Watch the presentation of this webinar here: https://bit.ly/3vQyN7K Bitter medicines are an important issue, especially for pediatric applications. As several APIs have bitter tasting components, high intensity sweeteners for taste optimization are of great interest. Join our webinar to discover our new sweetener toolbox enabling safe and stable formulations. Mask bitter aftertaste for a sweeter pill to swallow! Patients’ compliance and the therapeutic benefit are supported by a pleasant taste of pharmaceutical formulations. With the high intensity sweeteners Neotame and Sucralose, you have efficient tools at hand which are superior to other sweeteners in many aspects: • excellent sugar-like taste profile • outstanding sweetness factors • use effectiveness • enhanced stability We will present our new toolbox of two high performance sweeteners and focus on aspects of stability, safety, the application in various dosage forms, and market perception. In this webinar, you will learn: • How to optimize the patients' taste experience of your pharmaceuticals • How sweeteners can be differentiated by their sensory profiles and features • How our new product offering Neotame can be effectively used in your targeted formulations Presented by: Almut von der Brelie, Senior Manager Strategic Marketing, Excipients for Solid Applications

1. The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
Almut von der Brelie
Darmstadt, 26th April 2022
The High-Intensity Sweeteners
Neotame and Sucralose
2 WAYS TO ACE
THE PATIENT’S
TASTE TEST!

2. The life science business
of Merck KGaA, Darmstadt,
Germany operates as
MilliporeSigma in the U.S.
and Canada

3. Bitter medications are an important issue for the pharmaceutical industry
and pediatric medications as several APIs have a bitter taste.
THE IMPORTANCE
OF TASTE OPTIMIZATION
Pharmaceutical formulations with a pleasant taste
are preferred over a competitor's product and
support patients’ compliance and the therapeutic
benefit.

4. 4
2 ways to ace the taste test
The importance of taste optimization
Neotame and Sucralose
are the ideal taste optimizer
in your oral solid, liquid and film applications
Increased sweetness factors
Superior to other sweeteners in several important ways:
Excellent sugar-like taste profile
Enhanced stability
No Phenylketonuria warning label

5. Agenda
1
2
3
The sweet duo:
Neotame and Sucralose
Sensory properties
and profiles
Features and
Stability
4 NEW! Neotame

6. 6 Introduction of Neotame | February 2022
The NEW! Neotame Emprove® Essential NF
• Article Number: 107071
• Chemical Name: N-[N-(3,3-dimethylbutyl)-L-
alpha-aspartyl]-L-phenylalanine-1-methyl
ester
• CAS-No: 165450-17-19
• Chemical formula: C20H30N2O5
• Packaging sizes:
10 g sample pack, 250 g and 1 kg
• Appearance: white to off-white powder
• Target Applications:
tablets, liquids, oral films
NEOTAME
a dipeptide methyl ester derivate of Aspartame
Complies with USP
NF Monograph for
excipient use
NEWCOMER!
Complementing
our Sweetener
Portfolio!
2 ways to ace the taste test

7. 7 Introduction of Neotame | February 2022
Sucralose - in 2 qualities tailored to your needs
• Article Number: 100894
• Packaging sizes:
10 g sample pack
1 kg and 10 kg
• Appearance: almost white
• Recommended Applications:
solids, liquids
• Particle size:
d90: ≤12 µm
SUCRALOSE
• Article Number: 100895
• Packaging sizes:
10 g sample pack
1 kg and 10 kg
• Appearance: almost white
• Recommended
Applications: liquids
• Particle size:
d90: > 80 µm
071
• Chemical Name: 1´, 6´dichloro-1´,6-dideoxy-beta-D-
fructofuranosyl-4-chloro-4-deoxy-alpha-D-galactopyranoside
• Chemical formula: C12H19Cl3O8
• CAS-No: 56038-13-2
10 g
2 ways to ace the taste test
Sucralose granular EMPROVE®
ESSENTIAL Ph Eur,NF,JPE
Sucralose powder EMPROVE®
ESSENTIAL Ph Eur,ChP,NF,JPE
POWDER
GRANULES

8. 8
Neotame
EMPROVE® ESSENTIAL
Sucralose powder
EMPROVE® ESSENTIAL
Sucralose granular
EMPROVE® ESSENTIAL
Taste
Clean, sugar-like taste
slightly delayed onset and lasting sweetness
Sweetness potency
vs. Sucrose
8,000-13,000 400-800
Pharmacopeia
NF
listed in IID*
Ph Eur, ChP, NF, JPE
listed in IID*
Ph Eur, NF, JPE
listed in IID*
Safety profile Widely approved food additives (FDA, EU, China; safety evaluation by JECFA)
Recommended
Dosage
1-750 ppm 0.05 – 2.0 %
Cost-efficiency +++ +
Heat stability
in solid
formulations**
+++ ++ +
Solid Applications
Liquid Applications
Oral Film Applications
* IID: FDA Inactive
Ingredient Database
** see detailed info on
slide 12
Make your choice tailored to your formulations needs
2 ways to ace the taste test
Neotame and Saccharose | April 2022

9. 2 ways to ace the taste test
Neotame and Sucralose feature a high and use-effective sweetness
Neotame and Saccharose | April 2022
9
Synthetic
high-intensity
sweeteners
Relative
sweetness ranges
in relation to
Sucrose=1
Acesulfame K 130-200
Aspartame 120-220
Cyclamate 20-40
Neotame 8,000-13,000
Saccharin 200-700
Sucralose 400-800
Typical concentration
in pharmaceutical
applications:
1 – 750 ppm
NEOTAME
1 % SUCRALOSE
Note: Sensory impressions may depend on matrices
(solid/liquid) and formulations, and the API. In scientific
literature values for relative sweetness ranges can be found
due to the subjectivity of sensory methods.
depending on
target formulation
and API

10. Reverse scale for Sweetness
Lower scores
indicate
better
performance!
SENSORY SPIDERWEB
Scale for Bitterness: 0 = not perceptible; 7 = very strong
Sucralose is the
golden sensory
standard
for overall and aftertaste
sweetness and enables the
lowest overall bitterness.
The sensory profile of
Neotame is comparable to
that of Aspartame, but
Neotame is superior to
Aspartame in use
effectiveness and stability.
Na-Saccharin is perceived
as bitter in aftertaste.
Bitterness surrogate:
0.06% quinine
N=12, mean of
3 replications
10
NOTE: The usage level of the sweeteners in
the formulations considers the different
individual sweetness factors.
Click here for
more information
0
1
2
3
4
5
6
7
Onset Sweetness
Onset Bitterness
Overall Sweetness
Overall Bitterness
Aftertaste Sweetness
Aftertaste Bitterness
Sucralose 1.0%
Aspartame 2.66%
Na-Saccharin 1.33%
Neotame 0.075%
Neotame and Saccharose | April 2022

11. BITTERNESS PROFILING
0
1
2
3
4
5
Sucralose 1.0%
Aspartame 2.66%
Na-Saccharin 1.33%
Neotame 0.075%
Onset Aftertaste
Overall
Neotame and Saccharose | April 2022
11
11
Bitterness
Neotame
and
Sucralose
are effective
and potent
alternatives
to Aspartame
Bitterness surrogate:
0.06% quinine
5-points-scale:
0 = not perceptible
5 = medium to strong
lower scores indicate
better performance
N=12, mean of 3
replications
NOTE: The usage level of the sweeteners
in the formulations considers the different
individual sweetness factors.
Click here for
more information

12. Neotame and Sucralose | April 2022
12
Information about stability
2 ways to ace the taste test
Stability is always dependent on pH, temperature and time
and the composition of your formulation and the API.
Neotame has superior
stability to aspartame*
and does not release
phenylalanine under
normal storage
conditions.
* May lose sweetness when heated; maillard type
reaction with primary amino group possible
Sources:
Asian Journal of Chemistry, Satyavathi et al.,
Vol. 22, No.7, 5792
EFSA Supporting publication 2021:EN-6918
Neotame
• Substance: stable in dry state during storage at 15 – 25°C;
passed 3 months accelerated stability test at 40°C
• Solid applications: supports heat treatment over short periods of time;
suitable for wet granulation
• Liquid applications: max. stability at pH 4.5
Sucralose
• Substance: stable during storage at 15° - 25°C, dry heat > 25°C to be avoided
• Solid applications: best stability at a water content of 0.5 – 2%
• Liquid applications: aqueous stability over a wide range of pH values

13. MASK
AFTERTASTE.
UNCOVER NEW
OPPORUTNITIES.
.
High-Intensity Sweetener
NEOTAME

14. Product features
Neotame and Sucralose | April 2022
14
Neotame is superior to other sweeteners in many aspects
Proven safety
widely approved food additive: e.g. in USA (since 2002), EU (since 2010 / with E 961); safety evaluated by JECFA
No PKU warning label requested in difference to aspartame
suitable for individuals with phenylketonuria (PKU) and diabetes type 2 (zero glycemic index)
Excellent clean, sugar-like taste profile – can modify or mask bitterness
similar taste to that of sucrose, no bad aftertaste and good mouthfeel
Excellent stability
chemically stable under standard ambient conditions; more heat stable than Aspartame*
Cost-efficiency due to higher sweetness potency
by sweetness factor 8,000 to 13,000 greater than sucrose, 40-60 greater than Aspartame
Compatible with other sweeteners
such as sucralose, acesulfame, sucrose, and reducing sugars; synergistic effects possible in combination
* May lose sweetness when heated

15. • maximum potency per unit dose: 1.35 mg in powder, for solution (oral route)
Neotame is not considered new and may require a less extensive review the next time it
is included in a new drug product. Approved in a certain dosage form at a certain potency,
a sponsor could consider it safe for use in a similar manner for a similar type of product.
Neotame EMPROVE® ESSENTIAL NF
Safety information from US FDA
15
Inactive Ingredient Search for Approved Drug Products (fda.gov)
• derived ADI: 18 mg/person/day
• no indications for carcinogenicity, chronic or reproductive toxicity
• no bioaccumulation at expected human intake levels
• approval for the use in foods at GMP - without a numeric max. level
https://www.govinfo.gov/app/details/FR-2002-07-09/02-17202
Entry in FDA Inactive Ingredient Database
No specific
restrictions for
the use in
pediatric
formulations
Widely
approved
as food
additive
https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=172.829
Safety evaluation for use as sweetener agent
and flavor enhancer in foods provided by US FDA
Other Sources:
Asian Journal of Chemistry, Satyavathi et al., Vol. 22, No.7, 5792 (2010)
Ullmann’s Encyclopedia of Industrial Chemistry, Sweeteners, R. Lipinsky (2015)
NF monograph
available!
Established
excipient for oral
applications

16. 16 Neotame and Sucralose | April 2022
Neotame EMPROVE® ESSENTIAL NF - Specification
PARAMETER SPECIFICATION
Assay (HPLC, calc. on anhydrous substance) (NF) 97.0-102.0 %
Identity (IR) passes test
Spec. rotation [α]20/D
(calc. on anhydrous substance)
-43.4 to -40.0 °
Pb (Lead) ≤ 1 ppm
Pd (Palladium) ≤ 1 ppm
Related compounds (compound A) (NF) ≤ 1.5 %
Related compounds (compound B) ≤ 0.1 %
Related compounds (compound C) ≤ 0.1 %
Related compounds (compound D) ≤ 0.1 %
Related compounds (all impurities except A) (NF) ≤ 2.0 %
Methanol ≤ 3000 ppm
Other residual solvents (ICH Q3C) excluded by
production process
Sulfated ash (600 °C) ≤ 0.2 %
Water (according to Karl Fischer) ≤ 5.0 %
PARAMETER SPECIFICATION
Microbiological purity
(Total aerobic microbial count (TAMC)
≤ 1000 CFU/g
Microbiological purity
(Total yeast and mould count (TYMC)
≤ 100 CFU/g
Bile tolerant Gram negative Bacteria
(absent in 1 g)
passes test
Escherichia coli (absent in 1 g) passes test
Pseudomonas aeruginosa (absent in 1 g) passes test
Staphylococcus aureus (absent in 1 g) passes test
Candida albicans (absent in 1 g) passes test
Salmonella ssp (absent in 10 g) passes test
Our product complies with NF Monograph for excipient use

17. 17 Neotame and Sucralose | April 2022
Neotame EMPROVE® ESSENTIAL NF
Applications and content uniformity
Premix neotame with excipients of your formulation
- e.g. 10% of an excipient
DOSAGE FORMS:
orally disintegrating tablets
liquid formulations
oral films
lozenges
effervescent tablets
Recommendations for solid applications:
SUGAR-LIKE CLEAN SWEETNESS
WITHOUT ADDING SIGNIFICANT BULK
Coated tablets: Neotame may be incorporated in the coating

18. Neotame and Sucralose | April 2022
18
THE EMPROVE® DOSSIER LIBARY
Material
Qualification
Dossier
Information to start a
material qualification
Quality
Management
Dossier
Answers questions
during risk assessment
Operational
Excellence
Dossier
Supports process
optimization
Your
benefits:
• Reduce complexity
• Navigate regulatory challenges
• Increase process efficiency
• Risk mitigation
Neotame EMPROVE® ESSENTIAL, NF
meets the highest quality standards such as EXCiPACTTM.
It is complemented with 3 different types of dossiers supporting you throughout the different
stages of your operations:
Qualification, risk assessment, and process optimization
Visit: SigmaAldrich.com/emprove
Neotame EMPROVE® ESSENTIAL NF
Regulatory support and risk management
DESIGNED TO SPEED TO MARKET

19. High-Intensity Sweeteners Neotame and Sucralose
MASK BITTER
AFTERTASTE
FOR A SWEETER PILL
TO SWALLOW

20. Almut von der Brelie
E-Mail: almut.vonderbrelie@emdgroup.com
Contact
The vibrant M, Emprove and SAFC are trademarks of Merck KGaA, Darmstadt, Germany or its affiliates. All other trademarks are the property of their respective owners.
Detailed information on trademarks is available via publicly accessible resources.
© 2022 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.

21. 21 Neotame and Sucralose | April 2022
Descriptor Definition 7-point-scale
Neutralizing with one sip of water
Onset Sweetness sweet intensity that immediately develops in the mouth 0 = very strong
7 = not perceptible
Onset Bitterness Intensity of bitterness that immediately develops in the mouth 0 = not perceptible
7 = very strong
Overall Sweetness sweet impression, which develops after 2x rubbing on the palate;
sweet tip
0 = very strong
7 = not perceptible
Overall Bitterness bitter impression, which develops after 2x rubbing on the palate;
bitter tip
0 = not perceptible
7 = very strong
Swallowing the sample
Aftertaste of sweetness Sweet impression, which develops approx. 5 sec. after swallowing 0 = very strong
7 = not perceptible
Aftertaste of bitterness Bitter impression created approx. 5 sec. after swallowing 0 = not perceptible
7 = very strong
Neutralizing and 2 minutes break
2 ways to ace the taste test
Sensory Study: Attributes and Definition
The study was conducted with a panel of professional taste testers by an external company.
The panel was compiled according to DIN EN ISO 13299.
Bitterness surrogate: 0.06% quinine
Back to sensory
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