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Self-emulsifying pellets in a lab-scale high shear mixer: Formulation and production design
Powder Technology 207 (2011) 113–118
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Powder Technology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p ow t e c
Self-emulsifying pellets in a lab-scale high shear mixer: Formulation and production design E. Franceschinis a,⁎, C. Bortoletto a, B. Perissutti b, M. Dal Zotto a, D. Voinovich b, N. Realdon a a b
Department of Pharmaceutical Sciences, University of Padua, Via Marzolo 5, 35131 Padua, Italy Department of Pharmaceutical Sciences, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy
a r t i c l e
i n f o
Article history: Received 11 May 2010 Received in revised form 30 September 2010 Accepted 16 October 2010 Available online 25 October 2010 Keywords: High shear wet granulation Piroxicam Self-emulsifying drug delivery system Process optimization
a b s t r a c t In this investigation, the preparation of solid self-emulsifying drug delivery systems (solid-SEDDS) by means of a wet granulation process was optimized in a lab-scale high shear mixer in order to improve the dissolution rate of piroxicam, a poorly water-soluble model drug. With this aim, the classic liquid granulation binder was replaced with an oil-in-water microemulsion, loaded with the drug. The microemulsion formulations were first selected on the basis of phase diagrams and their physicochemical properties, such as viscosity and droplet size. The best microemulsions were then used to prepare solid-SEDDS while maintaining the composition of the solid carrier and the operating conditions of the lab-scale high shear mixer used in this study. These pellets demonstrated an emulsifying capability and their piroxicam release was significantly enhanced with respect to pure drug. Since their dissolution was a function of pellet size fraction, in the subsequent step the yield of the best performing fraction was further increased by modifying experimental conditions for pellet production (impeller speed and amount of povidone). In this way, the 400 μm pellet size fraction of the selected formulation was produced with a percentage yield of 42.5 by wt., with satisfactory technological properties and unchanged drug dissolution performance. © 2010 Elsevier B.V. All rights reserved.
1. Introduction Self-emulsifying drug delivery systems (SEDDS) are lipid-based formulations [1] and are defined as isotropic mixtures of natural or synthetic oils, surfactants and/or co-surfactants, which form microemulsion droplets on dilution with physiological fluid. They are able to spread readily in the gastrointestinal (GI) tract, where the digestive motility of the stomach and intestine provides the agitation necessary for self-emulsification. The self-emulsification process is specific to the nature of the oil/ surfactant pair, surfactant concentration, oil/surfactant ratio and temperature at which self-emulsification occurs. Some parameters have been proposed to characterize the self-emulsifying performance; these include rate of emulsification, microemulsion size distribution and the charge of resulting droplets. Among them, microemulsion droplet size is considered a decisive factor in self-emulsification/ dispersion performance since it determines the rate and extent of drug release and absorption. The key step for SEDDS formulation is to find a suitable oil surfactant mixture that can dissolve the drug within
⁎ Corresponding author. Tel.: +39 049 8275339; fax: +39 049 8275366. E-mail address: [email protected] (E. Franceschinis). 0032-5910/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.powtec.2010.10.016
the required therapeutic concentration. Liquid SEDDS can then be used to fill either soft or hard gelatin capsules [2,3]. The drawback of this system includes GI tract irritation due to high surfactant concentrations, high manufacturing costs, interaction of the fill with the capsule shell, as well as problems due to storage temperature [4,5]. These inconveniences can be avoided by preparing solid self-emulsifying drug delivery systems (solid-SEDDS). Such systems require the solidification of SEDDS into powder/nanoparticles to create various solid dosage forms. Solid-SEDDS combine the advantages of solid dosage forms (e.g. low production costs, high stability and reproducibility) with those of SEDDS (i.e. enhanced solubility and bioavailability) [6–8]. According to the Biopharmaceutic Drug Classification System (BCS) proposed by Amidon et al. [9], piroxicam, chosen as the model drug, is a class II molecule and its dissolution is the ratecontrolling step in vivo drug absorption. Several techniques have been used to improve the oral bioavailability of piroxicam by accelerating its dissolution rate. These include mainly solid dispersion techniques based on cyclodextrin inclusion complexes, polyvinylpyrrolidone, and polyethylene glycols 4000 and 6000 [10–13]. The aim of this study was to prepare solid-SEDDS by the high shear wet granulation process using a microemulsion as a liquid binder in order to increase the dissolution rate of piroxicam. Further experiments have been conducted with the purpose of optimizing the formulation of a solid carrier and experimental conditions.
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2. Materials and methods
analyzed after filtration. The results are averaged from three-replicated experiments.
2.1. Materials 2.5. Preparation of solid self-emulsifying systems (solid-SEDDS) Piroxicam (PX) EP-grade was provided by FIS (Vicenza, Italy). Propylene glycol-monolaurate (Lauroglycol™ 90), Diethylene glycol monoethyl ether (Transcutol® HP), medium chain triglycerides (Labrafac™ Lipophile WL1349), oleoyl macrogolglycerides (Labrafil® M1944 CS®) and caprylocaproyl macrogolglycerides (Labrasol®) were obtained from Gattefossé (Saint-Priest, France). Polyoxyl-35castor oil (Cremophor® EL) was supplied by BASF (Ludwigshafen, Germany) and Monohydrate Lactose (LAC) by Meggle (Wasserburg, Germany). Microcrystalline Cellulose (MCC) and Polyvinylpyrrolidone K 90 (PVP) were purchased from ACEF (Fiorenziuola D'Arda, Italy). All other chemicals and solvents were of analytical grade and were used without further purification. 2.2. Solubility study Piroxicam solubility was determined in various oils, surfactants and co-surfactants by pouring an excess of drug into 5 ml glass vials containing 2 g of different vehicles. Mixtures were mixed continuously for 24 h (previously determined to be adequate time for equilibration) at 25 °C in a thermostated water bath and then centrifuged at 5000 g for 10 min to separate the undissolved drug. Aliquots of supernatant were diluted with methanol and the PX content was quantified by the UV–VIS spectrophotometry technique (Cary 50 Scan spectrophotometer, Varian, Sydney, Australia) at 353 nm. 2.3. Construction of pseudo-ternary phase diagrams The boundaries of the microemulsion domains in the triangular diagrams were determined by the water titration method. Mixtures of oil and surfactant/co-surfactant at certain weight ratios were progressively enriched in aliquots of purified water in a drop-wise manner. Each mixture was observed visually. The tendency to emulsify was judged good when droplets spread easily in water and formed a fine milky microemulsion. Phase diagrams were constructed using 1:0.5, 1:1, 1:2 and 1:3 (w/w) specific ratios of surfactant/cosurfactant. 2.4. Physicochemical characterization of microemulsions 2.4.1. Stability evaluation Stability of microemulsions with and without drug as a function of storage time was routinely evaluated by visual inspection of the samples on a daily basis over a period of 4 weeks. Stable systems were identified as those free of any physical change, such as phase separation, flocculation and/or precipitation. Stability was monitored at room temperature. 2.4.2. Determination of microemulsion viscosity A Rotovisco RV 20 viscometer (Haake, Karlsruhe, Germany) and a rheocontroller RC 20 with a M5 sensor system were used. Measurements were taken at shear rates from 0 to 700 s−1 at 20 °C using NV equipment. 2.4.3. Droplet size measurements A laser light scattering technique (Malvern Particle Size Analyzer Model No. 2000, Worcestershire, UK) was used to determine the droplet size of the initial microemulsion and after release from the pellets. In the case of the microemulsion, 1 ml of microemulsion was diluted with 200 ml of water and gently mixed before analysis. For pellets, about 2 g of solid-SEDDS was dispersed in 200 ml of simulated intestinal fluid and gently mixed. The resulting suspensions were
Solid-SEDDS were obtained using a lab-scale high shear mixer (Rotolab®, Zanchetta SpA, Lucca, Italy) comprising of a 2 l thermostated bowl equipped with an impeller (minimum 120 rpm, maximum 1200 rpm speed) and a chopper with a working speed of 3000 rpm. The apparatus also has a tilting system used to move the material during the drying or massing phases. A set of preliminary trials was conducted to select operating parameters and powder mixture compositions. The following conditions were then used: 200 g batches, composed of 70% MCC, 27% LAC and 3% (w/w) PVP, were dry-mixed using an impeller speed of 120 rpm for 10 min. Then 140 g of microemulsions containing PX was dropped onto dry powders using a 10 ml/min drop rate. At the end of the wetting phase, impeller speed was increased to 600 rpm for 2 min (“standard conditions”). In subsequent optimization experiments, the amount of PVP was increased by 1% and the impeller speed reduced by 200 rpm, according to the factorial experimental plan reported in Table 3. At the end of the granulation process, pellets were dried at 40 °C until constant weight was achieved. Dry granules were sieved in order to remove lumps larger than 3 mm and were stored in well-closed bags for 10 days before characterizations. 2.6. Granule characterizations 2.6.1. Sieve analysis For the size distribution analysis 100 g of pellets was poured over a set of sieves (2000, 1000, 800, 600, 500, 400, and 300 μm). A vibrating apparatus (Octagon 200, Endecotts, London, UK) was used at a medium vibration level for 20 min. The fractions were then collected and weighed. 2.6.2. Disintegration test of pellets The disintegration time of the pellets was evaluated in deionized water at 37 °C using a disintegration apparatus (FUI XII ed., Sotax DT2, Sotax, Allschwil, Switzerland) modified with a 100 μm wire net at the base of the tubes. Pellet samples of 200 mg from each formulation were tested (n = 6). The endpoint was taken as the time at which no obvious particles were present on the sieve in each disintegration basket. 2.6.3. Crushing strength of pellets For each batch, the crushing strength of 10 pellets (mean and standard deviation of the obtained results were calculated) was determined using a mod. TA-HDi Texture Analyzer (Stable Micro System, Surrey, UK) operating with a 250 kg load cell. The pellet was placed on the lower flat plate, and centred under the 6 mm diameter upper punch, which then moved downwards at a constant rate of 0.1 mm/s until 50% of the strain was reached. Force–time plots were recorded using the texture analyzer pc software (Texture Expert Exceed, Stable Micro System, Surrey, UK). 2.6.4. In vitro drug dissolution tests In vitro drug dissolution tests were performed using the USP 24 method with a dissolution apparatus 2 (Sotax AT7 Smart). The dissolution tests were carried out at 37 ± 0.5 °C in 900 ml of simulated intestinal fluid (SIF, phosphate buffer pH 6.8) at 100 rpm. Results are averaged from three-replicated experiments. During the release studies, 1 ml of SIF sample was withdrawn and PX quantification was performed using UV/Vis spectrophotometry (Cary 50 Scan spectrophotometer, Varian, Sydney, Australia). The withdrawn volume was replaced each time with fresh thermostated SIF.
E. Franceschinis et al. / Powder Technology 207 (2011) 113–118 Table 1 Mean solubility values of piroxicam in various vehicles at 25 °C (n = 3). Vehicles
PX solubility (mg/ml)
Lauroglycol™ 90 Labrafac™Lipophile WL1349 Labrasol® Cremophor® EL Transcutol®HP Labrafil®M 1944CS Deionised water SIF
2.73 ± 0.35 1.73 ± 0.12 1.53 ± 0.11 8.28 ± 0.71 14.50 ± 0.20 2.33 ± 0.08 0.01 ± 0.01 0.44 ± 0.03
3. Results and discussion Absorption of compounds with aqueous solubility lower than 0.1 mg/ml (class II molecule) is often limited by the low dissolution rate. In this case, oral bioavailability can be increased by improving the drug dissolution rate using lipid formulations such as solid-SEDDS. These systems can be produced by a wet granulation process using a microemulsion as the liquid binder. The most important criterion for the selection of the components of microemulsion is to select the
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formulations in which the highest solubility of drug can be achieved. Consequently, the solubility of piroxicam (water solubility of 0.0088 mg/ml), chosen as the model drug in this study, was tested in various vehicles and the results are reported in Table 1. Among the surfactants tested in this study, Cremophor® EL (a polyoxyl castor oil derivative surfactant with HLB 12-14) was selected as the surfactant because it allows the greatest drug solubility, and for its ability to enhance intestinal absorption of drugs and inhibit Pglycoprotein [14-16]. Lauroglycol™ 90 was selected as the oily phase since it permits higher drug solubility than Labrafac™ Lipophile WL1349 and has a good ability to form a microemulsion with Cremophor® EL. Finally, Transcutol® HP was selected as a solvent and co-surfactant because it is a good drug solvent resulting in improved drug loading. In addition, it leads to the formation of spontaneous fine microemulsion. Pseudoternary phase diagrams were constructed to visually determine the formation of microemulsions to be used as a fluid binder in granulation trials. Three components were employed: oily phase (Lauroglycol™ 90), mixture of surfactant and co-surfactant (Cremophor® EL and Transcutol® HP, respectively) and water phase. In particular, 4 pseudo-ternary phase diagrams were constructed with
Fig. 1. Pseudo-ternary phase diagrams using a Cremophor® EL/Transcutol® HP wt ratio of: a) 1:0.5; b) 1:1; c) 1:2 and d) 1:3.
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Table 2 Composition (w/w) of stable microemulsions containing piroxicam and results of relative characterizations (n = 3). Formulation
Cremophor®EL (%)
Lauroglycol™90 (%)
Transcutol®HP (%)
Water (%)
Amount of PX loaded (mg/g)a
Modal droplet size of empty ME (μm)
Modal droplet size of ME with PX (μm)
Viscosity (mPa*s)
A7 B6 B7 B8 C8 C9 D5 D8 D9
6.7 5 5 5 3.3 3.3 2.5 2.5 2.5
40 30 40 50 50 60 20 50 60
3.3 5 5 5 6.7 6.7 7.5 7.5 7.5
50 60 50 40 40 30 70 40 30
2.1 1.9 2.3 2.6 2.7 3.1 1.9 2.8 3.1
7.4 5.9 6.7 64.5 2.9 42.4 6.1 4.4 70.6
6.0 5.8 6.5 62.3 3.2 43.4 6.0 4.5 71.1
0.050 0.015 0.027 0.070 0.055 0.058 0.014 0.050 0.052
a
mg of PX loaded per g of microemulsion.
the following surfactant:co-surfactant weight ratios 1:0.5, 1:1, 1:2 and 1:3 (Fig. 1). The droplet size distribution of these systems was monomodal and the peak frequency value of the droplets ranged from 3 to 71 μm. These modal sizes confirm the formation of microemulsion systems. These droplet size values are very promising in terms of the possible in vivo behaviour of the formulations. In fact, such small oil droplets provide a large interfacial area for pancreatic lipase to hydrolyse triglycerides and thus promote greater drug release and/or formation of mixed micelles of the bile salts containing the drug. In addition, the microemulsion droplets lead to a greater and very uniform distribution of the drug in the gastrointestinal tract, minimizing irritation due to contact between the drug and gut wall. This is a key point in the case of gastro irritant drugs, such as PX. Moreover, a similar droplet size is also indicative of the potential of these systems in terms of stability. It is well known that a small droplet size of the oily phase provides a stable microemulsion [17]. Literature reports also suggest that drugs loaded in microemulsions and SEDDS may have some effect on stability and selfemulsifying performance [4]. Consequently, each stable microemulsion was prepared by adding PX. The amount of drug loaded is a function of the composition of each microemulsion and is calculated on the basis of PX solubility. The microemulsions containing PX were then observed visually. In this way, the number of stable microemulsions was reduced to nine and their composition is listed in Table 2. Droplets did not differ significantly from empty microemulsions (see Table 2). Stable microemulsions containing PX were then characterized by means of viscosity measurements and the results are reported in
Table 2. Since preliminary trials have demonstrated that microemulsions with a viscosity greater than 0.05 mPa*s cannot be homogeneously dispersed on the solid carrier in our apparatus, formulations B8, C8, C9 and D9 were discarded. Among the remaining microemulsions, formulations A7 and D8 were selected in consideration of their higher drug content (0.28 and 0.21, respectively), thus guaranteeing the development of a formulation with a small volume and high PX concentration. These two microemulsions were used to prepare solid-SEDDS according to “standard conditions”. Batches of 200 g, composed of 70% MCC, 27% LAC and 3% (w/w) PVP were dry-mixed using an impeller speed of 120 rpm for 10 min; 140 g of microemulsions containing PX was then dropped onto dry powders at 10 ml/min drop rate. At the end of the wetting phase, impeller speed was increased to 600 rpm for 2 min. At the end of the granulation procedure, the pellets were dried and sieved in order to evaluate mean diameter and particle size distribution. The 400, 600 and 800 μm pellet fractions for both formulations were characterized by a dissolution test performed in simulated intestinal fluid (SIF). The dissolution profiles obtained are shown in Figs. 2 and 3 and were used to derive the amount of PX released in 30 min (Table 3). In the same conditions the capability of both solidSEDDS to self-emulsify was also checked. The results, reported in Table 3, show that the droplet size of reconstituted microemulsions is analogous to, or even less than, initial microemulsions. Further, the dissolution results provide evidence of the benefits of microemulsion systems since both the D8 and A7 formulations showed a remarkably faster drug release performance than pure drug. These results may be explained in several ways: first, the small dimensions (less than 3.5 μm each) of the oil droplets provide a large
Fig. 2. Effect of particle size fraction on the dissolution profile of PX. Drug released from A7 pellets as a function of time for 400 μm (■), 600 μm (○) and 800 μm (●) size fractions compared to pure drug (□).
Fig. 3. Effect of particle size fraction on the dissolution profile of PX. Drug released from D8 pellets as a function of time for 400 μm (■), 600 μm (○) and 800 μm (●) size fractions compared to pure drug (□).
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Table 3 Characterization results of different size fractions of the 2 selected pellet formulations (mean ± S.D.). Formulation
Particle size fraction (μm)
t50% (min)
Amount of PX released in 30 min (%) (n = 3)
Disintegration time (min) (n = 6)
Crushing strength (kg) (n = 10)
Droplet modal size (μm)a (n = 3)
A7
800 600 400 800 600 400
4.1 ± 0.7 3.2 ± 0.2 2.2 ± 0.3 3.3 ± 0.7 2.2 ± 0.4 2.2 ± 0.6
83.3 ± 3 90.7 ± 2.7 98.6 ± 1.9 74 ± 3.5 78.3 ± 1.5 84.1 ± 3
6.5 ± 1.27 5.3 ± 0.98 4.2 ± 1.34 3.8 ± 1.02 2.9 ± 0.78 1.1 ± 0.30
75.793 ± 7.158 69.161 ± 7.034 54.601 ± 7.826 71.534 ± 6.202 65.379 ± 5.485 53.855 ± 8.370
0.65 ± 0.08
D8
a
3.50 ± 0.25
Droplets released from pellets in the same medium (SIF) used for dissolution tests.
specific surface area in contact with the dissolution medium. Second, the drug is in a molecularly dispersed state that is released more easily than the original solid drug. Therefore, a further explanation regarding the dissolution enhancement compared with the pure drug can be added, that is, the ability to enhance drug wettability and solubility and dissolution of the surfactant. Different features were attained from various pellet size fractions of the two formulations. As expected, the fastest release rate was obtained from the smallest diameter pellets (400 μm), which also have less crushing strength and faster disintegration times (Table 3). Of the two formulations, A7 provided a higher amount of PX released in all cases. This can be explained on the basis of the composition of the initial microemulsions that contain the highest amount of Cremophor® EL. This amount appears to be necessary to achieve the almost complete release of the drug. Further, oil droplets released from A7 solid-SEDDS, are the smallest and hence produce the largest superficial area. It can be concluded that 400 μm pellet size fraction A7 was the best performing in terms of dissolution. However, this fraction represented only 6.7% by weight of the A7 pellets as reported in Fig. 4A. Consequently, the yield of this fraction was improved in the next step modifying formulation and process parameters. In particular, on the basis of preliminary trials and our
experience, the amount of PVP was increased to 4% and the impeller speed during massing time was reduced to 400 rpm following a factorial design (Table 4). The effects of PVP percentage and impeller speed on mean diameter are reported in Fig. 4. A higher amount of 400 μm of the size fraction (42.5%) as well as a narrow particle size distribution was obtained by using a 3% PVP and 400 rpm impeller speed (Fig. 4C). This behaviour may be due to part of the liquid being squeezed out to the pellet surface at high impeller speeds [18,19]. This liquid is available for binding other particles. Consequently, higher impeller speeds produce larger diameters (Fig. 4A,B). As for the PVP effect, an increase in the content leads to an increase in the particle size (Fig. 4B,D). In fact, PVP exhibits a pronounced hydration capacity with a tendency to form gels [20]. When it is present at higher percentages, it therefore increases the viscosity of the solution used as a binder. In these conditions, the distribution of microemulsions on a powder is difficult, and a very hard, unbreakable mass may be produced with the consequence of an increased particle size. All the pellets underwent a dissolution test in order to verify the impeller speed and influence of PVP quantity on dissolution performances. The data reported in Table 4 demonstrate that the two variables have no significant influence (p = 0.05) on t50% and amount of PX released in 30 min.
Fig. 4. Graph-mode representation of the effect of the amount of PVP and impeller speed on particle size distribution of pellets produced using emulsion A7 as the liquid binder.
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Table 4 Characteristics of pellets produced using formulation A7 as binder and different experimental conditions (mean ± S.D.; n = 3). Experiment
Impeller speed (rpm)
Amount of PVP (%)
Yield of 400 μm size fraction (% by wt.)
t50% (min)
Amount of PX released in 30 min (%)
A B C D
600 600 400 400
3 4 3 4
6.7 5.1 42.5 12.1
2.2 ± 0.3 3.3 ± 0.3 2.7 ± 0.5 2.6 ± 0.3
98.6 ± 1.9 94.6 ± 2.0 96.3 ± 3.7 97.1 ± 2.0
4. Conclusions The results show that the correct selection of microemulsion is a key factor in the preparation of self-emulsifying pellets in a high shear mixer, in order to be able to tailor appropriately the stability and amount of drug loaded and, in particular, to ascertain a suitable fluid binder and to obtain final pellets with the desired drug release characteristics. Once the pellet formulation matching all these requirements is defined, the best performing pellet size fraction can be optimized in terms of yield through the appropriate selection of formulation and process parameters of the high shear granulation. In this investigation, the preparation of solid-SEDDS in a high shear wet granulator has been optimized by setting the experimental variables, thereby obtaining a viable drug delivery system for increasing the dissolution rate of class II molecules. On-going studies are aimed at confirming the in vitro dissolution enhancement with in vivo studies on animal models. References [1] A.J. Humberstone, W.N. Charman, Lipid-based vehicles for the oral delivery of poorly water soluble drugs, Adv. Drug Deliv. Rev. 25 (1997) 103–128. [2] C.J.H. Porter, C.W. Pouton, J.F. Cuine, W.N. Charman, Enhancing intestinal drug solubilization using liquid-based delivery systems, Adv. Drug Deliv. Rev. 60 (2008) 673–691. [3] P.P. Costantinides, Lipid micromicroemulsions for improving drug dissolution and oral absorption: physical and biopharmaceutical aspects, Pharm. Res. 12 (1995) 1561–1569. [4] B.G. Prajapati, M. Patel, Conventional and alternative methods to improve oral bioavailability of lipophilic drugs, Asian J. Pharm. 1 (2007) 1–8. [5] C.W. Pouton, Lipid formulations for oral administration of drugs: non-emulsifying, self-emulsifying and self-microemulsifying drug delivery systems, Eur. J. Pharm. Sci. S2 (2000) S93–S98. [6] E. Atef, A.A. Belmonte, Formulation and in vitro and in vivo characterization of a phenytoin self-emulsifying delivery system (SEDDS), Eur. J. Pharm. Sci. 35 (2008) 257–263.
[7] P. Balakrishnan, B.J. Lee, D.H. Oh, J.O. Kim, M.J. Hong, J.-P. Jee, J.A. Kim, B.K. Yoo, J.S. Woo, C.S. Yong, H.G. Choi, Enhanced oral bioavailability of dexibuprofen by a novel solid self-emulsifying drug delivery systems (SEDDS), Eur. J. Pharm. Biopharm. 72 (2009) 539–545. [8] B. Tang, G. Cheng, J.C. Gu, C.H. Xu, Development of solid self-emulsifying drug delivery systems: preparation techniques and dosage forms, Drug Discov. Today 13 (2008) 606–612. [9] G.L. Amidon, H. Lennernas, V.P. Shah, J.R. Crison, A theoretical basis for a biopharmaceutic drug classification: the correlation of the in vivo drug product dissolution and in vivo bioavailability, Pharm. Res. 3 (1995) 413–420. [10] A. Karataş, N. Yüksel, T. Baykara, Improved solubility and dissolution rate of piroxicam using gelucire 44/14 and labrasol, Farmaco 60 (2005) 777–782. [11] H. Validadeh, P. Zakeri-Milani, M. Baregar-Jalali, G. Mohammadi, M.A. DaneshBahreini, K. Adidkia, A. Nokhodchi, Preparation and characterization of solid dispersions of piroxicam with hydrophilic carriers, Drug Dev. Ind. Pharm. 33 (2007) 45–46. [12] V. Tantishaiyakul, N. Kaewnopparat, S. Ingkatawornwong, Properties of solid dipersions of piroxicam in polyvinylpyrrolidone, Int. J. Pharm. 181 (1999) 143–151. [13] K. Wu, J. Li, W. Wang, D.A. Winstead, Formation and characterization of solid dispersions of piroxicam and polyvinylpyrrolidone using spray drying and precipitation with compressed antisolvent, J. Pharm. Sci. 7 (2009) 982422–982431. [14] B.D. Rege, J.P.Y. Kao, J.E. Polli, Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers, Eur. J. Pharm. Sci. 12 (2002) 237–246. [15] Z. Ge, X.X. Zhan, L. Gan, Y. Gan, Redispersible, dry microemulsion of lovastatin protects against intestinal metabolism and improves bioavailability, Acta Pharmacol. Sin. 8 (2008) 990–997. [16] C.M. O'Driscoll, B.T. Griffin, Biopharmaceutical challenges associated with drugs with aqueous solubility. The potential impact of liquid based formulations, Adv. Drug Deliv. Rev. 60 (2008) 617–624. [17] F. Serdoz, D. Voinovich, B. Perissutti, L. Magarotto, F. Carli, Design, development and bioavailability assessment of oxytetracycline hydrochloride double O/W/O micromicroemulsion formulation, J. Drug Deliv. Sci. Technol. 18 (2008) 404–409. [18] M. Balaxi, I. Nikolakakis, K. Kachrimanis, S. Malamataris, Combined effects of wetting, drying and microcrystalline cellulose type on the mechanical strength and disintegration of pellets, J. Pharm. Sci. 98 (2009) 676–689. [19] J.M. Newton, Microcrystalline cellulose as a molecular sponge as an alternative concept to the crystallite-gel model for extrusion and spheronization, Pharm. Res. 4 (1998) 509–512. [20] R. Rowe, P.J. Sheskey, S.C. Owen, Handbook of Pharmaceutical Excipients, fifth edition, Pharmaceutical Press, London, 2006, p. 214.
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Powder Technology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / p ow t e c
Self-emulsifying pellets in a lab-scale high shear mixer: Formulation and production design E. Franceschinis a,⁎, C. Bortoletto a, B. Perissutti b, M. Dal Zotto a, D. Voinovich b, N. Realdon a a b
Department of Pharmaceutical Sciences, University of Padua, Via Marzolo 5, 35131 Padua, Italy Department of Pharmaceutical Sciences, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy
a r t i c l e
i n f o
Article history: Received 11 May 2010 Received in revised form 30 September 2010 Accepted 16 October 2010 Available online 25 October 2010 Keywords: High shear wet granulation Piroxicam Self-emulsifying drug delivery system Process optimization
a b s t r a c t In this investigation, the preparation of solid self-emulsifying drug delivery systems (solid-SEDDS) by means of a wet granulation process was optimized in a lab-scale high shear mixer in order to improve the dissolution rate of piroxicam, a poorly water-soluble model drug. With this aim, the classic liquid granulation binder was replaced with an oil-in-water microemulsion, loaded with the drug. The microemulsion formulations were first selected on the basis of phase diagrams and their physicochemical properties, such as viscosity and droplet size. The best microemulsions were then used to prepare solid-SEDDS while maintaining the composition of the solid carrier and the operating conditions of the lab-scale high shear mixer used in this study. These pellets demonstrated an emulsifying capability and their piroxicam release was significantly enhanced with respect to pure drug. Since their dissolution was a function of pellet size fraction, in the subsequent step the yield of the best performing fraction was further increased by modifying experimental conditions for pellet production (impeller speed and amount of povidone). In this way, the 400 μm pellet size fraction of the selected formulation was produced with a percentage yield of 42.5 by wt., with satisfactory technological properties and unchanged drug dissolution performance. © 2010 Elsevier B.V. All rights reserved.
1. Introduction Self-emulsifying drug delivery systems (SEDDS) are lipid-based formulations [1] and are defined as isotropic mixtures of natural or synthetic oils, surfactants and/or co-surfactants, which form microemulsion droplets on dilution with physiological fluid. They are able to spread readily in the gastrointestinal (GI) tract, where the digestive motility of the stomach and intestine provides the agitation necessary for self-emulsification. The self-emulsification process is specific to the nature of the oil/ surfactant pair, surfactant concentration, oil/surfactant ratio and temperature at which self-emulsification occurs. Some parameters have been proposed to characterize the self-emulsifying performance; these include rate of emulsification, microemulsion size distribution and the charge of resulting droplets. Among them, microemulsion droplet size is considered a decisive factor in self-emulsification/ dispersion performance since it determines the rate and extent of drug release and absorption. The key step for SEDDS formulation is to find a suitable oil surfactant mixture that can dissolve the drug within
⁎ Corresponding author. Tel.: +39 049 8275339; fax: +39 049 8275366. E-mail address: [email protected] (E. Franceschinis). 0032-5910/$ – see front matter © 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.powtec.2010.10.016
the required therapeutic concentration. Liquid SEDDS can then be used to fill either soft or hard gelatin capsules [2,3]. The drawback of this system includes GI tract irritation due to high surfactant concentrations, high manufacturing costs, interaction of the fill with the capsule shell, as well as problems due to storage temperature [4,5]. These inconveniences can be avoided by preparing solid self-emulsifying drug delivery systems (solid-SEDDS). Such systems require the solidification of SEDDS into powder/nanoparticles to create various solid dosage forms. Solid-SEDDS combine the advantages of solid dosage forms (e.g. low production costs, high stability and reproducibility) with those of SEDDS (i.e. enhanced solubility and bioavailability) [6–8]. According to the Biopharmaceutic Drug Classification System (BCS) proposed by Amidon et al. [9], piroxicam, chosen as the model drug, is a class II molecule and its dissolution is the ratecontrolling step in vivo drug absorption. Several techniques have been used to improve the oral bioavailability of piroxicam by accelerating its dissolution rate. These include mainly solid dispersion techniques based on cyclodextrin inclusion complexes, polyvinylpyrrolidone, and polyethylene glycols 4000 and 6000 [10–13]. The aim of this study was to prepare solid-SEDDS by the high shear wet granulation process using a microemulsion as a liquid binder in order to increase the dissolution rate of piroxicam. Further experiments have been conducted with the purpose of optimizing the formulation of a solid carrier and experimental conditions.
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2. Materials and methods
analyzed after filtration. The results are averaged from three-replicated experiments.
2.1. Materials 2.5. Preparation of solid self-emulsifying systems (solid-SEDDS) Piroxicam (PX) EP-grade was provided by FIS (Vicenza, Italy). Propylene glycol-monolaurate (Lauroglycol™ 90), Diethylene glycol monoethyl ether (Transcutol® HP), medium chain triglycerides (Labrafac™ Lipophile WL1349), oleoyl macrogolglycerides (Labrafil® M1944 CS®) and caprylocaproyl macrogolglycerides (Labrasol®) were obtained from Gattefossé (Saint-Priest, France). Polyoxyl-35castor oil (Cremophor® EL) was supplied by BASF (Ludwigshafen, Germany) and Monohydrate Lactose (LAC) by Meggle (Wasserburg, Germany). Microcrystalline Cellulose (MCC) and Polyvinylpyrrolidone K 90 (PVP) were purchased from ACEF (Fiorenziuola D'Arda, Italy). All other chemicals and solvents were of analytical grade and were used without further purification. 2.2. Solubility study Piroxicam solubility was determined in various oils, surfactants and co-surfactants by pouring an excess of drug into 5 ml glass vials containing 2 g of different vehicles. Mixtures were mixed continuously for 24 h (previously determined to be adequate time for equilibration) at 25 °C in a thermostated water bath and then centrifuged at 5000 g for 10 min to separate the undissolved drug. Aliquots of supernatant were diluted with methanol and the PX content was quantified by the UV–VIS spectrophotometry technique (Cary 50 Scan spectrophotometer, Varian, Sydney, Australia) at 353 nm. 2.3. Construction of pseudo-ternary phase diagrams The boundaries of the microemulsion domains in the triangular diagrams were determined by the water titration method. Mixtures of oil and surfactant/co-surfactant at certain weight ratios were progressively enriched in aliquots of purified water in a drop-wise manner. Each mixture was observed visually. The tendency to emulsify was judged good when droplets spread easily in water and formed a fine milky microemulsion. Phase diagrams were constructed using 1:0.5, 1:1, 1:2 and 1:3 (w/w) specific ratios of surfactant/cosurfactant. 2.4. Physicochemical characterization of microemulsions 2.4.1. Stability evaluation Stability of microemulsions with and without drug as a function of storage time was routinely evaluated by visual inspection of the samples on a daily basis over a period of 4 weeks. Stable systems were identified as those free of any physical change, such as phase separation, flocculation and/or precipitation. Stability was monitored at room temperature. 2.4.2. Determination of microemulsion viscosity A Rotovisco RV 20 viscometer (Haake, Karlsruhe, Germany) and a rheocontroller RC 20 with a M5 sensor system were used. Measurements were taken at shear rates from 0 to 700 s−1 at 20 °C using NV equipment. 2.4.3. Droplet size measurements A laser light scattering technique (Malvern Particle Size Analyzer Model No. 2000, Worcestershire, UK) was used to determine the droplet size of the initial microemulsion and after release from the pellets. In the case of the microemulsion, 1 ml of microemulsion was diluted with 200 ml of water and gently mixed before analysis. For pellets, about 2 g of solid-SEDDS was dispersed in 200 ml of simulated intestinal fluid and gently mixed. The resulting suspensions were
Solid-SEDDS were obtained using a lab-scale high shear mixer (Rotolab®, Zanchetta SpA, Lucca, Italy) comprising of a 2 l thermostated bowl equipped with an impeller (minimum 120 rpm, maximum 1200 rpm speed) and a chopper with a working speed of 3000 rpm. The apparatus also has a tilting system used to move the material during the drying or massing phases. A set of preliminary trials was conducted to select operating parameters and powder mixture compositions. The following conditions were then used: 200 g batches, composed of 70% MCC, 27% LAC and 3% (w/w) PVP, were dry-mixed using an impeller speed of 120 rpm for 10 min. Then 140 g of microemulsions containing PX was dropped onto dry powders using a 10 ml/min drop rate. At the end of the wetting phase, impeller speed was increased to 600 rpm for 2 min (“standard conditions”). In subsequent optimization experiments, the amount of PVP was increased by 1% and the impeller speed reduced by 200 rpm, according to the factorial experimental plan reported in Table 3. At the end of the granulation process, pellets were dried at 40 °C until constant weight was achieved. Dry granules were sieved in order to remove lumps larger than 3 mm and were stored in well-closed bags for 10 days before characterizations. 2.6. Granule characterizations 2.6.1. Sieve analysis For the size distribution analysis 100 g of pellets was poured over a set of sieves (2000, 1000, 800, 600, 500, 400, and 300 μm). A vibrating apparatus (Octagon 200, Endecotts, London, UK) was used at a medium vibration level for 20 min. The fractions were then collected and weighed. 2.6.2. Disintegration test of pellets The disintegration time of the pellets was evaluated in deionized water at 37 °C using a disintegration apparatus (FUI XII ed., Sotax DT2, Sotax, Allschwil, Switzerland) modified with a 100 μm wire net at the base of the tubes. Pellet samples of 200 mg from each formulation were tested (n = 6). The endpoint was taken as the time at which no obvious particles were present on the sieve in each disintegration basket. 2.6.3. Crushing strength of pellets For each batch, the crushing strength of 10 pellets (mean and standard deviation of the obtained results were calculated) was determined using a mod. TA-HDi Texture Analyzer (Stable Micro System, Surrey, UK) operating with a 250 kg load cell. The pellet was placed on the lower flat plate, and centred under the 6 mm diameter upper punch, which then moved downwards at a constant rate of 0.1 mm/s until 50% of the strain was reached. Force–time plots were recorded using the texture analyzer pc software (Texture Expert Exceed, Stable Micro System, Surrey, UK). 2.6.4. In vitro drug dissolution tests In vitro drug dissolution tests were performed using the USP 24 method with a dissolution apparatus 2 (Sotax AT7 Smart). The dissolution tests were carried out at 37 ± 0.5 °C in 900 ml of simulated intestinal fluid (SIF, phosphate buffer pH 6.8) at 100 rpm. Results are averaged from three-replicated experiments. During the release studies, 1 ml of SIF sample was withdrawn and PX quantification was performed using UV/Vis spectrophotometry (Cary 50 Scan spectrophotometer, Varian, Sydney, Australia). The withdrawn volume was replaced each time with fresh thermostated SIF.
E. Franceschinis et al. / Powder Technology 207 (2011) 113–118 Table 1 Mean solubility values of piroxicam in various vehicles at 25 °C (n = 3). Vehicles
PX solubility (mg/ml)
Lauroglycol™ 90 Labrafac™Lipophile WL1349 Labrasol® Cremophor® EL Transcutol®HP Labrafil®M 1944CS Deionised water SIF
2.73 ± 0.35 1.73 ± 0.12 1.53 ± 0.11 8.28 ± 0.71 14.50 ± 0.20 2.33 ± 0.08 0.01 ± 0.01 0.44 ± 0.03
3. Results and discussion Absorption of compounds with aqueous solubility lower than 0.1 mg/ml (class II molecule) is often limited by the low dissolution rate. In this case, oral bioavailability can be increased by improving the drug dissolution rate using lipid formulations such as solid-SEDDS. These systems can be produced by a wet granulation process using a microemulsion as the liquid binder. The most important criterion for the selection of the components of microemulsion is to select the
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formulations in which the highest solubility of drug can be achieved. Consequently, the solubility of piroxicam (water solubility of 0.0088 mg/ml), chosen as the model drug in this study, was tested in various vehicles and the results are reported in Table 1. Among the surfactants tested in this study, Cremophor® EL (a polyoxyl castor oil derivative surfactant with HLB 12-14) was selected as the surfactant because it allows the greatest drug solubility, and for its ability to enhance intestinal absorption of drugs and inhibit Pglycoprotein [14-16]. Lauroglycol™ 90 was selected as the oily phase since it permits higher drug solubility than Labrafac™ Lipophile WL1349 and has a good ability to form a microemulsion with Cremophor® EL. Finally, Transcutol® HP was selected as a solvent and co-surfactant because it is a good drug solvent resulting in improved drug loading. In addition, it leads to the formation of spontaneous fine microemulsion. Pseudoternary phase diagrams were constructed to visually determine the formation of microemulsions to be used as a fluid binder in granulation trials. Three components were employed: oily phase (Lauroglycol™ 90), mixture of surfactant and co-surfactant (Cremophor® EL and Transcutol® HP, respectively) and water phase. In particular, 4 pseudo-ternary phase diagrams were constructed with
Fig. 1. Pseudo-ternary phase diagrams using a Cremophor® EL/Transcutol® HP wt ratio of: a) 1:0.5; b) 1:1; c) 1:2 and d) 1:3.
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Table 2 Composition (w/w) of stable microemulsions containing piroxicam and results of relative characterizations (n = 3). Formulation
Cremophor®EL (%)
Lauroglycol™90 (%)
Transcutol®HP (%)
Water (%)
Amount of PX loaded (mg/g)a
Modal droplet size of empty ME (μm)
Modal droplet size of ME with PX (μm)
Viscosity (mPa*s)
A7 B6 B7 B8 C8 C9 D5 D8 D9
6.7 5 5 5 3.3 3.3 2.5 2.5 2.5
40 30 40 50 50 60 20 50 60
3.3 5 5 5 6.7 6.7 7.5 7.5 7.5
50 60 50 40 40 30 70 40 30
2.1 1.9 2.3 2.6 2.7 3.1 1.9 2.8 3.1
7.4 5.9 6.7 64.5 2.9 42.4 6.1 4.4 70.6
6.0 5.8 6.5 62.3 3.2 43.4 6.0 4.5 71.1
0.050 0.015 0.027 0.070 0.055 0.058 0.014 0.050 0.052
a
mg of PX loaded per g of microemulsion.
the following surfactant:co-surfactant weight ratios 1:0.5, 1:1, 1:2 and 1:3 (Fig. 1). The droplet size distribution of these systems was monomodal and the peak frequency value of the droplets ranged from 3 to 71 μm. These modal sizes confirm the formation of microemulsion systems. These droplet size values are very promising in terms of the possible in vivo behaviour of the formulations. In fact, such small oil droplets provide a large interfacial area for pancreatic lipase to hydrolyse triglycerides and thus promote greater drug release and/or formation of mixed micelles of the bile salts containing the drug. In addition, the microemulsion droplets lead to a greater and very uniform distribution of the drug in the gastrointestinal tract, minimizing irritation due to contact between the drug and gut wall. This is a key point in the case of gastro irritant drugs, such as PX. Moreover, a similar droplet size is also indicative of the potential of these systems in terms of stability. It is well known that a small droplet size of the oily phase provides a stable microemulsion [17]. Literature reports also suggest that drugs loaded in microemulsions and SEDDS may have some effect on stability and selfemulsifying performance [4]. Consequently, each stable microemulsion was prepared by adding PX. The amount of drug loaded is a function of the composition of each microemulsion and is calculated on the basis of PX solubility. The microemulsions containing PX were then observed visually. In this way, the number of stable microemulsions was reduced to nine and their composition is listed in Table 2. Droplets did not differ significantly from empty microemulsions (see Table 2). Stable microemulsions containing PX were then characterized by means of viscosity measurements and the results are reported in
Table 2. Since preliminary trials have demonstrated that microemulsions with a viscosity greater than 0.05 mPa*s cannot be homogeneously dispersed on the solid carrier in our apparatus, formulations B8, C8, C9 and D9 were discarded. Among the remaining microemulsions, formulations A7 and D8 were selected in consideration of their higher drug content (0.28 and 0.21, respectively), thus guaranteeing the development of a formulation with a small volume and high PX concentration. These two microemulsions were used to prepare solid-SEDDS according to “standard conditions”. Batches of 200 g, composed of 70% MCC, 27% LAC and 3% (w/w) PVP were dry-mixed using an impeller speed of 120 rpm for 10 min; 140 g of microemulsions containing PX was then dropped onto dry powders at 10 ml/min drop rate. At the end of the wetting phase, impeller speed was increased to 600 rpm for 2 min. At the end of the granulation procedure, the pellets were dried and sieved in order to evaluate mean diameter and particle size distribution. The 400, 600 and 800 μm pellet fractions for both formulations were characterized by a dissolution test performed in simulated intestinal fluid (SIF). The dissolution profiles obtained are shown in Figs. 2 and 3 and were used to derive the amount of PX released in 30 min (Table 3). In the same conditions the capability of both solidSEDDS to self-emulsify was also checked. The results, reported in Table 3, show that the droplet size of reconstituted microemulsions is analogous to, or even less than, initial microemulsions. Further, the dissolution results provide evidence of the benefits of microemulsion systems since both the D8 and A7 formulations showed a remarkably faster drug release performance than pure drug. These results may be explained in several ways: first, the small dimensions (less than 3.5 μm each) of the oil droplets provide a large
Fig. 2. Effect of particle size fraction on the dissolution profile of PX. Drug released from A7 pellets as a function of time for 400 μm (■), 600 μm (○) and 800 μm (●) size fractions compared to pure drug (□).
Fig. 3. Effect of particle size fraction on the dissolution profile of PX. Drug released from D8 pellets as a function of time for 400 μm (■), 600 μm (○) and 800 μm (●) size fractions compared to pure drug (□).
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Table 3 Characterization results of different size fractions of the 2 selected pellet formulations (mean ± S.D.). Formulation
Particle size fraction (μm)
t50% (min)
Amount of PX released in 30 min (%) (n = 3)
Disintegration time (min) (n = 6)
Crushing strength (kg) (n = 10)
Droplet modal size (μm)a (n = 3)
A7
800 600 400 800 600 400
4.1 ± 0.7 3.2 ± 0.2 2.2 ± 0.3 3.3 ± 0.7 2.2 ± 0.4 2.2 ± 0.6
83.3 ± 3 90.7 ± 2.7 98.6 ± 1.9 74 ± 3.5 78.3 ± 1.5 84.1 ± 3
6.5 ± 1.27 5.3 ± 0.98 4.2 ± 1.34 3.8 ± 1.02 2.9 ± 0.78 1.1 ± 0.30
75.793 ± 7.158 69.161 ± 7.034 54.601 ± 7.826 71.534 ± 6.202 65.379 ± 5.485 53.855 ± 8.370
0.65 ± 0.08
D8
a
3.50 ± 0.25
Droplets released from pellets in the same medium (SIF) used for dissolution tests.
specific surface area in contact with the dissolution medium. Second, the drug is in a molecularly dispersed state that is released more easily than the original solid drug. Therefore, a further explanation regarding the dissolution enhancement compared with the pure drug can be added, that is, the ability to enhance drug wettability and solubility and dissolution of the surfactant. Different features were attained from various pellet size fractions of the two formulations. As expected, the fastest release rate was obtained from the smallest diameter pellets (400 μm), which also have less crushing strength and faster disintegration times (Table 3). Of the two formulations, A7 provided a higher amount of PX released in all cases. This can be explained on the basis of the composition of the initial microemulsions that contain the highest amount of Cremophor® EL. This amount appears to be necessary to achieve the almost complete release of the drug. Further, oil droplets released from A7 solid-SEDDS, are the smallest and hence produce the largest superficial area. It can be concluded that 400 μm pellet size fraction A7 was the best performing in terms of dissolution. However, this fraction represented only 6.7% by weight of the A7 pellets as reported in Fig. 4A. Consequently, the yield of this fraction was improved in the next step modifying formulation and process parameters. In particular, on the basis of preliminary trials and our
experience, the amount of PVP was increased to 4% and the impeller speed during massing time was reduced to 400 rpm following a factorial design (Table 4). The effects of PVP percentage and impeller speed on mean diameter are reported in Fig. 4. A higher amount of 400 μm of the size fraction (42.5%) as well as a narrow particle size distribution was obtained by using a 3% PVP and 400 rpm impeller speed (Fig. 4C). This behaviour may be due to part of the liquid being squeezed out to the pellet surface at high impeller speeds [18,19]. This liquid is available for binding other particles. Consequently, higher impeller speeds produce larger diameters (Fig. 4A,B). As for the PVP effect, an increase in the content leads to an increase in the particle size (Fig. 4B,D). In fact, PVP exhibits a pronounced hydration capacity with a tendency to form gels [20]. When it is present at higher percentages, it therefore increases the viscosity of the solution used as a binder. In these conditions, the distribution of microemulsions on a powder is difficult, and a very hard, unbreakable mass may be produced with the consequence of an increased particle size. All the pellets underwent a dissolution test in order to verify the impeller speed and influence of PVP quantity on dissolution performances. The data reported in Table 4 demonstrate that the two variables have no significant influence (p = 0.05) on t50% and amount of PX released in 30 min.
Fig. 4. Graph-mode representation of the effect of the amount of PVP and impeller speed on particle size distribution of pellets produced using emulsion A7 as the liquid binder.
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Table 4 Characteristics of pellets produced using formulation A7 as binder and different experimental conditions (mean ± S.D.; n = 3). Experiment
Impeller speed (rpm)
Amount of PVP (%)
Yield of 400 μm size fraction (% by wt.)
t50% (min)
Amount of PX released in 30 min (%)
A B C D
600 600 400 400
3 4 3 4
6.7 5.1 42.5 12.1
2.2 ± 0.3 3.3 ± 0.3 2.7 ± 0.5 2.6 ± 0.3
98.6 ± 1.9 94.6 ± 2.0 96.3 ± 3.7 97.1 ± 2.0
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