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To Overcome Formulation Challenges
Using
Excipient Purity
Excipient Purity
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Presentation Overview
The Role of Excipients in Health Care Formulations
High Purity Excipients to Address Formulation Challenges Reduced Cellular Irritation Enhanced Excipient Stability Enhanced API Stability
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Excipients in Pharmaceuticals
Functional excipients provide critical benefits in pharmaceutical formulation development…
Drug Delivery
Emulsification
Solubilization
Stability Enhancement
Controlled Release
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Market Drivers for Excipient
Innovation
Demand for novel
drug delivery
Increased issues
with API stability
Poor efficacy
of certain drugs
High costs for certain APIs
Excipient Purity
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Meeting the Challenges
Meeting Formulation Challenges
Standard compendial
excipients for routine
applications
High Purity (HP) excipients for
enhanced stability
Super Refined excipients for the greatest level of
purity for superior stability and
reproducibility
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Super Refining™ Technology
Adsorption Chromatography to remove Polar impurities
Color, odor, taste Peroxides & secondary oxidation
products Pesticide residues Heavy metals Catalyst residues
Leaves excipients chemically unchanged
Before After
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Super Refining™ Benefits
Lot to lot consistency Improved analytical clarity Higher purity excipient ideal
for formulating with sensitive APIs
Reduce the potential for cellular irritation
Increased oxidative stability can reduce API degradation which may extend the shelf life of actives
Optimal Formulation & Drug Stability for Better Performance
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MALDI-MS: Polysorbate 80 Comparisons
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Reproducibility of MALDI-MS
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Super Refined Polar Excipients
Super Refined Arlasolve DMI Super Refined Oleic Acid* Super Refined Polysorbate 20* Super Refined Polysorbate 60* Super Refined Polysorbate 80* Super Refined PEG 300* Super Refined PEG 400* Super Refined PEG 600* Super Refined Propylene Glycol * 3 Pharmacopoeia Compliant
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Super Refined Non-Polar Excipients
Super Refined Castor Super Refined Corn Super Refined Cottonseed Super Refined Crodamol IPM * Super Refined Novol Super Refined Olive Super Refined Peanut Super Refined Safflower Super Refined Sesame* Super Refined Crodamol SCO Super Refined Soybean
* 3 Pharmacopoeia Compliant
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Audience Poll 1
In which applications/areas do you envision using Super Refined excipients? Formulation stability Processing aids in API manufacturing API solubility Actives delivery Formulation toxicology API stability
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Reduced Potential
for Cellular Irritation
Addressing
Formulation Challenges
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Super Refined Polysorbate Cellular Irritation Study
MATERIALS & METHODS Super Refined & High Purity grades of polysorbate 20 & 80 Polysorbates incorporated into simple formulation Trans-epithelial Permeability Assay - MDCK cells Formulations contacted with cells for 15 min at RT Cells washed with PBS Na- Fluorescein added to monolayer with PBS in well below DETECTION METHOD 30 minutes: optical density of well fluid Na- Fluorescein leakage = Cellular irritation
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Super Refining Reduces Irritation Potential by 40%
0
10
20
30
40
50
60
70
80
90
100
1:100 1:150 1:200 1:250 1:300
Percent Intracellular
Leakage
Surfactant to Water Ratio (to simulate normal dilution)
0% Tween 80 10% Tween 80 HP 10% Super Refined Polysorbate 80
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Super Refining Reduces Irritation Potential by 73%
0
10
20
30
40
50
60
70
80
90
100
1:100 1:150 1:200 1:250 1:300
0% Tween 20 10% Tween 20 HP 10% Super Refined Polysorbate 20
Percent Intracellular
Leakage
Surfactant to Water Ratio (to simulate normal dilution)
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Enhanced Excipient Stability
Addressing
Formulation Challenges
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Importance of Oxidative Stability
Peroxides and formaldehydes are major oxidation products of wide range of excipients
API’s are susceptible to degradation due to peroxides and formaldehydes
Lowering the impurities such as peroxide and especially formaldehyde content would increase the shelf life and efficacy of APIs
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Improved Oxidative Stability
0
10
20
30
40
50
60
70
80
1 2 3 4
Peroxide Value (ppm) Initial Week 4
Super Refined PEG 400 NF Lot A
Super Refined PEG 400 NF Lot B
PEG 400 NF Lot A
PEG 400 NF Lot B
Accelerated storage conditions 50ºC – 4.45 cm headspace HPLC with PDA detector at 207 nm
Super Refining Reduces Peroxide Values
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Improved Oxidative Stability
0
5
10
15
20
25
30
35
40
1 2 3 4
Formaldehyde Content (ppm)
Initial Week 4
Super Refined PEG 400 NF Lot A
Super Refined PEG 400 NF Lot B
PEG 400 NF Lot A
PEG 400 NF Lot B
Accelerated storage conditions 50ºC – 4.45 cm headspace HPLC with PDA detector at 410 nm
Super Refining Reduces Formaldehyde Content
Excipient Purity
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0
2
4
6
8
10
12
Polysorbate 20 Polysorbate 80
Formaldehyde (ppm)
HP Grade Super Refined
Reduction of Formaldehyde in Super Refined Polysorbates
Formaldehyde is a major oxidation product and known cellular irritant
Super Refined 46% less
formaldehyde
Super Refined 80% less
formaldehyde
Excipient Purity
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Lipid Oxidative Stability
Presence of polar impurities in lipid excipients have the potential for interacting with APIs
Can readily oxidize if highly unsaturated to form
primary oxidation products such as hydroperoxides
Hydroperoxides further oxidize into secondary oxidation products of aldehdes and ketones
Interactions can lead to reduced API stability
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Reducing the Impact of Lipid Oxidation Objective: The objective of this study was to assess and compare
the effect of lipid oxidation on Super Refined lipid excipients versus standard lipid excipients
Materials: Super Refined Corn Oil vs. Corn Oil NF Super Refined Cottonseed Oil vs. Cottonseed Oil NF Super Refined Soybean Oil vs. Soybean Oil USP Super Refined Castor Oil vs. Castor Oil USP
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Methods 5 Lots of each Super Refined oil 5 Lots of each std compendial grade oil Samples incubated at 50ºC Analysis at 0, 2, 4, 6 and 8 weeks
Analysis Methods Peroxide Value USP test method Iodine Value USP test method Gardner Color Method Carbonyl Value Analysis
0.00
1.00
2.00
3.00
4.00
5.00
0 2 4 6 8 10
SR Castor Oil vs. Castor Oil USP
Carbonyl Values
0.00
1.00
2.00
3.00
4.00
5.00
0 2 4 6 8 10
SR Cottonseed Oil vs. Cottonseed Oil NF
0.00
1.00
2.00
3.00
4.00
5.00
6.00
0 2 4 6 8 10
SR Soybean Oil vs. Soybean Oil USP
µ/gram
µ/gram
µ/gram
Time (weeks)
Time (weeks)
Time (weeks)
Cottonseed NF - Unsat
Cottonseed NF - Sat
SR Cottonseed - Unsat
SR Cottonseed - Sat
Castor USP - Unsat
Castor USP - Sat
SR Castor - Unsat
SR Castor- Sat
Soybean USP - Unsat
Soybean USP - Sat
SR Soybean - Unsat
SR Soybean - Sat
0.00
1.00
2.00
3.00
4.00
5.00
6.00
7.00
0 2 4 6 8 10
SR Olive Oil vs. Olive Oil NF
µ/gram
Time (weeks)
Olive NF - Unsat
Olive NF - Sat
SR Olive - Unsat
SR Olive - Sat
80
81
82
83
84
85
86
0 2 4 6 8 10
SR Castor Oil vs. Castor Oil USP
Iodine Values
105
106
107
108
109
110
111
112
113
114
0 2 4 6 8 10
SR Cottonseed Oil vs. Cottonseed Oil NF
SR Cottonseed Oil
Cottonseed Oil NF
Time (weeks)
g Iodine/
100g
g Iodine/
100g
Time (weeks)
SR Castor Oil
Castor Oil USP
122
124
126
128
130
132
134
0 2 4 6 8 10
SR Soybean Oil vs. Soybean Oil USP
SR Soybean Oil
Soybean Oil NF
Time (weeks)
g Iodine/
100g
USP min spec
76
78
80
82
84
86
88
90
0 2 4 6 8 10
SR Olive Oil vs. Olive Oil NF
g Iodine/
100g
Time (weeks)
Olive Oil NF
Peroxide Values
0.00 2.00 4.00 6.00 8.00 10.00
0
2
4
6
8
SR Cottonseed Oil vs. Cottonseed Oil NF
Cottonseed Oil NF
SR Cottonseed Oil
Time (weeks)
meq active oxygen / Kg
Time (weeks)
meq active oxygen / Kg 0.00 2.00 4.00 6.00 8.00
0
2
4
6
8
SR Soybean Oil vs. Soybean Oil USP
Soybean Oil USPSR Soybean Oil
Time (weeks)
meq active oxygen / Kg
0.00 2.00 4.00 6.00 8.00 10.00
0
2
4
6
8
SR Castor Oil vs. Castor USP
Castor Oil USP
SR Castor Oil
0.00 2.00 4.00 6.00 8.00
0
2
4
6
8
SR Olive Oil vs. Olive Oil NF
Olive Oil NFSR Olive Oil
Time (weeks)
meq active oxygen / Kg
Excipient Purity
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Conclusions for Lipid Studies
Super Refined excipients have: Improved quality Increased longevity Significant decrease in lipid oxidation
The purity and integrity of lipophilic excipients
and the prevention of lipid oxidation are critical for maintaining the stability and integrity of the formulation design
Excipient Purity
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Recent Results: Rancimat
Measures oxidative stability of oils Volatile oxidation products (mainly formic acid)
cause an increase in conductivity in trap water Results expressed as induction time – longer
time = more stable
Excipient Purity
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Rancimat Results
0 0.5 1 1.5 2 2.5 3
PS80 Int
SR PS80
Oleic Acid
SR Oleic Acid
Cottonseed
SR Cottonseed
Induction Time (hours) at 120ºC
2-fold increase
5-fold increase
5½-fold increase
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Audience Poll 2 What data would you be interested in seeing to further support the use of high purity excipients in your formulations?
More API drug stability Reduction of protein aggregation Topical drug penetration Aesthetic impact of an excipient Toxicity data Reduction in nano particle aggregation Dissolution data Other
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Improved API
Stability
Addressing
Formulation Challenges
Excipient Purity
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Purpose: To assess the relationship between excipient stability and API stability by comparing SR PEG 400 and SR DMI to their standard grades
Side by side comparisons were made at multiple time
points by measuring % API recovered
API analysis was conducted using HPLC
API Stability Study #1
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Benzocaine in PEG 400
80
85
90
95
100
0 5 10 15 20 25
% B
enzo
cain
e of t
otal
area
Weeks on stability
_____ SR PEG 400 _____ Standard PEG 400
5-10% loss in stability with lower grade excipient
Excipient Purity
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Benzocaine in DMI
75
80
85
90
95
100
0 1 2 3 4 5 6 7 8 9 10
% B
enzo
cain
e pr
esen
t in
tota
l are
a
Weeks on stability
Even greater losses in stability with lower grades of DMI – attributed to higher formaldehyde levels
_____ SR DMI _____ Standard DMI
Excipient Purity
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Purpose: To monitor and assess the metabolic stability of perphenazine in a solution of propylene glycol for a period of 6 weeks at 50ºC
Side by side comparisons were determined looking at multiple time points over the 6 week period of time
Analysis was conducted using LC-MS
API Stability Study #2
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Stability Data of Perphenazine in Propylene Glycol Time on Stability 0 12 hours 24 hours 48 hours 1 week 2 weeks 3 weeks 4 weeks 5 weeks 6 weeks
Propylene Glycol USP 100 100 98 96 92 90 87 78 76 75
Super Refined Propylene Glycol 100 100 100 100 100 100 100 98 96 96
70
75
80
85
90
95
100
Time
~
12 hrs
24 hrs
48 hrs
1 wk
2 wks
3 wks
4 wks
5 wks
6 wks
0
%
Recovery
Super Refined Propylene Glycol
96% API Recovery
Propylene Glycol USP
75% API Recovery
Perphenazine in Propylene Glycol
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Purpose: To monitor and assess the stability of Lidocaine in a solution of isopropyl myristate for a period of 60 days at 60ºC
Side by side comparisons (SR Crodamol IPM vs. commerical IPM) were determined looking at multiple time points over the 60 day period of time
Analysis was conducted using LC-MS
API Stability Study #3
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Lidocaine in IPM
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Purpose: To evaluate the stability of lidocaine in Super Refined and compendial sesame oil for a period of 28 days at 50ºC
Analysis was conducted using HPLC – reversed phase
API Stability Study #4
Excipient Purity
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AU
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
0.55
0.60
0.65
0.70
0.75
0.80
Minutes 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00
Sesa
mol
in
Sesa
min
Sesa
mol
Sesame oil NF
Super Refined Sesame NF - NP
Oil Comparison, T=0 days
Excipient Purity
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AU
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
0.55
0.60
0.65
0.70
0.75
0.80
Minutes 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00
Lid
ocai
ne
Sesame oil NF
Super Refined Sesame NF – NP
Lidocaine in Oil Comparison, T=0 days
Excipient Purity
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AU
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
0.55
0.60
0.65
0.70
0.75
0.80
Minutes 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00
Lid
ocai
ne
Lid
ocai
ne D
egra
datio
n
Sesame oil NF
Super Refined Sesame NF – NP
Lidocaine in Oil Comparison, T=28 days
Excipient Purity
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Sesame Oil NF
Super Refined Sesame NF-NP
Lidocaine degradation
Crystallization
Sesamin / Sesamolin degradation
Lidocaine – Intact
No Crystallization
Analytical Clarity
API Stability Study #4 - Summary
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Audience Poll 3
Besides BCS II class drugs, are there other APIs that you would like to see tested with high purity excipients?
Monoclonal Antibodies BCS IV class drugs BCS III class drugs Peptides Proteins Vaccines Other
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Final Thoughts
As drug actives present a challenge to formulators, one of the easiest ways to manage your formulation efforts is by selecting a high quality, high purity excipient
Quality and handling of excipients will not only enhance the drug profile, but will streamline and accelerate all efforts in the development phases
Novel high performance excipients exist for use with a wide range of active pharmaceutical ingredients Polar excipients Non-polar excipients
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To Overcome Formulation Challenges
THANK YOU!
Using
Excipient Purity
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Super Refined™ Topical Penetration Enhancers
Super Refined Arlasolve™ DMI high purity dimethyl isosorbide
Super Refined Crodamol™ IPM high purity isopropyl myristate
Super Refined Novol™ high purity oleyl alcohol
Super Refined Oleic Acid
Sample Assortments Available
Super Refined™ Lipids
Super Refined Castor
Super Refined Cottonseed
Super Refined Olive
Super Refined Sesame
Super Refined Soybean
Super Refined™ Polysorbate Range
Super Refined Polysorbate 20
Super Refined Polysorbate 60
Super Refined Polysorbate 80
Super Refined™ PEG Range
Super Refined PEG 300
Super Refined PEG 400
Super Refined PEG 600
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Samples
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