The objective of a medicinal formulation development project is to deliver drug to the patient in the required amount, at the required rate, consistently within a batch, from batch to batch, and over the product's shelf life. 

The US Food and Drug Administration's Quality in the 21st Century initiative, which includes the quality by design (QbD) and process analytical technologies (PAT) initiatives, requires that the pharmaceutical industry better understand its product formulations and manufacturing unit processes. In addition, 

), links in to the common technical document (CTD) and suggests the need for greater understanding in the design and development of pharmaceutical formulations and processes.  

Consequently, industry is expected to demonstrate that it understands its formulations and processes and can define the appropriate design space that will allow the routine manufacture of pharmaceutical products that deliver the correct amount of drug to the patient, at the required rate, consistently from dose to dose and from lot to lot, over the shelf-life of the product (

A formulation that is able to accommodate the typical variability seen in the API, excipients, and process without the manufacture, stability, or performance of the product being compromised.

The larger the design space, the more likely we will produce a robust formulation. 

 Most formulations have three components: the active pharmaceutical ingredient drug (API), the excipient(s), and the manufacturing process(es) (see Figure 1). In some instances, there is a fourth component: the primary packaging. 

 Figure 1: Components of a medicinal product.			

To understand product variability, we must understand input variability. The variability of the API, excipients, and process parameters are obvious components of the overall variability. Nonetheless, other factors could affect the manufacture, stability, or performance of the product. For example, how materials are fed into the unit process, how materials interact together during processing, and how an operator carries out the operations can all affect the final product attributes. 

Thus, for a given formulation and process, we must understand variability in the raw materials and their interactions to define the process and then demonstrate sufficient understanding of the process to define the design space for the product. We can represent this process schematically using variance as a measure of variability (see Figure 2). 			

 Two main approaches can be used to achieve consistent products. The traditional approach is to specify the input parameters more tightly, particularly the excipients and process (but also the API), and to limit the product variability by limiting the input variability. This approach does not address the variability in interactions. This interaction factor, the sum of all the interactions, also can cause problems (see equation in Figure 2). 

Figure 2. Sources of product variability. 

A second, more modern approach is to accept that there will be input variability and work to gain a sufficient understanding of the process to define an appropriate process end-point. A particular unit process is thus continued until the end-point is achieved. This second approach seems better matched to the intent of the QbD initiative, and also is likely to give a larger design space, and, thus, a more flexible formulation and process. 

Functionality, functionality-related characteristics, and excipients performance

Functionality applies equally to APIs and excipients. Functionality has been defined as:  

A desirable property of a [material] that aids manufacturing and improves the manufacture, quality or performance of the drug product 

In the context of pharmaceutical formulations and products, each formulation will have its own peculiar requirements for functionality. Thus, functionality can only be properly tested by the manufacture and subsequent testing of a batch of product. This process is less than desirable. 

An approach currently in vogue is to identify a surrogate test, usually a physical test, that bears some relation to the required functionality. The 

 defines such properties as "functionality-related characteristics"; the 

 proposes to define functionality-related characteristics as they relate to pharmacopeia materials as follows:  

Physical and/or physicochemical characteristics that are critical to the typical uses of an excipient

In the context of a pharmacopoeia monograph, the term "typical" raises the question: what can be done for atypical uses? Will there eventually be further regulatory "creep" in Europe requiring formulators to stick to "typical" uses in the design and development of new medicines? To many pharmaceutical scientists, this would be an anathema because it suggests that we should stifle innovation in the use of excipients, without which the drug delivery sector of our industry would never have emerged.  

This leads to a further point: most excipients are included in many different products and may impart several different types of functionality depending on a particular type of application. Is it better, in the context of the pharmacopeias, to try to define the functionality-related characteristics for a particular material? Or, to define the types of functionality for a particular application and then to suggest tests that may be appropriate as a performance test? 

One final point is that excipients are a very diverse group of materials with a diverse range of properties and functionalities. We still do not know in detail why many excipients work as they do. Can we define what we do not understand? Can we specify what we cannot define? 

In some instances, product manufacturers have established a correlation between a product and/or manufacturing performance and some physicochemical property of a key ingredient. In such circumstances, the product manufacturer may request an additional test to be included in its specification for that ingredient. 

As a short-term fix for existing formulations or, in some cases, as a longer-term strategy, excipient companies are frequently approached by customers to supply material to a tighter specification than the regular material. How valid is such an approach? 

It is important to remember that many excipients are not produced using simple batch processing. Most of the large-use excipients are produced using some form of continuous processing (24–7 operation). For such manufacture, the lot number refers to a defined time in the plant, and the lot size is governed by the risk to the manufacturer of a recall. The capacity of such manufacturing plants is rated in thousands of tons per annum. The plants are operated to produce material that passes specification, but there is an inherent variability in the output that cannot be avoided. In addition, the pharmaceutical usage of many excipients is small in comparison with the overall output. 

If the excipient manufacturer is approached to undertake extra testing to select the lot(s) to be delivered to a customer, what are the implications? This is represented schematically in Figure 3. We have assumed that upper and lower limits exist for the "functionality" parameter (performance parameter or functionality-related characteristic). In cases for which there is only an upper or a lower limit, the following discussion may be amended appropriately. 

Figure 3. Excipient variability and lot selection.			

The three batches are represented in Figure 3a. The key issue is to understand how the inherent variability affects the "functionality."  

In Figure 3b, the effect of the variability is small in relation to the required specification. In this situation, there a negligible effect for either the excipient manufacturer or the user beyond the cost of the extra testing (of which more later). Nonetheless, this is frequently not the case.  

The alternative scenario whereby only a proportion of batches meet the criteria is shown in Figure 3c. In this example, approximately 50% of batches meet the criteria. The schematics are idealized and show a very regular cyclical variation. Reality is not as regular, and the issue of how many lots must be tested to identify one lot that meets the criteria is economically important. In this example, three or four lots may need to be tested for each order.  

Figures 3d and 3e are examples in which the required specification is at one or other extreme of the observed variability. In these examples, about 10% of excipient lots would meet specification, and 10 or more lots may need to be tested for each order.  

In addition, the continuity of supply is an issue when lot selection is used. The excipient manufacturer may be forced to set aside particular lots for the particular customer to maintain supply continuity, which adds to the costs associated with the order. It is questionable in the circumstances depicted in Figures 3d and 3e whether lot selection is a viable strategy for supply and, thus, product manufacturing continuity.  

Excipients, for the most part, are commodity items and are priced accordingly. Though some of the smaller-volume excipients are priced above $100/kg, most of the larger-volume excipients (

 microcrystalline cellulose and lactose) are less than $10/kg.  

It is also important to understand how much of that amount is profit. Net profit for many excipients is about 5%. The market is competitive, with little room for slack. When the excipient user requests extra testing from its supplier, the economic effect can be considerable. It can mean the difference between profit and loss at these margins (see Table I). 

The examples shown in Table I assume the following: the manufacturer does not routinely use the tests for the product and the equipment is not currently available (

 either the equipment must be purchased or the work contracted out by the supplier). Given the profit structures in Table I,  any account taking less than about 50 tons per annum will scarcely break even that year, whatever the price of the testing. Under such circumstances, can we expect the excipient manufacturer to undertake the extra testing and stay in the pharmaceutical business? An alternative might be for the excipient purchaser to undertake the necessary testing. 

What happens if we lose suppliers of pharmacopeia-grade materials?

If we make testing requirements too onerous for manufacturers, they may cease to supply material that is designated as pharmacopeia grade. If  suppliers stop distributing USP or NF material, the consequences can be considerable for the excipient user, particularly in terms of regulatory updates, revalidation, and further stability.  

The excipient user has two options: to change to a new supplier of the NF material or continue to purchase the material from the original supplier and do the necessary testing in-house and undertake the necessary auditing of the excipient manufacturing site on a regular basis. 

Can it happen? It already has in the past few years. A major supplier of corn syrup NF ceased supplying material with the NF designation although it continued to manufacture to the same specification, in the same plant, and under the same quality management system. NF-quality propylene glycol stearate is no longer available. Propylene glycol stearate may not be a large volume excipient, but it was a major headache for companies using it in either investigational medicinal products or commercial products. The corn syrup issue had wider ramifications because many oral solution and suspension products are formulated using corn syrup. 

We must improve the way we specify and test excipients. In part, this improvement will be the result of revisions to the monograph (

 to include more modern analytical techniques). But, we must consider the roles of the regulatory agencies and the pharmacopeias. 

In the United States, FDA's remit is to safeguard the public health. The 

 supports this effort through the development of official standards for pharmaceutical materials and products. The Pharmacopeia is concerned with the purity, safety, and efficacy of drugs and medicines. For excipients, the issues are really safety and adulteration. Is chemical purity, in the absence of pharmacodynamic effect, something with which we should be concerned? 

Excipients are seldom "pure" materials. Most excipients, with the exception of those intended for parenteral or other similar products, are mixtures of materials. Their functionality arises from the presence of other components that are crucial to the performance of the excipient. These other components have been variously termed "essential minor components" or "functional components." In the 

 they are referred to as "concomitant components."  

The problem is testing and controlling these concomitant components. At the same time, we must keep any potentially toxic components to an appropriately low level. Unfortunately, we are probably not there yet. We do not always know which concomitant component (there may be several) is critical for a particular application, and we do not necessarily have methods suitable for routine measurement. Thus, we must continue to use performance tests for the foreseeable future. 

So, what can be done? Obviously we must continue to develop our understanding of both materials and unit processes, and how they interact. Some recent initiatives such as the National Institute of Pharmaceutical Technology and Education may help. The pharmacopeias can also help by providing the necessary standardized methods for performance tests. 

There appears to be broad agreement that such tests should not be mandatory and should not have limits imposed by the pharmacopeias. Nonetheless, there seems to be disagreement on how to incorporate such tests into the pharmacopeias. The 

 appears to favor designating the appropriate tests in the individual monographs, but including the list in a "nonmandatory" section of the monograph. The USP favors a nonmandatory General Information Chapter approach based on what types of tests might be applicable for specific applications rather than a specific excipient. TriPEC's (an umbrella international organization comprising the three regional Excipient Councils; the International Pharmaceutical Excipients Council of the Americas, the International Pharmaceutical Excipients Council of Europe, and the Japanese Pharmaceutical Excipients Council) position is straightforward. A harmonized approach is needed. Whether all these different views can be resolved easily remains to be seen. 

This article is intended as an overview. Though many details could be discussed further, some broad conclusions can be drawn. 

Articles

This article provides an overview of functionality, functionality-related characteristics, and excipients performance.

Functionality and Performance of Excipients

The dividing line between excipients and active ingredients is becoming increasingly blurred. The big pharmaceutical companies traditionally have regarded excipients as relatively marginal to the main business of producing blockbusting active ingredients, but this view is changing rapidly under the pressures of an evolving market and increased costs. These trends, combined with new technological developments, mean excipients are being given greater functionality than they ever had before. 

Excipients are usually defined as the nonactive ingredients that are mixed with pharmacologically active compounds to form medicines, particularly tablets. The behavior and effectiveness of many drugs are governed in part by excipients. Some ingredients are used to ensure that a preparation has great crushability and therefore is easy to manufacture in tablet and capsule forms. Others give tablets a sweet taste. Still other excipients may ensure slow release of the drug or provide great compressibility so that a pill can be made smaller. Excipients also can improve a drug's general efficacy, safety, stability, and storage. The main categories of excipients include:  					

The trend toward greater public awareness of food additives and ingredients has led inevitably to greater attention to pharmaceuticals. Consumers are becoming increasingly curious about which substances are used in the manufacture of drugs. The result has been a growing interest in excipients and a drive to establish standards for quality and control. 

In the United States, the use of excipients is controlled by the US Pharmacopeial Convention, an independent body that publishes and maintains the 

 standards) with which excipients must comply. 

In the European Union, a similar system is in place. Excipients must conform to monographs that are published in the 

 although US standards are accepted where no European monograph exists. Japan also has its own monographs governing the use of excipients, published in either the 

Significant efforts are being made to harmonize international standards of monographs to pave the way for easy and fast development and approval of excipients, but this goal is still some way off. In the short to medium term, pharmaceutical companies face increased costs resulting from the various testing procedures that must be applied to the same products serving different areas of the world. 

Regulatory developments are one of the major agents of change in the excipients industry. The most recent are the guidelines from the International Pharmaceutical Excipients Council (IPEC) and the Pharmaceutical Quality Group (PQG). IPEC is a global organization representing producers, suppliers, and end users of excipients. The body has three divisions in Europe, Japan, and the United States, each of which focuses on local regulations concerning the excipients market, as well as on new research and business practices. PQG is an association that publishes monographs and provides training and information for quality professionals within the pharmaceutical industry. 

One of the most important aspects of the guidelines is their focus on "one-up–one-down" traceability. This means that companies at each level of the supply chain must be able to trace where their materials or supplies came from and where their products have ended up. This means pharmaceutical companies will have to find more resources for administration and documentation to achieve this traceablility. 

Though the guidelines currently are voluntary, they provide much of the focus of current thinking on manufacturing practices for excipients. Implementing them is a must for companies that wish to stay competitive and not be left behind on safety and public-health grounds. Pharmaceutical companies must implement quality procedures that at least meet, if not exceed, the legal requirements. The guidelines also represent an opportunity to move toward a common set of standards that can be applied to excipients. 

Big pharmaceutical companies no longer can rely in the long term on the blockbusting drugs that traditionally have been their cash cows. This is because the patents on a great number of the more established brands were granted decades ago and are now expiring. As patents expire, generic copies can enter the market. The copies often are produced by smaller, independent companies that can compete on price—particularly because they don't face the same research and development costs as the original producers. 

By 2008, more than $80 billion worth of blockbuster drugs will face patent expiration, and hence competition, from producers of generic brands. When the generics hit the market, the established drugs will risk losing more than 80% of their market share, according to a report by business intelligence firm Cutting Edge Information (1). 

Added to this is the fact that pharmaceutical companies are developing fewer blockbuster drugs. This is partly because the market emphasis is moving away from the traditional pharmaceutical model of producing widely used drugs that can treat as many diseases as possible to more targeted, compartmentalized treatments. The process has been accelerated by the failure of some high-profile blockbusters. This leaves many of the big players in the industry facing tougher competition as they are challenged by generics producers that compete much more on cost. 

While the increased competition from generics producers is driving down the price of ingredients, and therefore revenues, Big Pharma is being squeezed in other ways. Pressure on the top line is coming from healthcare management organizations and governmental bodies wanting to spend less for their drugs. Meanwhile, the increased costs of regulation and quality-assurance compliance are affecting the bottom line. 

This squeeze is forcing excipient companies to readdress their efforts focusing on continually enhancing their good manufacturing practices and developing innovative drug-delivery solutions. Drug manufacturers increasingly are looking toward low-cost natural excipients to replace their high-cost synthetic solutions. 

Counterfeit medicines are another challenge affecting not just excipients, but the pharmaceutical industry as a whole. This phenomenon, which has long affected the developing world, appears to be on the rise in industrialized countries. According to a study carried out by the Council of Europe's 

group on counterfeit medicines, counterfeit medicines in Europe may have a market share as large as 10% (2). Counterfeit medicines are a significant threat to patient safety because they often lack any therapeutic benefit or may contain toxic ingredients. They also undermine trust at a time when pharmaceutical companies are coming under closer public scrutiny than ever before. 

One solution to rising costs and shrinking revenues is to invest in raising manufacturing standards. Such investments, however, are not always easy to justify because they do not always provide an immediate return through increased sales or higher prices. Smaller companies will find it more difficult to justify investing significantly in raising standards, which means they are likely to struggle to survive in competing with the largest producers. 

Many companies find that using starch-based excipients entails significantly lower costs than using cellulose-based or synthetic excipients and can help lower formulation costs and increase functionality. One example is producing tablets by direct compression using directly compressible binders. 

Using excipients with multiple functionalities is another solution. For example, C*PharmGel directly compressible starch (Cargill Pharma and Personal Care, Mechelen, Belgium) can be used as a binder, diluent, and disintegrant is available. 

Many companies are starting to look again at pharmaceutical grades of maltodextrin as an alternative to povidone. Meanwhile, certain directly compressible starches on the market such as C*PharmDry (Cargill Pharma and Personal Care, Mechelen, Belgium) offer strong binding capability, thereby allowing for lower inclusion rates and reduced cost of producing the finished tablets. 

Compressible starches with good flowability and polyols also can be used to increase production capacity of tablets, and highly compressible polyols enable smaller tablets to be produced—again lowering costs. 

Many pharmaceutical companies, facing rising costs from various sources and declining profit margins, are trying to find ways to cut development costs without compromising the quality of their products. This has led to the increasing use of excipients as a low-cost way of adding further functionality to their preparations without affecting the bottom line. 

Excipients can enable enhanced drug effectiveness in important ways. They already are used to control the drug's absorption into the body. Disintegrants, for example, allow the tablet to break up into particles that are small enough to enter blood vessels. Excipients can perform many other functions such as improving the safety, stability, and storage of medicines. So, it is no surprise that excipients are becoming a more important aspect in tablet manufacture than they were previously and are even helping innovate drug formulations. 

Excipient production is overwhelmingly based in North America and Europe. These two regions currently account for more than 75% of the market, according to a Frost and Sullivan study (3). Demand is likely to increase as further innovations take hold and excipients are adapted for more uses. 

While the European and North American markets are anticipated to continue growing during the next five years, both China and India will be in a position to enter the market during this time. The ability of both countries to combine low-cost manufacturing capability without compromising on quality will certainly have a significant effect on the established markets. 

Excipients historically have been overlooked by many in the pharmaceutical industry in favor of active ingredients. In the light of the challenges from generics producers, falling revenues, and the decline of the blockbuster drugs as big revenue generators, however, excipients offer many opportunities to meet some of these challenges. In particular, excipients can be used to cut drug-development costs without adversely affecting the quality of the products. 

The line between active ingredients and excipients has therefore become more blurred as the latter increasingly are coming to be seen as functional materials rather than inactive bulking agents. New developments such as the use of natural starch-based products, biotechnological research, and the use of nanotechnology to manipulate small molecules all mean that the range and uses for excipients are likely to increase. Examples in recent years include using mannitol in oral-dispersal tablets and speciality starch grades for slow-release applications. 

Excipients' functional characteristics and increasing attractiveness to Big Pharma for cost-reduction reasons make it likely that market conditions for excipients will remain promising for the next few years. 

 is category leader at Cargill Pharma and Personal Care, Bedrijvenlaan, 9, 2800 Mechelen, Belgium, tel. 132 0 15 400 508, fax 132 0 15 400 591, 

 1. "Combating Generics: Pharmaceutical Brand Defense," Cutting Edge Information (Research Triangle Park, NC, 2006) 

Facing cost pressures and regulatory changes, pharmaceutical companies address the need for increased functionality by looking to excipients.

Current Trends and Challenges in the Excipients Market

During the past several years, there has been rapid growth in the number of orally disintegrating tablets (ODT) available on the market. An ODT is generally recognized as a solid dosage form containing a medicinal substance that disintegrates rapidly and dissolves in the mouth without water within 60 seconds or less. ODTs are also known as quick dissolves, fast melts, or fast-dissolving, rapid-dissolve, or orally dissolving tablets. The 

 recognizes ODTs as orodispersible tablets or tablets intended to be placed in the mouth that subsequently disperses rapidly before being swallowed (1). These products have increased in popularity because consumers, old and young, find them convenient and easy to use. In addition, pharmaceutical companies have found an opportunity to extend product life cycles or differentiate their products by offering new dosage forms (2). 

Today, ODTs are available in a range of sizes and shapes, with some requiring special packaging.  In general, ODTs can accommodate as much as 500 mg of active ingredient, although 100–200 mg is a reasonable limit for more rapid disintegration (3). 

Several technologies are available to manufacture ODTs. The most common preparation methods are molding, lyophilization or freeze-drying, and direct compression. Other methods include cotton-candy, spray drying, and sublimation (4), and each offers advantages and disadvantages. For example, although lyophilization produces tablets with very fast disintegration (<5 s), the tablets are often less robust and usually require special packaging. 

Direct compression is a commonly used tablet manufacturing process to produce ODTs. Because it uses existing high-speed tablet press equipment and common excipients, it is often favored over other manufacturing processes for ODTs. A direct-compression formulation has better physical properties relative to other methods that may eliminate the need for special packaging such as blister packages.  

Excipients in direct-compression ODT formulations

A direct-compression ODT formulation usually contains diluent, disintegrant, lubricant, flow aid, flavor, sweetener, and often color. A review of currently marketed ODT product labels shows that mannitol is a commonly used diluent or bulk excipient. Directly compressible mannitol grades exhibit an appropriate balance of sweetness, mouth feel, solubility, and rapid dispersibility because of wicking (5). As a result, mannitol has gained in popularity for ODTs over other diluents typically used in direct compression such as lactose. 

To achieve rapid disintegration, direct-compression ODT formulations typically contain high levels of a superdisintegrant. Depending on the level and characteristics of the active pharmaceutical ingredient (API) and the desired release profile, the levels of superdisintegrant used can be 10–20 wt % of the formulation, and it can be higher or lower in some cases. Thus, in developing an ODT formulation for direct compression, choosing the optimal superdisintegrant is critical.  

As with most direct-compression formulations, additional excipients are likely to include a suitable flow aid and lubricant for tablet manufacture. Because the tablet is intended to dissolve in the mouth, ODTs often include flavors and sweeteners to mask the taste of bitter actives. Finally, color may be added to the formulation to add elegance and to aid in identification of the final dosage form. 

Although the superdisintegrant primarily affects the rate of disintegration, when used at high levels it can also affect mouth feel, tablet hardness, and friability. Thus, several factors must be considered when selecting a superdisintegrant. 

 The disintegrant must quickly wick saliva into the tablet to generate the volume expansion and hydrostatic pressures necessary to provide rapid disintegration in the mouth.  

 When manufacturing an ODT, it is desirable to have tablets with acceptable hardness at a given compression force to produce robust tablets that avoid the need to use specialized packaging while maximizing production speed. Thus, a more compactable disintegrant will produce stronger, less-friable tablets. 

To achieve patient compliance, ODTs must provide a palatable experience to the patient. Large particles can result in a gritty feeling in the mouth. Thus, small particles are preferred. If the tablet forms a gel-like consistency on contact with water, however, it produces a gummy texture that many consumers find objectionable. 

 As with all direct-compression tablet formulations, attaining good flow and content uniformity is important to achieving the required dosage per unit. In typical tablet formulations, superdisintegrants are used at 2–5 wt % of the tablet formulation. With ODT formulations, disintegrant levels can be significantly higher. At these higher use levels, the flow properties of the disintegrant are more important because it makes a greater contribution to the flow characteristics of the total blend. 

The selection of the optimal disintegrant for a formulation depends on a consideration of the combined effects of all of these factors.  

Evaluating physical characteristics of commercial superdisintegrants

Currently available disintegrants were evaluated for particle size, particle-size distribution, flowability, compactability, particle shape, and morphology. The following superdisintegrants were studied:  					

crospovidone A1 (standard particle-size grade) (Polyplasdone XL, International Specialty Products, Wayne, NJ);

crospovidone A2 (fine particle-size grade) (Polyplasdone XL-10, ISP);

crospovidone B (Kollidon CL, BASF, Ludwigshafen, Germany);

sodium starch glycolate (Explotab, JRS Pharma, Patterson, NY);

croscarmellose sodium(Ac-Di-Sol, FMC, Philadelphia, PA).

Table I: Particle size and flowability index.			

Crospovidone is an insoluble, neutral cross-linked homopolymer of N-vinyl-2-pyrrolidone. It is available in various particle sizes. The 

 defines sodium starch glycolate as the sodium salt of a carboxymethyl ether of starch or of a cross-linked carboxymethyl ether of starch, and croscarmellose sodium is defined as the sodium salt of a cross-linked, partly O-(carboxymethylated) cellulose. 			

 A comparison of particle sizes of various disintegrants is shown in Table I and Figure 1. Sodium starch glycolate and croscarmellose sodium show similar average particle sizes; however, sodium starch glycolate has a narrower distribution, which contributes to the good flow properties. The particle size differences between the various types of crospovidones are shown. Because crospovidone A2 offers the smallest average particle size (~30 μm), it is often preferred because small particles result in a smoother mouth feel.  

 Flowability index results are shown in Table I. Sodium starch glycolate provides the best flow as a result of its spherical particle morphology and narrow particle size distribution.  

  When examined under a scanning electron microscope, sodium starch glycolate particles are spherical (see Figure 2). Crospovidone particles appear granular and highly porous, although crospovidone B particles appear less porous. This porous particle morphology facilitates rapid wicking of liquid into both particle and tablet and contributes to the compactability of the material. Croscarmellose sodium particles have a fibrous structure. 

 The compactability of each of the disintegrants was evaluated by comparing the breaking force, at various compression forces, of pure compacts of each disintegrant with small amounts of lubricant and glidant added (see Figure 3). Results indicate that crospovidone is the most highly compactable disintegrant tested, thus producing the highest tablet-breaking force at a given compression force.  

Figure 3: Compaction profile of pure compacts.			

Nonetheless, the results also show that crospovidone A1 and B, with similar particle size, perform significantly differently. Crospovidone A1 is more compactable than crospovidone B. 

Example 1: Compaction profile evaluation of placebo tablets. 

In recent studies, 1-g placebo tablets were prepared with 20 w/w % of each disintegrant according to the formulation shown in Table II. The ingredients were dry blended and then compressed using an instrumented rotary press (Stokes B2) at three compaction forces (8.9, 17.8, and 26.7 kN) using half-inch round, flat-faced tooling. 

Figure 4: Placebo tablet-breaking force.			

The tablets were evaluated for breaking force and friability. At the highest compaction force (26.7 kN), capping was observed with tablets containing sodium starch glycolate (see Figure 4). Note that at the lowest compaction force, all of the tablets were extremely friable (>5%), so these results were included in Figure 5. Subsequently, the disintegration time for each tablet was evaluated (see Figure 6). 

The results show that acceptable tablet-breaking force was achieved at the two highest compaction forces for all the superdisintegrants, although crospovidone shows significantly higher tablet breaking force at equivalent compaction force than the other disintegrants. The friability results also reflect this trend. Crospovidones A1 and A2 showed the lowest friability, with results below 0.4% at the highest compaction force. The disintegration results show crospovidone achieved the fastest disintegration (<30 s) and croscarmellose sodium provided the slowest disintegration (>1 min). 

Figure 6: Placebo tablet disintegration.			

When representative placebo tablets with crospovidone A2, sodium starch glycolate, and croscarmellose sodium were placed in a Petri dish with a small amount of water, the relative ability of the various disintegrants to wick water into the tablet was observed (see Figure 7). One minute after contact with water, the tablet containing crospovidone A2 was fully hydrated and soft throughout because crospovidone quickly wicks water into the tablet. Meanwhile, the centers of the tablets made with sodium starch glycolate and croscarmellose sodium remained dry and hard. Although the tablet with sodium starch glycolate swelled, the outer edge appeared gel-like. 

Table III: Acetaminophen ODT formulation.			

Example 2: Compaction profile evaluation of acetaminophen tablets with various superdisintegrants.

 In this study, 158-mg acetaminophen tablets (1 g total weight) were prepared with 20 w/w % of each disintegrant according to the formulation in Table III.  

To mask the taste of the active, an encapsulated acetaminophen (88% active acetaminophen) was selected. The active level in the tablet formulation is representative of currently marketed ODT products. To prepare this formula with acetaminophen, the level of mannitol was reduced compared with that used in the placebo while all other ingredients were held constant. The formulation was dry blended and then compacted under three different compaction forces as in the placebo study. 

Figure 8: Acetaminophen tablet compaction profiles.			

Once again, the tablets were evaluated for breaking force, friability, and disintegration (see Figures 8–10). At all compaction forces, the acetaminophen tablets with croscarmellose sodium were highly friable (>5%), so the results are not shown in Figure 9. 

Figure 9: Acetaminophen tablet friability.			

Similar to the results from the placebo study, crospovidone produced the strongest tablets at a given compaction force. Compared with the results from the previous study, the overall breaking force of the tablets was somewhat reduced because of the replacement of the mannitol with the active. The friability also followed the same trend as outlined in the previous example. The disintegration results show that crospovidone produced the fastest disintegration. 

Figure 10: Acetaminophen tablet disintegration.			

The increasing popularity of orally disintegrating tablets has led to growing interest in the advantages of superdisintegrants. This article presents some practical considerations in selecting these ingredients.

Selecting Superdisintegrants for Orally Disintegrating Tablet Formulations

Despite a rising interest in controlled-release drug delivery systems, the most common tablets are those intended to be swallowed whole, disintegrating and releasing their medicaments rapidly in the gastrointestinal tract. A 

 is a substance in a tablet formulation that enables the tablet to break up into smaller fragments upon contact with gastrointestinal fluids. Such a rapid rupture of the tablet matrix increases the surface area of the tablet particles, thereby increasing the rate of absorption of the active ingredient and producing the desired therapeutic action (1). 

The proper choice of disintegrant and its consistency of performance are critical to formulation development of such tablets. In the past, starch was one of the most widely used, inexpensive, and effective tablet disintegrants. A high concentration of starch is required to bring about effective disintegration. Scientists' search for disintegrating agents with efficient disintegrating properties at relatively low concentrations has led to the development of some new compounds with excellent disintegrating properties.  

Superdisintegrants generally are used at a low level in the solid dosage form, typically 1–10% by weight relative to the total weight of the dosage unit. Examples of superdisintegrants are crosscarmelose, crospovidone, and sodium starch glycolate, which are a crosslinked cellulose, crosslinked polymer, and a crosslinked starch, respectively. BASF is one manufacturer of crospovidone under the trade name of insoluble "Kollidon" grades. Another manufacturer is ISP's "Polyplasdone XL" grade. Crosscarmelose is marketed mainly as the brand name of "Ac-Di-Sol" by FMC BioPolymer and sodium starch glycolate as "Primojel" from DMV International. 

Insoluble grades of Kollidon (crospovidone) are manufactured by a polymerization process that yields crosslinked insoluble polyvinyl-pyrrolidone in the form of a "popcorn" polymer. The polymerization is performed using an aqueous system. No organic solvents are involved at any stage. The crosslinking is of chemical and physical nature, which is mainly achieved by the entanglement of the polymer chains and dominates the product's properties. 

Unlike povidone, crospovidone is completely insoluble in solvents and the corresponding products cannot be named according to a K-value or a molecular weight. The product differentiation is conducted mainly by the particle-size distribution. The bulk density and swelling behavior also play an important role in disintegration behavior (2). (BASF supplies the following insoluble grades of Kollidon: Kollidon CL, Kollidon CL-F, Kollidon CL-SF, and Kollidon CL-M, which all comply with current monographs in the European, Japanese, and US pharmacopeias.)  

Insoluble Kollidon grades are supplied as fine, white, and almost-white powders. They have a slight characteristic odor and are practically tasteless. They are insoluble in all usual solvents. 

Bulk and tapped densities of Polyplasdone XL are lower than those of Kollidon CL, perhaps because of the porous structure of Polyplasdone XL or the smoother surface area of Kollidon CL. In consequence of the smaller particle size, bulk densities of Kollidon CL-F and Kollidon CL-SF are lower than the bulk density of Polyplasdone XL grades. Because of its smooth particle surface, Primojel had the highest bulk and tapped densities of all disintegrants. The density of Ac-Di-Sol is between those of Kollidon CL and Primojel (3) (see Table I). 

Table I: Characteristics of various disintegrants.			

The average particle sizes of Kollidon CL-F and Kollidon CL-SF are significantly lower than those of Kollidon CL and Polyplasdone XL. Kollidon CL-M has the lowest particle size. Polyplasdone XL-10 exhibits a similar particle size as Kollidon CL-F. Ac-Di-Sol and Primojel are significantly finer than Kollidon CL and Polyplasdone XL but coarser than the other disintegrants (Particle size was measured on a "Mastersizer," Malvern Instruments) (3) (see Table I).  

One of the most important properties of the insoluble Kollidon-CL grades used as tablet disintegrants are their property to swell very fast and predictably without forming a gel. Several methods are described in the literature for measuring swelling properties in aqueous media. The swelling pressure was measured with a powder mass of 0.3 g and a punch diameter of 25 mm (see Table II) 

Table II:  Swelling pressures, swelling volumes, and hydration capacities of various disintegrants.			

The swelling pressure depends on the rate and extent of uptake of water as well as the porosity of the polymer, which can be dictated by the basic nature of the polymer chain, degree of crosslinking, and type of crosslinkage. Ac-Di-Sol shows the highest swelling pressure, followed by Kollidon CL and Primojel. Kollidon CL had the quickest increase of swelling pressure, which may contribute to the superdisintegration properties of this material. In general, crosslinked polyvinyl-pyrrolidone (PVP) grades show a limited swelling behavior to a certain particle volume, whereas Ac-Di-Sol and Primojel have more or less unlimited swelling and form a gel. It is also noteworthy that neither swelling pressure nor volume expansion alone can explain the disintegration efficacy of excipients (3). 

Swelling of disintegrant particles is perhaps the most widely accepted mechanism for tablet disintegration, primarily because almost all disintegrants swell to some extent. To determine swelling volume in water, 10 g of polymers were weighed into a 100-mL graduated cylinder. The graduated cylinder was filled with water, closed, and shaken very well. The sediment volume was determined after 24 h. 

Polyplasdone XL and XL-10 showed higher swelling volumes than Kollidon CL. Kollidon CL-F has similar swelling volume to Polyplasdone. Furthermore, it is noticeable that Kollidon CL-SF exceeds all other cross-linked PVPs. Ac-Di-Sol and Primojel have the highest swelling volume. 

Crosslinked PVP has been reported as a better disintegrant than either starch or alginic acid, attributed to the substance's capacity to absorb more than 50% of its own weight in water. Because of its low bulk density (0.26 g/mL), it tends to distribute evenly in the tablet matrix, thereby increasing surface area and the number of sites for capillary action (4).  

To determine the hydration capacity, 2 g of polymer were weighed into a centrifuge vessel with 40 mL of water. The polymer swelled for 15 min, and the suspension was centrifuged at 2000 rpm for 15 min. The supernatant was poured off, and the residual weight was determined. The hydration capacity of Polyplasdone XL was higher than those of Kollidon CL and Polyplasdone XL-10, but comparable with Kollidon CL-F. Kollidon CL-SF had the highest hydration capacity of all crosslinked PVP (see Table II). 

Crospovidone is one of the three superdisintegrants described in the literature. The mechanism of action is a capillary action with a secondary swelling effect. The improvement of tablet disintegration also has been observed through predictable swelling without gel formation. Crospovidone is a disintegrating agent at the 2–5% level and is an effective binder–disintegrant in tablets prepared using wet granulation. Furthermore, swelling properties paired with particle-size distribution make the finer grades of crospovidone work efficiently in fast-disintegrating formulations. The following formulations were tested to determine the disintegration properties: 

 Formulation 1 consisted of 467.50 mg "Ludipress LCE" (BASF), 30.00 mg disintegrant, and 2.50 mg magnesium stearate. The tablet weight was 500.00 mg. Ludipress LCE is a combination of lactose monohydrate and povidone. All the ingredients were weighed, sieved (0.8 mm), mixed for 10 min, and compressed into tablets. 

Figure 1: Disintegration time of various disintegrants (Formulation 1).			

 Formulation 2 comprised 250.00 mg AAS-powder, 250.00 mg paracetamol crystals, 0.2–0.5 50.00 mg caffeine granules, 27.50 mg povidone K30, 16.00 mg disintegrant, and 5.00 mg magnesium stearate. The tablet weight was 598.50 mg. The formulation was performed using wet granulation. The active ingredients and povidone were initially granulated with water. To dry, the granules were spread on a tray, stored for two days at ambient conditions, and sieved again in a horizontal sieve (Alexanderwerk). 

Figure 2: Disintegration time of various disintegrants (Formulation 2).			

The study compared various superdisintegrants in terms of physicochemical properties and use in direct compression and compression after wet granulation. Polyplasdone XL and Kollidon CL displayed obvious differences in various parameters. The particle-size distribution of Polyplasdone XL is broader, and the swelling volume is bigger than those of Kollidon CL. Kollidon CL-F and SF grades had a substantially smaller particle size than Kollidon CL and Polyplasdone XL and showed higher swelling volumes and hydration capacities.  

In contrast to crospovidone, Ac-Di-Sol and Primojel generate a gel-like consistency upon contact with water, causing high swelling volume and medium-to-high swelling pressure. The disintegration effect should be correlated with particle size. This study indicated that a combination of various properties, including swelling pressure and volume, hydration capacity, and swelling behavior create a good disintegrant.  

* is a technical manager for Pharma Solutions at BASF Corporation, 1705 Route 46 W, Ledgewood, NJ 07852, tel. 973.448.5313, fax 973.448.5334, 

 is a manager of research and development for Pharma Solutions at BASF AG, Ludwigshafen, Germany. 

*To whom all correspondence should be addressed. 

 1. R. Shangraw, A. Mitrevej, and M. Shah, "A New Era of Tablet Disintegrants," 

 4. R. Shangraw, J. Wallace, and F. Bowers, "Morphology and Functionality in Tablet Excipients for Direct Compression," 

Evaluating disintegrant properties and consistency in performance is an essential part of tablet formulation.

A Comparative Study of Current Superdisintegrants

Despite the increasing recognition of dietary fiber as an important constituent of a healthy diet, refined, modern diets still provide less than half the 30-g daily-recommended amount of fiber. The American Association of Cereal Chemists defines 

 as "the edible parts of plants or analogous carbohydrates that are resistant to digestion and absorption in the human small intestine with complete or partial fermentation in the large intestine."  

Besides maintaining general digestive health, fibers also promote beneficial physiological effects such as an attenuation of blood cholesterol and triglycerides as well as a reduction in glucose responses. In addition, some fibers contribute to prebiotic effects in the digestive tract and improve colonic health (1). On the basis of their water-solubility, dietary fibers are classified into two major categories, and a balanced intake of both types is recommended for optimum digestive health. Insoluble fibers consist of lignin, cellulose, hemicellulose, and bran as well as digestion-resistant starches and soluble fibers, including polyfructoses (inulin, fructooligosaccharides [FOS]), galactooligosaccharides, gums, mucilages, and pectins. 

A variety of fiber supplements are available currently as reconstitutable powders, drink mixes, capsules, as well as swallowable or chewable tablets to correct dietary fiber deficiencies. Fiber supplements based on psyllium or methylcellulose generally swell in water, becoming sticky or gummy, imparting high viscosity and a gritty mouthfeel. Such fibers must be consumed with large quantities of fluids and have a low consumer acceptance.  

Consequently, many recently marketed nutraceutical and over-the-counter fiber supplements have focused on using fully soluble, low-viscosity fibers such as inulin, FOS, and hydrolyzed guar gum. These fibers generally are available in a fine-powder form and suffer from poor flow and lack of direct compressibility, thereby necessitating additional agglomeration or granulation before formulating into tablets or drink mixes. Some low-viscosity fibers such as inulin and FOS also present the disadvantages of poor heat and acid stability, off-taste, and low digestive tolerance.  

An ideal soluble dietary fiber should exhibit instant and complete water solubility, low viscosity, neutral taste, high fiber content, high digestive tolerance, excellent stability (

heat and acid), and easy processability (

 good flow and direct compressibility). A novel soluble dextrin fiber, possessing all the abovementioned characteristics, can overcome the stability and application limitations of most soluble fibers (2). 

Dextrins are generally obtained by treating starch with a food-grade acid at elevated temperature, which enables the addition of 1-2 and 1-3 glycosidic links to the starch polymer. The 1-2 and 1-3 glycosidic links cannot be digested by any of the normal human enzymes and hence, dextrins are classified as fiber. The dextrinization process generates a product with a broad molecular weight range, leading to high viscosity upon solubilization in water, discoloration, and the development of off-taste (3). Narrowing the molecular-weight distribution by eliminating higher molecular-weight fractions can reduce the viscosity of the resulting solution. Eliminating low molecular-weight fractions can make the dextrin sugar-free and significantly improve its digestive tolerance and reduce hygroscopicity. 

Spray agglomeration of the purified dextrin solution provides a granular, free-flowing, and directly compressible fiber product. The high stability (heat and acid) and excellent digestive tolerance allow use of the soluble dextrin fibers in a variety of fiber supplements such as reconstitutable powders, beverages, nutrition bars, or directly compressed tablets as well as clinical enteral nutrition formulations. Such improved fiber excipients ultimately allow faster processing times, significant cost savings, and shorter cycle-time for the manufacturer while promising a highly stable and more acceptable fiber supplement for the consumer. 

Neutral taste and excellent heat and acid stability determine application versatility

Many soluble fibers impart characteristic taste to the formulations into which they are incorporated, thus limiting their level of use or requiring taste masking. Results from a taste panel in Table I show that a 10% aqueous solution of dextrin fiber exhibits neutral taste compared with other fibers, implying minimal impact on the overall formulation taste.  

Table I: Comparison of taste and sweetness characteristics of some soluble fibers.			

In addition to taste, many acidic formulations demand high stability of the fiber excipient at low pH. As shown in Figure 1, the stability of a 10% aqueous solution of fibers such as inulin or FOS under acidic pH of 3.5 or 2.0 is quite low compared with that of dextrin fiber (2). Thus, inulin or FOS may not be the soluble fibers of choice for use in acidic formulations. 			

Many fiber-fortified, ready-to-drink beverages must be pasteurized or sterilized to ensure long-term shelf stability. Figure 2 shows the excellent postpasteurization stability of dextrin fiber compared with FOS in an acidic beverage. Similar results also have been observed in acidic beverages that were sterilized at 110 °C for 50 min (unpublished data). 			

The neutral taste and excellent thermal and pH stability of the novel dextrin fiber are direct consequences of its purity and robust chemical structure, thus enabling its use in various fiber formulations in which stability and taste are important.  

Figure 1: Comparative stability of FOS and dextrin fiber under acidic conditions.

High tolerance and prebiotic effects enhance digestive health

Many commonly used soluble fibers undergo fermentation in the digestive tract, leading to the generation of gas, uncomfortable bloating, and flatulence. Fibers containing smaller molecular-weight components also tend to induce significant laxation and diarrhea. Soluble fibers such as inulin and FOS are well known to exhibit low digestive tolerance, thereby causing laxation and flatulence at relatively low doses. In a randomized, double-blind, placebo-controlled clinical trial involving 48 healthy men, the dextrin soluble fiber was shown to exhibit no laxation at a 90 g/day dose, which is significantly higher than most other soluble fibers (4, 5). An individual could thus obtain the daily-recommended fiber requirement (30 g/day/person) entirely by consuming the dextrin fiber without experiencing any unwanted digestive side effects.  

Besides good digestive tolerance, the prebiotic effects of soluble fibers also are important. A variety of microorganisms tend naturally to flourish in the human digestive tract; exposure to stress or use of antibiotics, however, can diminish the population of these good bacteria. Some soluble fibers act as prebiotics, nourishing and replenishing beneficial microorganisms such as 

 and Bacteroides in the digestive tract while limiting the growth of harmful bacteria such as Clostridia. Prebiotics also have been associated with a variety of health benefits such as preventing diarrhea, controlling ulcers, reducing cholesterol, enhancing immunity, and preventing colon cancer.  

Figure 2: Comparative postpasteurization stability of FOS and dextrin fiber.

These effects have been attributed to a reduction in the colonic pH, as a result of a generation of short-chain fatty acids (SCFA) by increases in the levels of α- and β-glucosidase enzymes. In a randomized, double blind, placebo-controlled clinical trial involving 48 healthy men, the dextrin soluble fiber exhibited a significant pH lowering in the digestive tract along with an increase in levels of glucosidases after 35 days of administration (see Figure 3). This was accompanied by an increase in 

 (beneficial bacteria) levels from 7.2 to 8.2 log cfu/g and Bacteroides (responsible for SCFA generation) levels from 8.5 to 8.9 log cfu/g with a 45-g dose of dextrin. On the other hand, levels of harmful Clostridia were lowered from 5.9 to 5.6 log cfu/g (6). The excellent digestive tolerance and beneficial prebiotic effects (7) make this new dextrin the ideal soluble fiber to enable significant improvement in overall digestive health. 

Figure 3: Effect on fecal pH and glucosidase levels following 35-day administration of dextrin fiber.			

Improved processability of fibers enables cost-savings and shorter cycle time

Most soluble fibers are currently available as fine powders, suffering from problems of poor flow and lack of compressibility. Using these fine powders in formulating drink mixes, bulk fiber supplements, or tablets mandates the use of granulation or agglomeration processes to improve the flow or compressibility. Such processing takes time, requires elaborate equipment, and is labor intensive and expensive.  

Figure 4 shows the direct-compression tableting profile of this dextrin fiber exhibiting good tablet hardness and low friability. The granular nature of dextrin fibers thus enables good flow and direct compressibility, allowing their use in the preparation of fiber supplemented swallowable caplets and chewable tablets by direct compression without any need for additional agglomeration. 

Figure 4: Compression and tablet hardness profile of dextrin fiber. 			

Future trends in fiber supplementation and innovation

Formulations containing a novel soluble dextrin fiber have been shown to exhibit several advantages in processibility and clinical response over those containing existing fibers.

Pharmaceutical Technology-10-01-2006

Functionality and Performance of Excipients

Current Trends and Challenges in the Excipients Market

Selecting Superdisintegrants for Orally Disintegrating Tablet Formulations

A Comparative Study of Current Superdisintegrants

New Dextrins: Supplementing Fiber with Innovation