NYSAS Seminar LC-IR To Characterize Polymeric Excipients In Pharmaceutical Formulations 10-27-2010

LC-IR to Characterize Polymeric Excipients

in Pharmaceutical Formulations

Ming Zhou & Tom Kearney

Spectra Analysis Instruments, Inc.

Oct. 27, 2010

Contact: [email protected]

Tel. 508-281-6276

1

Seminar at NY Section ofSociety for Applied Spectroscopy

OUTLINE

LC-IR Hyphenated Technology: Instrumentation

Excipient Characterization: Copovidone PVP/VAc

Excipient Degradation from HME Process:

HPMCAS, Eudragit L100-55 (PEA/MAA)

Stability Study: PEG by HPLC-IR

Summary: LC-IR Applications in Pharma Formulations

Q & A

2

December 2009 3

2004: Founded with Substantial Commercial

Experience in FTIR, LC-MS, GC

2005 & 2006: Developed LC-IR Technology

(Patent Protected)

2008: Received R&D Magazine‟s „Top 100‟ Product Award.

2009: Received Massachusetts Life Science Center‟s Award & Certification.

2007-2009: Sales to „Top Tier‟ Customers: Forensics, National Labs, Polymers

2009-Present: Explosive Activities for Pharmaceutical Excipients

The Company

257 Simarano Drive

Marlborough, MA 01752

Scientific Excellence

4

Sid Bourne, PhD

Co-founder

Chief Scientist

Developed the first GC-IR product

while at the Argonne National

Laboratory.

Developed the “Tracer” at Bio-Rad.

Founded Bourne Scientific, Inc and

the “Detective”.

University of Minnesota, PhD.

Organic Chemistry.

William W. Carson, PE

Co-founder

V P Engineering

Over $1b revenue generated by

products covered by his 19 US patents

and 75 corresponding patents.

Registered Professional Engineer.

Former Assistant professor at Cornell

University.

Massachusetts Institute of Technology,

MS Mechanical Engineering.

Hyphenated Technologies &

Major Applications

Liquid Chromatography

Mass

SpectroscopyInfra Red

Spectroscopy

Separation

Applications Small Molecules, Proteins Polymers

Detection &

Data Analysis

LC-MS LC-IR

Pharma API‟s Polymeric Excipients

6

LC-IR Hyphenated System

Dell Desktop ComputerThermo-GRAMS /32 Software Package

•Library Search & Creation

•Ratio Chromatograms

•CFR 21-Part 11 Compliant

DiscovIR Users

Merck Pharma

Johnson & Johnson Pharma

Shire Pharmaceuticals Pharma

Novartis Pharma

Du Pont Polymers

Dow Chemical Polymers

Lawrence Livermore National Lab Trace Analysis

Oak Ridge National Laboratory Environmental

Naval Research Laboratory Organics

US Army Aberdeen Proving Ground Forensics

Pennsylvania State Police Forensics

Alabama Department of Forensics Forensics

Vermont State Police Forensic lab Forensics

Direct Deposition FTIR

& Data Processing (GPC-IR)

ZnSe Disk

How Does It Work?

How is the Solvent Removed?

Cyclone

EvaporatorThermal Nebulization

From LC

N2 Addition

Chilled

Condenser

Waste Solvent

Particle Stream to DiscovIR

Air Cooled

Condenser

Cyclone

Evaporator

Patent pending: PCT/US2007/025207

ZnSe Sample Disk

Auto sampler compatible

Unattended overnight runs

The ZnSe sample disk (yellow) is under vacuum without moisture or CO2 interference

Re-usable after solvent cleaning

Transmission IR analysis is done on the solid deposit.

Direct Deposition IR in Action

12

What is Direct Deposition FTIR?

Continuous Polymer Tracks (GPC-IR)Separated Dots from HPLC-IRSeparated Dot Depositing on Disk

Features of DiscovIR-LC

High Quality Solid Phase Transmission IR Spectra

Real-Time On-line Detection

Microgram Sensitivity

Compatible with all LC Solvents and Gradients

• e.g. Water, ACN, Methanol, THF, Chloroform, HFIP

Compatible with all GPC/SEC Solvents

Fully Automated Operation: No Fractionation

Multi-Sample Processing: 10 Hr ZnSe Disk Time

OUTLINE

LC-IR Hyphenated Technology: Instrumentation

Excipient Characterization: Copovidone PVP/VAc

Excipient Degradation from HME Process:

HPMCAS, Eudragit L100-55 (PEA/MAA)

Stability Study: PEG by HPLC-IR

Summary: LC-IR Applications in Pharma Formulations

Q & A

16

Compositional Drift Analysis of

Copolymer Poly(A-B) by GPC-IR

Ratio 10/8 12/12 2/4 Total 24/24

A% 56% 50% 33% 50%

High MW Low MW Molar Mass

Ab

so

rpti

on

A/B RatioA

B

Compositional Heterogeneity of

Copolymer Poly(A-B)

High MW Low MW Molar Mass

Ab

so

rpti

on

Ratio 10/8 12/12 2/4 Total 24/24

A% 56% 50% 33% 50%

GPC-IR

Regular FTIR Bulk 50% (NMR)

GPC

(MS)

IR Spectrum of Copovidone

Excipient - VP/VAc Copolymer

Peak 1680 cm-1 from VP comonomer

Peak 1740 cm-1 from VAc comonomer

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

% a

ceta

te c

om

onom

er

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

Copovidone: sample A

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

106 104 103 102105Molecular Weight

Copovidone: sample A

30

35

40

45

50

% a

ceta

te c

om

onom

er

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

24

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.

HPMCAS Grade-to-Grade

Difference (LF/MF/HF) by GPC-IR

M

OCH3

2830

C/HP

OH

3470

HP

CH3

1372

A

Acetyl

1235

AS

C=O

1740

HOOC-CH2-CH2-C=O

CH3-C=O

-C-O-C-

1060

IR Band Identifications of HPMCAS

Excipients for Ratio Drift Analysis

CH3

HP

o

HOOC-CH2-CH2-C=O

O

CH3-C=O

CH3-C=O

O

CH3

O

S

A

A

MM M

M

M

M M

Groups HP M C A AS Notes

CH3 1372 HP

OCH3 2830 M

OH 3470 (Unsub. OH & HP OH) OH

COCH3 1235 A

Total C=O 1740 AS

CH2 2935 2935 2935 2935 CH2

C-O-C 1060 BackBone

(BB)

C

HPMCAS Grade-to-Grade

Difference (HF/MF/LF) by GPC-IR

Acetyl / C=O (total AS)

HF—0.8

MF—0.5

LF—0.4

Acetyl/TotalEster Ratio Drifts of 4 MF

Lots Compared to LF & HF HPMCAS

-- LF ---------

-- HF ---------

OUTLINE

LC-IR Hyphenated Technology: Instrumentation

Excipient Characterization: Copovidone PVP/VAc

Excipient Degradation from HME Process:

HPMCAS, Eudragit L100-55 (PEA/MAA)

Stability Study: PEG by HPLC-IR

Summary: LC-IR Applications in Pharma Formulations

Q & A

29

30

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

Excipient HPMCAS Degradation

in Hot Melt Extrusion Process

Unprocessed

Processed at 160C

Processed at 220C

Degradant

Degradant from HPMCAS (220C)

in Hot Melt Extrusion Process

IR Database Search Result: Succinic Acid

HPMCAS Degradation

in Hot Melt Extrusion Process

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

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

Excipient Blends with Plasticizers and Additives

CH3-C=O

HOOC-CH2-CH2-C=O

Eudragit L100-55 Samples

from Hot Melt Extrusion Process

35

Sample # Extrusion

Temp.

Screw

Speed

Sample

Color

Sample

in THF

(~0.5%)

Degradant

Formed

?

Polymer

Changed

?

S0 Not

Processed

White Clear

Solution

S1 130 C 250 rpm Off

White

Clear

Solution

S2 160 C 250 rpm Off

White

Clear

Solution

S3 190 C 250 rpm Brownish Some

Residue

? ?

Note: Samples S1-S3 contain 20% plasticizer to assist extrusion process.

GPC-IR Operating Conditions

& Sample Preparation

GPC Chromatograph: Agilent® 1200

• GPC Column Temperature: Ambient

• Solvent: THF at 1.0 ml/min

• Column: Jordi Gel DVB Mixed Bed– 250 x 10 mm

• Sample Injections: 100 ml at ~0.5% weight / volume THF

IR Detection

• DiscovIR-LC® solvent-removing direct-deposition solid phase FTIR

• Cyclone Temperature: 150oC

• ZnSe Disk Temperature: -10 ~ -15oC

Sample Preparation:

• 0.050 g excipient solid samples were dissolved in 10 ml THF in ~1

hr and filtered with 0.45 mm PTFE syringe filter before GPC injection

Eudragit L100-55 Characterization by GPC-IR (Chromatograph + IR Spectra)

Eudragit L100-55 Compositional Drift at

Different Elution Times (Red 8‟ & Blue 10‟)

COOH

1705

COOEt

1735

CH2 CH3

Areas: L R

Acid / Ester Co-Monomer Ratio ~ Acid / Ester Peak Area Ratio = [(L+R)-2L] / (2L)

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

39

S0 – Green Ref

S1 – Pink 130C

S2 – Blue 160C

S3 – Black 190C

COOEt

1735

COOH

1705

CO-OH

NCE?

1805 cm-1

Excipient L100-55 Crosslinked from

COOH to Anhydride at Higher Temp

40

COOEt

1735

COOH

1705

S0 – Green Ref

S1 – Pink 130C

S2 – Blue 160C

S3 – Black 190C

NCE?

1805 cm-1

Summary: Eudragit L100-55

Degradation & Stability from HME

41

Sample # Extrusion

Temp.

Screw

Speed

Sample

Color

Sample

in THF

(~0.5%)

Degradant

Formed

Polymer

Change

S0 Not

Processed

White Clear

Solution

None None

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

Excipient Degradation Analysis

in HME Process by GPC-IR

42

Detect Degradation Intermediates with MW Distributions

Detect Functionality Changes

Probe Polymer Degradation Mechanism

Solve Degradation Problems

Define Safe Process Window: QbD

Understand Excipient / API Interactions

HME Process Monitoring: PAT

Various Polymeric Excipients

Excipient Blends with Plasticizers and Additives

OUTLINE

LC-IR Hyphenated Technology: Instrumentation

Excipient Characterization: Copovidone PVP/VAc

Excipient Degradation from HME Process:

HPMCAS, Eudragit L100-55 (PEA/MAA)

Stability Study: PEG by HPLC-IR

Summary: LC-IR Applications in Pharma Formulations

Q & A

43

Forced Degradation Study of PEG Excipient by HPLC-IR

Reverse-Phase HPLC-IR with H2O/ACN; PEG-1000 before Degradation

AU Scale for all traces

1116 cm-1 band chromatogram

1607 cm-1 band chromatogram

Blue Trace: No Carboxylates

1719 cm-1 band chromatogram

Red Trace: No Aldehydes

Degradation Intermediates Detected by

HPLC-IR from Degraded PEG

Three Chromatographic displays generated from one time ordered set of FTIR Spectra

PEG-1000 Sample Air Bubbled Overnight at 55C

IR Identification of Degraded Intermediates

(Aldehydes & Carboxylates)

11.45 minutes

4.93 minutes

1.50 minutes

Na+ or K+ Cation

Carboxylate Salt

1607

Aldehyde

1719

Typical IR Spectra of PEG in Black

Proposed Mechanism of PEG Oxidation

Supported by HPLC-IR Data

OUTLINE

LC-IR Hyphenated Technology: Instrumentation

Excipient Characterization: Copovidone PVP/VAc

Excipient Degradation from HME Process:

HPMCAS, Eudragit L100-55 (PEA/MAA)

Stability Study: PEG by HPLC-IR

Summary: LC-IR Applications in Pharma Formulations

Q & A

48

Common Polymeric Excipients

49

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

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

• 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.

Excipient QbD Space

GPC-IR-Performance

Slide from USP International Excipient Workshop (July 2009)

GPC

IR

Performance

GPC-IR

Excipient Analysis with LC-IR

in Pharmaceutical 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