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Effect of drug substance particle size on the characteristics of granulation manufactured in a high-shear mixer.

DPC 963 is a non-nucleoside reverse transcriptase inhibitor with low aqueous solubility. The effect of DPC 963 drug substance particle size on the characteristics of granules manufactured by high-shear wet granulation was evaluated. The wet granulation process was used to manufacture a DPC 963 formulation with high drug loading. The formulation was manufactured using drug substance lots with different particle size distributions. Granulation particle size distribution, porosity, and compressibility were determined. A uniaxial compression test was also performed on moist compacts of the formulation prepared with different particle size distributions. Particle agglomeration behavior was affected by drug substance particle size. Granulation geometric mean diameter and fraction with particle size greater than 250 microm was inversely proportional to the drug substance particle size. Mercury intrusion porosimetry revealed higher pore volumes for the granules manufactured using the drug substance with the smaller particle size, suggesting lower tendency for granule densification than for that manufactured with the larger drug substance particle size. Granulation compressibility was also sensitive to changes in drug substance particle size. A decreased drug substance particle size led to increased granulation compressibility. Results from the uniaxial compression experiments suggested that the effect of particle size on granulation growth is the result of increased densification propensity, which in turn results from increased drug substance particle size.

Chemistry, Pharmaceutical↗

In situ determination of delavirdine mesylate particle size in solid oral dosage forms.

PURPOSE: The in-situ particle size of delavirdine mesylate in dry mix and tablets was determined. METHODS: Optical microscopy and fluorescence microscopy combined with image analysis were used for qualitative and quantitative measurements. RESULTS: Using optical microscopy, it was demonstrated qualitatively that fragmentation of the large drug particles was occurring during tablet compression. Quantitative comparisons between dry mix and tablet samples showed that in the dry mix, drug particles remain intact, with particle lengths exceeding 200 microm. In the tablets, no particles longer than 100 microm had been observed. Analysis of multiple tablet lots revealed consistent in-situ drug particle size distributions, regardless of the original bulk drug particle size. CONCLUSIONS: Bulk drug particle size of delavirdine mesylate is not predictive of the particle size in the tablet due to fragmentation of particles during compression. Optical and fluorescence microscopy are valuable tools for probing in-situ particle size in complex matrices.

Administration, Oral↗

Use of a fluidized bed hammer mill for size reduction and classification: effects of process variables and starting materials on the particle size distribution of milled lactose batches.

The process capability of a fluidized bed hammer mill was investigated with respect to four process variables, namely, rotational speeds of beater system and classifier wheel, airflow rates and length of grinding zones, as well as the particle size and flow property of the starting materials. The size distributions of all the milled lactose batches could be fitted to the Rosin Rammler distribution (RRD) function. The characteristic particle size (De) and uniform coefficient (n), which were derived from the RRD function, complemented the size at the 99th percentile of the cumulative undersize distribution (D99) to characterize the lactose batches. Lower De and D99 values indicate a finer powder while a higher n value indicates a narrower size distribution. The beater speed played a critical role. Increasing the beater speed from 12000 to 21000 rpm generally resulted in an increase in n and a decrease in D99 values due to the greater amount of milling energy supplied. The particle size and flow property of the starting material also played an important role at beater speed of 12000 rpm, where the lowest amount of milling energy was supplied. When a higher amount of milling energy was provided, the effect of particle size of the starting material was less significant. The other process variables exerted varying effects. Increasing the classifier wheel speed from 5000 to 15000 rpm decreased the De and D99 and increased the n values of the milled lactose batches, provided sufficient milling energy was supplied to the lactose particles. Changing airflow rates from 80 to 90 m3/h generally resulted in larger De and D99 values and lower n values as the higher airflow rate provided greater airflow-induced kinetic energy that facilitated the passage of lactose through the classifier wheel. However, changing the long grinding zone to a short one did not significantly affect the De, D99 and n values of the milled lactose batches produced. Small lactose particles of narrow size distribution could be obtained using the fluidized bed hammer mill upon gaining a better understanding of the milling process.

Air Movements↗

Evidence of a critical leucite particle size for microcracking in dental porcelains.

The leucite particles in dental porcelains are often partially encircled by microcracks that are the result of the thermal expansion mismatch between leucite and the surrounding glass matrix. Although the magnitude of the stress at the particle-matrix interface is independent of the particle size (Selsing, 1961), Davidge and Green (1968) showed experimentally that there is a critical particle size below which microcracking is absent. The critical particle size is explained by a Griffith-type energy balance criterion: Below the critical size, the stress magnitude may be sufficient to cause cracking, but there is insufficient strain energy for the creation of the new surfaces of the microcrack. The purpose of the present study was to determine whether the mean leucite particle size of a dental porcelain influences the degree of microcracking in the porcelain. Microcrack density, leucite particle surface area per unit volume, and leucite mean volume-surface diameter, D3,2, were determined by quantitative stereology on 10 specimens each of 6 dental porcelains and Component No. 1 of the Weinstein et al. patent (US Patent 3,052,982, 1962). The fraction of leucite particles with microcracks around them, f(mc), was estimated for each porcelain from the microcrack density and the leucite surface area. Using the equations of Selsing (1961) and Davidge and Green (1968), we calculated the critical particle diameter, Dc, for leucite to be 4 microm. The porcelains were partitioned according to whether their mean leucite particle diameters, D3,2, fell above or below Dc, and their values of f(mc) were analyzed by a permutation test with random re-sampling. The porcelains with mean leucite particle diameters below Dc had a significantly lower fraction of cracked particles compared with the porcelains with mean leucite particle diameters above Dc (p < 0.05). This study provides evidence that microcracking in dental porcelain can be minimized by a reduction of the mean leucite particle diameter to less than 4 microm.

Aluminum Silicates↗

Effect of particle size on lead absorption from the gut.

The relationship between particle size and absorption of lead particles from the gastrointestinal tract of the rat has been investigated. Preparations of metallic lead of particle size between 0 and 250 micron were incorporated in laboratory rat diets and absorption determined by measurement of tissue lead concentrations attined under standard conditions. An inverse relationship was found between particle size and lead absorption; this relationship was most marked in the 0 to 100 micron range. A five-fold enhancement of absorption was observed from the diet with lead particles of mean size 6 micron, compared with 197 micron particle size. Lead absorption from dried pain films containing lead chromate and lead octoate was measured using a similar technique. A marked enhancement of absorption was observed for both paints when particle size was reduced from 500 to 1,000 micron to less than 50 micron.

Animals↗

The effect of reducing alfalfa haylage particle size on cows in early lactation.

The objective of this experiment was to evaluate effects of reducing forage particle size on cows in early lactation based on measurements of the Penn State Particle Separator (PSPS). Eight cannulated, multiparous cows averaging 19 +/- 4 d in milk and 642 +/- 45 kg BW were assigned to one of two 4 x 4 Latin Squares. During each of the 23-d periods, animals were offered one of four diets, which were chemically identical but included alfalfa haylage of different particle size; short (SH), mostly short (MSH), mostly long (MLG), and long (LG). Physically effective neutral detergent fiber (peNDF) was determined by measuring the amount of neutral detergent fiber retained on a 1.18 mm screen and was similar across diets (25.7, 26.2, 26.4, 26.7%) but the amount of particles >19.0 mm significantly decreased with decreasing particle size. Reducing haylage particle size increased dry matter intake linearly (23.3, 22.0, 20.9, 20.8 kg for SH, MSH, MLG, LG, respectively). Milk production and percentage fat did not differ across treatments averaging 35.5 +/- 0.68 kg milk and 3.32 +/- 0.67% fat, while a quadratic effect was observed for percent milk protein, with lowest values being observed for LG. A quadratic effect was observed for mean rumen pH (6.04, 6.15, 6.13, 6.09), while A:P ratio decreased linearly (2.75, 2.86, 2.88, 2.92) with decreasing particle size. Total time ruminating increased quadratically (467, 498, 486, 468 min/d), while time eating decreased linearly (262, 253, 298, 287 min/d) with decreasing particle size. Both eating and ruminating per unit of neutral detergent fiber intake decreased with reducing particle size (35.8, 36.7, 44.9, 45.6 min/kg; 19.9, 23.6, 23.5, 23.5 min/kg). Although chewing activity was closely related to forage particle size, effects on rumen pH were small, indicating factors other than particle size are critical in regulating pH when ration neutral detergent fiber met recommended levels. Feeding alfalfa haylage based rations of reduced particle size resulted in animals consuming more feed but did not affect milk production.

Ammonia↗

Dermally adhered soil: 2. Reconstruction of dry-sieve particle-size distributions from wet-sieve data.

In the evaluation of soil particle-size effects on environmental processes, particle-size distributions are measured by either wet or dry sieving. Commonly, size distributions determined by wet and dry sieving differ because some particles disaggregate in water. Whereas the dry-sieve distributions are most relevant to the study of soil adherence to skin, soil can be recovered from skin only by washing with the potential for disaggregation whether or not it is subsequently wet or dry sieved. Thus, the possibility exists that wet-sieving measurements of the particle sizes that adhered to the skin could be skewed toward the smaller fractions. This paper provides a method by which dry-sieve particle-size distributions can be reconstructed from wet-sieve particle-size distributions for the same soil. The approach combines mass balances with a series of experiments in which wet sieving was applied to dry-sieve fractions from the original soil. Unless the soil moisture content is high (i.e., greater than or equal to the water content after equilibration with water-saturated air), only the soil particles of diameters less than about 63 microm adhere to the skin. Because of this, the adhering particle-size distribution calculated using the reconstruction method was not significantly different from the wet-sieving determinations.

Adsorption↗

Modeling steady-state particle size spectra.

Fractal dimensions of marine aggregates are often estimated from the measured slopes of particle size spectra. One technique uses dimensional analysis to determine the dependence of the spectrum's slope with fractal dimension. In this paper, we use numerical simulations to examine the assumptions underlying the dimensional analysis approach to particle size spectra. We find that the slopes of numerically computed steady-state particle size spectra disagree with those predicted by dimensional analysis. The assumptions underlying the dimensional analysis approach that are responsible for the disagreement are as follows: only one coagulation mechanism operates in each particular particle size range, particle loss through sedimentation occurs at particle sizes larger than those for which differential sedimentation dominates, particles only interact with like-sized particles. Including disaggregation steepens the slope of the particle size spectrum for both large and small particles and changes the shape of the spectrum. These results indicate that one should exercise caution when using the measured slopes of particle size spectra to estimate aggregate fractal dimension.

Eutrophication↗

Cumulative frequency fit for particle size distribution.

A cumulative frequency distribution fit method is presented for analyzing particle size distributions by minimizing the summation of the square of cumulative frequency errors. Compared to the frequency fit method, the cumulative frequency fit method yields a more accurate solution. Based upon this, a spreadsheet was developed for analyzing multi-modal particle size distribution. The motivation for the work presented in this article was the current interest in ultra-fine and nano-sized particle exhaust emissions from heavy-duty diesel engines. The new spreadsheet provides a quick and convenient way to conduct particle size distribution analysis.

Mathematics↗

Effects of bronchodilator particle size in asthmatic patients using monodisperse aerosols.

Aerosol particle size influences airway drug deposition. Current inhaler devices are inefficient, delivering a heterodisperse distribution of drug particle sizes where, at best, 20% reaches the lungs. Monodisperse aerosols are the appropriate research tools to investigate basic aerosol science concepts within the human airways. We hypothesized that engineering such aerosols of albuterol would identify the ideal bronchodilator particle size, thereby optimizing inhaled therapeutic drug delivery. Eighteen stable mildly to moderately asthmatic patients [mean forced expiratory volume in 1 s (FEV1) 74.3% of predicted] participated in a randomized, double-blind, crossover study design. A spinning-top aerosol generator was used to produce monodisperse albuterol aerosols that were 1.5, 3, and 6 microm in size, and also a placebo, which were inhaled at cumulative doses of 10, 20, 40, and 100 microg. Lung function changes and tolerability effects were determined. The larger particles, 6 and 3 microm, were significantly more potent bronchodilators than the 1.5-microm and placebo aerosols for FEV1 and for the forced expiratory flow between exhalation of 25 and 75% of forced vital capacity. A 20-microg dose of the 6- and 3-microm aerosols produced FEV1 bronchodilation comparable to that produced by 200 microg from a metered-dose inhaler. No adverse effects were observed in heart rate and plasma potassium. The data suggest that in mildly to moderately asthmatic patients there is more than one optimal beta2-agonist bronchodilator particle size and that these are larger particles in the higher part of the respirable range. Aerosols delivered in monodisperse form can enable large reductions of the inhaled dose without loss of clinical efficacy.

Administration, Inhalation↗

A quantitative description of vehicle exhaust particle size distributions in a highway tunnel.

During the period May 18-May 22, 1999, a comprehensive study was conducted in the Tuscarora Mountain Tunnel on the Pennsylvania Turnpike to measure real-world motor-vehicle emissions. As part of this study, size distributions of particle emissions were determined using a scanning mobility particle sizer. Each measured size distribution consisted of two modes: a nucleation mode with midpoint diameter less than 20 nm and an accumulation mode with midpoint diameter less than 100 nm. The nucleation and accumulation components in some distributions also exhibited second maxima, which implies that such particle size distributions are superpositions of two particle size distributions. This hypothesis was utilized in fitting the particle size distributions that exhibited second maxima with four lognormal distributions, two for the nucleation mode and two for the accumulation mode. The fitting assumed that the observed particle size distribution was a combination of two bimodal log-normal distributions, one attributed to the heavy-duty diesel (HDD) vehicles and another attributed either to a different class of HDD vehicles or to the light-duty spark ignition vehicles. Based on this method, estimated particle production rates were 1.8 x 10(13) and 2.8 x 10(14) particles/vehicle-km for light-duty spark ignition and HDD vehicles, respectively, which agreed with independently obtained estimates.

Models, Theoretical↗

A standard procedure for measuring rodent bedding particle size and dust content.

Hardwood dust can cause dermatitis, respiratory disease, allergies and nasal cancer in humans. A major concern with animal hardwood bedding is its dust content and its possible effects on animals and animal technicians. Previous reports on the quality control of rodent bedding did not specify sample size or shake time for measuring bedding particle size and dust content. These variables could alter particle size analyses. In an effort to more accurately characterize bedding particle size and dust content, 50g and 100g samples of hardwood bedding were shaken for 0.5, 1, 2, 3, 4, or 5 minutes in a portable sieve shaker containing U.S. standard sieves (Nos. 8, 20, 30 and 50) to determine optimum sample size and shake time. Significant differences (P less than 0.05 or greater) were observed in the percent of bedding retained on a No. 8 sieve when 50g and 100g samples were taken for 30 seconds or for 1 minute. Samples shaken for 2 or more minutes did not show any statistical differences in the percent of bedding which was retained on or passed through the different sieves. Major differences occurred in the percent of bedding which was retained or passed through the different sieves, when the shake time was varied from 0.5 to 5 minutes. These results indicated that 0.5 or 1 minute was definitely not enough time to accurately measure bedding particle size and dust content and that the sample size and shake time must be consistent in order to accurately compare the particle size and dust content of different shipments of bedding or to compare bedding from different vendors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

A comparison between data analysis methods concerning particle size distributions obtained by mastication in man.

Three mixtures of chewed food particles (coarse, medium and fine) were quantified by measuring the particle sizes with an optical scanning device. The particle sizes were described by three different particle-size distributions: a cumulative volume, a volume and a number distribution. The median particle size was determined from each of the distribution functions. Suitability for characterizing a mixture of chewed food particles was tested, showing that the median particle size as obtained from a cumulative volume (or weight) distribution should be preferred. It was shown to be the most sensitive measure for characterizing mixtures of chewed food.

Calibration↗

Association of heterozygous familial hypercholesterolemia with smaller HDL particle size.

Small, dense HDL particles have been associated with factors known to increase the risk of cardiovascular disease, such as obesity, hypertriglyceridemia, small dense LDL particles, decreased HDL-cholesterol levels and increased apoA-I fractional catabolic rate from plasma. In order to assess the potential contribution of HDL particle size to atherosclerosis in heterozygous familial hypercholesterolemia (FH), we examined the electrophoretic characteristics of HDL particles in a large cohort of well defined FH heterozygotes and controls. A total of 259 FH heterozygotes and 208 controls participated in the study. FH subjects were carriers of one of the nine French Canadian mutations in the LDL receptor gene. All subjects were apoE3 homozygotes. HDL particles were characterized by non-denaturing polyacrylamide gradient gel electrophoresis following a 6-week lipid-lowering drug-free baseline period. The integrated HDL size was significantly smaller in the FH group compared to controls (FH=87.3+/-5.2 Angstroms versus controls=91.6+/-4.9 Angstroms, P<0.0001). In each groups, men had smaller HDL particles than women. Multiple regression linear analyses showed that the FH/Control status accounted for 20.3% of the variance in the integrated HDL size. These results suggest that the FH/control status was independently associated with variations in HDL particle size and that these variations could contribute to the development of premature atherosclerosis in these patients.

Adult↗

Investigating the effect of storm events on the particle size distribution in a combined sewer simulator.

The changes in particle size of sewer sediment particles rapidly eroded from a previously deposited sediment bed are described, using a rotating annular flume as a laboratory scale sewer simulator. This is the first time that particle size distributions of eroded sewer sediments from a previously deposited sediment bed have been monitored in such a controlled experimental environment. Sediments from Loenen, The Netherlands and Dundee, UK were used to form deposits in the base of the annular flume (WL Delft Netherlands) with varying conditions for consolidation in order to investigate the effect of changing consolidation time, temperature and sediment type on the amount and size of particles eroded from a bed under conditions of increasing shear. The median size of the eroded particles did not change significantly with temperature, although the eroded suspended solids concentration was greater for the higher temperature under the same shear stresses, indicating a weaker bed deposit. An increase in consolidation time caused an increase in median size of eroded solids at higher bed shear stresses, and this was accompanied by higher suspended solids concentrations. As the shear stress increased, the solids eroded from the bed developed under a longer consolidation time (56 hours) tended towards a broad unimodal distribution, whilst the size distribution of solids eroded from beds developed under shorter consolidation times (18 or 42 hours) retained a bi- or tri-modal distribution. Using different types of sediment in the flume had a marked effect on the size of particles eroded.

Netherlands↗

The vibratory consolidation of particle size fractions of powders.

The use of controlled sinusoidal vibration as a means of consolidating packings of lactose within small containers has been examined. Vertical vibration was found significantly more effective and reproducible than horizontal vibration in terms of the degree of consolidation achieved. An optimum frequency range was identified within which the densification was greatest, and this range was largely independent of particle size for particle size fractions of mean volume diameters ranging from 15.6 to 155 micrometers. The consolidation increased with increasing vibration acceleration up to a level beyond which no further decrease in porosity resulted. Typical effective vibration conditions were characterized by amplitudes of an order of magnitude similar to the particle sizes studied. For particle size fractions of mean diameters 17.8, 37.5 and 80.8 micrometers, there is evidence that an optimum particle size range exists, within which energy requirements for consolidation are at a minimum.

Lactose↗

LDL particle size in relation to intima-media thickness and plaque occurrence in the carotid and femoral arteries in patients with hypercholesterolaemia.

OBJECTIVES: Small LDL particle size has been shown to be associated with coronary artery disease. However, no previous study has been performed relating LDL particle size to ultrasound measurement of atherosclerosis in hypercholesterolaemic subjects. The main aims of the present study were therefore: (i) to investigate the relationship between intima-media thickness (IMT) of the carotid bulb and LDL particle size in patients with primary hypercholesterolaemia (n = 102) and in matched normocholesterolaemic controls (n = 102); and (ii) to investigate the relationship between plaque occurrence in the carotid and femoral arteries and LDL particle size. LDL particle size was determined by subjecting serum to 2-16% polyacrylamide gradient gel electrophoresis. RESULTS: The results showed that patients with primary hypercholesterolaemia had smaller LDL peak particle size compared with healthy control subjects (P < 0.001 for men, P = 0.006 for women). However, the difference in LDL peak particle size between patients with hypercholesterolaemia and controls disappeared when adjusting for serum triglycerides. There was no association between increasing IMT of the carotid bulb and decreasing LDL peak particle size or between the occurrence of moderate to large plaques in the carotid and femoral arteries and small LDL peak particle size. However, metabolic variables such as serum triglycerides, HDL, blood glucose, body mass index, and also systolic blood pressure were associated with LDL peak particle size. CONCLUSION: The lack of an association between atherosclerosis, as measured by ultrasound, and small LDL particle size in patients with hypercholesterolaemia implies that other risk factors, such as hypercholesterolaemia and high blood pressure, may overshadow any importance of small LDL particle size.

Adult↗

Effect of starting material particle size on its agglomeration behavior in high shear wet granulation.

The effect of anhydrous lactose particle size distribution on its performance in the wet granulation process was evaluated. Three grades of anhydrous lactose were used in the study: "as is" manufacturer grade and 2 particle size fractions obtained by screening of the 60M lactose. Particle growth behavior of the 3 lactose grades was evaluated in a high shear mixer. Compactibility and porosity of the resulting granules were also evaluated. A uniaxial compression test on moist agglomerates of the 3 lactose grades was performed in an attempt to explain the mechanism of particle size effect observed in the high shear mixer. Particle growth of anhydrous lactose in the high shear mixer was inversely related to the particle size of the starting material. In addition, granulation manufactured using the grade with the smallest particle size was more porous and demonstrated enhanced compactibility compared with the other grades. Compacts with similar porosity and low liquid saturation demonstrated brittle behavior and their breakage strength was inversely related to lactose particle size in the uniaxial compression test, suggesting that material with smaller particle size may exhibit more pronounced nucleation behavior during wet granulation. On the other hand, compacts prepared at higher liquid saturation and similar compression force exhibited more plastic behavior and showed lower yield stress for the grade with smallest particle size. The lower yield stress of compacts prepared with this grade may indicate a higher coalescence tendency for its granules during wet granulation.

Compressive Strength↗