Fluidised-Bed Granulation: A Chronology

Abstract

This paper is a chronological survey of published work in the field of pharmaceutical fluidised-bed granulation. It begins with early experiments in the 1960s and continues to include all relevant published work up to 1990. To aid the reader find published material for further in-depth reading a cross reference to published articles on a subject basis is provided in tabular form.     

Alternative Granulation Technique: Melt Granulation

A melt granulation process has been investigated (1, 2) which efficiently agglomerates pharmaceutical powders for use in both immediate- and sustained-release solid dosage forms. The process utilizes materials that are effective as granulating fluids when they are in the molten state. Cooling of the agglomerated powders and the resultant solidification of the molten materials completes the granulation process. Both the molten agglomeration and cooling solidification were accomplished in a high shear Collette Gral mixer equipped with a jacketed bowl. Hence, the melt granulation process replaces the conventional granulation and drying operations which use water or alcohol solutions. The melt granulation process has been investigated using immediate- and sustained-release TAVIST® (clemastine fumarate USP) tablet formulations. The TAVIST granulations have been characterized by power consumption monitoring, measurement of the granulation particle size distribution, bulk and tapped density determinations, and loss-on-drying measurements. Scale-up of the melt granulation process for the sustained release TAVIST tablet formulation was judged successful based on a comparison of the hardness, friability, weight uniformity during compression, disintegration time, and dissolution rate data obtained at different manufacturing scales.     

Alternative Granulation Technique: Melt Granulation

Abstract

A melt granulation process has been investigated (1, 2) which efficiently agglomerates pharmaceutical powders for use in both immediate- and sustained-release solid dosage forms. The process utilizes materials that are effective as granulating fluids when they are in the molten state. Cooling of the agglomerated powders and the resultant solidification of the molten materials completes the granulation process. Both the molten agglomeration and cooling solidification were accomplished in a high shear Collette Gral mixer equipped with a jacketed bowl. Hence, the melt granulation process replaces the conventional granulation and drying operations which use water or alcohol solutions. The melt granulation process has been investigated using immediate- and sustained-release TAVIST® (clemastine fumarate USP) tablet formulations. The TAVIST granulations have been characterized by power consumption monitoring, measurement of the granulation particle size distribution, bulk and tapped density determinations, and loss-on-drying measurements. Scale-up of the melt granulation process for the sustained release TAVIST tablet formulation was judged successful based on a comparison of the hardness, friability, weight uniformity during compression, disintegration time, and dissolution rate data obtained at different manufacturing scales.     

Granulation: A Review on Pharmaceutical Wet-Granulation

Recent developments in pharmaceutical wet granulation techniques are reviewed with the main emphasis on granulation in fluidized beds and high shear mixers. The following items are dealt with: Fundamentals of granule growth, granulation methods and equipments, granulation variables, scaling-up and end-point control.     

Granulation: A Review on Pharmaceutical Wet-Granulation

Abstract

Recent developments in pharmaceutical wet granulation techniques are reviewed with the main emphasis on granulation in fluidized beds and high shear mixers. The following items are dealt with: Fundamentals of granule growth, granulation methods and equipments, granulation variables, scaling-up and end-point control.     

Granulation of ferrosilicon alloy by rotary multi-nozzles cup atomizer: Granulation behavior and model formation

Nowadays, ferroalloys are mainly produced by mold casting and crushing process in China which have obvious drawbacks like low efficiency and high energy consumption. In the present study, a novel process which was based on a rotary multi-nozzles cup atomizer (RMCA) was suggested on FeSi75 (alloy containing 75?wt.% Si). A circle of water curtain was set around the rotary multi-nozzles cup atomizer. According to the calculation results of atomization mechanism, the granulation process agreed with Rayleigh’s mechanism. During the breakup of the alloy ligament, the surface tension plays an important role on the formation of droplet, and the effect of centrifugal force on the diameter of the alloy droplets becomes obvious with the increasing of the rotating speed. In the current study, the models of the traveling trajectories and the heat transfer of the alloy droplet are established. It is found that the solidification time of droplet with different thickness of solidification layer increase with the increase the alloy droplets’ diameter. And the thickness of water curtain required for cooling the alloy increases with increasing the rotating speed.     

A Process to Produce Effervescent Tablets: Fluidized Bed Dryer Melt Granulation

The purpose of the present study was to apply melt granulation in a fluidized bed dryer (fluidized bed dryer melt granulation) to manufacture one-step effervescent granules composed of anhydrous citric acid and sodium bicarbonate to make tablets. This study permitted us to establish that such process parameters as concentrations of polyethylene glycol (PEG) 6000, residence times in the fluidized bed dryer, fineness of PEG6000, fineness of initial mixture effervescent systems, and efficiency of two lubricants markedly affect some granule and tablet characteristics. It is a dry process that is simple, rapid, effective, economical, reproducible, and particularly adapted to produce effervescent granules that are easily compressed into effervescent tablets.     

Multiphase versus Single Pot Granulation Process: Influence of Process and Granulation Parameters on Granules Properties

ABSTRACT

High-shear wet granulation is widely used for the production of pharmaceutical dosage forms. Different equipment is available for high-shear granulation and drying. This review focuses on two main processes for granules production: multiphase consisting of high-shear granulation followed by drying in a separate apparatus, and single pot granulation/drying. At present, formulas are specifically developed with regard to the production equipment, which raises many problems when different industrial manufacturing equipment is used. Indeed, final granules properties are likely to depend on equipment design, process, and formulation parameters. Therefore, a good understanding of these parameters is essential to facilitate equipment changes.

The aim of this review is to present the influence of equipment, process, and formulation parameters on granules properties, considering both the granulation and the drying steps of multiphase and single pot processes.     

Melt Granulation in A Laboratory Scale High Shear Mixer

Abstract

The applicability of a 10 litre high shear mixer for melt granulation of dicalcium phosphate and lactose is examined. Polyethylene glycol (PEG) 3000 and 6000 were used as melting binders in concentrations of 15-20% w/w. The effects of binder concentration, massing time, impeller speed, and particle size of the PEG 6000 on granule size, granule size distribution and intragranular porosity are investigated.

It is shown that pellets of a narrow size distribution can be produced by the use of a high impeller speed. Granule size and size distribution are markedly influenced by binder concentration and massing time. The particle size of the PEG has only a minor effect on the granule growth. Granule growth mechanisms by melt granulation are discussed on the basis of the liquid saturations and the amounts of binder liquid and are compared with previous results on wet granulation.     

Melt Granulation in A Laboratory Scale High Shear Mixer

The applicability of a 10 litre high shear mixer for melt granulation of dicalcium phosphate and lactose is examined. Polyethylene glycol (PEG) 3000 and 6000 were used as melting binders in concentrations of 15-20% w/w. The effects of binder concentration, massing time, impeller speed, and particle size of the PEG 6000 on granule size, granule size distribution and intragranular porosity are investigated.

It is shown that pellets of a narrow size distribution can be produced by the use of a high impeller speed. Granule size and size distribution are markedly influenced by binder concentration and massing time. The particle size of the PEG has only a minor effect on the granule growth. Granule growth mechanisms by melt granulation are discussed on the basis of the liquid saturations and the amounts of binder liquid and are compared with previous results on wet granulation.     

Carboxymethylstarches in Wet Granulation

Commercialized carboxymethystarches (CMS) are both carboxyme-thylated and cross linked potato starch.

The influence of carboxymethylation and cross linkage on the disintegrating properties of starch are studied.

Tablets are made with acetaminophen as drug, Emcompress as diluant, Magnesium stearat as lubricant, and potato starch or its derivatives as disintegrants.

Tablets are prepared by direct compression or by wet granulation with the disintegrant intervening only in internal phasis.

Five disintegrants were studied, with two different concentrations:

native potato starch

potato starch simply cross linked

potato starch simply carboxymethylated

two potato starches both cross linked and carboxymethylated at two different degrees

Compressibility of powders blending and grain for compression are discussed.

The hardness, the tablet disintegration and the rate of drug dissolution are studied.

The results showed that the simply carboxymethylated starch has a totally different behaviour after direct compression or wet granulation. The poor results after wet granulation could be imputed to the bursting of starch granules during grain drying. Since it has lost its granular structure, the carboxymethylated starch will only allow a poor disintegration and a slow dissolution of the drug.

A very similar behaviour of native and simply cross linked starch: the results of which are bad for tablets either prepared by wet granulation or direct compression.

A very similar behaviour of the starches both carboxymethylated and cross linked, allowing a very good disponibility, either with tablets prepared by direct compression or wet granulation. These experiments prove :

the need for an sufficient cross linkage for CMS in a wet granulation process     

Carboxymethylstarches in Wet Granulation

Abstract

Commercialized carboxymethystarches (CMS) are both carboxyme-thylated and cross linked potato starch.

The influence of carboxymethylation and cross linkage on the disintegrating properties of starch are studied.

Tablets are made with acetaminophen as drug, Emcompress as diluant, Magnesium stearat as lubricant, and potato starch or its derivatives as disintegrants.

Tablets are prepared by direct compression or by wet granulation with the disintegrant intervening only in internal phasis.

Five disintegrants were studied, with two different concentrations:

native potato starch

potato starch simply cross linked

potato starch simply carboxymethylated

two potato starches both cross linked and carboxymethylated at two different degrees

Compressibility of powders blending and grain for compression are discussed.

The hardness, the tablet disintegration and the rate of drug dissolution are studied.

The results showed that the simply carboxymethylated starch has a totally different behaviour after direct compression or wet granulation. The poor results after wet granulation could be imputed to the bursting of starch granules during grain drying. Since it has lost its granular structure, the carboxymethylated starch will only allow a poor disintegration and a slow dissolution of the drug.

A very similar behaviour of native and simply cross linked starch: the results of which are bad for tablets either prepared by wet granulation or direct compression.

A very similar behaviour of the starches both carboxymethylated and cross linked, allowing a very good disponibility, either with tablets prepared by direct compression or wet granulation. These experiments prove :

the need for an sufficient cross linkage for CMS in a wet granulation process     

Comparison of Moisture-Activated Dry Granulation Profess with Conventional Granulation Methods for Sematilide Hydrochloride Tablets

During the development of a tablet formulation of a cohesive, fluffy investigational drug, a novel moisture-activated dry granulation (MADG) process was studied in comparison with two conventional granulation methods, i.e., wet granulation and dry granulation with a roller compactor, as well as with a direct compression formulation method. The MADG method produced granules with excellent flowability which were equivalent in a number of ways to those produced by either conventional wet granulation or dry granulation methods and which were much better than the powder blend from the direct compression formulation. The tablets prepared using the MADG method had better content uniformity than those made using material from wet and dry granulation processes. Other tablet properties, such as weight variation, friability and dissolution, were similar among the tablets produced by the four processes     

Effectiveness of Binders in Wet Granulation: A Comparison Using Model Formulations of Different Tabletability

Based on an analysis of model granulates and tablets, a comparison was made of the effectiveness of the binders PVP K30 PH, Cellulose HP-M 603, Lycatab DSH, Lycatab PGS, and L-HPC (type LH 11). A high shear mixer was used to prepare two model granulates (placebo and paracetamol) under processing conditions which were, as far as possible, comparable. The binders were added as proportions of 2%, 6%, and 10%. Water was used as the granulating liquid. The properties of the placebo granulates (particle size distribution, bulk and tapped density, granule strength, flow properties), and those of the tablets (crushing strength, friability) prepared from these granulates under different compaction forces, were generally good. However, with PVP, Cellulose HP-M603, and Lycatab, the disintegration time of the tablets did not meet pharmacopoeial requirements even though a “disintegrant” was used in the “outer phase.” The paracetamol formulations were prime examples of high-dose drug substances with particularly poor granulating and tabletting properties, well suited to reveal differences between the binders. The paracetamol granulates were of higher friability and less flowability than the placebo granulates. The tablets tended to cap, friability was (with few exceptions) high, and disintegration times were long. In the preparation of model tablets containing paracetamol, PVP K30 PH (6%). and Cellulose HP-M 603 (6%) turn out to be the binders of choice with respect to crushing strength, but the disintegration times are too long. Lycatab PGS, Lycatab DSH, and L-HPC-LH 11 could not be used to produce paracetamol tablets that met the requirements.     

Granulation Rheology I: Equipment Design and Preliminary Testing

One of the most common pharmaceutical dosage forms is the compressed tablet, and of the several methods of preparing tablets, wet granulation remains widely used throughout the pharmaceutical industry. An apparatus was designed to follow the physical changes occurring in the granulation process. Its operation and preliminary results are presented.

As dry solid is wetted with granulating liquid, it passes through several stages, as it becomes wetter, it should exhibit a resistance to flow analagous to a viscous liquid. This resistance (force) can be measured. The test procedure follows the material from a dry powder through its maximum resistance and finally to a slurry. Such profiles could represent a characterization method for the solid and/or the liquid.

Materials tested included six common tablet excipients; these have been limited to single component granulations. Results indicate this apparatus is reproducible for these simple systems. Materials are shown to behave differently in the granulation process, and the apparatus appears capable of distinguishing between different materials.     

Granulation Moisture Content Analysis: An Evaluation of Two Instruments

Abstract

Reliable methods of determining moisture content of granulations are essential to develop products that are readily and consistently manufactured. This study evaluated two instruments for loss on drying (LOD) measurement, the Computrac model MA-5 and the Mark-I, Both instruments were evaluated using the USP oven method for LOD determination as a standard. All of these instruments/methods involved thermgravimetric analysis (TGA). Computrac MA-5 utilizes a heating coil as heat source and Mark-I uses four parallel quartz infrared heaters as heat source. Results showed that the Mark-I moisture analyzer and the oven method gave values much closer to those predicted for the compounds tested, while the Computrac seems to be inconsistent in determining the LOD of materials which are in equilibrium with their bound water of hydration and their evolved volatile compounds.