Tablet diluents direct compression

Armstrong NA, Palfrey LP. The effect of machine speed on the consolidation of four directly compressible tablet diluents. J Pharm Pharmacol 1989 41 149-151. 

The first direct compression excipient, spray-dried lactose, was introduced in the early 1960s as a filler specifically designed for direct compression processes. Over many years, more direct compression API and excipients, especially diluents and binders, were developed. Since these are now commercially available, design of direct compression formulations is readily possible. However, despite the simplicity of the direct compression process, the pharmaceutical industry still produces most tablets by wet granulation methods.1... 

Microcrystalline cellulose (Avicel) is purified partially depolymerized cellulose, prepared by treating a-cellulose with mineral acids. In addition to being used as a filler, it is also used as dry binder and disintegrant in tablet formulations. Depending on the preparation conditions, it can be produced with a variety of technical specifications depending on particle size and crystallinity. It is often used as an excipient in direct compression formulations but can also be incorporated as a diluent for tablets prepared by wet granulation, as a filler for capsules and for the production of spheres. 

Available as anhydrous and monohydrate anhydrous material used for direct compression due to superior compressibility Originally direct-compression excipient, now often included in granulations due to its excellent compressibihty Direct-compression diluent, often used in chewable tablets Was widely used as sweetener/filler in effervescent tablets and chewable tablets less popular nowadays due to cariogenicity Versatile material that can be used as diluent binder, and disintegtant Brittle material... 

The true direct compression process as described earlier almost invariably applies to formulations containing potent active ingredients and where the direct compression properties derive from the diluent. A few substances do possess adequate flow and cohesive properties without the need for pretreatment. These are usually crystalline inorganic salts such as sodium chloride and potassium chloride. Direct compression forms of less potent active ingredients are available e.g., paracetamol and ascorbic acid. These can be directly compressed into tablets, perhaps after the addition of a lubricant. However, such substances are more accurately described as pre-granulated, in that the granulation process—either wet granulation or precompression—has been carried out by the excipient manufacturer. 

If a major component of the formulation such as the diluent were to possess the necessary degrees of fluidity and compressibility, granulation would be unnecessary. This is the basis of the direct compression method of tablet manufacture. 

At about the same time, two materials were introduced that were specifically designed to act as tablet diluents and would not require preliminary treatment. These were spray-dried lactose and microcrystalline cellulose, introduced in 1962 and 1964, respectively. These two substances can be said to have initiated the direct compression revolution. Since that time, a wide range of direct compression tablet diluents has become available. The properties of some of these materials will be reviewed later in this article. 

The primary limitation on the use of direct compression is that it depends on the fluidity and compressibility of a tablet diluent. Therefore, it cannot be used for low potency, high dose active ingredients where the inclusion of sufficient diluent in the formulation to permit direct compression would lead to unacceptably large tablets. Thus, active ingredients such as paracetamol and aspirin do not lend themselves to the direct compression process. However, as stated earlier, such ingredients are often available in pregranulated form. 

The simplicity of the direct compression process should obviously bring financial benefits. However, it must be borne in mind that direct compression tablet diluents are considerably more expensive than conventional diluents such as a-lactose monohydrate. 

Regulatory considerations also play a part in a decision whether or not to use the direct compression process. Several years may elapse between the finalizing of a tablet formulation and its marketing. During this period, stability testing of the product will have occurred. The formulator must be confident that a chosen direct compression diluent will still be available for a considerable time after product marketing otherwise reformulation with all its attendant delay and expense will be required. A number of direct compression diluents have been marketed that were withdrawn after only a few years because of lack of market penetration. 

FACTORS INFLUENCING THE CHOICE OF A DIRECT COMPRESSION TABLET DILUENT... 

Most direct compression diluents are available from only one source, but a few can be obtained from more than one manufacturer. If multiple sources are available, they will be offered under individual registered names. For example, microcrystalline cellulose is available under a number of brand names such as Avicel (FMC Corporation), Emcocel (Edward Mendell), and Vivacel (J. Rettenmaier). Chemical properties of such materials will be similar if not completely identical, especially if there are pharmacopeial standards for identity and purity. However, it cannot be assumed that products from different manufacturers will have the similar physical properties which will govern their performance in the tabletting process. 

Several authors have listed the attributes of the ideal direct compression diluent. " However, it must always be borne in mind that the diluent will invariably form part of a multicomponent mixture. At the very least, the diluent will be mixed with the active ingredient, and almost invariably a lubricant will also be present. The greater the proportion of active ingredient in the formulation, the less influence the diluent will have on the properties of the tablet. 

By definition, direct compression diluents are intended to be mixed with other ingredients. Therefore, not only should the pressure-tablet strength profile of the diluent be determined, but also should those of mixtures of the diluent with an active ingredient. The capacity of a direct compression diluent is the proportion of another ingredient that can be mixed with it while still obtaining tablets of acceptable quality. The definition of acceptable will depend on the purpose for which the tablets are required. 

The magnitude of the effect that a given active ingredient will have on tablet properties will clearly depend on the tabletting properties of that substance. If it is also capable of direct compression, then the effect will not be great. If, however, it is a substance that is difficult to compress into tablets, then it will cause a marked deterioration in tablet quality when mixed with the diluent. Therefore, for a reliable test of capacity, the direct compression diluent should be mixed with a standard substance and tabletted under standardized conditions. The pressure-strength profiles of the mixtures can then be constructed. Paracetamol and ascorbic acid have been used as standards. 

A faulty batch of tablets can sometimes be recovered by grinding up the tablets and recompressing them, a process which is known as reworking and is analogous to the dry granulation method of tablet manufacture. This can sometimes cause problems with a direct compression formulation. Many direct compression diluent particles are in the form of aggregates, e.g., spray-dried lactose is composed of small crystals of lactose embedded in amorphous lactose. If these aggregates are compressed, their structure may be broken down to such an extent that subsequent recompression will result in impaired tablet quality. 

The technique of Malkowska and Khan, " used as described before to determine the capacity of a direct compression diluent, was originally developed as a method of expressing the ability of a formulation to be reworked. Referring to Fig. 2, the upper curve represents the strength of tablets prepared without reworking and the lower curve is the strength of reworked tablets. The reworking index is calculated from the ratio of the areas under the curves as described previously. 

Powdered cellulose has been used as a direct compression diluent. Though it forms hard tablets, fluidity is poor and dilution potential is low. Like microcrystalline cellulose it has some self-lubricating properties, but addition of a lubricant is usually necessary, causing a marked reduction in tablet strength. ... 

Sorbitol can exist in four crystalline forms. Guyot-Hermann, Leblanc, and Draguet-Brugmans compared 11 commercially available varieties of sorbitol, and found three of these four forms to be present. y-Sorbitol was found to be the most useful as a tablet diluent. The method of manufacture has also been shown to affect tabletting properties, differences being attributed to variations in particle shape and surface properties. Spray-dried varieties of sorbitol are available as direct compression diluents which are claimed to have overcome problems associated with the different crystalline forms. ... 

Though numerous direct compression diluents are available, none is ideal. For example, spray-dried lactose flows easily but forms relatively weak tablets. 

Minchom, C.M. Armstrong, N.A. A proposed technique for expressing the capacity of directly compressible tablet diluents. J. Pharm. Pharmacol. 1989, 39, 69. 

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