Agglomeration in the Pharmaceutical Industry

Many solid drugs are being agglomerated in some form. Even certain suppositories (suspension suppositories) are, in the widest sense, agglomerates. However, the most important forms are granulated, spheronized, and tabletted as well as coated. For example, Voigt estimates that, today, at least 40% of all solid drugs are tabletted . 

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While the emphasis of this chapter cannot be directed toward providing a complete and exhaustive coverage of agglomeration in the pharmaceutical industry, each of the major methods will be reviewed and pharmaceutical applications will be briefly discussed. This treatment will provide an indication of what is being done, where one can turn to for additional information, and what type of new technologies are emerging. 

W. Pietsch, Size enlargement by agglomeration in the pharmaceutical industry with special emphasis on pressure agglomeration. Course notes. Workshop at Interphex - USA New York, NY (1993). 

Size enlargement by agglomeration in the pharmaceutical industry with special emphasis on pressure a lomeration. 

Although die compaction is used most widely in applications (such as tableting in the pharmaceutical industry) requiring strict specifications for the agglomerate, there are a few applications in which piston-type machines are used simply to compress particulates into a larger size suitable for further processing without regard to fine detail. 

Fig. 7.9. Batch fluid bed spray granulator used to produce tablet granulations in the pharmaceutical industry. Air-flow necessary for fluidization is generated by a suction-fan (2) mounted in the top portion of the unit, directly driven by an electric motor. The air being used is heated to the desired temperature by an air heater (5). Prefilters remove all impurities at the air inlet (6). The material to be processed has been loaded into the material container (1). The container bottom consists of a perforated plate above which a fine mesh stainless steel retaining screen is fitted. Exhaust filters (7) mounted above the product container retain fines and dust. The granulating liquid (3) is sprayed as a fine mist through a mechanical or pneumatically actuated nozzle (4) onto the finely dispersed, fluidized material to form the desired agglomerates. (Courtesy Aeromatic AG.)...

Soon to follow the stone grinder were the roll crusher and lump breaker. While still in use today, the roll crusher is more apt to be found size reducing rocks and other aggregates in a more industrial setting. The lump breaker similarly is also commonly used in the food industry although it is still occasionally used in the pharmaceutical industry for size reducing agglomerates. The pharmaceutical industry demanded a more refined approach to repeatability led to the invention of the hammermill, oscillator, and conical screen mill. 

For these reasons, agglomeration is generally to be avoided. The use of additives (Myerson, 2001, p. 146) may be considered for minimizing agglomeration. However, the use of additives in the pharmaceutical industry—particularly for final products—is generally not done for regulatory reasons barring extreme need. 

In some industries, special material characteristics, such as heat and/or pressure sensitivity, toxicity, reactivity, etc., are of importance. Particularly in the pharmaceutical industry and some sectors of chemistry these parameters must be considered. While pressure agglomeration methods have only limited applicability for heat- and/or pressure-sensitive materials, toxicity may limit the appeal of tumble agglomeration because of the difficulty to contain dust and avoid contamination of the environment. 

For accurately shaped compacts with extreme demands on tolerance only the confined die approach of pressure agglomeration is applicable. Such requirements exist, for example, in the pharmaceutical industry where tabletting machines are used to carry out the task. None of the growth agglomeration methods can yield products with these specifications. 

The type of movement required for mixing particulate matter also produces ideal conditions for agglomeration by coalescence. Therefore, unwanted agglomeration is often observed in powder mixers, especially if the particle size of the solids is small and/or a small amount of moisture is present. Considerable problems can arise if components of the bulk mass have different particle sizes because, in that case, the smaller fractions may selectively agglomerate, thus making it impossible to obtain an ideal mixture. Such selective agglomeration is of particular concern in the pharmaceutical industry where an extremely small amount of a finely divided active substance must often be mixed uniformly and reliably with a relatively large amount of inert filler material. 

As mentioned before, this is of particular importance in the pharmaceutical industry where small amounts of medicinally active components must be mixed with extreme accuracy into an inert mbcture. Small variations may result in either insufficient or toxic reactions. Therefore, the particle size or mass of the active substance must be such that the necessary (low) variation coefficient can be obtained whereby M, the mass of the sample, is a multiple of the unit mass of the pharmaceutical speciality (e.g. tablet, capsule, etc.). For example, referring to Figure 136, if the unit mass of the pharmaceutical speciality is one third of the sample mass, only the finest distribution of the black (additive) component (m/=l/27) results in an acceptable distribution. In that case, to avoid segregation, the mixture is stabilized by agglomeration (Figure 137). 

Newer final forms of agglomerated products, such as spheronized and and instantized materials, were developed during the twentieth century but have already found many diversified applications and gained wide acceptance. Therefore, the most diverse, mainly small scale use of agglomeration methods can be found in the pharmaceutical industry. 

At the same time, the more traditional tabletting techniques in the pharmaceutical industry were improved and modernized which led to higher production capacities, better tablet qualities, as well as more variability in product shape and composition. Other agglomeration methods were also introduced such as fluidized and spouted beds, mixers of various kinds, etc. 

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