Characterization and Control of Reactive Components in PVA-based Film Coatings

Thomas P. Farrell, Ph.D. Colorcon, Inc. November 15, 2010

The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.

Presentation Outline

Prior work on reactive impurities in coating formulations

Colorcon work on reactive impurities

Conclusions: Impurity control strategies

The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.

Potentially Reactive Excipients & Excipient Impurities

Aldehydes formaldehyde Hydroperoxides Organic acids citric acid formic acid Reducing sugars dextrose/glucose lactose Metals Solvents Water
Proposed Mechanism for Oxidative Degradation of Polyethylene Glycol to Form Formaldehyde and Formic Acid

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Reaction of Varenicline with Formaldehyde & Formic Acid (Pfizer, 2008)

Two degradants formed (20% of API degraded after 6 weeks at 40oC/75% relative humidity). NFV from reaction with formic acid NMV from sequential reaction with formaldehyde and then formic acid Both formaldehyde and formic acid originated from PEG 3350 in the coating (also comprising cellulose acetate). Degradants were controlled by lowering the PEG concentration in the coating so that the PEG remained compatible with cellulose acetate i.e. not free to migrate into the core.
Waterman, KC, Arikpo, WB, Fergione, MB., Graul, TW, Johnson, BA, MacDonald, BC, Roy, MC, Timpano, RJ. N-Methylation and N-Formylation of a Secondary Amine Drug (Varenicline) in an Osmotic Tablet, J Pharm Sci. 2008;97(4):1499-1507.
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Reaction of Irbesartan with Formaldehyde (BMS/Novatia, 2008)

A degradant (reaction product of formaldehyde with irbesartan) was characterized in

tablets coated with Opadry II comprising PEG. The degradant was initially detected after long-term stability storage of the coated tablets at 50oC for 9 weeks. Degradant formation was confirmed by evaluating a binary blend of the coating with irbesartan after 8 days at 65oC. Degradant formation was ultimately controlled by removing PEG from the coating.
Wang G, Fiske JD, Jennings SP, Tomasella FP, Venkatapuram AP, Ray, KL. Identification and Control of a Degradation Product in AvaproTM Film-Coated Tablet : Low Dose Formulation, Pharm Dev Tech. 2008 13(5):393399.
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Amgen Work on Formic Acid and Formaldehyde (2006)

Quantified formic acid and formaldehyde in pharmaceutical excipients: Excipient HPMC (LV) PEG 400 PEG 3500 PEG 4000 Povidone K-25 Starch 1500 MCC Formic acid (ppm) 58.3, 86.4 469.0 1.7, 2.3 1.7, 14.0 3080.3, 1990.5 3.0 4.0, 9.3,11.8, 23.9 Formaldehyde (ppm) 11.1, 15.7 85.8 0.3, 1.2 0.9, 3.6 <0.2, 0.4 <0.2 <0.2, 0.3, 0.9, 1.0

Del Barrio MA, Hu J, Zhou P, Cauchon N. J Pharm Biomed Anal. 2006;41:738743

Formic acid and formaldehyde are present in a variety of excipients.

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Formic Acid and Formaldehyde Detection in Film Coating Components (Colorcon, 2008)
Excipient Polyvinyl alcohol HPMC 2910 (3 cP) HPMC 2910 (6 cP) HPMC 2910 (15 cP) PEG 400 (no BHT) PEG 3350 (no BHT) Number of Lots 12 6 6 6 3 3 Formic acid (ppm) 34.2 + 6.0 57.7 + 10.7 97.5 + 27.5 67.7 + 25.9 14.7 + 7.6 10.3 + 2.1 Formaldehyde (ppm) 5.6 + 2.6 9.0 + 0.6 14.7 + 3.3 12.8 + 5.7 7.7 + 2.3 <5

PEG 3350 (w/ BHT) Triacetin

3 3

ND 16.3 + 5.5

ND ND

ND = not detected (no evidence of any peaks).

Farrell TP, Ferrizzi DF. Determination of Trace Formic Acid and Formaldehyde in Film Coatings Comprising Polyvinyl Alcohol (PVA). 2008 AAPS Annual Meeting (Atlanta, GA), Poster W4262.
The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.

Formic Acid & Formaldehyde Levels in PVA-based Opadry II Formulations Comprising PEG with or without BHT
Formic Acid Level (ppm) vs. Retain Age (months) 100 80 60 40 20 0 0 10 No BHT 20 30 With BHT 10 8 6 4 2 0 0 10 No BHT 20 30 Formaldehyde Level (ppm) vs. Retain Age (months)

With BHT

Retrospective stability investigation all retains were stored in sealed containers at temperatures < 30oC.
Farrell TP, Ferrizzi DF. Determination of Trace Formic Acid and Formaldehyde in Film Coatings Comprising Polyvinyl Alcohol (PVA). 2008 AAPS Annual Meeting (Atlanta, GA), Poster W4262.

The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.

Formic Acid & Formaldehyde Levels in a PVA-Based Opadry II Formulation (w/ TiO2; BHT-free PEG)
Formic Acid Level (ppm) vs. Storage Condition
80 70 60 50 40 30 20 10 0 25/60 30/65 40/75
Time 0

Formaldehyde Level (ppm) vs. Storage Condition

80 70 60 50 40
3 months 30 6 months 20 12 months 10

0 25/60 30/65 40/75

Study Design Product: PVA-based Opadry II white dry powder (BHT-free PEG) Packaging: standard commercial containers (polyethylene bag within a cardboard box) Storage conditions: 25oC/60%RH, 30oC/65%RH, 40oC/75%RH Pulls: 3, 6, 12, 24 & 36 months (40/75 through 6 months only) Analytical methods: standard methods previously described

Formic acid and formaldehyde levels modestly increase and then plateau.
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Formic Acid & Formaldehyde Levels in a PVA-Based Opadry II Formulation (w/TiO2, Red 30 and Red 40 lakes; BHT-free PEG)
Formic Acid Level (ppm) vs. Storage Condition
80 70 60 50 40 30 20 10 0 30/65 40/75
Time 0

Formaldehyde Level (ppm) vs. Storage Condition

80 70

60
50 40
3 months 30 6 months 20 12 months 10

0 30/65 40/75

Study Design Product: PVA-based Opadry II red aluminum lake colorants (BHT-free PEG) Packaging: standard commercial containers (polyethylene bag within a cardboard box) Storage conditions: 25oC/60%RH, 30oC/65%RH, 40oC/75%RH (25oC back up only) Pulls: 3, 6, 12, 24 & 36 months (40/75 through 6 months only)

Formic acid and formaldehyde levels were significantly lower when lakes were used.

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Forced Degradation of Excipients at 60oC in Sealed Ampoules

Formic acid concentration in ppm
Excipient PVA HPMC 6 cP PEG 3350 (no BHT) PEG 3350 (with BHT) PVA-PEG Copolymer Time Zero 41 59 5 <5 2817 4 Weeks 42 72 802 25 4765 8 Weeks 45 83 782 52 4898 T8/T0 1.01 1.41 156.40 ~10.00 1.74

PVA-MMA-AA Copolymer
PEG Stearates

41
18

48
29

50
32

1.22
1.77

Formic acid levels increase at the fastest rates for pure PEGs.

The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.

Forced Degradation of Excipients at 60oC in Sealed Ampoules

Formaldehyde concentration in ppm
Excipient PVA HPMC 6 cP PEG 3350 (no BHT) Time Zero 6 11 5 4 Weeks 5 16 20 8 Weeks 5 18 28 T8/T0 0.83 1.64 5.60

PEG 3350 (with BHT)

PVA-PEG Copolymer

<5
450

6
666

9
599

~2.00
1.33

PVA-MMA-AA Copolymer
PEG Stearates

5
16

5
5

5
6

1.00
0.38

Formaldehyde levels also increase at the fastest rates for pure PEGs.

The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.

Formic Acid Levels in 1:1 Colorant-Excipient Blends After 8 Weeks in Sealed Ampoules at 60oC
YIO 8 wk result = 17,000 ppm 10000 9000

Formic Acid (PPM)

8000 7000 6000 5000 4000 3000 2000 1000 0 0 4 8 10 0 4 8 10 0 4 8 10 0 4 8 10 0 4 8 10 0 4 8 10

PEG Stearates

PVA-PEG Copolymer

HPMC 6 cP

PEG 3350 (No BHT)

PVA

PVA-MMA-AA Copolymer

Formic
Blue#2 Lake (11-14% Dye Strength) Red Iron Oxide Talc Black Iron Oxide Yellow Iron Oxide Titanium Dioxide -

Yellow#6 Lake (15-18% Dye Strength) -

Excipient Alone -

Iron and other residual transition metals promote PEG degradation. Aluminum lakes appear to inhibit formic acid formation or complex it once formed.
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Formaldehyde Levels in 1:1 Colorant-Excipient Blends After 8 Weeks in Sealed Ampoules at 60oC
YIO 8 wk result = 1,800 ppm 1000 900

Formaldehyde (PPM)

800 700 600 500 400

300
200 100 0 0 4 8 10 0 4 8 10 0 4 8 10 0 4 8 10 0 4 8 10 0 4 8 10

PEG Stearates

PVA-PEG Copolymer

HPMC 6 cP

PEG 3350 (No BHT)

PVA

PVA-MMA-AA Copolymer

Formaldehyde
Blue#2 Lake (11-14% Dye Strength) Red Iron Oxide Talc Yellow#6 Lake (15-18% Dye Strength) Black Iron Oxide Yellow Iron Oxide Titanium Dioxide Excipient Alone -

Formaldehyde levels follow the same trends although they are significantly lower.
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Formic Acid Levels in PVA-based Opadry II Formulae in Sealed Ampoules at 40 & 60oC (PEG with or without BHT)
80 70 Formic Acid (PPM) 60 50 40 30 20 10 0 0 5 Weeks BHT (40C) No BHT (40C) BHT (60C) 10 15 Formic Acid (PPM) 60000 50000 40000 30000 20000 10000 0 0 5 Weeks No BHT (60C) 10 15

BHT significantly inhibits formic acid formation at both 40 and 60oC.

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Formaldehyde Levels in PVA-based Opadry II Formulae in Sealed Ampoules at 40 & 60oC (PEG with or without BHT)
40 Formaldehyde (PPM) Formaldehyde (PPM) 0 5 Weeks BHT (40C) No BHT (40C) BHT (60C) 10 15 400

30

300

20

200

10

100

0
0 5 Weeks No BHT (60C) 10 15

BHT inhibits formaldehyde formation at 60oC. Very low levels of formaldehyde were detected after storage at 40oC in both cases.

The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.

Conclusions: Formaldehyde and Formic Acid Control Strategies

Controlling impurities may not necessarily mean eliminating excipients

Use antioxidants with PEG-containing excipients.

Fully assess the impact of using excipients/colorants comprising redox active metals when PEG-containing excipients are used: evaluate film coatings with aluminum lake pigments Examine temperature dependence of degradant formation and consider processing and storage temperature limitations. Reduce the level of PEG-containing excipients. Explore substitution of PEG-containing excipients when other control strategies are unsuccessful.

The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.

Acknowledgements

Mr. David Ferrizzi Sr. Manager - Analytical Services (Colorcon) Mr. Marvin Ridley Sr. Analytical Scientist (Colorcon)

The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.

Characterization and Control of Reactive Components in PVA-based Film Coatings

Thomas P. Farrell, Ph.D. Roundtable Presentation, AAPS, November 15, 2010
The information contained herein, to the best of Colorcon, Inc.s knowledge, is true and accurate. Any recommendations or suggestions of Colorcon, Inc. with regard to the products provided by Colorcon, Inc. are made without warranty, either implied or expressed, because of the variations in methods, conditions and equipment which may be used in commercially processing the products, and no such warranties are made for the suitability of the products for any applications that you may have disclosed. Colorcon, Inc. shall not be liable for loss of profit or for incidental, special or consequential loss or damages. Colorcon, Inc. makes no warranty, either expressed or implied, that the use of the products provided by Colorcon, Inc., will not infringe any trademark, trade name, copyright, patent or other rights held by any third person or entity when used in the customers application. All trademarks, except where noted, are property of BPSI Holdings, LLC. Copyright, Colorcon, Inc. 2010

The information contained in this presentation is proprietary to Colorcon and may not be used or disseminated inappropriately.