New LC-IR Technique To Characterize Polymeric Excipients In Pharmaceutical Formulations

New LC-IR Technique to Characterize Polymeric

Excipients for Lot-to-Lot Variations, Degradation

and Stability in Pharmaceutical Formulations

Ming Zhou, PhD

Director of Applications Engineering

Spectra Analysis Instruments, Inc.

Contact: [email protected]

Tel. 508-281-62761

AAPS NERDG 2011 Meeting 4/15/11

http://www.spectra-analysis.com/index.htm

OUTLINE

LC-IR Hyphenated Technology

Excipient Characterization: Copovidone PVP/VAc

Excipient Degradation from Thermal Processing:

HPMCAS, Eudragit L100-55 (PEA/MAA)

Summary

2


Hyphenated Technologies &

Major Applications

Liquid Chromatography

Mass

SpectroscopyInfra Red

Spectroscopy

Separation

Applications Small Molecules,Proteins Copolymers / Mixtures

Detection &

Data Analysis

LC-MS LC-IR

Pharma API’s Polymeric Excipients


LC-IR Hyphenated System


Features of LC-IR System

Real-Time On-line Detection

Microgram Sensitivity

All HPLC Solvents, Gradients & Volatile Buffers

• e.g. Water, ACN, Methanol, THF, DMSO …

All GPC/SEC Solvents: e.g. THF, TCB, HFIP, Chloroform, DMF

High Quality Solid Phase Transmission IR Spectra

Fully Automated Operation: No More Manual Fractionation

Multi-Sample Processing: 10 Hr ZnSe Disk Time


GPC-IR Direct Deposition

& Data Processing

ZnSe Disk

6


7


GPC-IR to Characterize Compositional

Variations of Copolymer Poly(A-B)

8

high MW low MW

mol

ar m

ass

comonomer A

comonomer B

A/B compositionratio

polymer chains

Ab

so

rba

nce

Bulk 50% (NMR)


GPC-IR Spectrum Snapshot of

Copovidone- VP/VAc Copolymer

Peak 1680 cm-1 from VP comonomer

Peak 1740 cm-1 from VAc comonomer

VP VAc


GPC-IR Chromatogram Overlay with Comonomer IR Peak Ratios

Excipient Compositional Drift

w/ MWD Vs. Bulk Average

Abs. Peak Ratio: AVA / AVP = (k1*b*MVA) / (k2*b*MVP) = k (MVA / MVP) ~ Comonomer Ratio

(Molecular Weight Distribution)

Bulk Average

Copovidone


0

.1

.2

.3

.4

.5

.6

106 104 103 102105

ma

x. IR

ab

so

rba

nce

Molecular Weight

Copovidone: sample A

30

35

40

45

50

molecular weight

distribution

% V

Ac

co

mo

no

mer

comonomer composition

distribution

Excipient Compositional Drift

w/ MWD Vs. Bulk Average

Bulk Average

40% VAc


0

.1

.2

.3

.4

.5

.6

106 104 103 102105Molecular Weight


sample B

sample C

Copovidone MW Distributions from

Different Suppliers (Manf. Processes)

ma

x. IR

ab

so

rba

nce

Copovidone A gave clear tablets while Copovidone C led to cloudy ones.


0

.1

.2

.3

.4

.5

.6



30

35

40

45

50

% V

Ac

Co

mo

no

mer

Comonomer Composition

Distribution

sample B

sample C

0

.1

.2

.3

.4

.5

.6

106 104 103 102105

sample B

sample C

Bulk 40% VAc

ma

x. IR

ab

so

rba

nce Molecular Weight

Distribution

Copovidone Compositional Drifts

from Different Manf. Processes

Copovidone A gave clear tablets while Copovidone C led to cloudy ones.


Excipient Characterization

by LC-IR in Pharma Formulations

14

Copolymer Compositional Analysis with MW Distributions

• Comonomer Ratio Drift (Functional Groups) vs. Bulk Average

• Excipient Lot-to-Lot Variations: QbD Studies

Excipient Performance & Functional Group Correlations

• Hydrophobic/Hydrophilic Ratio Drift vs. Phase Separations

• Effects on Excipient Dissolution Behavior

Reference

(1) Chemical Heterogeneity on Dissolution of HPMC,

EU J. of Pharma Sci., P392 (2009), A. Viriden et al.

(2) Comp Drift Effect on Dissolution of PMMA/MAA,

Materials Letters, P1144 (2009), E. Manias et al.


15

Excipient Degradation from

Hot Melt Extrusion Process

Hot Melt Extrusion Process: To Make Solid Dispersions

for Low Solubility Drugs to Improve Bioavailability

Degradation Issues

• Excipient & API Degradation at High Temp. (100-200C)

• Discoloration / Residues

• Degradant / API Interactions

Process Variables

• Temperature

• Time (Screw Speed)

• Torque

• Screw / Die Designs


GPC-IR for HPMCAS Degradation

in Hot Melt Extrusion Process

Unprocessed

Processed at 160C

Processed at 220C

Low MW

Degradant ?

Polymer Change ?


Degradant from HPMCAS (220C)


IR Database Search Result: Succinic Acid


HPMCAS Polymer Degradation


Functional Group Ratio Changes from High Temp Process (220C)

OH

-C=O


GPC-IR Analysis of HPMCAS

Degradation in HME Process

Fig. A Schematic Structure of HPMC-AS

Detected Degradants: Succinic Acid & Derivatives

Detected Functionality Ratio Change: Hydroxyl Vs. Carbonyl

Help Understand Excipient Degradation Mechanism

Study Excipient / API Interactions

Define Safe Process Window: QbD – OK at 160C, Problem at 220C

Excipient Blends with Plasticizers and Additives

CH3-C=O

HOOC-CH2-CH2-C=O


GPC-IR Characterization of Eudragit

L100-55 from Hot Melt Extrusion Process

IR Spectrum at Red Cursor

IR Spectrum at Blue Cursor

GPC Chromatogram by Max IR Band


IR Spectra of L100-55 Samples atPolymer Peak Center (Elution Time ~9.4’)

21

S0 – Green Ref

S1 – Violet 130C

S2 – Blue 160C

S3 – Black 190C

COOEt

1735

COOH

1705

CO-OH

NCE?

1805 cm-1


http://en.wikipedia.org/wiki/File:Generic_Anhydride.png

Excipient L100-55 Crosslinked from

COOH to Anhydride at Higher Temp

22

COOEt

1735

COOH

1705

S0 – Green Ref

S1 – Violet 130C

S2 – Blue 160C

S3 – Black 190C

NCE?

1805 cm-1


http://en.wikipedia.org/wiki/File:Generic_Anhydride.png

QbD Study: Eudragit L100-55

Degradation & Stability from HME

23

Sample # Extrusion

Temp.

Screw

Speed

Sample

Color

Sample

in THF

(~0.5%)

Degradant

Formed

Polymer

Change

S0 Not

Processed

White Clear

Solution

Ref. Ref.

S1 130 C 250 rpm Off

White

Clear

Solution

Trace

Anhydrides

S2 160 C 250 rpm Off

White

Clear

Solution

Anhydrides Acid/Ester

Ratio

Decreased

S3 190 C 250 rpm Brownish Some

Residue

Anhydrides Acid/Ester

Ratio

Decreased


Common Polymeric Excipients

24

Cellulose Derivatives

• HydroxyPropyl Methoxy Cellulose (Hypromellose): HPMC

• HPMC Acetate Succinate: HPMC-AS

• HPMC Phthalate: HPMC-P

• HydroxyPropyl Cellulose: HPC

Copovidone: PolyVinyl Pyrrolidone / Vinyl Acetate – PVP/VAc

SoluPlus Terpolymer: PEG / PVAc / PVCap

Methacrylic or Methacrylate Copolymers: Eudragit Polymers

Polyethylene Oxide: PEO (MW > 20K) or PEG (MW < 20K), PEG/PPG

PLGA Copolymers: Biodegadable

Excipient Combinations with Plasticizers and Additives


LC-IR Applications for Excipient

Analysis in Drug Formulations

Excipient

Manufacturing

• Process Control

• Lot-to-lot Variations

• CoA

• Novel Excipient R&D

• Trouble Shooting

Formulation Develop. Drug Manufacturing

• Incoming QC-Variations

• Excipient Functionality

• Formulation Development

• QbD

• Process Degradation (Hot Melt Extrusion)

• Define Safe Process Window / QbD

• Process Monitoring

• Trouble Shooting

Formulated Drugs

Shelf Life Stability

• Stressed Degradation

• De-Formulate Excipient Blends

• Trouble-Shoot Problem Drugs in the Market

Users: Excipient Pharma Co. Pharma Co.

Manufacturers HME Service Providers Generic Drug Co.


Summary: GPC-IR Characterization

of Excipient Copolymers Poly(A-B)

High MW Low MW GPC

Elution

Time

Ab

so

rban

ce

A/B RatioA

B

Map out copolymer compositions across MWD (sizes)

IR Spectra




High MW Low MW GPC

Elution

Time

Ab

so

rban

ce

A/B RatioA

B


Lot-to-lot or supplier-to-supplier variations

IR Spectra




High MW Low MW GPC

Elution

Time

Ab

so

rban

ce

A/B RatioA

B



Degradation from processing:

Loss of functional group

Cross-linking

Break down, Low MW degradant

IR Spectra


0

.1

.2

.3

.4

.5

.6


Break down

30

35

40

45

50

A %

0

.1

.2

.3

.4

.5

.6

Cross-linked

Starting Excipient

ma

x. IR

ab

so

rba

nce

Low MW

Degradant

Compositional / MWD Changes from

Excipient Processing Degradation

Cross Linking Break down




High MW Low MW GPC

Elution

Time

Ab

so

rban

ce

A/B RatioA

B



Degradation from processing:

Loss of functional group

Cross-linking

Break down, Low MW degradant

Validate Excipient Stability: To define safe processing window (QbD)

IR Spectra


Summary: LC-IR Analysis of

Excipients in Drug Formulations

Polymeric Excipient Characterization

Compositional Variations with MWD: Functional Group Ratios

Lot-to-Lot, Supplier-to-Supplier Variations

Degradation Analysis in Thermal Process (HME)

Detect Degradants (Low MW)

Polymer Structural Changes:

• Cross-Linking (New Chemical Entity)

• Functional Group Changes

Stability Study under Forced Conditions


Business

New LC-IR Technique To Characterize Polymeric Excipients In Pharmaceutical Formulations