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To Overcome Formulation Challenges

Using

Excipient Purity

Excipient Purity


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


Excipients in Pharmaceuticals

Functional excipients provide critical benefits in pharmaceutical formulation development…

Drug Delivery

Emulsification

Solubilization

Stability Enhancement

Controlled Release


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


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

Excipient Purity


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

Excipient Purity


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


MALDI-MS: Polysorbate 80 Comparisons


Reproducibility of MALDI-MS

Excipient Purity


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

Excipient Purity


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

Excipient Purity


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


Reduced Potential

for Cellular Irritation

Addressing

Formulation Challenges

Excipient Purity


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

Excipient Purity


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

Excipient Purity


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)


Enhanced Excipient Stability

Addressing


Excipient Purity


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


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


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


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


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

Excipient Purity


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

Excipient Purity


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

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

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


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


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


Soybean Oil USPSR Soybean Oil

Time (weeks)


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


Olive Oil NFSR Olive Oil

Time (weeks)


Excipient Purity


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


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

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&docid=3YBc5iLvpmAE6M&tbnid=lhU-JWSyDrbDNM:&ved=0CAUQjRw&url=http://www.cyclochem.com/cyclochembio/research_e/035.html&ei=k0dNU-_dGsekyQHHpoHYDg&bvm=bv.64764171,d.aWc&psig=AFQjCNHepFKg3K454Pkly8KG7ZZljv4vqQ&ust=1397659798248867

Excipient Purity


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

Excipient Purity


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


Improved API

Stability

Addressing


Excipient Purity


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

Excipient Purity


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


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


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



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

Excipient Purity


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


Excipient Purity


Lidocaine in IPM


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


Excipient Purity


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


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


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


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

Excipient Purity


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

Excipient Purity


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


To Overcome Formulation Challenges

THANK YOU!

Using

Excipient Purity


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™ PEG Range

Super Refined PEG 300



Click to Order

Samples

http://www.croda.com/samplerequest.aspx?eventID=9ea88b3c-0975-499c-af05-c7264ff3cdf3&lid=2370

Excipient Purity


Additional Information

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