USP updates on Excipient Monograph Modernization and FDA Modernization Task Group list

Catherine M. Sheehan, M.S., M.S.Sr. Director, Excipients US Pharmacopeiacxs@usp.org

ExcipientFest Baltimore, MD April 30-May1, 2013

USP Monograph Modernization Initiative

– Background

USP Monograph modernization strategy and approaches

FDA Modernization Task Group (MMTG)/FDA ORA – Review the FDA Lists of priority excipients

USP Monograph modernization – Progress on NF Excipients– Collaborative efforts with stakeholders– USP Lab method development in collaboration with stakeholders

“Ethylene Glycol, Diethylene Glycol, and Triethylene Glycol in Ethoxylated Substances”

Topics

Primary driver is maintaining up-to-date quality standards to support USP’s commitment to public health

Need for modernization– Monographs have been official for several years, decades in some

cases

– Content does not reflect current expectations for procedures and acceptance criteria

– Complaints from the public

– General lack of specificity

Modernization is a subset of USP’s ongoing revision work, started using the term “modernization” in 2009

FDA Modernization Task Group ( Nov. 2010)

List of priority excipients - most recent, July 2012 list of 13.

USP Monograph Modernization

Benefits Strengthens the public standards

Moves from non-specific to specific procedures

Considers practical factors – removes unnecessary tests

– Safety/environmental issues such as eliminating use of chlorinated solvents

– hard to find equipment

Increases consistency across monographs

USP Monograph Modernization

ExcipientFest 2011: Keynote Speaker - Dr. Steven Wolfgang, Ph.D. , “A Vision for Total Excipient Control”

Calcium Benzoate (FCC) was identified as a potential monograph for modernization due to a nonspecific assay based solely on the titration of the metallic ions.

The monograph did not contain a method confirming the organic portion of the molecule.

USP R&D lab developed a HPLC method for a quantitative assay based on the amount of benzoic acid in the benzoate salts.

Two NF monographs Sodium Benzoate (NF and FCC), Potassium Benzoate (NF and FCC) were modernized using the same HPLC method.

Most importantly:

The USP Lab developed HPLC method showed that the commercial samples of Calcium Benzoate failed the HPLC assay.

Calcium Benzoate FCC Modernization

Overlaid Chromatograms of Calcium Benzoate Samples

AU

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USP Ca Benzoate RS

Commercial Ca benzoate sample

Diluent

Chromatographic conditions: HPLC method for benzoates assay

Calcium Benzoate USP Lab. Investigation

Method USP Calcium Benzoate RS Commercial Calcium Benzoate

Titration 99.3% 99.6% (CofA)

HPLC(% w/w Assay)

99.3% 43.8% Propionic acid Peak observed

LOD 15.2% 10.7% (5.1% in CofA)

FT-IR Typical spectrum Peaks in ~2900 cm-1

(asymmetric C-H stretch)

1H NMR 100% benzoate 36% benzoate : 64% propionate (mol % basis)

Raman (Dispersive and FT)

Typical spectrum Peaks specific to propionate

AA Spectroscopy 11.0% of Ca 16.0% Ca

MW # Water %Water Theor %Ca

336.35 3 16.1 11.9

300.33 1 6.0 13.3

282.31 0 0.0 14.2

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Calcium Benzoate and Calcium Propionate Structures

Calcium Propionate

Formula C6H10CaO4

Weight 186.22 Preservative, mold inhibitor

Calcium Benzoate

Formula C14H10CaO4 · nH20

Weight Anhydrous 282.31Preservative, antimicrobial agent

Compound Name Amount, g

MW, g/mol

Cost*, $

Ca Benzoate 100 336.35 129.84

Ca Propionate 100 186.22 30.30

*Fisher

Potassium Benzoate NF and Sodium Benzoate NF - PF 38(3)

Assay: Proposal to replace the current nonspecific titrimetric procedure based

on the titration of the metallic ions with a stability-indicating HPLC quantitative

procedure based on the amount of benzoic acid in the benzoate salts.

Definition: revise the acceptance criteria from “NLT 99.0% and NMT 100.5%” to

“NLT 99.0% and NMT 101.0%”. The upper limit of the Assay acceptance criteria

range is widened by 0.5% to account for the performance of the HPLC method.

Identification:

Replace the wet chemistry test for Benzoate <191> with the HPLC Assay method by RT agreement with the major peak.

Add an Infrared Absorption <197K> test.

Add a USP Reference Standards section containing USP Potassium Benzoate

RS, USP Benzoic Acid RS, and USP Salicylic Acid RS.

The Importance of USP Compendial Monograph Modernization

USP’s greatest challenge is obtaining updated procedures and acceptance criteria—manufacturers are encouraged to submit proposals to USP

Pace of monograph modernization is linked to availability of procedures

Excipient monograph modernization is a major initiative in the 2010-2015 revision cycle.

USP is devoting resources to this effort -

USP expansion includes establishment of global laboratory sites.

Collaboration with FDA, industry and other stakeholders is key to advancing the work.

USP Monograph Modernization

April 24, 2010

Resolutions Supporting Public Health Adopted by Convention

Strengthen USP’s Relationship with the U.S. Food and Drug

Administration. USP resolves to strengthen its relationship with the

Food and Drug Administration (FDA), and work with FDA and other

public and private stakeholders to explore mechanisms to enable

USP to provide and maintain up-to-date national standards for

legally marketed drugs and excipients in the United States.

2010-2015 revision cycle: USP Commitment

Continued Collaboration with FDA and Industry

Prioritization

Timing considerations

Monograph Modernization Strategy and Approaches

Modernization of monographs achieved by

– Replacing outdated technology and methodology with more current procedures

– Adding critical tests to the monograph

– Deleting non-value added tests, as needed (e.g., odor test, melting point)

Follows the USP standards-setting process (i.e., with publication in PF for 90-day comment period)

FDA to provide input to USP on prioritization (FDA MMTG and ORA lists)

Other considerations

–Use procedures from other pharmacopeias–May need RS materials –Revising the monograph “family”, as needed

USP Monograph Modernization Process

No Identification or non-specific Identification procedures

No Assay or non-specific Assay procedures

Stainless steel/packed column GC procedures

Titration to GC/HPLC where appropriate

No impurity test, (e.g., Povidones and peroxides)

Safety-related concerns (e.g., chlorinated solvents).

Labeling deficiencies , e.g., when used in parenteral/injectable grade applications

–Missing specific tests to control quality (e.g., Microbial/BE)

Excipient Monograph Modernization: Prioritization of Categories

Monograph and Reference Material Procurement and Development

Traditional donor model (‘externally sourced’)– Very difficult to engage sponsors

USP laboratories (‘internally sourced’)– New technologies in Rockville labs (eg, UPLC, High Res. MS)

– Extensive testing facilities in India for reference procedure development

– Collaborative testing sites in India, China and Brazil (in addition to Rockville)

– MOU with China - excipient monograph development

FDA (CRADA: ORA Labs)

Adapt/Adopt (Other Pharmacopeias e.g. B.P., ChP)

Monograph Updating Strategies

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AnalyticalLaboratories

USP

USP Global Laboratory Capabilities

Global Laboratory Capacity Square Footage

USP US 43,000 sq. ft.

USP India 65,000 sq. ft.

USP China Current: 3,000 sq. ft.Jan ‘14: 55,000 sq. ft.

USP Brazil 6,400 sq. ft.

Global USP Laboratory Capacity

USA Laboratory Capacity Square Footage

Research & Development 15,500 sq. ft.

Biologics and Biotechnology

4,500 sq. ft.

Reference Standards Laboratory

19,000 sq. ft.

Dosage Form Performance 4,000 sq. ft.

Research and Development Laboratories– Monograph Development and Modernization

• Chemical Medicines, Excipients, Foods, Dietary Supplements, Biologics

Isolation and Characterization of Impurities

Complex Materials Characterization/Authentication

– Dosage Form Performance Lab

Reference Standards Laboratory– Testing of Candidate Reference Standards

• Identification; Structure Verification, Purity determination

– Investigations / Complaints – Continued Suitability for Use testing

New to USP Technology Program

Dissolution Research and PVT RS Development

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USP US Laboratory Facility

R&D Laboratory Capabilities

Biologics Laboratory•Cell biology and bioassay•Protein Analysis•Enzyme Assays•Amplification (QPCR, RT-PCR)•Nucleic Acid Analysis

Analytical Laboratory•NMR•MS•MS/MS•LCMS•IR, Raman, FTIR•ICP/ICP-MS

•HPLC, UHPLC•GC, GC/MS•IC, Titration, TLC•TGA, DSC•Vapor Sorption Analysis•KF, LOD, ROI

Dosage Form Laboratory•Dissolution•PVT Formulation

RS Candidates are evaluated on the following:

Appearance

Identification Tests

(IR, NMR, MS, Chromatography)

Purity tests (mass balance )

– Chromatographic purity (HPLC, GC) – Inorganic contaminants determination (ROI)– Volatiles (KF, LOD, GC-Headspace)

Indirect purity tests

– Melting range – Specific rotation

– Refractive index

USP US Activities – Reference Standards Laboratory

Analytical Techniques Used in RSL:– Chromatography

– HPLC, UHPLC, GC, IC, TLC– Spectroscopy

– FTIR, UV, MS, NMR– Other Compendial Techniques

– KF, LOD, TGA/DSC, MP, RI, OR, ROI, CHN

- ISO 9001:2008 certified (BSI)

- ISO 17025:2005 certified (ACLASS)

Quality Systems

Excipients FDA High Priority List – Monograph Modernization Task Group (MMTG) listMonograph List FDA recommend Modernization progress

PovidoneCrospovidoneCopovidone

Letter 1 Nov 2010 Replace non-specific N determination Assay <461> Kjeldahl methodAdd Peroxide test

Povidones Expert Panel formedJune 2011.PDG S6 – Peroxide , hydrazine tests added

Talc Letter 1 Nov 2010 Replace Limit of Asbestos and update Definition and Labeling

Talc Expert Panel formedAim: publish Stim article in PF 39(6)

Butylated Hydroxyanisole

Lette

r 3

Jul 2

012

Lack

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peci

fic ID

tes

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Butylated Hydroxytoluene USP labs – Add Chromatographic Assay – ID test add RT agreement

Dextrose Excipient

Silicon Dioxide (Colloidal)

Titanium Dioxide

Croscarmellose Sodium(Croslinked CMC sodium)

USP labs – IR test

CarboxymethylcelluloseSodium (CMC sodium)

Gelatin PDG Stage 6 published as RB

Guar Gum USP labs: ID: chem. comp. by TLC

Microcrystalline Cellulose USP labs – ID by IR test

Pregelatinized Starch

USP labs – ID:IR and TLC methodsShellac

Harmonization with PDG S6 Mg(St)2Published in PF 39(4)

Calcium Stearate

FDA High Priority Excipients - ORA list of deficiencies -

Monograph Deficiency Modernization progress

Aspartame “Replace non specific assay titration and add impurities test” HPLC Procedure For LIMIT OF

5-BENZYL-3,6-DIOXO-2-PIPERAZINEACETIC ACID . USP Labs: EVALUATE FOR USE INASSAY

Titanium Dioxide (also on MMTG list)

“Assay method is out of date, involves digestion with concentrated acids, etc.” FDA recommendation: Use advanced methods for quantitation of TiO2 (Ref: "A novel volumetric method for quantitationof titanium dioxide in cosmetics," Journal of Cosmetic Science, Volume 57, Issue 5, Pages377-383, 2006).

USP Labs: evaluate method

Glycerin “Current assay method for glycerin is out of date (periodate method)).” FDA recommendation. Replace periodate method with quantitative GC method (USP method for determination of quantities of DiethyleneGlycol and Ethylene Glycol is a GC method).

Glycerin Expert Panel formed in Dec. 2012PDG monographUSP labs: evaluate method

Crospovidone(also on MMTG list)

“Test method for Peroxides is outdated”

FDA recommendation: Quantitative determination of trace levels of hydrogen peroxide in crospovidone and a pharmaceutical product using HPLC with coulometric detection." International Journal of Pharmaceutics, Volume 375, Issues 1–2, 2009, Pages 33–40).

Povidones Expert Panel formed in Jan. 2011PDG monographUSP Labs: evaluate method

Monograph Completed PF Sponsor Modernization Priority

Compressible Sugar PF38(6) USP Lab/Industry ID by FTIR, Assay by HPLC USP weblist

Confectioner’s Sugar PF38(6) USP Lab ID by Spec Rot, Assay by HPLC Content of Sucrose USP weblist

Sugar Spheres PF38(6) USP Lab ID by Spec Rot, Assay by HPLC USP weblist

Lecithin PF38(6) Industry/USP labsID by updated TLC for chem comp. Assay, add Content of Phospholipids by HPLC-ELSD. Update the Labeling requirements

USP weblist

Squalane PF38(6) USP LabsID by RT agreement with Assay. Assay by GC.

USP weblist

Ascorbyl Palmitate PF38(6) USP LabsID by RT agreement with Assay

Assay from titration to HPLC USP weblist

Gelatin (H6)PF37(1) Revision

BulletinEP/JP/USP (PDG)

Stage 6 posted on USP website/harmonizationSept 2012, official April 2013

USP weblist/MMTG llist

High Fructose Corn Syrup PF39(1) (IRA) Industry/USP lab Content of Fructose USP weblist

Succinic Acid PF39(2) USP LabsID by RT agreement with Assay.Assay from titration to a HPLC

USP weblist

Cholesterol PF39(3) USP Labs Add ID by FTIR USP weblist

Purified Stearic Acid PF39(1) PDG S6 Stearic acid ID by RT agreement with Assay. Assay by GC cap USP weblist

Sodium Stearate PF39(3)Mg (St)2 PDG S6/USP labs

ID by RT agreement with Assay. Assay by GC cap USP weblist

Calcium Stearate PF39(3)Mg (St)2 PDG S6/USP Labs

ID A from wet-chemistry to FTIRID by RT agreement with Assay. Assay by GC cap

USP weblist/MMTG llist

Excipient modernizations for USP 37-NF 32

Monograph Modernization in progress Stakeholder Priority list

Methylparaben sodium Add Assay and related substances USP Labs/PDG S6 USP weblist

Propylparaben sodium Add Assay and related substances USP Labs/PDG S6 USP weblist

Mannitol (H) Introduce FTIR in ID test USP Labs/EP USP weblist

Polysorbate 80Introduce FTIR in ID test USP Labs/EP USP weblist

Guar Gum Update ID USP Labs/EP/Industry USP weblist/MMTG llist

Anise oil Update Definition /Assay by GC USP Labs/EP USP weblist

ShellacIntroduce FTIR and chemical composition TLC in ID test

Industry/USP Labs USP weblist/MMTG llist

Butylated HydroxytolueneIntroduce ID by RT . Add Assay -HPLC /GC methods under evaluation

USP Labs USP weblist/MMTG llist

Sucrose Introduce FTIR in ID testUSP Labs

USP weblist

Potassium SorbateIntroduce FTIR in ID test. Replace Assay by titration with GC

USP LabsUSP weblist

Glycerin Expert panel formed to develop S3 draft Industry FDA ORA list

Aspartame Replace Assay titration with HPLC USP labs FDA ORA list

Microcrystalline Cellulose Introduce FTIR in ID test USP labs FDA MMTG list

Croscarmellose Sodium(Croslinked CMC sodium)

Introduce FTIR in ID test USP labs FDA MMTG list

Carboxymethylcellulose Sodium (CMC sodium)

Introduce FTIR in ID test USP labs FDA MMTG list

Excipient modernizations in development

Chinese Pharmacopoeia Commission (ChP) - USP MOU Working group #1 – Documentary standards and Reference Materials – Excipients

– 13th meeting of MOU discussion. USP first visit to China in 1990. Initial MOU signed 2005

– Cooperate to develop quality standards for excipients in the global supply chain

– Establish the 22 nd Medicines Expert Committee East Asia Expert committee (EAEC) to work on development of excipient monographs to support the Medicines Compendium and for potential adoption by both ChP and NF.

– Dr Jiasheng Tu serves as Chair of the ChP Commission Expert Committee on Excipients and a member of the Expert committee of Center for Drug evaluation, SFDA. He is also Chair of the USP EAEC, China and a member of the USP Excipient EC, USA.

– Ms. Han Peng is the ChP liaison to the MCEA EC.

– Provincial lab support.

Chinese Pharmacopoeia Commission – USP MOU

ChP also modernizing several excipients in ChP 2010 that appear on the USP web list

ChP reviewed USP’s Excipient modernization web list

USP Excipient Expert Committee agree to start work on the following excipients

– Calcium Stearate (USP Lab work complete)– Calcium Sulfate– Carnauba Wax– Cholesterol (USP Lab work complete)– Diethyl Phthalate– Ethyl Acetate– Hydrogenated Castor Oil (USP Lab in dev.)– Maltodextrin (Working with Industry) – Monobasic Potassium Phosphate– Sulfuric Acid– White Wax– Xanthan Gum (USP Lab in dev.)

ChP-USP work on excipient modernization

USP Rockville reviewed the ChP list of 150 monographs targeted for development in ChP 2015 edition

USP and ChP selected 15 new excipient monographs for development

Nine are at various stages of development:

– Sodium Oleate– Cholic acid– Potasium stearate – Aluminum stearate – Sodium Caseinate – Benzyl paraben– Rosin – Dimethyl ether – Sodium nitrate

First 6 by 22 nd MC EAEC and USP China Lab

Last 3 by 22nd MC EAEC and CFDA -China provincial labs.

ChP-USP work on excipient monograph development

USP effortsUSP will continue to use its lab resources and engage stakholders

Sourcing procedures from other compendia, literature, other

Form Expert Panels, as needed, to address specific topics

Collaboration Explore possible lab support from CRADA with the FDA

Collaborate with FDA MMTG, refine priorities as needed

ChP - USP list of 15 new monographs and12 modernizations

Engage with other stakeholders

Moving Forward

• Excipient monograph modernization is a major initiative in the 2010-2015 revision cycle

• USP is devoting resources to this effort – new laboratory capabilities

• Collaboration with FDA, industry and other stakeholders is key to advancing the work

• Long-term goal is to implement a regular monograph review process to monitor the needs for further modernization

• USP’s Challenges

– Obtaining procedures and acceptance criteria– Prioritizing and requesting submissions - with FDA involvement ,

the hope is that industry is much more likely to come to the table

Conclusion

Upcoming USP – Excipient related meetings

• The USP ExcipientsStakeholder Forum

– Planned for June 7, 2013,USP Headquarters, Rockville, Maryland

– Objective: focus on science and compliance topics related to pharmaceutical excipients.

– Industry and stakeholder participation in USP's public standards-setting process is essential to the development of authoritative, relevant USP–NF monographs.

– Free registration -open to all users, makers and distributors.

– Web based allowing greater access and global participation.

• USP Science & Standards Symposium – Excipients track

– September 18–19, 2013, Baltimore Marriott Waterfront, Baltimore, Maryland

– Excipient track• Track Session 1: Modernization of NF Excipient monographs.

• Track Session 2: Developing / harmonizing excipient monograph standards.

• Track Session 3: Defining Excipient Quality

Ethylene Glycol, Diethylene Glycol, and Triethylene Glycol in Ethoxylated Substances.

USP Lab. Method development in collaboration with stakeholders

K. Gilbert, C. Chisolm, K. Ramakrishna, H. Wang, E. Biba and S. WahabSeparation Sciences Laboratory, U.S. Pharmacopeia, Rockville, MD 20852

Background

Samples

Method

Results

Conclusion

Outline

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USP currently undergoing a resolve to modernize and strengthen the monographs

of ethoxylated substances by adding testing for ethylene glycol (EG), diethylene

glycol (DEG), and triethylene glycol (TEG). An analytical gas chromatographic

procedure was developed and validated by our laboratory.

Currently, a general chapter <469> will be proposed in PF 39(4)[June-July 2013] for

public comment to include testing for ethylene glycol, diethylene glycol and

triethylene glycol in ethoxylated substances.

USP took into consideration the EP chapter 2.4.30. ETHYLENE GLYCOL AND

DIETHYLENE GLYCOL IN ETHOXYLATED SUBSTANCES and industry methods

in the development of the USP chapter.

Following testing, this method was found to be applicable to 17 different excipient

monographs.

Background

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Ethoxylation is a manufacturing process in which ethylene oxide is combined with alcohols and phenols to produce surfactants. The most common surfactants are synthesized by the ethoxylation process, which include alcohol ethoxylates, alcohol propoxylates and alcohol ethoxysulfates.

Ethoxylation Definition

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Ethylene oxide

Ethoxylated Substances in the Pharmaceutical Industry

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Ethoxylated substances such as polyoxyl fatty acid esters, polyethylene glycols and polysorbates are commonly used as pharmaceutical excipients in different formulations.

Example: Tween 20 (Polysorbate 20)

x+y+w+z =20

Blank: acetone

IS (Internal standard solution): 40 μg/mL solution of 1,3-butanediol in acetone.

Standard Solution: 25 μg/mL of EG and 40 μg/mL each of DEG and TEG diluted in IS.

EG Sensitivity Solution: 1.2 μg/mL of EG, 2.0 μg/mL of DEG and TEG diluted in IS.

DEG and TEG Sensitivity Solution: 0.8 μg/mL of EG and 1.2 μg/mL of DEG, TEG diluted in IS.

Sample Solutions: 40 mg/mL of the ethoxylated substance sample diluted in IS.

Sample Preparations

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Instrument: Gas chromatograph with flame ionization detectionCarrier Gas: HeliumLiner: Straight liner with wool Injector port: 270°Injector mode: SplitSplit ratio:2:1 Septum Purge Rate: 5 mL/minInjection volume: 1.0 μL Column: Restek Rtx-50; 0.53-mm x 30-m fused-silica analytical column; 1.0-μm layer of phase G3Column Mode: Constant flow Column flow rate: 5.0 mL/minOven Program:

Initial Temp.(°C) Time Ramp (°C/min) Final Temp.(°C) Hold time at Final Temp.(min.) 40 10 60 560 10 170 0 170 15 280 0, 60

Detector Temperature: 290°

Method

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The following ethoxylated compounds were tested and validated in four groups as follows:

Polysorbates Polyethylene Glycols Solid Polyoxyls Miscellaneous Liquids

Polysorbate 20 PEG 200 Polyoxyl 8-stearate Octoxynol-9 Polysorbate 40 PEG 300 Polyoxyl 20 Cetostearyl ether Nonoxynol-9Polysorbate 60 PEG 400 Polyoxyl 15 Hydrostearate PEGMME-350Polysorbate 80 PEG 600 PEGMME-550

Polyoxyl 35 castor oil

Compounds Tested

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Typical Chromatogram of Standard Solution

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EG

–62

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TE

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Polysorbate Chromatograms

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pA

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Polysorbate 20

Polysorbate 40

Polysorbate 60

Polysorbate 80

DE

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Concentration of EG, DEG, and TEG Found in Polysorbates

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Average Concentrationa (ppm)

EG DEG TEG

Commercial A Polysorbate 20 12.8 10.0 15.7

Commercial A Polysorbate 40 2.0 312 717

Commercial A Polysorbate 60 15.6 12.0 29.1

Commercial A Polysorbate 80 5.7 8.9 20.9

Commercial B Polysorbate 20 9.5 12.2 26.7

Commercial B Polysorbate 80 4.4 7.7 20.6aAverage of two determination

Recovery Rates of EG, DEG, and TEG in Some Samples

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Compound PolysorbatesRecovery Rates

Solid Polyoxyl SamplesRecovery Rates

Miscellaneous Liquid SamplesRecovery Rates

EG 80-107% 106- 115% 109- 118%

DEG87-115% 88- 101% 93-111%

TEG 82-105% 92- 118% 100-116%

GroupAverage:EGDEGTEG

90%98%90%

110%101%103%

112%105%106%

•The developed method has a broad applicability.

•EG, DEG, and TEG are well separated from each other and from other peaks found in matrix.

• LOD solution 0.27 µg/mL of EG, 0.4 µg/mL of DEG and TEG-(S/N) 10- very sensitive

•Good precision- ≤ 2.0%

•Has not been introduced into specific monographs.

__________________________________________________

Conclusion

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