Characterization and Control of Reactive Components in PVA-based Film Coatings Thomas P. Farrell, Ph.D. Colorcon, Inc. November 15, 2010
Presentation Outline
Prior work on reactive impurities in coating formulations
Colorcon work on reactive impurities
Conclusions: Impurity control strategies
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
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.
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 50 oC for 9 weeks.
Degradant formation was confirmed by evaluating a binary blend of the coating with irbesartan after 8 days at 65 oC.
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):393 –399.
Amgen Work on Formic Acid and Formaldehyde (2006)
Quantified formic acid and formaldehyde in pharmaceutical excipients:
Excipient
Formic acid (ppm)
Formaldehyde (ppm)
58.3, 86.4
11.1, 15.7
PEG 400
469.0
85.8
PEG 3500
1.7, 2.3
0.3, 1.2
PEG 4000
1.7, 14.0
0.9, 3.6
Povidone K-25
3080.3, 1990.5
<0.2, 0.4
Starch 1500®
3.0
<0.2
4.0, 9.3,11.8, 23.9
<0.2, 0.3, 0.9, 1.0
HPMC (LV)
MCC
Del Barrio MA, Hu J, Zhou P, Cauchon N. J Pharm Biomed Anal. 2006;41:738 –743
Formic acid and formaldehyde are present in a variety of excipients.
Formic Acid and Formaldehyde Detection in Film Coating Components (Colorcon, 2008)
Excipient
Number of Lots
Formic acid (ppm)
Formaldehyde (ppm)
Polyvinyl alcohol
12
34.2 + 6.0
5.6 + 2.6
HPMC 2910 (3 cP)
6
57.7 + 10.7
9.0 + 0.6
HPMC 2910 (6 cP)
6
97.5 + 27.5
14.7 + 3.3
HPMC 2910 (15 cP)
6
67.7 + 25.9
12.8 + 5.7
PEG 400 (no BHT)
3
14.7 + 7.6
7.7 + 2.3
PEG 3350 (no BHT)
3
10.3 + 2.1
<5
PEG 3350 (w/ BHT)
3
ND
ND
Triacetin
3
16.3 + 5.5
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.
Formic Acid & Formaldehyde Levels in PVA-based Opadry® II Formulations Comprising PEG with or without BHT Formic Acid Level (ppm) vs. Retain Age (months)
Formaldehyde Level (ppm) vs. Retain Age (months) 10 8 6 4 2 0
100 80 60 40 20 0 0
10 No BHT
20
30
With BHT
0
10 No BHT
20
30
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.
Formic Acid & Formaldehyde Levels in a PVA-Based Opadry II Formulation (w/ TiO2; BHT-free PEG) Formic Acid Level (ppm) vs. Storage Condition
Formaldehyde Level (ppm) vs. Storage Condition
80
80
70
70
60
60
50
50
40
Time 0
30
3 months 30
20
6 months 20
10
12 months10
0
0 25/60
30/65
40/75
40
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: 25 oC/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.
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
Formaldehyde Level (ppm) vs. Storage Condition
80
80
70
70
60
60
50
50
40
Time 0
30
3 months 30
20
6 months 20
10
12 months10
0
0 30/65
40/75
40
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: 25 oC/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.
Forced Degradation of Excipients at 60oC in Sealed Ampoules Formic acid concentration in ppm Excipient
Time Zero
4 Weeks
8 Weeks
T8/T0
PVA
41
42
45
1.01
HPMC 6 cP
59
72
83
1.41
PEG 3350 (no BHT)
5
802
782
156.40
PEG 3350 (with BHT)
<5
25
52
~10.00
PVA-PEG Copolymer
2817
4765
4898
1.74
PVA-MMA-AA Copolymer
41
48
50
1.22
PEG Stearates
18
29
32
1.77
Formic acid levels increase at the fastest rates for pure PEGs.
Forced Degradation of Excipients at 60oC in Sealed Ampoules Formaldehyde concentration in ppm Excipient
Time Zero
4 Weeks
8 Weeks
T8/T0
PVA
6
5
5
0.83
HPMC 6 cP
11
16
18
1.64
PEG 3350 (no BHT)
5
20
28
5.60
PEG 3350 (with BHT)
<5
6
9
~2.00
PVA-PEG Copolymer
450
666
599
1.33
PVA-MMA-AA Copolymer
5
5
5
1.00
PEG Stearates
16
5
6
0.38
Formaldehyde levels also increase at the fastest rates for pure PEGs.
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
) M P P ( d i c A c i m r o F
8000 7000 6000 5000 4000 3000 2000 1000 0 0
4
8
10
0
PEG Stearates
4
8
PVA-PEG Copolymer
10
0
4
8
10
0
HPMC 6 cP
4
8
10
PEG 3350 (No BHT)
0
4
8
PVA
10
0
4
8
PVA-MMA-AA Copolymer
Formic Blue#2 Lake (11-14% Dye Strength) -
Black Iron Oxide -
Red Iron Oxide -
Yellow Iron Oxide -
Talc -
Titanium Dioxide -
Yellow#6 Lake (15-18% Dye Strength) -
Excipient Alone -
10
Iron and other residual transition metals promote PEG degradation. Aluminum lakes appear to inhibit formic acid formation or complex it once formed .
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
) M P P ( e d y h e d l a m r o F
800 700 600 500 400 300 200 100 0 0
4
8
10
PEG Stearates
0
4
8
PVA-PEG Copolymer
10
0
4
8
HPMC 6 cP
10
0
4
8
10
PEG 3350 (No BHT)
0
4
8
PVA
10
0
4
8
PVA-MMA-AA Copolymer
Formaldehyde Blue#2 Lake (11-14% Dye Strength) -
Black Iron Oxide -
Red Iron Oxide -
Yellow Iron Oxide -
Talc -
Titanium Dioxide -
Yellow#6 Lake (15-18% Dye Strength) -
Excipient Alone -
10
Formaldehyde levels follow the same trends although they are significantly lower.
Formic Acid Levels in PVA-based Opadry II Formulae in Sealed Ampoules at 40 & 60oC (PEG with or without BHT) 80
60000
70
50000
) M60 P P ( 50 d i c 40 A c i 30 m r o F 20
) M P 40000 P ( d i c 30000 A c i m r 20000 o F
10000
10 0
0 0
5
10
15
0
Weeks BHT (40°C)
No BHT (40°C)
5
10
Weeks BHT (60°C)
No BHT (60°C)
BHT significantly inhibits formic acid formation at both 40 and 60 oC.
15
Formaldehyde Levels in PVA-based Opadry II Formulae in Sealed Ampoules at 40 & 60oC (PEG with or without BHT) 40
400
) M30 P P ( e d y h 20 e d l a m r 10 o F
) M300 P P ( e d y h 200 e d l a m r 100 o F
0
0 0
5
10
15
0
5
Weeks BHT (40°C)
No BHT (40°C)
10
15
Weeks BHT (60°C)
No BHT (60°C)
BHT inhibits formaldehyde formation at 60 oC. Very low levels of formaldehyde were detected after storage at 40 oC in both cases.
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.
Acknowledgements
Mr. David Ferrizzi – Sr. Manager - Analytical Services (Colorcon)
Mr. Marvin Ridley – Sr. Analytical Scientist (Colorcon)
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 dam ages. Colorcon, Inc. makes no warranty, either expressed or implied, that the use of t he 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 customer’s application. All trademarks, except where noted, are property of BPSI Holdings, LLC. © Copyright, Colorcon, Inc. 2010
