Flowability of binary mixtures of commercial and reprocessed ibuprofen through high shear wet milling (HSWM) with lactose

This study investigates the flow properties of binary mixtures of both commercial ibuprofen and reprocessed ibuprofen through high shear milling with lactose powders. Ibuprofen is recrystallized in a 30% water–ethanol mixture before high shear wet milling (HSWM). In-situ Process Analytical Techniques (PAT) (Labmax®) is used to study the HSWM process dynamics, with particle size measured by a Lasentec Focused Beam Reflectance Measurement, FBRM®. The flow properties of the binary mixtures of the different ibuprofen particles and its binary mixtures with lactose were measured using a Schulze® RST-XS ring shear tester. Results show that the morphology of ibuprofen was changed from needle to hexagonal like crystals during recrystallization and crystal size was reduced dramatically by HSWM for 1 h. The flowability of milled ibuprofen powders is reduced significantly due to its reduced size and change of surface morphology. Mixing the HSWM ibuprofen powders with lactose enhanced its flow properties. However, the increase of the mixture flowability for HSWM ibuprofen is less significant in comparison to the binary mixtures of lactose with commercial ibuprofen.     

粉体粒度分布分形维数与流动性及硬脂酸镁改进流动性关系

粉体的粒度分布与粉体流动特性密切相关,粉体粒度分布分形维数可以很好地表征粉体的粒度分布情况。本文中在颗粒流动性测试时引入粒度分布分形维数,通过采用利用颗粒几何特征、便于采用数字显微和图像处理计算粉体粒度分布分形维数值的数学模型,得到粉体粒度分布分形维数值,探讨颗粒流动性表征参数与粉体粒度分布分形维数值间的关系;并就流动助剂硬脂酸镁对粉体流动性能的改进与粉体粒度分布分形维数值关系进行了初步探讨。结果表明:粉体粒度分布分形维数值可以用于表征粉体流动性能,粉体粒度分形维数值可作为指导掺杂流动助剂量的参数。     

Effect of Compressibility and Powder Flow Properties on Tablet Weight Variation

A powder flowmeter has been designed to provide both quantitative and qualitative data relating to powder flowability. Three directly compressible powders, Emdex, Emcompress and magnesium oxide as well as a three component powder mixture was assessed for flowability, angle of repose and particle size. Compressibility indices were determined for all the above materials as well as for the fractions of each which consisted of a particle size below 315 μm. Sieve analysis was performed on the above powders in order to establish groups consisting of cohesive, mildly cohesive and non-cohesive fractions and their respective flow-time profiles were subsequently determined. Scanning electron microscopic analysis was performed to obtain information on the particle size, shape and size distribution. The interrelationships between flow rate, angle of repose, compressibility index and coefficient of tablet weight variation were established using both a single punch and a high-speed rotary tabletting machine.

A three-dimensional plot was constructed to illustrate the influences of flow rate, angle of repose and compressibility index on the coefficient of tablet weight variation. Whilst it was established that particle size has a significant effect on uniformity of flow, the data also indicated that when the compressibility index exceeded a value of about 20% a significant increase in tablet weight variation resulted irrespective of the powder flow rate.     

Effect of Compressibility and Powder Flow Properties on Tablet Weight Variation

A powder flowmeter has been designed to provide both quantitative and qualitative data relating to powder flowability. Three directly compressible powders, Emdex, Emcompress and magnesium oxide as well as a three component powder mixture was assessed for flowability, angle of repose and particle size. Compressibility indices were determined for all the above materials as well as for the fractions of each which consisted of a particle size below 315 μm. Sieve analysis was performed on the above powders in order to establish groups consisting of cohesive, mildly cohesive and non-cohesive fractions and their respective flow-time profiles were subsequently determined. Scanning electron microscopic analysis was performed to obtain information on the particle size, shape and size distribution. The interrelationships between flow rate, angle of repose, compressibility index and coefficient of tablet weight variation were established using both a single punch and a high-speed rotary tabletting machine.

A three-dimensional plot was constructed to illustrate the influences of flow rate, angle of repose and compressibility index on the coefficient of tablet weight variation. Whilst it was established that particle size has a significant effect on uniformity of flow, the data also indicated that when the compressibility index exceeded a value of about 20% a significant increase in tablet weight variation resulted irrespective of the powder flow rate.     

A vibrating tube method for evaluating flowability of a small amount of sample particles

To reduce the sample amount required for the measurement and evaluation of particle flowability, a simple method has been developed through experimental research. The principle of this measurement is based on the vibrating tube method. The sample particles used in the experiment were pulverized ZrO₂ and granulated WO₃ with different concentration of fine particles. After a small amount of sample particles were put into a tube, vibration was applied at a constant frequency and amplitude, and the mass of particles discharged from the tube was measured at constant time intervals. The experimental results showed that the minimum sample amount required for the measurement to evaluate the particle flowability was 10 g. The factors to evaluate the flowability in this simple vibrating tube method were the flow time and the characteristic mass flow rate.     

Characterization and selection of suitable grades of lactose as functional fillers for capsule filling: part 1

The purpose of this work is to characterize thermal, physical and mechanical properties of different grades of lactose and better understand the relationships between these properties and capsule filling performance. Eight grades of commercially available lactose were evaluated: Pharmatose 110?M, 125?M, 150?M, 200?M, 350?M (α-lactose monohydrate), AL (anhydrous lactose containing ～80% β-AL), DCL11 (spray dried α-lactose monohydrate containing ～15% amorphous lactose) and DCL15 (granulated α-lactose monohydrate containing ～12% β-AL). In this study, different lactose grades were characterized by thermal, solid state, physical and mechanical properties and later evaluated using principal component analysis (PCA) to assess the inter-relationships among some of these properties. The lactose grades were characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray diffraction (XRD), moisture sorption/desorption isotherms, particle size distribution; the flow was characterized by Carr Index (CI), critical orifice diameter (COD) and angle of friction. Plug mechanical strength was estimated from its diametric crushing strength. The first and second principal components (PC) captured 47.6% and 27.4% of variation in the physical and mechanical property data, respectively. The PCA plot grouped together 110?M, AL, DCL11 and DCL15 on the one side of plot which possessed superior properties for capsule formulation and these grades were selected for future formulation development studies (part II of this work).     

Flowability measurement of pulverized and granulated materials using vibrating tube method

To develop a method for measuring the flowability of MOX (mixed oxide of uranium and plutonium) particles used in the simplified MOX pellet fabrication process, the flowability of model particles has been investigated by the vibrating tube method. As model particles, pulverized ZrO₂ and granulated WO₃ were used. To prepare a variety of samples, coarse particles of 106–250 μm in diameter were mixed with fine particles smaller than 45 μm in diameter in different concentrations. The prepared particles were put into the vibrating tube and the amplitude of vibration was increased at a constant rate for a period of time and then decreased. The mass of particles discharged from the tube was measured at constant time intervals. From the experimental data, the relationships between the mass flow rate and the vibration acceleration (i.e. flowability profiles) were obtained. Two factors (i.e. ‘critical vibration acceleration’ to make the particles flow and ‘characteristic mass flow rate’) were selected to analyze the flowability profiles. The hysteresis of the flowability between increasing and decreasing vibration accelerations was also evaluated.     

Effect of Primary Particle Size on Granule Growth and Endpoint Determination in High Shear Granulators

ABSTRACT

Three different grades of lactose monohydrate having widely differing mean particle sizes, yet similar tap densities, were granulated using a 25L instrumented Fielder mixer. The size distribution, porosity, and pore saturation of the wet granules were determined using a combination of “frozen granule” sieve analysis, mercury pycnometry, and oven drying. The granulating system was found to operate at quasi-steady-state, as granule growth ceased afler liquid addition was terminated. The resultant granule size distributions were strongly dependent on lactose grade. with coarser grades yielding larger granules for identical process conditions. In contrast. the magnitude of the power curves decreased with increasing primary particle size. Both of these observations are consistent with the fact that both the capillary and viscous interparticle fluid forces, which are believed to provide the main interparticle bonding forces in the wet mass, are inversely proportional to particle size.     

Experimental investigation on the flowability properties of cohesive carbonaceous powders

The flowability properties of two carbonaceous powers (anthracite coal and petroleum coke), including angle of repose (AOR), Hausner ratio (HR) and powder compressibility (C), etc., were determined. The effects of particle size, external moisture content (MC) and power type on powder flowability properties were investigated. The results indicate that as the powder particle size increases, the AOR, HR and C decrease, respectively, and the powder flowability becomes better. As the powder external MC increases, the AOR, HR and C increase, respectively, and the powder flowability becomes worse. The anthracite coal has lower values of AOR, HR and C, and higher values of flow function (FF) than those values of petroleum coke. Therefore, anthracite coal has better flowability compared to petroleum coke. Meanwhile, there exists a good linear correlation between AOR and HR.     

Preparation and evaluation of high drug content particles

To determine how to prepare high drug content particles using a Wurster fluidized bed to determine realizing the miniaturization of solid dosage forms, aspirin was selected as the model drug and granulated without any additive. In this study, the emphasis was on evaluating the key operation factors of airflow rate and atomizing flow volume. The properties of the resulting particles, such as the average diameter, particle strength, appearance, and compressibility using different airflow rates and atomizing flow volumes, were investigated. Furthermore, detailed optimization of the operation conditions was conducted by artificial neural network (ANN) analysis. The relationship between the controlling factors (powder supplied, concentration of spray liquid, the amount of consumed spray liquid, and spray rate) and the response variables (product yield, median diameter, angle of repose, and degradation of aspirin) was investigated after evaluating the airflow rate and atomizing flow volume effects. The resulting granules under optimum operation conditions showed excellent physicochemical properties such as particle size uniformity, flowability, and compressibility.     

Cohesion of lactose powders at low consolidation stresses

The flow characteristics of a powder system are known to be influenced by particle size distribution, particularly the content of fine particles, and interparticle forces. This paper reports an investigation that has identified and quantified links between physical properties, viz size distribution, bulk density and particle density, and cohesion in compacted beds of powder. An annular shear cell was used in the determination of the cohesion of cohesive and free-flowing milled lactose powders at low consolidation stresses in the range 0.31–4.85 kPa and under ambient conditions. Following consideration of the compaction and shearing processes, it was postulated and confirmed that cohesion could be expressed as a function of powder surface area per unit volume and dimensionless preconsolidation stress. It was shown that care is needed in the measurement of surface–volume mean diameter when applying correlations developed from the experimental data.     

Evaluation of Ludipress as a “Multipurpose Excipeent” for Direct Compression: Part I: Powder Characteristics and Tableting Properties

The powder characteristics and tableting properties of Ludipress, a lactose-based, free flowing granule containing povidone and crospovidone have been evaluated and compared to the physical blend of the base materials in Ludipress and to other filler/binders including Cellactose and Avicel PH 200.

The data were determined in order to evaluate flowability, bulk density, tapped density, Hausner ratio, angle of repose and particle size distribution. The particle morphology and constitution were examined using scanning electron microscopy (SEM). Differential scanning calorimetry (DSC) was used to detect differences between lactose based products.

Several Ludipress samples exhibited a good batch-to-batch uniformity and flow characteristics compared to the physical blend and other excipients investigated.

The tableting parameters tested were crushing strength, friability and disintegration time. The ability to form coherent compacts was similar for Ludipress, Cellactose and Avicel PH 200, whereas tablets made from the physical blend resulted significantly softer. Determination of tablet disintegration time revealed a disintegration time minimum at about 100 MPa for Ludipress compacts. By augmenting compaction load from 100 to 185 MPa Cellactose showed an increase in disintegration time to more than 20 minutes. The disintegration times of Avicel PH 200 compacts were nearly constant and were also the shortest in the compaction load range examined.     

Evaluation of Ludipress as a “Multipurpose Excipeent” for Direct Compression: Part I: Powder Characteristics and Tableting Properties

The powder characteristics and tableting properties of Ludipress, a lactose-based, free flowing granule containing povidone and crospovidone have been evaluated and compared to the physical blend of the base materials in Ludipress and to other filler/binders including Cellactose and Avicel PH 200.

The data were determined in order to evaluate flowability, bulk density, tapped density, Hausner ratio, angle of repose and particle size distribution. The particle morphology and constitution were examined using scanning electron microscopy (SEM). Differential scanning calorimetry (DSC) was used to detect differences between lactose based products.

Several Ludipress samples exhibited a good batch-to-batch uniformity and flow characteristics compared to the physical blend and other excipients investigated.

The tableting parameters tested were crushing strength, friability and disintegration time. The ability to form coherent compacts was similar for Ludipress, Cellactose and Avicel PH 200, whereas tablets made from the physical blend resulted significantly softer. Determination of tablet disintegration time revealed a disintegration time minimum at about 100 MPa for Ludipress compacts. By augmenting compaction load from 100 to 185 MPa Cellactose showed an increase in disintegration time to more than 20 minutes. The disintegration times of Avicel PH 200 compacts were nearly constant and were also the shortest in the compaction load range examined.     

Formulation and evaluation of insulin dry powder for inhalation

PURPOSE: Dry powder formulation of insulin for pulmonary administration was prepared to obtain increased drug deposition in the alveolar absorptive region. The deposition was studied by investigating the dispersion and deaggregation of insulin from the carrier lactose using an Andersen cascade impactor and twin stage impinger. The subsequent absorption following the deposition was studied by in vivo method. METHODS: Insulin in solution with absorption promoters was lyophilized. The powder was incorporated with lactose of different grades and their combinations as carriers to deliver using an inhaler device. Solid-state characteristics of the carrier as well as the drug powder were assessed by particle size and distribution measurement. The flow properties such as moisture content, powder density, angle of repose, and carr's compressibility index of the powder mixture were determined. The aerosol behavior of the powder was studied by dispersion using rotahaler(c) connected to a twin-stage impinger (TSI) and an eight-stage Andersen cascade impactor (ACI) operating at different flow rates of 30-90 l/min. The in vivo performance was studied by deliverance to the respiratory tract of guinea pigs. The intratracheal bioavailability with respective to intravenous route was calculated by measuring the blood glucose reduction. RESULTS: The coarser particles of lactose in fractions of carrier containing a wide particle size distribution impacted in the preseperator of cascade impactor, and only the particle less than 10 microm size entered stage 0-stage 7. Formulation containing 1:1 mixture of Respitose ML006 (62%<50 microm) and Respitose ML003 (37.8%<50 microm) as carrier imparts well deaggregation of insulin, and higher deposition leads to 52.3% of fine particle fraction at 60 Lit/min and in vivo bioavailability of 82%. CONCLUSIONS: Insulin formulations containing 1:1 mixture of Respitose ML006 and Respitose ML003 as carrier can impart deeper deposition of drug particles and cause higher bioavailability. This suggests that carrier used in the formulation influenced the amount of insulin deposition in the alveolar region of the lung. Hence, it was concluded that the availability of insulin for systemic absorption depends on the particle size of the drug as well as the carrier lactose.     

Preparation and Evaluation of High Drug Content Particles

Abstract

To determine how to prepare high drug content particles using a Wurster fluidized bed to determine realizing the miniaturization of solid dosage forms, aspirin was selected as the model drug and granulated without any additive. In this study, the emphasis was on evaluating the key operation factors of airflow rate and atomizing flow volume. The properties of the resulting particles, such as the average diameter, particle strength, appearance, and compressibility using different airflow rates and atomizing flow volumes, were investigated. Furthermore, detailed optimization of the operation conditions was conducted by artificial neural network (ANN) analysis. The relationship between the controlling factors (powder supplied, concentration of spray liquid, the amount of consumed spray liquid, and spray rate) and the response variables (product yield, median diameter, angle of repose, and degradation of aspirin) was investigated after evaluating the airflow rate and atomizing flow volume effects. The resulting granules under optimum operation conditions showed excellent physicochemical properties such as particle size uniformity, flowability, and compressibility.     

Measurement methods for quantifying powder flowability and velocity in cold spray systems

Four powders with varying bulk densities, Al, Al₂O₃, Sn, and Cu, were used to determine quantifiable relationships between powder flowability, mass flow rate, and powder velocity with particle morphology and particle distribution in a cold spray system. High particle density results in good powder flowability, specifically when the powders are spherical relative to irregular morphology. Particle velocity during cold spray, measured with a double disk rotary system, increases non-linearly with an increase of inlet pressure. The increase in mass flow rate from the hopper and the resulting mass output of the cold spray system shows a consequence of good powder flowability. Conversely, a high mass flow rate decreases the particle velocity during the cold spray process, with better flowability leading to decreases on the order of 10% in particle velocity in the cold spray system. The described methods, proposed tools, and findings can be easily made with cost-effective and on-the-spot measurements.     

Optimal Massing Liquid Volume Determination by Energy Consumption Measurement: Study of the Influence of Some Physical Properties of Solvents and Products Used

This study tried to investigate, by the power comsumption technique, the influence of the powder's and solvent's properties on wet granulation.

It could be shown that the required amount of granulation liquid decreases when the particle size of the powder to be granulated increases. This relationship is however only true when the particle size distribution of the powder to be granulated is rather narrow.

Powders having the same solubility in different solvents require the same optimal liquid quantity for granulation, but the properties of resulting granules depend on surface tension and wetting properties of the solvent.

When the powder to be granulated contains crystallisation water, the temperature rising in the mixer can be sufficient to liberate this water, which must be taken into account in the optimal granulation liquid requirement.

The effect of a macromolecular binder (PVP, HPMC) has also been studied: the optimal liquid quantity required changes with the kind of binder used and the manufacturing process (binder used in solution or added as dry powder).

It was also shown that in the case of lactose, the optimal quantity of PVP or HPMC can be determined from the power consumption records and from the granules friability studies     

Measurement of flowability of lubricated powders by the vibrating tube method

Background: The evaluation of lubricity or flowability of pharmaceutical powders is important for consistent production and quality control of drug products. However, there have been only a few studies on quantitative measurements of the properties of lubricated powders.

Method: Magnesium stearate (MgSt) and sodium stearyl fumarate (SSF) were used as lubricants. Lubricated powders were prepared by adding lubricants to spray-dried lactose under different conditions. To evaluate flowability, the vibrating tube method was used. In this method, the vibration amplitude of the tube is increased at a constant rate, and the mass of the powder discharged from the tube is recorded. Flowability profiles, i.e. the relationships between the mass flow rate and vibration acceleration, were obtained experimentally. To characterize static and dynamic friction properties of powders, critical vibration acceleration required to make powder particles flow and the average mass flow rate were determined.

Results: Addition of 0.5% MgSt was sufficient for the reduction of static friction between particles. Blending time of the lubricants had little effect on the average mass flow rate of lubricated powders. On the other hand, addition of SSF resulted in an increase in static friction at the beginning of blending, and after a certain blending time, flowability improved. The combination of MgSt and SSF improved both static and dynamic friction properties irrespective of the blending time.

Conclusion: The vibrating tube method can be used to evaluate the flowability properties of lubricated powders, and the experimental results provide useful information on the production of pharmaceutical solid dosage forms.     

煤粉气-固两相流的超声衰减特性

以颗粒相在整个检测空间内均匀分布为前提,采用McClements理论和Bouguer-Lambert-Beer定律共同描述煤粉气-固两相流中超声衰减特性,建立超声衰减系数与气-固两相流相关参数的理论关系,通过数值模拟,分析超声衰减随着颗粒相体积分数、超声频率、颗粒粒径变化的规律。结果表明,超声频率越高衰减系数越大;声衰减系数随着颗粒相体积分数的增大线性递增;选用某固定频率检测,测得2个体积分数下的声衰减系数即可确定衰减-体积分数曲线斜率,从而实现任意衰减系数对应的颗粒相体积分数测量;在相同的体积分数下,煤粉颗粒粒径为10～200μm,声衰减系数随着颗粒粒径的增大单调递减,当煤粉颗粒粒径大于200μm时,声衰减系数对煤粉颗粒粒径不再敏感。     

Optimal Massing Liquid Volume Determination by Energy Consumption Measurement: Study of the Influence of Some Physical Properties of Solvents and Products Used

Abstract

This study tried to investigate, by the power comsumption technique, the influence of the powder's and solvent's properties on wet granulation.

It could be shown that the required amount of granulation liquid decreases when the particle size of the powder to be granulated increases. This relationship is however only true when the particle size distribution of the powder to be granulated is rather narrow.

Powders having the same solubility in different solvents require the same optimal liquid quantity for granulation, but the properties of resulting granules depend on surface tension and wetting properties of the solvent.

When the powder to be granulated contains crystallisation water, the temperature rising in the mixer can be sufficient to liberate this water, which must be taken into account in the optimal granulation liquid requirement.

The effect of a macromolecular binder (PVP, HPMC) has also been studied: the optimal liquid quantity required changes with the kind of binder used and the manufacturing process (binder used in solution or added as dry powder).

It was also shown that in the case of lactose, the optimal quantity of PVP or HPMC can be determined from the power consumption records and from the granules friability studies