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Co-Processed Excipients: New Era in Pharmaceuticals

Article · January 2019

DOI: 10.5958/2231-5659.2019.00001.8

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 Asian Journal of Research in Pharmaceutical Sciences. 9(1): January- March, 2019

ISSN 2231–5640 (Print) Available online at

2231–5659 (Online) www.anvpublication.org
DOI: 10.5958/2231-5659.2019.00001.8

Vol. 09 |Issue-01| Asian Journal of

January- March 2019 Research in Pharmaceutical Sciences
Home page www. ajpsonline.com

REVIEW ARTICLE:

Co-Processed Excipients: New Era in Pharmaceuticals

Ashok Thulluru*, C. Madhavi, K. Nandini, S. Sirisha, D. Spandana
Sree Vidyanikethan College of Pharmacy, A. Rangampet, Tirupati-517102, Chittoor (Dist.), A.P., India.
*Corresponding Author E-mail: ashokthulluru@gmail.com

ABSTRACT:
Co-processing is the way that new excipients coming to the market without undergoing rigorous safety testing of
completely as new chemical. It can be defined as combining two or more established excipients by an
appropriate process. Co-processing of excipients could lead to formation of excipients with superior properties
compared to simple physical mixtures of their components. The main aim of co processing is to obtain product
with an added value related to the ratio of its functionality and / or price.

KEYWORDS: Co-processed excipients, formation, physical mixtures, established excipients.

INTRODUCTION: Segregation is diminished by adhesion of the actives on

Development of co-processed excipients starts with the the porous particles making process validation and in
selection of the excipients to be combined, their targeted process control easy and reliable. The excipients industry
proportion, selection of preparation method to get to date has been an extension of the food industry1.
optimized product with desired physio-chemical Moreover, excipients are products of the food industry,
parameters and it ends with minimizing avoidance with which has helped to maintain a good safety profile.
batch-to-batch variations. An excipient of reasonable Increasing regulatory pressure on purity, safety, and
price must be combined with the optimal amount of a standardization of the excipients has catalyzed the
functional material in order to obtain integrated product, formation of an international body, the International
with superior functionality than the simple mixture of Pharmaceutical Excipients Council (IPEC)2. IPEC is a
components. Co-processing is interesting because the tripartite council with representation from the United
products are physically modified in a special way States, Europe, and Japan and has made efforts to
without altering the chemical structure. A fixed and harmonize requirements for purity and functionality
homogenous distribution for the components is achieved testing3. The development of new excipients to date has
by embedding them into mini granules. been market driven (i.e., excipients are developed in
response to market demand) rather than marketing
driven (i.e., excipients are developed first and market
demand is created through marketing strategies) and has
not seen much activity as shown by the fact that, for the
past many years, not a single new chemical excipient has
been introduced into the market. The primary reason for
Received on 19.01.2019 Modified on 28.01.2019 this lack of new chemical excipients is the relatively
Accepted on 15.02.2019 © A&V Publications All right reserved high cost involved in excipients discovery and
Asian J. Res. Pharm. Sci. 2019; 9(1):01-05.
DOI: 10.5958/2231-5659.2019.00001.8 development. However, with the increasing number of
new drug moieties with varying physicochemical and
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 Asian Journal of Research in Pharmaceutical Sciences. 9(1): January- March, 2019

stability properties, there is growing pressure on excipients10.

formulators to search for new excipients to achieve the
desired set of functionalities. Other 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 excipients3-5.
• 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 agglomeration6.
• The lack of excipients that address the needs of a
specific patient 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 bioavailability7, 8.

Co-processing of Excipients:
The actual process of developing a co-processed
excipient involves the following steps9:
1 Identifying the excipients group to be co-processed Fig.1. Diagrammatic representation of co-processing of excipients
by carefully studying the material characteristics and
functionality requirements.
2 Electing the proportions of various excipients.
3 Assessing the particle size required for co processing.
This is especially important when one of the Properties and advantages of the co-processed
components is processed in a dispersed phase. Post excipients:
processing the particle size of the latter depends on Several authors have reported the advantages and
its initial particle size. possible limitations of the properties of co-processed
4 Selecting a suitable drying process such as spray- or excipients such as solidified microcrystalline
flash- drying optimizing the process (because even cellulose (SMCC), Cellactose, and Ludipress.
this can contribute to functionality variations). Fig.1.
shows a schematic representation of the co-
processing method10 and Table 1. Shows summary of
various methods to prepare co-processed

Table1. Summary of various methods to prepare co-processed excipients

Method Advantage and limitation Example
Chemical modification Expensive, time consuming, require toxicological data Ethyl cellulose, methyl cellulose, hydroxypropyl
methyl cellulose, lactitol, cyclodextrin from starch
Physical modification Simple and economical Sorbitol, dextrates and compressible sugars
Grinding or sieving Compressibility may alter because of change in particle Dibasic dicalcium phosphate, αlactose monohydrate
properties
Crystallization Impart flow ability to excipient but not self-binding Dipac, β-lactose
properties, require stringent control on processing
Spray drying Spherical shape and uniform size give spray dried Emdex, Avicel PH, advantose100, karion instants
material good flowability, poor rework ability
Granulation/ Transfer poor flow, cohesive, small particle into flowable Granulated lactitol, tablettose
agglomeration and directly compressible
Dehydration Increase binding properties by thermal and chemical Anhydrous α-lactose
modification

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 Asian Journal of Research in Pharmaceutical Sciences. 9(1): January- March, 2019

a. Absence of chemical change: compressible, and as a result, excipients must have better
Many detailed studies of excipients chemical properties compressibility properties to retain good compaction
after co-processing have proven that these excipients do even when diluted with a poorly compressible agent.
not show any chemical change. Detailed studies of Cellactose is shown to have a higher dilution potential
SMCC with X-ray diffraction analysis, solid-state than a physical mixture of its constituent excipients21.
nuclear magnetic resonance (NMR), IR spectroscopy,
Raman spectroscopy, and C13 NMR spectroscopy have b.4. Fill weight variation:
detected no chemical MCC11 changes and indicate a In general, materials for direct compression tend to show
similarity to the physicochemical properties. This high fill weight variations as a result of poor flow
absence of chemical change helps reduce a company’s properties, but co-processed excipients, when compared
regulatory concerns during the development phase12. with simple mixtures or parent materials, have been
shown to have fewer fill‐weight variation problems. The
b. Physico mechanical properties: primary reason for this phenomenon is the impregnation
b.1. Improved Flow Properties: of one particle into the matrix of another, which reduces
Controlled optimal particle size and particle‐size the rough particle surfaces and creates a near‐optimal
distribution ensures superior flow properties of co- size distribution, causing better flow properties.
processed excipients without the need to add glidants. Fill‐weight variation tends to be more prominent with
The volumetric flow properties of SMCC were studied in high‐speed compression machines. Fill‐weight variation
comparison with MCC. The particle‐size range of these was studied with various machine speeds for SMCC and
excipients was found to be similar to those of the parent MCC, and SMCC showed less fill‐weight variation than
excipients, but the flow of co-processed excipients was MCC.
better than the flow of simple physical mixtures. A
comparison of the flow properties of Cellactose was also b.5. Reduced lubricant sensitivity:
performed. The angle of repose and the Hausner’s ratio Most co-processed products consists of a relatively large
were measured, and Cellactose was found to have better amount of brittle material such as lactose monohydrate
flow characteristics than lactose or a mixture of cellulose and a smaller amount of plastic material such as
and lactose13. The spray‐dried product had a spherical cellulose that is fixed between or on the particles of the
shape and even surfaces, which also improved the flow brittle material22. The plastic material provides good
properties14. bonding properties because it creates a continuous
matrix with a large surface for bonding. The large
b.2. Improved compressibility: amount of brittle material provides low lubricant
Co-processed excipients have been used mainly in direct sensitivity because it prevents the formation of a
compression tabletting because in this process there is a coherent lubricant network by forming newly exposed
net increase in the flow properties and compressibility surfaces upon compression, thus breaking up the
profiles and the excipient formed is a filler–binder15. The lubricant network.
pressure– hardness relation of co-processed excipients,
when plotted and compared with simple physical b.6. Other properties:
mixtures, showed a marked improvement in the Co-processed excipients offer the following additional
compressibility profile. The compressibility performance advantages23:
of excipients such Cellactose16, SMCC17, 18 and • Pharmaceutical manufacturers have the option of
Ludipress19 are superior to the simple physical mixtures using a single excipient with multiple functional
of their constituent excipients. Although direct properties, thereby reducing the number of excipients
compression seems to be the method of choice for in inventory.
pharmaceutical manufacturing, wet granulation is still • Improved organoleptic properties: Such as; Avicel
preferred because it has the potential advantages of CE‐15 (FMC Corp., Philadelphia, PA), which is a co-
increasing flow properties and compressibility when an processed excipient of MCC, and guar gum were
extra granular binder introduced, and it achieves a better shown to have distinctive advantages in chewable
content uniformity in case of low‐dose drugs. Excipients tablets in terms of reduced grittiness, tooth packing
such as MCC lose compressibility upon the addition of and chalkiness. Over all improved mouth feel and
water, a phenomenon called quasihornification20. This palatability.
property is improved, however, when it is co-processed • The overall product cost decreases because of
into SMCC. improved functionality and fewer test requirements
compared with individual excipients.
b.3. Better dilution potential: • Because they can retain functional advantages while
Dilution potential is the ability of the excipient to retain selectively reducing disadvantages, co-processed
its compressibility even when diluted with another excipients can be used to develop tailor‐made
material. Most active drug substances are poorly
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 Asian Journal of Research in Pharmaceutical Sciences. 9(1): January- March, 2019

designer excipients. perspective of the excipient mixtures with the absence of

• This can be helpful in reducing the time required to a chemical change during processing, co-processed
develop formulations. excipients can be considered generally regarded as safe
• Co-processed excipients can be used as proprietary (GRAS) if the parent excipients are also GRAS-certified
combinations, and in‐house formularies maintained by the regulatory industry until it exhibits significant
by pharmaceutical companies, which could help in advantages in the tablet compaction when compared to
developing a formulation that is difficult to reproduce the physical agencies. Hence, these excipients do not
and provides benefits in terms of intellectual property require additional toxicological studies. Excipient
rights. mixtures or co-processed excipients have yet to find their
way into official monographs, which is one of the major
Commercial status of co-processed excipients: obstacles to their success in the market place.
Many co-processed excipients have been launched in the
market in the past few years, and a few formulations are A regulatory perspective of the co-processed
commercially available. excipients:
With the absence of a chemical change during
Table 2. Lists some of the marketed co-processed processing, co-processed excipients can be considered
excipients along with their manufacturers and benefits10. generally regarded as safe (GRAS) if the parent
excipients are also GRAS-certified by the regulatory
Limitations of co-processed excipients: industry until it exhibits significant advantages in the
Major limitation of co-processed excipient mixture is tablet compaction when compared to the physical
that the ratio of the excipients Major limitation of co- agencies. Hence, these excipients do not require
processed excipients are the ratio of the excipients in a additional toxicological studies. Excipient mixtures or
mixture is fixed and in developing a new formulation, a co-processed excipients have yet to find their way into
fixed ratio of the excipients may not be an optimum official monographs, which is one of the major obstacles
choice for the API and the dose per tablet under to their success in the market place. The mixture of
development. Co-processed adjuvant lacks the official excipients was presented as a topic to the National
acceptance in pharmacopoeia. For this reason, a Formulary and was assigned a priority on the basis of the
combination filler binder will not be accepted by the use of the mixture in marketed dosage forms in which
pharmaceutical mixtures of the excipients. Although the processing has provided added functional value to the
spray crystallized dextrose-maltose (Emdex) and excipient mixture.
compressible sugar are co-processed products as single
components and are official in USP/NF.A regulatory

Table2. Marketed co-processed excipients

Brand name Adjuvant Application Advantages Company, country
Cellactose MCC, High-dosage tablet, herbal formulations Highly compressible, Meggle,
Lactose good mouth feel, low cost Germany
Pearlite SD Granulated Mannitol for chewable and effervescent tablet, _ Roquette,
Diluents for capsules and sachets may France
require higher level of lubricant
(magnesium stearates)
Ludipress Lactose, For use in chewable tablets andlozenges, good flowability, low BASF,
PVP, Crosspovidone foreffervescent tablets and as bulking hygroscopicity, hardness Germany
agent for modified Release independent of machine
formulations. speed
Starlac Lactose, _ Good flow Roquette,
maize Starch France
Pharmatose Anhydrous lactose, _ High compressibility, low DMV,
DCL 40 lactitol lubricant sensitivity Netherlands
Prosolv MCC, colloidal Silica _ better flow, hardness, Penwest,
reduced friability USA

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 Asian Journal of Research in Pharmaceutical Sciences. 9(1): January- March, 2019

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