Dissolution Rate A Measurement of the Deaggregation of Furosemide Agglomerates During An Interactive Mixing Process

Abstract

Agglomerates of drug particles must be broken down and single particles attached to the carrier to ensure a completely random interactive mixture. Here it was found that the dissolution rates of samples from interactive mixtures compared to suspended furosemide was an indication of the deaggregation of furosemide agglomerates during an interactive mixing process. Deaggregation depended on the forces generated during mixing and was quicker when a high density carrier such as sodium chloride was used.     

Influence of Magnesium Stearate on the Homogeneity of a Prednisone-Granule Ordered Mix

The use of ordered systems has been advocated in the formulation of microdose delivery systems to improve and maintain drug homogeneity during mixing. This study considered the effect of a lubricant such as magnesium stearate on the degree of homogeneity and stability of a preformed prednisone-granule ordered mix. Micronized prednisone was mixed with starch-lactose granules to produce an ordered mix of satisfactory homogeneity. Magnesium stearate in concentrations above and below the theoretical surface saturation of the granule caused negligible change in the degree of homogeneity. Sieve analysis of the mix and subsequent analysis of size fractions for prednisone allowed the prednisone distribution within the mix to be determined. Prednisone was found to be associated with the granules in all the mixes; the magnesium stearate did not compete for the surface adsorption sites and did not dislodge the drug from the granule surface, during mixing and mild demixing conditions. However, a decrease in surface adsorbed prednisone occurred in all mixes (with and without magnesium stearate) under more severe segregating conditions.

Recent research in drug homogeneity studies in microdose tablets has highlighted serious problems in dosage variation¹. Drugs are frequently micronized to improve their release from the solid dosage form. Micronization produces drug particles which are extremely cohesive and interactive. In practice, the adequate mixing of micronized powders with other excipients may be difficult to achieve since this cohesiveness produces aggregation of drug particles and interaction of the drug with the mixer surfaces. In recent years some research effort has been applied to using the interactive nature of drug particles to improve the homogeneity of mixes^2,3. Controlled adsorption of a micronized drug particle onto a carrier particle to produce an “ordered unit” has been shown to minimize segregation within the mix^4,5. Some of the factors affecting the degree of homogeneity of “ordered mixes” have been studied^6,7. However, little research has been conducted on the influence of other excipients on the homogeneity and stability of preformed ordered mixes. A cautionary note on the use of magnesium stearate in ordered mixtures indicated that the lubricant may displace salicylic acid from a sucrose carrier under conditions of segregation⁸. The purpose of this study, therefore, was to evaluate the influence of a third component such as magnesium stearate on the degree of homogeneity and stability of a preformed prednisone-starch lactose granule ordered system during a mixing process.     

Polydisperse Powder Mixtures: Effect of Particle Size and Shape on Mixture Stability

ABSTRACT

The effect of the shape and size of the components on the stability of mixtures was evaluated in binary mixtures of drug and carrier. Aspirin was used as model drug; spray-dried lactose and microcrystalline cellulose were used as carriers. The coefficient of variation (CV) of the drug in the mixture at various time intervals during mixing was used as a measure of homogeneity. The stability of mixtures was assessed under conditions that were conducive to segregation—in this case, prolonged mixing. The pattern of change in CV with time was analyzed in terms of convective, shear, and diffusive mixing stages. The variation resulting from a change in the shape of the carriers was smaller than that resulting from size differences. The segregation rate constant, calculated on the assumption of a first-order mixing process, was found to be larger in mixtures having components of different shape than in mixtures having components of similar shape. In mixtures of micronized drug and carrier, the pattern of change in the CV of drug with mixing time was attributed to the distribution of agglomerates of micronized drug during convective mixing, followed by shearing of agglomerates and, finally, the distribution of the primary particles during diffusive mixing. Mixtures of non-cohesive powders of similar size and shape behaved like random mixtures of non-interacting components.     

Interactive mixture as a rapid drug delivery system

The effectiveness of an interactive mixture as a rapid drug delivery system is compared with that of a solid dispersion. The influences of drug load, particle size, and crystallinity of these test systems are investigated. The interactive mixtures and solid dispersions were prepared from polyethylene glycol (PEG) 3350 and hydrophobic nifedipine drug by means of physical mixing and melting methods, respectively. The formed products were subjected to drug particle size and crystallinity analyses, and dissolution tests. In comparison with the interactive mixtures, the solid dispersions with low drug load were more effective as a rapid drug delivery system, as the size of a given batch of drug particles was markedly reduced by the molten PEG 3350. The rate and extent of drug dissolution were mainly promoted by decreasing effective drug particle size. However, these were lower in the solid dispersions than in the interactive mixtures when a high load of fine drug particles was used as the starting material. This was attributed to drug coarsening during the preparation of the solid dispersion. Unlike solid dispersions, the interactive mixtures could accommodate a high load of fine drug particles without compromising its capacity to enhance the rate and extent of drug dissolution. The interactive mixture is appropriate for use to deliver a fine hydrophobic drug in a formulation requiring a high drug load.     

Interactive Mixture as a Rapid Drug Delivery System

The effectiveness of an interactive mixture as a rapid drug delivery system is compared with that of a solid dispersion. The influences of drug load, particle size, and crystallinity of these test systems are investigated. The interactive mixtures and solid dispersions were prepared from polyethylene glycol (PEG) 3350 and hydrophobic nifedipine drug by means of physical mixing and melting methods, respectively. The formed products were subjected to drug particle size and crystallinity analyses, and dissolution tests. In comparison with the interactive mixtures, the solid dispersions with low drug load were more effective as a rapid drug delivery system, as the size of a given batch of drug particles was markedly reduced by the molten PEG 3350. The rate and extent of drug dissolution were mainly promoted by decreasing effective drug particle size. However, these were lower in the solid dispersions than in the interactive mixtures when a high load of fine drug particles was used as the starting material. This was attributed to drug coarsening during the preparation of the solid dispersion. Unlike solid dispersions, the interactive mixtures could accommodate a high load of fine drug particles without compromising its capacity to enhance the rate and extent of drug dissolution. The interactive mixture is appropriate for use to deliver a fine hydrophobic drug in a formulation requiring a high drug load.     

Polydisperse powder mixtures: effect of particle size and shape on mixture stability

The effect of the shape and size of the components on the stability of mixtures was evaluated in binary mixtures of drug and carrier. Aspirin was used as model drug; spray-dried lactose and microcrystalline cellulose were used as carriers. The coefficient of variation (CV) of the drug in the mixture at various time intervals during mixing was used as a measure of homogeneity. The stability of mixtures was assessed under conditions that were conducive to segregation—in this case, prolonged mixing. The pattern of change in CV with time was analyzed in terms of convective, shear, and diffusive mixing stages. The variation resulting from a change in the shape of the carriers was smaller than that resulting from size differences. The segregation rate constant, calculated on the assumption of a first-order mixing process, was found to be larger in mixtures having components of different shape than in mixtures having components of similar shape. In mixtures of micronized drug and carrier, the pattern of change in the CV of drug with mixing time was attributed to the distribution of agglomerates of micronized drug during convective mixing, followed by shearing of agglomerates and, finally, the distribution of the primary particles during diffusive mixing. Mixtures of non-cohesive powders of similar size and shape behaved like random mixtures of non-interacting components.     

Pharmaceutical Powder Mixing from Randomization to Homogenization

ABSTRACT

The process of powder mixing is one of the most important unit operations during the production of pharmaceutical solid dosage forms. This presentation will address the principle stages of pharmaceutical powder mixing, including: expansion of solid particles, application of three-dimensional shear force to the powder bed, and randomization of particles and maintenance of randomization (no segregation). Theories of powder mixing will also be discussed including random mixing theory (shear mixing, diffusive mixing, convective mixing), non-random mixing theory and ordered mixing theory. A special emphasis will be put on ordered (interactive) mixing because of its relevance to the pharmaceutical systems. Authors' experience in this field will be highlighted.     

Isothermal and Dynamic Microcalorimetry for Quantifying the Crystallization of an Amorphous Drug during Interactive Powder Mixing

This study reports the crystallization of amorphous nifedipine during an interactive mixing process quantified by using isothermal and dynamic microcalorimetry. Interactive mixtures of amorphous nifedipine and uniform glass beads were prepared by mixing in a Turbula® mixer. The difference in the extent of crystallization of amorphous nifedipine during mixing was characterized by the time it took for the crystallization of a known amount of amorphous nifedipine in isothermal calorimetry and the change in the height of the crystallization peak at 65°C in dynamic calorimetry. It was found that both isothermal and dynamic microcalorimetry are useful techniques for quantifying the physical transition of amorphous nifedipine during interactive mixing. The rate and extent of crystallization of amorphous nifedipine depended on both mixing time and speed, but mixing time played a more dominant role because the transformation of amorphous to crystalline nifedipine was greater after 3180 revolutions (9.7%) than after 405 revolutions (0.9%) at 27 rpm. The same trend was observed at 109 rpm, but the percentage of crystalline nifedipine after 3180 revolutions was only 5.2%. This meant that an increase in mixing time rather than speed increased the rate of amorphous to crystalline transformation. The greatest cause for crystal transformation during interactive mixing was the presence of crystal seeds of the thermodynamically stable nifedipine Modification I because the amount of amorphous to crystalline transformation increased from 2.6% for a completely amorphous mixture to 6.6% for a 92:8 mixture of amorphous and crystalline nifedipine when mixed for 30 minutes at 106 rpm.     

Effect of paddle rotational speed on particle mixing behavior in electrophotographic system by using parallel discrete element method

The objective of this paper is to investigate the effect of paddle rotational speed on the mixing behavior in an agitation process of an electrophotographic system by using parallel DEM. The mixing behaviors of beads with different sizes and densities were measured at various paddle rotational speeds by using a high-speed video camera, and were compared with the simulation results. A good agreement in the mixing behavior was obtained and the changes in particle velocity during the mixing were comparable. The simulation for mixing behavior of larger carrier particles suggested that the radial particle mixing was much faster than the axial one. The faster radial mixing is attributed to the fact that there are two radial flows in the system; the one is over the shaft, the other is between the paddle and shaft. The extent of mixing depended on the number of paddle rotations when the rotational speed is larger than 100 rpm, while the mixing under 50 rpm is completed at a smaller number of rotations.     

Isothermal and Dynamic Microcalorimetry for Quantifying the Crystallization of an Amorphous Drug during Interactive Powder Mixing

ABSTRACT

This study reports the crystallization of amorphous nifedipine during an interactive mixing process quantified by using isothermal and dynamic microcalorimetry. Interactive mixtures of amorphous nifedipine and uniform glass beads were prepared by mixing in a Turbula® mixer. The difference in the extent of crystallization of amorphous nifedipine during mixing was characterized by the time it took for the crystallization of a known amount of amorphous nifedipine in isothermal calorimetry and the change in the height of the crystallization peak at 65°C in dynamic calorimetry. It was found that both isothermal and dynamic microcalorimetry are useful techniques for quantifying the physical transition of amorphous nifedipine during interactive mixing. The rate and extent of crystallization of amorphous nifedipine depended on both mixing time and speed, but mixing time played a more dominant role because the transformation of amorphous to crystalline nifedipine was greater after 3180 revolutions (9.7%) than after 405 revolutions (0.9%) at 27 rpm. The same trend was observed at 109 rpm, but the percentage of crystalline nifedipine after 3180 revolutions was only 5.2%. This meant that an increase in mixing time rather than speed increased the rate of amorphous to crystalline transformation. The greatest cause for crystal transformation during interactive mixing was the presence of crystal seeds of the thermodynamically stable nifedipine Modification I because the amount of amorphous to crystalline transformation increased from 2.6% for a completely amorphous mixture to 6.6% for a 92:8 mixture of amorphous and crystalline nifedipine when mixed for 30 minutes at 106 rpm.     

Interactive mixing between agglomerated drug particles and coarse carrier particles

The equation of Egermann¹ was used to calculate the theoretical coefficient of variation in drug content of completely random interactive mixtures containing furosemide and sodium chloride. These coefficients of variation (CV) were compared to that obtained experimentally. Although no free furosemide agglomerates or aggregates were present in the mixtures, the experimental values were consistently higher. This could only be explained if small furosemide aggregates accumulated in clefts and crevices in the sodium chloride particle surfaces. For the system examined random interactive mixtures were produced with furosemide concentrations between 0.05 and 4%     

The Effect of Mixing Variables on the Dissolution Properties of Direct Compression Formulations of Furosemide

The particles of a number of poorly water soluble drugs, for instance furosemide, tend to agglonierate spontaneously and as a result decrease the drug's dissolution properties. This phenomena is undesirable when the drug is to be formulated in a direct compressible formulation. Interactive or ordered mixing with a filler usually rectifies this problem but the drug load is limited to a maxirnuni of ± 5% of the mixture. This is well below the formulation requirements of hrosemide (25 %) and below the maximum drug load which can be handled in dircct compression formulations (± 35 %). The effect of two types of mixers, the mixing time and drug load were investigated for a direct compression formulation of furosemide tablets. A Turbula and a V mixer, both with a volume of 720 ml, were used. The drug was formulated with Ludipress (a commercial direct compression filler, BASF, Germany) at two drug loadings of 20 and 25 %. Magnesium stearate (1 %) was added as a lubricant. A mixture was prepared for each experimental condition. After mixing the whole mixture (120 gram) was tabletted on a Korsch single punch machine producing ± 500 tablets. The crushing strength, mass and disintegration time of ten tablets and the dissolution of six tablets were measured. Dissolutions were donc according to the USP XXII - method 2¹ - in 0, 1 M HCI and a phosphate buffer with pH = 5.8. The intrinsic dissolution rates of some of the mixtures were also deterniined in the two dissolution media. The dissolution properties of the formulations were compared with the properties of Lasix®, a commercially available furoseniide product. which is not manufactured by dircct compression. The dissolution rates of the formulations mixed in the Turbula mixer were significantly higher than those mixed in the V miser. The area under the dissolution curves increased as a function of niixing time for both mixers. The best dissolution results were obtained for formulations with a 20 % drug load and mixed for 120 minutes in the Turbula miser. The dissolution curves for these formulations compared well with the curves for the commercial tablets. Intrinsic dissolution rates were also a hnction of niising time, which indicates that the increase in dissolution properties is probably a result of the deagglomeration of the agglomerated furosemide particles. The Turbula mixer, which can develop more shear force, breaks the agglomerates quicker and to a larger extend than the V mixer. It can be concluded that the type of mixer, mixing time and drug load control the dissolution properties of direct compression formulations of poorly water soluble drugs in which the drug particles form agglomerates.     

Interactive mixing between agglomerated drug particles and coarse carrier particles

Abstract

The equation of Egermann¹ was used to calculate the theoretical coefficient of variation in drug content of completely random interactive mixtures containing furosemide and sodium chloride. These coefficients of variation (CV) were compared to that obtained experimentally. Although no free furosemide agglomerates or aggregates were present in the mixtures, the experimental values were consistently higher. This could only be explained if small furosemide aggregates accumulated in clefts and crevices in the sodium chloride particle surfaces. For the system examined random interactive mixtures were produced with furosemide concentrations between 0.05 and 4%     

The Effect of Mixing Variables on the Dissolution Properties of Direct Compression Formulations of Furosemide

Abstract

The particles of a number of poorly water soluble drugs, for instance furosemide, tend to agglonierate spontaneously and as a result decrease the drug's dissolution properties. This phenomena is undesirable when the drug is to be formulated in a direct compressible formulation. Interactive or ordered mixing with a filler usually rectifies this problem but the drug load is limited to a maxirnuni of ± 5% of the mixture. This is well below the formulation requirements of hrosemide (25 %) and below the maximum drug load which can be handled in dircct compression formulations (± 35 %). The effect of two types of mixers, the mixing time and drug load were investigated for a direct compression formulation of furosemide tablets. A Turbula and a V mixer, both with a volume of 720 ml, were used. The drug was formulated with Ludipress (a commercial direct compression filler, BASF, Germany) at two drug loadings of 20 and 25 %. Magnesium stearate (1 %) was added as a lubricant. A mixture was prepared for each experimental condition. After mixing the whole mixture (120 gram) was tabletted on a Korsch single punch machine producing ± 500 tablets. The crushing strength, mass and disintegration time of ten tablets and the dissolution of six tablets were measured. Dissolutions were donc according to the USP XXII - method 2¹ - in 0, 1 M HCI and a phosphate buffer with pH = 5.8. The intrinsic dissolution rates of some of the mixtures were also deterniined in the two dissolution media. The dissolution properties of the formulations were compared with the properties of Lasix®, a commercially available furoseniide product. which is not manufactured by dircct compression. The dissolution rates of the formulations mixed in the Turbula mixer were significantly higher than those mixed in the V miser. The area under the dissolution curves increased as a function of niixing time for both mixers. The best dissolution results were obtained for formulations with a 20 % drug load and mixed for 120 minutes in the Turbula miser. The dissolution curves for these formulations compared well with the curves for the commercial tablets. Intrinsic dissolution rates were also a hnction of niising time, which indicates that the increase in dissolution properties is probably a result of the deagglomeration of the agglomerated furosemide particles. The Turbula mixer, which can develop more shear force, breaks the agglomerates quicker and to a larger extend than the V mixer. It can be concluded that the type of mixer, mixing time and drug load control the dissolution properties of direct compression formulations of poorly water soluble drugs in which the drug particles form agglomerates.     

THE STATISTICS OF THE POWDER COATING PROCESS

General expressions are developed for the limiting variance values of complete segregation and random distribution for agglomerated powder mixtures. In the limits of non-agglomeration these expressions reduce to the established values for free flowing powder mixtures.

The general expressions for agglomerating powders are of little value unless the composition distribution of the agglomerates can be predicted. This has been done for the special case of mixing by the 'coating' process in which fine particles coat the surface of larger carrier particles. The model used assumed that the particles are spherical, that only single coarse particles exist within an agglomerate, that the fine particles will either form a single layer on the coarse carrier or will agglomerate on a nucleus of a single fine particle.     

A method for dispersing dry nano-sized particles in a liquid using carrier particles

A method for dispersing dry particles in a liquid is described. The method involves coating large carrier particles with fine particles. When two types of particles having different sizes are mixed in dry conditions, the particles adhere to one another, and the large particles become coated with small particles. When the large core particles are coated with a mono-layer of small particles, further agglomeration is inhibited. Because the single small particles generated by the disruption adhere to the core particles, we presumed that, if the small particles that are adhered to large particles could be separated from the large particles by a sonication in a liquid, the dry fine particles could be dispersed in a liquid.The dispersion experiments conducted using spherical silica particles having a count median diameter D_p50 of 74 nm as small particles and spherical glass beads as large particles. In this situation, the large particles carry the small particles from a dry condition into a liquid. We refer to the large particles as carrier particles. The experiments revealed that the proposed dispersion procedure results in a superior product, compared to sonication only. The effect of carrier size on dispersion performance is also investigated. The findings indicate and an optimum carrier size exists. Observations of the carrier particle surfaces after dry mixing indicate that the optimum condition is the condition at which a mono-layer of Silica particles is formed.     

AGGREGATION DURING THE DISSOLUTION OF DIAZEPAM IN INTERACTIVE MIXTURES

The dissolution of micronized diazepam (1.0-10.0%) in interactive mixtures with lactose-povidone, Emdex®, TabBase® and Compactrol® as carriers was investigated using the USP paddle method and distilled water as the dissolution medium. Dissolution rate of the binary diazepam-carrier mixtures increased using more soluble carriers such as lactose-povidone and decreased as the diazepam concentration of the mixtures increased. The data were interpreted by considering dissolution from both dispersed and aggregated particles and modelled using monoexponential and biexponential equations allowing the estimation of reciprocal dissolution rate constants for dispersed and aggregated particles (k_d and k_a and initial aggregate concentrations (C_a). The estimated k_d parameters were independent of carrier and diazepam concentration while the ka. parameters varied and were dependent on the aggregate size distribution in the interactive mixtures studied. The degree of aggregation increased markedly with increasing diazepam concentration and was greatest for the less soluble carrier, Compactrol®. Ternary surfactant interactive mixtures containing diazepam and sodium lauryl sulphate (100:2) adhered to the carrier surface were developed and demonstrated improved dissolution rates which were attributed to the deaggregation effect of the surfactant in the aggregate microenvironment. The effect was most noticeable at 10 percent drug loadings where the surfactant concentration was greatest and where both the k_a and C_a parameters were minimized.     

Influence of the cohesive behaviour of small particles on the solid-state photolytic degradation of furosemide

The effect of the cohesive behaviour of small particles on the solid-state photochemical degradation of furosemide is reported. Samples of agglomerated and recrystallised separated particles were exposed to direct sunlight for up to 240 hours, and the furosemide content measured with time. The solid-state photolytic degradation of furosemide proceeds from a nucleation period, through a growth period and eventual deceleration of the reaction. The kinetic process was best described by a power law dependence of the fraction degraded on time for the nucleation period and first order kinetics with asymptote, Prout-Tompkins equation, for the growth of the nuclei. The first order rate constants for the degradation of the agglomerated and the separated particles were 1.20 × 10^-2 hour^-1 and 1.48 × 10^-2 hour^-1 respectively for the nucleation period and 2.85 × 10² hour^-1 and 2.45 × 10^-2 hour^-1 for the growth period. Although the mean particle size of the particles which made up the agglomerates was significantly smaller (2.5 μm) than the separated particles (22 μm), the separated particles degraded more than the agglomerates. The maximum, infinite, fraction degraded ($aL∞,) was 0.450 for the agglomerates and 0.660 for the separated particles. It seemed as though nucleation depended on the surface area exposed to irradiation. Agglomeration decreased the surface area available and therefore nucleation was less. Degradation during the growth period appeared to occur inside the particles and was limited by the extent of nucleation.     

A Comparison of Interaction and Solvent Deposition Mixing

Abstract

The mixing of microingredients with diluents may be conducted by various methods. The purpose of this report is to compare the uniformity of mixing of finely powdered reserpine after mixing by an interactive and a solvent deposition method. Reserpine was used in concentrations of 0.25% with Avicel PH 102 and Sorbit Instant as carrier materials. The uniformity of the mixtures was compared by coefficients of variation (CV) of the content of powder or tablet samples. The dissolution of powder samples was measured in a rotating bottle apparatus. Interactive mixing with Avicel produced samples with larger variation in reserine content compared to solvent deposition. The variation in content was not significantly different when the drug was mixed interactively or by solvent deposition on Sorbit. Smaller coefficients of variation in content were observed for tablet samples compared to powder samples in most cases. The CVs obtained with powder samples for all the mixtures. except for solvent deposition on Avicel, were larger than 5% and would therefore not comply with pharmaceutical content uniformly standards. The CVs for all tablet samples, however, were less than 5%, and based on these results all the mixtures were sufficiently mixed so that the tablets complied with content uniformity standards. The dissolution profiles were not influenced by mixing method.     

PARAMETERS INFLUENCING TONER CHARGING CHARACTERISTICS IN ELECTROPHOTOGRAPHIC PRINTING

ABSTRACT

The charge-to-mass ratio, q/m, of a two-component developer is the important factor in an electrophotographic system, since the toner charge controls the developed tone mass and the print quality. This article investigates the charging properties of differently shaped toners (spherical and irregular), and carrier particles that differ in their composition and surface oxide layer thickness by adjusting the applied current. The parameters for toner charging involving the mixing force, the toner concentration, the shape of the toner, the carrier type, and the current of the carrier surface are studied. The print quality is evaluated by focusing on the solid density, 60 and 40% halftone densities, background density, and edge sharpness of the characters. An explanation of the force between the toner and carrier particles is proposed.