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.

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 ofsome 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.