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The Rheological Properties of Modified Microcrystalline Cellulose Containing High Levels of Model Drugs
The Rheological Properties of Modified Microcrystalline Cellulose Containing High Levels of Model Drugs PAUL E. KNIGHT,1 FRIDRUN PODCZECK,2 J. MICHAEL NEWTON2 1
The School of Pharmacy, University of London, Brunswick Square, London WC1N 1AX, UK
2
Department of Mechanical Engineering, University College London, Torrington Place, London WC1E 7JE, London, UK
Received 11 April 2008; revised 28 July 2008; accepted 27 August 2008 Published online 29 September 2008 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21587
ABSTRACT: The rheological properties of different types of microcrystalline cellulose (MCC) mixed with model drugs and water have been evaluated to identify the influence of sodium carboxymethylcellulose (SCMC) added to the cellulose during preparation. A ram extruder was used as a capillary rheometer. The mixtures consisted of 20% spheronizing agent (standard grade MCC or modified types with 6% or 8% of low viscosity grade SCMC) and 80% of ascorbic acid, ibuprofen or lactose monohydrate. The introduction of SCMC changed all rheological parameters assessed. It produced more rigid systems, requiring more stress to induce and maintain flow. Degree of nonNewtonian flow, angle of convergence, extensional viscosity, yield and die land shear stress at zero velocity, and static wall friction were increased, but recoverable shear and compliance were decreased. The presence of SCMC did not remove the influence of the type of drug. The mixture of ibuprofen and standard MCC had the lowest values for shear stress as a function of the rate of shear, extensional viscosity, and angle of convergence, but the highest values for recoverable shear and compliance. The findings indicate that the system has insufficient rigidity to form pellets. ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2160–2169, 2009
Keywords:
extrusion; formulation; polymers; spheronization; viscosity
INTRODUCTION The ability of wet powder masses to be transformed into pellets by the process of extrusion/ spheronization is a complex function of the solid/ liquid composition. As yet, however, it is not possible to identify what physical characteristics of the wet mass are required for successful processing. Statistically designed experiments have been employed as a method of identifying suitable formulations and processing conditions,
Correspondence to: Fridrun Podczeck (Telephone: þ44-207679-7178, Fax: þ44-20-7388-0180; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 98, 2160–2169 (2009) ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association
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e.g.,1,2 but these do not identify the reasons for success or failure of a given composition and process variables. Using a statistical designed experiment, it was possible to identify potential relationships between the model drug properties and the best water content for a particular grade of MCC,3 but even here, the accuracy of prediction was only 35% for a linear model and 50% for a nonlinear model. A recent study has established that modification of the composition of a standard grade of microcrystalline cellulose (MCC) by adding sodium carboxymethylcellulose (SCMC) to the wet cake, changed the properties of the basic material so that it was able to form spherical pellets by extrusion and spheronization with a high level of the model drug ibuprofen.4 This had
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not been possible with the standard MCC grade (Avicel PH101). Two more model drugs (lactose monohydrate, ascorbic acid), which formed pellets with standard MCC, were also studied and they also formed pellets with the modified materials. The improved performance of the modified types of MCC appeared to be associated with the increase in the capacity of these materials to hold water within their structure when subjected to pressure.4 The change in the water holding ability proved beneficial to the complex process of extrusion/spheronization, where the wet mass is extruded through a die under pressure, prior to the wet extrudate being subjected to centripetal forces on the spheronizer plate. The water content and its mobility in the systems will clearly influence the rheological properties of the wet mass, as illustrated by several workers.5–11 The diverse systems studied have all been shown to be visco-elastic and non-Newtonian. The study by Raines et al.6 established that the formulations with defined rheological parameters produced smooth extrudate in long dies, but the rheological parameters measured in this study did not appear to be related to the ability of the extrudate to form pellets. The finding that the addition of SCMC during the process of preparing microcrystalline cellulose converts a system that will not produce pellets to one that will,4 offers the opportunity to establish whether the change in composition leads to changes in the rheological properties of the wet mass, which could be used to identify specific parameters which could be indicative of the required rheological characteristics for pellet formation. Previous studies of the rheological properties of wet powder masses have involved the use of the ram extruder as a capillary rheometer to derive classical rheological parameters.5–11 This procedure, plus the application of the approach provided by Benbow et al.12 to evaluate the properties of pastes were employed here. The ram extrusion system has some limitations, as the pastes are non-Newtonian and the presence of fluid mobility can alter the composition of the mixture and hence properties one is trying to measure. It does, however, have some advantage in that it operates at shear rates associated with the process of preparation of pellets by extrusion/ spheronization and therefore has the potential to provide information about the ability to process the wet powder mass. If carried out carefully, the results have been demonstrated to be reproducible.5–11 DOI 10.1002/jps
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MATERIALS AND METHODS Materials The standard grade of microcrystalline cellulose used was Avicel PH101 (FMC, Philadelphia, USA). The modified types of MCC were prepared and supplied by FMC (Philadelphia, USA) and were the two types that had been identified as showing the ability to form pellets with 80% of the model drugs.4 They will be designated as B6 and B8, as they contain approximately 6% and 8% of SCMC, respectively. The model drugs were those used in the previous study,4 namely, ascorbic acid, ibuprofen and lactose monohydrate, whose volume mean particle size had been determined as 38.3, 46.0 and 45.0 m, respectively. The water used was purified water produced by reverse osmosis (USR Elga Ltd., High Wycombe, UK).
METHODS The wet masses containing 80% of the model drug and 20% of one of the different types of MCC at a time, were prepared and extruded as described previously.4 The levels of water used were those associated with systems, which had produced satisfactory pellets in that study. These were 21.26 (ascorbic acid), 23.08 (ibuprofen) and 29.58% (lactose monohydrate) of the wet weight of the MCC/model drug powder mixtures. The wet mass was allowed to equilibrate overnight in sealed containers prior to being extruded. The steady state extrusion force produced by extrusion of the wet masses at 50, 100, 200 and 400 mm/min through dies of 1mm diameter and lengths of 2, 4, 6 and 8 mm was taken as the horizontal section of the force/displacement curve obtained on the XY recorder (Recorderlab, Gould, Surrey, UK). The results are the mean of three runs, whereby the values varied by less than 5%. To test whether there was migration of water, the measurements of extrusion pressure were made at descending order of speed. When the slowest speed was reached, the crosshead was reversed and the extrusion pressure measured at each crosshead speed. Only if the final speed provided extrusion pressure values that were within 5% of the original value was the run accepted. It was possible to achieve the level of reproducibility with all the systems tested. This provided a clear indication that liquid migration had not occurred JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 6, JUNE 2009
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during the extrusion process.13 The extrudates were always smooth and free of surface defects. The pH of saturated solutions of the drugs in water was checked using a pH meter (Hydrus 300, Fisher Scientific, Loughborough, UK). The pH for the demineralised water was found to be 5.13. The viscosity of the solutions used as binder liquids in the preparation of the wet masses for extrusion/spheronization was determined using a U-tube viscometer as described in the British Pharmacopoeia, Appendix V–H. Regression analysis was undertaken using SPSS 15.0 (SPSS Inc., Woking, UK), to obtain values for slopes and intercepts, where appropriate.
RESULTS AND DISCUSSION As demonstrated previously,4 there are varying degrees of water mobility during the extrusion of the systems. This is more noticeable for the drug/ standard MCC systems, especially the ibuprofen/ standard MCC mixture. Here there is often a limited steady state flow region, which will always be associated with a higher level of water than in the original mixture. The water level of the mixture may vary slightly with the ram speed and thus the results may not be exactly those at
the original composition. Unfortunately this cannot be controlled and the results will be taken as representative of the original water content of the mixture.
Shear Rate/Shear Stress To provide the classical shear rate/shear stress graphs, the graphs of the extrusion pressure/ die length to radius ratio are first obtained.14 The graphs for the B8 type of MCC with the three model drugs are shown in Figure 1 as an example. The slope of the graphs allows the calculation of the shear stress of the system and from the dimensions and rate of movement of the ram the rate of shear g can be derived. The results for all the systems studied are shown in Figure 2 and demonstrate that the flow in all cases is nonNewtonian, and all formulations demonstrate various degrees of shear thinning. The inclusion of the SCMC into the MCC results in an increase in the shear stress required to induce flow of the wet masses of the three model drugs. This effect corresponds to the differences in shear rate/shear stress curves for standard MCC (Avicel PH101) and an MCC grade co-processed with SCMC (Avicel RC591) mixed with an equal quantity of lactose, which has been reported previously.8 Except for the B6 system, the order of resistance
Figure 1. Extrusion pressure as a function of die length to radius ratio (L/R) for 80% mixtures of ascorbic acid, ibuprofen or lactose monohydrate and 20% B8 type of MCC and water at ram speeds of 50, 100, 200 and 400 mm/min. (Each point is the mean and standard deviation of six values for the extrusion pressure.) JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 6, JUNE 2009
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Figure 2. Die wall shear stress t as a function of rate of shear g for mixtures of 80% ascorbic acid, ibuprofen or lactose monohydrate and 20% standard MCC, B6 or B8 type of MCC and water.
to flow is ibuprofen < lactose monohydrate < ascorbic acid. An increase in the SCMC content generally increases the resistance to shear, except for the lactose monohydrate B6 system. There does not appear to be a simple reason as to why the B6 lactose monohydrate system should be irregular in behaviour. Thus both the model drug and the type of MCC influence this aspect of the flow properties of the systems. The systems are certainly different in that ibuprofen is highly insoluble and will therefore be present as ‘solid’ particles, whereas both the lactose monohydrate and the ascorbic acid will dissolve in the water used to form the wet mass. The former produced a neutral (pH 7.31), unionised solution, whereas the latter provided an acidic (pH 1.65), ionised solution. Saturated solutions of these two model drugs had a low viscosity (1.05 and 1.48 Pa s, respectively), which are unlikely to result in the magnitude of the changes observed in the resistance to shear demonstrated for the wet masses. The non-Newtonian flow properties of the systems can be confirmed by the value of the power law coefficient n, i.e. the slope of the doublelogarithmic version of the shear rate/shear stress graph, being less than 1, see Table 1. Including the SCMC reduced the value of the power-law coefficient n and increased the value of the consistency k, indicating an increase in the DOI 10.1002/jps
‘structure’ of the systems15 with the introduction of the polymer into the MCC. However, the lowest values for the power law coefficient and the highest values for k were always found for the B6 grade. The further increase in the content of SCMC to 8% appears to reduce this process of structure formation.
Die Entry Pressure The values of the die entry pressure Pe, obtained as the intercept on the Bagley graphs14 (Fig. 1), as a function of the shear stress are presented in Table 1. Power-Law Coefficient n (Degree of NonNewtonian Flow) and Consistency k of the Formulations Derived from the Double-Logarithmic Graphs of the Die Wall Shear Stress as a Function of the Rate of Shear Model Drug
Type of MCC
n
k (Pa sn)
Ascorbic acid
Standard MCC B6 B8 Standard MCC B6 B8 Standard MCC B6 B8
0.499 0.078 0.172 0.482 0.106 0.160 0.295 0.078 0.161
1.25 209.41 104.71 4.62 100.92 60.53 3.21 152.75 51.76
Ibuprofen
Lactose Monohydrate
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Figure 3. Die entry pressure Pe as a function of die wall shear stress t for mixtures of 80% ascorbic acid, ibuprofen of lactose monohydrate with 20% standard MCC, B6 or B8 type of MCC and water.
Figure 3. In general, the entry pressure increased with the shear stress, the magnitude of the increase varying with the model drug and the presence of the polymer in the MCC. This is in agreement with the results for standard MCC (Avicel PH 101) and a grade with added SCMC (Avicel RC591) mixed with an equal quantity of lactose.8 The systems with the lowest shear stress were those of the model drugs with standard MCC, in the order of ibuprofen < lactose monohydrate ascorbic acid. For ascorbic acid, the values for the entry pressures increased when there was polymer incorporated into the MCC. For ibuprofen, the incorporation of 6% SCMC resulted in an increase in the shear stress, but not the entry pressure, while for 8% SCMC there was an increase in entry pressure without further increase in shear stress. For lactose monohydrate the shear stress increased with addition of 6% and 8% of SCMC, but the entry pressure values became more and narrower in the range they span. All the mixtures formed pellets, except for the standard MCC/ibuprofen system.16 It would appear that the value of the entry pressure is not a useful indicator of the ability of the mixtures to form pellets except that the curve for ibuprofen/ standard MCC was at the lower shear stress end of the graphs. This system appears to be too easily deformed during processing. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 6, JUNE 2009
Natural Angle of Convergence The graph of the natural angle of convergence u (‘‘convergent entry angle’’) as a function of the normalised entry pressure represents the angle, which forms in the wet mass as it transforms from the diameter of the barrel to that of the die and is derived as described by Chohan and Newton.8 The results show that the various mixtures fall on a consistent line, Figure 4. The ibuprofen/standard MCC system is found again at the extreme of the relationship, with the lowest values for the convergent entry angle but requiring high entry pressures. The addition of the polymer to the MCC tends to increase the value of the convergent entry angle for all the systems. This change in the natural angle of convergence was also observed when standard MCC (Avicel PH101) and a grade with added SCMC (Avicel RC591) were mixed with an equal quantity of lactose.8
Extensional Flow As with the lactose monohydrate/MCC systems,8 when incorporating the model drugs into standard and modified MCC, the extensional viscosity EV decreases as the stretch rate ESR determined as described by Chohan and Newton,8 increases, see Figure 5. On the double-logarithmic scale the results fall approximately on a common trend line, DOI 10.1002/jps
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Figure 4. Angle of convergence of flow from the barrel into the die u (‘‘natural angle of convergence’’) as a function of normalised entry pressure for mixtures of 80% ascorbic acid, ibuprofen or lactose monohydrate with 20% standard MCC, B6 or B8 type of MCC and water.
with the ibuprofen/standard MCC system here forming an extreme set of high values for the extensional viscosity at low stretch rates. The addition of the polymer reduces the extensional viscosity for all of the three model drugs, an effect
previously reported by Chohan and Newton8 for a system containing equal quantities of standard MCC (Avicel PH101) and lactose in comparison to one containing MCC co-processed with SCMC (Avicel RC591).
Figure 5. Extensional viscosity (EV) as a function of stretch rate ESR for mixtures of 80% ascorbic acid, ibuprofen or lactose monohydrate with 20% standard MCC, B6 or B8 type of MCC and water. DOI 10.1002/jps
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Figure 6. Recoverable shear RC as a function of shear stress t for mixtures of 80% ascorbic acid, ibuprofen or lactose monohydrate with 20% standard MCC, B6 or B8 type of MCC and water.
Measures of Elasticity For the same reasons as discussed by Chohan and Newton,8 values for the recoverable shear RS and the compliance C have been used as measures of the elastic properties, and for the extrusion of polymers, the higher the value of RS and C, the less rigid is the system. These measures of elasticity were previously used to characterise
wet powder masses containing MCC and lactose monohydrate,8 different grades of MCC and water,9 MCC and self-emulsifying systems,11 and MCC with three model drugs.16 Here the results for the recoverable shear are presented in Figure 6, and due to the large range of values, the results for the compliance are presented as double-logarithmic graph in Figure 7. The system with the least rigidity, as expressed as recoverable
Figure 7. Compliance C as a function of shear stress t for mixtures of 80% ascorbic acid, ibuprofen or lactose monohydrate with 20% standard MCC, B6 or B8 type MCC and water. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 6, JUNE 2009
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shear of compliance, is the ibuprofen/standard MCC system, i.e. the system which did not produce pellets.16 The lactose monohydrate/standard MCC system has the next highest values for recoverable shear and compliance, but these mixtures did form satisfactory pellets.16 The limiting values for the recoverable shear and compliance, which might predict the processability, lay therefore in the region between the values for the ibuprofen and the lactose monohydrate systems. The values increase (RS) or remain constant (C) with shear stress for the lactose monohydrate systems but decrease for the ibuprofen systems. This could be associated with the relative mobility of the water during the extrusion of the two systems, those for the ibuprofen being more sensitive to extrusion rate than the lactose monohydrate systems. The inclusion of the SCMC into the MCC increases the rigidity of the mixtures but even then, the rigidity of the standard MCC/ibuprofen system is the lowest of the three drugs, see Figure 7. This increase in rigidity produced by the addition of SCMC to MCC was also reported for systems mixed with an equal quantity of lactose when comparing a standard grade of MCC (Avicel PH101) with a grade co-processed with SCMC (Avicel RC591).8
The values of these parameters were obtained as is described by Benbow and Bridgwater13 from graphs of extrusion pressure as function of ram speed, for each die length to radius ratio. The values of the coefficients a and b were found to vary with the speed of the ram, which was observed previously for MCC/lactose monohydrate systems17 and will therefore not be reported here. The values for s y0 and t0 and the ratio t 0 =s y0 , which represents the coefficient of static friction for the extrudate m, which has been shown to be an important parameter for controlled extrusion of ceramic pastes,18 are listed in Table 2. The values of s y0 for all the systems were higher than those observed for mixtures providing low surface impairment reported by Raines et al.,6 and indeed all the extrudates produced here were smooth. The addition of the SCMC increased the values of s y0 , t0 and m, especially the latter which reflects the greater resistance to flow of the systems containing the added polymer. The increase in the values of t0 and m is often 10-fold. The differences do not appear to be associated with the ability to produce pellets from the extrudate but this is perhaps not surprising, as the approach of the analysis is associated with the extrusion stage of the process rather than the spheronization stage.
Benbow and Brigdwater Approach
CONCLUSIONS
The complex flow behaviour of paste systems has lead Benbow et al.12 and Benbow and Bridgwater13 to introduce a new approach to their rheological characterisation, providing additional parameters to try and assist with the design of formulations for the extrusion of ceramic pastes. Raines et al.6 found that the approach provided a parameter, which helped to define whether or not a formulation would suffer from surface defects when extruded. The basic equation is: D0 L P ¼ ðs y0 þ aVÞ ln ðt0 þ bVÞ (1) þ2 R D where P is the total extrusion pressure, s y0 is the yield stress at zero velocity, a is the velocity coefficient for convergent flow into the die, V is the velocity of the extrudate in the die, D is the diameter of the die, D0 is the diameter of the barrel, L is the length of the die, R is the radius of the die, t0 is the initial shear stress to induce flow, and b is the velocity coefficient for flow in the die. DOI 10.1002/jps
Within the constraints of the capillary rheometer system, the results provide a characterisation of the wet powder masses. The introduction of SCMC
Table 2. Parameters Die Entry Yield Stress s y0 , Initial Shear Stress to Induce Flow into the Die t0, and Coefficient of Static Friction for the Extrudate m for the Mixtures of 80% Model Drug with 20% of Different Types of MCC and Water, Obtained by the Approach of Benbow and Bridgwater13 Model Drug
Type of MCC s y0 (MPa) t0 (MPa)
Ascorbic acid Standard MCC B6 B8 Ibuprofen Standard MCC B6 B8 Lactose Standard MCC Monohydrate B6 B8
0.74 0.80 1.50 0.59 1.46 1.19 0.56 1.45 1.17
0.023 0.392 0.479 0.018 0.635 0.307 0.070 0.635 0.396
m 0.031 0.490 0.319 0.032 0.435 0.258 0.125 0.438 0.339
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clearly changes all the various rheological parameters assessed. It produces systems, which are more rigid, requiring more stress to induce and maintain flow. It increases the degree of shear thinning, results in higher values for the consistency, increases the angle of convergence from the barrel into the die, the extensional viscosity, the yield stress and die land shear stress at zero velocity, and the coefficient of static friction for the extrudate, but results in lower values for recoverable shear and compliance. The presence of the polymer does not remove the influence of the type of drug on the rheological behaviour of the wet mass, as the formulations with the three drugs respond differently. The mixture of ibuprofen and standard MCC, which had been shown not to produce pellets by extrusion/spheronization, has the lowest values for the shear stress as a function of the rate of shear, the extensional viscosity, and the convergent entry angle from the barrel into the die, but the highest values for recoverable shear and compliance. This appears to indicate that the system has insufficient rigidity to form pellets. The high degree of water mobility in this system is, however, clearly implicated in that it would allow the pellets to coalesce during the spheronization process.
NOMENCLATURE B6 B8 C D D0 ESR EV k L MCC n P Pe R RS SCMC V
MCC co-processed with 6% SCMC MCC co-processed with 8% SCMC compliance die diameter barrel diameter stretch rate extensional viscosity consistency length of die microcrystalline cellulose power law coefficient total pressure drop die entry pressure radius of die recoverable shear sodium carboxymethylcellulose velocity of extrudate
Greek Letters a b
velocity sensitive factor for bulk yield stress velocity sensitive factor for shear stress in the die
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g u m s s y0 t t0
rate of shear angle of convergence of flow from barrel into the die coefficient of static friction bulk yield stress bulk yield stress at zero velocity shear stress in the die shear stress in die at zero velocity
ACKNOWLEDGMENTS The authors wish to acknowledge FMC for the preparation of the samples and the grant to support Dr Paul Knight in this study.
REFERENCES 1. Goskonda SR, Hileman GA, Upadrashta SM. 1994. Controlled release pellets by extrusion–spheronization. Int J Pharm 111:89–97. 2. Fitzpatrick S, Taylor S, Booth SW, Newton JM. 2006. The development of a stable coated pellet formulation of a water-sensitive drug, a case study: Development of a stable core formulation. Pharm Dev Technol 11:521–528. 3. Jover I, Podczeck F, Newton JM. 1996. Evaluation, by statistically designed experiment, of an experimental grade of microcrystalline cellulose, Avicel 955, as a technology to aid the production of pellets of high drug loading. J Pharm Sci 85:700–705. 4. Podczeck F, Knight PE, Newton JM. 2008. The evaluation of modified microcrystalline cellulose for the preparation of pellets with high drug loading by extrusion/spheronization. Int J Pharm 350:145– 154. 5. Harrison PJ, Newton JM, Rowe RC. 1986. The application of capillary rheometry to the extrusion of wet powder masses. Int J Pharm 37:81–83. 6. Raines CL, Newton JM, Rowe RC. 1990. Extrusion of microcrystalline cellulose formulations. In: Rheology of food, pharmaceuticals, and biological materials with general rheology. Carter RE, editor. London: Elsevier Applied Science. pp. 248–257. 7. Anderson AH, Newton JM. 1990. Influence of moisture content and particle size of barium sulphate on the extrusion properties of mixtures with microcrystalline cellulose. In: Carter RE, editor. Rheology of food, pharmaceuticals and biological materials with general rheology. London: Elsevier Applied Science. p 258–267. 8. Chohan RK, Newton JM. 1996. Analysis of extrusion of some wet powder masses used in extrusion/ spheronization. Int J Pharm 131:201–217. DOI 10.1002/jps
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9. Luukkonen P, Newton JM, Podczeck F, Yliruusi J. 2001. Use of a capillary rheometer to evaluate the rheological properties of microcrystalline cellulose and silicified microcrystalline cellulose. Int J Pharm 216:147–157. 10. MacRitchie KA, Newton JM, Rowe RC. 2002. The evaluation of the rheological properties of lactose/ microcrystalline cellulose and water mixtures by controlled stress rheometry and the relationship to the production of spherical pellets by the process of extrusion/spheronization. Eur J Pharm Sci 17:43–50. 11. Newton JM, Bazzigialuppi M, Podczeck F, Booth S, Clarke A. 2005. The rheological properties of selfemulsifying systems, water and microcrystalline cellulose. Eur J Pharm Sci 26:176–183. 12. Benbow JJ, Oxley EW, Bridgwater J. 1987. The extrusion mechanics of pastes—the influence of paste formulation. Chem Eng Sci 42:2151–2162.
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13. Benbow JJ, Bridgwater J. 1993. Paste flow and extrusion. Oxford series on advanced manufacturing. Oxford, UK: Clarendon Press. 14. Bagley EB. 1957. End correction in the capillary flow of polyethylene. J Appl Phys 28:624–627. 15. Barnes HA, Hutton JF, Walters K. 1989. An introduction to rheology. Amsterdam, Netherlands: Elsevier. 16. Podczeck F, Knight PE. 2006. Evaluation of formulations for the preparation of pellets with high drug loading by extrusion/spheronization. Pharm Dev Technol 11:263–274. 17. Raines CL. 1990. The extrusion of various formulations of microcrystalline cellulose. PhD Thesis. UK: University of London. 18. Wight JF Jr, Reed JS. 2002. Nonaqueous aluminium nitride extrusion. II. Die—land flow and tribology. J Am Ceram Soc 85:1689–1694.
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The School of Pharmacy, University of London, Brunswick Square, London WC1N 1AX, UK
2
Department of Mechanical Engineering, University College London, Torrington Place, London WC1E 7JE, London, UK
Received 11 April 2008; revised 28 July 2008; accepted 27 August 2008 Published online 29 September 2008 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jps.21587
ABSTRACT: The rheological properties of different types of microcrystalline cellulose (MCC) mixed with model drugs and water have been evaluated to identify the influence of sodium carboxymethylcellulose (SCMC) added to the cellulose during preparation. A ram extruder was used as a capillary rheometer. The mixtures consisted of 20% spheronizing agent (standard grade MCC or modified types with 6% or 8% of low viscosity grade SCMC) and 80% of ascorbic acid, ibuprofen or lactose monohydrate. The introduction of SCMC changed all rheological parameters assessed. It produced more rigid systems, requiring more stress to induce and maintain flow. Degree of nonNewtonian flow, angle of convergence, extensional viscosity, yield and die land shear stress at zero velocity, and static wall friction were increased, but recoverable shear and compliance were decreased. The presence of SCMC did not remove the influence of the type of drug. The mixture of ibuprofen and standard MCC had the lowest values for shear stress as a function of the rate of shear, extensional viscosity, and angle of convergence, but the highest values for recoverable shear and compliance. The findings indicate that the system has insufficient rigidity to form pellets. ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2160–2169, 2009
Keywords:
extrusion; formulation; polymers; spheronization; viscosity
INTRODUCTION The ability of wet powder masses to be transformed into pellets by the process of extrusion/ spheronization is a complex function of the solid/ liquid composition. As yet, however, it is not possible to identify what physical characteristics of the wet mass are required for successful processing. Statistically designed experiments have been employed as a method of identifying suitable formulations and processing conditions,
Correspondence to: Fridrun Podczeck (Telephone: þ44-207679-7178, Fax: þ44-20-7388-0180; E-mail: [email protected]) Journal of Pharmaceutical Sciences, Vol. 98, 2160–2169 (2009) ß 2008 Wiley-Liss, Inc. and the American Pharmacists Association
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e.g.,1,2 but these do not identify the reasons for success or failure of a given composition and process variables. Using a statistical designed experiment, it was possible to identify potential relationships between the model drug properties and the best water content for a particular grade of MCC,3 but even here, the accuracy of prediction was only 35% for a linear model and 50% for a nonlinear model. A recent study has established that modification of the composition of a standard grade of microcrystalline cellulose (MCC) by adding sodium carboxymethylcellulose (SCMC) to the wet cake, changed the properties of the basic material so that it was able to form spherical pellets by extrusion and spheronization with a high level of the model drug ibuprofen.4 This had
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not been possible with the standard MCC grade (Avicel PH101). Two more model drugs (lactose monohydrate, ascorbic acid), which formed pellets with standard MCC, were also studied and they also formed pellets with the modified materials. The improved performance of the modified types of MCC appeared to be associated with the increase in the capacity of these materials to hold water within their structure when subjected to pressure.4 The change in the water holding ability proved beneficial to the complex process of extrusion/spheronization, where the wet mass is extruded through a die under pressure, prior to the wet extrudate being subjected to centripetal forces on the spheronizer plate. The water content and its mobility in the systems will clearly influence the rheological properties of the wet mass, as illustrated by several workers.5–11 The diverse systems studied have all been shown to be visco-elastic and non-Newtonian. The study by Raines et al.6 established that the formulations with defined rheological parameters produced smooth extrudate in long dies, but the rheological parameters measured in this study did not appear to be related to the ability of the extrudate to form pellets. The finding that the addition of SCMC during the process of preparing microcrystalline cellulose converts a system that will not produce pellets to one that will,4 offers the opportunity to establish whether the change in composition leads to changes in the rheological properties of the wet mass, which could be used to identify specific parameters which could be indicative of the required rheological characteristics for pellet formation. Previous studies of the rheological properties of wet powder masses have involved the use of the ram extruder as a capillary rheometer to derive classical rheological parameters.5–11 This procedure, plus the application of the approach provided by Benbow et al.12 to evaluate the properties of pastes were employed here. The ram extrusion system has some limitations, as the pastes are non-Newtonian and the presence of fluid mobility can alter the composition of the mixture and hence properties one is trying to measure. It does, however, have some advantage in that it operates at shear rates associated with the process of preparation of pellets by extrusion/ spheronization and therefore has the potential to provide information about the ability to process the wet powder mass. If carried out carefully, the results have been demonstrated to be reproducible.5–11 DOI 10.1002/jps
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MATERIALS AND METHODS Materials The standard grade of microcrystalline cellulose used was Avicel PH101 (FMC, Philadelphia, USA). The modified types of MCC were prepared and supplied by FMC (Philadelphia, USA) and were the two types that had been identified as showing the ability to form pellets with 80% of the model drugs.4 They will be designated as B6 and B8, as they contain approximately 6% and 8% of SCMC, respectively. The model drugs were those used in the previous study,4 namely, ascorbic acid, ibuprofen and lactose monohydrate, whose volume mean particle size had been determined as 38.3, 46.0 and 45.0 m, respectively. The water used was purified water produced by reverse osmosis (USR Elga Ltd., High Wycombe, UK).
METHODS The wet masses containing 80% of the model drug and 20% of one of the different types of MCC at a time, were prepared and extruded as described previously.4 The levels of water used were those associated with systems, which had produced satisfactory pellets in that study. These were 21.26 (ascorbic acid), 23.08 (ibuprofen) and 29.58% (lactose monohydrate) of the wet weight of the MCC/model drug powder mixtures. The wet mass was allowed to equilibrate overnight in sealed containers prior to being extruded. The steady state extrusion force produced by extrusion of the wet masses at 50, 100, 200 and 400 mm/min through dies of 1mm diameter and lengths of 2, 4, 6 and 8 mm was taken as the horizontal section of the force/displacement curve obtained on the XY recorder (Recorderlab, Gould, Surrey, UK). The results are the mean of three runs, whereby the values varied by less than 5%. To test whether there was migration of water, the measurements of extrusion pressure were made at descending order of speed. When the slowest speed was reached, the crosshead was reversed and the extrusion pressure measured at each crosshead speed. Only if the final speed provided extrusion pressure values that were within 5% of the original value was the run accepted. It was possible to achieve the level of reproducibility with all the systems tested. This provided a clear indication that liquid migration had not occurred JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 6, JUNE 2009
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during the extrusion process.13 The extrudates were always smooth and free of surface defects. The pH of saturated solutions of the drugs in water was checked using a pH meter (Hydrus 300, Fisher Scientific, Loughborough, UK). The pH for the demineralised water was found to be 5.13. The viscosity of the solutions used as binder liquids in the preparation of the wet masses for extrusion/spheronization was determined using a U-tube viscometer as described in the British Pharmacopoeia, Appendix V–H. Regression analysis was undertaken using SPSS 15.0 (SPSS Inc., Woking, UK), to obtain values for slopes and intercepts, where appropriate.
RESULTS AND DISCUSSION As demonstrated previously,4 there are varying degrees of water mobility during the extrusion of the systems. This is more noticeable for the drug/ standard MCC systems, especially the ibuprofen/ standard MCC mixture. Here there is often a limited steady state flow region, which will always be associated with a higher level of water than in the original mixture. The water level of the mixture may vary slightly with the ram speed and thus the results may not be exactly those at
the original composition. Unfortunately this cannot be controlled and the results will be taken as representative of the original water content of the mixture.
Shear Rate/Shear Stress To provide the classical shear rate/shear stress graphs, the graphs of the extrusion pressure/ die length to radius ratio are first obtained.14 The graphs for the B8 type of MCC with the three model drugs are shown in Figure 1 as an example. The slope of the graphs allows the calculation of the shear stress of the system and from the dimensions and rate of movement of the ram the rate of shear g can be derived. The results for all the systems studied are shown in Figure 2 and demonstrate that the flow in all cases is nonNewtonian, and all formulations demonstrate various degrees of shear thinning. The inclusion of the SCMC into the MCC results in an increase in the shear stress required to induce flow of the wet masses of the three model drugs. This effect corresponds to the differences in shear rate/shear stress curves for standard MCC (Avicel PH101) and an MCC grade co-processed with SCMC (Avicel RC591) mixed with an equal quantity of lactose, which has been reported previously.8 Except for the B6 system, the order of resistance
Figure 1. Extrusion pressure as a function of die length to radius ratio (L/R) for 80% mixtures of ascorbic acid, ibuprofen or lactose monohydrate and 20% B8 type of MCC and water at ram speeds of 50, 100, 200 and 400 mm/min. (Each point is the mean and standard deviation of six values for the extrusion pressure.) JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 6, JUNE 2009
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Figure 2. Die wall shear stress t as a function of rate of shear g for mixtures of 80% ascorbic acid, ibuprofen or lactose monohydrate and 20% standard MCC, B6 or B8 type of MCC and water.
to flow is ibuprofen < lactose monohydrate < ascorbic acid. An increase in the SCMC content generally increases the resistance to shear, except for the lactose monohydrate B6 system. There does not appear to be a simple reason as to why the B6 lactose monohydrate system should be irregular in behaviour. Thus both the model drug and the type of MCC influence this aspect of the flow properties of the systems. The systems are certainly different in that ibuprofen is highly insoluble and will therefore be present as ‘solid’ particles, whereas both the lactose monohydrate and the ascorbic acid will dissolve in the water used to form the wet mass. The former produced a neutral (pH 7.31), unionised solution, whereas the latter provided an acidic (pH 1.65), ionised solution. Saturated solutions of these two model drugs had a low viscosity (1.05 and 1.48 Pa s, respectively), which are unlikely to result in the magnitude of the changes observed in the resistance to shear demonstrated for the wet masses. The non-Newtonian flow properties of the systems can be confirmed by the value of the power law coefficient n, i.e. the slope of the doublelogarithmic version of the shear rate/shear stress graph, being less than 1, see Table 1. Including the SCMC reduced the value of the power-law coefficient n and increased the value of the consistency k, indicating an increase in the DOI 10.1002/jps
‘structure’ of the systems15 with the introduction of the polymer into the MCC. However, the lowest values for the power law coefficient and the highest values for k were always found for the B6 grade. The further increase in the content of SCMC to 8% appears to reduce this process of structure formation.
Die Entry Pressure The values of the die entry pressure Pe, obtained as the intercept on the Bagley graphs14 (Fig. 1), as a function of the shear stress are presented in Table 1. Power-Law Coefficient n (Degree of NonNewtonian Flow) and Consistency k of the Formulations Derived from the Double-Logarithmic Graphs of the Die Wall Shear Stress as a Function of the Rate of Shear Model Drug
Type of MCC
n
k (Pa sn)
Ascorbic acid
Standard MCC B6 B8 Standard MCC B6 B8 Standard MCC B6 B8
0.499 0.078 0.172 0.482 0.106 0.160 0.295 0.078 0.161
1.25 209.41 104.71 4.62 100.92 60.53 3.21 152.75 51.76
Ibuprofen
Lactose Monohydrate
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Figure 3. Die entry pressure Pe as a function of die wall shear stress t for mixtures of 80% ascorbic acid, ibuprofen of lactose monohydrate with 20% standard MCC, B6 or B8 type of MCC and water.
Figure 3. In general, the entry pressure increased with the shear stress, the magnitude of the increase varying with the model drug and the presence of the polymer in the MCC. This is in agreement with the results for standard MCC (Avicel PH 101) and a grade with added SCMC (Avicel RC591) mixed with an equal quantity of lactose.8 The systems with the lowest shear stress were those of the model drugs with standard MCC, in the order of ibuprofen < lactose monohydrate ascorbic acid. For ascorbic acid, the values for the entry pressures increased when there was polymer incorporated into the MCC. For ibuprofen, the incorporation of 6% SCMC resulted in an increase in the shear stress, but not the entry pressure, while for 8% SCMC there was an increase in entry pressure without further increase in shear stress. For lactose monohydrate the shear stress increased with addition of 6% and 8% of SCMC, but the entry pressure values became more and narrower in the range they span. All the mixtures formed pellets, except for the standard MCC/ibuprofen system.16 It would appear that the value of the entry pressure is not a useful indicator of the ability of the mixtures to form pellets except that the curve for ibuprofen/ standard MCC was at the lower shear stress end of the graphs. This system appears to be too easily deformed during processing. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 6, JUNE 2009
Natural Angle of Convergence The graph of the natural angle of convergence u (‘‘convergent entry angle’’) as a function of the normalised entry pressure represents the angle, which forms in the wet mass as it transforms from the diameter of the barrel to that of the die and is derived as described by Chohan and Newton.8 The results show that the various mixtures fall on a consistent line, Figure 4. The ibuprofen/standard MCC system is found again at the extreme of the relationship, with the lowest values for the convergent entry angle but requiring high entry pressures. The addition of the polymer to the MCC tends to increase the value of the convergent entry angle for all the systems. This change in the natural angle of convergence was also observed when standard MCC (Avicel PH101) and a grade with added SCMC (Avicel RC591) were mixed with an equal quantity of lactose.8
Extensional Flow As with the lactose monohydrate/MCC systems,8 when incorporating the model drugs into standard and modified MCC, the extensional viscosity EV decreases as the stretch rate ESR determined as described by Chohan and Newton,8 increases, see Figure 5. On the double-logarithmic scale the results fall approximately on a common trend line, DOI 10.1002/jps
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Figure 4. Angle of convergence of flow from the barrel into the die u (‘‘natural angle of convergence’’) as a function of normalised entry pressure for mixtures of 80% ascorbic acid, ibuprofen or lactose monohydrate with 20% standard MCC, B6 or B8 type of MCC and water.
with the ibuprofen/standard MCC system here forming an extreme set of high values for the extensional viscosity at low stretch rates. The addition of the polymer reduces the extensional viscosity for all of the three model drugs, an effect
previously reported by Chohan and Newton8 for a system containing equal quantities of standard MCC (Avicel PH101) and lactose in comparison to one containing MCC co-processed with SCMC (Avicel RC591).
Figure 5. Extensional viscosity (EV) as a function of stretch rate ESR for mixtures of 80% ascorbic acid, ibuprofen or lactose monohydrate with 20% standard MCC, B6 or B8 type of MCC and water. DOI 10.1002/jps
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Figure 6. Recoverable shear RC as a function of shear stress t for mixtures of 80% ascorbic acid, ibuprofen or lactose monohydrate with 20% standard MCC, B6 or B8 type of MCC and water.
Measures of Elasticity For the same reasons as discussed by Chohan and Newton,8 values for the recoverable shear RS and the compliance C have been used as measures of the elastic properties, and for the extrusion of polymers, the higher the value of RS and C, the less rigid is the system. These measures of elasticity were previously used to characterise
wet powder masses containing MCC and lactose monohydrate,8 different grades of MCC and water,9 MCC and self-emulsifying systems,11 and MCC with three model drugs.16 Here the results for the recoverable shear are presented in Figure 6, and due to the large range of values, the results for the compliance are presented as double-logarithmic graph in Figure 7. The system with the least rigidity, as expressed as recoverable
Figure 7. Compliance C as a function of shear stress t for mixtures of 80% ascorbic acid, ibuprofen or lactose monohydrate with 20% standard MCC, B6 or B8 type MCC and water. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 98, NO. 6, JUNE 2009
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shear of compliance, is the ibuprofen/standard MCC system, i.e. the system which did not produce pellets.16 The lactose monohydrate/standard MCC system has the next highest values for recoverable shear and compliance, but these mixtures did form satisfactory pellets.16 The limiting values for the recoverable shear and compliance, which might predict the processability, lay therefore in the region between the values for the ibuprofen and the lactose monohydrate systems. The values increase (RS) or remain constant (C) with shear stress for the lactose monohydrate systems but decrease for the ibuprofen systems. This could be associated with the relative mobility of the water during the extrusion of the two systems, those for the ibuprofen being more sensitive to extrusion rate than the lactose monohydrate systems. The inclusion of the SCMC into the MCC increases the rigidity of the mixtures but even then, the rigidity of the standard MCC/ibuprofen system is the lowest of the three drugs, see Figure 7. This increase in rigidity produced by the addition of SCMC to MCC was also reported for systems mixed with an equal quantity of lactose when comparing a standard grade of MCC (Avicel PH101) with a grade co-processed with SCMC (Avicel RC591).8
The values of these parameters were obtained as is described by Benbow and Bridgwater13 from graphs of extrusion pressure as function of ram speed, for each die length to radius ratio. The values of the coefficients a and b were found to vary with the speed of the ram, which was observed previously for MCC/lactose monohydrate systems17 and will therefore not be reported here. The values for s y0 and t0 and the ratio t 0 =s y0 , which represents the coefficient of static friction for the extrudate m, which has been shown to be an important parameter for controlled extrusion of ceramic pastes,18 are listed in Table 2. The values of s y0 for all the systems were higher than those observed for mixtures providing low surface impairment reported by Raines et al.,6 and indeed all the extrudates produced here were smooth. The addition of the SCMC increased the values of s y0 , t0 and m, especially the latter which reflects the greater resistance to flow of the systems containing the added polymer. The increase in the values of t0 and m is often 10-fold. The differences do not appear to be associated with the ability to produce pellets from the extrudate but this is perhaps not surprising, as the approach of the analysis is associated with the extrusion stage of the process rather than the spheronization stage.
Benbow and Brigdwater Approach
CONCLUSIONS
The complex flow behaviour of paste systems has lead Benbow et al.12 and Benbow and Bridgwater13 to introduce a new approach to their rheological characterisation, providing additional parameters to try and assist with the design of formulations for the extrusion of ceramic pastes. Raines et al.6 found that the approach provided a parameter, which helped to define whether or not a formulation would suffer from surface defects when extruded. The basic equation is: D0 L P ¼ ðs y0 þ aVÞ ln ðt0 þ bVÞ (1) þ2 R D where P is the total extrusion pressure, s y0 is the yield stress at zero velocity, a is the velocity coefficient for convergent flow into the die, V is the velocity of the extrudate in the die, D is the diameter of the die, D0 is the diameter of the barrel, L is the length of the die, R is the radius of the die, t0 is the initial shear stress to induce flow, and b is the velocity coefficient for flow in the die. DOI 10.1002/jps
Within the constraints of the capillary rheometer system, the results provide a characterisation of the wet powder masses. The introduction of SCMC
Table 2. Parameters Die Entry Yield Stress s y0 , Initial Shear Stress to Induce Flow into the Die t0, and Coefficient of Static Friction for the Extrudate m for the Mixtures of 80% Model Drug with 20% of Different Types of MCC and Water, Obtained by the Approach of Benbow and Bridgwater13 Model Drug
Type of MCC s y0 (MPa) t0 (MPa)
Ascorbic acid Standard MCC B6 B8 Ibuprofen Standard MCC B6 B8 Lactose Standard MCC Monohydrate B6 B8
0.74 0.80 1.50 0.59 1.46 1.19 0.56 1.45 1.17
0.023 0.392 0.479 0.018 0.635 0.307 0.070 0.635 0.396
m 0.031 0.490 0.319 0.032 0.435 0.258 0.125 0.438 0.339
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clearly changes all the various rheological parameters assessed. It produces systems, which are more rigid, requiring more stress to induce and maintain flow. It increases the degree of shear thinning, results in higher values for the consistency, increases the angle of convergence from the barrel into the die, the extensional viscosity, the yield stress and die land shear stress at zero velocity, and the coefficient of static friction for the extrudate, but results in lower values for recoverable shear and compliance. The presence of the polymer does not remove the influence of the type of drug on the rheological behaviour of the wet mass, as the formulations with the three drugs respond differently. The mixture of ibuprofen and standard MCC, which had been shown not to produce pellets by extrusion/spheronization, has the lowest values for the shear stress as a function of the rate of shear, the extensional viscosity, and the convergent entry angle from the barrel into the die, but the highest values for recoverable shear and compliance. This appears to indicate that the system has insufficient rigidity to form pellets. The high degree of water mobility in this system is, however, clearly implicated in that it would allow the pellets to coalesce during the spheronization process.
NOMENCLATURE B6 B8 C D D0 ESR EV k L MCC n P Pe R RS SCMC V
MCC co-processed with 6% SCMC MCC co-processed with 8% SCMC compliance die diameter barrel diameter stretch rate extensional viscosity consistency length of die microcrystalline cellulose power law coefficient total pressure drop die entry pressure radius of die recoverable shear sodium carboxymethylcellulose velocity of extrudate
Greek Letters a b
velocity sensitive factor for bulk yield stress velocity sensitive factor for shear stress in the die
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g u m s s y0 t t0
rate of shear angle of convergence of flow from barrel into the die coefficient of static friction bulk yield stress bulk yield stress at zero velocity shear stress in the die shear stress in die at zero velocity
ACKNOWLEDGMENTS The authors wish to acknowledge FMC for the preparation of the samples and the grant to support Dr Paul Knight in this study.
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13. Benbow JJ, Bridgwater J. 1993. Paste flow and extrusion. Oxford series on advanced manufacturing. Oxford, UK: Clarendon Press. 14. Bagley EB. 1957. End correction in the capillary flow of polyethylene. J Appl Phys 28:624–627. 15. Barnes HA, Hutton JF, Walters K. 1989. An introduction to rheology. Amsterdam, Netherlands: Elsevier. 16. Podczeck F, Knight PE. 2006. Evaluation of formulations for the preparation of pellets with high drug loading by extrusion/spheronization. Pharm Dev Technol 11:263–274. 17. Raines CL. 1990. The extrusion of various formulations of microcrystalline cellulose. PhD Thesis. UK: University of London. 18. Wight JF Jr, Reed JS. 2002. Nonaqueous aluminium nitride extrusion. II. Die—land flow and tribology. J Am Ceram Soc 85:1689–1694.
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