CLARIANT

CLARIANT PRODUKTE (DEUTSCHLAND) GMBH Industrial & Consumer Specialties

Industriepark Höchst
Gebäude G 860
65926 Frankfurt am Main
Deutschland
www.clariant.com

CLARIANT PRODUKTE (DEUTSCHLAND) GMBH INDUSTRIAL & CONSUMER

65926 FRANKFURT AM MAIN DEUTSCHLAND SPECIALTIES

DR. WIBKE STELTER

To our customers
Tel. +49 69 305 22327
Fax +49 69 305 38466
E-Mail Wibke.Stelter@clariant.com

Frankfurt am Main, 29.01.2018

Polyethylene glycols (Macrogols): Clariant Polglykol 200 USP, 300 to 3000,

4000 to 35000 and Lanogen® 15oo* (except Polyglykol 3350 types)
Correlations between Ph. Eur. Resp. USP/NF methods and Clariant methods

The Clariant analytical department decided for a number of quality release tests for Poly-
glykols to use a more up to date method and/or a method which indicates higher accuracy
than the method described in one of the pharmacopoeia monographs.
Please find a detailed comparison:

* just valid for products with Pharma specification and batch number DE....

Geschäftsführer: Handelsregister: Sitz der Gesellschaft: Bankverbindung:

Oliver Kinkel (Vorsitz) Frankfurt am Main, HRB 42045 Frankfurt am Main Deutsche Bank AG
Lars Jansson IBAN: DE93500700l0009187o600 EUR
IBAN: DE3950070010009187o6o2 USD
Aufsichtsratsvorsitzender: SWIFT: DEUTDEFFXXX
Patrick Jany
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USP 41-NF 36/ Polyethylene Glycol

ASSAY (Average molecular weight):
The average molecular weight is calculated from Hydroxyl value (see below), which is similar to the proce-
dure given in the USP-NF method. Specification ranges are set according to or in some cases even nar-
rower than the acceptance criteria given in the monograph.
Hydroxyl value:
Hydroxyl value is not specified directly in the monograph for the Polyethylene Glycols, but just basis for
the determination of the average molecular weight (see above).
Clariant has compared the methods for determination of the OH- value by titration described in the mono-
graphs USP- NP', Ph. Eur., JP and DIN The comparison showed that the methods are comparable with
each other (validation report available). Clariant uses the reference method DIN EN ISO 4629
DIN EN ISO 4629 was validated against the viscosity method (DIN 51562) which is equal to Ph. Eur.
method (2.2.9), but a more detailed description (validation report available).
The "Hydroxyl value" is given in the specification as specification item "OH value" measured by refer-
ence method DIN EN ISO 4629.
IMPURITIES (Residue on Ignition):
<281> residue on ignition
Clariant uses an own ICP-OES method. This method has been compared to the Ph. Eur. (Sulphated ash)
and the USP-NF (Residue on Ignition), which all describe the same aspect. The limit given in the USP-NF
method is lower than the limit in the Ph. Eur. and the limit in the JP. Therefore Clariant uses the lower
specification limit of 0.1% for both specification items.
This is given in the specification as specification item "Sulphated ash".
The measurement is performed by a periodic testing procedure (Validation report is available).
Heavy Metals:
<231> Heavy Metals
Clariant uses an own ICP-OES method, which is, compared to the USP-NF method, much more reliable.
The measurement is performed by a periodic testing procedure (validation report available).
This is given in the specification as specification item "Heavy metals (Pb)".
Limit of free Ethylene Oxide and 1,4-Dioxane:
Chromatographic system LC <621>, System Suitability
Clariant uses an own GC method, which is validated acc. to ICH Q2 (Clariant method and validation re-
port available).
Limit of Ethylene Glycol and Diethylene Glycol:
Chromatographic system LC <621>, System Suitability (average molecular weight less than 450)
UV absorbance method (average molecular weight 450 or above but not more than 1000)
Clariant uses an own GC method, which is validated acc. to ICH Q2 (Clariant method and validation re-
port available). Clariant performs this test additionally also for higher molecular Polyethylene glycols up
to an average molecular weight of max. 6000.
This aspect is given in the specification as specification item "Ethylene- and diethylene glycol".
pH <791>:
Clariant uses DIN EN 1262, which is comparable to USP-NF <791>, but a more detailed description.
This is given in the specification as specification item "pH value 5% in water".
Completeness and color of solution:
Instead of 9% water solution Clariant tests the 25 % solution according to Ph. Eur.
Viscosity:
Capillary Method <911>
Clariant uses validated calculations between the DIN 51562 and the USP-NF method (validation report
available).
This is given in the specification as specification item "Viscosity at 98.9°C".

Geschäftsführer: Handelsregister: Sitz der Gesellschaft: Bankverbindung:

Oliver Kinkel (Vorsitz) Frankfurt am Main, HRB 42045 Frankfurt am Main Deutsche Bank AG
Lars Jansson IBAN: DE93500700m009o87o600 EUR
IBAN: DE3950070010009187o6o2 USD
Aufsichtsratsvorsitzender: SWIFT: DEUTDEFDOZX
Patrick Jany

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Ph.Eur. 9.0 to 9.5 / Macrogols

Appearance of solution (Transparency of solution):
2.2.1 clarity and degree of opalescence of liquids
Instead of a comparison of a 25% water solution with water R and reference suspension I, Clariant
conducts a more reliable, validated photometric method based on the official Ph. Eur. Test method
2.2.2 - INSTRUMENTAL METHOD (correlation study available).
This is given in the specification as specification item "Solubility 25% a. i. in water visual".
Appearance of solution (Colour of solution):
2.2.2 degree of coloration of liquids
Instead of a comparison of a 25% water solution with reference solution BY6, Clariant conducts a more
reliable, validated photometric method (EN 1557, correlation study available).
This is given in the specification as specification item "Hazen colour 25% a. i. in water".
IDENTIFICATION A
(Viscosity)
Clariant conducts only Test A. As the production process is conducted in dedicated vessels it is ex-
cluded that other products besides ethoxylated Polyglykols are present. Therefore identification tests B
and C are not done. Details regarding Test A are given under the item "viscosity" separately.
IDENTIFICATION B
(reaction with sulfuric acid and mercuric chloride solution)
Identification test B is just proving that the products tested are ethoxylated. Due to the fact that the pro-
duction process is conducted in dedicated vessels and just ethoxylated products are produced in the
plant, this testing is not unique for the Macrogols. Therefore Clariant skips identification tests B and C
and just Test A is conducted.
IDENTIFICATION C
(reaction with potassium thiocyanate and cobalt nitrate)
Identification test C is just proving that the products tested are ethoxylated. Due to the fact that the pro-
duction process is conducted in dedicated vessels and just ethoxylated products are produced in the
plant, this testing is not unique for Macrogols. Therefore Clariant skips identification tests B and C and
just Test A is conducted.
Viscosity:
2.2.9 capillary viscometer method (dynamic viscosity)
Average molecular weight of 300 to 8000:
Clariant uses DIN 51562, which is identical to Ph.Eur. 2.2.9, but a more detailed description. As
described in Ph. Eur. method 2.2.9, the dynamic viscosity is calculated from determined kinematic
viscosity. The value is given in the specification as specification item:
"Viscosity at 20°C" (300 and 400) or "Viscosity at 20°C of 50% solution"(600 to 8000)

Average molecular weight of 10000 and higher:

Clariant uses ISO 6388 (rotating viscometer method), instead of Ph. Eur. 2.2.9. ISO 6388 is identical to
Ph.Eur. 2.2.10, but a more detailed description.
This is given in the specification as specification item: "Viscosity at 20°C of 50% solution"

Geschäftsführer: Handelsregister: Sitz der Gesellschaft: Bankverbindung:

Oliver Kinkel (Vorsitz)
Lars Jansson
Aufsichtsratsvorsitzender:
Patrick Jany
Frankfurt am Main, HRB 42045 Frankfurt am Main Deutsche Bank AG
IBAN: DE93500700t0009187o600 EUR
IBAN: DE39500700t0009187o6o2 USD
SWIFT: DEUTDEFF/00(

Seite 3 von 5
 CLARIANT

Viscosity:
2.2.9 capillary viscometer method (kinematic viscosity)
Average molecular weight of 300 to 8000:
Clariant uses DIN 51562, which is identical to Ph. Eur. 2.2.9, but a more detailed description. As de-
scribed in Ph. Eur. method 2.2.9, the kinematic viscosity is determined in order to calculate the dy-
namic viscosity by multiplying with the density of Macrogols.

Average molecular weight of 10000 and higher:

Clariant uses ISO 6388 instead of Ph. Eur. 2.2.9 to determine the dynamic viscosity. ISO 6388 is identi-
cal to Ph.Eur. 2.2.10, but a more detailed description. The kinematic viscosity is calculated from dy-
namic viscosity divided by the density of Macrogols.
Due to this, the specification requirement is covered by the dynamic viscosity specification and it is not
given separately as external specification item on the CoA.
Acidity or Alkalinity
Clariant uses validated calculations between the Ph.Eur. Method and the pH value measurement by
DIN EN 1262 (validation report available).
This is given in the specification as specification item "Acidity ml 0.1M NaOH/5g; titrimetric".
Water (Karl Fischer):
2.5.12 water: semi-micro determination
Clariant uses DIN 51777, which is comparable to Ph. Eur. 2.5.12 and USP-NF <921>, but a more de-
tailed description.
Ethylene oxide and dioxane (ethylene oxide):
2.4.25 Ethylene oxide and dioxane
Clariant uses an own GC method, which is validated acc. to ICH Q2 (Clariant method and validation
report available).
Ethylene oxide and dioxane (dioxane):
2.4.25 Ethylene oxide and dioxane:
Clariant uses an own GC method, which is validated acc. to ICH Q2 (Clariant method and validation
report available).
Reducing substances:
2.2.2 degree of coloration of liquids, method I
The test item Reducing Substances is tested in a skipped testing_procedure (validation report available).
Hydroxyl value
Clariant has compared the methods for determination of the OH- value by titration described in the
monographs USP- NF, Ph. Eur., JP and DIN The comparison showed that the methods are compara-
ble with each other (validation report available). Clariant uses the reference method DIN EN ISO 4629
DIN EN ISO 4629 was validated against the viscosity method (DIN 51562) which is equal to Ph. Eur.
method (2.2.9), but a more detailed description (validation report available).
The "Hydroxyl value" is given in the specification as specification item "OH value" measured by ref-
erence method DIN EN ISO 4629.
Molar Mass calculated of OH value:
Clariant
This item is not part of Ph. Eur. but still given at Clariant 's specifications and CoAs. It is calculated
from Hydroxyl Value.
Ethylene glycol and diethylene glycol [2.2.28]
Test requirement is valid only if Macrogol has a molecular mass below 1000. Clariant uses an own GC
method, which is validated acc. to ICH Q2 and compared with Ph.Eur. Method (Clariant method and
validation report available).

Geschäftsführer: Handelsregister: Sitz der Gesellschaft: Bankverbindung:

Oliver Kinkel (Vorsitz)
Lars Jansson
Aufsichtsratsvorsitzender:
Patrick Jany
Frankfurt am Main, HRB 42045 Frankfurt am Main Deutsche Bank AG
IBAN: DE9350070010009187o600 EUR
IBAN: DE39500700100091870602 USD
SWIFT: DEUTDEFFXXX

Seite 4 von 5
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Freezing point:
2.2.18 - Freezing point
For Polyethylene Glycols with a molecular weight of < / = 1500 g/mol, Clariant uses a validated
method (calculation out of viscosity) instead of the time consuming Ph. Eur. 2.2.18 method (validation
report available).
For Polyethylene Glycols with a molecular weight of> / = 2000 g/mol Clariant uses a DSC method in-
stead of the time consuming Ph. Eur. 2.2.18 method (validation report available).
As this aspect is not defined in the above mentioned monograph for the Polyethylene Glycol types with
molecular weight 10000 g/mol and 12000 g/mol, this aspect is not specified in the general Clariant
specification of these types.
This item is given in the specification as specification item "Solidification point".
Sulfated ash:
2.4.14 Sulfated ash
Clariant uses an own ICP-OES method. This method was compared to the Ph.Eur. (Sulfated ash) and
USP-NF (Residue on ignition) methods, which describe the same aspect. The limit given in the USP-NF
method is lower than the Ph. Eur. limit. Therefore Clariant uses the lower specification limit of 0.1%
for both specification items. The measurement is performed through a periodic testing procedure (vali-
dation report available).
Formaldehyde:
2.2.25 absorption spectrophotometry ultraviolet and visual
Clariant conducts the Ph.Eur. method (photometric).
This is given in the specification as specification item "Formaldehyde Ph. Eur.".

Please feel free to contact us again for questions.

This Letter of Commitment shall be valid for two years after the date written above.

Yours sincerely

Clariant Produkte (Deutschland) GmbH

On behalf of the selling Clariant Group Company

Luk
Dr. Wibke Steltr, 2,\
Gesche Rauch
Pharma Pharma Polyglykols
Technicäl AppliCationSMEA Technical Application EMEA

Geschäftsführer: Handelsregister: Sitz der Gesellschaft: Bankverbindung:

Oliver Kinkel (Vorsitz) Frankfurt am Main, HRB 4 2045 Frankfurt am Main Deutsche Bank AG
Lars Jansson IBAN: DE935007o010009187o600 EUR
IBAN: DE3950070010009187o6o2 USD
Aufsichtsratsvorsitzender: SWIFT: DEUTDEFFXXX
Patrick Jany

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