Co-Processed Directly Compressible Adjutants

By: Pharma Tips | Views: 9172 | Date: 14-May-2011

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.

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 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.

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 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.

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 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."

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 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 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.

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


Brand Name (Mfg.)


Ascorbic acid

C-95 (Hoffman La Roche)

Ascorbic acid (95%) Methyl Cellulose (3 %)

C-97 (Takeda)

Ascorbic Acid (97 %)

Starch (3 %)


Ascorbic Acid (97 %)

HPMC (3 %)

Sodium Ascorbate

SA-99 (Takeda)

Sodium ascorbate (99 %)

Food starch (I %)


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 %)


DCI-90 (Mallinckrodt)

Ibuprofen (90 %)

Corn starch and PVP (l0 %)


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 %)

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