INTRODUCTION:

Orally disintegrating tablets (ODTs) have been referred to as fast melt tablets, orodispersible tablets, fast disintegrating dosage forms among others and these terms are often used interchangeably. In 1998, ODTs were classed as a new dosage form by the United States Food and Drug Administration (US FDA) Center of Drug Evaluation and Research (CDER) and defined as: “solid dosage form containing medicinal substances which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue.”

A guidance document for the industry published by the FDA in 2008 further describes an ODT as a dosage form that can be administered with or without water¹ and disintegrates within 30 sec. based on the United States Pharmacopoeia disintegration test method or alternative. While arbitrary, the criteria of 30 sec. disintegration time as well as a tablet weight of not more than 500mg are intended to differentiate ODTs from chewable and conventional compressed tablets².

Disintegrants are agents added to tablet and some encapsulated formulations to promote the breakup of the tablet and capsule “slugs’ into smaller fragments in an aqueous environment there by increasing the available surface area and promoting a more rapid release of the drug substance. They promote moisture penetration and dispersion of the tablet matrix. Oral route of drug administration is perhaps the most appealing route for the delivery of drugs. Of the various dosage forms administered orally, the tablet is one of the most preferred dosage form because of its ease of manufacturing, convenience in administration, accurate dosing, stability compared with oral liquids and because it is more tamper proof than capsules. The gastrointestinal tract provides sufficient fluid to facilitate disintegration of the dosage form and dissolution of the drug. The large surface area of gastric mucosa favors the drug absorption. Therefore, the oral route has continued to be the most appealing route for drug delivery despite the advancements made in the new drug delivery systems. Rapidly disintegrating tablets have received much attention in recent years, as they are preferred by pediatric and geriatric patients.

Moreover, the drug dissolution is facilitated by the tablets’ quick disintegration. The simplest way to achieve quick disintegration is to use a superdisintegrant in concert with suitable diluents. Superdisintegrants such as croscarmellose sodium, crospovidone, and sodium starch glycolate are frequently used in tablet formulations to improve the rate and extent of tablet disintegration and thereby increase the rate of drug dissolution. Oral tablet administration to patients is a significant problem and has become the object of public attention. The problem can be resolved by the creation of rapidly dispersing or dissolving oral forms, which do not require water to aid swallowing. Among the various methods to design an ODT dosage form, the use of co-processed, functional excipients customized for ODT development is an attractive option to achieve optimal product design with good manufacturing performance. These co-processed excipients are predominantly based on polyols (mannitol, xylitol, sorbitol, etc.) or carbohydrates, in combination with disintegrants and in some instances, with binders, silicon dioxide and inorganic materials. The combination is designed to physically modify their properties in a manner not achievable by simple physical mixing and without significant chemical change. On the whole, these co-processed excipients claim to have improved physico-mechanical properties (e.g. pleasant mouthfeel, low hygroscopicity, better flow and compactibility) to support processing particularly by direct compression on conventional tablet presses to manufacture harder and less friable ODTs without compromising disintegration times².

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 use.”

What is co-processing?

“It is a combination of two or more compendial or non-compendial excipients designed to physically modify their properties in a manner not achievable by simple physical mixing and without significant chemical change.” Co-processing was initially used by the food industry to improve stability, wettability and solubility and to enhance the gelling properties of food ingredients. Improve compressibility, drug aqueous solubility, improve flow properties and bioavailability¹.

Principle of co-processing:

Basic fundamental of co-processing is based on particle engineering. Solid substances are characterized by three levels of solid state- 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 comprises of large no. of particles together and their properties such as flowability, compressibility, and dilution potential, which are critical factors in the performance of excipients². Co-processing is based on the novel concept of two or more excipients interacting at the subparticle level, the objective of which is to provide a synergy of functionality improvements as well as masking the undesirable properties of individual excipients. Development of co-processed directly compressible adjuvant starts with the selection of the excipients to be combined, their targeted proportion, selection of preparation method to get optimized product with desired physicochemical parameters and it ends with minimizing avoidance with batch-to-batch variations (Figure 1). An excipient of reasonable price has to be combined with the optimal amount of a functional material in order to obtain integrated product, with superior functionality than the simple mixture of components. The use of one-body components is justified if it results in a potentiation of the functionalities over that of the dry blend of the components prepared by gravity mixture. This synergistic effect should improve the quality of the tablet equally in all aspects ranging from hardness to dissolution and/or stability.

Figure 1: Schematic representation of co-processing method

Merits of co-processing:

· 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.

· Improved Compressibility: Co-processed excipients have been used mainly in direct compression because in this process there is a net increase in the flow properties, which results in improved compressibility. The pressure hardness relation of coprocessed excipients, when plotted and compared with simple physical mixtures, showed a marked improvement in the compressibility profile.

· 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 agent.

· Fill weight variation: Co-processed excipients, when compared with simple mixtures or parent materials, have been shown to have fewer fill weight variation problems.

· Reduced lubricant sensitivity: Most 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 bonding. 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.

Drawbacks:

· 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 the dose per tablet under development¹⁰.

· Co-processed excipient lacks the official acceptance in pharmacopeia. For this reason a combination filler binder will not be accepted by the pharmaceutical industry until it exhibits significant advantages in the tablet compaction when compared to the physical mixtures of the excipients.

Techniques for manufacturing of Co-processed materials:

1. Spray Drying technique:

This technique enables the transformation of feed from a fluid state into dried particulate form by spraying the feed into a hot drying medium (Figure 2). It is a continuous particle processing drying operation. Because of the spherical nature of liquid particles after evaporation of water, the resulting spray-dried materials consist of porous, spherical agglomerates of solid particles that are fairly uniform in size. Amorphous component generated by rapid cooling and crystallization acts as a binder. Atomization process, drying chamber, cooling rate of the solution and rate of crystallization are the major factors that govern the shape and size of the spray-dried product. The feed can be a solution, suspension, dispersion or emulsion. The dried product can be in the form of powders, granules or agglomerates depending upon the physical and chemical properties of the feed, the dryer design and final powder properties desired³. Hence the spray drying process can be described as consisting of four events:

· Atomization of the liquid into droplets

· Contact of the droplets with the warm drying gas

· Rapid evaporation of the droplets to form dry particles

· Recovery of the dry particles from the drying gas, using a cyclone/filter.

· Lactose was the first pharmaceutical excipient to successfully exemplify the spray drying technology.

Figure 2: Schematic diagram of spray drying technique

2. Crystallization technique⁴:

Crystallization is the (natural or artificial) process of formation of solid crystals precipitating from a solution, melts or more rarely deposited directly from a gas. For crystallization to occur from a solution it must be supersaturated. This means that the solution has to contain more solute entities (molecules or ions) dissolved than it would contain under the saturated solution. This can be achieved by various methods, with (a) solution cooling, (b) addition of a second solvent to reduce the solubility of the solute, (c) chemical reaction and (d) change in pH being the most common methods used in industrial practice (Figure 3). Plastic deformation may occur depending on the dislocations and slip planes in the crystals. Crystalline substances are subject to such deformations depending on the symmetry within the crystal lattice. The crystal structure that has greater degree of symmetry will be more prone to deformation on compression and compaction. α-lactose monohydrate is obtained by crystallization at temperature below 93ºC while β - lactose is obtained by crystallization from a supersaturated solution at temperature exceeding 93ºC. Example: Sugar Tab [Sucrose, Invert sugar].

Figure 3: Steps for crystallization method

3. Melt agglomeration technique:

Melt extrusion is a process of formation of small beads, pellets from the molten mass which is extruded through extruder. Hot melt extrusion is carried out using an extruder. Extruders consist of four distinct parts; (a) An opening though which material enters the barrel that may have a hopper that is filled with the materials to be extruded. (b) A conveying section (process section), which comprises the barrel and the screws that transport, and where applicable, mix the material. (c) An orifice for shaping the material as it leaves the extruder. (d) Downstream auxiliary equipment for cooling, cutting and/or collecting the finished product⁵. Example: Compressol S [Mannitol, Sorbitol]

Figure 3: Melt agglomeration technique

4. Wet granulation/agglomeration technique:

Granulation and agglomeration represent the transformation of small, cohesive, poorly flowable powders into a flowable and directly compressible from. Granulation results in nearly spherical particles with relatively high bulk density and strength⁶. Co-processing of excipients using wet granulation technique simply involves wet massing of the blend of the excipientsto be co-processed with a granulating liquid, wet sizing, drying and finally screening of dry granules. Wet granulation is a cost-effective method of co-processing as it can be adopted for conventional equipments like a planetary mixer/high shear mixer and requires validation of fewer process variables. Agglomeration on the other hand, leads to irregularly shaped porous particles with relatively low bulk density and strength. When the primary particles have binding properties of their own, the addition of binder is not necessary (i.e. Tablettose).

5. Roller Compaction / Dry granulation technique:

In this technique a uniform powder blend of the excipients to be co-processed is compressed between counter rotating rollers to form a ribbon of compacted material that is then milled into granules. As no liquid or drying step is involved, roller compaction is suitable for co-processing of moisture or heat sensitive excipients. The novel excipient, thus, developed has higher bulk density as compared to the starting powder mixture and was used as dispersion or suspension stabilizer in the manufacture of liquid and semi-solid preparation.

Figure 4: Roller compaction technique

6. Roller drying technique:

Co-processing of excipients via roller drying involves preparing a homogenous solution or dispersion of the excipient to be co-processed and then drying of the resultant solution or dispersion on a roller dryer⁷. This technique has been adopted by Meggelaars et al. (1996) for co-processing lactose with sugar alcohol. The sugar alcohol is preferably sorbitol or lactitol. In this particularcase, the rolling temperature should be sufficiently high, so as to obtain a product that consists principally of α-lactose in crystalline form.

Figure 5: Roller drying technique

7. Co-transformation:

Co-processing of excipients via co-transformation involves the application of heat or a solvent to temporarily “open-up” the particles of one excipient and then adding another excipient into the “opened-up” particles.

8. Milling:

Milling or dry grinding for the production of co-processed excipients may be carried out in a roller mill, a ball mill, a bead mill, a millstone mill, a jet mill, and a hammermill. Ball milling has been adopted by Rao et al. (2012) for co-processing cross-linked polyvinyl pyrrolidone and calciumsilicate. In this particular case, ball mill was operated for 2hours at a speed of 200 rpm using 25 stainless steel balls. The co-processed binary mixture of cross-linked polyvinyl pyrrolidone and calcium silicate enhances the rate and extent of dissolution of a poorly soluble drug.

Figure 6: Milling technique

Directly Compressible Co-Processed Excipients:

Ludiflash:

Ludiflash is a formulation for fast disintegrating dosage forms. It is designed to disintegrate readily within a few seconds in oral cavity with pleasant mouth feel. It is specially designed for direct compression on standard high speed tablet machine. It gives extremely fast release rate. It has neutral to mildly sweet, pleasant taste and sugar free composition¹⁴.

F-MELT:

F-MELT is designed not only for manufacturing ODTs, but also suitable for soft chewable tablets. It is suitable for direct compression manufacturing of ODTs by simple blending with active pharmaceutical ingredients (APIs) and lubricants. F-MELT exhibits excellent tabletting properties and it has advantages of disintegration time within 30 seconds. It is cost effective, less sticking or capping and has pleasant mouth feel¹³.

Pharmaburst:

Pharmaburst is a Quick Dissolving delivery system in which there is addition of active drug in a dry blend with Pharmaburst excipients and compress by tablet machine. Pharmaburst was found to be significantly more compactable, less friable, and more rapidly disintegrating. Pharmaburst is a coprocessed excipient system with specific excipients, which allows rapid disintegration and low adhesion to punches. Pharmaburst is smooth and creamy and helps to mask taste and grittiness of the actives. Main advantages Pharmaburst is highly compatible, rapid disintegration and cost effective¹⁵.

Modified Mannitol:

· Pearlitol 200 SD: It is white, odourless, slightly sweet tasting and crystalline powder. It has a unique blend of exceptional physical and chemical stability, with great organoleptic, sugar free properties. It can be used in different processes like dry granulation, direct compression, and compaction. Pearlitol SD dissolves very rapidly because of its porous crystalline particles⁹.

· Mannogem EZ: Mannogem EZ is spraying dried Mannitol, specially designed for direct compression tablet. It has advantages of highly compatible, non hygroscopic, chemically inert, narrow particle size distribution and mainly rapid disintegration property benefits quick dissolve application. It is highly stable and inert to many of the chemical reactions which are problematic with lactose, microcrystalline cellulose or starch¹⁰.

Modified Sugars^9-11

· Advantose 100: Advantose 100 is spray dried particles which are spherical in shape and is made up of fine and coarse particles of sugars which provide superior flow properties. The safety and mouth feel qualities of maltose are well known. By spray drying, the flow and tabletting properties are greatly improved.

· GalenIQ: It is a novel multifunctional sugar free excipient. GalenIQ is white, odourless, water soluble, crystalline substance derived from sucrose. It has very low hygroscopic nature, excellent chemical stability. The direct compressible grades of GalenIQ have high tableting properties due to their excellent compactability. The main properties of direct compressible GalenIQ in tableting are excellent flow; unique morphology of GalenIQ ensures homogeneity of the mixture and content uniformity.

· Glucidex IT: It is developed by Roquette. Glucidex IT is obtained by moderate hydrolysis of starch. It is micro granulated form enables almost instantaneous dispersal and dissolution in water. Different range of Glucidex IT products is available. It has properties like free flowing due to fewer fine particles and it mainly used as diluent for tablet, capsule.

Starch 1500:

It is a directly compressible, free flowing, USP grade of partially pregelatinized maize starch. It is prepared by subjecting corn starch to physical compression or shear stress in high moisture condition causing an increase in temperature and a partial gelatinization of some of the starch granules. Typically, pregelatinized starch contains 5% free amylase, 15% of free amylopectin, and 80% unmodified free starch. It provide fair to good binding properties but requires high pressures to produce hard compacts. Its dilution potential is minimal, and it is not generally used as the filler-binder in direct compression, but as a direct compression disintegrant. The major advantage of starch 1500 is that it retains the disintegrant properties of starch without increasing the fluidity and compressibility of the total formulation, which is not the case with plain starch. Starch 1500 has self-lubricating property. It has poor flowability compared to other directly compressible adjuvants³. However, lubricants markedly decrease its binding properties. It is also use as filler in capsule formulation.

MicroceLac®100:

MicroceLac®100, marketed by Meggle, is a spray-dried compound contanning 75% α-lactose monohydrate and 25% microcrystalline cellulose dry matter, unlike Cellectose ®80, which contains powdered cellulose. In MicroceLac®100 particles, the microcrystalline cellulose fibers are shorter and more entrapped, which promotes a more spherical form. MicroceLac®100 had superior flow and binding properties. Good adhesion of a low-drug showed that MicroceLac decreased segregation¹⁶.

Example of Directly Compressible Excipients Lactose:

· α-Lactose monohydrate: In direct compression, coarse sieved fraction of α-lactose monohydrate (100 mesh) is used due to its flowability, it contains one mole of water per mole of lactose (5% w/w). Compared to other filler-binders, α-lactose monohydrate exhibits relatively poor binding properties. It consolidates mainly by fragmentation. It has higher brittleness compared to spray-dried lactose and anhydrous β-lactose36. The strength of tablets compressed from α-lactose monohydrate increases with a decrease in particle size of the excipient. α-lactose monohydrate (100 mesh) is often combined with microcrystalline cellulose. This combination results in a stronger synergistic effect on disintegration time, whereas the crushing strength increases as the percentage of microcrystalline cellulose in the blend is increased.

· Anhydrous α-lactose: Binding capacity of α-lactose monohydrate increase dramatically by thermal or chemical dehydration38. During dehydration, α-lactose monohydrate changes from single crystals into aggregates of anhydrous α-lactose particles. The anhydrous crystals are softer, weaker and less elastics, undergoes brittle fracture much more readily and at lower stresses than the lactose monohydrate. The relative slow disintegration of tablets containing anhydrous lactose is the major disadvantage39. e.g. Pharmatose DCL 30 (DMV).

· Anhydrous β-lactose: The most common form of anhydrous β-lactose is produced by crystallization above 93ºC. This is carried out on stem-heated rollers; the resultant cake being dried, ground, and sieved to produce the desiredsize40. It is available in a white crystalline form that has good flow properties, excellent compaction properties and low lubricant sensitivity. Its compressibility profile is similar to that of Flast-Flo lactose. It has It exhibits less brittleness than the α-lactose monohydrate36. Due to low moisture content of anhydrous β-lactose than regular lactose, it is an ideal excipient for moisture sensitive drugs. Anhydrous β-lactose possesses excellent dissolution properties certainly as good as, if not better than, α-lactose monohydrate. e.g. Pharmatose DCL 21 (DMV).

· Spray-Dried lactose³: Spray-dried lactose was the first excipient to be used successfully as filler- binder in direct compression of tablets. This in spite of its hygroscopic behavior, which is caused by the presence of amorphous lactose. A better understanding of the relationship between particle structure, physical properties, and mechanisms of consolidation and compaction enabled the development of improved spray-dried lactose for direct compaction. A better understanding of the relationship between particle structure, physical properties, and mechanisms of consolidation and compaction enabled the development of improved spray-dried lactose for direct compaction. In the production of spray-dried lactose, lactose is first placed in an aqueous solution which is treated to remove impurities. Partial crystallization is then allowed to occur before spray-drying the slurry. The resulting product is composed of spherical particles, containing 80%–85% crystals of α-lactose monohydrate and 15%–20% amorphous lactose. It has excellent flow properties and binding properties. The compressibility is due to the nature of the aggregates and the percentage of amorphous material present and the resulting plastic deformation, which occurs under compaction pressure. Spray-dried lactose is an effective direct-compression filler when it makes up the major portion of the tablet (more than 80 %), but it is not effective n diluting high-dose drugs whose crystalline nature and poorly compressible.

Microcrystalline cellulose:

Microcrystalline cellulose (MCC) was introduced as a direct compressible agent in the early 1960s and stands today as the single most important tablet excipient developed in modern times. It is purified partially depolymerized cellulose. It is derived from a special grade of purified α-cellulose by severe acid hydrolysis to remove the amorphous cellulose portions, yielding particles consisting of bundles of needle like microcrystals. It is a white, crystalline powder composed of agglomerated porous microfibers. After purification by filtration and spray-drying dry, porous microcrystals are obtained. Microcrystalline Cellulose occurs as a white odorless, tasteless crystalline powder composed of porous particles of an agglomerated product. Microcrystalline cellulose performs many functions in direct compression: Strong, dry binder, high dilution potential due to low bulk density, high tablet hardness at low pressures, low tablet friability, excellent tablet disintegrant, flow-aid^16,19.

Sugars and oligosaccharides:

· Directly compressible sucrose: Sucrose has been extensively used in chewable tablets both as filler, usually in the form of confectioner sugar and in the form ofa solution (syrup) as a binder in wet granulation. Attempts to directly compress sucrose crystals have never been successful, but various modified sucrose have been introduced onto the direct-compression market place. Directly compressible sugar from SPI Polyols is a co-processed excipient consisting of 95% sucrose and 5% polyol, it is produced by a special crystallization process, and the combination of these two ingredients makes an extremely compressible sugar with a pleasant taste. Tablets made with this product disintegrate quickly and are non friable. The SEM photographs show an open crystalline matrix, which explains why this new product dissolves twice as fast in water as sucrose or dry blended sucrose/sorbitol. Tablets made with this new excipient were stronger and disintegrated faster than tablets made with some other commercially available compressible sugars¹⁷.

· Di-Pac: Di-Pac is a directly compressible, co-crystallized sugar consisting of 97%sucrose and 3% highly modified dextrin5. Each Di-Pac granule consists ofhundreds of small sucrose crystals “glued” together by the modified dextrin. Ithas good flow properties and needs a glidant only when atmospheric moisturelevels are high. At high moisture level, Di-Pac begins to cake and lose fluidity. Ithas excellent color stability on aging, probably the best of all the sugars. Tablets containing a high proportion of Di-Pac tend to harden after compression at higher relative humidity. Its sweet taste makes it suitable for most directly compressible chewable tablets. The dilution potential of Di-Pac and most other sucrose is average, ranging from 20 to 30% active ingredients³.

· NuTab: NuTab is a roller compacted granulated sucrose based product consist of processed sucrose, invert sugar (4%), corn starch (0.1-0.2%) and magnesium stearate as processing aids50. It has better fluidity due to relatively large particle size distribution which makes for good fluidity but could cause blending problems if co-fillers and drugs are not carefully controlled relative to particle size and amounts. In formulations NuTabhas poor color stability compared to other directly compressible sucrose and lactose. It’s mostly use in chewable tablets prepared by direct compression¹⁷.

· Emdex: Emdex is produced by hydrolysis of starch and consists of aggregates of 90 to 92% dextrose microcrystals, 3 to 5% maltose intermixed and cohered with a small quantity of higher glucose polysaccharides. It is available as both an anhydrous and a hydrous product. Emdex occurs as white free flowing, porous spheres which are water soluble and non-hygroscopic. Emdex generally is used in directly compressible chewable tablets because of its sweet taste and negative heat of solution. It has good binding properties and slight lubricant sensitivity. Itexhibits high moisture sensitivity, at room temperature and 50% RH, the crushing strength of tablets decreases dramatically, whereas during storing at 85% RH tablets liquefy.

· UNI-PURE® LD: UNI-PURE LD is a speciality corn starch that is co-processed with tapioca maltodextrin. It is marketed by National Starch and Chemical Company. The product has a remarkably low bulk density (about 0.15 gm/ml) and good plastic deformation properties52. It is primarily used to increase the hardness of tablets and to reduce capping. UNI-PURE LD powder consists of hollow spherical particles, which contribute to the very low density. Together with the small particle size, the low density results in poor flow properties. For this reason, it is commonly mixed in percentages between 2% and 10% with another filler binder such as microcrystalline cellulose or dicalcium phosphate dihydrate³. It has been shown that ascorbic acid tablets with 38% microcrystalline cellulose and 2% UNI-PURE LD had a higher crushing strength than did tablets prepared with 40%microcrystalline cellulose alone. Heckel plots indicate that an increase in UNIPURE LD content reduced the pressure required for plastic deformation (i.e., yield pressure) in blends with microcrystalline cellulose. In a blend with dicalcium phosphate dihydrate, the better compactibility was ascribed to the induction of plastic flow in the predominantly brittle system.

· Maltose: Maltose is a non-hygroscopic sugar that is widely used in food products.Crystalline maltose is available in both spray dried and crystalline forms. Spray dried crystalline maltose has recently been used as a directly compactible tablet excipient and marketed by SPI Polyols as Advantose®. As a result of the spray drying process, this crystalline maltose consists almost entirely of almost spherical particles with very good flow properties. The material is highly compactible and shows no capping when compacted at high forces. If blended with other filler-binders such as microcrystalline cellulose or granular mannitol, crystalline maltose improves compaction and flow properties and decreases capping tendencies when subjected to high loads. Another advantage of crystalline maltose is its low lubricant sensitivity. Spray-dried crystalline maltose can be used for both chewable and disintegrating tablets³.

· Inulin: Inulin is a frucan-type carbohydrate that consists of linear chains offructose units linked via a β-2–1-bond and with a glucose unit at the end. It is widely used as a diagnostic agent for renal function and is described in the USP and BP. Recently inulin has been evaluated as a filler-binder for tablets prepared by direct compaction55. Inulin, as such, has a high bonding capacity, which depends on the degree of crystallinity, percentage of included air, particle size and degree of polymerization. Amorphous inulin with a degree of polymerization (DP) of about 10, prepared by spray drying, has good binding properties, but its plastic deformation behavior leads to a rather high lubricant sensitivity. Using particles with entrapped air can decrease this lubricant sensitivity, since because of their high porosity, these particles fragment before plastic deformation commences. A lubricant film formed during the mixing process will thus be destroyed during particle fragmentation. Due to the low degree of polymerization, spray-dried amorphous inulin is soluble in water, and this promotes tablet disintegration. Crystalline inulin can only be prepared with a high DP, which makes it insoluble in water. Although crystalline inulin has good binding properties, tablet disintegration is slow.

Polyols:

Nowadays there is an increasing interest in sugar substitutes such as mono- and disaccharide alcohols, also called polyols, in pharmaceutical formulations. The reason for this interest is their sweetness, reduced calorie content, and noncariogenic characteristics. In addition, the majority of these polyols can be consumed by diabetics without any significant increase in body glucose, insulin, or lactic acid concentration unlike the conventional saccharides such as sucrose, glucose, and lactose. In addition to sorbitol and mannitol, several other polyols have been marketed as direct compaction filler-binders in recent years.

· Mannitol: In pharmaceutical preparations it is primarily used as a diluent (10-90% w/w) in tablet formulations, where it is of particular value since it is nothygroscopic and may thus be used with moisture-sensitive active ingredients. Mannitol is water soluble and most commonly used as an excipient in themanufacture of chewable tablet formulations because of its negative heat ofsolution, sweetness and ‘mouth feel’. It can be advantageously combinedwith other direct compression excipients¹³.

· Lactitol: Lactitol is produced by the catalytic hydrogenation of lactose. It isapproximately 0.4 times as sweet as sucrose and is widely used as a replacementfor sucrose in foodstuffs. Granulated lactitol is a form of lactitol designed for useas a direct compaction tablet diluent, and it is marketed as Finlac® DC by Xyrofin.Granulated lactitol is prepared by a water granulation process. The product iscomposed of microcrystalline agglomerates with a mean particle size of 160 μm.The flow properties, measured as tablet weight variation coefficient and Hausnerratio are good. Compression pressures up to 300 MPa resulted in tablets with atensile strength of approximately 3.4 MPa with no sign of lamination. Thismeans that the compressibility of granulated lactitol is higher than for manyother direct compression excipients of carbohydrate origin. Granulated lactitolneeds only a low concentration of lubricant (about 0.2%) and has a low lubricantsensitivity. The latter may be attributed to the granular structure of the product, since during compression, any lubricant film will be destroyed as a consequenceof particle fragmentation. Being freely soluble in water, tablets compressed fromgranulated lactitol erode from the outside rather than disintegrate. Both theaddition of a disintegrant and differences in concentration of magnesiumstearate had an insignificant effect on disintegration time. Reworking had littleeffect on tablet strength⁹.

· Xylitol: Because of the sweet taste—xylitol is the sweetest sugar alcohol—and itshigh negative heat of solution, xylitol is a good candidate as an excipient forchewable tablets. Agglomerated xylitol is available as Xylitab® (American XyrofinInc). Xylitab 100 is granulated with 3% polydextrose, Xylitab 200 is granulatedwith 1.5% sodium carboxymethylcellulose, and Xylitab 300 is granulated with axylitol solution and is intended for use in blends with other filler-binders. In aninvestigation of Xylitab 100 and Xylitab 200, it was shown that the flowproperties, measured as tablet weight uniformity, were excellent. In order toprevent die wall and punch sticking, a combination of 0.5% magnesium stearateand 0.5% stearic acid gave the best performance. Using this combination of lubricants, reasonable tablet hardness could be obtained and no cappingtendencies were detected. Heckel analysis showed that both products exhibitedbrittle and viscoelastic densification behavior and underwent elastic recoveryprimarily in the die^3,9,11.

· Isomalt: Isomalt is a mixture of hydrogenated mono- and disaccharides whose principal components are the disaccharide alcohols 1-O-α-D-glucopyranosyl-D mannitol dehydrate and 6-O-α-D-glucopyranosyl-D-sorbitol. Isomalt has a sugar like taste with about half the sweetening power of sucrose and a low negative heat of solution. It has several advantages over other sugars: it is noncariogenic and has a low energetic value, because it is not absorbed in the small intestine but mainly fermentated by bacteria in the large intestine. Due to its stable glycosidic bond, isomalt is resistant to chemical degradation. Isomalt is the only polyol produced from sucrose and is marketed by Palatinit GmbH. It meets the specification of Isomalt Ph.Eur., and will have soon a monograph in the USP/NF. Isomalt is available in different particle size fractions and with two different solubilities (25 g and 42 g/100 g solution, respectively). The difference insolubility is a result of the change in molecule ratio to a higher 6-O-α-Dglucopyranosyl-D-sorbitol content. The compaction properties of the different ypes of isomalt were studied by Ndindayino et al. Evaluation by Heckel plot analysis showed that isomalt exhibits plastic behavior and undergoes elastic recovery primarily in the die. This means that the deformation behavior is similar to sorbitol and mannitol, but differs from the deformation behavior of otherpolyols such as xylitol and lactitol, which are mainly brittle materials. As an effectof the low hygroscopicity, tablets produced with isomalt are more stable thantablets containing saccharose or sorbitol. Recently an isomalt variant especiallydesigned as a filler-binder for direct compaction has been developed. It is anagglomerated product consisting of small primary particles. It has an excellentflowability, does not stick to tableting tools and offers a very good compactibility^3,12. Due to its favorable organoleptic properties it is particularly suitable forapplications in chewable tablets and lozenges.

· Sorbitol: Sorbitol is a D-glucitol. It is a hexahydric alcohol related to mannose and is isomeric with mannitol. It is act as a Humectant; plasticizer; sweetening agent; tablet and capsule diluent. Sorbitol occurs as and odourless, white or almost colorless, crystalline, hygroscopic powder. Sorbitol is available in a wide range of grades and polymorphic forms such as granules, flakes, or pellets which tend to cake less than the powdered form and have more desirable compression characteristics. Sorbitol has a pleasant, cooling, sweet taste and has approximately 50-60% the sweetness of sucrose. Sorbitol is widely used as an excipient in pharmaceutical formulations. It is also used extensively in cosmetics and food products. Sorbitol is used as diluent in tablet formulations prepared by eighter wet granulation or direct compression. It is particularly useful in chewable tablets due to its pleasant, sweet taste and cooling sensation. In capsule formulations it is used as a plasticizer for gelatin. Sorbitol is relatively chemically inert and compatible with most excipients. It is stable in air in the absence of catalysts and in cold, dilute acids and alkalis. It is nonflammable, noncorrosive and nonvolatile^5,9.

· Maltitol: Coating agent; diluent; granulating agent; sweetening agent.Maltitol occurs as a white, odorless, sweet, crystalline powder. It is a disaccharide consisting of one glucose unit linked with one sorbitol unit via an α-(1→4) bond. Maltitol is widely used in the pharmaceutical industry in the formulation of oral dosage forms. It is a noncariogenic bulk sweetener, approximately as sweet as sucrose, well adapted as a diluent for different oral dosage forms, wet granulation, and hard coating. Maltitol has good thermal and chemical stability. When it is heated at temperatures above 200°C, decomposition begins (depending on time, temperature, and other prevailing conditions). Maltitol does not undergo browning reactions with amino acids, and absorbs atmospheric moisture only at relative humidity of 89% and above, at 20°C. Maltitol is used in oral pharmaceutical formulations, confectionery, and food products and is considered to be noncariogenic. It is generally regarded as a nontoxic, nonallergenic, and nonirritant material^3,9. Accepted for use as a food additive in Europe. Included in oral pharmaceutical formulations included in oral pharmaceutical formulations.

· Erythritol: it is a sugar alcohol (or polyol) that has been approved for use as a food additive in the United States and throughout much of the world. It was discovered in 1848 by British chemist John Stenhouse. It occurs naturally in some fruits and fermented foods.At the industrial level, it is produced from glucose by fermentation with a yeast, Moniliellapollinis. It is 60–70% as sweet as table sugar yet it is almost noncaloric, does not affect blood sugar, does not cause tooth decay, and is partially absorbed by the body, excreted in urine and feces. It is less likely to cause gastric side effects than other sugar alcohols because of its unique digestion pathway. Because 90% of erythritol is absorbed before it enters the large intestine, it does not normally cause laxative effects, as are often experienced after consumption of other sugar alcohols (such as xylitol and maltitol), although extremely large doses can cause nausea and borborygmi (stomach rumbling). Erythritol has a strong cooling effect (endothermic, or positive heat of solution) when it dissolves in water, which is often combined with the cooling effect of mint flavors. The cooling effect is present only when erythritol is not already dissolved in water, a situation that might be experienced in an erythritol-sweetened frosting, chocolate bar, chewing gum, or hard candy. The cooling effect of erythritol is very similar to that of xylitol and among the strongest cooling effects of all sugar alcohols. Erythritol is commonly used as a medium in which to deliver high-intensity sweeteners, especially stevia derivatives, serving the dual function of providing both bulk and a flavor similar to that of table sugar. Diet beverages made with this blend, thus, contain erythritol in addition to the main sweetener. Beyond high-intensity sweeteners, erythritol is often paired with other bulky ingredients that exhibit sugar-like characteristics to better mimic the texture and mouth feel of sucrose. The cooling effect of erythritol is rarely desired, hence other ingredients are chosen to dilute or negate that effect. Erythritol also has a propensity to crystallize and is not as soluble as sucrose, so ingredients may also be chosen to help negate this disadvantage. Furthermore, erythritol is not hygroscopic, meaning it does not attract moisture, which can lead to the drying out of products, in particular baked goods, if another hygroscopic ingredient is not used in the formulation.

· Pearlitol: ROQUETTE has played a role in this evolution by developing a new generation of co-processed mannitol-based excipients for formulation: PEARLITOL®Flash is a compound of mannitol and starch, specially designed to disintegrate rapidly, providing a smooth texture without the addition of a superdisintegrant. It have aExcellent compactibility, High dilution potential,Simplified formulation,Low lubricant level required, No superdisintegrant needed,Traditional blister packaging, Robust tablets^11,12.

Maltodextrins:

Maltodextrins are composed of water-soluble glucose polymers obtained by partial hydrolysis of starch with acid and/or enzymes, whereby the basic polymeric structure is retained. Just as all starch derivatives, maltodextrin has a high lubricant sensitivity. Another objective is the retardant effect of hydrophobic lubricants on drug release of tablets containing water-insolubleactive ingredients63. The retardant effect was not exhibited with mixtures containing a water soluble drug substance. Mollanet. al. compared a spraydried maltodextrin (Maltrin® M510), three fluidized-bed agglomeratedmaltodextrins (Maltrin M500, Malta*Gran® TG, and Malta*Gran 10), and anexperimental roller-compacted maltodextrin. Maltrin and Malta*Gran are brandnames for maltodextrins from Grain Processing Corp and Zumbro IFP, respectively. The commercially available maltodextrins underwent plasticdeformation and formed strong tablets, but showed high lubricant sensitivity. Tablets compressed from the experimental roller-dried maltodextrin were stronger and less sensitive to lubrication than those of the other maltodextrins.This effect was attributed to the larger surface area, the higher bulk density, and more fragmentary failure of the roller-compacted product.It has been shown that maltodextrins easily sorb and desorb moisture from theatmosphere and that the moisture content of the maltodextrin strongly influences both compaction and post compaction behavior. Compaction behavior of the maltodextrins was more fragmentary under conditions of low humidity and became more plastically deforming as the moisture content increased. The disintegration time of tablets containing maltodextrins were found in general to be prolonged, an effect which was attributed to the formation of a rate limiting gel layer around the tablets.

Polacrilin Potassium:

It is a Tablet and capsule disintegrant. Polacrilin potassium occurs as a cream-colored, odorless and tasteless, free-flowing powder. Aqueous dispersions have a bitter taste. Polacrilin potassium is a cation-exchange resin used in oral pharmaceutical formulations as a tablet disintegrant. Concentrations of 2–10% w/w have been used for this purpose although 2% w/w of polacrilin potassium is usually sufficient. Other polacrilin ion-exchange resins have been used as excipients to stabilize drugs, to mask or modify the taste of drugs, and in the preparation of sustained-release dosage forms and drug carriers. Polacrilin potassium and other polacrilin resins are stable to light, air, and heat up to their maximum operation temperature; Excessive heating can cause thermal decomposition of the resins and may yield one or more oxides of carbon, nitrogen, sulfur, and/or amines. Polacrilin resins should be stored in well-closed containers in a cool, dry place. Incompatible with strong oxidizing agents amines, particularly tertiary amines, and some other substances that interact with polacrilin resins. Polacrilin potassium and other polacrilin resins are used in oral pharmaceutical formulations and are generally regarded as nontoxic and nonirritant materials. However, excessive ingestion of polacrilin resins may disturb the electrolyte balance of the body.

Trade Name	Composition	Manufacturer	Country
Pearlitol 200 SD	Mannitol (80%) & Starch (20%)	Roquette	China
F-Melt Type C^a	Carbohydrates, disintegrants and inorganics	Fuji Chemicals	Japan
Ludiflash	Mannitol, Kollidon CLSF, Kollicoat SR 30D	BASF	Germany
Ludipress	Lactose, Kollidon 30, Kollidon CL	BASF	Germany
MicroceLac	MCC, Lactose	Meggle	Germany
PharmatoseDCL 40	Beta-Lactose, Lactitol	DMV Veghel	Netherland
Starcap 1500	Corn starch, Pregelatinized Starch	Colorcon	Goa
Star Lac	Lactose, Maize starch	Roquette	China
Pearlitol Flash	Mannitol (80%) & starch (20%)	Roquette	China
Glucidex IT	Maltodextrin & dried glucose syrup	Roquette	China
Pharmaburst XP-500	Polyol and disintegrant	SPI Pharma	USA
Mannogem EZ	Spray dried Mannitol	SPI Pharma	USA
Advantose^TM 100	Spray dried carbohydrate	SPI Pharma	USA
Parteck ODT	D-mannitol and croscarmellose sodium	Merck	USA
Trehalose P, Trehalose G	Trehalose powder or granules	Asahi-Kasei	Japan
GalenIQ^TM720 & 721^a	Isomalt	BANEO-Palatinit	Germany
Avicel HFE 102	MCC, Mannitol	FMC Biopolymer	USA
Barcroft CS 90	Calcium Carbonate, starch	SPI Polyols	France
Barcroft Premix St	Al2(OH)3,Mg2(OH)3 and Sorbitol	SPI Polyols	France
Carbofarma GM11	Calcium Carbonate, Maltodextrin	Resinas Industriales	Argentina
Destab 90	Calcium Sulphate, Starch	Desmo Chemical Co.	USA