INTRODUCTION:

Tablets are the most preferred dosage form of pharmaceutical scientists because they can be accurately dosed and provide good patient compliance. They are easy for companies to manufacture and they can be produced at a relatively low cost. The development in the field of APIs, excipients and tabletting machines during the past decades has made tablet manufacturing a science and the tablets the most commonly used dosage form¹^‐².This popularity of tablets coupled with an increased understanding of the physics of compression and of manufacturing process variables have matured the manufacture of tablets as a science in its own right³

Tablets are manufactured primarily by either granulation compression or direct compression. The latter involves the compression of a dry blend of powders that comprises drugs and various excipients. The simplicity and cost effectiveness of the direct‐compression process have positioned direct compression as an attractive alternative to traditional granulation technologies. The demand of excipients with improved functionalities, mainly in terms of flow and compression properties, has increased with the advancement of tablet manufacturing process. Co-processed excipients are a mixture of two or more existing excipients at subparticle level, offer substantial benefits of the incorporated excipients and minimize their drawbacks. These multipurpose excipients have significantly reduced the number of incorporating excipients in the tablet. The present review discusses the sources of new excipients, potential advantages of co-processed excipients, material characteristics required for co-processing, methods of preparing directly compressible adjuvants and various co-processed excipients for direct compression available in the market.

NEED FOR DEVELOPING NEW EXCIPIENTS:

The excipients industry to date has been an extension of the foodindustry⁴. Moreover, excipients are products of the food industry, which has helped maintain a good safety profile. Increasing regulatory pressure on purity, safety, and standardization of the excipients has catalyzed the formation of an international body, the International Pharmaceutical Excipients Council (IPEC) ⁵. IPEC is a tripartite council with representation from the United States, Europe, and Japan and has made efforts to harmonize requirements for purity and functionality testing⁶. The development of new excipients to date has been market driven (i.e., excipients are developed in response to market demand) rather than marketing driven (i.e., excipients are developed first and market demand is created through marketing strategies) and has not seen much activity as shown by the fact that, for the past many years, not a single new chemical excipient has been introduced into the market. The primary reason for this lack of new chemical excipients is the relatively high cost involved in excipients discovery and development. However, with the increasing number of new drug moieties with varying physicochemical and stability properties, there is growing pressure on formulators to search for new excipients to achieve the desired set of functionalities. Other factors driving the search for new excipients are:

• The growing popularity of the direct‐compression process and a demand for an ideal filler–binder that can substitute two or more excipients

• Tableting machinery’s increasing speed capabilities, which require excipients to maintain good compressibility and low weight variation even at short dwell times.

• Shortcomings of existing excipients such as loss of compaction of microcrystalline cellulose (MCC) upon wet granulation, high moisture sensitivity, and poor die filling as a result of agglomeration⁷.

• The lack of excipients that address the needs of a specific patient such as those with diabetes, hypertension, and lactose and sorbitol sensitivity.

• The ability to modulate the solubility, permeability, or stability of drug molecules.

• The growing performance expectations of excipients to address issues such as disintegration, dissolution, and bioavailability.

Particle engineering as source of new excipients:

Solid substances are characterized by three levels of solid-state: the molecular, particle, and bulk level. These levels are closely linked to one another, with the changes in one level reflecting in another level. The molecular level comprises the arrangement of individual molecules in the crystal lattice and includes phenomena such as polymorphism, pseudo-polymorphism, and the amorphous state. Particle level comprises individual particle properties such as shape, size, surface area, and porosity. The bulk level is composed of an ensemble of particles and properties. The fundamental solid-state properties of the particles such as morphology, particle size, shape, surface area, porosity, and density influence excipient functionalities such as flowability, compactability, dilution potential, disintegration potential, and lubricating potential. Hence, the creation of a new excipient must begin with a particle design that is suited to deliver the desired functionalities⁸.

Varying the crystal lattice arrangement by playing with parameters such as the conditions of crystallization and drying can create particles with different parameters. Lactose is examples in which such an approach has been successfully applied. However, particle engineering of a single excipient can provide only a limited quantum of functionality improvement. Co processing is based on the novel concept of two or more excipients interacting at the sub particle level, the objective of which is to provide a synergy of functionality improvements as well as masking the undesirable properties of individual excipients⁹ .The availability of a large number of excipients for co processing ensures numerous possibilities to produce tailor-made” designer excipients” to address specific functionality requirements or improve the desired properties of excipients. For example, if a substance used as a filler–binder has a low disintegration property, it can be co- processed with another excipient that has good wetting properties and high porosity because these attributes will increase the water intake, which will aid and increase the disintegration of the tablets.

Table 1: Various particle properties influencing excipient functionality

Particle property	Excipient functionality
Enlargement of particle size	Flowability, compressibility
restricting particle size distribution	Segregation potency
Enlargement of particle porosity	Compressibility, solubility
Surface roughness	Flowability, Segregation Potency

Co processing of Excipients:

The actual process of developing a co processed excipient involves the following steps:

1. Identifying the excipients group to be co processed by carefully studying the material characteristics and functionality requirements

2. Electing the proportions of various excipients

3. Assessing the particle size required for co processing. This is especially important when one of the components is processed in a dispersed phase. Post processing the particle size of the latter depends on its initial particle size.

4. Selecting a suitable drying process such as spray- or flash drying optimizing the process (because even this can contribute to functionality variations).

There are three ways to give an Excipient a new or Improved Functionality:

1. Chemical modification

2. Physical modification

3. Co-processing of excipients or drugs and excipients

Co-processing seems to be an interesting chance because the products are in a special way physically modified without losing their chemical structure and stability. The aim is to excipients which meet the requirements of modern tablet manufacture.

Role of Material Science in Co-Processing:

Material science plays a significant role in altering the physicomechanical characteristics of a material, especially with regard to its compression and flow behavior. Co-processing excipients offers an interesting tool to alter these physicomechanical properties. Materials, by virtue of their response to applied forces, can be classified as elastic, plastic, or brittle materials. In the truest sense, materials cannot be classified in one category absolutely. Pharmaceutical materials exhibit all three types of behavior, with one type being the predominant response. This makes it difficult to demarcate which property is good for compressibility. Co-processing is generally conducted with one excipient that is plastic and another that is brittle. A combination of plastic and brittle materials is necessary for optimum tabletting performance. Hence, co-processing these two kinds of materials produces a synergistic effect, in terms of compressibility, by selectively overcoming the disadvantages. Such combinations can help improve functionalities such as compaction performance, flow properties, strain‐rate sensitivity, lubricant sensitivity or sensitivity to moisture, or reduced hornification.

Advantages of Co-Processing:

1) Absence of Chemical Change:

Many detailed studies of excipients chemical properties after co-processing have proven that these excipients do not show any chemical change. The absence of chemical changes help to reduce a company’s regulatory concerns during the devolvement phase¹⁰.

2) Improved Flow Properties:

Controlled optimal particle size and particle‐size distribution ensures superior flow properties of co-processed excipients without the need to add glidants. The flow of co-processed excipients was better than the flow of simple physical mixtures^11-12.

3) Improved compressibility:

Co-processed excipients have been used mainly in direct compression tabletting because in this process there is a net increase in the flow properties and compressibility profiles and the excipient formed is a filler–binder. The pressure–hardness relation of co-processed excipients, when plotted and compared with simple physical mixtures, showed a marked improvement in the compressibility profile^13-15.

4) Better Dilution Potential:

Dilution potential is the ability of the excipient to retain its compressibility even when diluted with another material. Most active drug substances are poorly compressible, and as a result, excipients must have better compressibility properties to retain good compaction even when diluted with a poorly compressible agent¹⁶.

5) Fill Weight Variation:

In general, materials for direct compression tend to show high fill weight variations as a result of poor flow properties, but co-processed excipients, when compared with simple mixtures or parent materials, have been shown to have fewer fill‐weight variation problems. The primary reason for this phenomenon is the impregnation of one particle into the matrix of another, which reduces the rough particle surfaces and creates a near‐optimal size distribution, causing better flow properties. Fill‐weight variation tends to be more prominent with high‐speed compression machines¹⁷.

6) Reduced Lubricant Sensitivity:

Most of the co-processed products consist of a relatively large amount of brittle material such as lactose monohydrate and a smaller amount of plastic material such as cellulose that is fixed between or on the particles of the brittle material. The plastic material provides good bonding properties because it creates a continuous matrix with a large surface for bonding¹⁸.

The large amount of brittle material provides low lubricant sensitivity because it prevents the formation of a coherent lubricant network by forming newly exposed surfaces upon compression, thus breaking up the lubricant network.

Disadvantages of co-Processed Excipients:

· Major limitation of co-processed excipients mixture is the ratio of the excipients in a mixture is fixed and in developing a new formulation, a fixed ratio of the excipients may not be an optimum choice for the API and dose per tablets under development.

· Co-processed adjutants lack the official acceptance in pharmacopoeia.

Direct compression:

Previously, the word ‘direct compression’ was used to identify the compression of a single crystalline compound (i.e. sodium chloride, potassium chloride, potassium bromide, etc.) into a compact form without the addition of other substances. Current usage of the term ‘direct compression’ is used to define the process by which tablets are compressed directly from the powder blends of active ingredients and suitable excipients. No pretreatment of the powder blends by wet or dry granulation is involved¹⁹.

The simplicity of the direct compression process is apparent from a comparison of the steps involved in the manufacture of tablets by wet granulation, roller compaction and direct compression techniques²⁰.It has been estimated that less than 20 percent of pharmaceutical materials can be compressed directly into tablets. The rest of the materials lack flow, cohesion or lubricating properties necessary for the production of tablets by direct compression. The use of directly compressible adjuvants may yield satisfactory tablets for such materials. Although simple in terms of unit processes involved, the direct compression process is highly influenced by powder characteristics such as flowability, compressibility, and dilution potential. Tablets consist of active drugs and excipients, and not one drug substance or excipient possesses all the desired physicomechanical properties required for the development of a robust direct‐compression manufacturing process, which can be scaled up from laboratory to production scale smoothly. Most formulations (70–80%) contain excipients at a higher concentration than the active drug. Consequently, the excipients contribute significantly to a formulation’s functionality and processability.In simple terms; the direct‐compression process is directly influenced by the properties of the excipients. The physicomechanical properties of excipients that ensure a robust and successful process are good flowability, good compressibility, low or no moisture sensitivity, low lubricant sensitivity, and good machinability even in high‐speed tabletting machinery with reduced dwell times. The majority of the excipients that are currently available fail to live up to these functionality requirements, thus creating the opportunity for the development of new high functionality excipients²¹.

Directly Compressible Adjuvants:

The International Pharmaceutical Excipients Council (IPEC) defines excipient as Substances, other than the API in finished dosage form, which have been appropriately evaluated for safety and are included in a drug delivery system to either aid the processing or to aid manufacture, protect, support, enhance stability, bioavailability or patient acceptability, assist in product identification, or enhance any other attributes of the overall safety and effectiveness of the drug delivery system during storage or use²². Solvents used for the production of a dosage form but not contained in the final product are considered to be excipients, i.e. the granulation fluids, which might be dried off later, should comply with relevant requirements of pharmacopoeia unless adequately justified. Excipients no longer maintain the initial concept of "inactive support" because of the influence they have both over biopharmaceutical aspects and technological factors. The desired activity, the excipients equivalent of the active ingredient's efficacy, is called its Functionality. The inherent property of an excipient is its functionality in the dosage form. Determination of excipients functionality is important to the excipient manufacturer in its assessment of the proper level of GMP, and yet the drug manufacturer may withhold this information until well into the development process²³.

In order to deliver a stable, uniform and effective drug product, it is essential to know the properties of the active ingredient alone and in combination with all other ingredients based on the requirements of the dosage form and processes applied. Excipients are usually produced by batch process; hence, there is a possibility of batch‐to batch variation from the same manufacturer. Excipients obtained from the different sources may not have identical properties with respect to use in a specific formulation. To assure interchangeability in such circumstances, users may wish to ascertain equivalency in tests are thus related to the functionality, that the excipient impart to a specific formulation²⁴.In order to manufacture any finished product with consistent quality, standardization of raw materials in the drug formulation is necessary for its acceptance by regulatory authorities and pharmaceutical formulators. Unfortunately, such performance standards have not been included in pharmacopoeia primarily because their specifications have always been based on chemical purity and because it is not possible to standardize performance criteria²⁵. Pharmacopoeial standards do not take into account particle characteristics or powder properties, which determine functionality of excipients²⁶.Control of functionality is important as a control of identity and purity. The following reasons can be cited:

• Many excipients have multiple functions (e.g. microcrystalline cellulose, starch).

• There is lack of awareness that the excipients behave differently, depending upon the vendor (i.e. microcrystalline cellulose).

• As a consequence, excipients with optimal functionality are needed to ensure smooth tablet production on modern machines. The introduction of special force feeder to improve flow of granules from hopper marked a significant advancement in direct compression technology.

Ideal Requirements of Directly Compressible Adjuvants:

The directly compressible adjuvant should be free flowing. Flowability is required in case of high‐speed rotary tablet machines, in order to ensure homogenous and rapid flow of powder for uniform die filling. During the short dwell‐time (milliseconds), the required amount of powder blend should be transferred into the die cavities with reproducibility of + 5%. Many common manufacturing problems are attributed to incorrect powder flow, including non-uniformity in blending, under or over dosage and inaccurate filling²⁶.Compressibility is required for satisfactory tabletting, i.e., the mass must remain in the compact form once the compression force is removed. Few excipients can be compressed directly without elastic recovery. Hence, the directly compressible diluents should have good compressibility, i.e. relation between compaction pressure and volume .Dilution potential can be defined as the amount of an active ingredient that can be satisfactorily compressed in to tablets with the given directly compressible excipient. A directly compressible adjuvant should have high dilution potential so that the final dosage form has a minimum possible weight. The dilution potential is influenced by the compressibility of the active pharmaceutical ingredient. A directly compressible adjuvant should be capable of being reworked without loss of flow or compressibility. On recompression, the adjuvant should exhibit satisfactory tabletting characteristics. The adjuvant should remain unchanged chemically and physically. The directly compressible adjuvant should not exhibit any physical or chemical change on ageing and should be stable to air, moisture and heat.

A directly compressible adjuvant should have a particle size equivalent to the active ingredients present in the formulation. The particle size distribution should be consistent from batch to batch. Reproducible particle size distribution is necessary to achieve uniform blending with the active ingredient(s) in order to avoidsegregation²⁷.Filler‐binders should not accelerate the chemical and/or physical degradation of the API(s) or excipients. It should not interfere with the biological availability of active ingredient/s. It should be compatible with all the adjuvants present in the formulation²⁸. It should be physiologically inert. It should not interfere with the disintegration or dissolution of the active ingredient. It should be colorless and tasteless. It should be relatively cost effective and available in desired time. It should accept colorants uniformly. It should show low lubricant sensitivity. It should show batch‐to‐batch reproducibility of physical and physicomechanical properties. It should possess proper mouth fill, which is defined as the feel or the sensation in the mouth, produced when the excipient is used in chewable tablets.

Advantages of direct compression:

The prime advantage of direct compression over wet granulation is economic since the direct compression requires fewer unit operations. This means less equipment, lower power consumption, less space, less time and less labour leading to reduced production cost of tablets. Direct compression is more suitable for moisture and heat sensitive APIs, since it eliminates wetting and drying steps and increases the stability of active ingredients by reducing detrimental effects. Changes in dissolution profiles are less likely to occur in tablets made by direct compression on storage than in those made from granulations. This is extremely important because the official compendium now requires dissolution specifications in most solid dosage forms. Disintegration or dissolution is the rate‐limiting step in absorption in the case of tablets of poorly soluble API prepared by wet granulation. The tablets prepared by direct compression disintegrate into API particles instead of granules that directly come into contact with dissolution fluid and exhibits comparatively faster dissolution. The high compaction pressure involved in the production of tablets by slugging or roller compaction can be avoided by adopting direct compression. The chances of wear and tear of punches and dies are less. Materials are ‘in process’ for a shorter period of time, resulting in less chance for contamination or cross contamination, and making it easier to meet the requirement of current good manufacturing practices. Due to fewer unit operations, the validation and documentation requirements are reduced. Due to the absence of water in granulation, chance of microbial growth is minimal in tablets prepared by directcompression²⁹. Table 2 describes the examples of some directly compressible adjuvants.

Limitations of Direct Compression:

Direct compression is more prone to segregation due to the difference in density of the API and excipients. The dry state of the material during mixing may induce static charge and lead to segregation. This may lead to the problems like weight variation and content uniformity. Directly compressible excipients are the special products produced by patented spray drying, fluid bed drying, roller drying or co‐crystallization. Hence, the products are relatively costly than the respective raw materials. Most of the directly compressible materials can accommodate only 30‐40 % of the poorly compressible active ingredients like acetaminophen that means the weight of the final tablet to deliver the 500 mg of acetaminophen would be more than 1300 mg. The large tablets may create difficulty in swallowing. All the spray‐dried directly compressible adjuvants show poor rework ability since on preparation of tablets the original spherical nature of the excipient particles is lost. API that has poor flow properties and/or low bulk density is difficult to process by direct compression.

Lubricants have a more adverse effect on the filler, which exhibit almost no fracture or shear on compression (e.g. starch 1500). The softening effects as well as the hydrophobic effect of alkaline Stearates can be controlled by optimizing the length of blending time to as little as 2‐5 min. There is a lack of awareness in some situations that the excipient behave differently, depending upon the vendor so much so that substitution from one source to that of another is not possible. Hence, there is a need for greater quality control in purchasing of raw material to assure batch uniformity.

Methods of preparing directly compressible excipients:

Directly compressible adjuvants can be prepared by various methods. The outline and main features of the methods are depicted in Table 3. Co‐processing is the one of the most widely explored and commercially utilized method for the preparation of directly compressible adjuvants ^30-31.

Table 2: Examples of some directly compressible adjuvants

Excipient	Brand Name (Manufacturer, Country)
Lactose	Tablettose (Meggle, Germany), Pharmatose (DMV, the Netherland), Fast Flo Lactose (Foremost)
Sucrose	Di‐pac (American sugar company, USA), Nutab (Ingredient technology) Inc., USA)
Dextrose	Emdex (Edward mendell, USA), Can Tab (Penwest, USA)
Mannitol	Mannogem 2080 (SPI Polyols, France)
Sorbitol	Neosorb 60 (Roquette, France), Sorbogem (SPI Polyols, France), Sorbidex P (Cerestar, USA)
Lactitol	Finlac DC (Danisco, USA), Lacty‐TAB (Purac, USA)
Xylitol	Xylitab ( Danisco, USA
Maltodextrin	Maltrin (GPC, USA)
Microcrystalline Cellulose)	Avicel PH (FMC, USA),Emocel(Edward mendell, USA), Vivacel (JRS, USA)

Table.3.summary of various methods used to prepare directly compressible adjuvants:

Method	Advantage & limitation	Example
Chemical modification	Expensive, time consuming, require toxicological data	Ethyl cellulose, methyl cellulose, Hydroxy propylmethyl cellulose, lactitol, cyclodextrin from starch
Physical modification	Simple and economical	Sorbitol, dextrates and compressible Sugars
Grinding or sieving	Compressibility may alter because of change in particle properties	Dibasic dicalcium phosphate, α-lactose monohydrate
Crystallization	Impart flow ability to excipient but not self-binding properties, require stringent control on processing	Dipac, β-lactose
Spray drying	Spherical shape and uniform size gives spray dried material good flowability, poor rework ability	Emdex, Avicel _P^H, advantose100,karion instants
Granulation/agglomeration	Transfer poor flow, cohesive, small particle into flow able and directly compressible	Granulated lactitol, tablettose
Dehydration	Increase binding properties by thermal and chemical modification	Anhydrous α-lactose

Table.4.examples of marketed co-processed excipients:

Trade name	Manufacturer	Components	%	Claimed benefits
Ludipress ®	BASF	Lactose PVP	93 7	Low hygroscopicity, Good Flow ability, Constant tablet weight.
Avicel ® CE-15	FMC	MCC Guar	85 15	Less grittiness, Improved tablet palatability.
Pharmatose ® DCL40	DMV	β lactose Lactitol	95 5	High compressibility, Low lubricant sensitivity
Di-Pac®	Domino	Sucrose Maltodextrin	97 3	For direct compression.
StarCap1500®	Colorcon	Maize starch Pregel Starch		Tablet disintegration and dissolution independent of _P^H.

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Received on 16.01.2015 Modified on 01.02.2015

Res. J. Pharm. Dosage Form. & Tech. 7(2): April-June, 2015; Page 149-155

DOI: 10.5958/0975-4377.2015.00022.1