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CO-PROCESSED EXCIPIENTS: AN OVERVIEW

Article · January 2019

DOI: 10.20959/wjpr201715-10078

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 World Journal of Pharmaceutical Research
Desu et al. SJIF Impact
World Journal of Pharmaceutical Factor 7.523
Research
Volume 6, Issue 15, 224-237. Review Article ISSN 2277– 7105

CO-PROCESSED EXCIPIENTS: AN OVERVIEW

B. Mamatha1, D. Srilatha1, C. H. Sivanarayani1, Prasanna Kumar Desu*1 and

P. Venkateswara Rao2

1
Department of Pharmaceutics, ST. Mary’s Group of Institutions Guntur, Chebrolu (V& M),
Guntur (Dt), Andhra Pradesh, India – 522212.
2
Department of Pharmaceutical Chemistry, ST. Mary’s Group of Institutions Guntur,
Chebrolu (V& M), Guntur (Dt), Andhra Pradesh, India – 522212.

ABSTRACT
Article Received on
22 Sept. 2017, This main aim of the current review article is to provide a complete
Revised on 12 Oct. 2017, overview on recent development in excipients technology and the
Accepted on 02 Nov. 2017
DOI: 10.20959/wjpr201715-10078
approaches involved in development of such excipients. Formulation
scientists recognized that single component excipients do not always
provide the requisite performance to allow certain active
*Corresponding Author
pharmaceutical ingredients to be formulated or manufactured
Prasanna Kumar Desu
Department of adequately and they have focused their attention on the production of
Pharmaceutics, ST. Mary’s multifunctional excipients with enhanced performance to meet the
Group of Institutions needs of formulation experts in terms of costs of production, enhanced
Guntur, Chebrolu (V& M),
excipient functionality and quality of tablets. Co-processed excipients
Guntur (Dt), Andhra
help to overcome the deficiencies occurring with the use of general
Pradesh, India – 522212.
grade excipients. The co-processed excipients retain favourable
attributes and are supplemented with new ones. As the chemical change is absent, they are
considered to retain the “GRAS” (Generally Regarded as Safe) status. Co-processed
excipients are believed to bring a drastic change in the field of pharmaceutical Research. Co-
processing is interesting because the products are physically modified in a special way
withoutaltering the chemical structure.

KEYWORDS: Co-Processing, Excipient Technology, pharmaceutical Research, chemical

structure.

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INTRODUCTION
In recent years scientists have found out that single-component excipients do not always
provide the requisite performance to allow certain active pharmaceutical ingredients to be
formulated or manufactured.[1] The excipients industry to date has been an extension of the
food industry.[2] Moreover, excipients are products of the food industry, which has helped
maintain a good safety profile. Increasing regulatory pressure on purity, safety and
standardization of the excipients has catalyzed the formation of an international body, the
International Pharmaceutical Excipients Council (IPEC).[3]

Pharmaceutical excipients are any substance other than the active drug product which has
been appropriately evaluated for safety and is included in a drug delivery system to either aid
processing of the system during manufacture or protect, support or enhance stability,
bioavailability, or patient acceptability or assist in product identification or enhance any other
attribute of the overall safety and effectiveness of the drug product during storage and use.
According to International Pharmaceutical Excipient Council (IPEC), co-processed excipient
is “a combination of two or more compendial or non-compendial excipients designed to
physically modify their properties in a manner not achievable by simple physical mixing and
without significant chemical change”.

There is considerable activity in the development of new and innovative excipients. Excipient
Innovations include excipients for orally disintegrating tablets and controlled-release
formulations. New technologies are being evaluated to increase the amount or rate of
absorption of drugs with new excipients. In the future, the application of nanotechnology may
be evaluated for developing novel excipients for new therapeutic solutions.

Thus this work focused on development of directly compressible co-processed excipients

comprising of polyethylene oxide and Hydroxyl propyl methyl cellulose by roller compaction
method and evaluation as a sustained release matrix forming polymer using water soluble
Metoprolol succinate and poorly water soluble anhydrous Theophylline as model drugs.is
formed into solid compacts and sheets. Roller compaction basically consists of three steps,
i.e., powder feeding, predensification and ribbon formation. During the feeding step, the
powder material was fed into two counter-rotating rolls by either gravity or force-feeds
screws. Once the powder material was drawn into the nip angle area, it rubs against the roll
surface and undergoes the pre-densification process. The predensified powder material was
further subjected to pass through the rotating rolls and particles are deformed or fragmented

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to form ribbons under hydraulic pressure. These ribbons were then sized through desired
screens to produce granules to be compressed into tablets.

Polymers were accurately weighed as per specified ratio (1:9 to 9:1) and mixed for 10 min to
form uniform blend. These blends were used for compaction using roller compactor (Clit
roller compactor, India). The obtained ribbons were screened through 40# and 60# sieve. The
obtained fine powder was further recycled to get granules of uniform size. About 9 cycles of
roller compaction were performed to obtain the granules of desired size. Material retained on
60 # sieve was used for further study. Physical mixtures of Polyox® WSR 301 and
Methocel® K4M were also prepared in same ratio in a lab scale double cone blender.

Advantages of Co-Processed Excipients

 Provide a single excipient with multiple functionalities.
 Overcome the limitation of existing excipients.
 Improvement of organoleptic properties.
 Production of synergism in functionality of individual components.
 Improvement in physico-chemical properties has expanded their use in the
pharmaceutical industry.
 Changes in dissolution profiles are less likely to occur in tablets made by direct
compression on storage than in those made from granulations.
 The prime advantage of direct compression over wet granulation is economic since the
direct compression requires fewer unit operations
 This is extremely important because the official compendium now requires dissolution
specifications in most soliddosage forms.
 The chances of wear and tear of punches and dies are less.
 Better mouth feel and improved palatiblity
 Removal of undesirable properties.
 Improvement of organoleptic properties
 Delivery of low doses of very potent compounds that require contaminent.
 Improved Flow properties.
 Improved compressibility.
 Better dilution potential.
 Fill weight variation.
 Reduced lubricant sensitivity.

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DIS-ADVANTAGES
 Specalised filling equipment and high temperature processing are required.
 Some lipidic excipients are not well tolerated by pre-clinical species.
 The high materials losses.
 Process is expensive because of labour, space, time special equipment and energy
requirement.
 Loss of material during various stages of processing.
 Moisture sensitive and thermolabile drugs are poor cancidates.
 The frequency of direct interaction of the formulator with the production personal in the
manufacturing area will be reduced.
 Long duration.
 Large number of equipment are needed.
 High material loss.

Co-Processed Excipients Enhanced Performance[4]

Combination (“intimate” mixtures) of established excipients that possess performance
advantages and improvements: increased surface area, improved flow, compaction, etc.
Covalent bonds usually not formed
High-functionality excipients (perform multiple functions)
Produced using specialized manufacturing process: high shear dispersion, granulation,
spray drying, melt extrusion
One or more components may be formed in situ
Appropriate for monograph consideration in the United States Pharmacopeia/National
Formulary
Several listed in FDA Inactive Ingredient Database
May create new intellectual property

Sources of New Excipients

Excipients with improved functionality can be obtained by developing new chemical
excipients, new grades of existing materials and new combinations of existing materials4.
Any new chemical excipient being developed as an excipient must undergo various stages of
regulatory approval aimed at addressing issues of safety and toxicity, which is a lengthy and
costly process. In addition, the excipient must undergo a phase of generic development,
which shortens the market exclusivity period.[5] The high risk and significant investment

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involved are not justified in view of the meagre returns from the new excipients. A plausible
solution is for excipient and pharmaceutical manufacturers to develop drug products jointly,
during which a new excipient becomes part and parcel of the eventual new drug application.
This type ofarrangement already has been successfully applied in theintravenous delivery
field, in which CyDex and Pfizer workedcollaboratively to obtain the approval of a
solubilizer.[6,7]

The combined expertise of pharmaceutical and excipient companies can lead to the
development of tailor made innovative excipients. Developing new grades of existing
excipients (physicochemical) has been the most successful strategy for the development of
new excipients in past three decades[8], a process that has been supported by the introduction
of better performance grades of excipients such as pre gelatinized starch, croscarmellose and
crospovidone9. However, functionality can be improved only to a certain extent because of
the limited range of possible modifications. A new combination of existing excipients is an
interesting option for improving excipient functionality because all formulations contain
multiple excipients. Many possible combinations of existing excipients can be used 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 subparticle level, called co processed excipients, has gained importance.
New physical grades of existing excipients and co processed excipients are discussed further
in the following section of this article that explains particle engineering. Particle engineering
is a broad based concept that involves the manipulation of particle parameters such as shape,
size, size distribution, and simultaneous minor changes that occur at the molecular level such
as polytypic and polymorphic changes. All these parameters are translated into bulk level
changes such as flow properties, compressibility, moisture sensitivity, and machinability.

Particle engineering as source of new excipients Solid substances are characterized by three
levels of solid-state: the molecular, particle, and bulk level. These levels are closely linked to
one another, with the changes in one level reflecting in another level. The molecular level
comprises the arrangement of individual molecules in the crystal lattice and includes
phenomena such as polymorphism, pseudo-polymorphism and the amorphous state. Particle
level comprises individual particle properties such as shape, size, surface area and porosity.
The bulk level is composed of an ensemble of particles and properties. The fundamental

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solid-state properties of the particles such as morphology, particle size, shape, surface area,
porosity and density influence excipient functionalities such as flowability, compactibility,
dilutionpotential |disintegration potential, and lubricating potential. Hence, the creation of a
new excipient must begin with a particle design that is suited to deliver the desired
functionalities10.Varying the crystal lattice arrangement by playing with parameters such as
the conditions of crystallization and drying can create particles with different parameters.

Lactose is examples in which such an approach has been successfully applied. However,
particle engineering of a single excipient can provide only a limited quantum of functionality
improvement. Co processing is based on the novel concept of two or more excipients
interacting at the sub particle level, the objective of which is to provide a synergy of
functionality improvements as well as masking the undesirable properties of individual
excipients.[9] The availability of a large number of excipients for co processing ensures
numerous possibilities to produce tailor-made “designer excipients” to address specific
functionality requirements 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 co- processed
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: Various particle properties influencing excipient functionality.[10]

Particle property Excipient functionality
Enlargement of particle size Flowability,compressbility
estricting particle size distribution Segregation potency
Enlargement of particle porosity Compressibility, solubility
Surface roughness Flowability, Segregation potency

Properties and advantages of the co processed excipients

Several authors have reported the advantages and possible limitations of the properties of co
processed excipients such as SMCC, Cellactose and Ludipress.

a) Absence of chemical change

Many detailed studies of excipients chemical properties after co processing have proven that
theseexcipients do not show any chemical change. Detailed studies of SMCC with X-ray
diffraction analysis, solidstate nuclear magnetic resonance (NMR), IR spectroscopy, Raman
spectroscopy and C13 NMR spectroscopy have detected no chemical changes and indicate a

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similarity to the physicochemical properties of MCC.[11] This absence of chemical change

helps reduce a company’s regulatory concerns during the development phase.

b) Physico mechanical properties.

1. Improved Flow Properties
Controlled optimal particle size and particle size, distribution ensures superior flow properties
of co-processed excipients without the need to add glidants. The volumetric flow properties
of SMCC were studied in comparison with MCC. The particle size range of these excipients
was found to be similar to those of the parent excipients, but the flow of coprocessed
excipients was better than the flow of simple physical mixtures. A comparison of the flow
properties of Cellactose was also performed. The angle of repose and the Hausner ratio were
measured and Cellactose was found to have better flow characteristics than lactose or a
mixture of cellulose and lactose.[12] The spray dried product had a spherical shape and even
surfaces, which also improved the flow properties.

2. Improved compressibility
Coprocessed excipients have been used mainly in direct compression tabletting 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 pressure– hardness relation of coprocessed
excipients, when plotted and compared with simple physical mixtures, showed a marked
improvement in the compressibility profile. The compressibility performance of excipients
such Cellactose[13], SMCC[14,15] and Ludipress[16] are superior to the simple physical mixtures
of their constituent excipients. Although direct compression seems to be the method of choice
for pharmaceutical manufacturing, wet granulation is still preferred because it has the
potential advantages of increasing flow properties and compressibility when an extra granular
binder introduced, and it achieves a better content uniformity in case of low dose drugs.
Excipients such as MCC lose compressibility upon the addition of water, a phenomenon
called quasihornification.[17] This property is improved, however, when it is co-processed into
SMCC.

3. 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

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diluted with a poorly compressible agent. Cellactose is shown to have a higher dilution
potential than a physical mixture of its constituent excipients.[18]

4. Fill weight variation

In general, materials for direct compression tend to show high fill weight variations as a
result of poor flow properties, but co-processed 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. Fill weight variation tends to be more prominent
with high speed compression machines. Fill weight variation was studied with various
machine speeds for SMCC and MCC and SMCC showed less fill weight variation than MC.

5. Reduced lubricant sensitivity

Most co-processed 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 material.[19] 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.[20]

Table: 2 Co-processed directly compressible excipients.

Coprocessed excipients Trade name Manufacturer advantage
Basfag, Low degree of hygroscopicity, good
Lactose,3.2% kallidone
Ludipress ludwigshafen, flowability, tablet hardness independent of
kallidone cl
germany machine speed
Megglegmbh & Highly compressible, good mouthfeel, better
Lactose,25% cellulose Cellactose
co. Kg, germany tabletting at low cost
Sucrose 3%, dextrin Penwest Directly compressible, Better flow, reduced
Microcrystalline cellulose, Dipac Prosolv pharmaceuticals sensitivity to wetgranulation, better
silicon dioxide company hardness of tablet, reduced friability
Microcrystalline cellulose, Avicelce
Fmc corporation Less grittiness, minimal chalkiness
guar gum 15
Calcium carbonate,
Formaxx Merck Controlled particle size distribution
sorbitol
Capable of formulating high dose, small
Microcrystalline cellulose,
Microlela Meggle tablets with poorly flowableactive
lactose
ingredients
95% β lactose + 5% Lactitol Pharmatose
Dmvveghel High compressibility
lactitol dcl 40

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Types of Excipients
Generally types of excipients were classified into 4 types which were given below.
 Single entity excipients.
 Mixtures or blends of multiple excipients.
 Novel excipients or new chemical entities.
 Co-processed excipients.

Co-processing of Excipients
The actual process of developing a co-processed excipient involves the following steps:
 Studying the material characteristics and functionality requirements by identifying the
group of excipients to be co-processed.
 Selecting the proportions or concentrations of various excipients.
 Assessing the particle size required for co-processing. 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 process.[21]

Principle Involved In Co-processing

Solid substances are characterized by three levels of solid state: the molecular, particle and
bulk level. These levels are closely linked to one another, with the changes in one level
reflecting in another level. The molecular level comprises the arrangement of individual
molecules in the crystal lattice and includes phenomena such as polymorphism, pseudo-
polymorphism and the amorphous state. Particle level comprises individual particle
properties such as shape, size, surface area and porosity. The bulk level is composed of an
ensemble of particles and properties such as flowability, compressibility and dilution
potential, which are critical factors in the performance of excipients. This interdependency
among the levels provides the scientific framework for the development of new grades of
existing excipients and new combinations of existing excipients. The fundamental solidstate
properties of the particles such as morphology, particle size, shape, surface area, porosity and
density influence excipient functionalities such as flowability, compactability, dilution
potential, disintegration potential and lubricating potential. Hence, the creation of a new
excipient must begin with a particle design that is suited to deliver the desired functionalities.
However, particle engineering of a single excipient can provide only a limited quantum of
functionality improvement. A much broader platform for the manipulation of excipient

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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. The
availability of a large number of excipients for coprocessing ensures numerous possibilities to
produce tailor-made “designer excipients” to address specific functionality requirements.

1. Standard Excipients
Are defined as compendial or non-compendial substances that are neither mixed excipients
nor co-processed excipients. They may contain other components including concomitant
components, residual processing aids and/or additives.

2. Mixed Excipients
A mixed excipient is defined as a simple physical mixture of two or more compendial or non-
compendial excipients produced by means of a low- to mediumshear process where the
individual components are mixed but remain as discrete chemical entities, i.e. the nature of
the components is not chemically changed,. Mixed excipients may be either solid or liquid.

3. Co-processed Excipients
A co-processed excipient is a combination of two or more compendial or non-compendial
excipients designed to physically modify their properties in a manner not achievable by
simple physical mixing and without significant chemical change. Many different co-
processing methods may be used, including standard unit operations such as granulation,
spray drying, melt extrusion, milling etc. The choice for a specific application will depend on
the materials used, their form (e.g. whether dry powders or liquid) and the specific physical
properties desired. Likewise the ratios of the components mayvary depending on the desired
performance.

Need For Co-Processed Excipients

It has been found that less than 20 per cent of pharmaceutical materials can be compressed
directly into tablets due to lack of flow, cohesion properties and lubrication. Therefore, they
must be blended with other directly compressible ingredients to manufacture satisfactory
tablets. In the development of directly compressible granules by the modification of a single
substance, Co-processing involves interaction of two or more excipients at the sub-particle
level, aimed at providing a synergy of functionality improvements, as well as masking the

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undesirable properties of the individual excipients. The composite particles or co‐processed

multi‐component‐based excipients are introduced to achieve better powder characteristics and
tableting properties than a single substance or the physical mixture. The availability of a large
number of excipients for co-processing provides a plethora a opportunities to produce tailor
made designer excipients catering to specific functionality requirements.[22] The combination
of excipients chosen for co-processing 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 co-processed 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.

Opportunities to produce tailor made designer excipients catering to specific functionality

requirements.[23] The combination of excipients chosen for co-processing 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 co-processed 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.

Difference between physical mixtures and co-processed excipients

Physical mixtures, as the name suggests, are simple admixtures of two or more excipients
typically produced by short duration low-shear processing. They may be either liquids or
solids and are generally used for convenience rather than for facilitating the manufacturing
process or improving the resultant pharmaceutical product.[24] Co-processed excipients are
combinations of two or more excipients that possess performance advantages that cannot be
achieved using a physical admixture of the same combination of excipients. Typically they
are produced using some form of specialized manufacturing process. The performance
benefits relate to the manufacture or performance of the finished pharmaceutical product.[25]
Co-processed excipients are appropriate for consideration as new monographs because one or
more of the components may be formed in situ, or the component may not be isolated prior to
co-processing.

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Limitation of co-processed Excipient

Major limitation of co-processed excipient mixture is that the ratio of the excipients in a
mixture is fixed and in developing a new formulation, a fixed ratio of the excipients may not
be an optimum choice for the API and the dose per tablet under development. Co processed
adjuvant lacks the official acceptance in pharmacopoeia. For this reason, a combination filler
binder will not be accepted by the pharmaceutical mixtures of the excipients. Although the
spray crystallized dextrose-maltose.[26] (Emdex) and compressible sugar are co-processed
products as single components and are official in USP/NF.

A regulatory perspective of the excipient mixtures

With the absence of a chemical change during processing, co processed excipients can be
considered generally regarded as safe (GRAS) if the parent excipients are also GRAS-
certified by the regulatory industry until it exhibits significant advantages in the tablet
compaction when compared to the physical agencies.[27] Hence, these excipients do not
require additional toxicological studies. Excipient mixtures or co processed excipients have
yet to find their way into official monographs, which is one of the major obstacles to their
success in the market place. 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
excipients mixture.

CONCLUSION
This main aim of the current review article is to provide a complete overview on recent
development in excipients technology and the approaches involved in development of such
excipients. Formulation scientists recognized that single component excipients do not always
provide the requisite performance to allow certain active pharmaceutical ingredients to be
formulated or manufactured adequately and they have focused their attention on the
production of multifunctional excipients with enhanced performance to meet the needs of
formulation experts in terms of costs of production, enhanced excipient functionality and
quality of tablets. Co-processed excipients help to overcome the deficiencies occurring with
the use of general grade excipients. The co-processed excipients retain favourable attributes,
and are supplemented with new ones. As the chemical change is absent, they are considered
to retain the “GRAS” (Generally Regarded as Safe) status. Co-processed excipients are
believed to bring a drastic change in the field of pharmaceutical Research. Co-processing is

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Desu et al. World Journal of Pharmaceutical Research

interesting because the products are physically modified in a special way withoutaltering the
chemical structure.

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