Pharmaceutical Granules Research Articles

Microwave vacuum drying of porous media: experimental study and qualitative considerations of internal transfers

This paper deals with experimental results obtained on a laboratory scale dryer. Two porous media were dried, a packing of initially water saturated glass beads and a packing of initially unsaturated pharmaceutical granules. For the first one, the main parameter is permeability of the bed varying the beads diameter and for the second one it is the porosity of the bed varying the amount of product. These experiments were carried out at fixed incident power and pressure level. In the first period of the drying, it was observed that permeability was a limiting parameter to internal mass transfers when free liquid water is expulsed, revealing high gas pressure gradients inside the product. They occur when we have a massive vaporisation with ebullition. As for the porosity of the granules bed, it has no effect on mass transfers. In the second period, we have no influence of both parameters on the drying kinetics. In the last period, so in the hygroscopic field or below the irreducible saturation, the internal mass transfers are governed by the electromagnetic energy absorption.

Scale-Up and Endpoint Issues of Pharmaceutical Wet Granulation in a V-Type Low Shear Granulator

ABSTRACTA 32 factorial experiment is conducted in a 57 liter low shear granulator to evaluate the influence of changes in binder strength and agitator speed on the response variables of granule size, granule morphology, granule density and torque input. Results are compared to previous work in a 2 liter granulator and scale-up issues between the two granulators are addressed.

MICROWAVE VACUUM DRYING OF POROUS MEDIA: VERIFICATION OF A SEMI-EMPIRICAL FORMULATION OF THE TOTAL ABSORBED POWER

Vacuum drying experiments were performed on a laboratory scale dryer with two porous materials: a packing of initially saturated glass beads and of unsaturated pharmaceutical granules. Several incident powers and two vacuum pressure levels were tested in order to demonstrate different drying mechanisms. The drying kinetics, temperature of the product and the absorbed power are presented and the coupling between the drying rate and the absorbed power is shown. A semi-empirical formulation of the total absorbed power is proposed taking into account the water content, the temperature and the dielectric properties of each phase. This formulation is based on a quasi-static assumption which allows the local electric field inside the material to be expressed with an analytical equation.

Scaleup of a Pharmaceutical Granulation in Planetary Mixers

The scaleup of a pharmaceutical granulation in a series of planetary mixers with increasing bowl capacity between 5 and 200 liters has been studied by applying the classical dimensionless numbers of Power, Reynolds, and Froude to define the power consumption profile of each mixer as a function of the processing conditions in dimensionless form. Experiments were performed using a formulation based on dicalcium phosphate dihydrate containing pregelatinized starch, with water being added at a fixed rate. Samples were taken at different power consumptions and assessed using mixer torque rheometry. Geometrically similar machines gave the same dimensionless relationship, but when similarity was compromised by the use of modified bowls and blades, different relationships occurred. The results show that, for geometrically similar machines, it is possible to calculate the power consumption at a predefined granulation endpoint at any given operating condition at any scale.

Mercury Porosimetry of Pharmaceutical Powders and Granules

Effect of scanning speed and moisture content of the sample on the result of mercury porosimetry analysis of mannitol and microcrystalline cellulose (Emcocel® 50M) powders and granules produced by wet granulation were studied. In high-pressure porosimetry analysis, the smallest pores (diameter <20 nm) of the powders and granules could not be detected accurately when high scanning speeds were used. If the total pore volume is the only parameter of interest, fast scanning speed can be used, because the scanning speed does not affect this value. In high-pressure porosimetry analysis, the volume of the smallest pores (diameter <40 nm) of mannitol and microcrystalline cellulose granules increased with increasing water content. For powders, no effect of moisture on the volume of the smallest pores was observed. Thus, the increase in the volume of the smallest pores of granules with increasing moisture is related to the structure of the granules. Measurement of the water content of the samples together with proper drying of the samples before the porosity measurement is extremely important.

Book Reviews

Handbook of Pharmaceutical Granulation Technology, Edited by Dilip M. Parikh. Published by Marcel Dekker, Inc., 270 Madison Avenue, New York, NY 10016–0602, USA. Hardcover, 536 pages, $175.00.Mechanisms of Transdermal Drug Delivery, edited by Russell O. Pons and Richard H. Guy. Published by Marcel Dekker, Inc., 1997; 270 Madison Avenue, New York, NY 10016; 376 pages, hard cover, $150.

The effect of batch size on scale-up of a pharmaceutical granulation in a fixed bowl mixer granulator

The effect of two batch sizes of a pharmaceutical granulation processed in a fixed bowl mixer granulator has been evaluated using the classical dimensionless numbers, Power, Reynolds and Froude recently shown to apply to this type of mixer. Despite a correction for the differences in the heights of the powder bed the relationships were significantly different. This is thought to be due to the differences in the downward force acting on the impeller as a result of the changes in flow pattern as the powder bed contacts the sloping sides at the top of the mixer.

Scale-up of a pharmaceutical granulation in fixed bowl mixer-granulators

Scale-up in fixed bowl mixer-granulators has been studied by applying the classical dimensionless numbers of Power, Reynolds and Froude to end-point prediction in a range of geometrically similar machines. The simple relationship of Power number/Reynolds number, as suggested by previous workers, has been found to be inappropriate for large-scale production machines where corrections have to be made for gross vortexing and powder bed height variation by the incorporation of the Froude number and a scaling factor. When corrections are made, data from 25-, 100- and 600-1 machines all fall on the same curve allowing predictions of optimum granulation end-point conditions to be made for production-scale equipment from measurements on laboratory-scale equipment and vice-versa.

Image processing for on-line monitoring of granule size distribution and shape in fluidized bed granulation

A particle image probe comprising a CCD camera and an image processing system has been developed for on-line monitoring of granule size distribution and shape in a fluidized bed granulation. Continuous granule measurements by the image probe were digitized and processed by the image processing system, and granule size distribution and shape were computed in real time. The developed system was applied to the monitoring of granule growth in pharmaceutical granulation and its validity was confirmed. Application of this system to the dynamic control of granule size and shape was also demonstrated.

Evaluation of Microwave Drying for Pharmaceutical Granulations

AbstractThe experiments were designed to compare the granule characteristics following the microwave drying and conventional tray drying. The formulations were designed to study the effect of microwave radiation under different conditions. This later criterion was studied by using granules prepared with different granulating fluids. The granules were prepared by using sulfathiazole as a model drug, lactose as a diluent, and starch as a disintegrating agent. The granulating fluids were 5% solution of PVP in 100% water, 50% water 50% ethanol, and 100% ethanol, respectively. The granules were dried in a microwave oven and in a conventional tray oven at 40±2° C. The loose and bulk densities were measured in a 100 ml glass cylinder. The granule morphology was examined using a scanning electron microscope. Dissolution rates of the granules were monitored using a rotating paddle dissolution apparatus. The loose and tapped bulk densities, the percentage compressibility, hardness, and the time required for 100% di...

Infrared imaging of pharmaceutical materials undergoing compaction.

The goal of this study was to use infrared thermography as a new technique to investigate the heat released during compaction and consolidation of pharmaceutical powders and granules. Real-time temperature measurements without physical contact with tablets were provided by a highly sensitive (+/- 0.1 degrees C at 30 degrees C) infrared camera (Agema Infrared Systems, Model 470 with CM-SOFT software). High-resolution images were captured at the takeoff point, i.e., less than 1 sec after compaction, stored on floppy disks, and then analyzed on a regular PC equipped with a VGA color monitor. Thermal surface profiles of tablets were obtained with high geometric and temperature resolution. Reproducibility of the camera readouts was better than 3%. The model granulation used was a direct compression blend of microcrystalline cellulose, spray-dried lactose, and magnesium stearate. This blend was compressed using an instrumented Korsch PH106 rotary press fitted with 1 station of 19.1 x 7.9-mm (0.750 x 0.312-in.) capsule-shaped tools. The effects of compaction force (6-20 kN), rate (130- to 360-msec contact time), and lubricant level (0.5 and 1.0%) on postcompaction temperature rise, caused by heat released during compaction, were investigated. The presence and location of nonhomogeneous heat distribution were assessed as well. Results have shown that the heat released during compaction increases with compaction force. Tablet surface temperatures of 33.8 +/- 0.7 degrees C were observed at 20 kN compaction force in contrast to 29.5 +/- 0.3 degrees C at 6.7 kN.(ABSTRACT TRUNCATED AT 250 WORDS)

The development of a microwave fluid-bed processor. I. Construction and qualification of a prototype laboratory unit.

The static bed- and planetary-type microwave dryers currently available to process pharmaceutical materials are not designed to use hot-air fluidization for the purpose of maximizing microwave energy inputs and particle drying. To take advantage of the benefits offered by fluidization, a 1-kg Uni-Gatt laboratory fluid bed processor was modified to support microwave-assisted fluid bed drying of several representative pharmaceutical granulations. The construction, design features, and validation of this new microwave fluid bed processor are presented.

The development of a microwave fluid-bed processor. II. Drying performance and physical characteristics of typical pharmaceutical granulations.

Four typical pharmaceutical granulations were used to measure the enhanced drying performance of a laboratory-sized microwave fluid-bed processor, the design and construction of which were presented in Part I of this work (preceding paper). Results demonstrate improvements in observed drying rates by as much as sixfold depending upon the granulation type and drying conditions. At a low inlet temperature (30 degrees C), drying was achieved with microwave power inputs of 100-125 W/liter of working capacity, whereas similar targeted moisture levels were unattainable using conventional fluid-bed drying. Microwave energy available for heating and drying was 68 to 86% of the total microwave energy inputted.

NONDESTRUCTIVE &lt;i&gt;IN SITU&lt;/i&gt; FTIR MEASUREMENT BY DIFFUSE REFLECTANCE SPECTROMETRY

The penetration depth in diffuse reflection was found to be dependent on the design of optics, i.e. incidental angle, reflection collecting angle, and azimuthal angle which is the directional angle between the incidental and reflection collecting axis projected on the surface plane. The possibility for quantitative application was examined in respect of matrix choice and KMC linearity with concentration. Surface and interior analysis of pharmaceutical granules for an anticholesterol tablet was performed with microspectroscopy in diffuse reflection mode, and the increase of drug concentration on the surface relative to that in the interior was clarified.

The effect of Mill Variables on a Granulation Milling Process

AbstractAn instrumented mill was used to evaluate the milling of a pharmaceutical granulation. The effects of changing mill speed, screen hole size, impeller type, and impeller-screen clearance on milling time and work, as well as particle size reduction were investigated. Screen hole size had the largest effect on milling time and work as well as particle size reduction, while impeller type had the largest effect on overall milling performance. A new impeller design was tested and found to enhance milling efficiency by improving both particle size reduction and mill output rate.

Analysis of Solid-State Carbon-13 NMR Spectra of Polymorphs (Benoxaprofen and Nabilone) and Pseudopolymorphls (Cefazolin)

The solid-state 13C-NMR spectra of the polymorphs of benoxaprofen, nabilone, and cefazolin are reported using the crosspolarization/magic-angle spinning (CP/MAS) technique. In general, the spectra of the diffrent crystal forms are different. In favorable cases the spectra of the drug in a pharmaceutical granulation can be discerned. These results provide a preliminary indication that solid-state NMR spectroscopy is a useful technique for the investigation of drug polymorphs and drugs in their dosage forms.

The Quantitative Evaluation of a Granulation Milling Process II. Effect of Ouput Screen Size, Mill Speed and Impeller Shape

AbstractThe processing variables associated with the comminution of pharmaceutical granulations were investigated. The three variables chosen were mill speed, output screen size and impeller shape. Experiments were performed on an aspirin granulation using proper techniques of experimental design. Analysis showed that the three mill variables cannot be considered independently but rather at the level of combinations. A complete characterization of the mill output according to particle size distribution is then possible based upon these combinations of mill variables.

Grinding and granulation in a vibratory ball mill

In the grinding of paracetamol, lactose and sucrose in a vibratory ball mill, it is found that an equilibrium is rapidly attained due to the agglomeration of ground particles. The existence of this agglomerative phase of comminution has been extensively reported in the literature. This study investigates prolonged vibratory ball milling as a means of pharmaceutical granulation. The granules are produced from the agglomeration of very fine particles and become more compacted as comminution proceeds.

Granulation using the agglomerative phase of comminution

Aggregation and agglomeration have been extensively reported in the literature during the prolonged milling of powders. This phase is usually considered non-productive and is delayed by the use of grinding aids. The agglomeration phase of sucrose, sodium chloride, lactose and paracetamol has been studied as a possible method of producing pharmaceutical granules. In this paper the mechanism of agglomeration at the particulate level is examined. It is shown, that following particle size reduction, there is agglomeration of the fine coherent particles into a loose granular structure. This granule is then either compressed into a harder granule or remilled to produce fine powder. Finally, an equilibrium between size reduction and agglomeration is attained.

The influence of binder concentration on the intra- and intergranular porosity of pharmaceutical granules

Characterization of the surface topography of dicalcium phosphate dihydrate, granulated with starch binder, by nitrogen adsorption and mercury intrusion techniques has shown the presence of microvoids within the granules. Micro and mesopore analysis, of particles and granules, from adsorption isotherms has quatified the intra- and interparticle porosity of the particlemucilage bond formation in the size range 0.5 –100 nm while mercury intrusion, which is restricted to macropores and voids in the size range 3.5 nm to 80 μm, has quantified the interparticle structure of the granules.