The tensile strength was then calculated as surface tensile strength sf (s) from (Shipway and Hutchings, 1993): 0.4F sf (s) 5 ]] pR 2
211
(1)
where F is the breaking load, and R is the average radius of the pellet batch. The results are the mean and standard deviation of 50 pellets.
2.5. Dynamic Mechanical Analysis ( DMA) DMA was performed for individual pellets using a DMA7 (Perkin Elmer Corp., High Wycombe, UK) with a parallel plate geometry (3 mm diameter of the top moving plate). Samples were equilibrated at 2060.1 8C and purged with Helium (20 ml min 21 ) during testing. The results are the mean and standard deviation of 20 pellets. Static scans to obtain a value for the elastic modulus of the pellets were performed between 0 and 2600 mN at a rate of increase of 200 mN min 21 at a frequency of 1 Hz. Dynamic scans to evaluate the viscoelastic properties of the pellets and the properties of the film coating were undertaken employing a static force of 2000 mN, static force tension control of 120% and a frequency of 1 Hz. The dynamic force was varied between 0 and 600 mN at a rate of increase of 25 mN min 21 . From dynamic scans, a wide variety of measures can be obtained. Here, the storage modulus and the phase angle as a function of the dynamic force were recorded in order to get a first insight into the problem. The storage modulus is a measure of the elastic energy stored during deformation. The phase angle will be zero if the material behaves fully elastic during deformation, whereas a value of 908 is found for fully viscous behaviour. Any phase angle between these two threshold values indicates the degree of viscoelasticity of the test object under load.
2.6. Scanning Electron Microscopy ( SEM) Scanning electron microscopy was performed on a Phillips XL20 (Phillips Analytical, Endhoven, The Nether-
The tensile strength of the uncoated pellets is reported in Table 1. Statistically (ANOVA), these results are all significantly different, although batches SP and DS are very close in their mean values. In addition, Weibull analysis (Stanley and Newton, 1977; Salako et al., 1998) was performed to get a better insight into the brittle nature of the pellets. The Weibull modulus is also reported in Table 1. The pellets produced by extrusion / spheronisation using an ethanol–water mixture as binder liquid showed an exceptional low tensile strength, combined with less brittleness. Pellet batches AL, GR and DS had a similar porosity between 36 and 37%, and hence the lower strength cannot be the result of a larger porosity as a result of different drying properties due to the more volatile binder solution. All four batches also had statistically similar residual moisture contents (Table 1). On the other hand, the surface area by volume of these pellets was found to be significantly reduced (Chopra et al., 2001). This indicates that the shrinking process during drying produced cracks mainly inside the pellets of this batch, whereas the drying of the aqueous binder liquid produced a continuously porous structure for the other three pellet batches (DS, SP GR). The SEM photographs presented in Fig. 1 support this. The internal cracks proposed for batch AL would propagate easily during the diametral compression test, hence being the reason for the lower strength. There is not a large difference in the Weibull modulus of the four pellet batches, and the generally low values confirm the brittle nature of the pellets.
3.2. Elasticity and viscoelastic behaviour of the uncoated pellets The modulus of elasticity of the pellets can be calculated from the slope of the linear portion of the stress–strain curve obtained from a static scan using DMA. The values for the uncoated pellets are reported in Table 1. For pellet batch SP a significantly smaller porosity of 34% (Chopra et al., 2001) had been reported. As the modulus of elasticity has been empirically related to the porosity of test specimens of various geometry and nature (Spriggs, 1961; Spinner et al., 1963; Lewis, 1993), the considerably larger value found for batch SP is most likely the result of a reduced pellet porosity. The viscoelastic properties of the pellets were evaluated from dynamic scans as follows: (a) The storage modulus as a function of dynamic force applied was found to change
212 F. Podczeck, S.M. Almeida / European Journal of Pharmaceutical Sciences 16 (2002) 209 – 214
Fig. 1. SEM photographs comparing the internal structure of pellets from batch SP (a), AL (b), GR (c) and DS (d).
F. Podczeck, S.M. Almeida / European Journal of Pharmaceutical Sciences 16 (2002) 209 – 214
initially, i.e. at low dynamic force values rapidly in a non-linear fashion. At higher dynamic forces this function became linear. The onset of the linear portion, i.e. the dynamic force for this to occur was determined. In addition, the storage modulus at the maximum dynamic force of 600 mN and the slope of the linear portion of the function were obtained (Fig. 2). (b) The phase angle as a function of the dynamic force employed increased steadily with increasing dynamic force. The phase angle at the onset of the linear portion of the storage modulus–dynamic force curve was read after smoothing of the phase angle curve using standard algorithms and a window size of 300 points. The slope of the linear portion of the storage modulus– dynamic force curve is the only property obtained from dynamic scans, which appears to be related to the macroscopic properties of the pellets. Here, an increase in pellet porosity is accompanied by an increase in the value of the slope (Fig. 3). The change in storage modulus with increasing dynamic force is a result of increasing elastic deformation. As elasticity has been linked to specimen porosity (see above), the dependence of the change in elasticity with dynamic force on porosity of the pellets appears reasonable. None of the parameters, i.e. the dynamic force and the phase angle at the onset of the linear portion of the storage modulus–dynamic force curve and the maximum storage modulus at a dynamic force of 600 mN (Table 2) appear to be closely related to the macroscopic properties of the pellets or the slight variations of the process by which they were made, except that directly spheronised pellets (batch DS) show larger variability in the storage modulus than those batches, where the wet mass was pre-compressed and shaped by extrusion (SP, AL) or granulation (GR). This indicates a wider variability in the inner pellet structure.
213
Fig. 3. Slope of the linear portion of the storage modulus–dynamic force curve as a function of the pellet porosity.
Table 2 Pellet batch
DF (mN)
S (MPa N 21 )
Gmax (MPa)
PA (8)
SP AL GR DS
237626 275623 375637 182623
52615 139628 222618 101620
350634 491642 122611 198682
2.260.3 2.560.3 2.660.3 2.160.4
Dynamic force at the onset of the linear portion of the storage modulus–dynamic force curve DF, slope of the linear portion S, maximum storage modulus at a dynamic force of 600 mN Gmax , and phase ¯ angle at DF (PA) for uncoated pellets (36s, n520).
The differences between the pellet batches in all values observed were statistically significant (ANOVA). The application of the film coating increases the values of the phase angle (Table 3), indicating a slightly viscous behaviour. The dynamic force values at the onset of the linear proportion of the storage modulus–dynamic force curves (Table 3) are no longer statistically significantly different between the batches except for batch DS (ANOVA). This indicates that for pellet batches SP, AL and GR the test results now indeed reflect the mechanical properties of the film coating. The maximum storage modulus at a dynamic force of 600 mN (Table 3) is also very similar for all the coated pellets batches, and the values obtained are all significantly higher than those of Table 3
Fig. 2. Determination of the dynamic force at the onset of the linear portion of the storage modulus–dynamic force curve DF, slope of the linear portion S, and maximum storage modulus at a dynamic force of 600 mN Gmax from DMA measurements.
Pellet batch
DF (mN)
S (MPa N 21 )
Gmax (MPa)
PA (8)
SP AL GR DS
393631 363634 377630 329644
124626 145624 154638 182652
1062695 1032646 1118674 1114685
2.660.2 2.960.2 2.860.2 2.560.2
Dynamic force at the onset of the linear portion of the storage modulus–dynamic force curve DF, slope of the linear portion S, maximum storage modulus at a dynamic force of 600 mN Gmax , and phase ¯ angle at DF (PA) for coated pellets (36s, n520).
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F. Podczeck, S.M. Almeida / European Journal of Pharmaceutical Sciences 16 (2002) 209 – 214
the uncoated pellets (ANOVA). Hence, also this value represents the viscoelastic behaviour of the film coating. The slope of the linear portion of the storage modulus– dynamic force curves (Table 3), however, appears still to change proportionally to the change in pellet porosity from batch SP to the other three batches. Hence, the latter parameter does not appear to be able to reflect the sole film properties.
4. Conclusions The work has shown that the mechanical properties of pellets and film coatings applied to pellets can be assessed in situ on pellets, coated with a plasticised ethylcellulose film coat, sprayed from organic solvents, of average thickness of 25 mm. Hence, DMA has the potential to aid the development of film coatings for pellets to be used in tabletting to produce controlled-release dosage forms.
Acknowledgements S.A. is grateful to the SOCRATES scheme to provide the financial support to undertake the research at the School of Pharmacy, University of London, UK.
References ´ Bechard, S.R., Leroux, J.C., 1992. Coated pelletized dosage form: effect of compaction on drug release. Drug Dev. Ind. Pharm. 18, 1927–1944. Chopra, R., Newton, J.M., Alderborn, G., Podczeck, F., 2001. Preparation of pellets of different shape and their characterisation. Drug Dev. Technol. 6 (4), 495–503. Lewis, G., 1993. Dependence of modulus of elasticity on porosity for polycrystalline YBa 2 Cu 3 O 72x . J. Can. Ceram. Soc. 62, 258–262. ˚ Lundqvist, A.E.K., Podczeck, F., Newton, J.M., 1998. Compaction of and drug release from coated pellets mixed with other pellets. Eur. J. Pharm. Biopharm. 46, 369–370. Salako, M., Podczeck, F., Newton, J.M., 1998. Investigations into the deformability and tensile strength of pellets. Int. J. Pharm. 168, 49–57. Shipway, P.H., Hutchings, I.M., 1993. Fracture of brittle spheres under compression and impact loading: I—Elastic stress distributions. Philos. Mag. A67, 1389–1404. Spinner, S., Knudson, F.P., Stone, L., 1963. Elastic constant porosity relations for polycrystalline theria. J. Res. Nat. Bur. Stand. C67, 39. Spriggs, R.M., 1961. Expression for effect of porosity on elastic modulus of polycrystalline refractory materials, particularly alumina oxide. J. Am. Ceram. Soc. 44, 628–629. Stanley, P., Newton, J.M., 1977. Variability in the strength of powder compacts. J. Powder Bulk Solids Technol. 1, 13–19.
Determination of the mechanical properties of pellets and film coated pellets using Dynamic Mechanical Analysis (DMA) Fridrun Podczeck*, Susana M. Almeida The School of Pharmacy, University of London, 29 /39 Brunswick Square, London WC1 N 1 AX, UK Received 24 October 2001; received in revised form 16 May 2002; accepted 29 May 2002
Abstract The elastic and viscoelastic properties of pellets and film coatings applied to pellets were studied using Dynamic Mechanical Analysis (DMA). Four batches of spherical pellets produced with different methods were compared without film coating and after application of a plasticised ethylcellulose film of average thickness of 25 mm. The modulus of elasticity of the uncoated pellets was found to be related to the porosity of the pellets, as was the slope of the linear portion of the storage modulus–dynamic force curves. None of the other parameters obtained from DMA of the uncoated pellets appeared to be related to the macroscopic properties of these pellets. After application of the film coating the dynamic force at the onset of the linear portion of the storage modulus–dynamic force curve and the maximum storage modulus obtained at a dynamic force of 600 mN were found to be significantly different from the values of the uncoated pellets, but similar for all four coated pellet batches. Hence these parameters represented the viscoelastic behaviour of the film coatings. 2002 Elsevier Science B.V. All rights reserved. Keywords: Dynamic Mechanical Analysis (DMA); Film coating; Pellets; Tensile strength
1. Introduction Pellets are used as multiple-unit dosage form for controlled-release preparations. For this the pellets are coated with a controlled-release film and then either filled into hard shell capsules or compressed into tablets. The latter process requires the addition of special cushioning excipi´ ents in powder (Bechard and Leroux, 1992) or pellet form (Lundqvist et al., 1998) in order to avoid damage to the film coat due to the pressure applied and the close interparticulate contact. The advantage of using ‘soft’ pellets as cushioning material is that the particles of the mixture are all of similar size and shape, and hence segregation of the drug-containing pellets is less likely. To test how ‘soft’ or ‘hard’ pellets are, however, is rather difficult. The tensile strength of pellets can be determined by diametral compression (Salako et al., 1998). Such results can also provide, additionally to the physical strength, an assess*Corresponding author. Tel.: 144-20-7753-5857; fax: 144-20-77535857. E-mail address: [email protected] (F. Podczeck).
ment of brittleness but it is obtained by final destruction of the individual pellet. To determine truly elastic or ductile properties of pellets requires the evaluation of stress–strain curves. Although these can be obtained from some strength testers, due to the normally larger load cell capacity (5 kg or above), such assessments are never very accurate (the breaking load of individual 1 mm pellets is often below 1 kg, depending on the composition and manufacturing process). The success of the tabletting process to form single doses from pellets depends not only on the properties of the drug-containing pellets and the cushioning material, but also on the properties of the film. Mechanical properties of films are usually assessed on so-called ‘free’ or ‘cast films.’ However, it is questionable how well such films will represent the properties of coatings when applied to the surface of pellets or tablets. It would hence be helpful if a method of testing was developed, which could describe the mechanical properties of film coatings in situ, for example, on pellets. The aim of this work was to determine the elastic and viscoelastic properties of pellets using a non-destructive technique with high sensitivity, i.e. Dynamic Mechanical
0928-0987 / 02 / $ – see front matter 2002 Elsevier Science B.V. All rights reserved. PII: S0928-0987( 02 )00104-5
210
F. Podczeck, S.M. Almeida / European Journal of Pharmaceutical Sciences 16 (2002) 209 – 214
Analysis (DMA). A further goal was to develop a screening process for the in-situ testing of film coatings applied to pellets in order to estimate the mechanical properties of such films.
2. Materials and methods
2.1. Materials The materials used were all of Ph. Eur. quality and were used as supplied. The model drug included was paracetamol, fine powder (Bechpharm, Harlow, UK). The basic material used to ensure successful extrusion / spheronisation was microcrystalline cellulose (Avicel PH101 , FMC Corp., Cork, Ireland). A further aid to extrusion was the inclusion of glyceryl monostearate supplied as Imwitor 940 ¨ Milton Keynes, UK). The filler included as a water (Huls, insoluble material was barium sulphate (Chemische Werke GmbH, Sachtleben, Germany). The water used as an essential fluid for processing was purified by reverse osmosis. For one set of pellets this was replaced with a 70 v / v% solution of ethanol (Merck, Poole, UK) in water. The basic formulation was paracetamol 10%, glyceryl monostearate 16%, microcrystalline cellulose 50%, barium sulphate 24% and liquid q.s.
2.2. Pellet manufacture Pellets of different shape were prepared as described by Chopra et al. (2001). The object was here to produce spherical pellets with different mechanical properties. To this end the wet mass was either subjected to a standard process of extrusion and spheronisation, or the wet mass was passed through an oscillating granulator (ERWEKA type FGS, Heusenstamm, Germany) fitted with a 1 mm square aperture mesh, set at an oscillation speed of 4. In a further experiment the wet mass was processed directly from the planetary mixer. The wet mass was produced by dry mixing the powders for 5 min in a planetary mixer (Hobart, London, UK). The necessary quantity of fluid was gradually added and mixing was continued for 10 min, scraping the sides of the bowl at regular intervals. Samples to be extruded were processed with a capillary extrusion rheometer (ACER 2000, Rheometric Scientific, Loughborough, UK), fitted with a die of 1 mm diameter and 4 mm length with a 608 entry angle. The ram speed employed was 200 mm min 21 . The extrusion process was repeated until there was sufficient extrudate, at least 500 g, to process for 10 min unless otherwise stated on a 22.5 cm diameter radial geometry plate fitted to a spheroniser (GB Caleva, Stourminster Newton, UK) rotating at 1000 rpm. The wet mass from both the granulation and planetary mixing were subjected to the same spheronisation conditions. The pellets were dried for 24 h at 45 8C in an oven (Hotbox size 1,
Gallenkamp, London, UK). Each batch of pellets was sieved (Endecotts, London, UK) to obtain a 1–1.4 mm size fraction. The residual moisture content of the pellets was evaluated as loss on drying (Sartorius Thermo Control ¨ moisture balance YTC 01L, Sartorius GmbH, Gottingen, Germany) prior to testing. The values are the mean and standard deviation of three replicates (Table 1). All pellets (uncoated and coated) were stored and tested at ambient temperature (20–22 8C) and relative humidity (43–47%). The four pellet batches produced can be described as follows: • batch SP (extrusion / spheronisation) • batch AL (extrusion / spheronisation using 70% ethanol as binder liquid) • batch GR (granulation / spheronisation) • batch DS (direct spheronisation)
2.3. Film coating procedure A desirable film coating thickness of about 25 mm was chosen. The amount of coating material required per gram of pellets was estimated taking into account the mean diameter and surface area of the pellets and the calculated volume of the coating layer and its density. Preliminary experiments established that a 3% solution of ethylcellulose (Ethocel , Dow Chemical Company, Midland, MI, USA) in ethanol (Finsprit 95 v / v%, Kemetyl, Stockholm, Sweden) containing 17.5% of povidone (PVP; Kollidon K90, BASF, Ludwigshafen, Germany) provided a film coat with pores which would allow controlled release of the model drug (paracetamol). The film coating was carried out using the ‘Gandalf 0’ ¨ ¨ fluidised bed coater (Astra Hassle, Molndal, Sweden), which had a 10 cm diameter perforated bottom plate and a 5 cm diameter Wurster cylinder and was fitted with a bottom spray pneumatic nozzle (Schlich 970, Germany). Preliminary studies established that the optimum conditions, i.e. even coating with no pellet agglomeration, were batch size 400 g, inlet temperature 50 8C, outlet temperature 31 8C, atomising air flow 1.33 m 3 h 21 , fluidising air flow 34 m 3 h 21 , atomising air pressure 169 kPa, pump speed 46 min 21 and coating solution 1202 g. Under these conditions of operation without spraying fluid less than 5 g of weight loss of pellets was observed in any of Table 1 Pellet batch
sf (s) (MPa)
m
Eo (MPa)
RMC (%)
SP AL GR DS
0.35660.010 0.27160.005 0.39060.009 0.36260.011
4.974 6.360 5.757 4.131
18.564.8 15.264.2 15.462.8 16.563.5
0.2360.04 0.2560.03 0.2660.03 0.2360.03
¯ Surface tensile strength sf (s) (36s, n520), Weibull modulus m, ¯ modulus of elasticity Eo (36s, n520), and residual moisture content ¯ RMC (36s, n53) of uncoated pellets.
F. Podczeck, S.M. Almeida / European Journal of Pharmaceutical Sciences 16 (2002) 209 – 214
the formulations. Thus, pellets were not subjected to gross size changes caused by their friable nature. The equipment was set up and the pellets placed into the coating chamber. After the optimum conditions were achieved the coating cycle lasted 115 min.
lands) after gold sputter coating for 2 min (K550, Emitech, Ashford, Kent, UK).
3. Results and discussion
3.1. Tensile strength of uncoated pellets
2.4. Tensile strength measurements The tensile strength of the uncoated pellets was determined using a mechanical testing machine (CT–5, Engineering Systems, Nottingham, UK), equipped with a 5 kg load cell. Pellets were checked for true tensile failure to have occurred. The tensile strength was then calculated as surface tensile strength sf (s) from (Shipway and Hutchings, 1993): 0.4F sf (s) 5 ]] pR 2
211
(1)
where F is the breaking load, and R is the average radius of the pellet batch. The results are the mean and standard deviation of 50 pellets.
2.5. Dynamic Mechanical Analysis ( DMA) DMA was performed for individual pellets using a DMA7 (Perkin Elmer Corp., High Wycombe, UK) with a parallel plate geometry (3 mm diameter of the top moving plate). Samples were equilibrated at 2060.1 8C and purged with Helium (20 ml min 21 ) during testing. The results are the mean and standard deviation of 20 pellets. Static scans to obtain a value for the elastic modulus of the pellets were performed between 0 and 2600 mN at a rate of increase of 200 mN min 21 at a frequency of 1 Hz. Dynamic scans to evaluate the viscoelastic properties of the pellets and the properties of the film coating were undertaken employing a static force of 2000 mN, static force tension control of 120% and a frequency of 1 Hz. The dynamic force was varied between 0 and 600 mN at a rate of increase of 25 mN min 21 . From dynamic scans, a wide variety of measures can be obtained. Here, the storage modulus and the phase angle as a function of the dynamic force were recorded in order to get a first insight into the problem. The storage modulus is a measure of the elastic energy stored during deformation. The phase angle will be zero if the material behaves fully elastic during deformation, whereas a value of 908 is found for fully viscous behaviour. Any phase angle between these two threshold values indicates the degree of viscoelasticity of the test object under load.
2.6. Scanning Electron Microscopy ( SEM) Scanning electron microscopy was performed on a Phillips XL20 (Phillips Analytical, Endhoven, The Nether-
The tensile strength of the uncoated pellets is reported in Table 1. Statistically (ANOVA), these results are all significantly different, although batches SP and DS are very close in their mean values. In addition, Weibull analysis (Stanley and Newton, 1977; Salako et al., 1998) was performed to get a better insight into the brittle nature of the pellets. The Weibull modulus is also reported in Table 1. The pellets produced by extrusion / spheronisation using an ethanol–water mixture as binder liquid showed an exceptional low tensile strength, combined with less brittleness. Pellet batches AL, GR and DS had a similar porosity between 36 and 37%, and hence the lower strength cannot be the result of a larger porosity as a result of different drying properties due to the more volatile binder solution. All four batches also had statistically similar residual moisture contents (Table 1). On the other hand, the surface area by volume of these pellets was found to be significantly reduced (Chopra et al., 2001). This indicates that the shrinking process during drying produced cracks mainly inside the pellets of this batch, whereas the drying of the aqueous binder liquid produced a continuously porous structure for the other three pellet batches (DS, SP GR). The SEM photographs presented in Fig. 1 support this. The internal cracks proposed for batch AL would propagate easily during the diametral compression test, hence being the reason for the lower strength. There is not a large difference in the Weibull modulus of the four pellet batches, and the generally low values confirm the brittle nature of the pellets.
3.2. Elasticity and viscoelastic behaviour of the uncoated pellets The modulus of elasticity of the pellets can be calculated from the slope of the linear portion of the stress–strain curve obtained from a static scan using DMA. The values for the uncoated pellets are reported in Table 1. For pellet batch SP a significantly smaller porosity of 34% (Chopra et al., 2001) had been reported. As the modulus of elasticity has been empirically related to the porosity of test specimens of various geometry and nature (Spriggs, 1961; Spinner et al., 1963; Lewis, 1993), the considerably larger value found for batch SP is most likely the result of a reduced pellet porosity. The viscoelastic properties of the pellets were evaluated from dynamic scans as follows: (a) The storage modulus as a function of dynamic force applied was found to change
212 F. Podczeck, S.M. Almeida / European Journal of Pharmaceutical Sciences 16 (2002) 209 – 214
Fig. 1. SEM photographs comparing the internal structure of pellets from batch SP (a), AL (b), GR (c) and DS (d).
F. Podczeck, S.M. Almeida / European Journal of Pharmaceutical Sciences 16 (2002) 209 – 214
initially, i.e. at low dynamic force values rapidly in a non-linear fashion. At higher dynamic forces this function became linear. The onset of the linear portion, i.e. the dynamic force for this to occur was determined. In addition, the storage modulus at the maximum dynamic force of 600 mN and the slope of the linear portion of the function were obtained (Fig. 2). (b) The phase angle as a function of the dynamic force employed increased steadily with increasing dynamic force. The phase angle at the onset of the linear portion of the storage modulus–dynamic force curve was read after smoothing of the phase angle curve using standard algorithms and a window size of 300 points. The slope of the linear portion of the storage modulus– dynamic force curve is the only property obtained from dynamic scans, which appears to be related to the macroscopic properties of the pellets. Here, an increase in pellet porosity is accompanied by an increase in the value of the slope (Fig. 3). The change in storage modulus with increasing dynamic force is a result of increasing elastic deformation. As elasticity has been linked to specimen porosity (see above), the dependence of the change in elasticity with dynamic force on porosity of the pellets appears reasonable. None of the parameters, i.e. the dynamic force and the phase angle at the onset of the linear portion of the storage modulus–dynamic force curve and the maximum storage modulus at a dynamic force of 600 mN (Table 2) appear to be closely related to the macroscopic properties of the pellets or the slight variations of the process by which they were made, except that directly spheronised pellets (batch DS) show larger variability in the storage modulus than those batches, where the wet mass was pre-compressed and shaped by extrusion (SP, AL) or granulation (GR). This indicates a wider variability in the inner pellet structure.
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Fig. 3. Slope of the linear portion of the storage modulus–dynamic force curve as a function of the pellet porosity.
Table 2 Pellet batch
DF (mN)
S (MPa N 21 )
Gmax (MPa)
PA (8)
SP AL GR DS
237626 275623 375637 182623
52615 139628 222618 101620
350634 491642 122611 198682
2.260.3 2.560.3 2.660.3 2.160.4
Dynamic force at the onset of the linear portion of the storage modulus–dynamic force curve DF, slope of the linear portion S, maximum storage modulus at a dynamic force of 600 mN Gmax , and phase ¯ angle at DF (PA) for uncoated pellets (36s, n520).
The differences between the pellet batches in all values observed were statistically significant (ANOVA). The application of the film coating increases the values of the phase angle (Table 3), indicating a slightly viscous behaviour. The dynamic force values at the onset of the linear proportion of the storage modulus–dynamic force curves (Table 3) are no longer statistically significantly different between the batches except for batch DS (ANOVA). This indicates that for pellet batches SP, AL and GR the test results now indeed reflect the mechanical properties of the film coating. The maximum storage modulus at a dynamic force of 600 mN (Table 3) is also very similar for all the coated pellets batches, and the values obtained are all significantly higher than those of Table 3
Fig. 2. Determination of the dynamic force at the onset of the linear portion of the storage modulus–dynamic force curve DF, slope of the linear portion S, and maximum storage modulus at a dynamic force of 600 mN Gmax from DMA measurements.
Pellet batch
DF (mN)
S (MPa N 21 )
Gmax (MPa)
PA (8)
SP AL GR DS
393631 363634 377630 329644
124626 145624 154638 182652
1062695 1032646 1118674 1114685
2.660.2 2.960.2 2.860.2 2.560.2
Dynamic force at the onset of the linear portion of the storage modulus–dynamic force curve DF, slope of the linear portion S, maximum storage modulus at a dynamic force of 600 mN Gmax , and phase ¯ angle at DF (PA) for coated pellets (36s, n520).
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the uncoated pellets (ANOVA). Hence, also this value represents the viscoelastic behaviour of the film coating. The slope of the linear portion of the storage modulus– dynamic force curves (Table 3), however, appears still to change proportionally to the change in pellet porosity from batch SP to the other three batches. Hence, the latter parameter does not appear to be able to reflect the sole film properties.
4. Conclusions The work has shown that the mechanical properties of pellets and film coatings applied to pellets can be assessed in situ on pellets, coated with a plasticised ethylcellulose film coat, sprayed from organic solvents, of average thickness of 25 mm. Hence, DMA has the potential to aid the development of film coatings for pellets to be used in tabletting to produce controlled-release dosage forms.
Acknowledgements S.A. is grateful to the SOCRATES scheme to provide the financial support to undertake the research at the School of Pharmacy, University of London, UK.
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