Release Behaviour of Clozapine Matrix Pellets Based on Percolation Theory

Depósito de investigación de la Universidad de Sevilla https://idus.us.es/ “This is an Accepted Manuscript of an article published by Elsevier in INTERNATIONAL JOURNAL OF PHARMACEUTICS on 14 February 2011, available at: https://doi.org/10.1016/j.ijpharm.2010.11.024.” 1 Title: Release behaviour of clozapine matrix pellets based on percolation theory. Author names and affiliations: Ángela Aguilar-de-Leyva a . Tahmer Sharkawi b Bernard Bataille b Gilles Baylac b Isidoro Caraballo a a Department of Pharmacy and Pharmaceutical Technology. University of Seville. Profesor Garcia González, 2. 41012. Seville. Spain. b Laboratoire de Pharmacy Galénique et Genie Pharmaceutique. Université Montpellier 1. 15 Avenue Charles Flahault BP 14491 34093 Montpellier Cedex 5. France. Corresponding author: Ángela Aguilar-de-Leyva. Department of Pharmacy and Pharmaceutical Technology. University of Seville. Profesor García González, 2. 41012. Seville. Spain Telephone number: +34676212688 Fax number: +34954556085 e-mail address: [email protected]. 2 Abstract The release behaviour of clozapine matrix pellets was studied in order to investigate if it is possible to explain it applying the concepts of percolation theory, previously used in the understanding of the release process of inert and hydrophilic matrix tablets. Thirteen batches of pellets with different proportions of clozapine/ microcrystalline cellulose (MCC)/ hydroxypropylmethyl cellulose (HPMC) and different clozapine particle size fractions were prepared by extrusion-spheronisation and the release profiles were studied. It has been observed that the distance to the excipient (HPMC) percolation threshold is important to control the release rate. Furthermore, the drug percolation threshold has a big influence in these systems. Batches very close to the drug percolation threshold, show a clear effect of the drug particle size in the release rate. However, this effect is much less evident when there is a bigger distance to the drug percolation threshold, so the release behaviour of clozapine matrix pellets is possible to be explained based on the percolation theory. Keywords: Pellets, Clozapine, Hydroxypropylmethyl cellulose, Percolation threshold. 3 1. Introduction The pelletization process involves the agglomeration of active pharmaceutical ingredients and excipients in spherical units of size comprised between 0.5 and 1.5 mm called pellets (Bataille et al., 1993). These multiparticulate systems offer a wide range of therapeutic as well as technological advantages compared with monolithic systems: they disperse as individualized units in the gastrointestinal tract reducing high local drug concentration (minimising side effects like the irritation of the gastric mucosa), maximising drug absorption and reducing peak plasma fluctuation. Another additional therapeutic advantage is that these dosage forms eliminate the dependence of the drug effect on gastric emptying, thus reducing intra and interindividual variability of the drug plasma concentrations (Bechgaard and Hegermann Nielsen, 1978; Bodmeier, 1997). Examples of technological advantages of the pellets are their spherical shape, their narrow particle size distribution and their low friability which provide them very good flow properties and make it easier to coat them or include them into hard gelatin capsules as well as compress them into tablets (Reynolds, 1970). Moreover, these dosage forms allow combining non-compatible drugs or different drug release profiles in the same formulation (Pinto et al., 2001; Quintavalle et al., 2008). Pellets can be manufactured in different ways. Nevertheless, the most popular method of producing pellets is by an extrusion-spheronisation process which involves four different stages: preparation of the wet mass (granulation), extrusion of the granulated mass to obtain cylindrical extrudates, rounding of the extrudates into spheres (spheronisation) and finally, drying of the spheres (Reynolds, 1970; Vervaet et al., 1995). The excipient most used to produce pellets by this technique is the microcrystalline cellulose due to its favourable plastic properties (Chatlapalli and Rohera, 1998; Delalonde et al., 1997). Clozapine is an atypical antipsychotic which main indication is the treatment of resistant schizophrenia, although it has also demonstrated efficacy in the treatment of other conditions like schizoaffective disorders, bipolar depression and some neurological disorders. One important advantage of this drug is its low risk of producing side effects like extrapyramidal side effects, tardive diskynesia or elevated prolactine levels compared with other antipsychotics (Elizondo, 2008; Iqbal et al., 2003), which makes it one of the most used drugs in the treatment of schizophrenia. 4 To our knowledge, no pellet formulation of clozapine has been investigated; we therefore undertook formulation studies in order to take advantage of these dosage forms for clozapine treatment. The percolation theory was introduced into the pharmaceutical field by Leuenberger and co-workers (Blattner et al., 1990; Bonny and Leuenberger, 1991; Bonny and Leuenberger, 1993; Holman and Leuenberger, 1988; Leuenberger and Leu, 1992; Leuenberger et al., 1987), retrieving practical consequences from the theoretical principles of the percolation theory. These findings have been applied nowadays to the design and optimisation of an increasing number of pharmaceutical formulations. In relation with this theory, a cluster is defined as a group of neighbouring particles of the same component and is considered infinite or percolating when it extends from one side to the other side of the system (Stauffer and Aharony, 1992). Percolation threshold corresponds to the concentration of one component for which there is a maximum probability of appearance of an infinite cluster of it. At this concentration point, it is expected that some properties of the system change suddenly. Numerous studies applying the concepts of the percolation theory to the release behaviour of inert and hydrophilic matrix systems have been carried out. In inert matrix, the drug is released through both, the initial pores of the matrix and the pores formed when the drug has been dissolved (Caraballo et al., 1993). Therefore, the ideal formulation of an inert matrix, according to the percolation theory, would be above the drug percolation threshold since this fact assures the release of the total drug dose. The excipient must also be above its percolation threshold to avoid the disintegration of the matrix during the release process and to control the drug release (Bonny and Leuenberger, 1991; Bonny and Leuenberger, 1993; Caraballo et al., 1999; Melgoza et al., 1998). In the case of the hydrophilic matrix, the ideal formulation is above the excipient percolation threshold, since at that point a percolating cluster of the excipient is formed controlling the hydration and the release rate of the drug through the gel layer formed. Below the excipient percolation threshold the gel layer is less coherent resulting in a fast erosion of the matrix and conducting to a rapid diffusion of the drug (Caraballo, 2009). The aim of this study is to investigate, for the first time, if the release behaviour of matrix pellets containing clozapine can be explained using the concepts of percolation theory, which have been previously used in the understanding of the release process of inert and hydrophilic matrix tablets. 5 2. Material and Methods 2.1 Materials The following materials were used as matrix forming materials: hydroxypropylmethyl cellulose (Metolose 4.000 and Metolose 100.000, Shin-Etsu Chemical Co. Ltd, Japan), microcrystalline cellulose (Vivapur 101, J. Rettenmaier&Söhne GmbH + Co. KG, Germany), Magnesium Stearate (Cooper, France) and clozapine (Ningbo Yuanfang Biochemicals Co. Ltd, China). Ethanol (Merck, Germany) and distilled water were used as granulation liquid. All reagents and solvents used were of analytical grade. Water was always used in demineralized quality. 2.2 Methods 2.2.1 Preparation of the pellets Table 1 describes the studied formulations. Thirteen batches of 100 g of pellets with different proportions of clozapine/ MCC/ HPMC were prepared. The batches prepared contained 20%, 30% or 40% of clozapine. The drug particle size employed is indicated in Table 1. The content of HPMC was 2% for batches A, B, C and D, 10% for batch 1 and 40% for batches 2 to 9. The powders were blended in a Turbula mixer (Willy A. Bachofen, Basle, Switzerland) for 5 minutes and the wetting was done in a planetary mixer (Kenwood Major, U.K.) during 20 minutes with ethanol-water mixtures in different proportions for batches 1 to 9 and distilled water for batches A to D. Extrusion was performed on a single screw axial extruder (Pharmex 35T Gabler Machinenbau, Ettlingen, Germany) equipped with a 1 mm screen and operated at 50 rpm. Spheronisation was carried out on a Sphaeromat SPH 250 MA spheroniser (Gabler Machinenbau, Ettlingen, Germany) equipped with a serrated plate of 250 mm diameter and operated at different speeds depending on the batch. The spheronisation time also varied from 2 min to 3 min 30 sec depending on the formula. An additional spheronisation time at a different speed was necessary for some batches (the speed of this additional spheronisation period is expressed in parentheses in Table 1). All the batches were dried in a ventilated oven (Binder FP400, Germany) at a temperature of 50ºC during 20 hr. 2.2.2 Analytical methods 2.2.2.1. Rheological studies of the drug and excipients Rheological studies for both, drug and excipients (clozapine, MCC, HPMC 4000 cp and HPMC 100000 cp) were carried out according to European Pharmacopoeia (2007). 6 The bulk and tapped densities were determined in triplicate for the excipients in a volumeter (type STAV II, J Engelmann AG, Germany). The bulk density (ρ bulk ) was determined by measuring the bulk volume (V bulk ) occupied by 75 g of sample filled into a 250 ml graduated cylinder readable to 2 ml. The tapped density (ρ tapped ) was determined from the tapped volume (V tapped ) occupied by the powder after repeated taps until the difference between successive measurements was less than 2 ml. The values of densities were calculated from the measured volumes and its weight according to equations (1) and (2): (1) bulkbulk Vm /= ρ (2) tappedtapped Vm /= ρ Obtained values of densities were used for calculating the compressibility index (CI) as indicated in equation (3): (3) ( ) 0 0 100 V VV CI f − = The Hausner ratio (HR) was calculated according to equation (4): (4) tappedbulk VVHR /= The flowability was performed also in triplicate in a granulate flow tester (Erweka GmbH type GTB, Heusenstamm, Germany) with an outflow opening diameter of 25±0.01 mm, for both, clozapine and excipients. The rest angle was also carried out in triplicate in a granulate flow tester (Erweka GmbH type GTB, Heusenstamm, Germany) , with an outflow opening diameter of 25±0.01 mm following the rule DIN 53916 and it was made only for clozapine. 2.2.2.2. Particle size analysis The particle size analysis of the drug and excipients was carried out using laser diffraction in a Mastersizer X 2.18 version (Malvern Instruments Ltd., UK) equipped with MSX dry powder feeder. The results are expressed as percentiles 10, 50 and 90 % of the volume diameter. Each sample was performed in duplicate and the results are expressed as the mean ± standard deviation. 2.2.2.3. Differential Scanning Calorimetry 7 Differential Scanning Calorimetry was performed in a Setaram 131, France DSC in order to investigate potential solid state interactions between drug and excipients. Standard aluminium sample pans (40 μl) were used and a heating rate of 10ºC/min was employed in the range of 25 – 400 ºC. 2.2.2.4. Optical Microscopy Olympus SZ binoculars with a magnification of 10X interfaced via a digital camera Moticam 2300 to a computer with the software Motic Image v.2.0 and Leica S8APO binoculars with a magnification of 10X interfaced via a digital camera Leica DC 300 v.2.0 to a computer with the software Leica IM50 v.1.20 were used to perform the image analysis of the drug, excipients, and pellets. 2.2.2.5. Pellets size Pellets produced were subjected to sieve analysis using a nest of standard sieves (Retsch, Germany). The fraction of pellets corresponding to the range 0.710 to 1mm of the different batches was used for further characterisation. Mean particle diameter was determined using an image analyzer program (Image-Pro Plus v.6). 2.2.2.6. Sphericity index The sphericity index (SI) of the fraction of pellets with size comprised between 0.710 and 1mm was determined by image analysis employing the program Image-Pro plus v.6. This index was calculated as indicated in equation (5): (5)         = max min D D SI min D and max D are the smallest and largest diameter of a pellet (Galland et al., 2005). 2.2.2.7. Scanning electron microscopy The morphology of the drug and excipients as well as the drug distribution within the pellets was studied by means of a scanning electron microscope (Philips XL-30, Eindhoven, Holland), after coating the samples with a thin layer of gold on a sputter coater (Edwards Pirani 501 Scan-Coat Six, Crawley, West Sussex, UK). Microphotographs were obtained at a magnification appropriate for particle size. 2.2.2.8. Particle density The particle density was determined for both, drug and excipients, using a helium pycnometer (Micromeritics SA type Multivolume pycnometer 1305), employing a known mass of powder between 7.5 and 10.5 g. The sample volume is determined using equation 6: 8 (6) )1/( 21 − −= PP V VV r cs Where Vs is the sample volume, Vc is the cell volume, Vr is the reference volume, P 1 is the initial pressure and P 2 is the final pressure. The density of the powder mass, ρ , is given by equation 7: (7) ρ = m/ Vs The test was repeated two times for each product. 2.2.2.9. Study of the drug release Hard gelatine capsules were filled with pellets of the different batches containing 25 mg of clozapine. The dissolution studies for batches 1 to 9 were performed using the basket method (European pharmacopoeia, 2007) in a dissolution tester (Pharmatest DT70, Germany). 900 ml of pH 4 acetate buffer dissolution media (USP, 2009) was used for the assay. The temperature was fixed at 37 ± 0.5ºC and the stirring speed was 50 rpm. Samples were analysed using a continuous flow-through system attached to an 8 cell UV/VIS (Specord 250, Germany) spectrophotometer. The wavelength was set to 260 nm. Readings of absorbance were taken every 10 minutes until 100% of the drug was released. For batches A to D, the dissolution studies were carried out using the basket method (European pharmacopoeia, 2007) in a Sotax AT7 smart (Allschwil, Switzerland). 900 ml of pH 4 acetate buffer dissolution media (USP, 2009) was used for the assay. The temperature was fixed at 37 ± 0.5ºC and the stirring speed was 50 rpm. 5 ml samples were withdrawn at each time period during 7 hours and measured in a UV/VIS Agilent 8453 (California, USA) at 260 nm. The clozapine content was calculated using a previously determined calibration curve. All the release data are expressed as the mean ± standard deviation (S.D.) of six samples. 2.2.2.10. Dissolution data analysis Drug release data (Mt/M∞ ≤ 0.9) were analyzed according to Higuchi (1963) (8), Korsmeyer et al. (1983) (9), Zero order (10), First order (11) and Peppas and Sahlin (1989) (12) equations: 15 the clusters connected with the pellet’s surface. Far above the drug percolation threshold, the effect of the drug particle size is clearly less evident. Acknowledgements This work has been supported by an F.P.U. grant from the Spanish Government. List of symbols and abbreviations MCC Microcrystalline cellulose HPMC Hydroxypropylmethyl cellulose cp Centipoise ρ bulk Bulk density V bulk Bulk volume ρ tapped Tapped density V tapped Tapped volume CI Compresibility index V 0 Initial volume of the poured powder V f Final volume of the tapped pwder HR Haussner ratio SI Sphericity index min D The smallest diameter of a pellet max D The largest diameter of a pellet V s Sample volume V c Cell volume V r Reference volume P 1 Initial pressure P 2 Final pressure ρ True density Mt Drug amount released at time t M ∞ Drug amount released at infinite time b Higuchi’s release rate constant k k Korsmeyer’s kinetic constant 16 k 0 Zero order release rate constant k 1 First order release rate constant n Korsmeyer’s time exponent k d Diffusional rate constant kr Relaxational rate constant m Purely Fickian diffusion exponent References Bataille, B., Ligarski, K., Jacob, M., Thomas, C., Duru, C., 1993. 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Tecnología Farmacéutica 1: Aspectos fundamentales de los sistemas farmacéuticos y operaciones básicas, Síntesis, Madrid. 20 Figure captions Figure 1. DSC thermograms of (from top to bottom): a) pure clozapine, b) 1:1 blend of clozapine with HPMC 4000 cp, c) 1:1 blend clozapine-HPMC 100000 cp, d) 1:1 blend clozapine- MCC and e) 1:1 blend clozapine-Mg stearate. Figure 2. Microphotograph corresponding to clozapine particles. Figure 3. Microphotograph corresponding to an uncut pellet from batch 2 (20% of clozapine (particle size smaller than 125 μm) /40% HPMC 100000 cp/40% MCC). Figure 4. Microphotograph corresponding to an uncut pellet from batch A (20% of clozapine (particle size smaller than 125 μm) /2% HPMC 4000 cp/78% MCC). Figure 5. Microphotograph corresponding to the cross section of a cut pellet from batch A (20% of clozapine (particle size smaller than 125 μm)/2% HPMC 4000 cp/78% MCC). Figure 6. Microphotograph corresponding to the cross section of a cut pellet from batch D (30% of clozapine (particle size bigger than 250 μm) /2% HPMC 4000 cp/68% MCC). Figure 7. Percentage of clozapine released versus time of batches 1 to 9. Figure 8. Percentage of clozapine released versus time of batches A to D, having batches A and B 20% of drug and batches C an D 30% of clozapine. Batches B and D contain the coarsest particles of clozapine. TABLE 1. Composition and spheronisation conditions of the different batches manufactured 1 2 3 4 5 6 7 8 9 A B C D Clozapine Mixture Size fraction: x < 125µm 125 < x < 250 µm x > 250 µm 20% 20% 20% 20% 30% 30% 30% 40% 20% 20% 20% 30% 30% HPMC 4000 cp 10% 2% 2% 2% 2% HPMC 100000 cp 40% 40% 40% 40% 40% 40% 40% 40% MCC 70% 40% 40% 40% 30% 30% 30% 20% 38.5% 78% 78% 68% 68% Mg stearate 1.5% Granulation liquid (ml): Ethanol/Water: (90%/10%) (85%/15%) (80%/20%) Distilled water: 140 240 236 238 240 240 248 233 240 85 88 65 60 Spheronisation Time (min) Speed (rpm) 3 1040 2 +1 a 1040 (1600) 2+1 a 1040 (1600) 2 1040 2+ 1.5 a 1040 (1600) 2+1 a 1040 (1600) 2+ 0.5 a 1040 (1600) 2+ 1 a 1040 (1460) 2 + 0.5 a 1040 (1460) 2 1040 2 1040 2 1040 2 1040 a Additional spheronisation time at the speed indicated in parenthesis TABLE 2 Densities of drug and excipients, Compressibility Index, Hausner Ratio, Rest angle and Flowability Sample Bulk density a Tapped density a Compressibility Index a Hausner Ratio a Rest angle a Flowability a (g/cm 3 ) (g/cm 3 ) ( 0 ) (g/s) MCC 0.335±0.003 0.477±0.002 29.65±0.99 1.42±0.02 0 HPMC 4000 cp 0.332±0.002 0.502±0.004 33.82±0.74 1.51±0.02 0 HPMC 100000 cp 0.310±0.003 0.493±0.006 37.28±0.12 1.59±0.00 0 Clozapine 36.67±2.67 79.04±2.11 a Mean value ± standar deviation (three replicates) TABLE 3 Malvern ® particle size analysis data for Clozapine, MCC, HPMC 4000 cp and HPMC 100000 cp powders Material D (v,0.1) a D (v,0.5) b D (v,0.9) c Clozapine 6.26±0.30 58.28±3.12 205.13±3.75 MCC 18.96±0.25 59.3±0.37 135.7±1.05 HPMC 4000 cp 22.36±0.14 72.53±0.25 181.6±1.20 HPMC 100000 cp 23.89±0.16 75.85±0.20 179.76±1.45 a Mean ± standard deviation (n = 2) of the percentile 10 of the volume diameter of particles b Mean ± standard deviation (n = 2) of the percentile 50 of the volume diameter of particles c Mean ± standard deviation (n = 2) of the percentile 90 of the volume diameter of particles TABLE 4. Pellets Mean Diameter (mm) and sphericity index Batch 1 Batch 2 Batch 3 Batch 4 Batch 5 Batch 6 Batch 7 Batch 8 Batch 9 Batch A Batch B Batch C Batch D Pellet mean diameter (mm) Mean 1.159 0.966 1.003 0.898 0.911 0.941 0.943 0.989 1.009 0.979 0.991 1.042 0.992 S.D. 0.200 0.144 0.173 0.123 0.121 0.104 0.147 0.139 0.123 0.122 0.118 0.093 0.107 Pellet sphericity index a Mean 0.698 0.668 0.651 0.699 0.673 0.717 0.656 0.628 0.613 0.771 0.792 0.812 0.801 S.D. 0.133 0.108 0.134 0.118 0.115 0.102 0.129 0.119 0.116 0.096 0.097 0.078 0.081 a Calculated as the mean ratio between the smallest and the largest diameter of 75 pellets TABLE 5. Mathematical modelling and drug release kinetics from pellets of the different batches a Higuchi release rate constant, b Korsmeyer’s kinetic constant, c Korsmeyer’s time exponent, d Zero order kinetic constant, e First order kinetic constant; f Peppas diffusion kinetic constant; g Peppas relaxation kinetic constant; h Determination coefficient. Batch Higuchi Korsmeyer Zero order First Order Peppas and Sahlin b a (min - 0. 5 ) r 2 h k k b (min - n ) n c r 2 h k 0 d (min - 1 ) r 2 h k 1 e (min - 1 ) r 2 h k d f (min - 0.425 ) k r g (min - 0.850 ) r 2 h 1 0.135 0.948 0.089 0.614 0.806 0.021 0.905 0.028 0.772 0.098 0.017 0.953 2 0.075 0.873 0.127 0.422 0.847 0.005 0.682 0.006 0.573 0.190 -0.009 0.933 3 0.044 0.919 0.145 0.328 0.922 0.002 0.754 0.003 0.665 0.128 -0.004 0.985 4 0.062 0.855 0.176 0.333 0.838 0.004 0.652 0.004 0.574 0.184 -0.009 0.950 5 0.076 0.926 0.002 1.294 0.655 0.005 0.809 0.014 0.357 0.125 0.000 0.926 6 0.100 0.925 0.001 1.468 0.720 0.009 0.918 0.026 0.482 0.038 0.013 0.942 7 0.090 0.977 0.105 0.479 0.947 0.008 0.838 0.010 0.756 0.145 -0.002 0.986 8 0.099 0.981 0.035 0.730 0.984 0.009 0.954 0.018 0.838 0.058 0.012 0.991 9 0.106 0.941 0.011 1.019 0.904 0.009 0.901 0.021 0.665 0.069 0.011 0.945 A 0.141 0.958 0.050 0.790 0.893 0.022 0.949 0.035 0.808 0.058 0.027 0.975 B 0.102 0.985 0.069 0.597 0.969 0.010 0.874 0.015 0.771 0.115 0.004 0.982 C 0.127 0.970 0.057 0.712 0.920 0.017 0.934 0.027 0.814 0.080 0.017 0.977 D 0.116 0.988 0.083 0.588 0.963 0.014 0.906 0.019 0.837 0.115 0.008 0.987