Measurement of physical strength of pharmaceutical extruded pellets

This paper describes a novel and simple method for measuring the physical strength of pharmaceutical pellets prepared by extrusion granulation. Pharmaceutical powders composed of lactose, cornstarch, and microcrystalline cellulose were kneaded with purified water and dry binder (hydroxypropylcellulose), then extruded through a dome-type extrusion granulator. The physical strength of the dried extruded pellets was measured with a novel system: pellets and grinding alumina media were both fed into a ball mill pot and then "grinding degree" was measured as defined by the ground fine powder fraction after being rotated in the pot. The grinding conditions such as grinding time and number of alumina balls were optimized. The measured physical strength and pellet strength measured with a typical strength tester was compared. Quantitative relationships between the strength and the physical properties of the pellets such as friability and disintegration time were also investigated. It was found that the newly developed system could easily and accurately evaluate the physical strength of extruded pellets and could also predict the various physical properties.     

Determination of optimal formulation for extrusion granulation by compression test of wet kneaded mass

The purpose of this study is to propose the application of a compression test to the determination of an optimal formulation for extrusion granulation. The electric current during extrusion was measured and the characteristics of the wet kneaded mass in the compression test were analyzed under various operating conditions, with different types of extruders and several formulations of kneaded mass. It was found that addition of a binder (HPC-L) to pharmaceutical powders lowered the load of a high-compressing type extruder, since the binder reduced the friction among the wet mass during extrusion. Also, the support stress was found to be proportional to the compression pressure without a binder, although an inflection point appeared on the support stress curve when a binder was present. This inflection point suggested large water retention of the wet kneaded mass, at which the medium of pressure was changed from a discontinuous solid powder to a continuous liquid, and large water retention contributed to the low friction of the wet mass. The friction of the wet kneaded mass and the aptitude of the formulation for extrusion were understood by using the compression test. The compression test is a very useful procedure at the first stage of a formulation study.     

Development of a novel compression tester and rheo-mechanical properties of wet-mass powder. I--Effect of kneading time on the rheo-mechanical properties

In our previous paper [Watano S., et al., Chem. Phram. Bull., 49(1), 64-68, (2001)], a compaction tester was developed to quantitatively evaluate the water dispersion condition of wet kneaded masses prepared by a paddle type kneader. It was also demonstrated that the physical properties of pellets prepared by extrusion granulation after the kneading could be well predicted by the vertical pressure transmission obtained through the compaction tester. However, in this compression tester, the vertical pressure transmission was just obtained and rheological and mechanical properties (so called rheo-mechanical properties) of wet mass-powder that should be the most important to determine the deformation process were not well studied. In this study, a novel compression tester, which can measure both vertical and radial pressure transmissions, has been developed. Based on the compression test, mechanical property (Young's modulus) and rheological property (effective internal friction) of wet mass powder prepared by different kneading times were quantitatively investigated. Granules (pellets) were then obtained through the extrusion granulation and fluidized bed drying, and the physical properties (strength and disintegration time) of the obtained pellet were evaluated. The relationship between the granule (pellet) physical properties and the mechanical and rheological (rheo-mechanical) properties was analyzed.     

Development of a novel vertical high shear kneader and its performance in wet kneading of pharmaceutical powders

A novel multi-functional vertical high shear kneader has been developed. Wet kneading of pharmaceutical powders was conducted under various blade components and operating conditions. Compression properties of wet kneaded mass was analyzed and dispersion of hinder liquid (water) among the mass was investigated by assaying tracer aqueous pigment. Pellets were produced through a dome type extrusion granulator with continuous extrusion pressure measurement device and a fluidized bed drier, and then the physical properties were measured. Quantitative relationship between the pellet's physical properties and the binder dispersion condition as well as the compression properties could be obtained. It was found that the newly developed kneader was very effective to uniformly disperse binder as well as impart high shear stress to the wet mass without generating obvious adhesion onto the vessel wall. It was also pointed out that the extrusion pressure could determine the physical strength of pellet. This method proposes a new methodology for continuous monitoring of kneading condition as well as predicting pellet's physical properties.     

Quantitative analysis of water dispersion conditions and pressure transmission characteristics of a wet kneaded mass

In our previous paper [Watano S. et al., J. Powder Technology Japan, 37, 362-370 (2000)], a novel compaction tester was developed to quantitatively evaluate the water dispersion condition of a wet kneaded mass prepared by a paddle type kneader. It has been demonstrated that the physical properties of pellets prepared by extrusion granulation after the kneading can be well predicted by the pressure transmission obtained through the compaction tester. This paper describes a more detailed investigation of the water dispersion, its mechanism and pressure transmission characteristics of wet kneaded masses prepared under various operating conditions. First, kneading by a paddle type kneader was conducted to prepare wet masses under various binder contents using different additional methods and different starting materials. Secondly, water dispersion and pressure transmission characteristics of wet masses were investigated. After the wet kneading, the wet kneaded masses were extruded through a dome type extruder and were dried by a fluidized bed to prepare dry pellets. The relationship between water dispersion and pressure transmission can be expressed by a single line, regardless of binder content or methods of addition. This implies that these parameters have no effect on the water dispersion condition of the wet kneaded mass prepared by a high shear paddle type kneader. Different water dispersion characteristics and the mechanism obtained by different starting materials can also be evaluated by the pressure transmission data. Properties of dry pellets can also be predicted by the pressure transmission. It can be concluded that the developed compaction tester can quantitatively evaluate the water dispersion condition of a wet kneaded mass and also predict properties of the final extruded products.     

Rheological analysis and quantitative evaluation of wet kneaded wax matrix

The properties of the wet kneaded wax matrix were evaluated using a compression tester, whereby a newly proposed sigma index for the plastic deformation was assessed in the pressure transmission diagram. The sigma index was indicative of a characteristic of the plastic yield point in the rheological behavior, and presented an initial and abrupt deformation of wet kneaded mass when the wet kneaded mass was subjected to the pressure. The value of sigma index was confirmed to decrease along with an increase in the plasticity of wet kneaded mass. The wet mass of wax matrix was prepared under various kneading time, and then extruded. The properties of the extruded granules such as pore volume, strength and dissolution were investigated. As a result, it was found that the sigma index decreased with an increase in kneading time. The granules with small value of sigma index showed few porosities, large strength and slow dissolution. It was demonstrated that the sigma index linked the characteristics of wet kneaded mass to the dissolution and the other granule properties. Existence of this link was revealed by sigma index evaluation relevant to the plasticity. The sigma index could be a decisive criterion to permit an in-process evaluation of the kneading progress quantitatively, and also useful for anticipating the dissolution of the final granules roughly.     

Development of a novel compression tester and rheo-mechanical properties of wet-mass powder. II--Effect of moisture content on the rheo-mechanical properties

In our previous paper [Watano S., et al., Chem. Pharm. Bull., 51(7), 747-750 (2003)], a novel compression tester, which enables the vertical and radial pressure transmission measurement, has been developed and quantitative analysis of rheo-mechanical properties of wet-mass powder prepared by different kneading times was conducted. In this study, the compression test was conducted by using the kneaded wet-mass powders prepared by different moisture contents. Pressure transmission characteristics and rheo-mechanical properties have been investigated to characterize the wet-mass powders. The relationship between these parameters and granule physical properties was also investigated.     

On-line monitoring of granule growth in high shear granulation by an image processing system

A novel system has been developed to continuously monitor granule growth in a high shear granulation. The system consists of an image processing system and a particle image probe comprising a CCD camera, lighting unit and air purge system. Segregation during powder mixing was investigated experimentally and the optimal positioning of the probe was determined. High shear granulation was conducted using pharmaceutical powders, and granule size and product's yield of various size ranges were continuously measured by the developed system. Sieve analysis of the granulated products sampled out during the granulation was simultaneously conducted, and the obtained data was compared with that by the on-line image processing system. An extremely close relationship could be found between both data, proving that the developed system could monitor the granule growth accurately and continuously throughout the granulation. An on-off control system was developed to control the granulation process, and the performance of the system was confirmed.     

Scale-up studies on high shear wet granulation process from mini-scale to commercial scale

A newly developed mini-scale high shear granulator was used for scale-up study of wet granulation process from 0.2 to 200 L scales. Under various operation conditions and granulation bowl sizes, powder mixture composed of anhydrous caffeine, D-mannitol, dibasic calcium phosphate, pregelatinized starch and corn starch was granulated by adding water. The granules were tabletted, and disintegration time and hardness of the tablets were evaluated to seek correlations of granulation conditions and tablet properties. As the granulation proceeded, disintegration time was prolonged and hardness decreased. When granulation processes were operated under the condition that agitator tip speed was the same, similar relationship between granulation time and tablet properties, such as disintegration time and hardness, between 0.2 L and 11 L scales were observed. Likewise, between 11 L and 200 L scales similar relationship was observed when operated under the condition that the force to the granulation mass was the same. From the above results, the mini-scale high shear granulator should be useful tool to predict operation conditions of large-scale granulation from its mini-scale operation conditions, where similar tablet properties should be obtained.     

Preparation of antipyretic analgesic by direct compression and its evaluation

Direct compression is able to produce tablets at a lower cost than wet granulation and tableting method, due to a fewer items of process validation. In this study, acetaminophen was used as a medicine with various granular diameters to formulate tablets by direct compression, thus evaluating their physical properties. Consequently, direct compression was found effective in formulating tablets with excellent physical properties, with the granular diameter taken into account. It was confirmed that tablets produced by direct compression were similar in physical properties in tablets produced by wet granulation and tableting method. Further, it was suggested that use of a dry-type binder would make it possible to provide a tablet having higher content of the medicine with excellent physical properties.     

Obtaining Granules from Waste Tannery Shavings and Mineral Additives by Wet Pulp Granulation

This paper presents the results of research on the granulation process of leather industry waste, i.e., tanning shavings. It is economically justified to granulate this waste together with mineral additives that are useful in the processes of their further processing. Unfortunately, the granulation of raw, unsorted shavings does not obtain desired results due to their unusual properties. In this study, the possibilities of agglomeration of this waste were examined by a new method consisting of the production and then the granulation of wet pulp. During granulation, no additional binding liquid is added to the granulated bed. As part of this work, the specific surface of granulated shavings, the granulometric composition of the obtained agglomerates, and their strength parameters were determined. The use of a vibrating disc granulator, the addition of a water glass solution (in the pulp), dolomite, and gypsum made it possible to obtain durable, mechanically stable granules.     

Scale-up of high shear granulation based on the internal stress measurement

Scale-up of wet granulation in a vertical high shear mixer was conducted. Pharmaceutical excipient powders composed of lactose, cornstarch and micro-crystallinecellulose, and hydroxypropylcellulose as a binder were mixed together and then granulated with purified water under various operating conditions and vessel scales. A novel internal stress measurement system was developed and stress of normal and tangential directions that granules received from the agitator blade during the granulation was continuously measured. The results indicated that granules received stress mainly from the tangential direction, which also showed the largest value near at the vessel wall. The effects of the agitator tip speed and the centrifugal acceleration on the measured stress was investigated. It was found that the tip speed of the agitator blade could be the main factor for the granule growth. The physical properties such as strength, size distribution and compressibility of granules prepared by changing the operating conditions and the vessel scales were evaluated and the scale-up characteristics of high shear granulation were investigated experimentally. The results showed that these physical properties had linear correlations with the tip speed. It was finally concluded that the scale-up of high shear granulation could be well conducted by means of the tip speed of the agitator blade.     

Blend uniformity evaluation during continuous mixing in a twin screw granulator by in-line NIR using a moving F-test

This study focuses on the twin screw granulator of a continuous from-powder-to-tablet production line. Whereas powder dosing into the granulation unit is possible from a container of preblended material, a truly continuous process uses several feeders (each one dosing an individual ingredient) and relies on a continuous blending step prior to granulation.     

A review on key aspects of wet granulation process for continuous pharmaceutical manufacturing of solid dosage oral formulations

Wet granulation process is a major unit operation in production of pharmaceuticals as solid dosage oral formulation. Indeed, granulation is used to improve the formulation properties such as flowability, compressibility, and so on for pharmaceutical manufacturing. Different types of granulations can be used in pharmaceutical manufacturing in which the selection of proper process depends on the operational conditions as well as formulation properties. In current decades, twin-screw wet granulation has been of paramount interest owing to its superior properties. Pharmaceutical manufacturing industry are trying to move towards continuous mode by which the efficiency can be improved compared to the batch mode. Therefore, development of continuous granulation process is of great importance. In this review article, various processing units applicable for wet granulation of pharmaceutical formulations for solid dosage forms are reviewed and discussed. The advantages and disadvantages of the processes are discussed and listed along with modeling approaches for simulation of process. The governing models and numerical schemes applicable for design of wet granulation are also critically discussed. The main focus is on wet granulation as this method has attracted much attention in pharmaceutical processing.     

Polysaccharide functionality through extrusion processing

Extrusion processing is a technology applied in the food and pharmaceutical industry for affecting product microstructure, product chemistry or the macroscopic shape of products. Starch based products are often extruded to break down the starch granule to render it digestible and to produce a shaped product. Encapsulation of flavors, nutrients and drugs is another frequent application of extrusion processing. This short review article is concerned with the use of extrusion processes to modify polysaccharide functionality. Extrusion processes are applied to polysaccharides for specific purposes such as physical modification or chemical modification (reactive extrusion), manufacture of confectionary gels and encapsulation of flavors or drugs. Non-starch polysaccharides and confectionary gels have also been extruded. Another application area is in the field of dietary fibers, obtained through extrusion processing of by- or waste-products of the food industry. The focus of this article is on extruding starch and other polysaccharides as an ingredient rather than as part of a final food product obtained by extrusion processing. It concludes with a discussion on extrusion as microstructure generating process and the relevance of this application to taste perception in semi-liquid foods.     

Waxes for powder coatings

Since the first beginnings at the end of the 50^th, the powder coating technology has become a perfected alternative in product and procedure respect to liquid paints. Powder coatings are primarily a mixture of synthetic resins, pigments and additives offering economical and ecological advantages compared to other coating systems. The raw materials are mixed, extruded and ground to coating powders. Waxes play an important part as additives in powder coatings. Production, storage and processing as well as the properties of the applied powder coating can be influenced positively by different waxes. Various waxes and their advantages are demonstrated by practical advantages.     

Analysis of the release process of phenylpropanolamine hydrochloride from ethylcellulose matrix granules V. Release properties of ethylcellulose layered matrix granules

In the pharmaceutical preparation of a controlled release drug, it is very important and necessary to understand the release properties. In previous papers, a combination of the square-root time law and cube-root law equations was confirmed to be a useful equation for qualitative treatment. It was also confirmed that the combination equation could analyze the release properties of layered granules as well as matrix granules. The drug release property from layered granules is different from that of matrix granules. A time lag occurs before release, and the entire release property of layered granules was analyzed using the combination of the square-root time law and cube-root law equations. It is considered that the analysis method is very useful and efficient for both matrix and layered granules. Comparing the granulation methods, it is easier to control the manufacturing process by tumbling granulation (method B) than by tumbling-fluidized bed granulation (method C). Ethylcellulose (EC) layered granulation by a fluidized bed granulator might be convenient for the preparation of controlled release dosage forms as compared with a tumbling granulator, because the layered granules prepared by the fluidized bed granulator can granulate and dry at the same time. The time required for drying by the fluidized bed granulator is shorter than that by the tumbling granulator, so the fluidized bed granulator is convenient for preparation of granules in handling and shorter processing time than the tumbling granulator. It was also suggested that the EC layered granules prepared by the fluidized bed granulator were suitable for a controlled release system as well as the EC matrix granules.     

Assessment of processing and polymorphic form effect on the powder and tableting properties of microcrystalline celluloses I and II

Microcrystalline cellulose I (MCCI) is an excipient used as a diluent, disintegrant, glidant and binder for the production of pharmaceutical tablets. In this work, microcrystalline cellulose II (MCCII) was obtained from cotton fibers by basic treatment with 7.5 N NaOH followed by an acid hydrolysis. MCCI and MCCII materials were processed by wet granulation, dry granulation and spray drying. Either the polymorphic form or processing had no effects on the particle morphology or particle size. However, MCCII powders had a higher porosity, less packing tendency, degree of crystallinity, degree of polymerization and density, but a faster disintegration than MCCI. The tensile strength of MCCI was highly affected by the wet and dry granulation processes. Most of the resulting powder and tableting properties were dependent on the polymorphic form of cellulose, rather than on the processing employed.     

Granulation of powdered materials in a high-speed granulator

Granulation of powdered materials in a drum-type high-speed granulator was studied. A mathematical model was constructed for describing the granulation in a high-speed granulator in which two processes, coagulation and disintegration, are combined. The constants of the integral transform core for coagulation and disintegration were determined from the experimental data obtained. The suggested mathematical model was shown to be adequate to the real process of granulation of a hydrophobic additive to asphalt concrete mix.     

Scale-up of wet kneading in a novel vertical high shear kneader

A novel multi-functional vertical high shear kneader has been developed and its performance in wet kneading has previously been reported [Watano et al., Chem. Pharm. Bull., 50(3), 341-345 (2002)]. In this study, scale-up of wet kneading in the novel vertical high shear kneader was conducted. Pharmaceutical excipients composed of lactose, cornstarch and micro-crystalline cellulose were used as powder samples. Kneading operations were conducted under various operating conditions and three different vessel scales. The dried pellets were then prepared by extruding the wet kneaded masses through a dome-type extruder and their drying by a fluidized bed. The physical properties such as strength and disintegration time of the dried pellets were evaluated. It was found that the properties of the dried pellets and their scale-up characteristics were well expressed by an agitation power per unit vessel volume and dimensionless Froude number.