Co-processed Excipients - IPEC Europeipec-europe.org/UPLOADS/9_H_Folttmann.pdf · What is a...

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.


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


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


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)



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


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


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



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.




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)



Safety

• Relevant analytical methods to prove the absence of

chemical changes include:

– X ray diffraction

– C13 NMR

– IR spectroscopy

– Raman spectroscopy


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.


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.*




Thank you for

your attention !

Co-processed Excipients - IPEC Europeipec-europe.org/UPLOADS/9_H_Folttmann.pdf · What is a...

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