Generally when preparing DPB, efforts to match particle size distribution and density of the Active Pharmaceutical Ingredient (API) to the major excipients helps minimize segregation. The particle size range should be relatively narrow. However, a 100 microns range for the particle size distribution or more could be satisfactory. The range may be less of a factor, so long as the excipient and API distributions overlap. The quantity and choice of the diluent depends on the effect the API has on flow and compressibility. A poorly flowing API requires a greater percentage of these excipients in order to maintain blend flowability. The capacity of an excipient to carry a poor flowing material is know as its dilution potential. An API can have very different affinities for diluents. Selecting even a different grade of a particular diluent can vastly improve the blend's flow properties. In cases where the API reduces blend compressibility, a dry binder can be added to the blend. For highly potent API, pre-blends can be prepared. A common practice used to improve DPB compaction is precompression during tableting.
This article gives an overview of the commonly used excipients for the preparation of DPB. These materials can be categorized by the function preformed in a formulation. However, many excipients have multiple functions. For example, microcrystalline cellulose can function as a diluent, a binder and a disintegrant. For the purpose of this paper, excipients have been grouped into the following five functionalities: adsorbents, binders/diluents (this also includes what have been called carriers, fillers, and bulking agents), disintegrants, glidents, and lubricants. For those requiring more information on these materials, several excellent books and review articles are referenced at the end of this article [1-8]. However, excipient suppliers should not be overlooked as a source of information. Some suppliers have done extensive research on their products and will gladly provide this information.
When an ingredient is a liquid it is necessary to convert it into a solid before blending it with the other ingredients to prepare tablets or capsules. Typically the liquid is of oily nature and can be adsorbed onto the surface of a solid. Adsorption, being a surface phenomenon, is most influenced by the available surface area on the solid. Thus, the most efficient adsorbents are very small particles. These materials often have low bulk densities with poor flow and compaction properties. The most commonly used adsorbents are the silicas, microcrystalline celluloses, starches and carbonates. Less important adsorbents for use in DPB are talc, magnesium oxide, tricalcium phosphate, magnesium aluminum silicate and clays.
Silicas are high purity sands with specific surface areas in the hundreds of m2/g. The particle size is typically less than 10 µm and these materials are characterized by very low bulk densities, 0.04-0.08g/cc. These materials can adsorb up to 1.6 ml of liquid per gram.
Microcrystalline celluloses, of small particle size, are used as adsorbent. These have far less surface area, 1.0m2/g, and much lower adsorptive capacity, 1/10ths of a ml per gram, than silicas. Silicified microcrystalline celluloses, microcrystalline cellulose co-processed with silica, have better adsorptive capacities.
Starches, particularly corn starch, have been used for a long time as an adsorbent. However, it is the least efficient of these materials. Specific surface area for corn starch is around 0.4m2/g, which is the highest of the common starches.
Carbonates of calcium and magnesium have been used as adsorbents. These have specific surface areas in the 6 15 m2/g range .
Binders/diluents are grouped together as a functional class, as many of these excipients have multiple functionalities. The distinction between a binder and diluent for a multifunctional excipient is based more on the use level in the formulation. For example, microcrystalline cellulose is used as a binder in the 5-20% range and as a diluent when it is the main excipient. All diluents are not necessarily good binders. However, most diluent used in DPB have some binding capacity. The greater the binding capacity of a material, the less compression force will be required to form a hard, non-friable tablet. Binders/diluents can be further classified into groups based on material type. The mineral acid salts, the most important of which are the calcium phosphates, are the least expensive. The sugars and polyols, which include lactose, directly compressible sugar, and mannitol, comprise the water soluble group. The celluloses and starches complete the groupings. The physical properties of selected grades of these materials are listed in Table 1. This data was obtained from vendor supplied information, published articles and books, and from independent laboratory results. It should be noted that published data for a particular material may vary greatly in the literature. This table lists, where available, bulk and tap density, Carr and Hausner Indexes, particle size data, and the angle of repose. The Carr and Hausner Indexes are calculations based on the bulk and tap densities of the material. These values are used to indicate a powder's flow properties. The lower the value, the more free flowing the powder. Carr Index (CI) values below 20% are considered to have good to free flowing properties. Hausner Index (HI) values less than 1.22 are associated with moderate to excellent flow. The angle of repose is also used to indicate a powders flow. Values less than 30° represent materials with good flow properties.
Celluloses as a group have low bulk and tap densities, usually less than 0.5g/cc and 0.6g/cc, respectively. One of the most commonly used excipients in DPB is microcrystalline cellulose (MCC). MCC is a strong binder with high dilution potential or carrying capacity. In levels from 5 to 20% it improves tablet hardness, acts as a disintegrant and has some lubricating properties. Metallic stearate lubricants have only a minor effect on the binding properties of MCC. Silicified microcrystalline celluloses (SMCC) have the same attributes as MCC, but with better flow properties. Both are available in various grades and particle sizes distributions. Low moisture grades are available for water sensitive API.
Mineral Acid Salts are widely used as diluents in capsules and tablets. These materials are characterized as having good flow, good binding capacity, but only fair dilution potential. Calcium carbonates are usually co-processed with other materials in order to produce a free flowing powder. Their main use is in nutraceuticals as a calcium supplement. Magnesium carbonate is another diluent used in DPB. It comes in both a heavy and light grade, 0.5g/cc and 0.12g/cc respectively. Calcium sulfate dihydrate is a non-hydroscopic excipient and free flowing grades are available. It is an inexpensive diluent with a high density and a mean particle size of 120mm. The calcium phosphates are the most commonly used of the mineral acids in DPB. These are supplied as the dicalcium dihydrate salt and as a tribasic anhydrous form. As with other mineral acid salts, these materials form insoluble compacts and disintregrents are needed. These materials are abrasive and usually require higher levels of lubricants, e.g. 1% magnesium stearate, than other diluents.
Starches are used in tablet and capsule formulations as diluents, binders and disintegrants. Pregelatinized starch comes in grades that have enhanced flow and compression qualities making these more suitable for use in DPB than other starches. They have fair to good binding properties and dilution potential. However, its binding properties are sensitive to over lubrication. As a binder it is used in the 5 to 20% range. Use can result in softer tablets and high compression forces are needed to produce hard tablets. Mixes with MCC have been used to increase tablet hardness without the need of higher compression forces.
Sugars/polyols comprise the most diverse group of binder/diluents. Lactose, milk sugar, is probably the most widely used diluent. Lactose comes in many grades suitable for DPB. However, lactose may react with API having primary amine functional groups. Spray drying produces a grade of lactose monohydrate that has excellent flow properties, fair to good binding and fair dilution potential. Granular or Direct Compression (DC) grades have many of the same attributes as Spray Dried (SD) forms. Anhydrous lactose is a low moisture lactose for use with moisture sensitive API. There are also several co-processed grades of lactose that have been designed for improved flow and binding potential. All lactoses require lubrication, and binding properties are relatively insensitive to over lubrication. Disintegrants are usually necessary, and high compression forces are generally required to form hard tablets if binders are not used.
Many other sugars and polysaccharides are used in the preparation of DPB, mostly for chewable tablets and lozenges. Directly compressible sugar is co-processed sucrose. Its tableting properties can be affected by moisture. Directly compressible dextrose is comparable to lactose as a diluent, but has a higher binding capacity. Co-processed fructose is suitable for DPB, while crystalline fructose has poor flow properties. Its large particle size provides excellent flow and it shows good compressibility. Fructose has been used in place of sucrose and dextrose as an excipient in nutraceuticals, chewable vitamins and for diabetic products. Its sweetness is perceived more rapidly than sucrose and dextrose and can be used to taste mask unpleasant API. Spray dried maltose has many of the characteristics of co-processed fructose, but is non-hygroscopic and has a smaller particle size. It is a good diluent for low bulk density, poor flowing API. Its binding capacity is not diminished by lubrication. Dextrates are free flowing polysaccharides that are readily soluble in water. Dextrates have excellent binding capacity and are good carriers for fine, hydrophobic API. It is non-hygroscopic and typically requires 0.5 to 1% magnesium stearate as a lubricant. Maltodextrins are prepared by the partial hydrolysis of starch into polyglucose. Maltodextrin are classified as having dextrose equivalent below 20, while corn syrup solids are above 20 DE. Many different grades of maltodextrin are available. The ones most suitable for DPB are agglomerated to increase particle size and improve flow. These free flowing, low density, non-sweet powders have excellent dissolution. They are used a binders in DPB in concentration of 2 to 40%. Certain grades have excellent dilution potential and can be used as carriers.
Polyols have many properties similar to sugars. These materials are typically sweet, readily soluble in water, do not react with primary amines like sugars, and impart a cooling sensation in the mouth due to their negative heat of solution. These materials are commonly used in the preparation of lozenges, chewable and fast dissolving tablets. Mannitol is the most commonly used. It is non-hygroscopic, unlike sorbitol. The granular and spray dried forms are most often used for DPB. Certain grades make excellent diluents and can impart flow to poor flowing API at loadings up to 25%. Lubricant levels are typically higher than normal, i.e. 1 2% magnesium stearate. Sorbitol, an isomer of mannitol, has many of the same properties as mannitol, but with one major distinction, sorbitol is hygroscopic. As sorbitol is the less expensive of the two isomers, some formulators will prepare blends with mannitol. This provides a non-hygroscopic blend at less cost and without loss of functionality. Like mannitol, sorbitol is available in many different grades. Xylitol is a noncariogenic polyol used primarily as alternative to sucrose in chewable tablets and lozenges. It has the lowest heat of solution of any of the polyols and has the sweetness of sucrose. Xylitol has been used as an alternative sweetener in diabetic products due to its low glycemic index. The granular and co-processed grades are used as diluents in DPB. The co-processed materials have better binding characteristics. Lubrication is recommend at 1%, using a 1:1 ratio of magnesium stearate and stearic acid. Lactitol is another noncariogenic sugar replacement. A direct compression grade is available. It has high solubility, low hygroscopicity, and tablet dissolution is unaffected by lubrication. Since preparations made with polyols typically dissolve and erode from the outside, tablets requiring rapid dissolution typically require a disintegrant [10,11].
Disintegrants are used to break-up a capsule or tablet. This improves the dissolution and can increase an API's bioavailability. Disintegrants work by wicking water into the tablet and by swelling, the combination of these actions being best. Pregelatinized starch typifies disintegration by swelling, while microcrystalline cellulose typifies wicking. By combining these materials in a DPB, a rapidly disintegrating tablet can be prepared. Sodium starch glycolate, cross-linked polyvinylpyrrolidone and croscarmellose sodium are considered super disintegrants due to the low amounts needed, from 0.5 5%. Calcium and sodium carboxymethylcellulose, low-substituted hydroxypropylcellulose and alginic acid and its sodium salt, are less commonly used disintegrants. These require higher concentration than the super disintegrants, in the 5-15% range. However, these materials can also act as dry binders, at the same level of use as for disintegration. The use levels for these materials are given in Table 2 [12,13].