Evaluation of Drug Layering and Coating: Effect of Process Mode and Binder Level

Top-spray layering and Wurster coating are common techniques for layering and coating operations, respectively. In the present study, the efficiency of these techniques was compared with rotolayering and rotocoating in the Niro-Aeromatic MP-1 Rotoprocessor. Also, three different polymers were evaluated as binding agents in the layering procedure. A solution containing drug and a suitable binder was layered onto nonpareil seeds followed by coating with a water-insoluble polymer. The pellets were evaluated for physical properties, surface characteristics and drug content (assay). The process efficiency was evaluated from process time, assay, and SEM data of the pellets. Efficiency of layering was compared between toplayering and rotolayering processes while efficiency of coating was compared between Wurster coating and rotocoating processes. The physical properties of pellets were used to explain the influence of binder nature and level of use in the layering process.     

Application of Powder-Layering Technology and Film Coating for Manufacture of Sustained-Release Pellets Using a Rotary Fluid Bed Processor

The main objective of this study was to prepare pellets in a Roto-processor using the powder-layering process onto inert nonpareils and to evaluate the applicability of the Roto-processor setup for film coating. Nonpareils were loaded with phenylpropanolamine hydrochloride and coated with ethyl cellulose polymeric dispersion (Surelease®). The drug loading was analyzed to test the eficiency of powder layering. The effect of polymer level on the drug release from the pellets and the pore size distribution in the membrane were studied. The yields for powder layering were greater than 90%. The dissolution studies on the Blm-coated pellets showed sustained release over a 10-hr period. The time required for 50% of drug release increased and the mean pore diameter decreased with an increase in polymer coating.     

The Effect of Polymer Coating Systems on the Preparation, Tableting, and Dissolution Properties of Sustained-Release Drug Pellets

The preparation of sustained-release (SR) drug pellets and their tablets was evaluated. Pellets containing indomethacin, pseudoephedrine hydrochloride (P-HCl), or pseudoephedrine (P) base were prepared by spraying a mixture of drug, Eudragit S-100 resins, dibutyl sebacate, and alcohol onto nonpareil seeds via the Wurster-column process. The oven-dried drug/Eudragit S-100 (DS) pellets were coated with different levels of Eudragit RS and Eudragit S-100 acrylic resins. Tablets containing P-HCl or P-base SR pellets, microcrystalline cellulose, and Methocel K4M were compressed. The solubility of the drug entity in the polymer solution was found to be the most critical factor affecting the yield and the physical properties of the resultant DS pellets. Dissolution studies of Eudragit RS coated drug pellets demonstrated that the release profiles depended not only on the physicochemical properties of the drug, particularly aqueous solubility, but also on the coating levels. The release rate profiles of the matrix tablets can be modified by varying the types of P-HCl or P-base SR pellets in the formulation. The release of drug from the matrix tablets is primarily matrix controlled.     

Drug-beta-cyclodextrin containing pellets prepared with a high-shear mixer

This work was aimed at investigating the preparation of β-cyclodextrin-microcrystalline cellulose pellets by means of a high-shear mixer, both in the absence or in the presence of ibuprofen as model drug. Drug loading of pellets was accomplished by means of two alternative techniques: 1) solution layering or 2) powder layering. The prepared pellets were characterised in terms of size distribution, shape factor, friability and dissolution rate. The interaction between ibuprofen and β-cyclodextrin was monitored by Differential Scanning Calorimetry (DSC). Micro Fourier Transform Infrared spectroscopy (MicroFTIR) was applied to determine the distribution of components within each pellet on a micro scale. Pellets with narrow size distribution and containing up to about 90% of BCD were prepared using water as binder. The process yield resulted around 84 and 63% for drug-free and medicate pellets respectively. Drug loaded pellets with favourable technological and biopharmaceutical characteristics can be obtained both by powder or solution layering techniques. The latter proved to be more suitable for producing pellets with high drug contents, reduced friability and high drug dissolution rates.     

三七超微粉体与细粉、不同目数范围粉体的粒度分布和显微形貌特征的比较

通过比较三七超微粉体、细粉(三七常规饮片)以及不同目数范围粉体(三七细粉经多次筛分得到的粉体)在粒度分布、显微形貌特征方面的差异,探讨了超微粉碎技术应用于中药三七加工的优势。应用激光粒度分析仪对三七超微粉体与细粉、不同目数范围粉体的粒度及其分布进行表征,观察其显微形貌特征。粒度分布测试和显微形貌观察的结果表明,超微粉粒度分布在0.30～24μm,大部分粉体达到了10μm以下,呈对称的单峰分布,引起团聚的作用力为各种表面力,说明超微粉体均匀度高质量易控。三七细粉及不同目数范围的粉体粒度分布范围在2～190μm,分布不对称,引起团聚的作用力为重力的等质量力,说明其均匀度差,质量难以控制。     

Coated pelletized dosage form: Effect of compaction on drug release

Abstract

The goal of this study was to investigate the effect of compaction of a coated pelletized dosage form on drug release. Three sizes of microcrystalline cellulose and hydrous lactose pellets containing 4% chlorpheniramine maleate (CPM) were manufactured using a rotogranulator (Glatt GPCG-1). Pellets having mesh cuts of: 590–840 μm (20/30 mesh); 420–590 μm (30/40 mesh); and 250–420 μm (40/60 mesh) were then coated with an aqueous ethylcellulose pseudolatex dispersion plasticized with 24% dibutyl sebacate (DBS). Percent weight gains were 25, 30 and 35% for the 20/30, 30/40 and 40/60 mesh pellets, respectively. Coated pellets were blended with 39.3% by weight excipients, then mixtures lubricated and compacted using a Korsch PH106 instrumented rotary press set at 5 kN and 20 rpm (0.30 s contact time). Magnesium stearate was used as the lubricant at a 0.7% level. Excipients used were microcrystalline cellulose, spray dried lactose, pregelatinized starch, dicalcium phosphate, spray dried sorbitol, polyethylene glycol 8000 powder and compressible sugar. Results indicated this coating to be suitable for the controlled release of CPM from small pellets (250–840 μm). However, films did not have the appropriate mechanical properties to withstand compaction stress without rupturing, regardless of the pellets particle size and excipients used. After compaction, depending on pellet size, between 65–100% CPM was released after one hour as opposed to 10–30% for the non-compacted material. The controlled release properties of the pellets were therefore lost during the process.     

Drug‐β‐Cyclodextrin Containing Pellets Prepared with a High‐Shear Mixer

This work was aimed at investigating the preparation of β‐cyclodextrin‐microcrystalline cellulose pellets by means of a high‐shear mixer, both in the absence or in the presence of ibuprofen as model drug. Drug loading of pellets was accomplished by means of two alternative techniques: 1) solution layering or 2) powder layering. The prepared pellets were characterised in terms of size distribution, shape factor, friability and dissolution rate. The interaction between ibuprofen and β‐cyclodextrin was monitored by Differential Scanning Calorimetry (DSC). Micro Fourier Transform Infrared spectroscopy (MicroFTIR) was applied to determine the distribution of components within each pellet on a micro scale. Pellets with narrow size distribution and containing up to about 90% of BCD were prepared using water as binder. The process yield resulted around 84 and 63% for drug‐free and medicate pellets respectively. Drug loaded pellets with favourable technological and biopharmaceutical characteristics can be obtained both by powder or solution layering techniques. The latter proved to be more suitable for producing pellets with high drug contents, reduced friability and high drug dissolution rates.     

Preparation and Evaluation of Sustained release Indomethacin Nonpareil Seeds

Abstract

A controlled release oral drug delivery system of Indomethacin was developed using nonpareil seeds as a matrix system. These seeds were coated with different concentrations of drug release controlling materials viz Eudragit RL100 and Eudragit RS100, and bees wax. The particle size of the seeds and the concentration as well as the type of the drug release controlling Eudragits has a pronounced effect on the release rate profile of Indomethacin. All types of formulations showed release rate pattern which can be described by both first-order and diffusion controlled mechanism.     

Effect of particle size distribution on hydrodynamics of pneumatic conveying system based on CPFD simulation

The effect of particle size distribution on the hydrodynamics of dilute-phase pneumatic conveying system was analyzed using computational particle fluid dynamics (CPFD) simulation. The influence of a simulation parameter, i.e., correction factor of drag coefficient (k), on the hydrodynamics of pneumatic conveying system was determined via CPFD simulation. When results of simulation were compared with experimental data of previous studies, the average error of pressure drop per length predicted by the CPFD approach with the correction factor was below 4.4%. Saltation velocity and the pressure drop per unit length declined as the drag force coefficient increased. Simulation results also revealed that the pressure drop per length and the saltation velocity were decreased when the fine powder fraction in the particle size distribution was increased, although the width of particle size distribution was widened, and the standard deviation was increased. Finally, the Relative Standard Deviation (RSD) of pressure drop per length was measured and compared with median diameter (d₅₀), Sauter mean diameter, geometric mean diameter, and arithmetic mean diameter. The RSD of the Sauter mean diameter was 5.8%, approximately twice less than the RSD value of d₅₀ commonly used in pneumatic conveying.     

Effect of vibro-milling time on phase formation and particle size of lead zirconate nanopowders

A perovskite phase of lead zirconate, PbZrO₃, nanopowder was synthesized by a solid-state reaction via a rapid vibro-milling technique. The effect of milling time on the phase formation and particle size of PbZrO₃ powder was investigated. Powder samples were characterized using TG-DTA, XRD, SEM and laser diffraction techniques. It was found that an average particle size of 50 nm was achieved at 25 h of vibro-milling after which a higher degree of particle agglomeration was observed upon continuation of milling to 35 h. In addition, by employing an appropriate choice of milling time, a narrow particle size distribution curve was also observed.     

Evaluation of A High-Speed Pelletization Process and Equipment

Abstract

A single step high-speed centrifugal pelletization procedure is described. Pellets of three model drugs of varying solubilities were prepared and characterized. Scanning electron microscopy showed that the external layer which is composed of binder and drug is very porous relative to the nonpareil seed core material. Bulk density measurements also confirmed the loose structural makeup of the drug layer. Preparation of pellets from small non-pareil seeds provided particles that have high drug content and are amenable to high dose formulations. Common wet granulation binders such as polyvinylpyrrolidone, sodium carboxymethylcellulose and gelatin exhibited good binding capacities and generated excellent pellets.     

Preparation of cobalt nanoparticles by hydrogen reduction of cobalt chloride in the gas phase

Cobalt nanoparticles were produced by the hydrogen reduction of cobalt chloride vapor in a multistage tubular aerosol flow reactor. Reaction zone temperature, preheating temperature, mole fractions of CoCl₂ and H₂, and residence time were considered as key process variables for the control of particle size and size distribution. Ranging from 50 to 78 nm in average diameter, cobalt nanoparticles with narrow size distributions were synthesized throughout our experiments. All of the considered process variables affected the particle size and size distribution in the synthesis of cobalt nanoparticles. As the reaction zone temperature and the CoCl₂ mole fraction increased, the average particle diameter increased. But the average particle diameter decreased as the residence time of reactants increased.     

The Effect of Particle Size on Some In-Vitro and In-Vivo Properties of Indomethacin-Polyethylene Glycol 6000 Solid Dispersions

Abstract

Drug release from indomethacin-polyethylene glycol solid dispersions has been examined using three different size fractions. Release rates at a stirring rate of 100 rpm were generally higher from the 250-375 micron fraction than from particles in the ranges 125-188 and 500-750 microns. Release rates were highest from dispersions containing 5% indomethacin and showed a 240-fold increase at 100 rpm and a 1200-fold increase at 50 rpm over those at the same stirring rate of indomethacin alone (125-188 microns). As the percentage of indomethacin in the dispersions increased (5 to 40%) the dissolution rates decreased and for dispersions containing .15% indomethacin, complete solution of the drug was not achieved within 2 hours. The 500-750 micron fraction of the dispersion containing 10% indomethacin was significantly more gastro-toxic than particles of 125-188 microns.     

Discharge Characteristics of Polydisperse Powders through Conical Hoppers. Part 1: Predictions for Fine, Granular, Free Flowing Powders

Discharge characteristics of fine polydisperse granular powders of equal-solid density and near-spherical particle shape through a conical hopper were investigated by measuring solid discharge rates of powders. Effects of orifice size of hopper and size distribution of powders on discharge rate were determined by means of experiments conducted for six different sizes of hopper orifice and three different powder types under gravity flow conditions. A new effective mean diameter characterizing polydisperse powders is first introduced and determined from the particle size versus weight fraction distribution of a powder as the size corresponding to 50% cumulative weight fraction. This effective mean diameter was efficiently used in two modified forms of the Beverloo equation to predict discharge rates of polydisperse powders through hopper orifices.     

Coated pelletized dosage form: Effect of compaction on drug release

The goal of this study was to investigate the effect of compaction of a coated pelletized dosage form on drug release. Three sizes of microcrystalline cellulose and hydrous lactose pellets containing 4% chlorpheniramine maleate (CPM) were manufactured using a rotogranulator (Glatt GPCG-1). Pellets having mesh cuts of: 590-840 μm (20/30 mesh); 420-590 μm (30/40 mesh); and 250-420 μm (40/60 mesh) were then coated with an aqueous ethylcellulose pseudolatex dispersion plasticized with 24% dibutyl sebacate (DBS). Percent weight gains were 25, 30 and 35% for the 20/30, 30/40 and 40/60 mesh pellets, respectively. Coated pellets were blended with 39.3% by weight excipients, then mixtures lubricated and compacted using a Korsch PH106 instrumented rotary press set at 5 kN and 20 rpm (0.30 s contact time). Magnesium stearate was used as the lubricant at a 0.7% level. Excipients used were microcrystalline cellulose, spray dried lactose, pregelatinized starch, dicalcium phosphate, spray dried sorbitol, polyethylene glycol 8000 powder and compressible sugar. Results indicated this coating to be suitable for the controlled release of CPM from small pellets (250-840 μm). However, films did not have the appropriate mechanical properties to withstand compaction stress without rupturing, regardless of the pellets particle size and excipients used. After compaction, depending on pellet size, between 65-100% CPM was released after one hour as opposed to 10-30% for the non-compacted material. The controlled release properties of the pellets were therefore lost during the process.     

The effect of particle size distribution on barite reduction

The present study is a follow-up of investigation on barite reduction to barium sulfide as a function of starting particle size distribution and temperature of reaction. In this work we study the high temperature reduction process of barite from the view point of particle size distribution. Conversion-time data have been obtained using iodometry method in each isothermal condition. A modified kinetic model used to express the carbothermic reduction process. To obtain the values of activation energy and frequency factor, the same expression was selected for each sample at all temperatures. The rate of reaction is found to be related to the particle size distribution and the gasification reaction of coke which has influence on reduction process. The kinetic parameters calculated from standard analysis of isothermal kinetic data indicated that the particle size of barite controlled the reaction when it was coarser than 400 mesh both in presence and absence of catalyst.     

Particle size induced heterogeneity in compacted powders: Effect of large particles

We investigated the effect of particle size distribution on heterogeneity of compacted powders. We used experiments and discrete particle based simulations to compact powders, test the mechanical strength of the compact, and study the microstructure of the compact. A metallic powder which has a wide particle size distribution was used in the experiments. We found that the compaction profile is not reproducible when particles larger than 1/6 of the die diameter are present in the powder sample. The presence of these large particles generate a highly heterogeneous inter-particle contact and bonding forces. The discrete particle simulations showed that for these heterogeneous compacts the tensile strength exhibits high variability, even for one compact if the diametrical compression force is applied along different axes. Based on these results, it is recommend that the largest particle in a powder compact should not exceed one sixth of the die diameter, which is the same as the recommendation of ASTM International D4767 - 11 for compression test of cohesive soils.     

Particle size distribution and dislocation density determined by high resolution X-ray diffraction in nanocrystalline silicon nitride powders

Two silicon nitride powders were investigated by high resolution X-ray diffraction. The first sample was crystallized from the powder prepared by the vapour phase reaction of silicon tetrachloride and ammonia while the second was a commercial powder produced by the direct nitridation of silicon. Their particle size and dislocation density were obtained by the recently developed modified Williamson–Hall and Warren–Averbach procedures from X-ray diffraction profiles. Assuming that the particle size distribution is log-normal the size distribution function was calculated from the size parameters derived from X-ray diffraction profiles. The size distributions determined from TEM micrographs were in good correlation with the X-ray results. The area-weighted average particle size calculated from nitrogen adsorption isotherms was in good agreement with that obtained from X-rays. The powder produced by silicon nitridation has a wider size distribution with a smaller average size than the powder prepared by vapour phase reaction. The dislocation densities were found to be between about 10¹⁴ and 10¹⁵ m⁻².     

Particle size distribution control and related properties improvements of tungsten powders by fluidized bed jet milling

Fine grinding process of different particle size tungsten powders was carried out by fluidized bed jet milling. The results showed that the jet milling treatment caused deagglomeration of tungsten powders, which led to particles sufficient dispersion and narrow particle size distribution. Grinding gas pressure of 0.70 Mpa made the particles achieve high speed which promoted the particles collision contributing to particle dispersion and shape modification. For tungsten powder with particle size of 3 μm FSSS, a higher packing density with 5.54 g/cm³ was obtained, compared with the 3.71 g/cm³ of the original powder. For tungsten powder with particle size of 1 μm FSSS, the big agglomerates disappeared and the particle size distribution become narrower, while small aggregates about 2–3 μm still exist after the jet milling process. For tungsten powder with particle size of 5 μm and 10 μm FSSS, different medium diameter particle size and narrow particle size distribution of monodisperse tungsten powders can be produced by the optimized jet milling parameters. More important, the effective dispersion, favorable shape modification and precise classification have been achieved in the simple process.     

Development of rapidly dissolving pellets within the Quality by Design approach

Abstract

The purpose of this study was the development of novel, fast disintegrating, effervescent pellets by employing the direct pelletization technique as a single step process. In line with the Quality by Design (QbD) regulatory framework, statistical experimental design was extensively applied to correlate significant formulation and process variables with the critical quality attributes of the product. Pellets were studied with regards to sphericity, size and size distribution. In contrast to the existing multiparticulate platforms, this development integrated only water-soluble excipients to facilitate the multifunctional use of the final dosage form. The application of a screening fractional factorial design augmented to a full factorial design set the roadmap for the rational selection of the composition and process parameters, revealing in parallel the positive contribution of the powder feeder on the CQAs, when the critical process and formulation factors were properly adjusted. The response surface methodology was exploited for the final process optimization phase, which allowed the construction of appropriate mathematical models connecting the input variables and the CQAs under study. The implementation of the desirability function, lead to the optimum formulation and process settings for the production of pellets with narrow size distribution and geometric mean diameter of approximately 800?μm. In conclusion, using a lean approach supported by design of experiments (DoE) techniques within the QbD framework, a novel multifunctional formulation platform has been developed.