Senin, 24 Mei 2010

Tablet Manufacturing Process


Over the past hundred years tablet manufacturers have developed materials and processes that can producecompressed tablets containing a precise amount of an active pharmaceutical ingredient (API) at high speed and at relatively low cost. The development in the field of APIs, excipients and tableting machines during the past decades has made tablet manufacturing a science and the tablets the most commonly used dosage form1,2. The ease of manufacturing, convenience in administration, accurate dosing, and stability compared to oral liquids, tamper-proofness compared to capsules, safe compared to parental dosage forms makes it a popular and versatile dosage form. Experts in the art of tableting are aware with the basic art of tableting by the three well-known methods, i.e. wet granulation, roller compaction and direct compression. The pros and cons of wet granulation and roller compaction are well documented in the literature 3, 4, 5. Prior to the late 1950s, the literature contained few references on the direct compression of pharmaceuticals. A great deal of attention has been given to both product and process development in the recent years. The availability of new materials, new forms of old materials and the invention of new machinery has allowed the production of tablets by simplified and reliable methods 1. In early 1960’s, the introduction of spray dried lactose (1960) and Avicel (1964) had changed the tablet manufacturing process and opened avenues of direct compression tableting. Shangraw6 conducted a survey of 58 products in United States of America for the preference for the granulation process. The results were in favour of direct compression. Of the five processes listed in the survey, the average score(1.0 being the perfect score) for direct compression was 1.5 compared to wet massing and fluid bed drying (2.0), wet massing and tray drying (2.5), all-in-one (3.3) and roller compaction (3.6). About 41% of the companies indicated that direct compression was the method of choice, and 41.1% indicated that they used both direct compression and wet granulation. Only 1.7% of the respondents indicated that they never used direct compression and 15.5% indicated that the process was not recommended. 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 compresseddirectly from the powder blends of active ingredients and suitable excipients. No pre-treatment of the powder blends by wet or dry granulation is involved 5. 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 techniques 4 (See Table 1). It has been estimated that less than 20 percent of pharmaceutical materials can be compressed directly into tablets 4. 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 adjuvant may yield satisfactory tablets for such materials.

Table 1 Comparison of Major Steps Involved In The Granulation Method
Step Direct Compression Dry Granulation Wet Granulation
1 Mixing/blending of API & Adjuvant 
Mixing/blending of API & Adjuvant
Mixing/blending of API & Adjuvant

2 Compression Compression in to slug
↓ Preparation of binder solution

3 Size reduction of slug & sieving
↓ Massing of binder solution of step 2 with powder mixture of step 1

4 Mixing of granules with pharmaceutical aid/s
Wet screening of step 1

5 Compression Drying of wet granulation

6 Resifting of dry granules & blending with the pharmaceutical aid/s

7Compression

2. TABLET MANUFACTURING PROCESS
[A] Wet granulation
Introduction
The most widely used process of agglomeration in pharmaceutical industry is wet granulation. Wet granulation process simply involves wet massing of the powder blend with a granulating liquid, wet sizing and drying.
Important steps involved in the wet granulation
i) Mixing of the drug(s) and excipients
ii) Preparation of binder solution
iii) Mixing of binder solution with powder mixture to form wet mass. 
iv) Drying of moist granules
v) Mixing of screened granules with disintegrant, glidant, and lubricant.

Advantages
(a) permits mechanical handling of powders without loss of mix quality:
(b) improves the flow of powders by increasing particle size and sphericity:
(c) increases and improves the uniformity of powder density:
(d) improves cohesion during and after compaction:
(e) reduces air entrapment:
(f) reduces the level of dust and cross-contamination:
(g) allows for the addition of a liquid phase to powders (wet process only): and
(h) Makes hydrophobic surfaces hydrophilic.
Limitation of wet granulation
i) The greatest disadvantage of wet granulation is its cost. It is an expensive process because of labor, time, equipment, energy and space requirements.
ii) Loss of material during various stages of processing
iii) Stability may be major concern for moisture sensitive or thermo labile drugs
iv) Multiple processing steps add complexity and make validation and control difficult
v) An inherent limitation of wet granulation is that any incompatibility between formulation components is aggravated.
[B] Dry granulation
Introduction
In dry granulation process the powder mixture is compressed without the use of heat and solvent. It is the least desirable of all methods of granulation. The two basic procedures are to form a compact of material by compression and then to mill the compact to obtain a granules. Two methods are used for dry granulation. The more widely used method is slugging, where the powder is recompressed and the resulting tablet or slug are milled to yield the granules. The other method is to precompress the powder with pressure rolls using a machine such as Chilosonator.
Roller compaction
The compaction of powder by means of pressure roll can also be accomplished by a machine called chilsonator. Unlike tablet machine, the chilsonator turns out a compacted mass in a steady continuous flow. The powder is fed down between the rollers from the hopper which contains a spiral auger to feed the powder into the compaction zone. Like slugs, the aggregates are screened or milled for production into granules.
Use: Use in the production of directly compressible excipients, the compaction of drugs and drug formulations, the granulation of inorganic materials, the granulation of dry herbal material and the production of immediate/sustained release formulations.

Processing steps:
Weighing of raw material-screening-mixing-compression to slugs-milling-mixing-compression to finished tablets
Advantages:
The main advantages of dry granulation or slugging are that it uses less equipments and space. It eliminates the need for binder solution, heavy mixing equipment and the costly and time consuming drying step required for wet granulation. Slugging can be used for advantages in the following situations:
i)  For moisture sensitive material
ii)  For heat sensitive material
iii) For improved disintegration since powder particles are not bonded together by a       binder
Disadvantages:
i)  It requires a specialized heavy duty tablet press to form slug
ii)  It does not permit uniform colour distribution as can be
iii) Achieved with wet granulation where the dye can be incorporated into binder liquid.
iv) The process tends to create more dust than wet granulation, increasing the potential contamination.

[D] The direct compression process
This method is used when a group of ingredients can be blended and placed in a tablet press to make a tablet without any of the ingredients having to be changed. This is not very common because many tablets have active pharmaceutical ingredients which will not allow for direct compression due to their concentration or the excipients used in formulation are not conducive to direct compression. Granulation is the process of collecting particles together by creating bonds between them. There are several different methods of granulation. The most popular, which is used by over 70% of formulation in tablet manufacture is wet granulation. Dry granulation is another method used to form granules.

Advantages of Direct Compression
1. Cost Effectiveness
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 labor leading to reduced production cost of tablets. 
2. Stability
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 granulations5. This is extremely important because the official compendium now requires dissolution specifications in most solid dosage forms10. 
3. Faster Dissolution
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. 
4. Less wears & tears of punches
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. 
5. Simplified Validation
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 direct compression.

Limitations of direct compression
1. Segregation
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. 
2. Cost
Directly compressible excipients are the speciality 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. 
3. Low dilution potential
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. 
4. Re-workability
All the spray-dried directly compressible adjutants 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. 
5. Lubricant sensitivity
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.
6. Variation in functionality
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.

3. DIRECTLY COMPRESSIBLE EXCIPIENTS
3.1 Introduction
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” 7. 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 justified7. 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 7. The inherent property of an excipient is its functionality in the dosage form. Determination of an 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 process 8. 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 final performance or determine such characteristics before use. Such tests are thus related to the functionality, that the excipient impart to a specific formulation 9. 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 criteria10. Pharmacopoeial standards do not take into account particle characteristics or powder properties, which determine functionality of excipients 11. Control of functionality is important as a control of identity and purity. The following reasons can be cited 10:
1. Many excipients have multiple functions (e.g. microcrystalline cellulose, starch).
2. 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 11. The introduction of special force feeder to improve flow of granules from hopper marked a significant advancement in direct compression technology 4.

3.2 Ideal requirements of directly compressible adjuvant
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 filling 14. Compressibility is required for satisfactory tableting, 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 3, 4. 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 tableting 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 12. 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 avoid segregation. Filler-binders should not accelerate the chemical and/or physical degradation of the API(s) or excipients 12. It should not interfere with the biological availability of active ingredient/s 13. It should be compatible with all the adjutants present in the formulation. It should be physiologically inert 5. 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 13.

Table 2.  Ideal requirements, advantages and limitations of direct compression
IDEAL REQUIREMENTS ADVANTAGE LIMITATION
Flowability Cost effective production Segregation
Compressibility Better solubility of API Variation on functionality
Dilution potential Faster dissolution Low dissolution potential
Re workability Less wear & tear punches Re workability
Stability Simplified validation Poor compressibility of API
Controlled particle size Lower microbial contamination Lubrication sensitivity

3.3 Methods of preparing directly compressible excipients
Directly compressible adjuvant can be prepared by various methods, the outline and main features of the methods are depicted in Table11, 17, 18. Co-processing is the one of the most widely explored and commercially utilized method for the preparation of directly compressible adjutants. Hence, co-processing is discussed in more depth in the present review.
Methods used for development of co-processed Excipients 
Following are the methods that can be used for manufacturing co-processed excipients. The most important features of various methods are depicted in Table 1.

Chemical Modification
Chemical modification is not preferred to a greater extent as it results in the formation of an altogether new chemical entity. One has to submit toxicological data for the new compound, which is quite cumbersome, time consuming, and relatively expensive e.g., ethyl cellulose, sodium carboxymethyl cellulose, methylcellulose, Hydroxypropyl methylcellulose from cellulose, and cyclodextrin from starch.'

Physical Modification
Physical modification is relatively simple and economical. The addition of impurities of similar structure to alter the crystal structure i.e. Dextrates or compressible sugar, i.e., Dicalcium phosphate, sorbitol.19 Researchers have also tried the simultaneous modification of both physical and chemical forms, e.g., pregelatinized starch or microcrystalline cellulose.'

Grinding and/or Sieving
The purpose of sieving or grinding materials for direct compression is primarily to control flow properties. The compressibility may also get altered because of changes in particle properties such as surface area and surface activation. Crystallized lactose monohydrate is either sieved or first ground and then sieved in order to make different sieve fractions available to the customers. Dicalcium phosphate dehydrate is commonly milled after crystallization for use in the wet granulation process. For direct compression, only the unmilled larger particles can be used, because they exhibit better flow and compaction properties.

Crystallization
Controlled crystallization would impart flowability to an excipient but not necessarily self-binding properties. The conditions of crystallization determine to a large extent the solid-state properties of directly compressible excipients. If polymorphism exists, the compactibility of the polymorphic forms may be quite different because of the internal arrangement of the molecules within the unit cells of crystals. 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 a greater degree of symmetry will be more prone to deformation on compression and compaction. (β-lactose monohydrate is obtained by crystallization at a temperature below 930 C while β-lactose is obtained by crystallization from a supersaturated solution at a temperature exceeding 93°C.

Spray Drying
Spray drying involves atomization of the aqueous solution or suspension into a spray. Contact between the spray and hot air in a drying chamber results in moisture evaporation and recovery of the dried product from the air. Because of the spherical nature of liquid particles after evaporation of water, the resulting spray dried material consist of porous spherical agglomerates of solid  particles that are fairly uniform size in the amorphous component generated by rapid cooling and crystallization act as a binder the atomization process drying chamber cooling rate of the solution, and rate of crystallization are the major factor that govern the shape and size of the spray- pharmaceutical excipient to successfully exemplify the spray drying technology. The other examples are depicted in Table 1.

Granulation /Aggiomeration
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 strength. Agglomeration on the other hand, leads to irregularly shaped porous particles with relatively low bulk density and strength. When the primary panicles have binding properties of their own, the addition of binder is not necessary.  

Limitation of co-proceeded excipients
A co-proceeded adjuvant lacks official acceptance in the pharmacopeia. For this reason, a combination filler binder will not be accepted by the pharmaceutical industry until it exhibits significant advantages in tablet compaction when compaired to the physical mixture of the Excipients. Exceptions are spread dried dextrose maltose and compressible sugar that although being co-processed product are official in USP/NF. The ratio of the excipients in a mixture is fixed and in developing a new formation. A fixed ratio of the excipient may not be an optimum choice for the API and the dose per tablet under development.

Table 3. Methods used for manufacturing of directly compressible excipients.
METOD ADVATAGES & LIMITATIONS EXAMPLE
Chemical modification Relative expensive,
Time consuming,
Require toxicological data Ethyl cellulose, Methyl cellulose,
Hydroxyl propyl methyl cellulose,
Na-CMC, Cyclodextrin.
Physical modification Relatively simple & economical Dextrates or compressible sugars, sorbitol.
Grinding &/or Sieving Compressibility may alter because of Change in partical properties such as Surface area. α-lactose monohydrate(100#), Dibasiccalciumphosphate.

Crystallization Impart flowability to excipients but not necessarily self-binding properties.  Β-lactose, Dipac.
Spray Drying Spherical shape & uniform size gives spray dried materials, good flowability & poor workability. Spray dried lactose, Emdex, fast flow lactose, Avicle PH, Karion instant, TRI-CAFOS S, Advantose 100. 
Granulation Transformation of small, cohesive & poorly flowable powders.  Granulated lacitol Tabletose.
Dehydration Increased binding properties by thermal & chemical dehydration. Anhydrous α-lactose

3.4 Example of directly compressible excipients
Lactose
It is one of the main constituents of human and mammalian milk. Lactose is produced from whey, as a byproduct of cheese and casein production. Lactose may appear in different polymorphs depending on the crystallization conditions. Each polymorph has its specific properties. α-lactose monohydrate has very hard crystals and is non-hygroscopic. Lactose is the most widely used filler-diluents in tablets. The general properties of lactose that contribute to its popularity as an excipient are cost effectiveness, easy in the availability, bland taste, low hygroscopicity, excellent physical and chemical stability and water solubility 26. Lactose from different suppliers exhibits different properties and therefore could not be treated as interchangeable in direct compression formulations. The compaction profile of the lactose samples depends on the machine speed 27. Crystalline lactose mainly consolidates by fragmentation and amorphous lactose by plastic deformation. Tablets containing amorphous lactose show high crushing strength with increasing water content 28. Lactose based tablets exhibit better stability than mannitol and cellulose containing tablets at 40° C and 90% RH over a 10 week period 29. The amorphous lactose yields tablets of higher tensile strength than crystalline lactose. Tensile strength increases with reduced particle size 30.
α- Lactose Monohydrate
 Coarse sieved fraction of α-lactose monohydrate (100mesh) is used in direct compression due to its flowability. It contains about 5% w/w water. 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 α-lactose 31. 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. The strength of tablets compressed from α-lactose monohydrate increases with a decrease in particle size of the excipient 32. Gohel et al. prepared and evaluated lactose based directly compressible diluents. The preparation method consisted of controlled freezing and thawing of lactose solution. They concluded that the concentration of lactose and controlled nucleation are the most important parameters. In another method, the saturated solution of lactose was used for preparation of free-flowing agglomerates of lactose, where the volume of saturated lactose solution was found to be the most significant processing parameter. The developed products exhibited satisfactory flowability and compressibility essential for directly compressible diluent33. Gohel et al. attempted to improve the flow and compressibility of lactose using a freeze-thaw method. They tried three binders like polyethylene glycol 6000, polyvinyl pyrrolidone and gelatin at 0.5, 1, 1.5, or 2% concentration. The agglomerates containing 1% PEG 6000 exhibited good direct compression characteristics. They compared its tableting performance with Microcelac using diclofenac sodium as a model drug candidate. The developed adjuvant exhibited satisfactory flowability, compressibility, granular friability and crushing strength of the tablets34. Michoel reported that the MicroceLac 100 has superior flow and binding properties compared to three different lactose mixed with microcrystalline cellulose. It also showed good adhesion of folic acid particles, which could decrease demixing and segregation. The improved characteristics of co-processed material are attributed to spray drying35. Gohel and Jogani developed and evaluated multifunctional co-processed directly compressible adjuvant containing lactose, polyvinylpyrrolidone, and croscarmellose sodium. This product has comparatively better flowability, compressibility and disintegration of the tablets than lactose monohydrate 36.
Anhydrous α-Lactose
Binding capacity of α-lactose monohydrate increases dramatically by thermal or chemical dehydration. During dehydration, α-lactose monohydrate changes from single crystals into aggregates of anhydrous α-lactose particles. The anhydrous crystals are softer, weaker and less elastic. It undergoes brittle fracture much more readily and at lower stresses than the lactose monohydrate 37. The relative slow disintegration of tablets αcontaining anhydrous lactose is the major disadvantage 38. The anhydrous lactose exhibits lesser tendency for maillard reaction and better reworkability without loss of compressibility than the spray-dried lactose 39.

Anhydrous β-Lactose
The commercial product consists of agglomerates of extremely fine crystals. It is produced by roller drying of solution of β-lactose monohydrate followed by subsequent comminution and sieving 40. It has excellent compaction properties and low lubricant sensitivity. It exhibits less brittleness than the β-lactose monohydrate 31. Due to low moisture content, anhydrous β- lactose is an ideal excipient for moisture sensitive APIs. The anhydrous β-lactose is produced by crystallization of lactose above 93°C by roller drying 41. It has relatively better rework ability than other forms of lactose. It has higher dissolution rate than a-lactose monohydrate. It has solubility up to 10 times higher than the β-lactose monohydrate. Below 55% RH, anhydrous lactose with high b-content absorbs very small amount of water and its compression properties were insignificantly
affected 42.

Spray-dried lactose
Spray-dried lactose is produced by spray drying the slurry containing lactose crystals. The final product contains mixture of crystals of lactose monohydrate and spherical agglomerates of small crystals held together by glass or amorphous material. The former contributes fluidity and the latter gives the compressibility to the product. It has excellent flow properties and binding properties. It deforms plastically compared to the same sized α-lactose monohydrate particles 32. Amorphous portion of the spray-dried lactose is responsible for the better binding and plastic deformation. Compressibility is affected if it is allowed to dry below a level of 3% w/w moisture. Disintegrant is required in the formulations containing spray-dried lactose. The tablets require a lubricant, but the lubricant does not affect binding. It has poor reworkability. Spray-dried lactose discolours with certain API containing an amine group. Guncel and Lachman were the first to describe the spray-dried lactose. They reported that the spray-dried lactose produces harder, less friable tablets, which were more susceptible to colour development following storage at elevated temperature than the tablet containing conventional lactose 43. Tablets containing spray dried lactose exhibited increase in crushing strength with decrease in the particle size. The spherical shaped spray-dried lactose particles resulted in the strongest tablets than the angular particles 44. The disintegration time of spray-dried lactose tablets was essentially independent of compaction force 45. The spray-dried lactose undergoes fragmentation 46. At low compaction pressure, tablets containing amorphous lactose disintegrated before gel or precipitate could block the pores. At higher compaction pressure, gelling and precipitation dominated the disintegration time. The lubricant present on the granules also influenced the disintegration time 47. Spray-dried lactose exhibited strong increase in disintegration time with increase in compression force 48.

Agglomerated Lactose
It is a granulated form of α-lactose monohydrate with improved binding properties. Tablettose is an example of agglomerated α-lactose demonstrates good flowability. It has binding property better than the α-lactose monohydrate but not as good as spray-dried lactose. Bolhuis concluded that excellent compactibility ofPharmatose DCL 15 (agglomerated lactose) was due to the presence of more α-lactose, providing strong intergranular cohesion 49.

Cellulose Derivatives
Microcrystalline Cellulose
Microcrystalline cellulose (MCC) is purified partially depolymerized cellulose, prepared by treating α-cellulose with mineral acids. It is a white, crystalline powder composed of agglomerated porous microfibers 17. After purification by filtration and spray-drying, porous microcrystal are obtained, microcrystalline cellulose occurs as a white odourless, tasteless crystalline powder composed of porous particles of an agglomerated product. Apart from its use in direct compression, microcrystalline cellulose is used as a diluent in tablets prepared by wet granulation, as filler in capsules and for the production of spheres. In the pharmaceutical market, microcrystalline cellulose is available under the brand names Avicel, Emcocel, Vivacel etc. Reier et al. reported that MCC tablets when exposed to increased humidity (75 %, 1 week) resulted in a softening and swelling of plain microcrystalline cellulose tablets. This change disappeared on removal of humid condition50. Microcrystalline cellulose products exhibit capping tendencies at high compression speeds, while dicalcium phosphate was highly resistant to capping. Dittgen reported no correlation between the crystallinity and tableting properties of MCC obtained from various suppliers (Hewenten 40 & 12, Vivacel 101 &102, Avicel PH 101 & 200 and Sanaq PH 101L & 102L). Authors also reported difficulty in obtaining satisfactory tablets by direct compression using Sanaq PH 101L & 102L and attributed this behavior to higher bulk volume and poor compressibility 51. Lahdenpaa et al. demonstrated that the tablets containing higher percentage of Avicel PH101 exhibited higher crushing strength and lower disintegration time, while the tablets containing Avicel PH102 and PH 200 showed lower crushing strength, shorter disintegration time and small weight variation 52. Avicel PH 102 exhibited a much better fluidity because of its more granular form 48. Larger particles of microcrystalline cellulose (PH 102, PH 302 and SMCC 90) had better flowability and lubricity but lower compressibility. Denser particles of microcrystalline cellulose (PH 301 and PH 302) showed improved flowability, reduced lubricity and reduced compressibility 53. Obae et al. reported increase in the tensile strength of the tablets with increase in the ratio of length to diameter of particles. Celous KR 801 with more number of rod shaped particles than Avicel PH 101 yielded tablets with gave significantly higher tensile strength 54. Hardness of MCC tablets was decreased with an increase in the % of magnesium stearate while the disintegration time was unaffected by addition of lubricant 55. The physical and tableting properties of Emcocel are similar to those of Avicel 56. Paronen reported that Avicel PH-101 undergoes plastic deformation 46. Tsai and coworkers have prepared codried mixture of MCC and α-cyclodextrin. Authors demonstrated that the co-processed material exhibited significant improvement in flowability and compressibility than the physical blend of MCC and α-cyclodextrin 57. Garr demonstrated that incorporating up to 1% polyethylene to a mixture of 25% DCP and 75% MCC gave the intact compacts at the relatively low compaction force 58. Rues-Medina et al. reported that the UicelR 102 is more elastic than Avicel PH102 due to difference in the polymorphic form of microcrystalline cellulose present. The Uicel 102 is consists of cellulose II lattice, while Avicel PH 102 contains cellulose I polymorph 59. Levis evaluated co-processed microcrystalline cellulose - sodium lauryl sulphate prepared by an ultrasonic homogenization process followed by spray drying. The author concluded that the co-processed excipients were inferior compared with microcrystalline cellulose in a tableting for paracetamol, resulting largely from poor flow 60. Comparative properties of various grades of Avicel are depicted in Table 5. Ishikawa et al. reported novel microcrystalline cellulose (PH-M Series) for preparation of rapidly disintegrating tablet using by direct compression. Study demonstrated that the acetaminophen or ascorbic acid tablets containing novel microcrystalline cellulose (PH-M Series; particle size, 7 - 32 micron) has decreased sensation of roughness and rapidly disintegrated by saliva when taken orally compared to conventional Avicel PH-102 61. Garzo´n reported that the co processed mixture of microcrystalline cellulose and calcium carbonate has compatibility equal or better than pure microcrystalline cellulose and tensile strength of the tablet decreased as the calcium carbonate increased 62. Kothari et al., compared the powder and mechanical properties of different batches of low crystallinity powdered cellulose (LCPC) with those of different grades of Avicel, Emcocel, Solka Floc BW-40 and Solka Floc BW-100 and concluded that the LCPC materials reported by them have powder properties that are quite different from the microcrystalline cellulose and powdered cellulose and can be recommended as a potential direct compression excipients 63. Hasegawa reported that the coarse grade microcrystalline cellulose 12 gives better results in terms if weight variation and content uniformity than the classic grade 102 64.

Silicified Microcrystalline Cellulose
A major development has been the introduction of silicified microcrystalline cellulose (SMCC). Although it is a coprocessed filler-binder, this product is discussed in this section because there are major differences between SMCC and other coprocessed excipients. The latter usu¬ally contain two components, both of which are fillers or filler-binders, whereas SMCC is a combination of a filler-binder and a glidant. It is marketed by Penwest Pharma¬ceuticals Co. (now Rettenmaier) as Prosolv SMCC®.[17] It is produced by coprocessing 98% microcrystalline cellu¬lose with 2% colloidal silicon dioxide. The excipient is available in two particle size grades, SMCC 50 and SMCC 90, which have particle size distributions equivalent to those of Emcocel® 50M and Emcocel 90M (Rettenmaier), respectively. In direct compaction, SMCC is 1 0%–40% more compactible than regular MCC and has a lower lubricant sensitivity. The flow properties of SMCC are better than those of regular microcrystalline cellulose.[18] The SMCC 90 flows better than SMCC 50 because of big¬ger particle size and higher density. The flow rate of SMCC 90 was found to be equivalent to that of the PH200 grade of MCC.[19] In addition to a better flowability, SMCC has a higher bulk density than does regular MCC, which can be explained by its improved flowability and packing properties.[20] Studies using helium pycnometry, laser light scattering, particle size analysis, Fourier trans-form infrared spectroscopy, gas adsorption, X-ray powder diffraction, solid state NMR, calorimetry, water vapor sorption, and Raman spectroscopy have all shown that silicification appears to have no discernible effect on the primary chemical and polymorphic characteristics of microcrystalline cellulose. The specific surface area of SMCC was found to be about five times higher than that of microcrystalline cellu¬lose, and the pore volume size distributions calculated from nitrogen adsorption isotherms showed that the total pore volume was greater for SMCCThis effect has been explained by the very high specific surface area of colloidal silicon dioxide. The pore size distribution characteristics determined by a mercury porosimeter were very similar for SMCC 90 and MCC 90This suggests that bulk modifi¬cation of MCC does not occur during silicification, and that the colloidal silicon dioxide, either by providing surface modification or by modifying strengthening interactions, is primarily responsible for the improvements in functional¬ity, in particular tablet strength. Scanning electron micros-copy studies together with electron probe microanalysis have demonstrated that silicon dioxide is primarily located in the surface of SMCC, but some silicon dioxide was detected in the internal regions of some particlesThe presence in the surface is an important observation, since this may alter characteristics such as interfacial strength and interactions with magnesium stearate. In a comparative study of the mechanical properties of unlubricated compacts of MCC and SMCC, it was found that at relatively slow compaction rates, compacts with a comparable relative density were found, which sug¬gests that the two materials exhibit a comparable compac¬tion behaviorNot only the tensile strength but also the stiffness and energy of failure were greater for compacts prepared from SMCC than for compacts prepared from MCC or blends of MCC and colloidal silicon dioxide. From these results, the authors concluded that the strength enhancement by silicification of MCC may be a conse¬quence of an interfacial interaction rather than modifica¬tion of the bulk MCC properties. In a recent study, Van Veen et alstudied the compaction mechanisms of unlubricated and lubricated MCC and SMCC. They found that neither colloidal silicium dioxide nor magnesium stearate facilitates the densification of MCC during com¬paction. The slightly higher relaxation of SMCC tablets showed that colloidal silicium dioxide has more negative than positive effect on interparticulate bonding. However, for lubricated MCC a larger increase in tablet relaxation at high compression speed was found than for lubricated SMCC tablets, so the decrease in tablet strength was larger for MCC tablets than for SMCC tablets when lubrication was applied. An examination of the tablet strength of tab-lets compressed from physical mixtures of MCC with increasing concentrations of colloidal silicium dioxide proved the slightly negative influence of silicon dioxide on the tablet strength of unlubricated MCC tablets and the positive effect of colloidal silicon dioxide addition on the strength of lubricated MCC tablets. The authors showed that coprocessing of MCC with colloidal silicon dioxide showed no extra contribution on the tablet strength of lubricated tablets above physical mixtures. The positive effect of colloidal silicium dioxide on the compactibility of MCC was elucidated by an interaction between magne¬sium stearate and colloidal silicon dioxide. Only the part of colloidal silicon dioxide that is fixed upon the surface of the SMCC particles (about 20%–30% of the 2% colloi¬dal silicon dioxide in SMCC) is working effectively in relation to the negative effect of magnesium stearate as lubricant on tablet strength.

Powdered Cellulose and Derivatives
It is well known that powdered cellulose has inferior binding properties when compared with those of microc¬rystalline cellulose. Recently, however, some modified powdered celluloses with improved compaction properties have been described. One of these is low crystallinity powdered cellulose (LCPC). It is prepared by controlled decrystallisation and depolymerisation of cellulose with phosphoric acidThe powder and mechanical proper-ties of different batches of low crystallinity powdered cellulose, ranging in crystallinity from 15% to 45%, were compared with those of different types of microcrystalline cellulose and powdered cellulose by Kothari et alLike microcrystalline cellulose, LCPC consists of aggregates of particles. Further, LCPC aggregates showed a smoother surface and were more densely packed than were the microcrystalline cellulose products. Although no definite relationship was observed between crystallinity and the true density or moisture content of the various materials, LCPC picked up higher moisture content at a given vapor pressure compared with the higher crystallinity products microcrystalline cellulose and powdered cellulose. The yield pressure of LCPC, calculated from Heckel plots, was significantly lower than that of microcrystalline and pow¬dered cellulose products. This suggests that LCPC under-goes plastic deformation at relatively lower compression pressures. Tensile strength values of tablets of LCPC were comparable to those for microcrystalline cellulose tablets. The disintegration times for LCPC tablets were much shorter than those for microcrystalline cellulose tablets. This effect was explained by the difference in crystallinity between the two materials as well as the ease of accessibil¬ity for water molecules to enter and interact with free hydroxyl groups.Another new cellulose-based tableting excipient, referred to as UICEL, was developed by the same group by treating cellulose powder with an aqueous solution of sodium hydroxide and subsequently precipitating it with ethyl alcoholIn contrast to microcrystalline cellulose, UICEL shows a cellulose II lattice, whereas microcrystal¬line cellulose belongs to the cellulose I polymorphic form. Both crystallinity and degree of polymerization were lower than for microcrystalline cellulose. Like microcrys¬talline cellulose type 102, the new product consists of a mixture of aggregated and nonaggregated fibers. Com¬pared to Avicel PH® 102, UICEL is denser and less duc¬tile. Although the compactibility of UICEL is much smaller than that of microcrystalline cellulose type 102, the tablet strength is high enough for pharmaceutical prac¬tice. A definite advantage of UICEL over microcrystalline cellulose is the much shorter tablet disintegration time. Even tablets compressed at high forces disintegrate within a few seconds, so that UICEL has the potential to be used in the design of fast disintegrating tablets. Another sig¬nificant difference between UICEL and microcrystalline and powdered cellulose is the different effect of compac¬tion force on the crystallinity of the products.

Table 3: Comparative properties of various grades of Avicel 
Avicel Grade Features
PH 101 Most widely used for direct compression tableting and wet granulation
PH 102 Larger particle size. Compression property similar to PH 101
PH 103
PH112
PH113 Reduced moisture content and ideal for moisture sensitive material
PH 105 Finest partial size and may be used in direct compression of coarser, granular or crystalline materials. It can be admixed with PH 101 and PH 102 to achieve specific flow and /or compression property 
PH 200 Larger particle size which offers increased flowability with minimum effect on compression characteristic. It can be used to reduce tablet weight variation a0nd to improve content uniformity.
PH 301 Higher density than its partical size equivalent to PH 101 providing increased flowability grater tablet weight uniformity and the potential for making smaller tabulate.
PH 302 Density characteristic similar to PH 301 with an average partial size of PH 102/ PH 302 offers increased flowability grater tablet weight uniformity and potential for smaller tablets.

Hydroxypropylcellulose
Alvarez-Lorenzo reported that the difference in flow and compaction properties, the mechanical and micro structural properties of the tablets prepared from various grades of low-substituted hydroxyl propyl celluloses is attributed to difference in the specific surface65.
Ethyl Cellulose
Crowley reported that the release rate of guaifenesin from ethyl cellulose matrix tablets prepared by direct compression was dependent on the ethyl cellulose particle
Size and compaction force 66.

Sugars
Sucrose
Sucrose is widely used as filler in chewable tablets and as a binder in wet granulation. Bowe et al reported a co-processed sucrose based directly compressible adjuvant containing 95% sucrose and 5% sorbitol. Authors demonstrated that tablets with higher strength, which disintegrates faster can be produced using this material than tablets made with commercially available directly compressible sugars. Recently, directly compressible sugar is introduced by British sugar. It is a free flowing, directly compressible sugar comprising 95% icing sugar and 5% malt dextrin. It confirms to British pharmacopoeia monograph for compressible sugar.
Di-Pac
Di-Pac is a directly compressible, co-crystallized sugar consisting of 97% sucrose and 3% modified dextrin 5. It is a free flowing, agglomerated product consisting of hundreds of small sucrose crystals glued together by the highly modified dextrin. At high moisture level, Di-pac begins to cake and loose its fluidity. 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. Rizzuto et al., demonstrated that co-crystallized sucrose and dextrin deformed readily by plastic fracture to provide much harder compacts than those obtained from sucrose crystals alone 67.

Nu-Tab
Nu-Tab is a roller compacted granulated product consisting of sucrose, invert sugar, and cornstarch and magnesium stearate. It has better flowability due to relatively larger particles but has poor colour stability compared to other directly compressible sucrose and lactose. It is primarily used for preparation of chewable tablets by direct compression.

Emdex and Maltrin
Emdex is produced by hydrolysis of starch and consists of aggregates of dextrose microcrystals intermixed and cohered with a small quantity of higher molecular weight sugars. Emdex occurs as white, free flowing, porous spheres which are water soluble and non hygroscopic. Emdex is generally used in directly compressible chewable tablets because of its sweet taste. It has good binding properties and slight lubricant sensitivity. It exhibits high moisture sensitivity, at room temperature and at 50% RH, the crushing strength of tablets decreases dramatically, whereas during storage at 85% RH tablets liquefy 68. Tablets containing theophylline prepared using Emdex exhibited higher
mechanical strength, faster disintegration and rapid drug release than the tablets prepared from Maltrin M150 69.

Maltose
Advantose 100 is a spray-dried maltose having spherical particles with an optimal combination of fine and coarse particles that contributes superior flow. Compared to microcrystalline cellulose, spray dried maltose can tolerate significantly greater compression force without capping upon ejection from the tablet die; it has low hygroscopicity and low reactivity than microcrystalline cellulose 25.

Maltodextrin
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. The DE value is less than twenty. Just as all starch derivatives, maltodextrin has a high lubricant sensi¬tivity. Another objective is the retardant effect of hydro-phobic lubricants on drug release of tablets containing water-insoluble active ingredientsThe retardant effect was not exhibited with mixtures containing a water soluble drug substance. Mollan and Çelik compared a spray-dried maltodextrin (Maltrin® M510), three fluidized-bed agglomerated maltodextrins (Maltrin M500, Malta*Gran® TG, and Malta*Gran 10), and an experimental roller-com¬pacted maltodextrin. Maltrin and Malta*Gran are brand names for maltodextrins from Grain Processing Corp and Zumbro IFP, respectively. The commercially available maltodextrins underwent plastic deformation and formed strong tablets, but showed high lubricant sensitivity. Tab-lets compressed from the experimental roller-dried malto¬dextrin 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 des-orb moisture from the atmosphere and that the moisture content of the maltodextrin strongly influences both com¬paction and postcompaction 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 disinte¬gration 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.

Polyols
Mannitol
It is water soluble, non-hygroscopic and produces a semi-sweet, smooth, cool taste. It can be advantageously combined with other direct compression excipients. Sangekar et al. reported mannitol as a best sugar for chewable tablet formulation prepared by direct compression out of twenty-four formulations of placebo tablets, made from 8 excipients and 3 disintegrants 70.

Starch
Mullick et al. reported that dextrinized rice, corn wheat and tapioca starches prepared by dextrinization exhibited very good flow, compression properties and disintegration qualities for direct compression tableting. Dextrinized tapioca starch was found to be the best 71. Preflo starch exhibited high bulk density and good flowability than starch 1500 and Star Tab as directly compressible excipients. Preflo starch containing tablets exhibited prolonged disintegration time (30   min) than the Starch 1500 (3.5 min). Preflo cornstarch formed harder tablets compared to Preflo potato starch 72. The directly compressible starch (Starch 1500) is relatively fluid, did not require a lubricating agent when compressed alone, more effective as a dry binder and gives equivalent or faster disintegration and dissolution compared to starch USP 73. Due to improved flowability and   compressibility pregelatinzed starch can be used as a binder in direct compression74.

Starch 1500
It is a directly compressible, free flowing, USP grade of partially hydrolyzed cornstarch. It is prepared by subjecting cornstarch to physical compression or shear stress in high moisture conditions causing an increase in temperature and a partial gelatinization of some of the starch granules. The product is consists of about 5% free amylose, 15% amylopectin and 80% unmodified starch 18. It provides fair to good binding properties and dilution potential, but requires high pressures to produce hard tablets. It also produces a dense tablet with good disintegration properties. Starch 1500 exhibits self-lubricating property. It has poor flowability compared to other directly compressible adjuvants and shows higher lubricant sensitivity. It is also used as filler in capsule formulation. Monedero Perales et al. demonstrated that Starch 1500 exhibited better flowability and lower binding property and plasticity than the Sepistab 20075. Terfenadine tablets prepared using rice starch (Era Tab) exhibited higher crushing strength and lower friability than partially pregelatinized starch, Super-Tab, Emcompress and lower than Avicel PH 101 76. Uni-Pure is a fully gelatinized maize starch. It gives tablets with strong binding properties and significantly faster disintegration 74. Clausen reported co-processed polymethacrylic acid-starch as a pH-sensitive directly compressible excipient for controlled delivery of model drugs amoxicillin and rifampicin77.

Calcium salt
Dicalcium Phosphate Dihydrate
Dicalcium phosphate is the most common inorganic salt used in direct compression as a filler-binder. Advantage of using dicalcium phosphate in tablets for vitamin and mineral supplement is the high calcium and phosphorous content. Dicalcium phosphate dihydrate is slightly alkaline with a pH of 7.0 to 7.4, which precludes its use with active ingredients that are sensitive to even small amount of alkali (i.e. ascorbic acid). It exhibits high fragmentation propensity. Rees et al., studied time        dependent deformation of few directly compressible excipients. Authors reported that the increase in dwell time had insignificant effect on dicalcium phosphate dihydrate compacts whereas increase in dwell time increased the consolidation of other materials in the rank order sodium chloride, anhydrous lactose, micro crystalline cellulose and modified starch 78. Panaggio et al. studied the effects of varying proportions of dicalcium phosphate dihydrate and modified starch matrices in tablets prepared by direct compression and observed that at some concentrations, properties of tablets were intermediate between those of the pure components and varied linearly with small changes in relative proportions 79. Water of crystallization of dicalcium phosphate dihydrate could possible be released during processing and thus chemically interact with hydrolysable drug 80. Schüssele characterized the flowability of commonly used directly compressible adjuvants using Sotax Powder Flow Tester from good flow to poor flow in following order: Emcompress, Tablettose 80, Fujicalin, Tablettose 100, Starch and Avicel 81. Holte reported use of directly compressible alginates (Protanal LF 120 L, Protanal LF 120M, Protanal LV 120D, Protanal SF 120) in combination of dicalcium phosphate in formulation of sustained release acetyl salicylic acid directly compressible tablets 82.

Emcompress
Emcompress consists of aggregates of small primary particles of dicalcium phosphate. Unlubricated Emcompress tablets are difficult to eject from dies, therefore, it requires high lubrication. Hardness of tablets containing Emcompress is insensitive to tablets machine speed and lubricant such as magnesium stearate due to the fragmentation behaviour during compression and consolidation. It can be good directly compressible adjuvant when used in combination with microcrystalline cellulose or starch 45. Dolden et al   reported that intraparticulate porosity and mean yield pressure of the dicalcium phosphate anhydrous product are higher than that of the dicalcium phosphate dihydrate (Emcompress). Authors further demonstrated that Compacts of the anhydrous product disintegrated much more rapidly in distilled water than did those of the dihydrate 83.

Table 4: Examples of some directly compressible adjuvants
Excipient Brand name(Manufacturer, Country)
Lactose Tablettose (Maggle, Germany)   Pharmatose(DMV, The netherland) 
Fastflow lactose(Foremost)
Sucrose Dipac(American suger company, USA) Nutab (Ingradent Technology Inc., USA)
Dextrose Emdex(Edward mendell, USA) Cantab(Penwest, USA)
Starch Starch 1500(Colorcon, USA) Spress-B-820(GPC, USA) Eratab (Erawan, Thailand) Pharm-DC-93000 (Cerestar, USA)
Mannitol Mannogem-2080(Spi polyols, France) 
Sorbitol Neosorb(Roquette, France) Sorbogem(SPI Polyols, France) Sorbidex-p(Cerester, USA)
Lactilol Finlac-DC(Danisco, USA) Lacty-TAB(Purac, USA)
Xylitol Xylitab(Danisco, USA)
Maltodextrin Maltrin(GPC, USA)
MCC/Cellulose Avicel PH(FMC, USA) Emcocel(Edward mendell, USA) 
Powdered Cellulose Elcema-50 (Degussa, USA)
Di-calcium Phosphate Emcompress(Edward mendell, USA) Atab(Rhodia, USA) Ditab(Rhodia, USA)
Tri-Calcium Phosphate Tritab (Rhodia, USA) 
Calcium Sulphate Delaflo(JWS-Delavau, USA) 
Calcium Lactase Penta hydrade Puracal-DC(Purac, USA) 
Calcium Lactate Tri-Hydrade Puracal-TP(Purac, USA)
Aluminium Hydroxide Barcroft-USP-321(SPI Polyols, France)

Fujicalin
Fujicalin is a spherically granulated dicalcium phosphate anhydrous prepared by spry-drying. It has lower particle size, high porosity and high specific surface area. Fujicalin gives significantly stronger tablets than Di-Cafos 80.
Insulin
Eissens reported effect of chain length, particle size and amount of included air in the particles of insulin on flow properties and tableting properties. Particles with larger size showed better flowability. A high lubricant sensitivity was found for amorphous insulin with a low amount of entrapped air. The disintegration/dissolution time increased with decreasing chain length of the insulin 84. Hollow insulin particles have an increased compactibility as compared with solid insulin particles and a strongly reduced lubricant sensitivity 85.

4. CO-PROCESSING
4.1 Introduction
Co-processing is another way that new excipients are coming to market without undergoing the rigorous safety testing of a completely new chemical 19. It can be defined as combining two or more established excipients by an appropriate process11. Co-processing of excipients could lead to the formation of excipients with superior properties compared to the simple physical mixtures of their components. The main aim of co-processing is to obtain a product with added value related to the ratio of its functionality/price. 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 physico-chemical parameters and it ends with minimizing avoidance with batch-to-batch variations. 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. Co-processing is interesting because the products are physically modified in a special way without altering the chemical structure. A fixed and homogenous distribution for the components is achieved by embedding them within minigranules. Segregation is diminished by adhesion of the actives on the porous particles making process validation and in process control easy and reliable20. The randomized embedding of the components in special minigranules minimizes their anisotropic behaviour. So, deformation can occur along any plane and multiple clean surfaces are formed during the compaction process. Thus, the use of the co-processed excipient combines the advantages of wet granulation with direct compression20. The use of one-body components is justified if it results in a potentiation of the functionalities over that of the mere 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. Excipient mixtures in co-processing are produced to make use of the advantages of each component and to overcome specific disadvantages, if any. Most important characteristics are the binding and blending properties of the co-processed excipients, which must be better than those of a physical mixture of the starting materials. Cost is another factor to be considered in the selection of co-processed product. Major limitation of co-processed excipient mixture is that 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 development18. Coprocessed adjuvant lacks the official acceptance in pharmacopoeia. For this reason, a combination fillerbinder 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. Although the spray-crystallized dextrose-maltose (Emdex) and compressible sugar are co-processed products, they are commonly considered as single components and are official in USP/NF. Table 4 shows examples of co-processed directly compressible adjuvants.
4.2 Need for directly compressible co-processed excipients
The reasons driving the search for new excipients are:
1. The growing popularity of the direct-compression process and a demand for an ideal filler--binder that can substitute two or more excipients
2. Increasing tablet machine speed, which require excipients to maintain good compressibility and low weight variation even at short dwell times
3. 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 agglomeration'
4. The lack of excipients that address the needs of specific patients such as those with diabetes, hypertension, and lactose and sorbitol sensitivity
5. To develop the ability of excipients to modulate the solubility, permeability, or stability of drug molecules and to increase the performance of Excipients to address issues such as disintegration, dissolution, and bioavailability.
The development of new excipients to date has been market driven (i.e. excipients are developed in response to market demand) 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 excipient 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. Development of multi-functional co-processed excipients should significantly carry out the continued popularity of solid dosage forms and increase performance in the direct-compression technology.

 Table 4: Co-processed directly compressible excipients
Brand Name Adjutants Manufacturer, Country
Cellactose MCC, Lactose Meggle, Germany.
Xylitab Xylitol, Na CMC Meggle, Germany.
Ludipress Lactose, PVP, Crospovidone BASF, Germany.
Starlac Lactose, Maize starch Roquette, France.
Pharmatose DLC 40 Anhydrous lactose, lacitol DMV, Netherlands.
Avicel CE 15 MCC, Guar Gum FMC, USA.
Celocol MCC, Calcium phosphate FMC, USA.
Prosolv MCC, Colloidal Silica Penwest.
Di-pac Sucrose, Dextrin American sugar, USA.
Advantose FS 95 Fructose, starch SPI polysol, France.
Advantose 100 Maltose SPI polysol, France.
Barcoft CS 90 Calcium carbonate,Starch SPI polysol, France.
Barcoft premix St. Al-hydroxide,Mg-hydroxide, Sorbitol SPI polysol, France.
Plasdone S-630 Vinyl acetate, vinyl pyrrolidone ISP. USA.
Carbofarma G10 Calcium Carbonate Resins industries, Argentina.
Carbofarma G11 Maltodextrin Resins industries, Argentina.

4.3 co processing of pharmaceutical excipients
Nowadays, co-processing is a much broader platform for the manipulation of excipients' functionality and is the commercially utilized method for the preparation of directly compressible excipients. It can be defined as combining two or more established excipients by an appropriate process.' 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 to mask the undesirable properties of individual excipients. Development of a co-processed directly compressible adjuvant starts with the selection of the excipients to be combined, their targeted proportion, selection of the preparation method to get an 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 an integrated product, with superior functionality rather than the simple mixture of components. The use of one-body components is justified if it results in a potentiating 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 aspects ranging from hardness to dissolution and/or stability.

 Figure: Schematic representation of co-processing method8

4.4 Co-Processed Directly Compressible Adjutants

Ludipress
Ludipress, a co-processed product, consists of 93.4% α- lactose monohydrate, 3.2% polyvinyl Pyrrolidone (Kollidon 30) and 3.4% crospovidone (Kollidon CL). It consists of lactose powder coated with polyvinyl Pyrrolidone and crospovidone23. Although, Ludipress contains disintegrant, the disintegration of tablets takes longer than tablets containing α-lactose monohydrate, Tablettose and anhydrous α-lactose27. At low compression force Ludipress gives harder tablets but the addition of glidant and disintegrant is needed. It is reported that binding capacity of Ludipress was higher than that of microcrystalline cellulose. The dilution potential was high (upto 70%) when aspirin was used a model drug86. Baykara et al. reported that the dilution potential of LudipressR with paracetamol is lowerthan that of Avicel PH 101, Elcema G250 and Elcema P05087. The binding properties of Ludipress, both unlubricated and lubricated with 1% magnesium stearate was found to be much better than corresponding physical mixture87. Plaizier-Vercammen et al. reported that the addition of a lubricant was necessary and its mixing time had little effect on crushing strength of Ludipress tablets. Authors also reported that Ludipress exhibits better tableting characteristics for low dose APIs, and good batch-to-batch uniformity than Cellactose88. The compressibility of Ludipress is similar to that of Avicel PH 200. The disintegration time of Ludipress containing tablets remained unchanged at about 100 MPa compaction pressure while significant prolongation was observed with Cellactose89,90. Schmidt and Rubensdorfer reported that the tablets manufactured with Ludipress exhibited optimum disintegration time and compaction pressure independent dissolution of glibenclamide. While, increasing compaction pressure had a negative effect on drug dissolution from compacts containing Cellactose90. It has been reported that among various lactose based directly compressible excipients, Ludipress exhibited a better flow rate compared to Avicel PH 10191. Ludipress exhibited highest flowability followed by Cellactose, Tablettose, Fast Flo lactose and anhydrous lactose as demonstrated by lower static and dynamic angles of repose than the other excipients 92.  The values of compressibility could be ranked from maximum to minimum in the following order: Tablettose, Cellactose, Ludipress and Fast Flo lactose. Fragmentation propensity was from maximum to minimum in Tablettose, Cellactose, Ludipress and Fast-Flo lactose 93.

Cellactose
Cellactose is a co-processed product consisting α-lactose monohydrate (75%) and cellulose (25%). Apart from good flowability, it has good compactibility. The compactibility is attributed to a synergetic effect of consolidation by fragmentation of lactose and plastic deformation of cellulose94. Because the lactose covers the cellulose fibers, moisture sorption is much lower than that of microcrystalline cellulose alone. Aufmuth et al reported that the Cellactose exhibited increased crushing strength of the compacts along with reduced friability and lower disintegration time than the dry blend of lactose and cellulose20. Armstrong et al. pointed that Cellactose exhibit the dual consolidation behaviour since it contains a fragmenting component (lactose) and a substance that consolidates primarily by plastic deformation (Cellulose)95. Ruiz et al. and Reimerdes found that the Cellactose exhibited better compressibility compared to Ludipress, Fast Flo lactose, Tablettose, Di-pac and anhydrous lactose11,88. Belda and Mielck found that due to co-processing Cellactose exhibited enhanced crushing strength compared to the powder mixtures each containing 25% w/w Avicel PH-101 or Elcema P-100 and 75% w/w Tablettose or lactose (100#)96. Casalderrey et al reported that the Cellactose tablets prepared at a compression pressure that largely eliminated macro pores had better mechanical properties but much poorer disintegration than tablets of the other blends having similar composition, particle size, and true density at the same punch pressure. Authors further reported that the tensile strength and disintegration time of Cellactose tablets decreased rapidly as the compression pressure is reduced97. Gohel and Jogani prepared and evaluated co-processed directly compressible adjuvant containing lactose and microcrystalline cellulose using starch as a binder. The percentage fines, Carr’s index of the agglomerates as well as friability and tensile strength of the tablets were affected by the ratio of lactose to microcrystalline cellulose and percentage of starch in binder solution. A product containing lactose: microcrystalline cellulose (9:1) and 1% starch paste exhibited satisfactory flow, compressibility and friability. Tablets of diltiazem hydrochloride and acetaminophen prepared using the co-processed excipients exhibited satisfactory tableting properties98. Gohel et al. prepared and evaluated coprocessed diluents containing lactose and microcrystalline cellulose using a 23 factorial design. Ratio of lactose to MCC (75: 25 and 85:15), type of binder (hydroxypropyl methylcellulose or dextrin) and binder concentration (1 or 1.5%) were studied as independent variables. The results revealed that the lactose: microcrystalline cellulose ratio 75:25 and dextrin as a binder are better than the ratio of 85:15 and hydroxypropyl methylcellulose as a binder. The tableting properties of the developed adjuvant were ascertained using diltiazem HCl as a model drug99. Gohel and Jogani prepared co-processed directly compressible adjuvant containing lactose and microcrystalline cellulose using melt granulation technique 100. Gohel et al. demonstrated use of factorial design in development of directly compressible adjuvant of desired characteristics consisting of lactose, dicalcium phosphate and microcrystalline cellulose 101.

Microcelac
It is a spray dried co process excipient containing 75% lactose monohydrate & 25% MCC. Filling property of lactose & capacity of MCC have been synergistically co processed to a one body excipient providing better tableting performance at lower cost. It has good flowability & compactibility then cellactose. The compactibility is attributed to synergistic effect of consolidation by fragmentation of lactose & plastic deformation of MCC. Gohel et.al prepared & evaluated a coprocess directly compressible adjuvant containing lactose & MCC using starch as binder. The % fines, carr`s index of the agglomerates as well as friability & tancile strength of the tablet were affected by the ratio of lactose to MCC.A product containing lactose: MCC (9:1) & 1% starch paste exhibited satisfactory flow compressibility & friability.

Prosolv
It is co-processed silicified microcrystalline cellulose. It consists of 98% microcrystalline cellulose and 2% colloidal silicone dioxide. The manufacturer claim better flowability and compressibility compared to Emcocel and Avicel PH 101 or physical mixture of MCC with colloidal silicone dioxide53, 102. Allen reported that Prosolv containing tablets were significantly robust than those produced from regular cellulose by wet granulation. In the presence of magnesium stearate (0.5 %), tablets prepared with Prosolv maintained tensile strength profiles, whereas the tensile strength of regular cellulose was significantly affected. Author further reported that Prosolv is about 20% more compactable than regular cellulose103. Fraser et al reported that silicified microcrystalline cellulose has some improvement in flow but considerably enhanced mechanical properties104. Lahdenpaa et al. demonstrated that Silicified microcrystalline cellulose is useful to prepare tablet containing poorly compressible ingredients by direct compression105. The silicification affects the moisture sorption and the packing during tapping as well as the particle deformation during tableting. Prosolv showed slight increase in the tensile strength but marked increase in the disintegration time of the tablets compared to Avicel106. Bolhuis et al. Demonstrated that the co-processing of microcrystalline cellulose with colloidal silicone dioxide has no significant contribution on the tablet strength of lubricated tablets containing the physical mixture of microcrystalline cellulose and colloidal silicone dioxide 107.

Pharmatose DCL 40
It is a co-processed product consisting of 95% α-lactose and 5% anhydrous lactitol. Due to spherical shape and favorable particle size, it exhibits good flowability. It has high dilution potential than other lactose based products due to better binding property. It has very low water uptake at high humidity 18.
StarLac
Starlac is a co-processed excipient consists of lactose monohydrate and maize starch produced by spray drying108 The advantage of Starlac are its good flowability depending on the spray-drying process, an acceptable crushing force due to its lactose content, its rapid disintegration depending on starch109. Gohel and Jogani demonstrated use of multiple linear regression in development of co-processed lactose and starch. Authors concluded that as the lactose/starch ratio increased Carr’s index of the adjuvant and crushing strength of the tablets increased while friability decreased. Percentage of starch paste has inverse effect on the friability110. As discussed in this review, it is clear that no single excipient fulfils all the optimum requirements. In most instances evaluation of tableting properties of these excipients are required before selecting them as a part of formulation. Each directly compressible adjuvant has merits and demerits hence; there is still need for directly compressible adjuvant, which exhibits a satisfactory performance. 

Advantose F5 95
Advantose is a co-dried compound of 95% fructose and 5% starch, which turns fructose into an excellent excipient for pharmaceutical, nutraceutical, and chewable vitamin applications. It has lower hydroscopicity and a good flow property compared to standard fructose, making it easier to handle. Because fructose is 20% sweeter than and almost twice as soluble as sucrose, it can be used to mask undesirable flavors of components that may be in a tablet formulation."

Avicel CE 15
It is a co-processed mixture of microcrystalline cellulose and guar gum used in chewable tablet formulations. It provides excellent control of sensory factors that affect palatability. A smoother mouth feel can be attained- Grittiness and tooth packing can be significantly reduced. For improving patient compliance, Avicel CE-15 is used in direct compression formulations, producing comparably softer tablets that are less friable and disintegrate rapidly."

Avicel RC/CL
 It is a co-processed mixture of microcrystalline cellulose and sodium carboxymethyl cellulose (Na CMC) that are readily dispersible in water with moderate to high shear mixing to form white, opaque, colloidal thixotropic gels. The amount of Na CMC present can vary between 8.3% and 18.8% wise depending upon the grade material."

Celocal
It is a spray dried co-processed material consists of 30% of microcrystalline cellulose and 70% of anhydrous calcium sulfate. It combines the compressibility and disintegrant advantages of microcrystalline cellulose with the cost advantage of calcium sulfate. The product is significantly more compressible than a physical mixture of its component parts and produces tablets of much lower friability. It is also lesser subjected to lubricant softening effects due to its larger particle size-Celocal is composed of two water-insoluble substances; therefore, care should be taken in using it in formulation of drugs with low water solubility, particularly if the product is to be wet-granulated."

Di-Pac
Di-Pac is a directly compressible, co-crystallized sugar consisting of 97% sucrose and 3% modified dextrin 5. It is a free flowing, agglomerated product consisting of hundreds of small sucrose crystals glued together by the highly modified dextrin. At high moisture level, Di-pac begins to cake and loose its fluidity. 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. Rizzuto et al., demonstrated that co-crystallized sucrose and dextrin deformed readily by plastic fracture to provide much harder compacts than those obtained from sucrose crystals alone 67.

Nu-Tab
Nu-Tab is a roller compacted granulated product consisting of sucrose, invert sugar, and cornstarch and magnesium stearate. It has better flowability due to relatively larger particles but has poor colour stability compared to other directly compressible sucrose and lactose. It is primarily used for preparation of chewable tablets by direct compression.

Emdex and Maltrin
Emdex is produced by hydrolysis of starch and consists of aggregates of dextrose microcrystals intermixed and cohered with a small quantity of higher molecular weight sugars. Emdex occurs as white, free flowing, porous spheres which are water soluble and non hygroscopic. Emdex is generally used in directly compressible chewable tablets because of its sweet taste. It has good binding properties and slight lubricant sensitivity. It exhibits high moisture sensitivity, at room temperature and at 50% RH, the crushing strength of tablets decreases dramatically, whereas during storage at 85% RH tablets liquefy 68. Tablets containing theophylline prepared using Emdex exhibited higher
mechanical strength, faster disintegration and rapid drug release than the tablets prepared from Maltrin M150 69.

5.Co-processed active pharmaceutical ingredients
In the mid 1970s, Roche marketed ascorbic acid C-90 in which micronized ascorbic acid particles were granulated with starch paste. The product appears to be extruded through a compactor and then ground. Each larger particle is actually a granule of ascorbic acid and pasted starch, and is much more compressible than the pure crystalline material. More recently, Roche marketed C-95 ascorbic acid that contains only 5% excipients and utilizes methylcellulose rather than starch as the binder. Takeda chemical industries market both C-97 direct-compression ascorbic acid and SA-99, a direct-compression sodium ascorbate (Table 3).
Acetaminophen generally occurs as large monoclinic crystals, a crystal form which is not easily deformed and resists compaction. A direct-compression form of acetaminophen is available commercially from Mallinckrodt containing 90% acetaminophen and 10% of partially pregelatinized starch under the name COMPAP. The spherical nature of the particles indicates that the material is prepared by spray drying. Each particle is almost a perfect minigranules. Deformation can occur along any plane and multiple clean surfaces are formed during the compaction process. Tablets with rapid dissolution can be easily formed by the addition of small concentrations of AcDiSol (2%) and Mg. Stearate (0.5%). A self-lubricating version of this material is also available (COMPAP-L) as well as a combination of acetaminophen and codeine (Codacet-60).
Another direct compression acetaminophen product is marketed by Monsanto under the brand name DC-90. This product is prepared by fluidized bed granulation instead of spray drying. It has a compressibility profile similar to that of COMPAP but is only available in the self-lubricating form. The compressibility of both materials can be enhanced by the addition of 10 to 20% microcrystalline cellulose.

Examples of directly compressible active Pharmaceutical Ingredients
API Brand Name (Mfg.) Composition
Ascorbic acid C-95 (Hoffman La Roche) Ascorbic acid (95%) Methyl Cellulose (3 %)
C-97 (Takeda)  Ascorbic Acid (97 %) 
Starch (3 %)
C-97SF(Takeda) Ascorbic Acid (97 %) 
HPMC (3 %)
Sodium Ascorbate SA-99 (Takeda) Sodium ascorbate (99 %) 
Food starch (I %)
Acetaminophen Compap (Mallinckrodt) Acetaminophen (90 %) Pregelatinized starch (10%)
Compap L(Mallinckrodt) Acetaminophen (90%) Pregelatinized starch (10 %) Ac-Di-Sol (2%) 
Mg. Stearate (0.5 %)
DC-90 (Monsanto) Acetaminophen (90 %) Pregelatinized starch {10 %)
Ibuprofen DCI-90 (Mallinckrodt) Ibuprofen (90 %) 
Corn starch and PVP (l0 %)
Riboflavin High Flow 95 (Takeda) Riboflavin (95 %) 
Mannitol (5 %)
Thiamine Mononitrate
TM-97 (Takeda) Thiamine mono nitrate (97 %) Hydro propylcellulose (3 %)
Thiamine mononitrate Hoffman La Roche Thiamine mononitrate (97 %) Methyl Cellulose (2 %)

Summary:
Direct Compressible Excipients, which can be used universally with any of the APIs, can lead to a revolution in tablet manufacturing techniques by way of low cost and efficient tablet rnanufacturing. These economical advantages will be beneficial for both manufacturing and consumer, we can also go for certain synthetic but inert materials, and by using them we can produce tablets using ingredients than otherwise could not possibly be compressed to a tablet. From all this, the direct compression technique can be taken as the best alternative for conventional tablet manufacturing and is best suited to industrial expectations too. Nowadays, we have a long list of materials which can help in the direct compression of certain materials, which are otherwise not easy to be directly compressed, and this is done by imparting certain characteristics. To the materials to be compressed and by the use of certain new technologies, all together, these excipients can lead to easy manufacturing of tablet dosage forms for the APIs, which are not compatible with water, and thus make the use of the wet granulation technique difficult.