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1.  Influence of degree of polymerization on behavior of cellulose during homogenization and extrusion/spheronization 
AAPS PharmSci  2000;2(3):18-27.
The study objective was to investigate the influence of the degree of polymerization (DP) of cellulose materials (microcrystalline cellulose [MCC] and powder cellulose [PC]) on the behavior of these materials during homogenization and extrusion/spheronization processes. Suspensions of the cellulose types with different DP values were homogenized using a high-pressure homogenizer. The particle size, agglomeration index, and apparent viscosity of these suspensions was determined at different times after pouring. Additionally, these different cellulose types were processed into pellets using the extrusion/spheronization, method, and the water content and power consumption as a function of the DP were determined. Cellulose types with a high DP value showed greater particle size after homogenization, than the types with a low DP value. In contrast, no relevant relationship between the apparent viscosity and DP could be observed. During the extrusion process, water content in the extrudate and pellet porosity were increased as the DP was increased for the extrudates produced at the same level of power consumption. MCC types with various DPs compared with PC provided a novel way of understanding the role of cellulose in the extrusion process. The DP showed a remarkable influence on the physicochemical properties of the cellulose materials and, consequently, on the behavior of these materials during the extrusion/spheronization process. It is postulated that the sponge model is more appropriate for the cellulose type with high DP (PC), whereas the gel model is more applicable to cellulose types with lower DP (MCC).
doi:10.1208/ps020321
PMCID: PMC2761132  PMID: 11741237
2.  Influence of Starting Material Particle Size on Pellet Surface Roughness 
AAPS PharmSciTech  2013;15(1):131-139.
The purpose of this study was to investigate the effect of pelletization aids, i.e., microcrystalline cellulose (MCC) and cross-linked polyvinyl pyrrolidone (XPVP), and filler, i.e., lactose, particle size on the surface roughness of pellets. Pellets were prepared from powder blends containing pelletization aid/lactose in 1:3 ratio by extrusion–spheronization. Surface roughness of pellets was assessed quantitatively and qualitatively using optical interferometry and scanning electron microscopy, respectively. Both quantitative and qualitative surface studies showed that surface roughness of pellets depended on the particle size of XPVP and lactose used in the formulation. Increase in XPVP or lactose particle size resulted in rougher pellets. Formulations containing MCC produced pellets with smoother surfaces than those containing XPVP. Furthermore, surface roughness of the resultant pellets did not appear to depend on MCC particle size. Starting material particle size was found to be a critical factor for determining the surface roughness of pellets produced by extrusion–spheronization. Smaller particles can pack well with lower peaks and valleys, resulting in pellets with smoother surfaces. Similar surface roughness of pellets containing different MCC grades could be due to the deaggregation of MCC particles into smaller subunits with more or less similar sizes during wet processing. Hence, for starting materials that deaggregate during the wet processing, pellet surface roughness is influenced by the particle size of the material upon deaggregation.
doi:10.1208/s12249-013-0031-5
PMCID: PMC3909175  PMID: 24198222
extrusion–spheronization; filler; particle size; pelletization aid; surface roughness
3.  Extrusion/spheronization of pectin-based formulations. I. Screening of important factors 
AAPS PharmSciTech  2001;2(4):54-62.
This study investigated the possibility of producing pectin-based pellets by extrusion/spheronization. The study also identified factors influencing the process and the characteristics of the resulting product. Three types of pectin with different degrees of amid and methoxyl substitution were studied in combination with different granulation liquids (water, calcium chloride, citric acid, and ethanol) and/or microcrystalline cellulose. Pellets were prepared in a power-consumption-controlled, twinscrew extruder; then they were spheronized and dried. The products were characterized by image analysis, sieving analysis, and disintegration and dissolution tests. The results were evaluated by multivariate analysis. Different additives, either in the granulation liquid or in the powder mixture, influenced the ability of the extruded mass to form pellets (the processability) with this technique. However, the various pectin types responded to modifications to a different extent. Short, nearly spherical pellets are obtained with granulation liquids, such as ethanol, that reduce the swelling ability of pectin. Pellets produced with ethanol are, however, mechanically weak and tend to ditintegrate. Pectin molecules with a high degree of free carboxylic acid groups seem to be more sensitive to changes in the granulation liquid. Addition of microcrystalline cellulose as an extrusion aid generally resulted in improvements in shape and size. It was demonstrated that the processability of pectin as well as the characteristics of the products can be influenced in different ways during the process (eg, adding substances to the granulation liquid or to the powder mixture).
doi:10.1007/BF02830566
PMCID: PMC2784841  PMID: 14727863
Pectin; Pellets; Extrusion; Spheronization; Multivariate analysis
4.  Use of fine particle ethylcellulose as the diluent in the production of pellets by extrusion-spheronization 
The effect of small ethylcellulose particle size on the manufacture and properties of pellets produced by extrusion-spheronization was investigated. A factorial design revealed the effects of microcrystalline cellulose (MCC), polyethylene oxide (PEO), water, and spheronization speed and time on pellet properties. Response surface modeling allowed optimization of the responses with expansion to a central composite design. Pellet yield, size, shape, friability and drug release profile were studied, along with surface and interior morphology. Pellets were spherical irrespective of the formulation and process variables and exhibited physical and mechanical characteristics appropriate for further processing. Yield in the 12/20 mesh cut was lower with FPEC than observed with coarse particle ethylcellulose (CPEC), but FPEC-containing pellets were more rugged and the PEO to obtain optimal pellets was lower for FPEC compared to CPEC. Immediate release products were obtained and ethylcellulose particle size was of no consequence to drug release. Observed responses for the optimized product agreed with predicted values, demonstrating the success of the optimization procedure. These results suggest that FPEC is a good diluent for extrusion-spheronization.
doi:10.1016/j.jsps.2013.11.001
PMCID: PMC4142371  PMID: 25161381
Ethylcellulose; Extrusion; Microcrystalline cellulose; Pellets; Poly(ethylene oxide); Spheronization
5.  Moistening Liquid-Dependent De-aggregation of Microcrystalline Cellulose and Its Impact on Pellet Formation by Extrusion–Spheronization 
AAPS PharmSciTech  2014;15(3):753-761.
The wet-state particle size of microcrystalline cellulose (MCC) dispersed in different moistening liquids was characterized to elucidate the effect of moistening liquid type on the extent of MCC particle de-aggregation. Cohesive strength of moistened MCC masses was also assessed and pellet production by extrusion–spheronization attempted. MCC dispersed in alcohol or water–alcohol mixtures with higher alcohol proportions generally had larger particle sizes. Moistened mass cohesive strength decreased and poorer quality pellets were obtained when water–alcohol mixtures with higher alcohol proportions were used as the moistening liquid. MCC comprise aggregates of small sub-units held together by hydrogen bonds. As MCC particle de-aggregation involves hydrogen bond breaking, moistening liquids with lower polarity, such as water–alcohol mixtures with higher alcohol proportions, induced lesser de-aggregation and yielded MCC with larger particle sizes. When such water–alcohol mixtures were employed during extrusion–spheronization with MCC, the larger particle size of MCC and lower surface tension of the moistening liquid gave rise to moistened masses with lower cohesive strength. During pelletization, agglomerate growth by coalescence and closer packing of components by particle rearrangement would be limited. Thus, weaker, less spherical pellets with smaller size and wider size distribution were produced.
doi:10.1208/s12249-014-0098-7
PMCID: PMC4037494  PMID: 24554239
extrusion–spheronization; microcrystalline cellulose; moistening liquid; particle size; pellets
6.  Influence of chitosan type on the properties of extruded pellets with low amount of microcrystalline cellulose 
AAPS PharmSciTech  2007;8(3):E99-E109.
The purpose of this research was to study the influence of type of chitosan with different molecular weights, ie, 190 and 419 kDa, on properties of pellets prepared by extrusion/ spheronization. The formulations, consisting of acetaminophen as model drug, chitosan, microcrystalline cellulose (MCC), and dibasic calcium phosphate dihydrate with/without sodium alginate, were extruded using a twin-screw extruder and water as the granulating liquid. With 30% wt/wt MCC and no added sodium alginate, spherical pellets were produced containing low and high molecular weight chitosan at a maximum amount of 60% and 40% wt/wt, respectively. With sodium alginate (2.5% wt/wt), pellets with either type of chitosan (60% wt/wt), MCC (17.5% wt/wt), and acetaminophen (20% wt/wt) could be produced indicating an improved pelletforming ability. Type and amount of chitosan and added sodium alginate affected physical properties of pellets including size, roundness, crushing force, and drug release. Low molecular weight chitosan produced pellets with higher mean diameter, sphericity, and crushing force. Additionally, the pellets made of low molecular weight chitosan and added sodium alginate showed faster drug release in 0.1 N HCl but had slower drug release in pH 7.4 phosphate buffer. This indicated that drug release from pellets could be modified by the molecular weight of chitosan. In conclusion, the molecular weight of chitosan had a major influence on formation, physical properties, and drug release from the obtained pellets.
doi:10.1208/pt0803064
PMCID: PMC2750560  PMID: 18181559
Chitosan; sodium alginate; pellets; extrusion/spheronization; drug release
7.  Formulation and evaluation of sustained release enteric-coated pellets of budesonide for intestinal delivery 
Introduction:
The aim of present work was to develop intestinal-targeted pellets of Budesonide, a potent glucocorticoid, used for the treatment of ulcerative colitis and Crohn's disease by extrusion and spheronization method. Current available oral formulations of Budesonide have low efficacy because of the premature drug release in the upper part of the gastrointestinal tract. In this study, a pH-controlled intestinal-targeted pellet of budesonide was established using 32 full factorial design by giving an enteric coating with Eudragit S100.
Materials and Methods:
Budesonide-sustained release pellets were prepared by extruder and spheronization technique using a combination of water-soluble and permeable polymers by applying 32 full factorial design. The pellets were coated by spray coating technique using Eudragit S100 as an enteric polymer. The pellets were characterized for its flowability, sphericity, friability, and in vitro drug release. Release behaviour was studied in different pH media. The release profile was studied for the mechanism of drug release.
Result:
The optimized formulation showed negligible drug release in the stomach followed by release for 12 h in the intestinal pH. Differential scanning calorimetry and Fourier Transform Infrared Spectroscopy studies indicated no interaction between drug and polymer. Scanning Electron Microscopy image of coated pellets suggested a uniform and smooth coat over the surface of pellets. Accelerated stability studies showed a stable nature of drug in the formulation. All evaluation parameter showed that pellets were good in spherocity and flowability.
Conclusion:
Sustained release pellets of Budesonide could be prepared by extrusion and spheronization which released the drug in intestinal pH for an intestine to treat inflammatory bowel disease. A ratio of polymer combination could be decided using a full factorial design.
doi:10.4103/2230-973X.121294
PMCID: PMC3853760  PMID: 24350040
Budesonide; eudragit S100; extruder spheronizer; inflammatory bowel disease; spray coating; sustained release
8.  Importance of Small Pores in Microcrystalline Cellulose for Controlling Water Distribution during Extrusion–Spheronization 
AAPS PharmSciTech  2008;9(3):972-981.
The purpose of this research was to investigate the effects of particle size on the wet massing behavior of microcrystalline cellulose (MCC). In this study, a series of six fractionated MCC grades were customized and specially classified to yield different particle size varieties of the standard grade, Comprecel M101. All seven MCC grades were extensively characterized for the physical properties and wet massing behavior using mixer torque rheometry. Effects of MCC physical properties on the maximum torque (Torquemax) were determined using partial least squares (PLS) analysis. Most physical properties varied systematically with particle size and morphological changes. Marked differences were observed in the small pore volumes (VhighP) and BET surface areas of the MCC grades. Variables that exerted dominant influences on Torquemax were identified. In particular, the significance of VhighP in governing wet mass consistency was established. The role of VhighP has not been reported in any study because this small but significant variation is likely to be obliterated or compensated by variation in other physical properties from MCC grades from different suppliers. The findings demonstrated the role of small pores in governing the wet mass consistency of MCC and provide a better understanding of MCC’s superior performance as a spheronization aid by the ability to fulfill the function as a molecular sponge to facilitate pellet formation during wet granulation processes.
doi:10.1208/s12249-008-9134-9
PMCID: PMC2977047  PMID: 18720015
extrusion–spheronization; microcrystalline cellulose; spheronization aid; torque rheometry
9.  Importance of Wet Packability of Component Particles in Pellet Formation 
AAPS PharmSciTech  2013;14(3):1267-1277.
This work explored the importance of packability of component particles in the different wet processing steps of extrusion–spheronization and investigated different processing and formulation approaches for enhancing packing of component particles during extrusion–spheronization to produce spherical pellets with high yield and narrow size distribution. Various cross-linked polyvinyl pyrrolidone (XPVP) and lactose grades with different particle sizes were used as pelletization aid and filler in 1:3 binary powder blends. Loosely packed extrudates obtained from coarse XPVP/lactose blends possessed low cohesive strength and produced irregular shaped pellets with low yield whereas tightly packed, rigid extrudates obtained from XPVP/fine lactose grades possessed high cohesive strength and produced elongated pellets. Adjustment of spheronization tip speed to provide sufficient forces generated by the rotating frictional base plate for facilitating packing by rearrangement of component particles improved pellet quality. Double extrusion, decreasing particle size of the formulation component(s), and/or widening particle size distribution of the powder blend are approaches applicable to improve cohesiveness of moistened mass by closer packing of component particles for production of good quality pellets.
doi:10.1208/s12249-013-0022-6
PMCID: PMC3755152  PMID: 23955149
cross-linked polyvinyl pyrrolidone; extrusion; packing; spheronization
10.  Formulation and evaluation of olanzapine matrix pellets for controlled release 
Background and the purpose of the study
Olanzapine is an antipsychotic used in treatment of schizophrenia. This research was carried out to design oral controlled release matrix pellets of water insoluble drug Olanzapine (OZ), using blend of Sodium Alginate (SA) and Glyceryl Palmito-Stearate (GPS) as matrix polymers, micro crystalline cellulose (MCC) as spheronizer enhancer and Sodium Lauryl Sulphate (SLS) as pore forming agent.
Methods
OZ formulations were developed by the pelletization technique by drug loaded pellets and characterized with regard to the drug content, size distribution, Scanning Electron Microscopy (SEM), Differential Scanning Calorimetry (DSC), Fourier Transform Infrared Spectroscopy (FTIR) and X-ray Diffraction study (XRD). Stability studies were carried out on the optimized formulation for a period of 90 days at 40±2 °C and 75±5% relative humidity.
Results and major conclusion
The drug content was in the range of 93.34–98.12%. The mean particle size of the drug loaded pellets was in the range 1024 to 1087µm. SEM photographs and calculated sphericity factor confirmed that the prepared formulations were spherical in nature. The compatibility between drug and polymers in the drug loaded pellets was confirmed by DSC and FTIR studies. Stability studies indicated that pellets are stable. XRD patterns revealed the crystalline nature of the pure OZ. Loose surface crystal study indicated that crystalline OZ is present in all formulations and more clear in formulation F5. Drug release was controlled for more than 24 hrs and mechanism of the drug release followed by Fickian diffusion. It may be concluded that F5 is an ideal formulation for once a day administration.
PMCID: PMC3304385  PMID: 22615665
Pelletization; Microporous membrane; Release kinetics; SEM
11.  The Influence of Surfactant HLB and Oil/Surfactant Ratio on the Formation and Properties of Self-emulsifying Pellets and Microemulsion Reconstitution 
AAPS PharmSciTech  2012;13(4):1319-1330.
Self-emulsifying oil/surfactant mixtures can be incorporated into pellets that have the advantages of the oral administration of both microemulsions and a multiple-unit dosage form. The purpose of this work was to study the effects of surfactant hydrophilic–lipophilic balance (HLB) and oil/surfactant ratio on the formation and properties of self-emulsifying microcrystalline cellulose (MCC) pellets and microemulsion reconstitution. Triglycerides (C8–C10) was the oil and Cremophor ELP and RH grades and Solutol the surfactants. Pellets were prepared by extrusion/spheronization using microemulsions with fixed oil/surfactant content but with different water proportions to optimize size and shape parameters. Microemulsion reconstitution from pellets suspended in water was evaluated by turbidimetry and light scattering size analysis, and H-bonding interactions of surfactant with MCC from FT-IR spectra. It was found that water requirements for pelletization increased linearly with increasing HLB. Crushing load decreased and deformability increased with increasing oil/surfactant ratio. Incorporation of higher HLB surfactants enhanced H-bonding and resulted in faster and more extensive disintegration of MCC as fibrils. Reconstitution was greater at high oil/surfactant ratios and the droplet size of the reconstituted microemulsions was similar to that in the wetting microemulsions. The less hydrophilic ELP with a double bond in the fatty acid showed weaker H-bonding and greater microemulsion reconstitution. Purified ELP gave greater reconstitution than the unpurified grade. Thus, the work demonstrates that the choice of type and quantity of the surfactant used in the formulation of microemulsions containing pellets has an important influence on their production and performance.
doi:10.1208/s12249-012-9855-7
PMCID: PMC3513468  PMID: 23054984
disintegration and mechanical properties; FT-IR and H-bonding; microemulsion reconstitution; self-emulsifying pellets; surfactant HLB and oil/surfactant ratio
12.  Production of Ibuprofen Pellets Containing High Amount of Rate Retarding Eudragit RL Using PEG400 and Investigation of Their Physicomechanical Properties 
Objective(s)
The aim of this study was to investigate the possibility of production of ibuprofen pellets with high amount of rate retarding polymer by aid of PEG400 as plasticizer.
Materials and Methods
Polyethylene glycol (PEG400) in concentrations of 1, 3 or 5% w/w with respect to Eudragit RL was used in production of pellets containing 60% ibuprofen and 40% excipient (2% polyvinylpyrrolidone (PVP), 7.6 or 0% microcrystalline cellulose (MCC) and 30.4 or 38% Eudragit RL). Physicomechanical and release properties of pellets were evaluated.
Results
In presence of PEG400, formulations containing 30.4% Eudragit RL and 7.6% MCC could easily form pellets. In formulations without any MCC pellets were obtained only in presence of 3 or 5% PEG400. Pellets containing MCC with 0 or 1% PEG400 showed brittle properties but those with 3% or 5% PEG400 showed plastic nature under pressure. Elastic modulus dramatically decreased with increasing PEG400 indicating softening of pellets. This was due to shift of Eudragit structure from glassy to rubbery state which was supported by DSC studies. Mean dissolution time (MDT) increased with addition of 1 or 3% PEG400 but this was not the case for pellets with 5% PEG400.
Conclusion
Overall PEG400 is a potential plasticizer in production of pellets based on Eudragit RL and ibuprofen. The ease in process of extrusion-spheronization, increasing the mean dissolution time and change in mechanical properties of pellets from brittle to plastic behavior were advantages of using PEG400. Changes in mechanical properties of pellets are important when pellets are intended to be compressed as tablets.
PMCID: PMC3586828  PMID: 23492856
Eudragit RL; Extrusion-spheronization; Ibuprofen; Microcrystalline cellulose; Pellets; PEG400
13.  Development and Evaluation of a Solid Self-Nanoemulsifying Drug Delivery System for Loratadin by Extrusion-Spheronization 
Advanced Pharmaceutical Bulletin  2013;4(2):113-119.
Purpose: Recently the liquid nanoemulsifying drug delivery systems (SNEDDS) have shown dramatic effects on improving oral bioavailability of poorly soluble drugs. The main purpose of this study was to prepare a solid form of self-nanoemulsifying drug delivery system of loratadin by extrusion-spheronization. The liquid SNEDDS are generally prepared in a soft or hard gelatin capsules which suffers from several disadvantages. Therefore incorporation of SNEDDS into solid dosage form is desirable to get together the advantages of SNEDDS and solid multiparticualte systems.
Methods: The SNEDDS was consisted of liquid paraffin, capriole, span 20, transcutol and loratadin as a poorly soluble drug. A multilevel factorial design was used to formulation of SNEDDS pellets, liquid SNEDDS (20 and 30%) was mixed with lactose, microcrystallin cellulose (40%) and silicon dioxide (0, 5 and 10%), and Na- crosscarmelose (0, 5 and 10%). The resulting wet mass transformed into pellets by extrusion-spheronization. The pellets were dried and characterized for size (sieve analysis), shape (image analysis), mechanical strength (friability test), droplet size (laser light scattering) and drug release rate (dissolution test). Selected SNEDDS pellets were also compared with conventional loratadin pellet or tablet formulation.
Results: The resulting SNE pellets exhibited uniform size and shape. Total friability of pellets did not affected by formulation variables. The in vitro release of SNE pellets was higher than the liquid SNE and powder tablets.
Conclusion: Our studies demonstrated that extrusion-spheronization is a viable technology to produce self-emulsifying pellets in large scale which can improve in vitro dissolution with better solubility.
doi:10.5681/apb.2014.018
PMCID: PMC3915810  PMID: 24511474
Solid self-emulsifying drug delivery system; Extrusion-spheronisation; Pellets; Loratadin
14.  Direct pelletization in a rotary processor controlled by torque measurements. III. Investigation of microcrystalline cellulose and lactose grade 
AAPS PharmSciTech  2005;6(3):E495-E503.
The aim of the present study was to investigate the use of different grades of microcrystalline cellulose (MCC) and lactose in a direct pelletization process in a rotary processor. For this purpose, a mixed 2- and 3-level factorial study was performed to determine the influence of the particle size of microcrystalline cellulose (MCC), (≈60 and 105 μm) and lactose (≈30, 40, and 55 μm), as well as MCC type (Avicel and Emcocel) on the pelletization process and the physical properties of the prepared pellets. A 1∶4 mixture of MCC and lactose was applied, and granulation liquid was added until a 0.45 Nm increase in the torque of the friction plate was reached. All combinations of the 3 factors resulted in spherical pellets of a high physical strength. The particle size of MCC was found to have no marked effect on the amount of water required for agglomerate growth or on the size of the resulting pellets. An increasing particle size of lactose gave rise to more spherical pellets of a more narrow size distribution as well as higher yields. The MCC type was found to affect both the release of the model drug from the prepared pellets and the size distribution. Generally, the determined influence of the investigated factors was small, and direct pelletization in a rotary processor was found to be a robust process, insensitive to variations in the particle size and type of MCC and the particle size of lactose.
doi:10.1208/pt060362
PMCID: PMC2750396  PMID: 16354010
rotary processor; direct pelletization; torque measurement; microcrystalline cellulose
15.  Design and Evaluation of Self-Nanoemulsifying Pellets of Repaglinide 
AAPS PharmSciTech  2013;14(3):994-1003.
The aim of study was to develop self-nanoemulsifying pellets (SNEP) for oral delivery of poorly water soluble drug, repaglinide (RPG). Solubility of RPG in oily phases and surfactants was determined to identify components of self-nanoemulsifying drug delivery system (SNEDDS). The surfactants and cosurfactants were screened for their ability to emulsify oily phase. Ternary phase diagrams were constructed to identify nanoemulsification area for the selected systems. SNEDDS formulations with globule size less than 100 nm were evaluated for in vivo anti-hyperglycemic activity in neonatal streptozotocin rat model. A significant reduction in glucose levels was produced by optimized SNEDDS formulation in comparison to the control group. The optimized SNEDDS formulations were pelletized via extrusion/spheronization technique using microcrystalline cellulose and lactose. SNEP were characterized by X-ray powder diffraction and scanning electron microscopy. X-ray diffraction study indicated loss of crystallinity of RPG in SNEP. The SNEP exhibited good flow properties, mechanical strength and formed nanoemulsion with globule size less than 200 nm. SNEP showed in vitro release of more than 80% RPG in 10 min which was significantly higher than RPG containing reference pellets. In conclusion, our studies illustrated that RPG, a poorly water soluble drug can be successfully formulated into SNEP which can serve as a promising system for the delivery of poorly water soluble drugs.
doi:10.1208/s12249-013-9990-9
PMCID: PMC3755138  PMID: 23775389
anti-hyperglycemic activity; extrusion/spheronization; repaglinide; self-nanoemulsifying pellets
16.  Quantification of Mass Transfer During Spheronisation 
AAPS PharmSciTech  2012;13(2):493-497.
Spherical granules (pellets) are quite useful in many pharmaceutical applications. The extrusion spheronisation technique is well established as a method of producing pellets of a spherical shape and narrow size distribution. After the extrusion, the cylindrical extrudates are transformed to spherical pellets by spheronisation. The frequently used models consider deformation and breakage during this process. However, the adhesion of fine particles has been neglected as a mechanism in spheronisation for many years. This study quantifies the mass transfer between pellets during spheronisation. During the investigation, the pelletisation aids (microcrystalline cellulose and kappa-carrageenan), the drug (acetaminophen and ibuprofen) and water content were varied systematically. A novel parameter, namely, the "mass transfer fraction" (MTF), was defined to quantify the mass transfer between the pellets. All four investigated formulations had an MTF between 0.10 and 0.52 that implies that up to 50 % of the final pellet weight was involved in mass transfer. Both pelletisation aids showed similar MTF, independent of the drug used. Furthermore, an increase of the MTF, with respect to an increase of the water content, was found for microcrystalline cellulose formulations. In conclusion, the mass transfer between the pellets has to be considered as a mechanism for spheronisation.
doi:10.1208/s12249-012-9770-y
PMCID: PMC3364402  PMID: 22415640
carrageenan; MCC; mechanism; pellets; spheronisation
17.  Optimization of Pellets Containing Solid Dispersion Prepared by Extrusion/Spheronization Using Central Composite Design and Desirability Function 
Furosemide is a class IV biopharmaceutical classification system drug having poor water solubility and low bioavailability due to the hepatic first-pass metabolism and has a short half-life of 2 h. To overcome the above drawback, this study was carried to prepare and evaluate the pellets containing furosemide solid dispersion (SD) for oral administration prepared by extrusion/spheronization. SD of furosemide was prepared with Eudragit L-100 at a drug-to-polymer ratio of 1:2 by employing a solvent evaporation method and characterized. Further, microcrystalline cellulose pellets containing SD were consequently prepared using a lab scale extrusion/ spheronizer and evaluated for in vitro drug release studies. The influence of process parameters used during extrusion/spheronization on the pellet properties was also studied using 2-factor, 3-level central composite design in order to improve the product quality. Additionally, the desirability function approach was applied to acquire the preeminent compromise between the multiple responses. Pellets containing solid dispersion (PSD) were prepared using optimal parameter settings demonstrated 88.52 ± 0.69% of the drug was released in a sustained release manner till 12 h. In vitro drug release data were fitted to various release kinetics models to study the mechanism of drug release. Drug release from the PSD was found to follow zero-order and Higuchi's model. Both studied parameters had great influence on the responses. PSD showed augmentation in the drug release profile till 12 h. The final optimized formulation was obtained by encapsulating best SD formulation within the pellet core to release the drug in the most soluble form in stomach and a sustained fashion in intestine.
doi:10.4103/0975-1483.100020
PMCID: PMC3483524  PMID: 23112533
Central composite design; desirability function; furosemide; solid dispersion; sustained release pellets
18.  Pellet manufacturing by extrusion-spheronization using process analytical technology 
AAPS PharmSciTech  2005;6(2):E174-E183.
The aim of this study was to investigate the phase transitions occurring in nitrofurantoin and theophylline formulations during pelletization by extrusion-spheronization. An at-line process analytical technology (PAT) approach was used to increase the understanding of the solid-state behavior of the active pharmaceutical ingredients (APIs) during pelletization. Raman spectroscopy, near-infrared (NIR) spectroscopy, and X-ray powder diffraction (XRPD) were used in the characterization of polymorphic changes during the process. Samples were collected at the end of each processing stage (blending, granulation, extrusion, spheronization, and drying). Batches were dried at 3 temperature levels (60°C, 100°C, and 135°C). Water induced a hydrate formation in both model formulations during processing. NIR spectroscopy gave valuable real-time data about the state of water in the system, but it was not able to detect the hydrate formation in the theophylline and nitrofurantoin formulations during the granulation, extrusion, and spheronization stages because of the saturation of the water signal. Raman and XRPD measurement results confirmed the expected pseudopolymorphic changes of the APIs in the wet process stages. The relatively low level of Raman signal with the theophylline formulation complicated the interpretation. The drying temperature had a significant effect on dehydration. For a channel hydrate (theophylline), dehydration occurred at lower drying temperatures. In the case of isolated site hydrate (nitrofurantoin), dehydration was observed at higher temperatures. To reach an understanding of the process and to find the critical process parameters, the use of complementary analytical techniques are absolutely necessary when signals from APIs and different excipients overlap each other.
doi:10.1208/pt060226
PMCID: PMC2750529  PMID: 16353975
PAT; pelletization; theophylline; nitrofurantoin; NIR; Raman; XRPD
19.  Novel Sustained-Release of Propafenone through Pellets: Preparation and in Vitro/in Vivo Evaluation 
In this study, an extrusion-spheronization method was applied successfully to fabricate propafenone hydrochloride (PPF) sustained-release pellets. Using scanning electron microscopy, it was shown that the PPF pellets had a mean size of approximately 950 µm with a spherical shape. The in vitro release profiles indicated that the release of PPF from the pellets exhibited a sustained release behavior. The relatively high correlation coefficient (r) values obtained from the analysis of the amount of the drug released versus the square root of time indicated that the release followed a zero order kinetic model. A similar phenomenon was also observed in a pharmacokinetic study in dogs, in which the area under the curve (AUC) of the pellet formulation was 1.2-fold higher than that of PPF tablets. The present work demonstrated the feasibility of controlled delivery of PPF utilizing microcrystalline cellulose (MCC)-based pellets.
doi:10.3390/ijms150915503
PMCID: PMC4200845  PMID: 25184949
propafenone; pellets; sustained-release; pharmacokinetic; extrusion–spheronization method
20.  Controlled Release of Oral Tetrahydrocurcumin from a Novel Self-Emulsifying Floating Drug Delivery System (SEFDDS) 
AAPS PharmSciTech  2010;12(1):152-164.
The objectives of this study were to develop and evaluate a novel self-emulsifying floating drug delivery system (SEFDDS) that resulted in improved solubility, dissolution, and controlled release of the poorly water-soluble tetrahydrocurcumin (THC). The formulations of liquid self-emulsifying drug delivery system (SEDDS; mixtures of Labrasol, Cremophor EL, Capryol 90, Labrafac PG) were optimized by solubility assay and pseudo-ternary phase diagram analysis. The liquid SEDDS was mixed with adsorbent (silicon dioxide), glyceryl behenate, pregelatinized starch, sodium starch glycolate, and microcrystalline cellulose and transformed into pellets by the extrusion/spheronization technique. The resulting pellets with 22% liquid SEDDS had a uniform size and good self-emulsification property. The microemulsions in aqueous media of different self-emulsifying floating pellet formulations were in a particle size range of 25.9–32.5 nm. Use of different weight proportions of glyceryl behenate and sodium starch glycolate in pellet formulations had different effects on the floating abilities and in vitro drug release. The optimum formulation (F2) had a floating efficiency of 93% at 6 h and provided a controlled release of THC over an 8-h period. The release rate and extent of release of THC liquid SEDDS (80% within 2 h) and self-emulsifying floating pellet formulation (80% within 8 h) were significantly higher than that of unformulated THC (only 30% within 8 h). The pellet formulation was stable under intermediate and accelerated storage conditions for up to 6 months. Controlled release from this novel SEFDDS can be a useful alternative for the strategic development of oral solid lipid-based formulations.
doi:10.1208/s12249-010-9568-8
PMCID: PMC3066365  PMID: 21181511
controlled release; floating drug delivery systems; SEDDS; self-emulsifying systems; tetrahydrocurcumin
21.  The Use of ß-Cyclodextrin in the Manufacturing of Disintegrating Pellets with Improved Dissolution Performances 
AAPS PharmSciTech  2008;9(2):708-717.
It has recently been highlighted that the release behavior of pellets containing microcystalline cellulose (MCC) as the spheronizing agent may be impaired by the lack of disintegration. Although alternative spheronizing excipients have been proposed, their overall advantages have not thoroughly been assessed. In the present work, the possible use of β-cyclodextrin (βCD) was therefore explored for the manufacturing of pellets with a potential for effective disintegration and immediate release of poorly soluble active ingredients. MCC/βCD powder formulations containing no drug or model drugs with different water solubility, able to form inclusion compounds with the employed cyclodextrin, were pelletized by agglomeration in rotary fluid bed equipment. By applying successive statistical experimental designs, the most critical formulation and operating parameters were identified and optimal manufacturing processes were ultimately set up. High yields of pellets provided with satisfactory physical-technological characteristics were obtained using powder formulations with up to 80% βCD. Based on dissolution testing results, the suitability of βCD for the preparation of disintegrating MCC-containing pellets with improved dissolution performance was finally demonstrated.
doi:10.1208/s12249-008-9106-0
PMCID: PMC2976967  PMID: 18523889
β-cyclodextrin; design of experiments; microcrystalline cellulose; pellets; rotary fluid bed
22.  New Insights into the Pelletization Mechanism by Extrusion/Spheronization 
AAPS PharmSciTech  2010;11(4):1549-1551.
Pellet manufacturing by extrusion/spheronization is quite common in the pharmaceutical field because the obtained product is characterized by a high sphericity as well as a narrow particle size distribution. The established mechanisms only consider deformation of the initially fractured particles but do not account for mass transfer between the particles as a factor in achieving spherical particles. This study dealt with the visualization of mass transfer during spheronization. Therefore, two common pelletization aids, microcrystalline cellulose and kappa-carrageenan, were used alone as well as in combination with lactose as a filler. This study proves that mass transfer between particles must be considered in addition to plastic deformation in order to capture the spheronization mechanism. Moreover, it is evident that there are regional distinctions in the amount of mass transfer at the particle surface. Therefore, the commonly espoused pelletization mechanisms need to be extended to account for material transfer between pellet particles, which has not been considered before.
doi:10.1208/s12249-010-9532-7
PMCID: PMC3011062  PMID: 21042960
agglomeration; carrageenan; MCC; pelletization; spheronization; wet extrusion
23.  Sintering of wax for controlling release from pellets 
AAPS PharmSciTech  2007;8(3):E175-E183.
The purpose of the present study was to investigate incorporation of hydrophobic (ie, waxy) material into pellets using a thermal sintering technique and to evaluate the pellets in vitro for controlled release. Pellets prepared by extrusion-spheronization technology were formulated with a water-soluble drug, microcrystalline cellulose, and carnauba wax. Powdered carnauba wax (4%–20%) prepared by grinding or by emulsification was studied with an attempt to retard the drug release. The inclusion of ground or emulsified carnauba wax did not sustain the release of theophylline for more than 3 hours. Matrix pellets of theophylline prepared with various concentrations of carnauba wax were sintered thermally at various times and temperatures. In vitro drug release profiles indicated an increase in drug release retardation with increasing carnauba wax concentration. Pellets prepared with ground wax showed a higher standard deviation than did those prepared with emulsified wax. There was incomplete release at the end of 12 hours for pellets prepared with 20% ground or emulsified wax. The sintering temperature and duration were optimized to allow for a sustained release lasting at least 12 hours. The optimized temperature and duration were found to be 100° and 140 seconds, respectively. The sintered pellets had a higher hydrophobicity than did the unsintered pellets. Scanning electron micrographs indicated that the carnauba wax moved internally, thereby increasing the surface area of wax within the pellets.
doi:10.1208/pt0803074
PMCID: PMC2750570  PMID: 17915824
Controlled release; pellets; thermal sintering; waxes; theophylline
24.  Meltlets® of Soy Isoflavones: Process Optimization and the Effect of Extrusion Spheronization Process Parameters on Antioxidant Activity 
In the current research work an attempt was made to develop “Melt in mouth pellets” (Meltlets®) containing 40% herbal extract of soy isoflavones that served to provide antioxidants activity in menopausal women. The process of extrusion–spheronization was optimized for extruder speed, extruder screen size, spheronization speed, and time. While doing so the herbal extract incorporated in the pellet matrix was subjected to various processing conditions such as the effect of the presence of other excipients, mixing or kneading to prepare wet mass, heat generated during the process of extrusion, spheronization, and drying. Thus, the work further investigates the effect of these processing parameters on the antioxidant activity of the soy isoflavone herbal extract incorporated in the formula. Thereby, the antioxidant activity of the soya bean herbal extract, Meltlets® and of the placebo pellets was evaluated using DPPH free radical scavenging assay and total reduction capacity.
doi:10.4103/0250-474X.119831
PMCID: PMC3831727  PMID: 24302800
Antioxidant activity; DPPH; extrusion; excipients; fluid–bed; granulation; spheronization; mixing; soy isoflavones; Oyaizu method
25.  Evaluation of powder and tableting properties of chitosan 
AAPS PharmSciTech  2006;7(3):E152-E161.
The aim of this study was to analyze the process of tablet formation and the properties of the resulting tablets for 3 N-deacetylated chitosans, with a degree of deacetylation of 80%, 85%, or 90%. Material properties, such as water content, particle size and morphology, glass transition temperature, and molecular weight were studied. The process of tablet formation was analyzed by 3-D modeling, Heckel analysis, the pressure time function, and energy calculations in combination with elastic recovery dependent on maximum relative density and time. The crushing force and the morphology of the final tablets were analyzed. Chitosans sorb twice as much water as microcrystalline cellulose (MCC), the particle size is comparable to Avicel PH 200, a special type of MCC, the particles look like shells, and the edges are bent. Molecular weight ranges from 80 000 to 210 000 kDa, the glass transition temperature (Tg) was not dependent on molecular weight. The chitosans deform ductilely as MCC; however, plastic deformation with regard to time and also pressure plasticity are higher than for MCC, especially for Chit 85, which has the lowest crystallinity and molecular weight. At high densification, fast elastic decompression is higher. 3-D modeling allowed the most precise analysis. Elastic recovery after tableting is higher than for MCC tablets and continues for some time after tableting. The crushing force of the resulting tablets is high owing to a reversible exceeding of Tg in the amorphous parts of the material. However, the crushing force is lower compared with MCC, since the crystallinity and the Tg of the chitosans are higher than for MCC. In summation, chitosans show plastic deformation during compression combined with high elasticity after tableting. Highly mechanically stable tablets result.
doi:10.1208/pt070375
PMCID: PMC2750517  PMID: 17025255
3-D model; chitosans; compactibility; compression; elastic recovery; morphology

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