Direct compression excipients

Direct Compression Excipients: Properties and Uses

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Direct compression excipients also known as direct compressible excipients or direct compression filler/binders are pharmacologically inactive, non-medicinal substances which may be compacted with no difficulty and which may do so even when mixed with active drug substances. These filler/ binders play significant role in improving flowability and compressibility during the manufacture of tablets by direct compression method.

Prior to the late 1950s, the literature contains few references to the direct compression of pharmaceuticals. In recent times, a great deal of attention has been given to direct compression technology due to the development and commercial availability of new materials, new form of old materials and the invention and utilization of new machinery which has allowed the formulation of tablets by this simplified and reliable method.

The introduction of spray-dried lactose in 1960 as the first excipient specially designed for direct compression initiated the “direct compression revolution”. Other direct compressible excipients such as microcrystalline cellulose (the first effective dry filler and binder), Starch 1500 (a compressible starch which maintains its disintegrant properties), Emcompress (a free-flowing dicalcium phosphate) and a number of direct compression sugars also appeared in the pharmaceutical market.

This article will outline the various direct compressible excipients that have been used in the manufacture of tablets by direct compression method, with particular emphasis on what is expected from such excipients in terms of their functionality. A comprehensive understanding of the behaviour of these materials is essential to avoid potential problems during manufacturing as there is no chance to cover up flaws in raw materials in direct compression as there is in wet granulation process.




Properties of an ideal direct compression excipients

An ideal direct compression vehicle should preferably have the following properties:

  1. The materials should have high fluidity or flowability to enable uniform fill of the dies.
  2. It should have sufficient cohesive properties to form a firm, strong tablet under adequate compression force.
  3. It should be physiologically safe and it should not interfere with the bioavailability of the active drug substance.
  4. It should be compatible with all types of active ingredients.
  5. It should be compatible with the packaging material(s).
  6. It should not show any physical or chemical change on aging.
  7. It should be physically and chemically stable to air, heat and moisture.
  8. It should have a high “capacity” (dilution potential). This is defined as the amount of active ingredients that can be satisfactorily compressed into tablets with a direct compressible excipient.
  9. It should be capable of being reworked without loss of flow or compressibility.
  10. It should be colourless and tasteless.
  11. It should accept colourants uniformly.
  12. It should be relatively cheap and available preferably from multiple suppliers.
  13. It should possess proper “mouth feel” which is defined as the feel or the sensation in the mouth, produced when the material is used in chewable tablets.
  14. It should not contribute to the microbiological load of the formulation.
  15. It should have a particle size range which should be equivalent to most active ingredients.
  16. It should have a good pressure hardness profile.
  17. A direct compression blend should also possess an optimum bulk density and it should be acceptable. ‘Acceptability’ of an excipient is its ability to comply with pharmacopoeial requirements, relating to purity, inertness and compatibility.

It is worth knowing that these desirable properties are not found in a single material. It, therefore, becomes necessary to add other suitable materials to improve the physical and the tableting properties of the blend.

Classification of direct compression excipients

According to Wells and Langridge, direct compressible diluents may be classified based on their disintegration and flow properties into

  1. Disintegration agents with poor flow e.g. Microcrystalline Cellulose (Avicel, EMC Corp, Philadelphia), Microfine Cellulose (Elcema, Degttssa, Frankfurt), Directly Compressible Starch (StaRx 1500 Staley Mfg Co. Illinois).
  2. Free flowing materials which do not disintegrate e.g. Dibasic Calcium Phosphate (Emcompress, E Mendel Corp, New York).
  3. Free flowing powders which disintegrate by dissolution e.g. Spray Dried Lactose Anhydrous Lactose, Spray-Crystallized Maltose-Dextrose (Emdex. E. Mendel Corp., New York), Sucrose, Dextrose, Amylose, Mannitol.

Optimum tableting characteristics of compression vehicles may be expected from blends of materials with disintegrant properties (a & c) and free flow properties (b & c).

Methods of Preparing Directly Compressible Excipients

Chemical Modification

This describes the alteration of excipient properties by subjecting them to cross-linking or carrying out reactions like substitution, condensation, hydrolysis etc. The resulting material may be a modified form of the parent material or an entirely new chemical entity. This method is relatively expensive and time consuming. Direct compressible excipients prepared by chemical modification include Ethyl Cellulose, Methyl Cellulose, Hydroxypropyl Methylcellulose and Sodium Carboxymethyl Cellulose prepared from cellulose, Cyclodextrin prepared from starch, Lactitol from lactose etc.

 



Physical Modification

This method is relatively simple and economical. It involves varying and optimizing the physical properties of materials for specific application. Physical modification of excipient does not generally produce new or novel excipients. Examples of direct compression excipients prepared by this method include dextrates (compressible sugar) and sorbitol.

Grinding and/or Sieving

This process is primarily used to control flow properties of excipients.  It involves grinding and/or sieving of materials for direct compression. Changes in particle properties such as surface area and surface activation may alter the compressibility of the final product. α-Lactose monohydrate (100 #) and dibasic dicalcium phosphate are good examples of direct compression excipients prepared using this method.

Crystallization

This is the process of forming crystalline solid materials from aqueous solution or melt. Controlled crystallization impart flowability to excipients. It does not necessarily improve its self-binding properties. Crystallization as a method of preparing direct compression excipients requires stringent control on possible polymorphic conversions and processing conditions. Examples of excipients prepared by crystallization include β-Lactose and Di-pac®.

Spray Drying

This is a method of producing a dry powder from an aqueous or non-aqueous dispersion of materials by rapidly drying with a hot gas. This technique has been extensively used to prepare free flowing direct compression excipients such as spray-dried lactose, spray-crystallized maltose-dextrose (Emdex), Fast Flo lactose, Avicel PH, TRI-CAFOS S, Karion Instant, Advantose 100 etc. The spherical shape and uniform size give spray dried materials good flowability. Direct compressible excipients produced by this method have poor reworkability.

Granulation/ Agglomeration

This involves the addition of an aqueous dispersion of granulating agent to a previously mixed excipient blend, followed by drying and sieving. This method does not form spherical particles of small size. It is in itself a process of size enlargement whereby small, cohesive, poorly flowable powder particles are gathered into layers, and permanent aggregates (granules) to render them into free-flowing state. The main advantage of this technology is the production of free-flowing granules of low friability. Examples of excipients prepared by this method include granulated Lactitol and Tablettose.

Examples of some direct compression excipients

  1. Microcrystalline Cellulose (MCC)
  2. Microfine cellulose (MFC)
  3. Directly Compressible Starch (Sta-Rx 1500)
  4. Dibasic Calcium Phosphate (DCP)
  5. Spray Dried Lactose (SD lactose)
  6. Anhydrous Lactose (USP)
  7. Fast Flo® Lactose
  8. Spray-Crystallized Maltose and Dextrose (Emdex®) ‘
  9. Crystalline Sorbitol
  10. Mannitol
  11. Sucrose
    1. Di-Pac®
    2. NuTab®




Microcrystalline Cellulose (MCC)

Microcrystalline cellulose is a purified, partially depolymerized cellulose that occurs as a fine, white, tasteless, odourless, hygroscopic crystalline powder which consists of poor flowing non-fibrous particles. It is prepared by controlled hydrolysis with dilute mineral acid solutions of α-cellulose, obtained as a pulp from fibrous plant materials. Following hydrolysis, the hydrocellulose is purified by filtration and the aqueous slurry is spray dried to form dry, porous particles of a broad size distribution.

According to many publications, microcrystalline cellulose is an excipient of outstanding merit. It possesses the following desirable properties:

  1. It has the highest compressibility potential of all, known direct compression excipients and it can be directly compressed without addition of binder.
  2. It improves compressibility of other powder blends or granulations (only true effective dry binder)
  3. Hardness of its compacts increases directly with compaction pressure through a wide range of pressures.
  4. It is self-lubricating and can reduce lubricant level.
  5. It imparts low friability to finished tablets.
  6. It promotes fast tablet disintegration and enhances rapid drug availability of tablets. Its capacity exceeds 50%.
  7. It has a high absorption capacity hence excellent disintegrant properties.
  8. It has high dilution potential.
  9. It confers excellent batch to batch reproducibility in terms of physical properties to tablets.
  10. It has excellent physical and chemical stability.
  11. It confers high hardness to tablets at low machine pressures.

Microcrystalline cellulose is used in direct compression as a strong dry binder, tablet disintegrants, an absorbent, a lubricant, and anti-adherent. It is also used as a diluent in tablets prepared by wet granulation, as filler in capsules and for the production of spheres.

Attempts have been made to use it as the only filler-binder in low dose drugs but because of cost and density considerations, microcrystalline cellulose is generally not used as the only filler in a direct compression tablet. It is most often found in concentrations of 10-30 % as a filler-binder and disintegrant.

Microcrystalline cellulose is available in different particle sizes and moisture grades that have different properties and applications. In the pharmaceutical market, it is available under the brand names Avicel (FMC Corporation, USA), Emcocel and Vivapur (JRS Pharma GmbH & Co. KG, Germany), Vivacel etc.

In spite of its excellent compressibility, microcrystalline cellulose has shown to exhibit low bulk density, high lubricant sensitivity and poor flow characteristics.

Microfine cellulose (MFC)

Microfine cellulose also known as powdered cellulose or cellulose flocs is a white, odourless, compressible, self-disintegrating, anti-adherent substance, consisting of fibrous particles, exhibiting degrees of fineness, ranging from a free-flowing dense powder to a coarse, fluffy, non-flowing material. It is prepared by mechanically grinding high purity cellulose fibre, prepared by processing α-cellulose obtained as a pulp from fibrous plant materials. The fibres may also be chemically treated with sodium hypochlorite plus sodium hydroxide to assist in depolymerization of the cellulose.

Microfine cellulose is used as a self-disintegrating anti-adherent filler in direct compression. However, unlike microcrystalline cellulose it possesses poor dilution potential, losing its compressibility rapidly in the presence of non-compressible drugs.

Microfine cellulose deforms plastically as shown by considerable stress relaxation following compaction or by the changes in the stress density profile using different dwell times of compression.

In the pharmaceutical market, microfine cellulose is available under the brand names Elcema in powder (P050, P100), fibrous (F150), and granular form (G250). The Elcema G250 (JRS Pharma GmbH & Co. KG, Germany) consisting of granules prepared from the P100 quality (with mean particle size of about 250 µm) is the only form that possesses sufficient fluidity to be used in direct compression. Solka Floc from International Fiber Corp, (New York, USA) is also available in different grades under which a granular form (Solka Floc fine Granular) with a mean particle size of 234  µm.

Because of the inferior binding properties of microfine cellulose when compared with those of MCC, modified microfine cellulose with improved compaction properties have been developed. One of these is low crystalline powdered cellulose (LCPC) prepared by controlled decrystallization and depolymerization of cellulose with phosphoric acid.




Directly Compressible Starch (Sta-Rx 1500)

Starch is one of the most widely used tablet excipients but does not, in its native state, (that is, unmodified form), possess the two properties necessary for making good compacts namely – compressibility and fluidity. There have been many attempts to modify starch to improve its compressibility and flow properties. The only modification of starch which has received acceptance in direct compression is Sta-Rx 1500 (Staley, USA).

Sta-Rx 1500 is a directly compressible, partially hydrolysed cornstarch which is relatively free-flowing (when compared to starch U.S.P). 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 end product consists of about 5% free amylose, 15% amylopectin and 80% unmodified starch.

Sta-Rx 1500 is used as both direct compression filler/binder and as disintegrant. It compresses into a compact and still maintains its disintegrant properties. The excipient provides fair to good binding properties and dilution potential but requires high pressures to produce hard tablets. Also, it has relatively high moisture content. This moisture has not been found to accelerate the decomposition of moisture labile drugs.

Sta-Rx 1500 is self-lubricating but the addition of a lubricant may be necessary in certain formulation. Lubricants particularly the alkaline stearate soften tablets containing high concentrations of Sta-Rx 1500 and hence these lubricants should be avoided whenever possible when formulating tablets containing Sta-Rx 1500. Stearic acid or hydrogenated vegetable oil lubricants are preferred in such formulations.

Dibasic Calcium Phosphate

This is a fine, white, odourless, tasteless powder or crystalline solid. It is a dense inorganic tableting excipient widely used in tablet formulations both as an excipient and as a source of calcium and phosphorus in nutritional supplements. It is used as direct compression filler/ binder and the filler of choice for formulations containing water sensitive drugs. This is because it has low water of crystallization and has low affinity for atmospheric moisture. Its popularity in the pharmaceutical industry can also be attributed to its excellent flow and compaction properties.

Dibasic calcium phosphate has high degree of physical and chemical stability. It is non-hygroscopic and stable at room temperature. However, under certain conditions of temperature and humidity, it can lose water of crystallization below 100oC. This has implications for both storage of the bulk material and coating and packaging of tablets containing dibasic calcium phosphate dihydrate.

The fluidity of dibasic calcium phosphate is good and glidants are generally not necessary. Its great fluidity makes it ideal for compression on high-speed tablet press. Lubricants exert little or no effect on its bonding properties. Dibasic calcium phosphate has a high dilution potential and is widely used for those tablet formulations with less than 50% active ingredients. It is available in different hydrate forms and in a special particle size range. The milled grade is typically used in the manufacture of wet-granulated, slugged or roller-compacted formulations.  The ‘unmilled’ or coarse-grade material which is ideal for direct compression tableting is marketed under the name Emcompress® or Ditab®.

Calcium phosphates are usually manufactured by reacting very pure phosphoric acid with calcium hydroxide obtained from limestone, in stoichiometric ratio in aqueous suspension followed by drying at a temperature that will allow the correct hydration state to be achieved. After drying, the coarse-grade material is obtained by means of a classification unit; the fine particle-size material is obtained by milling.

 



Dibasic calcium phosphate dihydrate has been found to delay the absorption and bioavailability of tetracyclines and so should not be used to formulate tetracycline antibiotics. It has been reported to be incompatible with aspartame, ampicillin, cephalexin, erythromycin, indomethacin, and aspirin. The surface of dibasic calcium phosphate dihydrate is alkaline and consequently it should not be used with drugs that are sensitive to alkaline pH.  Being an inorganic salt, dibasic calcium phosphate can be abrasive on the tablet tooling.

Spray-Dried Lactose (SD lactose)

This is the earliest and still one of the most widely used direct compression excipient. It is a white to off-white, odourless, slightly sweet-tasting crystalline particles or powder which consists of a mixture of 80–90% specially prepared pure α -lactose monohydrate along with 10 –20% of amorphous lactose. It is one of the few direct compression excipients available from more than a single supplier.

Spray-dried lactose is produced by spray drying the slurry containing lactose crystals. The final product contains mixture of larger crystals of α-lactose monohydrate and spherical agglomerates of smaller crystals held together by glass or amorphous material.

Spray-dried lactose has excellent fluidity and possesses good compression characteristics. Its fluidity results from the large particle size and intermixing of spherical aggregates. The compressibility is due mainly to the percentage of amorphous material present and the resulting plastic flow which results under compaction pressure.

Spray-dried lactose is relatively non-hygroscopic but contains approximately 5% moisture most of which is water of hydration. The free surface moisture is less than 0.5% and does not cause significant formulation problems for moisture sensitive drugs. Compressibility is affected if the material is allowed to dry below a level of 3% w/w moisture.

Spray-dried lactose has relatively poor dilution potential. It is an effective direct compression filler at high loading, that is, when it makes up the major portion of the tablet (more than 80%), but it is not effective in diluting high dose drugs whose crystalline nature is, in itself, not compressible.

Spray-dried lactose is widely used as binder, filler-binder, and flow aid in direct compression tableting. Its use is limited by two major problems namely:

  1. Darkening of the tablets on aging
  2. Loss of flow and compressibility when re-worked or milled.

The browning or darkening effect is considered to be due to the presence of large amount of contaminants (mainly 5-hydroxy furfural) which was not removed from the mother liquid before spray-drying. Although the contaminants are now removed during the manufacturing process in many products the specter of browning still remains.

Spray-dried lactose is available from a number of commercial sources in a number of forms. Because the processing conditions used by different manufacturers may vary, all spray-dried lactoses do not necessarily have the same properties and so it should be validated before use.

Anhydrous Lactose (USP)

This is a white to off-white, free-flowing crystalline powder that is widely used in direct compression tableting.  It exists in two isomeric forms: α-lactose and β-lactose, with the commercially available anhydrous lactose typically containing 70–80% anhydrous β -lactose and 20–30% anhydrous α-lactose. The β form, in general, is more soluble, while the α-form shows poor disintegration properties.

Anhydrous lactose is made by roller drying of lactose solution above 93.5oC followed by milling and sieving.  The temperature of crystallization influences the ratio of α- and β-lactose present in the final product.

Anhydrous lactose has been found to have excellent tableting properties. It exhibits small weight variation, fast disintegration, low friability and lack of binding, sticking and capping of tablets. It exhibits lesser tendency for maillard reaction. It can be re-worked or milled with less loss of compressibility than occurs with other forms of lactose.

Anhydrous lactose has fairly high hardness pressure profile and exhibits a capacity of about 30 to 35 in compacting non-compressing materials. At high humidities, it absorbs moisture and converts into the monohydrate. This is often accompanied by an increase in the size of the tablets if the excipient makes up a large portion of the total weight.

Being a reducing sugar, anhydrous lactose can undergo reaction with primary and secondary amines when stored under conditions of high humidity for extended periods.




Fast Flo® Lactose

Fast Flo® lactose was introduced in the early 1970’s after many abortive attempts to improve on spray-dried lactose. It consists mainly of spherical aggregates of microcrystals. These microcrystals are lactose monohydrate, and they are held together by a higher concentration of glass than is found in regular spray-dried lactose. During the manufacturing process the microcrystals are agglomerated into spheres by spray-drying.

Fast Flo® lactose possesses relatively excellent flow characteristics because of the spherical nature of the spray-dried aggregates. It is non-hygroscopic. Tablets made from Fast Flo® lactose are three to four times harder than those made from regular spray-dried lactose at the same compression pressure.

Fast Flo® lactose has replaced regular spray-dried lactose in many new direct compression formulations as filler because of its high compressibility.

Spray-Crystallized Maltose and Dextrose (Dextrates)

Spray-crystallized maltose-dextrose is one of the most dramatic modifications of natural raw materials for improving tableting characteristics. It is a purified mixture of saccharides resulting from the controlled enzymatic hydrolysis of starch. This product is spray-crystallized and consists of dextrose microcrystals in the form of free-flowing porous spheres, maltose and higher glucose saccharides.

Spray-crystallized maltose-dextrose occurs as white, odourless, free-flowing, porous spheres with sweet taste (about half as sweet as sucrose). It is generally used as a directly compressible tablet diluent in chewable, non-chewable, soluble, dispersible, and effervescent tablets. It has good binding properties and slight lubricant sensitivity.

Spray-crystallized maltose-dextrose is available as both an anhydrous and a hydrous product. The anhydrous form is reported to be slightly more compressible than the monohydrate. Both anhydrous and hydrous spray-crystallized maltose-dextrose possess excellent compressibility and is second only to microcrystalline cellulose when not diluted with drugs or other excipients.

Both forms of dextrose become quite hygroscopic at approximately 75% RH. The tendency to absorb moisture increases if the excipient has been milled or sheared on the surface of a die table. Relative humidities above 80% lead to liquefaction of the material.

Spray-crystallized maltose-dextrose possesses the largest particle size of all the common direct compression excipients. Blending problems can occur if blends of other excipients are not used to fill in voids. Tablets produced from spray-crystallized maltose-dextrose show an increase in hardness of approximately up to 10 kg. The increase occurs in the first few hours after compression with no further significant hardening on long-term storage under ambient conditions. This increase in hardness has been found not to result in significant changes in rates of dissolution.

Spray-crystallized maltose-dextrose is incompatible with oxidizing agents. It may react with substances containing a primary amino group (Maillard reaction) at high temperatures and humidities. Spray-crystallized maltose-dextrose was formerly marketed under the name Celutab® but it is now available as Emdex®.

Crystalline Sorbitol

Sorbitol is an odourless, white or almost colourless, crystalline, hygroscopic powder with about half the sweetness of sucrose. It is a cool-tasting polyol that occurs naturally in the ripe berries of many trees and plants.  Industrially, sorbitol is prepared by high-pressure hydrogenation with a copper–chromium or nickel catalyst, or by electrolytic reduction of glucose and corn syrup. If cane or beet sugars are used as a source, the disaccharide is hydrolyzed to dextrose and fructose prior to hydrogenation.

Sorbitol exists in four polymorphic crystalline forms as well as an amorphous form that varies both in compressibility and stability. In the presence of moisture the less stable α- and β-polymorphs may convert to the more stable dendritic γ-form, which may cause powder caking. Direct compression sorbitols should be validated when changing from one supplier to the other. Failure to do so have caused major problems among users.

Recently more stable products e.g., Sorbitol® 834 and Neo-Sorb® 60 which seem to overcome some of the problems encountered with sorbitol have been introduced into the market. The interchange of one directly compressible form for another is not recommended without some preliminary testing of performance/ validation.

Sorbitol possesses a cool taste and a good mouthfeel.  It forms a relatively hard compact when compressed into tablets. Compression characteristics and the degree of lubrication required vary, depending upon the particle size and grade of sorbitol used.

Crystalline Sorbitol is used as diluent in tablets prepared by either wet granulation or direct compression. It is widely used as the sole ingredient in “sugar-free” tablets and as a filler and binder in chewable tablets. However, it is hygroscopic and may lose its fluidity at humidities above 65 %. Powder mix containing sorbitol clumps in the feed frame and stick to the surfaces of the die table when tableted in an area of high humidity.

Sorbitol is chemically relatively inert and is compatible with most excipients. It is stable in air in the absence of catalysts and in cold, dilute acids and alkalis. It does not darken or decompose at elevated temperatures or in the presence of amines.

Mannitol

This is another type of sugars used in direct compression technology. It is a white, odourless, crystalline powder, or free-flowing granules commercially produced by the catalytic or electrolytic reduction of monosaccharides such as mannose and glucose. It is widely used in the direct compression of reagent tablets where rapid and complete solubility is required and can be lubricated for this purpose with micronized polyethylene glycol 6000.

Mannitol possesses fairly good fluidity and compressibility. It is considered an ideal direct compressible excipient for chewable tablets largely because of its smooth mouth-feel and negative heat of solution, which gives a cooling effect. Furthermore, it is non-hydroscopic and hence it is recommended for moisture sensitive drugs. It is commonly a component of direct compression vehicles for moisture sensitive vitamins.

Mannitol is present in different polymorphic forms and they have different compression characteristics. The major drawback to its use are problems of unblending as a result of relatively large particle size and relatively high cost.

Sucrose

Over the years sucrose has been extensively used in tablets as a filler. Attempts over the years, however, to directly compress sucrose crystals have never been successful. In recent years, various modified sucroses have been introduced into direct compression formulations. These include Di-Pac® and NuTab®.

Di-Pac®

Di-Pac is a free-flowing, sweet-tasting, directly compressible, co-crystallized sugar consisting of 97% sucrose and 3% modified dextrin.  It is an agglomerated product consisting of hundreds of small sucrose crystals “glued” together by the highly modified dextrin.

Di-Pac has good flow properties but begins to cake and lose its fluidity at high relative humidity. Tablets containing a high proportion of Di-Pac tend to harden slightly within hours of compression, or when at high humidities. Di-Pac has excellent colour stability on aging, probably the best of all the sugars. Di-Pac has an average dilution potential in the range of 20 to 35%. It is usually employed compression filler/binder for chewable tablets.

 



NuTab®

NuTab is a roller compacted direct compression excipient composed of 95% sucrose, 4 % invert sugar and small amounts of cornstarch and magnesium stearate (about 0.1 – 0.2%). The latter two ingredients are process aids for the granulation rather than tableting disintegrant or lubricant. NuTab has a relatively large particle size distribution which makes for good flow but could cause blending problems if co-fillers and drugs are not carefully controlled relative to particle size and amounts. In formulations, NuTab has poor colour stability relative to other direct compression sucrose and lactose. It is primarily used in the manufacture of chewable tablets by direct compression.

Conclusion

Tablet manufacturing has taken a new dimension since the advent of direct compression technology. Although a vast majority of drug substances are not in themselves suitable for direct compression, the technique has recently grown in importance due to the commercial availability of suitable machinery and direct compressible excipients which possess good flow and compressibility properties.

References

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  • Gohel, M. (2005). A review of co-processed directly compressible excipients. Journal of Pharmaceutical Science, 8(1): 76-93.
  • Ofoefule, S. I. (2002). Textbook of Pharmaceutical Technology and Industrial Pharmacy. Nigeria: Samakin (Nig) Enterprise.
  • Patel, R. and Bhavsar, M. (2009). Directly Compressible Materials via Co-Processing. International Journal of PharmTech Research, 1(3): 745-753.
  • Rowe, R., Sheskey, P. and Quinn, M. (2006). Handbook of Pharmaceutical Excipients (6th). UK: Pharmaceutical Press and American Pharmacists Association.
  • Singh, P., Shuaib, M., Iqubal, A. and Singh, M. (2014). Recent Advances in Direct Compression technique for Pharmaceutical Tablet Formulation. International Journal of Pharmaceutical Research and development, 6(1): 49-57.
  • Wells, J., Langridge, J., (1981). Dicalcium Phosphate Dihydrate – Microcrystalline Cellulose Systems in Direct Compression Tabletting. International journal of pharmaceutical technology & product manufacture, 2:1-8.

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