Production of Carbopol® 974P and Carbopol® 971P Pellets by Extrusion‐Spheronization: Optimization of the Processing Parameters and Water Content

Pellets obtained by extrusion‐spheronization represent multiparticulate dosage forms whose interest in intestinal drug delivery can be potentiated and targeted through bioadhesive properties. However, adhesion itself makes the process difficult or even impossible. The problem of tackiness encountered with bioadhesive wet masses was previously eliminated by the use of electrolytes such as CaCl₂. This approach is known to reduce the viscosity of polyacrylic acids by disturbing the interactions between carboxylate groups on adjacent polymer molecules, thereby decreasing their bioadhesive properties. The present study aimed at producing pellets containing carbomers without addition of electrolytes in order to maintain their bioadhesive potentiality at its maximum. Carbopol® 974P (10%, 15% and 20%) and Carbopol® 971P (10%) were used in combination with Avicel® PH101. The extrusion speed (30, 45, 60, 90, and 150 rpm), spheronizer speed (350, 700, 960, 1000, and 1300 rpm), spheronization time (5, 10, 15, and 20 minutes) and amount of water (45%, 50%, 54%, and 58%) were optimized in order to obtain the highest yield of spherical pellets ranging 710–1000 µm in diameter. For pellets containing 10%, 15% Carbopol® 974P or 10% Carbopol® 971P and 45% water content, 30 rpm extrusion speed, 960 rpm, and 10 minutes spheronization speed and time led to the highest yields and sphericities, respectively, 72% and 0.91, 67% and 0.78, and 76% and 0.80. Production of pellets with 20% Carbopol® 974P could be achieved through the increase of the water content up to 58% and implementation of 30 rpm extrusion speed, 1300 rpm, and 10 minutes spheronization speed and time. The yield and sphericity were 42% and 0.78 respectively.     

Use of к-carrageenan,chitosan and Carbopol 974P in extruded and spheronized pellets that are devoid of MCC

The search for excipients to replace microcrystalline cellulose (MCC) in the production of pellets by extrusion-spheronization in cases of drug incompatibility or the lack of pellet matrix disintegration forms the basis of this study. A combination of к-carrageenan as a spheronization aid, chitosan as a diluent and Carbopol^® 974P as a binder in the production of pellets containing no MCC has been investigated using acetaminophen as a model drug. Design of experiments allowed assessment of formulation and processing effects on pellet responses that included size, shape, fines, yield and friability. Statistical analysis revealed that the main factors and some of the two-factor interactions had a significant effect on pellet characteristics. Formulations containing high levels of к-carrageenan required more water to produce a wetted mass with good extrudability and extrudate capable of being spheronized. Although only a low level of Carbopol was used in the formulation, it imparted cohesiveness to the wetted mass as well as the extrudate. Furthermore, it was discovered that Carbopol could act as an extrusion aid, enabling the wetted mass to flow easily through the extruder screen holes without building up heat. Spherical and rugged pellets were produced that met the immediate release criterion.     

Formulation and stability evaluation of ketoprofen sustained-release tablets prepared by fluid bed granulation with Carbopol 971P solution

The objectives of the present study were: (1) to investigate the possibility of using a Carbopol polymeric solution as granulating agent by the fluid bed granulating process; (2) to select a suitable method of tabletting for sustaining the release of ketoprofen for 12 hr; (3) to perform stability studies according to International Committee on Harmonization (ICH) guidelines and photostability on ketoprofen SR tablets; (4) to study the influence of the storage conditions on release kinetics and melting endotherm of ketoprofen; and (5) to predict the shelf-life of the ketoprofen SR tablets. Tabletting ingredients were ketoprofen, anhydrous dicalcium phosphate, Carbopol® 971P, talc, and magnesium stearate. Carbopol® 971P solution (0.8% w/v) was used as a granulating solution in the fluid bed granulator. For comparative evaluation, tablets were also prepared by direct compression and wet granulation, and subjected to dissolution. Tablets prepared by fluid bed granulation technique were stored in incubators maintained at 37, 40, 50, and 60°C, 40°C/75% RH, 30°C/60% RH, and 25°C/60% RH, and in a light chamber with light intensity of 600 ft candle at 25°C. Melting endotherms were obtained for the drug as well as the tablets during stability studies by differential scanning calorimetry. Tablets prepared by fluid bed granulation technique prolonged the release of ketoprofen better than tablets obtained by direct compression and wet granulation. Further, it complied with the requirements of ICH guidelines for stability testing. Higher temperature and humidity (40 ± 2°C/75% RH, 40°C, 50°C, and 60°C) adversely affected the rate and extent of the dissolution. Ketoprofen SR tablets stored in amber-colored bottles demonstrated a good photostability for 6 months at 600 ft candle. The shelf-life of the formulation was predicted as 32 months.     

Influence of process variables on physical properties of the pellets using extruder and spheronizer

Placebo pellets containing lactose and microcrystalline cellulose (Avicel PH101®) ratio 60:40 were prepared by the extrusion-spheronization process. The influence of processing variables, including the spheronizer speed, the spheronization time, the binder type, and the concentration and amount of water content on physical properties of the pellets, were studied. The sphericity of pellets was increased with increasing spheronizer speed during wet mass process. When spheronization time was increased, sphericity, smooth surface, and particle size of pellets were increased. Increasing binder concentration will increase particle size. Pellets using HPC-M® as a binder at high spheronizer speeds showed spherical shape, narrow size distribution, and good flow properties when compared with Methocel E-15LV®, HPC-L®, and Methocel A4M®. In addition, increasing HPC-M concentration had no effect on shape and particle size of pellets. The amount of water content was found to affect shape, flow rate, and density. In summary, suitable conditions consisted of 2% w/w of HPC-M, 40% w/w of water, and 15 min of spheronization time at 951 rpm of spheronizer speed.     

Production and characterization of pellets using Avicel CL611 as spheronization aid

Purpose: The study looked into the feasibility of producing pellet using Avicel CL611 as spheronization aid by the extrusion/spheronization technique.

Methods: Pellets were formulated to contain either 20% or 40% Avicel CL611 and lactose monohydrate as the other sole ingredient. Water is used as liquid binder. Quality of pellets and extrudates were analyzed for size distribution, shape, surface tensile strength and disintegration profile.

Results: More water was needed when higher Avicel CL611 fraction was used during the production of pellets. The pellets of larger size were obtained by increasing the water content. Pellets with aspect ratios of ～1.1 were produced with high spheronization speed at short residence time. Higher tensile strength was achieved when increasing the water content and the fraction of Avicel CL611 during pellet production. These pellets also took longer time to disintegrate, nonetheless all the pellets disintegrated within 15?min. A positive linear relationship was obtained between the tensile strength and time for pellets to disintegrate.

Conclusion: Strong but round pellets that disintegrate rapidly could be produced with Avicel CL611 as spheronization aid using moderately soluble compounds such as lactose.     

Oral sustained-release bioadhesive tablet formulation of didanosine

The objective of this study was to formulate a hydrogel-forming bioadhesive drug delivery system for oral administration of didanosine (ddI). The aim of this tablet dosage form is to improve the oral absorption of ddI by delivering it in small doses over an extended period and localizing it in the intestine by bioadhesion. Compressed tablets of ddI using Polyox® WSRN-303, Carbopol® 974P-NF, and Methocel® K4M as the bioadhesive release rate-controlling polymers were prepared. The effect of polymer concentration on the release profile and in vitro bioadhesion of the matrix tablets was studied. Tablet formulations with Polyox WSRN-303 (10%) and Methocel K4M (30%) showed 93 and 90% drug release, respectively, after 12 h. The drug release was found to be linear when fitted in the Higuchi equation (square-root time equation), suggesting zero-order release. Carbopol 974-P-NF was found to inhibit the complete release of ddI because of drug-polymer interaction; hence, is not suitable for formulation of ddI. Drug diffusion and swelling of the polymer (anomalous Fickian release) was found dominant in ddI release. In general, in vitro bioadhesion increased with an increase in polymer concentration. Tablets containing a single polymer can be designed to form hydrogels serving the dual purpose of bioadhesion and sustained release.     

Naproxen Controlled Release Matrix Tablets: Fluid Bed Granulation Feasibility

Abstract

The pellets of ascorbic acid were prepared from wet granulation using modifided spherical agglomeration technique, named as wet pelletization, in liquid media. The wet granules made by conventional method were placed into the baffled cylinderical vessel which was previously filled with water saturated ethylether. The wet granules were composed of ascorbic acid, microcrystalline cellulose and 3% of aqueous PVP K-30 solution as binding agent. To prepare highly spherical pellets with narrow size distribution, the system, at first, was agitated strongly about 1,500 rpm for 10 min with screw type agitator. Then the medium was changed to an anhydrous ethylether and agitated slowly about 900 rpm until pellets are shaped and densified. The shape and size distribution of pellets depend largely on the amounts of binding solution and the proportion of microcrystalline cellulose at fixed agitation speed. This wet pelletization technique was simple, reproducible and might have application for the spheronization of other hydrophilic drugs.     

The Preparation of Ascorbic Acid Pellets Using the Wet Pelletization Process in Liquid Media

The pellets of ascorbic acid were prepared from wet granulation using modifided spherical agglomeration technique, named as wet pelletization, in liquid media. The wet granules made by conventional method were placed into the baffled cylinderical vessel which was previously filled with water saturated ethylether. The wet granules were composed of ascorbic acid, microcrystalline cellulose and 3% of aqueous PVP K-30 solution as binding agent. To prepare highly spherical pellets with narrow size distribution, the system, at first, was agitated strongly about 1,500 rpm for 10 min with screw type agitator. Then the medium was changed to an anhydrous ethylether and agitated slowly about 900 rpm until pellets are shaped and densified. The shape and size distribution of pellets depend largely on the amounts of binding solution and the proportion of microcrystalline cellulose at fixed agitation speed. This wet pelletization technique was simple, reproducible and might have application for the spheronization of other hydrophilic drugs.     

Bioadhesive Polymer Buccal Patches for Buprenorphine Controlled Delivery: Formulation, In-vitro Adhesion and Release Properties

A new bioadhesive polymer patch formulation for buprenorphine controlled delivery and consisting of polyisobutylene, polyisoprene, and Carbopol® 934P was prepared using a two-roll milling method. Carbopol® 934P was the bioadhesive of choice for the current formulation because it demonstrated a higher average peeling strength than hydroxypropyl methylcellulose, chitosan, or acacia as measured during in vitro testing. Other in vitro analyses showed that the milling process did not alter the viscosity or the thermodynamic and rheologic properties of polyisobutylene and polyisoprene. Nearly 75% of the buprenorphine was released from the patches following a 24 hour incubation in phosphate buffer (pH = 7). Data obtained from dissolution studies suggested that the major mechanism of buprenorphine release is patch swelling. It was also shown that patch adhesion increased with increasing thickness and up to three months of aging had little effect on adhesive properties. In addition, this formulation maintained the majority of its adhesive strength for at least 24 hours with a linear decline in average peeling load thereafter. In conclusion, buccal patches consisting of a homogeneous mixture of polyisobutylene, polyisoprene, and Carbopol® 934P formed by a two-roll milling process appear to possess physical properties that are well suited for the transmucosal controlled delivery of buprenorphine.     

Use of crospovidone as pelletization aid as alternative to microcrystalline cellulose: effects on pellet properties

Background: Microcrystalline cellulose (MCC) is the most important pelletization aid in extrusion/spheronization. Because of known disadvantages, the search for substitutes is ongoing. In this context, crospovidone has proven to offer substantial advantages as pelletization aid because of its ability to turn low-soluble active ingredients into fast-dissolving stable pellets. Method: Pellets from crospovidone with different amounts of paracetamol, hydrochlorothiazide, and spironolactone as model drugs were prepared by extrusion/spheronization. For comparison, pellets with MCC as extrusion aid were also produced. The pellets of different formulations were evaluated in terms of yield, aspect ratio, mean Feret diameter, 10% interval fraction, tensile strength, disintegration, and drug release profile. Results: Only crospovidone types exhibiting small particle sizes are suitable as pelletization aid. While maintaining the pharmaceutical quality aspects, it was possible to incorporate up to 60% (w/w) active pharmaceutical ingredients (API) into pellets with crospovidone. The most distinguished differences between pellets based on crospovidone and MCC are the disintegration and drug release behavior. The pellets containing binary mixtures of the low-soluble APIs and crospovidone resulted in fast release in contrast to the pellets with MCC as pelletization aid, which exhibited a slow release. Conclusion: Crospovidone shows an excellent behavior as pelletization aid and produces fast-releasing pellets even with low-soluble APIs.     

Preparation of lipid aspirin sustained-release pellets by solvent-free extrusion/spheronization and an investigation of their stability

A novel solvent-free extrusion/spheronization technique was investigated for preparing stable aspirin sustained-release pellets. Lipids as binders and the matrix in this technique were extruded below their melting points, and spheronized in a thermomechanical process. Four types of lipids (adeps solidus, Compritol(?) 888 ATO, Precirol(?) ATO5 and Compritol(?) HD5 ATO) and their admixture in different ratios were used to obtain spherical and extended-release pellets. Pellets containing 80% aspirin, 15% adeps solidus and 5% Compritol(?) 888 ATO had the best spherical geometry and met the dissolution requirements of aspirin extended-release tablets in USP 31. Storage stability studies showed that the content of free salicylic acid increased sharply in the traditional pellets produced by wet extrusion/spheronization, from 1.91 to 7.84%, whereas there was little increase in the lipid pellets (from 0.48 to 1.08%). The dissolution rate from the optimal pellets (F11) stored at 26°C did not change, but became faster at 40°C/RH75% after 5 months. Powder X-ray diffraction, scanning electron microscopy (SEM) and differential scanning calorimetry were used to investigate the physical properties of the pellets during stability testing. The increase in the rate of drug release from aged pellets (40°C/RH75%) may result from the partially melted adeps solidus observed in SEM photographs. This study suggests that it is possible to prepare sustained-release pellets by solvent-free extrusion/spheronization using an appropriate mixture of lipids with high stability. In particular, this novel technique is excellent for hygroscopic drugs.     

Rheological,mechanical, and bioadhesive behavior of hydrogels to optimize skin delivery systems

Background: Hydrogels are widely used for cutaneous formulations; thereby comparing the bioadhesive properties of polymers with a view to prolong the residence time of topical drugs on the skin would be very useful to design novel topical drug delivery systems.

Aim: The objective of this study was to correlate data from rheological studies and texture profile analysis, with bioadhesion on the skin.

Methods: Polyacrylic acid polymers used were carbomer homopolymer type A (C971) and type B (C974), and polycarbophil (PP) dispersed in water at various concentrations (0.1, 0.5, 1.0, 1.5, 2.0, 3.0, 5.0%, w/v). Rheological, texture, and bioadhesive properties were determined to compare the hydrogels.

Results: Rheological analysis showed that all samples exhibited pseudoplastic behavior with thixotropy. Texture profile analysis showed that compressibility, hardness, and adhesiveness of the hydrogels were dependent on the polymer concentration, and the cohesion values were high. Bioadhesion of C974 and PP at 0.5 and 2% was of the same magnitude, while all samples of C971 had lower values. The bioadhesion of 5% C974 was the highest, while that 5% PP was lower, possibly because PP showed the greatest hardness and this rigidity may decrease the interaction of the polymer with the skin.

Conclusion: A comprehensive comparative rheological and textural analyses of several polymers for topical systems were undertaken in terms of their bioadhesion. Therefore, it is possible to conclude that these polymers can be used for optimization of drug delivery systems on the skin.     

Differences in characteristics of pellets prepared by different pelletization methods

Pellets are currently a very popular dosage form for oral application. They can be prepared by several pelletization techniques. Extrusion/spheronization, commonly used in the pharmaceutical industry, and modern agglomeration in a rotoprocessor were the methods chosen for pellet preparation in our study. Theophylline (in 10% to 65% concentration) was the model drug, lactose monohydrate was used as filler, microcrystalline cellulose Avicel® PH 101 was thespheronization enhancer, and the wetting agent was purified water. Both techniques led to the formation of pellets of appropriate shape and mechanical properties. Pellets of a higher density, hardness, lower friability, and slightly slower dissolution profiles were obtained by extrusion/spheronization. This method of pelletization also led to production of particles with narrower size distribution and bigger yield of pellets with the requested size.     

Development of a tamsulosin hydrochloride controlled-release capsule consisting of two different coated pellets

Tamsulosin hydrochloride (TSH) controlled-release capsule (pellets) was successfully prepared using a novel, simple, and flexible multiunit drug delivery system, which consisted of two different coated pellets. The TSH-loaded core pellets consisting of microcrystalline cellulose (MCC), lactose, Carbopol(R) 974P, and the active agent, were prepared by extrusion/spheronization method. Eudragit NE30D and Eudragit L30D-55 were used as the coating materials to prepare sustained-release (SR) pellets and enteric-release (ER) pellets. The coated pellets were prepared using two different equipments: centrifugal coater and fluidized-bed coater. By adjusting the ratio of SR and ER pellets, more than one blend ratios, which meet the in vitro release criterion were obtained. A similarity factor (f(2)) was employed to choose the optimum proportion compared with the commercial product (Harnal capsule). The morphology of the pellet surfaces was examined by scanning electron microscopy (SEM) before and after dissolution. The release profiles were significantly affected by changing the proportions of SR and ER. The optimum ratio is SR:ER = 2:1 using a centrifugal coater (f(2) = 61.93) and SR:ER = 3:1 using a fluidized coater (f(2) = 66.42). This result suggests that blending these two-part pellets (SR and ER) can provide an alternative to preparing a controlled-release dosage form, instead of blending of the coating polymer.     

Differences in Characteristics of Pellets Prepared by Different Pelletization Methods

Pellets are currently a very popular dosage form for oral application. They can be prepared by several pelletization techniques. Extrusion/spheronization, commonly used in the pharmaceutical industry, and modern agglomeration in a rotoprocessor were the methods chosen for pellet preparation in our study. Theophylline (in 10% to 65% concentration) was the model drug, lactose monohydrate was used as filler, microcrystalline cellulose Avicel® PH 101 was thespheronization enhancer, and the wetting agent was purified water. Both techniques led to the formation of pellets of appropriate shape and mechanical properties. Pellets of a higher density, hardness, lower friability, and slightly slower dissolution profiles were obtained by extrusion/spheronization. This method of pelletization also led to production of particles with narrower size distribution and bigger yield of pellets with the requested size.     

Preparation and characterization and release properties of Eudragit RS based ibuprofen pellets prepared by extrusion spheronization: effect of binder type and concentration

Objective: The effects of type and concentration of binding agent on properties of Eudragit RS based pellets were studied.

Materials and methods: Pellets containing ibuprofen (60%), Eudragit RS (30%), Avicel (10%) were prepared by extrusion spheronization. PVP K30, PVP K90, HPMC 6cp, HPMC K100LV or HPMC K4M were used as binders in concentrations of 2, 4 or 6% based on the total weight of formulation. The process efficiency, pellet shape, size distribution, crushing strength, elastic modulus and drug release were examined. The effect of curing on pellet properties was also investigated.

Results: The process of extrusion spheronization became difficult with increase in binder viscosity and/or concentration. An increase in binder viscosity and/or concentration resulted in reduction in the yield of pellets, wider particle size distribution and departure from spherical shape especially in the case of HPMC binder. The crushing strength and elastic modulus of pellets decreased with increase in PVPs concentration. However this was not the case for pellets containing HPMCs. Drug release rate increased as the concentration of binder increased. Pellets containing 2%w/w of PVP K30 showed the slowest release rate. For those pellets with brittle nature, curing changed the behavior of pellet under mechanical test to plastic deformation. Yield point and elastic modulus of all formulations decreased after curing. Curing decreased the drug release rate.

Conclusion: Binder type and concentration significantly affected the properties of pellets. For production of sustained release ibuprofen Eudragit RS based pellets lower viscosity binders (PVP K30) with concentrations less than 4%w/w was optimum.     

The Use of β-Cyclodextrin as a Pelletization Agent in the Extrusion/ Spheronization Process

Abstract

The use of β-cyclodextrin for the preparation of pellets by the extrusion/spheronization process is described for different formulations and processing conditions. Sieve analysis and friability tests were performed to assess the physical and technological characteristics of pellets. Satisfactory products were obtained with β-cyclodextrin contents up to 90% by weight.     

Influence of the standing time of the extrudate and speed of rotation of the spheroniser plate on the properties of pellets produced by extrusion and spheronization

The aim of the investigation was to study the influence of the standing time of the extrudate prior to spheronization and the speed of rotation expressed as linear peripheral velocity of the spheroniser plate on the properties of pellets using a 5² factorial experiment. Pellets composed of diclofenac sodium (5%), lactose monohydrate (20%) and microcrystalline cellulose (75%), prepared with water as the liquid binder (total solids to liquid ratio 1:0.675) using a screen extruder were produced after various standing times of the extrudate (ranging from immediate spheronization to 2 h) and at different rotational speeds ranging from 770 to 2900 rpm, which translates into a linear peripheral velocity of the friction plate from 4.84 to 18.22 m/s. The relative yield in the practically used pellet size fraction of 0.71–1.44 mm depended significantly on the standing time of the extrudate. Pellets produced at the lowest linear peripheral velocity were not round, and this was not affected by the standing time of the extrudate. Both the surface tensile strength and the density of the pellets were related to the extrudate standing time and the linear peripheral velocity, whereby the two factors were found to interact. However, neither of the process parameters nor the pellet properties themselves appeared to have an influence on the dissolution of the drug.     

A Factorial Approach to High Dose Product Development by an Extrusion/Spheronization Process

Extrusion/spheronization technology has been used for preparing high drug-loaded pellets. Typical formulations include 40-60% microcrystalline cellulose (MCC) to impart the plastic characteristics required for this process. Studies have suggested that pellets containing greater than 80% drug are difficult to process and require special grades of MCC. Most of these studies focused on either the process or formulation aspects of the product and failed to explore the interactions of process and product. Statistical experimental designs are well suited for exploring both process and product variables and their interactions with each other. This study addresses pelletization of a high dose drug with low density. A Nica® radial (basket-type) extruder was used in extrudate preparation, followed by spheronization on a serrated plate spheronizer. A Plackett-Burman screening design was employed to investigate product and process parameters affecting final pellet drug content, density and roundness. MCC type and concentration, water concentration, spheronizer speed and residence time and extruder screen size were found to be statistically significant in imparting desirable attributes to the final product. Wet mixing time, extruder feed rate and extrusion rate did not significantly affect pellet properties     

Development of a Tamsulosin Hydrochloride Controlled-Release Capsule Consisting of Two Different Coated Pellets

Tamsulosin hydrochloride (TSH) controlled-release capsule (pellets) was successfully prepared using a novel, simple, and flexible multiunit drug delivery system, which consisted of two different coated pellets. The TSH-loaded core pellets consisting of microcrystalline cellulose (MCC), lactose, Carbopol^® 974P, and the active agent, were prepared by extrusion/spheronization method. Eudragit^® NE30D and Eudragit^® L30D-55 were used as the coating materials to prepare sustained-release (SR) pellets and enteric-release (ER) pellets. The coated pellets were prepared using two different equipments: centrifugal coater and fluidized-bed coater. By adjusting the ratio of SR and ER pellets, more than one blend ratios, which meet the in vitro release criterion were obtained. A similarity factor (f₂) was employed to choose the optimum proportion compared with the commercial product (Harnal^® capsule). The morphology of the pellet surfaces was examined by scanning electron microscopy (SEM) before and after dissolution. The release profiles were significantly affected by changing the proportions of SR and ER. The optimum ratio is SR:ER?=?2:1 using a centrifugal coater (f₂?=?61.93) and SR:ER?=?3:1 using a fluidized coater (f₂?=?66.42). This result suggests that blending these two-part pellets (SR and ER) can provide an alternative to preparing a controlled-release dosage form, instead of blending of the coating polymer.