1. INTRODUCTION:

Pharmaceutical excipients are substances other than the pharmacologically active drug or prodrug which are included in the manufacturing process or are contained in a finished pharmaceutical product dosage form.¹ Like drug substances, excipients are derived from natural sources or are synthesized either chemically or by other means. They range from simple, usually highly characterized, organic, or inorganic molecules to highly complex materials that are difficult to fully characterize.

In earlier days, excipients were considered inactive ingredients. Over time pharmaceutical scientists learned that excipients are not inactive and frequently have substantial impact on the manufacture and quality, safety, and efficacy of the drug substance(s) in a dosage form.

Excipients provide wide variety of functionalities^2,3 such as

· Better possibility of different APIs into the dosage forms

· Better tablet binding

· Better tablet disintegration

· Better API stability

· Better API solubility

· Better API bioavailability

· Drug Release controlling agent

They are classified by the functions they perform in a pharmaceutical dosage form. Principal classification of the excipients based on their functions is given in table 1: ⁴

Out of all the dosage forms available, tablets formulations are the most preferred dosage form in pharmaceutical industry as well with the patients.

Wet granulation has been a method of choice for preparation of tablet dosage form; however with availability of excipients with good flow and compressibility and high speed compression machines, direct compression has gained popularity among the development scientists.

The majority of the excipients that are currently available individually fail to live up to the functionality requirements like good flowability, good compressibility, low or no moisture sensitivity, low lubricant sensitivity, and good machine ability even in high-speed tableting machinery with reduced dwell times, thus creating the opportunity for the development of new high-functionality excipients.

Factors driving the search for new excipients are:

· The growing popularity of the direct-compression process and a demand for an ideal filler–binder that can substitute two or more excipients.⁵

· Tableting machinery’s increasing speed capabilities, which require excipients to maintain good compressibility and low weight variation even at short dwell times.

· 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.^6,7

· The lack of excipients that address the needs of specific patients such as those with diabetes, hypertension, and lactose and sorbitol sensitivity.

· The ability to modulate the solubility, permeability, or stability of drug molecules

· The growing performance expectations of excipients to address issues such as disintegration, dissolution, and bioavailability.

New excipients development is possible through combinations of existing excipients to achieve the desired set of performance characteristics. However, the development of such combinations is a complex process because one excipient may interfere with the existing functionality of another excipient. Over the years, the development of single-bodied excipient combinations at a sub particle level, called coprocessed excipients, has gained importance.^8,9

2.0 COPROCESSING:

The fundamental solid-state properties of the excipient particles such as morphology, particle size, shape, surface area, porosity, and density influence excipient functionalities such as flowability, compatibility, dilution potential, disintegration potential, and lubricating potential. Hence, solid state properties of excipient particles are important for the existing excipients and new excipients under development. But development of a new excipient is limited because of high costs and regulatory hurdles. New combinations of existing excipients provide a method to not only enhance processibility, but also to add functionality.¹⁰

A much broader platform for the manipulation of excipient functionality is provided by coprocessing or particle engineering two or more existing excipients. Coprocessing is based on the novel concept of two or more excipients interacting at the subparticle level, the objective of which is to provide a synergy of functionality improvements as well as masking the undesirable properties of individual excipients.¹¹

Coprocessed excipients are prepared by incorporating one excipient into the particle structure of another excipient using processes such as co-drying. Thus, they are simple physical mixtures of two or more existing excipients mixed at the particle level. Coprocessing was initially used by the food industry to improve stability, wettability, and solubility and to enhance the gelling properties of food ingredients such as coprocessed glucomannan and galactomanan.¹² Coprocessing of excipients in the pharmaceutical industry can be dated back to the late 1980s with the introduction of coprocessed microcrystalline cellulose and calcium carbonate¹³, followed by Cellactose (Meggle Corp., Wasserburg, Germany) in 1990, which is a coprocessed combination of cellulose and lactose. A similar principle was applied in developing silicified microcrystalline cellulose (SMCC), which is the most widely used coprocessed excipient.^{14, 15, 16}

Coprocessing excipients have been developed primarily to address the issues of flowability, compressibility, and disintegration potential, with filler–binder combinations being the most commonly tried. The combination of excipients chosen should complement each other to mask the undesirable properties of individual excipients and, at the same time, retain or improve the desired properties of excipients. For example, if a substance used as a filler–binder has a low disintegration property, it can be coprocessed with another excipient that has good wetting properties and high porosity because these attributes will increase the water intake which will aid and increase the disintegration of the tablets. Table 1 gives the list of marketed coprocessed excipients.¹⁷

2.1 Steps for coprocessing of excipients:

The process of developing a coprocessed excipient involves the following steps:

· Identifying the group of excipients to be coprocessed by carefully studying the material characteristics and functionality requirements

· Selecting the proportions of various excipients

· Assessing the particle size required for coprocessing. This is especially important when one of the components is processed in a dispersed phase. Post processing the particle size of the latter depends on its initial particle size.

· Selecting a suitable method for coprocessing

· Selecting a suitable process of drying such as spray- or flash drying or any other suitable method.

· Optimizing the process (because even this can contribute to functionality variations).

2.2 Methods of co-processing:^{18- 20}

Different methods can be used for coprocessing of pharmaceutical excipients depending on heat stability, compatibility, solubility in particular solvents, crystallinity and other physical properties of the excipients to be used in combination. Various methods that can be used for coprocessing are:

· Wet granulation

· Dry blending

· Compaction- Formation of slugs

· Melt granulation

· Melt extrusion

· Formation of agglomerates

· Formation of thin films and sifting

· Spray drying – most efficient and widely used method

Table 2 gives all the methods of coprocessing along with the advantages, limitations and examples.

2.3 Properties and Advantages of co-processed excipients:²⁷

Ø The primary attribute associated with these excipients is that no chemical change exists during co-processing, and all the reflected changes show up in the physical properties of the excipients particles.

Table 1 : Function based Classification of Excipients

Binders

Disintegrants

Preservatives

Film formers/coatings

Solubilizers

Colors

Release Modulators

Suspending/dispersing agents

Glidants (flow enhancers)

Emulsifying agents

Flavors

Compression aids

Fillers (diluents)

Lubricants

Stabilizers

Table 1 List of marketed coprocessed excipients.

Excipients

Composition

Characteristics/Properties

Manufacturer

Captisol

Modified Cyclodextrin Sulfobutylether – Cyclodextrin

Improves API water solubility

CyDex

Pharmaceuticals, Inc. USA

KLEPROSE DC

cyclodextrin

Direct compression,

Insitu encapsulation of APIs

Rouquette Pharma,

France

galenI Q 721

Agglomerated isomalt

Direct compression, very fast disintegrating

Beneo Palatnit, Germany

Eudragit

Plasdone® S-630

Acrylic polymers

Vinyl acetate, Vinyl pyrrolidone

Controlled release

Tablet binder, improves compressibility of other binders and fillers

Evonik – Deguss a, Germany

International Specialty Products

USA

Kollidon® CL,

CL-F, CL-SF,

CL-M

Kollicoa® IR protect

Crosslinked water insoluble polyvinyl pyrrolidone

Polyvinyl alcohol polyethylene glycol graft copolymer, polyvinyl alcohol silicon dioxide

Size modification to application needs for disintegration and solubility enhancement

Instant release coating protective against moisture, taste masking

BASF, Germany

Ludipress®

LCE

Lactose, Kollidon 30,

Kollidon CL

Lactose; Povidone (Kollidon 30)

Direct compression, high powder flowability, tablet hardness, disintegration functionality

Direct compression auxiliary to use in chewable tablets, lozenges; effervescent tablets

BASF, Germany

Pharmactose®

DCL 40

lactose, lactitol

Co-pressed, high compatibility

DMV, Germany

StarLac®

Lactose, maize starch

Direct compression, high flowability, disintegration

Meggle GmbH, Germay

Cellactose

Lactose, Cellulose powder

Direct compression, high compressibility

Meggle GmbH, Germay

MicroceLac®

Prosolv®

MCC, lactose

MCC, Silicon dioxide

Direct compression, high flowability

Direct compression; Wet granulation

high compressibility, high flowability

Meggle GmbH, Germay

JRS Pharma USA

(Penewst USA)

Avicel® CELS

MCC, guar gum

Less grittiness, creamier mouth feel

FMC, USA

Avicel® HFE 102

Ceolus^TM RC

Ran Explo^TM C

MCC, mannitol

MCC, NaCMC

MCC, Silica crospovidone

Direct compression; maximizes compatibility at high lubricant level

Colloidal grade, suspension stabilization and granulation aid

Improved flowability; super disintegrant

FMC, USA

Asahi Kasel America, Inc.

RarQ

Pharmaceutical India

RanExplo^TM-S

MCC, silica, sodium starch glycolate

Improved flowability, super disintegrant

RarQ

Pharmaceutical India

StarCap® 1500

Corn starch, pregelatinized starch

Wet and dry granulation binder; enhances functionality of other binders

BPSI H ol dings, Inc.

Compressol® S

PanExcea^TM

MHC300G

Polyols

MCC, Hydroxypropyl methyl cellulose, crospovidone

Direct compression; superior compatibility, high active loading

Direct compression; Particle engineered with filler, binder and disintegrant functionality, high flowability, high

SPI, USA

Mallinckrodt

Baker, Inc.

Ø Absence of chemical change: - Detailed studies of SMCC with X-ray diffraction analysis, solid-state nuclear magnetic resonance (NMR), IR spectroscopy, Raman spectroscopy, and C13 NMR spectroscopy have detected no chemical changes and indicate a similarity to the physicochemical properties of MCC.^{28, 29}

Physicomechanical properties:

Ø Improved flow properties: Controlled optimal particle size and particle-size distribution ensures superior flow properties of coprocessed excipients without the need to add glidants.

Ø Improved compressibility: Coprocessed excipients have been used mainly in direct-compression tableting because in this process there is a net increase in the flow properties and compressibility profiles and the excipient formed is a filler–binder. The compressibility performance of excipients such Cellactose,³⁰ SMCC ^{31, 32} and Ludipress³³ have been reported to be superior to the simple physical mixtures of their constituent excipients.

Figure 1: Schematic representation of arrangement of Xanthan molecules in water

Ø Better dilution potential: Dilution potential is the ability of the excipient to retain its compressibility even when diluted with another material. Most active drug substances are poorly compressible, and as a result, excipients must have better compressibility properties to retain good compaction even when diluted with a poorly compressible agent.

Ø Fill weight variation: Materials for direct compression tend to show high fill-weight variations as a result of poor flow properties, but coprocessed excipients, when compared with simple mixtures or parent materials, have been shown to have fewer fill-weight variation problems. The primary reason for this phenomenon is the impregnation of one particle into the matrix of another, which reduces the rough particle surfaces and creates a near-optimal size distribution, causing better flow properties

Ø Reduced lubricant sensitivity: Most coprocessed products consist of a relatively large amount of brittle material such as -lactose monohydrate and a smaller amount of plastic material such as cellulose that is fixed between or on the particles of the brittle material³⁴. The plastic material provides good bonding properties because it creates a continuous matrix with a large surface for bonding. The large amount of brittle material provides low lubricant sensitivity because it prevents the formation of a coherent lubricant network by forming newly exposed surfaces upon compression, thus breaking up the lubricant network.

Ø Modulating Drug Release: Coprocessing can alter and improvise the mechanism of drug release and provide formulator opportunity to tailor the product and overcome limitation of single polymer. Coprocessed extended release polymers can provide better delay or control of release rate of a medicament or nutritional supplement creating a wide range of release profiles for a wide range of medicaments. Through coprocessing of polymers, it is possible to produce equivalent or enhanced tabletting performance for direct compression. These polymers not only improve sustained release characteristics when compared to the individual polymers, but in most cases, in tablet form have shown improved tablet hardness, improved tablet friability and a more manageable and predictable granulation endpoint

Figure 2: Schematic representation of Locust Bean Gum molecules in an aqueous gel

Other properties: Coprocessed excipients offer the following additional advantages:

§ Pharmaceutical manufacturers have the option of using a single excipient with multiple functional properties, thereby reducing the number of excipients in inventory.

§ Allow the development of tailor-made designer excipients with retention of functional and removal of undesirable properties, which can help in faster product development.

§ Improved organoleptic properties such as those in Avicel CE- 15 (FMC Corp., Philadelphia, PA), which is a coprocessed excipient of MCC, and guar gum were shown to have distinctive advantages in chewable tablets in terms of reduced grittiness, reduced tooth packing, minimal chalkiness, better mouthfeel, and improved overall palatability.

§ Reduce product cost due to improved functionality and fewer test requirements compared with individual excipients.

§ Provide intellectual benefits and opportunity for product life cycle extension.

3.0 Coprocessed excipients for MODIFIED release and Its Current Overview:

Once considered mainly an afterthought in a company's lifecycle-management strategy, controlled-release dosage forms are now positioned at the forefront of many formulation strategies. In contrast to drug discovery, formulation work focuses not only on the intricacies of the active pharmaceutical ingredient (API), but also on fine-

Table 2 Methods of coprocessing

Method	Advantages and limitations	Examples
Chemical Modification	Relatively expensive Requires toxicological data Time consuming	Ethyl cellulose, Methylcellolose, Hydroxypropyl methylcellulose, and sodium carboxymethyl cellulose from cellulose Cyclodextrin from starch²¹ Lactitol
Physical Modification	Relatively simple and economical	Dextrates or Compressbile sugar, sorbitol
Grinding and/or Sieving	Compressibility may also alter because of changes in particle properties such as survade area and surface activation	α-Lactose monohydrate (100#) Dibasic dicalcium phospate²²
Crystallization	Impact flowability to excipients but not necessarily self-binding properties. Requires stringent control on possible polymorphie conversions and processing conditions.	β-Lactose²³ Dipac
Spray Drying	Spherical shape and uniform size gives spray-dried materials good flow ability, poor re workability	Spray dried lactose, Emdex^24,25 Fast Flow Lactose, Avicel PH
Granulation/Agglomeration	Transformation of small into a flowable and directly compressible	Granulated Lactitol, Tablettose
Dehydration	Increased binding properties by thermal and chemical dehydration	Anhydrous α-Lactose

Table 3 Developmental and clinical benefits of TIMERx^® technology

Development Benefits

Clinical Benefits

· Shortens development time through cutting-edge research tools and efficient processes, providing a speed-to-market advantage.

· Reduces attrition rates for new active substances.

· Provides compatibility with a broad range of actives.

· Offers a range of flexible release profiles to meet your requirements.

· Provides patent protection.

· Requires no capital investment.

· Precisely controls drug delivery.

· Provides effective product segmentation.

· Improves efficacy, therapeutic performance, and outcomes.

· Reduces side effects.

· Reduces dosing frequency.

· Achieves new indications for broader prescribing options.

· Increases convenience and patient compliance.

· Enhances patient health and quality of life.

The TIMERx^® technology³⁷ is based on an agglomerated hydrophilic complex that forms a controlled-release matrix upon compression. The matrix consists of two polysaccharides, xanthan(X) and locust bean gum (LBG). Interactions between these components in an aqueous environment form a tight gel with a slowly-eroding core.

tuning the excipients, the release profile, and the delivery mechanism to provide optimal therapeutic benefit. Excipients such as polymers play important role in their development.

Most of the coprocessed excipients available in the market are developed for immediate release drug delivery system. However whenever it comes to modified release drug delivery, generally physical admixtures of the polymers are being used. Few excipient manufacturers have taken efforts towards development of coprocessed excipients for modified release and this will be area of interest in future Few of the major Pharmaceuticals or excipients manufacturing companies who have worked and commercialized products are Penwest Pharmaceuticals, BASF, Evonik, Dow Chemicals and Aqualon.

Aqueous dispersions of Methacrylic acid copolymers, Hydroxy Propyl Methyl Cellulose Phthalate (HPMCP), Cellulose Acetate Phthalate (CAP), Hydroxy Propyl Methyl Cellulose Phthalate Succinate (HPMCPS), Ethyl Cellulose (EC) are some very good examples of co-processed excipients which were developed with intention to convert non aqueous coating into eco-friendly aqueous systems.

Hypromellose (HPMC) a widely used hydrophilic rate-controlling polymer in oral controlled-release (CR) drug delivery applications since it offers flexibility in formulation and function for preparation of oral solid dosage forms. However, its application in direct compression (DC) tabletting processes is limited in some cases and complicated in others because of its poor powder flow properties. Recently Dow introduced Modified grade of HPMC with improved powder flow while maintaining suitable compressibility and CR performance and minimizing segregation.³⁵ This development is one of major efforts by the manufacturer to address and improvise the excipients functionality.

Various polymers can perform essentially the same function, but the key to developing products that will reach market acceptability is to prove a considerable processing or other functionality advantage. BASF developed its polyvinyl acetate (PVA)-based materials, Kollidon SR (PVA/PVP matrix) and Kollicoat SR 30D (30% aqueous dispersion of polyvinyl acetate stabilized with polyvinyl pyrrolidone), to deliver new performance characteristics to distinguish it from existing, well-accepted agents.

Identifiying disadvantages of existing CR polymers such poor flowability, compressibility, processing challenges, influence of ionic strength and pH on release, Kollidon SR was developed as a new direct compressible excipient for sustained release matrices. Kollidon SR is a formulated, free flowing, non-hygroscopic powder consisting of 8 parts (w/w) polyvinyl acetate and 2 parts (w/w) polyvinylpyrrolidone. Kollidon SR should retain the useful properties of a hydrophilic matrix forming agent, avoiding the drawbacks of the commercially available products.³⁶

Penwest Pharmaceuticals and their Technologies:

Penwest Pharmaceuticals have introduced coprocessed excipient for modified release which comprises of two polysaccharides. Penwest engineered the interaction between the two polymer molecules to allow them to become entwined, disentangled, more entangled or dissolved with time depending on the requirement or in response to physiological conditions. The keys that switch the molecular engine on and off are London- van der Waals, hydrogen and/or ionic bonds between the two heterodisperse polysaccharides. This technology is named TIMERx^®.

The TIMERx^® oral controlled release delivery system to modify the release of drugs to provide a therapeutic benefit to patients by delivering medicines that are more efficacious and provide greater patient compliance. The technology is cost-effective and easy to scale-up and manufacture.

Figure 3: Schematic representation of optimal synergistic interaction of LBG molecules with X in an aqueous gel.

Time Rx^® Technology:³⁷

TIMERx can be used in:

· Low to high dose drugs

· Insoluble to highly-soluble drugs

· Drugs with short half-life and/or narrow therapeutic window

TIMERx^® Benefits

TIMERx^® Provides Significant Advantages throughout the Drug Development Process

The TIMERx^® technology provides development benefits as well as clinical benefits.

In many cases the barrier zone is provided by a tablet coating or core matrix that remains in place and through which the drug moves i.e. a “fixed barrier” type of a release. Less commonly, the barrier does not remain in place but is ‘lifted’ with time by the actions of dissolution or diffusion which is a “lifted barrier” type of a release. TIMERx^® tablet technology (Penwest Pharmaceuticals) is capable of achieving both fixed barrier and lifted barrier type release control. In addition TIMERx^® technology allows “fixed-lifting” control systems in which the barrier zone can be lifted and then be replaced, to be lifted again at later time.

LBG is a long chain homopolysaccharide which is physicochemically more complex than LBG. LBG has two distinct regions alternating along the mannose backbone; “Hairy region” (region where galactose molecules stick out from the mannose backbone) and “Smooth region” (regions that are free of galactose molecules). The smooth regions allows two LBG molecules to become hydrogen bonded producing a three dimensional interlocking network of LBG molecules in water. LBG can form a true gel structure which requires energy and in case of pure LBG it only occurs when it is dispersed in water at ≥ 60°C. Hence LBG is unsuitable as a CR material when used alone.

LBG is mixed with X resulting in the rigid helices of X becoming incorporated into true gel structure of LBG molecules.

Interaction of LBG and X can be considered as synergistic because there is increase in viscosity when used in combination as compared to either material used alone. These interactions can be further enhanced by stimulating ionic interactions through incorporation of cations. Manipulations of the basic X/LBG synergistic interaction using third or fourth component materials are used to provide specific single-order release profiles, as well as multi-order drug release profiles.

The TIMERx^® molecular engine can be manipulated by formulation to provide the different interaction rate profiles required for different CR profiles.

Other technologies based on common TIMERx^® platform are Geminex^®, SyncroDose™, GastroDose technology.³⁸

In these newer technologies, such as Penwest pharmaceutical’s TIMERx hydrogel tablets, complex time-dependent physical chemical interactions between pharmacologically inert excipient molecules are used to control drug release. These specialized drug delivery ingredients form the molecular engines that power the new generation of CR tablets capable of more flexible drug delivery, such as biphasic or chronotherapeutic release, as well as straight line, zero order profiles, to get the best performance to the patient in a form that promotes treatment adherence.

4.0 A regulatory perspective of the excipient mixtures:^{39, 40}

There are no processes or mechanisms in place to evaluate the safety of pharmaceutical excipients independent of APIs, since excipients are only approved as a component of new drug products. The FDA requires that the new drug applications (NDAs) and Abbreviated New Drug Applications (ANDAs) include information about all components of the drug products, including excipients. To identify previously reviewed excipients, the FDA looks to several sources, such as Generally Recognized As Safe(GRAS) status, favorable reviews by the Joint Experts Committee on Food Additives, inclusion in USP/ NF, and/or reviews of other NDAs. These excipients are identified in FDA’s Inactive Ingredient Guide (IIG). However, the absence of excipient reviews that are independent of APIs present problems for companies that seeks to use new or novel excipients in their drug products. In its May 2005, Guidance for Industry, the FDA detailed recommendations on safety evaluations.^{41, 42}According to that guidance, with the absence of a chemical change during processing, coprocessed excipients can be considered generally regarded as safe (GRAS) if the parent excipients are also GRAS- certified by the regulatory agencies. Hence, these excipients do not require additional toxicological studies. Excipient mixtures or coprocessed excipients have yet to find their way into official monographs, which is one of the major obstacles to their success in the marketplace. The mixture of excipients was presented as a topic to the National Formulary and was assigned a priority on the basis of the use of the mixture in marketed dosage forms in which processing has provided added functional value to the excipient mixture.

5.0 CONCLUSION:

Need of industry for ease of processing and improved functionality has forced the excipient industry to search for new excipients. The excipient industry, have used coprocessing of excipients to deliver new excipients having better performance. Improved functionality is the key to success and acceptance of coprocessed excipients. The coprocessed excipients have lesser regulatory hurdles for approvals. Commercially number co-processed excipients are available for immediate release formulation; however there is need to have more of them for Modified release products. There is a need for to set up independent approval process to approve new excipient by regulatory bodies. Introduction of new excipients through coprocessing is gaining momentum due to need of improved functionality requirement for formulation of new synthetic and biopharmaceutical drugs. Number of new coprocessed excipients have arrived in market which are expected to deliver new performance characteristics which will distinguish them from existing, well-accepted agents.

6.0 REFERENCES:

1. IPEC–Americas, “Frequently Asked Questions” http://www.ipecamericas.org/public/faqs.html

2. Deorkar N, Baker M. High functionality Excipients: A Review. Tablets and Capsules, 2008.

3. Armstrong NA. Functionality Related Tests for Excipients. Int. J. Pharm. 1997; 155; 1-5.

4. Banker UV. Role of Ingredients and Excipients in Developing Pharmaceuticals. Manuf. Chem. 1994; 65: 32- 34.

5. Jivraj M, Martini LG and Thomson CM. An Overview of the Different Excipients Useful for the Direct Compression of Tablets. PSTT; 2000; 3; 58-63.

6. Tobyn MJ et al. Physicochemical Comparison between Microcrystalline Cellulose and Silicified Microcrystalline Cellulose. Int. J. Pharm. 1998; 169, 183–194.

7. Reier GE and Shangraw RF. Microcrystalline Cellulose in Tableting. J. Pharm. Sci.1966; 55; 510-514.

8. Moreton RC. Tablet Excipients to the Year 2001: A Look into the Crystal Ball. Drug Dev. Ind. Pharm. 1996; 22 (1), 11–23.

9. Khan KA and Rhodes CT. The Production of Tablets by Direct Compression. Can. J. Pharm. Sci. 1973; 8; 1-5.

10. Reimerdes D and Aufmuth KP. Tableting with Coprocessed Lactose– Cellulose Excipient. Manufacturing Chemist. 1992; 63(12); 23–24.

11. Reimerdes D. The Near Future of Tablet Excipients. Manufacturing Chemist. 1993; 64 (7), 14–15.

12. Modliszewski JJ and Ballard DA. Coprocessed Galctomannan– Glucomannan. US Patent No. 5,498,436 to FMC Corporation (Philadelphia , PA) 1996.

13. Dev KM et al. Coprocessed Microcrystalline Cellulose and Calcium Carbonate and Its Preparation. US Patent No. 744,987 to FMC Corporation (Philadelphia, PA) 1988.

14. Bolhius GK and Chowhan ZT. Materials for Direct Compaction. In Pharmaceutical Powder Compaction Technology, Edited by Alderborn G and Nystrom C. Marcel Dekker Inc., Madison Avenue, New York, NY 10016. 1996; 71; 419–500.

15. Fraser SD. Et al. Physicochemical and Mechanical Evaluation of a Novel high Density Grade of Silicified Microcrystalline Cellulose. Drug Dev. Ind. Pharm. 2004; 30; 103-109.

16. Allen JD. Improving DC with SMCC. Manuf. Chem. 1996; 67: 19-20and 23.

17. Bansal AK, Nachaegari SK. Improved Excipient Functionality by Coprocessing. In Excipient Development for Pharmaceutical Biotechnology and Drug Delivery Systems, Edited by Chaubal M, Katdare A. Informa healthcare, New York, London. 2006; Chapt. 9; 109-124.

18. Reimerdes D. The Near Future of Tablet Excipients. Manuf. Chem. 1993; 64; 14-15.

19. Shangraw RF. et al. Morphology and Functionality in Tablet Excipients for Direct Compression. Pharm. Technol. 1987,11; 136- 143.

20. Bolhius GK and Chowhan ZT. Materials for Direct Compaction. In Pharmaceutical Powder Compaction Technology, Edited by Alderborn G and Nystrom C. Marcel Dekker Inc., Madison Avenue, New York, NY 10016. 1996; 71; 419–500.

21. Manudhane KS. et al. Tableting Properties of a Directly Compressible Starch. J. Pharm. Sci. 1969; 58; 616- 620.

22. Doldan C. et al. Dicalcium Phosphate Dihydrate and Anhydrous Dicalcium Phosphate for Direct Compression: Comparative study. Int. J. Pharm. 1995; 124; 69-74.

23. Steven P. and Zimmerman K. Lactose: the Natural Excipient. Manuf. Chem. 1986; 57; 77-80.

24. Gunsel WC and Lachman L. Comparative Evaluation of Tablet Formulations Prepared from Conventionally processed and Spray-dried Lactose. J. Pharm. Sci. 1963; 52; 178-182.

25. Hasegawa M. Direct Compression Microcrystalline Cellulose Grade 12 versus Classic Grade 102. Pharm. Technol. 2002, 25; 50-60.

26. Bolhuis GK et al. Evaluation of Anhydrous Alpha-Lactose, a New Excipient in Direct Compression. Drug Dev. Ind. Pharm. 1985; 11; 1657-1681.

27. Nachaegari SK and Bansal AK. Coprocessed excipients for Solid Dosage Forms. Pharm. Technol. 2004; 28:11; 52-64.

28. Tobyn MJ. et al. Physicochemical Comparison between Microcrystalline Cellulose and Silicified Microcrystalline Cellulose. Int. J. Pharm.1998; 169; 183–194.

29. Lahdenpaa E et al. Direct Compression with Silicified and Non-Silicified Microcrystalline Cellulose: Study of Some Properties of Powders and Tablets. S. T. P. Pharm. Sci. 2001; 11; 129-135.

30. Belda PM and Mielck JB. The Tableting Behavior of Cellactose Compared with Mixtures of Celluloses with Lactoses. Eur. J. Pharm. Biopharm. 1996; 42 (5); 325–330.

31. Sherwood BE and Becker JW. A New Class of High Functionality Excipients: Silicified Microcrystalline Cellulose. Pharm. Technol. 1988; 22 (10); 78–88.

32. Allen JD. Improving DC with SMCC. Manufacturing Chemist. 1996; 67 (12); 19–20, 23.

33. Schmidt PC and Rubensdorfer CJW. Evaluation of Ludipress as a Multipurpose Excipient for Direct Compression Part I: Powder Characteristics and Tableting Properties. Drug Dev. Ind. Pharm. 1994; 20 (18), 2899–2925.

34. Maarschalk KVDV and Bolhius GK. Improving Properties of Material for Direct Compaction. Pharm. Technol. 1999; 23 (5); 34–46.

35. Using Dow Excipients for Controlled Release of Drugs in Hydrophillic Matrix Systems, http://www.dow.com/PublishedLiterature/dh_004e/0901b8038004ed9e.pdf?filepath=methocel/pdfs

36. Kollidone^® SR: A polyvinyl acetate based excipient for DC sustained- release oral dosage forms, http://www.iptonline.com/articles/public/IPTOLARTBASFNP.pdf

37. Staniforth JN and Baichwal AR. TIMERx^®: novel polysaccharide composites for controlled/ programmed release of drugs in the gastrointestinal tract. Drug Deliv. 2005; 2(3); 587- 595.

38. New Directions in Oral Drug Delivery – Drug Delivery Technologies (Penwest Pharmaceuticals) http://www.penw.com/drug_del_tech.html

39. Kristensen HG. Functionality – related characteristics of excipients. Pharmaceutical Technology. 2007; 134-140.

40. Rios M. Debating excipient functionality. Pharmaceutical Technology. 2006; 30; 50- 60.

41. Robertson MI. Regulatory Issues with Excipients. Int. J. Pharm. 1999; 187; 273-276.

42. Silverstein I. Excipient GMP Quality Standards One is Enough. Pharm. Technol. 2002; 25: 46-52.

Received on 25.09.2009 Modified on 22.11.2009

Research J. Pharm. and Tech. 3(1): Jan. - Mar. 2010; Page 50-57