Extrusion-spheronization Technique Research Articles

Preparation of benznidazole pellets for immediate drug delivery using the extrusion spheronization technique

Recent advances in the treatment of Chagas disease have followed combinations of drugs that act synergistically against infection, predominantly including benznidazole (BNZ) and azoles derivatives. Possible incompatibilities between these drugs, slow dissolution of BNZ and dose adjustment difficulties are technological obstacles to the development of multidrug formulations. Thus, in the present study, BNZ pellets were developed using extrusion spheronization for immediate drug delivery. Preformulation studies were then performed using thermal analysis and infrared spectroscopy and compatibility between the drug and selected excipients (polyethylene glycol 6000, sodium starch glycolate, microcrystalline cellulose and sodium croscarmellose) was investigated. No chemical decomposition of BNZ was observed, even in samples submitted to wet granulation and thermal stress. Subsequently, formulations were elaborated according to a simplex lattice experimental design using polyethylene glycol, sodium starch glycolate and sodium croscarmellose as disintegrating agents. In these experiments, BNZ pellets showed appropriate physicochemical characteristics, including high drug load capacity and excellent flow properties. The mixture experimental design allowed identification of adequate compositions of disintegrating agents and achieved rapid disintegration and dissolution of pellets. Optimum performance was achieved using polyethylene glycol and sodium croscarmellose at 5.0% w/w each. The present BNZ pellets are versatile alternatives to treat Chagas disease and provide insights into the preparation of multidrug systems.

Application of ethyl cellulose, microcrystalline cellulose and octadecanol for wax based floating solid dispersion pellets

The present study aimed to develop and optimize the wax based floating sustained-release dispersion pellets for a weakly acidic hydrophilic drug protocatechuic acid to achieve prolonged gastric residence time and improved bioavailability. This low-density drug delivery system consisted of octadecanol/microcrystalline cellulose mixture matrix pellet cores prepared by extrusion-spheronization technique, coated with drug/ethyl cellulose 100cp solid dispersion using single-step fluid-bed coating method. The formulation-optimized pellets could maintain excellent floating state without lag time and sustain the drug release efficiently for 12h based on non-Fickian transport mechanism. Observed by SEM, the optimized pellet was the dispersion-layered spherical structure containing a compact inner core. DSC, XRD and FTIR analysis revealed drug was uniformly dispersed in the amorphous molecule form and had no significant physicochemical interactions with the polymer dispersion carrier. The stability study of the resultant pellets further proved the rationality and integrity of the developed formulation.

Co-processed κ-carrageenan-pectin as pelletizing aid for immediate-release pellets

ABSTRACTThis study investigates the extrusion-spheronization performance of some mixtures of co-processed κ-carrageenan and pectin (as excipient), and sodium starch glycolate (as superdisintegrant). Attention is focused with an objective to improve the mechanical stability and the dissolution rate of poorly soluble domperidone (as a model drug). Initially, co-processed κ-carrageenan-pectin excipient is prepared with different ratios of κ-carrageenan and pectin. Different marketed brands of κ-carrageenan (Gelcarin, Aquagel and Eugel) were employed and dried by solvent evaporation method. Further characterization was carried out by SEM, XRD and FTIR analysis. Pellets were prepared using extrusion-spheronization technique. Pellets were evaluated for flow properties, particle size, sphericity, tensile strength, friability, disintegration time and in-vitro drug release studies. Solid-state characterization of pellets was also done by FTIR, DSC and SEM analysis. The mechanical stability and dissolution rate of prepared pellets were found to be dependent on the concentration of pectin and type of κ-carrageenan employed in the fabrication of pellets. The pellets made with a high proportion of Eugel showed a very high dissolution rate of domperidone and undergo rapid disintegration validating co-processed k-carrageenan-pectin as a promising pelletizing aid for immediate-release pharmaceutical formulations.

Investigation on release of highly water soluble drug from matrix-coated pellets prepared by extrusion–spheronization technique

The objective was to formulate itopride HCl (ITP) extended release matrix-coated pellets by extrusion–spheronization and to investigate the influence of concentration and viscosity grade of different polymers on release of a highly water soluble drug. The matrix pellet formulations consisted of polymers (10–30%) like hydroxypropyl methylcellulose (HPMC K4M, K15M, and K100M), ethyl cellulose (EC-7 cps), microcrystalline cellulose (10–30%) and a fixed quantity of lactose (10%). The initial fast drug release from the matrix pellets was effectively controlled by coating with 5% ethyl cellulose (10 cps) dispersion. The dissolution studies of coated formulations were carried out at different pH, and data were analyzed for drug release kinetics. Scanning electron microscope was used to examine the surface morphology and cross section of pellets. Kinetics of all coated formulations were best explained by Higuchi model (R 2 = 0.94–0.99). However, HPMC matrix-coated pellets (F1, F4 and F7) also followed Baker and Lonsdale model (R 2 = 0.96–0.99), whereas, EC matrix-coated pellets (F10) followed zero-order kinetics (R 2 = 0.99). Release mechanism of all coated formulations was non-fickian. Both uncoated and coated pellets were found to be spherical. Fourier transform infrared spectroscopy was conducted on the coated formulations and no drug–excipients interaction was found.

Hot Melt Coating of Pellets for a Water Soluble Drug using Combination of Waxes

Waxes retards drug release from dosage form based on their lipophilic characteristics. In this study, the effect of hot melt spray coated Verapamil pellets with composition of stearic acid, carnauba wax; glyceryl monostearate and polyethylene glycol on drug release and release kinetics were investigated. The verapamil pellets containing 70% microcrystalline cellulose (Avicel PH101) were prepared by extrusion-spheronization technique and spray coated with molten wax at various ratios and thickness in a hot-melt spray coating instrument. In-vitro drug release was studied using test method for Extended Release tablets USP 24. The drug release was decreased with increase in stearic acid concentration and addition of 5% carnauba wax to stearic acid minimized initial burst release but it also retarded drug release. Glyceryl monostearate 30%w/w as release modifier at 20%w/w coating level provided desired drug release while PEG 6000 provided similar results at 2.5%w/w concentration. The plot of log fraction drug unreleased versus time showed a good linear relationship. Glycerol monostearate at 30%w/w as release modifier showed higher release rate in initial hours which declined with time and also R2 value for first order release kinetics was found to be nearest to one indicating drug release was dependent on initial concentration present in pellets. A zero order release profile was obtained from verapamil HCl sustained release pellets prepared by hot melt spray coating of stearic acid with sitable combination of carnuba wax and PEG 6000.

Formulation and characterization of self emulsifing pellets of carvedilol

The purpose of present study was aimed at developing self emulsifying drug delivery system in liquid and then in pellet form that would result in improved solubility, dissolution and permeability of the poorly water soluble drug carvedilol. Pellets were prepared using extrusion-spheronization technique incorporating liquid SEDDS (carvedilol, capmul MCM EP, cremophore EL, tween 20, propylene glycol), adsorbents ( and crospovidone), microcrystalline cellulose and binder (povidone K-30). Ternary phase diagram was constructed to identify different oil-surfactant-cosurfactant mixtures according to the proportion of each point in it. The optimal CAR-SEDDS pellets showed a quicker redispersion with a droplet size of the reconstituted microemulsion being 160.47 nm, which was almost unchanged after solidification. SEM analysis confirmed good spherical appearance of solid pellets; DSC and XRD analysis confirmed that there was no crystalline carvedilol in the pellets. Pellets were then capable of transferring lipophilic compounds into the aqueous phase and significantly enhancing its release with respect to pure drug.

Dissolution rate improvement of telmisartan through modified MCC pellets using 32 full factorial design

Context: Microcrystalline cellulose (MCC) is the most widely used excipient for the production of pellets but it retards the release of poorly water soluble drugs. Objective: The present investigation reports incorporation of camphor, cross carmellose sodium (CCS) and spray dried lactose (SDL) into MCC pellets to enhance the dissolution rate of telmisartan. Materials and methods: A full factorial design (32) was used in the study. Concentration of camphor and CCS was selected as independent variables whereas percentage porosity and percentage drug release at 60min were selected as dependent variables. Pellets were produced by extrusion–spheronization technique and evaluated for percentage yield, particle size analysis, flow characteristics, percentage porosity, drug content and in vitro drug release. Contour plots and 3-D surface plots were presented for graphical expression of the results. Results and discussion: Pellet formulations exhibited acceptable morphological, flow and mechanical properties. As against to 38.54% drug release after 60min with MCC pellets, pellets prepared with optimized formulation, composed of proper combination of MCC, SDL, camphor and CCS, released 100% drug after 60min. Conclusion: Our study underlines the fact that dissolution of telmisartan from MCC pellets can be successfully enhanced by incorporating water soluble excipient, disintegrant and pore formers.

Modified extrusion-spheronization as a technique of microencapsulation for stabilization of choline bitartrate using hydrogenated soya bean oil.

Introduction:Choline bitartrate (CBT) is a vital nutrient for fetal brain development and memory function. It is hygroscopic in nature which is associated with stability related problem during storage such as development of fishy odor and discoloration.Aim:Microencapsulation method was adopted to resolve the stability problem and for this hydrogenated soya bean oil (HSO) was used as encapsulating agent.Materials and Methods:Industrially feasible modified extrusion-spheronization technique was selected for microencapsulation. HSO was used as encapsulating agent, hydroxypropyl methyl cellulose E5/E15 as binder and microcrystalline cellulose as spheronization aid. Formulated pellets were evaluated for parameters such as flow property, morphological characteristics, hardness-friability index (HFI), drug content, encapsulation efficiency, and in vitro drug release. The optimized formulations were also characterized for particle size (by laser diffractometry), differential scanning calorimetry, powder X-ray diffractometry (PXRD), Fourier transform infrared spectroscopy, and scanning electron microscopy.Results and Discussions:The results from the study showed that coating of 90% and 60% CBT was successful with respect to all desired evaluation parameters. Optimized formulation was kept for 6 months stability study as per ICH guidelines, and there was no change in color, moisture content, drug content, and no fishy odor was observed.Conclusion:Microencapsulated pellets of CBT using HSO as encapsulating agent were developed using modified extrusion spheronization technique. Optimized formulations, CBT 90% (F5), and CBT 60% (F10), were found to be stable for 4M and 6M, respectively, at accelerated conditions.

Gastric-resistant isoniazid pellets reduced degradation of rifampicin in acidic medium

Isoniazid and rifampicin are considered the first-line medication for preventing and treating tuberculosis. Rifampicin is degraded in the stomach acidic environment, especially when combined with isoniazid, factor contributing to treatment failure. In this study, gastric-resistant isoniazid pellets were obtained to physical contact of this drug with rifampicin and to bypass the stomach´s acidic environment. The pellets were fabricated using the extrusion-spheronization technique. The coating process was conducted in a fluid spray coater using Acrycoat L 100(r) solution as the coating agent. The pellets obtained were submitted to a dissolution test in HCl 0.1 N and phosphate buffer media. The results indicated that optimum gastric-resistance was only attained with the highest amount of coating material, with isoniazid almost fully released in phosphate buffer. The amount of rifampicin released from its mixture with non-coated isoniazid pellets in HCl 0.1 N was less than that released from its mixture with the enteric-coated pellets. Acrycoat L 100(r) was shown to be an effective enteric/gastric-resistant coating since the stability of rifampicin appeared to be enhanced when physical contact of this drug with isoniazid was prevented at low pH.

Extrusion-Spheronization of Talc using Microcrystalline Cellulose as a Pellet Aid: Part I

Purpose The aims of the present work were to pelletize talc by extrusion-spheronization technique using microcrystalline cellulose (MCC) as a pelletization aid and to study its performance as a neutral substrate for coating. A 32 factorial design was used to study the effect of independent variables (X1, amount of talc, and X2, MCC) on pellet properties.

The development and in vitro evaluation of herbal pellets coated with Eudragit FS 30

The objective of this study was to prepare pellets of thyme (Thymus vulgaris L.), stinging nettle (Urtica dioica L.) and sage (Salvia officinalis L.) dry extracts by extrusion–spheronization technique to improve technological properties and investigate dissolution profiles of pellets covered different levels of pH-sensitive polymer Eudragit® FS. Optimal sample of pellets were prepared using microcrystalline cellulose and lactose as excipients and demonstrated excellent technological quality properties such as Hausner ratio (1.07 ± 0.11) and compressibility index (6.73 ± 0.94%) value, spericity (0.87 ± 0.001) and friability (0.22 ± 0.08 N). Pellets were coated by 10–35% (w/w) of Eudragit® FS. Dissolution studies showed that less than 20% of coating could not prevent dissolution of phenols in pH 1.2, 20% Eudragit® FS coating is enough to prevent herbal extract against dissolution in the stomach. There were observed no statistical significant differences between 20% and 25% or higher amount of coating polymer to a dissolution of phenols in low pH.

Oral 5-fluorouracil colon-specific delivery through in vivo pellet coating for colon cancer and aberrant crypt foci treatment

In situ coating of 5-fluorouracil pellets by ethylcellulose and pectin powder mixture (8:3 weight ratio) in capsule at simulated gastrointestinal media provides colon-specific drug release in vitro. This study probes into pharmacodynamic and pharmacokinetic profiles of intra-capsular pellets coated in vivo in rats with reference to their site-specific drug release outcomes. The pellets were prepared by extrusion-spheronization technique. In vitro drug content, drug release, in vivo pharmacokinetics, local colonic drug content, tumor, aberrant crypt foci, systemic hematology and clinical chemistry profiles of coated and uncoated pellets were examined against unprocessed drug. In vivo pellet coating led to reduced drug bioavailability and enhanced drug accumulation at colon (179.13 μg 5-FU/g rat colon content vs 4.66 μg/g of conventional in vitro film-coated pellets at 15 mg/kg dose). The in vivo coated pellets reduced tumor number and size, through reforming tubular epithelium with basement membrane and restricting expression of cancer from adenoma to adenocarcinoma. Unlike uncoated pellets and unprocessed drug, the coated pellets eliminated aberrant crypt foci which represented a putative preneoplastic lesion in colon cancer. They did not inflict additional systemic toxicity. In vivo pellet coating to orally target 5-fluorouracil delivery at cancerous colon is a feasible therapeutic treatment approach.

Development of papain containing pellets produced by extrusion–spheronization: an operational stage approach

The performance of the standardized extrusion–spheronization technique, operational conditions, formulation parameters and storage of the final product over the bioactivity of papain containing pellets has been evaluated to obtain an insight into the potential of the technique for the manufacture of solid protein formulations. The pellets produced were assayed in terms of biological activity – monitored at each operational stage using N-benzoyl-dl-arginine ρ-nitroanilide as a substrate, and according to the physical properties – evaluated by means of size distribution, apparent density and friability. The produced pellets presented adequate physical and mechanical properties. Monitoring biological activity at each production stage revealed that the most critical steps corresponded to drying and storage, with bioactivity decay ranging from 5 to 30% and 5 to 20% for each process. Dry mixing and extrusion did not hold any influence over papain activity, while wet massing decreased the bioactivity by approximately 0–5% and the spheronization 0–2%. The results varied as a function of the experimental conditions and formulation components. In conclusion, the extrusion--spheronization technique was suitable to produce solid multiparticulate dosage forms for papain, considering the possibility to originate pellets with relatively low bioactivity decay. However, weak points of the technique corresponded to the wet massing and drying stages as well as storage.

Effect of Stearic Acid on Enalapril Stability and Dissolution from Multiparticulate Solid Dosage Forms

Enalapril maleate (EM) is a widely used anti-hypertensive drug which is unstable when mixed with excipients. Enalaprilate and diketopiperazine (DPK) are the main degradation products of enalapril. The in situ preparation of enalapril sodium salt (NaE) has been used to improve drug stability in dosage forms; however, gas release and product rejection ensue when the chemical reaction for obtaining the sodium salt is not completely finished before packaging. This study evaluated the effect of stearic acid (SA) on enalapril stability in microcrystalline cellulose (MCC) pellets containing EM or NaE. MCC pellets containing SA were prepared by the extrusion-spheronization technique and characterized. Enalapril stability and dissolution were then evaluated. DPK and enalaprilate formation were reduced by the addition of SA in pellets containing EM. The overall enalapril degradation in these formulations was lower when compared with pellets containing EM or even NaE prepared without SA. The immediate-release characteristic was maintained by the addition of 5% crospovidone to all the formulations tested. The incorporation of SA into NaE pellets resulted in unexpected enalapril degradation, caused by the interaction of these compounds, as suggested by a thermal analysis of the SA-NaE binary mixture. The findings presented here showed that formulations containing SA could substitute the formation of NaE, since they provide better enalapril stability in solid dosage forms. In addition, it is suggested that the stabilization effects would be observed for other N-carboxyalkyl dipeptide analogs with angiotensin converting enzyme inhibition activity, since these new entities share the same degradation pathway of enalapril.

Design of microcrystalline cellulose-free alginate spheroids by extrusion-spheronization technique

Conventional spheroid preparation by extrusion-spheronization technique requires microcrystalline cellulose (MCC) as processing aid to improve extrudability of wet mass and spheronization capacity of extrudates. The present study investigated formulation and processing attributes in extrusion and spheronization necessary for design of MCC-free alginate spheroids. The physicochemical characteristics of these spheroids were examined and compared against MCC-loaded alginate spheroids using chlorpheniramine maleate and tolbutamide as water-soluble and poorly water-soluble drugs respectively. Alginate spheroids demonstrated a slower release of hydrophilic drug due to ease of matrix swelling and aggregation in the absence of MCC. This reduced their specific surface area for drug dissolution. Crosslinking of alginate with soluble calcium densified the surface of spheroids and hindered matrix aggregation. It led to faster drug release from alginate than alginate-MCC spheroids. Fast drug release was also noted in spheroids embedded with hydrophobic drug when MCC was absent as drug adsorbent. A complete replacement of MCC with alginate can promote or retard drug release of spheroids as a function of drug–polymer interaction and state of matrix swelling and aggregation.

Formulation of lipid bearing pellets as a delivery system for poorly soluble drugs

The aim of this study was to develop and characterize phospholipid bearing pellets for a poorly water-soluble drug, nisoldipine. Pellets were prepared using extrusion-spheronization technique containing microcrystalline cellulose, soy phosphatidylcholine (SPC), granulating fluid and lactose. Operational parameters such as extrusion speed, spheronization speed and residence time were evaluated. Optimal extrusion speed was found to be 50 rpm with a spheronization speed of 60 Hz and residence time of 2 min. Pellets were characterized for their size, shape, density, flow properties, friability, moisture content, surface morphology and thermal properties. Pellets were evaluated for their assay and in vitro drug release. Mathematical modeling was used to determine the release patterns of the pellets. Pellets were found to be spherical, 600-850 μm size with <0.01% friability and had >70% yield. Scanning electron microscopic (SEM) studies showed a smoother external surface and a porous internal matrix. SPC incorporated pellets resulted in improved dissolution of the drug. Pellets with SPC (20 and 30%) released >90% of the drug within 24 h. The dissolution profiles of the pellets were best fitted to Korsmeyer-Peppas kinetic model. In this study, we could successfully incorporate a lipid and a water-insoluble drug into a pellet formulation with improved dissolution profile.

Preparation and Evaluation of Sustained-Release Doxazosin Mesylate Pellets

Doxazosin mesylate (DXM) sustained release pellets were prepared by an extrusion-spheronization and fluid-bed coating technique. The core pellets containing DXM were prepared by extrusion-spheronization technique, and coated by a fluid-bed coater to control the release of DXM. The factors affecting to properties of pellets, such as diluent content, type and coating level of coating agents and plasticizers were studied in the present study. Polymethacrylate derivatives (Eudragit® RS PO and RL PO) were used for coating agents, and polyethylene glycol 6000 (PEG 6000), triethyl citrate (TEC) and castor oil were as plasticizers. To evaluate the properties of prepared pellets, the size of prepared pellets was investigated by sieve analysis technique and the morphology of pellets was evaluated by scanning electron microscopy. Through the dissolution test, factors that have an effect on the dissolution of the drug were evaluated. As the content ratio of microcrystalline cellulose (MCC) had increased, the dissolution was proportionally sustained. Eudragit® RS PO had more marked sustaining effect on the dissolution rate than Eudragit® RL PO, and the effect was more pronounced with the increased coating level. PEG 6000 was an appropriate plasticizer for DXM pellets, and increasing the content of PEG 6000, was also slightly decreasing the dissolution rate.

Nanoemulsified orlistat-embedded multi-unit pellet system (MUPS) with improved dissolution and pancreatic lipase inhibition

The present research work explores an innovative technological solution to constraints in efficient oral delivery of poorly water-soluble anti-obesity drug orlistat. Nanoemulsion of orlistat and its subsequent transformation into multi-unit pellet system (MUPS) for improved oral delivery was developed. Orlistat nanoemulsion was developed with capryol PGMC as an oil phase and cremophor RH40 as an emulsifier using high-pressure homogenization. Influence of critical processing parameters on globule size distribution, polydispersity index and physical stability of nanoemulsion was evaluated. The optimized nanoemulsion was transformed into MUPS using an extrusion spheronization technique. Optimized formulation was characterized at nanoemulsion as well as MUPS stage. DLS and nanoparticle tracking analysis studies of orlistat nanoemulsion exhibited unimodal size distribution with polydispersity value <0.1. Confocal laser scanning microscopy (CLSM) studies confirmed the presence of uniform spherical nanosized oil droplets of nanoemulsified orlistat. DSC and PXRD studies of MUPS confirmed amorphization of embedded nanoemulsified orlistat. In-vitro dissolution studies in surfactant-reduced media demonstrated remarkable improvement in dissolution compared to pure orlistat and marketed formulation (Xenical Capsules 120 mg, Hoffman-La Roche, Basle, Switzerland). Comparative in-vitro bovine porcine pancreatic lipase inhibition studies of pure orlistat, marketed product and developed MUPS showed 13.57- and 2.41-fold higher lipase inhibition with developed MUPS compared to pure orlistat and marketed products, respectively.

Design of Pistacia lentiscus (mastic gum) controlled release spheroids and investigating the influence of roll compaction

A gum isolated from Pistacia lentiscus of Pistacia genus was used as a release modifier in the preparation of diclofenac sodium spheroids, using the extrusion–spheronization technique. Spheroids prepared were formulated using diclofenac sodium, mastic gum (2.5–15%) and microcrystalline cellulose. Here, variables were studied and spheroids were characterized for average size, surface morphology, friability, bulk density and flow properties. In vitro drug release profile indicated an increase in drug release retardation with increasing mastic gum concentration. The formulated spheroids were stable with respect to their physicochemical characters and drug content over a period of 60 days at different temperatures and relative humidity. The objective of this study was to evaluate the influence of roll compaction and tableting on release of diclofenac sodium. Tablets prepared at different compression force played a key role in the dissolution of drug. Finally, the sustained release properties of spheroids were also maintained after compression.

Pelletization by Extrusion Spheronization Technique: An Excipient Review

Pellets/spheres have gained wide popularity amongst solid dosage forms due to numerous advantages offered by their spheroid nature and each pellet acting as a seperate drug delivery device. At an industrial scale, pellets are manufactured by extrusion-spheronization technique (ES) however, alternative techniques are also available. Such pellets obtained may be used as neutral or drug loaded pellets. Till date, microcrystalline cellulose (MCC) was considered as a golden standard for ES. Prior to MCC, sugar pareils were used as inert cores for drug loading. But due to physicochemical interactions of MCC, and technological difficulties faced during processing of MCC and sugar pellets, the need for the search of newer excipients as a pelletization aid has been triggered. To name a few, chitosan, carrageenan, starch, pectin, talc etc are being explored. The present review is an attempt to take account of the excipients used to design multiple unit particulate systems (MUPS) by ES technique and propose prospective excipient combinations to overcome limitations of existing pellets and excipients thereof. Keywords: Excipients, extrusion-spheronization, microcrystalline cellulose, pellets, pelletization techniques, prospective excipients.