Lactose Particle Size Research Articles

Relationship between inhomogeneity phenomena and granule growth mechanisms in a high-shear mixer

A poorly understood phenomenon observed during high-shear granulation is the poor distribution of a drug in the granulate. To investigate the causes of this inhomogeneity, lactose of three different particle sizes was granulated with 0.1% micronized estradiol (5 μm) in a 10 l high-shear mixer. An aqueous solution of HPC was used as binder. Granulation with the largest lactose particles (141 μm) yielded a homogeneous granulate. However, at a prolonged process time demixing was observed. Contrary to the largest particles, granulation with the smaller lactose particles (50 and 23 μm) already leads to demixing in the first minute, although to a lesser extent. It was concluded that granulation with the largest particles resulted in breakage behavior of the granulate, thereby preventing demixing. However, once granules are strong enough (smaller particle size and prolonged process time) to survive the shear forces demixing is observed. Theoretical calculations of dynamic and static granule strength were used to explain the influence of lactose particle size and process time on breakage behavior. It was argued that once granules survive, preferential growth of the small estradiol particles in favor of the larger lactose particles causes the demixing. The extent of demixing depends on the particle size difference.

Factors affecting membrane-controlled drug release for an osmotic pump tablet (OPT) utilizing (SBE)7m-β-CD as both a solubilizer and osmotic agent

Purpose: The purpose of this study was to define membrane controlling factors responsible for drug release from a controlled-porosity osmotic pump tablet (OPT) that utilizes a sulfobutyl ether-β-cyclodextrin, (SBE)7m-β-CD, as both a solubilizing and osmotic agent. Method: The OPT was spray coated with cellulose acetate solutions varying the amount and size of micronized lactose, the amount of triethyl citrate (TEC) and the composition ratio of dichlormethane to ethanol. Chlorpromazine (CLP) was used as a model drug. The release of CLP from the OPTs was studied using the Japanese Pharmacopoeia dissolution method. The membrane surface area of the OPTs were measured with multi-point analysis by the gas absorption method. Results: The release rate of CLP from OPTs containing (SBE)7m-β-CD increased with increasing amounts of micronized lactose and decreasing amounts of TEC and lactose particle size in the membrane. Also, the CLP release rates from the spray-coated OPTs using mixtures of varying ratios of dichlormethane to ethanol were almost identical. The membrane surface area of the OPTs following release of membrane components had a linear relationship to CLP release rates from the OPTs. Conclusion: The present results confirmed that the membrane controlling factors responsible for the drug release were the amount and size of micronized lactose and the amount of TEC in the membrane.

Rheology and Filling Characteristics of Particulate Dispersions in Polymer Melt Formulations for Liquid Fill Hard Gelatin Capsules

The rheology and capsule filling properties of molten excipients, Dynafill, Dynasan-114, Lutrol-F68, and polyethylene glycols (PEG) 6000, 8000, 10,000, and 20,000 have been investigated. Lactose (α-monohydrate) was selected as a model particulate solid with low solubility in PEG in order to investigate the effects of disperse phase particle size, concentration, and PEG molecular weight on rheology and capsule filling properties of these systems. All excipients behaved as Newtonian fluids between 65 and 90°C, which was chosen as a possible temperature range for liquid filling of hard gelatin capsules. The excipients, apart from Dynasan-114 and PEG 20,000, showed satisfactory capsule filling properties at 70°C using a semiautomatic filling machine. Dynasan-114 (viscosity = 0.012 Pass at 70°C) leaked from the seals between the hopper and pump of the filling machine, whereas PEG 20,000 (viscosity = 24 Pas at 70⪚C) showed bridging of the molten polymer between successive capsule bodies during the filling process. The effect of disperse phase (lactose) particle size and concentration, and continuous phase (PEG) molecular weight on the apparent viscosity and filling properties of the non-Newtonian dispersions were investigated at 70°C. Satisfactory filling of the dispersions was achieved at 70°C up to a limiting concentration of disperse phase which was dependent upon disperse phase particle size and continuous phase molecular weight, and corresponded to a pronounced increase in apparent viscosity of the dispersion.

調剤時の細粒の分割・分包性と含量均一性

The object of this research is to determine the relationship between the characteristics of fine granules and the dividing and packaging characteristics during dispensing, in addition to the relationship between the preparation condition of fine granules and drug content uniformity.Fine granules of 7:3 lactose-corn starch mixtures were prepared by a high speed agitating granulator based on “The Standard Formula for Fine Granules” established by the Standard Formulation Reserach Association, the Particulate Preparation and Design Group, the Society of Powder Technology of Japan.Also, the influence of lactose particle size on drug content uniformity was investigated. As the results, the average partice size varied markedly due to the amount of added water in a range of from 100mL to 150mL.It was found that regardless of the particle size of lactose and the amount of HPC added as binding agent, the fine granules with an average particle size more than 130μm have suitable characteristics for dividing and packaging for dispensing.The drug contents of each fraction of particle size related closely to the amount of HPC added and particle size of lactose. Thus, the selection of the particle size of lactose was effective in reducing the variation of drug content during agitating granulation.

Sustained Release Mechanisms of Wax Matrix System for Controlled Release.

In order to elucidate the influence of the particle size of water-soluble ingredients in a wax matrix and the solubility of drugs on the drug dissolution rate from a dosage form, reservoir devices were prepared from a wax matrix layer consisting of hydrogenated caster oil (HCO) and lactose, a drug reservoir and a water non-permeable layer of HCO, and dissolution tests were then carried out. Drug permeability and water penetrability of the wax matrix layer were affected by the particle size of lactose incorporated into the wax matrix layer. Drug permeability and water penetrability could be decreased by using smaller lactose particles. Tortuosity in the wax matrix layer after the dissolution of lactose could be increased inversely proportional to the particle size. Permeability of the wax matrix layer differed depending on the kinds of drugs forming the drug reservoir, which was attributed to differences in the solubility and viscosity of the drug saturated solution formed in the drug reservoir.

The influence of lactose particle size on spheronization of extrudate processed by a ram extruder

The spheronization of extrudate produced by a ram extruder fitted with either 1.0 or 1.5 mm diameter dies from mixtures of mucrystalline cellulose, lactose (with median diameter of either 18.0 or 117.0 μm) and water has been observed. The spherical granules produced have been characterized in terms of their median length (number diameter by muscope) and width (weight diameter by sieving) and the roundness (‘One Plane Critical Stability’), width and length (muscope observation) of the most frequently occurring size fraction. Extrudate produced through both 1.0 and 1.5 mm diameter dies with the fine particle size lactose formed granules within 5 min which were well rounded and of a narrow size distribution. Extrudate produced through both the 1.0 and 1.5 mm diameter dies with the coarse grade of lactose, produced spheres, but these were considerably larger in size and had a larger range of size, due to agglomeration of the granules. The changes in shape and size could be observed within the spheronizer by using a photographic technique. The median diameter of spheroids produced by the controlled spheronization of the fine grade lactose mixture was about 1.2 times the diameter of the die producing the extrudate. The median diameter of the spheroids produced by the uncontrolled spheronization of the coarse grade lactose mixture was not related to the die diameter. In fact, extrudate produced from the 1.0 and 1.5 mm dies both produced spheroids of approx. 3.0 mm diameter. The reasons for the difference in processing of the two particle size fractions of lactose appear to be associated with the movement of water in the formulation.

Instrumentation of a Gravity Feed Extruder and the Influence of the Composition of Binary and Ternary Mixtures on the Extrusion Forces

A gravity feed extruder was adapted to monitor the extrusion forces, the temperature during processing and the rotational speed of the extruding cylinders. The extruder was used to evaluate the influence of particle size of insoluble material and of product solubility on the extrusion forces. Microcrystalline cellulose, dicalcium phosphate dihydrate and different lactoses were used as model compounds. Difference in lactose and microcrystalline cellulose particle size did not influence extrusion forces. The amount of water in the mixtures to be processed and the initial difference in solubility for some of the lactose types investigated influenced the extrusion forces dramatically. Extrusion forces recorded during processing of a mixture previously granulated in a high shear granulator were higher than when processed in a planetary mixture. Loss of water during high shear granulation is probably the main cause of this phenomenon.

The Effect of Lactose Particle Size on the Extrusion Properties of Microcrystalline Cellulose-Lactose Mixtures

Ram extrusion has been used to assess and compare the flow characteristics and quality of wet powder masses formed from mixtures of water with microcrystalline cellulose and two different particle size samples of lactose. The force-displacement profiles can reveal poor flow properties. Steady state flow was achieved for the mixture containing fine lactose which produced an extrudate of uniform moisture content at all extrusion rates except the lowest (5 cm min-1). Increasing the lactose particle size significantly altered the extrusion properties of the formulation with forced flow predominating and high extrusion pressures observed. Formulations showing that type of extrusion are to be avoided as they produce poor quality extrudate which may be unsuitable for spheronization. Flow visualization studies showed that problems associated with such mixtures are caused by failure to maintain a constant angle of convergence during extrusion, which is essential for maintenance of steady state flow. With the mixture made with coarse lactose, the extrudate quality could be improved by extruding at high velocities, information that may be of significance in the development of formulations for large-scale production. Differences between formulations may be expressed quantitatively by plotting the apparent shear stress-shear rate relationship. The curves are modified by the particle size of lactose included in the mixtures. Such curves have implications in predicting the suitability of an extrudate, produced under particular experimental conditions, for spheronization.

Studies on tableting properties of lactose. VII. The effect of variations in primary particle size and percentage of amorphous lactose in spray dried lactose products

Sieve fractions of α-lactose monohydrate and dicalcium phosphate dihydrate, respectively, suspended in solutions of lactose, were spray dried in order to obtain products with various amorphous lactose contents. The compactibility of the samples appeared to be a function of both the primary particle size and the amount of amorphous lactose. The lactose glass was considered to form a binding layer on the particle surface area. Its efficacy was found to be determined by the size and the consolidation of the particles at lower percentages, whereas the specific properties of fully amorphous spray dried lactose, e.g. its susceptibility to water uptake and magnesium stearate mixing, were brought out especially at high percentages.

Effect on particle size on the compaction mechanism and tensile strength of tablets.

The effect of particle size variation on tablet tensile strength for spray-dried lactose, Sta-Rx 1500 and Avicel PH-101 was investigated. Decreasing the particle size of spray-dried lactose and Sta-Rx 1500 resulted in stronger compacts whereas the tablet tensile strength of Avicel PH-101 was unaffected by particle size variation. The Heckel relationship, at two different contact times, was used to examine the predominant compaction mechanism. This was independent of the size fractions studied for all three materials. Angle of repose and Hausner ratio measurements indicated a correlation between the internal forces of friction and cohesion of the sized powders and the tensile strength of compacts formed from them.

The physicochemical parameters determining the size of agglomerate prepared by the wet spherical agglomeration technique

Lactose samples of five different particle sizes from 31 to 261 μm dispersed in chloroform were agglomerated with a small amount of saturated aqueous lactose solution which acted as a bridging liquid to wet the particles preferentially. The effects of raw particle size and the amount of bridging liquid on the average size of resultant agglomerate were investigated. The agglomerate size increased with decreasing size of lactose. This effect was enhanced by increasing the amount of bridging liquid for lactose less than 79 μm. A linear correlation on a log—log plot was observed between the agglomerate size and the saturation ratio of bridging liquid. The slope increased with decreasing particle size of lactose. The size distribution of agglomerates was also determined for the particle size of lactose and the amount of bridging liquid used. The physicochemical properties of the bridging liquid, i.e. contact angle and interfacial tension, were also taken into account for interpreting the agglomerate size. The correlation between the agglomerate size and the above parameters was represented quantitatively by eqn. (10) in the text. The parameter n, which varies directly with agglomerate size, increased with increasing saturation ratio, or with decreasing lactose particle size.

二成分粉体の湿式球形造粒 Ｉ 乳糖―スルフィゾミジン造粒体の粒度間含量変動

Binary mixtures of sulfisomidine and lactose particles were suspended in chloroform and were agglomerated with buffered sodium phosphate solutions (pH7.4). The agglomerate particles at 1.5min residence time were fractionated by sieves at six levels according to the particle size. The content ratio of sulfisomidine of the each fraction to the original feed powder was determined. The significant variance of the content ratio with the particle size of the agglomerates was found, which strongly depended on the particle size of lactose and the mixing ratio of sulfisomidine.With increasing the particle size of lactose and decreasing the mixing ratio of sulfisomidine, the content ratio in the agglomerate with over size (+12mesh) decreased, which indicates that the larger lactose particles are included more in the agglomerate with increasing the particle number of lactose in the system. The content variation disap Peared gradually when the agglomerate particles growing in the course of agitating the suspension. This suggests that the more preferential adhesion may occure between the larger lactose and sulfisomidine particles, leading to the formation of the agglomerate enriched with lactose.

The granulation of binary mixtures: the effects of the composition of the granulating solution and the initial particle size of one component on granule properties.

The effect of total solvent volume and the presence of dissolved material (other than binder) in the granulating solution, on the properties of granules prepared from lactose: boric acid mixtures has been studied. The total volume of binder solution available to powder mixtures during massing determines the ultimate average size of granules produced. Part-dissolution of powders being granulated contributes significantly to the average granule size by increasing the total solution volume and reducing the amount of powder to be wetted. Although the amount of PVP (binder) dissolved in the granulating solution contributed very little to granule size at the concentration examined, the combined effect of total volume of solution and amount of PVP present in the granulating solution determines granule strength and porosity. The effect of the initial particle size of lactose in a binary mixture with boric acid differs from its effect reported for single component systems.