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Co-processed Excipients
Hubertus Folttmann
IPEC Europe Secretary
BASF SE
What is a co-processed excipient?
• „Any mixture of compendial or non-compendial excipients
that has been designed to be physically co-processed in a
way which results in functional performance attributes when
used in a drug application and which are not seen if the
excipients are combined using simple mixing“*
• The processing should produce only a physical interaction,
such as hydrogen bonding or ionic association, rather than a
covalent chemical combination.*
• The only novel parameters are the physical form and the
functionality.
* The IPEC-Americas Co-processed Excipient Guide 2014
IPEC Europe Excipient Forum 2015
Are the following excipient combinations
regarded as co-processed excipients?
• Physical mixtures, e.g. colored coating systems
• Aqueous polymer dispersions manufactured by emulsion
polymerization (methacrylic acid or polyvinyl acetate
dispersions)
• PEGs and poloxamers are frequently stabilized with
antioxidants (antioxidants mentioned in respective
monographs)
• The term „co-processed excipient“ is not very precise.
• The most popular co-processed excipients are those
designed to ease the direct-compression process as an
attractive alternative to traditional granulation technologies.
IPEC Europe Excipient Forum 2015
Why is the number of co-processed
excipients rising so rapidly?
Three routes to new excipients:
• New grade of existing excipient
(line extension)
• New combinations of existing
materials (co-processed exc.)
• Chemically new excipients
(novel excipients)
Development time
Development costs
Potential for improvement
Because of the limitations of simple line extensions and
the commercial risk of novel excipients, co-processing
is an important path to innovation. IPEC Europe Excipient Forum 2015
Solid substances are characterized by
three levels of solid state:
• Molecular Level
– Arrangement of individual molecules in the crystal lattice (e.g.
polymorphism, pseudo-polymorphism and the amorphous
state)
• Particle Level
– Comprises individual particle properties, such as shape, size,
surface area and porosity
• Bulk Level
– Is composed of multiple particles and properties, such as
flowability, compressibilty etc.
Coprocessed Excipients for Solid Dosage Forms,
S.K. Nachaegari and A.K. Bansal, Pharmaceutical Technology, January 2004, p.52-64
IPEC Europe Excipient Forum 2015
What is the aim of co-processing in
combination with particle engineering?
• Co-processed excipients are
prepared by incorporation of one
excipient into the particle structure of
another excipient in order to
• Mask undesired properties of
individual materials and
• Retain or improve desired properties
of individual materials resulting in
performance enhancement.
Coprocessed Excipients for Solid Dosage Forms,
S.K. Nachaegari and A.K. Bansal, Pharmaceutical Technology, January 2004, p.52-64
IPEC Europe Excipient Forum 2015
Manufacturing of co-processed
excipients
• Selecting a suitable process depends on the characteristics
of the individual materials and the required functionality of
the co-processed excipient.
• Frequently used technologies are:
– Granulation, e.g. Fluid Bed Spray Granulation (FBSG)
– Co-drying, e.g. Spray Drying
• The manufacturer should ensure* that
– the process is operated to the appropriate standard of GMP
– the process is robust (composition and performance)
* The IPEC-Americas Co-processed Excipient Guide 2014
IPEC Europe Excipient Forum 2015
Marketed co-processed excipients
Examples (1)
Trade name Manufacturer Components Claim
Parteck® ODT Merck Millipore Mannitol
Croscarmellose Sodium
DC aid for ODTs,
low hygroscopicity,
suitable for moisture sensitive
APIs
Avicel® CE 15 FMC MCC
Guar Gum
DC aid for chewable tablets
RetaLac® Meggle HPMC (4000 mPa·s)
Lactose
DC aid for modified-release
tablets
Pearlitol® Flash Roquette Mannitol
Maize Starch
DC aid for ODTs,
creamy and smooth texture
Remark: Co-processed excipients usually consist of 2 to 5 components
IPEC Europe Excipient Forum 2015
Marketed co-processed excipients
Examples (2)
Trade name Manufacturer Components Claim
StarCap1500® Colorcon Maize Starch
Pregelatinized Starch
For use in capsules and tablets,
inert free-flowing, low dust
excipient
Compressol®
SM
SPI Pharma Mannitol
Sorbitol
DC aid especially suitable for
chewable tablets,
low hygroscopicity, suitable for
moisture sensitive APIs
Ludiflash® BASF Mannitol
Crospovidone
Polyvinyl Acetate
Povidone
DC aid for ODTs,
creamy and smooth texture
Prosolv® Easy
tab
JRS MCC
Silicon Dioxide
Sodium Starch Glycolate
Sodium Stearyl Fumarate
Ready-to-use, all-in-one
DC aid
Remark: Co-processed excipients usually consist of 2 to 5 components
IPEC Europe Excipient Forum 2015
Regulatory perspective (1)
Pharmacopoeia monograph
• With very few exceptions marketed co-processed excipients
are not described in major pharmacopoeias yet.
• Exceptions are co-processed excipients which are
commercially available for a long time, e.g.
– Compressible Sugar, USP-NF, BP
(Sucrose + Maltodextrin)
– Microcrystalline Cellulose and Carboxymethylcellulose Sodium,
USP-NF, Ph. Eur. = Dispersible Cellulose, BP
– Silicified Microcrystalline Cellulose (MCC + Silicon Dioxide),
USP-NF
IPEC Europe Excipient Forum 2015
Regulatory perspective (2)
Safety
• Since co-processed excipients, by definition, are not
intended to introduce new covalently bonded molecules, it
should be possible to bridge the safety of a novel co-
processed excipient to the safety of the individual
components.*
• For a co-processed excipient, a safety assessment will be
performed using a risk-based approach. In most cases only
analytical studies are required to demonstrate that no new
covalently bonded material was formed during co-
processing.
• In the absence of significant chemical change it should not
be necessary to perform a toxicological assessment.
* The IPEC-Americas Co-processed Excipient Guide 2014
IPEC Europe Excipient Forum 2015
Regulatory perspective (3)
Safety
• With the absence of a chemical change during processing,
co-processed excipients can be considered generally
recognized as safe (GRAS) if the parent excipients are also
GRAS-certified by the regulatory agencies.
Tablet Excipients to the Year 2001: A Look into the Crystal Ball,
R.C. Moreton, Drug Dev. Ind. Pharm. 22 (1), 11-23 (1996)
IPEC Europe Excipient Forum 2015
Regulatory perspective (4)
Safety
• Relevant analytical methods to prove the absence of
chemical changes include:
– X ray diffraction
– C13 NMR
– IR spectroscopy
– Raman spectroscopy
IPEC Europe Excipient Forum 2015
Future developments
• A narrow pipeline of chemically new excipients and the
pressure to speed up formulation and production processes
in the pharmaceutical industry will drive the development of
new and improved co-processed excipients.
• New formulation technologies and production machineries
will increase the demand for such new excipients.
IPEC Europe Excipient Forum 2015
Conclusion
• The large number of co-processed excipients launched in
recent years indicates that combining existing excipients incl.
particle engineering seems to be a cost-efficient source of
new products that provide more functionality and/or
convenience to the pharmaceutical industry.
• The fact that compendial acceptance of co-processed
excipients is still not given, seems not to prevent excipient
manufacturers to develop new such excipients or drug
makers to use them.
• It is strongly recommended that the user of co-processed
excipients enter into a supply agreement with the excipient
manufacturer to ensure supply.*
* The IPEC-Americas Co-processed Excipient Guide 2014
IPEC Europe Excipient Forum 2015
IPEC Europe Excipient Forum 2015
Thank you for
your attention !