The slides explore how the choice of excipients can improve API stability in a solid dosage drug formulation.

1. Merck KGaA
Darmstadt, Germany
Dr. Leo Ohrem
September 6, 2018
How can excipients support you?

2. The life science business of
Merck KGaA, Darmstadt, Germany
operates as MilliporeSigma
in the U.S. and Canada.
Webinar API stability in solid dose - How can excipients support you?2

3. In this webinar, you will learn about:
What is the impact of poor API stability?
What factors affect API stability?
How can excipients help?
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2
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Case studies
Key takeaways
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5Webinar API stability in solid dose - How can excipients support you?3

4. The need of good API stability
API stability has to be proven in registration
Acceptance by authorities
Short shelf life
Worse economics
Burden on supply chain
Difficult storage conditions
Accuracy of patient dosage
Reduced strength over shelf life
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2
3
4
Webinar API stability in solid dose - How can excipients support you?4

5. Reasons for lack of API stability
pH Sensitivity
Oxidation
Heat/
Temperature
Light
Sensitivity
Moisture
Biological
threats
Webinar API stability in solid dose - How can excipients support you?5

6. Excipients
typically thought
of as inert
What effect do excipients have?
Webinar API stability in solid dose - How can excipients support you?6
Fillers
Lubricants, flow enhancers,
disintegrants, binders, coatings,
pigments
No function
wanted
Physical
action
pH adjustment, preservatives,
antioxidants, scavengers, taste
modifiers
Chemical
activity
Wanted interaction with API:
Excipients to alter solubility,
recrystallisation, permeability, in situ
salt formation
complexation
Bioavailability

7. Factors affecting API stability
How to use traditional approaches to limit stability issues?
Direct
interaction /
reactivity
Granulation process
Compression force
Oxidation
Moisture content
Impurities
Hygroscopicity
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9. Examples:
 Lactose?
 Mg-Stearate?
 Ca-Phosphate?
Direct interaction
Are excipients inert?
Excipients can interact with APIs – Strategy: leave out when possible.
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11. Substance Water content
Starch < 15 %
MCC < 7 %
Isomalt < 7 %
Excipient System A < 5.75 %
Excipient System B < 3.5 %
Excipient System C < 3 %
Lactose monohydrate < 1 %
DC-Mannitol < 0.3 %
Excipients systems A-C are ready-to-use
systems of the following composition:
 A: lactose monohydrate, povidone,
crospovidone
 B: lactose monohydrate, cellulose
 C: lactose monohydrate, maize starch
Moisture Content
Water content of excipients matters
Mannitol is the best choice to use with moisture sensitive APIs
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Rowe, R. C., P. J. Sheskey, et al., Eds. (2009). Handbook of Pharmaceutical Excipients. 6th Edition. London,
Washington DC, Pharmaceutical Press and American Pharmacists Association or manufacturer’s information.

12. Hygroscopicity
Comparison of filler excipients
Least hygroscopicity for Mannitol
Even sorbitol may work well, if humidity can be controlled
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14. Keep it simple!
What you leave out, you do not need to worry about
Wu Y, Levons J, Narang AS, Raghavan K, Rao VM. Reactive Impurities in Excipients: Profiling, Identification and Mitigation
of Drug–Excipient Incompatibility. AAPS PharmSciTech. 2011;12(4):1248-1263. doi:10.1208/s12249-011-9677-z.
Impurities
Excipients and their impurities
Webinar API stability in solid dose - How can excipients support you?14
• MCC Water, glucose (reducing sugar), hydrogen bonding ( retardation),
aldehydes, free radicals/peroxides
• Glucose, Lactose Water, aldehydes, formic acid, reducing sugar
• Starch Water, reducing sugar, aldehydes
• HPMC Water, reducing sugar, retardation, aldehydes
• PEG, Tween Aldehydes, peroxides
• Povidone Peroxides, aldehydes, retardation
• Crospovidone Peroxides, aldehydes

15. How to minimize:
Commercial standard according to pharmacopoeia limits for polyols (mannitol, sorbitol)
Ph. Eur.  max. 0.10 %
USP  max. 0.30 %
Impurities
Reducing sugars are cause for instability and browning (Maillard reaction)
15 Webinar API stability in solid dose - How can excipients support you?
Is this limit sufficient for API stability?

16. Mannitol A with API, tested after storage (60°C, 7 days),
The content of the target impurity is 1.91%
Mannitol A & API, tested after blending
Mannitol B & API, tested after blending
Mannitol B with API, tested after storage (60°C, 7 days),
The content of the target impurity is 0.57%
Unwanted related substance from the reaction of API
impurity (amine) and the reducing sugars in the Mannitol.
min
signal
Impurities
Reaction of API impurity with reducing sugars in mannitol
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Impurity levels can be different between suppliers of the same type of excipient

17. Impurities
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DC Formulation with
Mannitol A
• Unwanted degradation
product of API: 6.5%
DC Formulation with Mannitol B
• Unwanted API degradation
product of API: 1.5%
• Many fewer types of
impurities identified
The choice of excipient and the respective level of impurities are critical factors
influencing API stability
Formulation of mannitols from different suppliers using direct compression

18. Impurities
Example: Reducing sugars in Parteck® M excipient batch to batch
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Typical values of an impurity are never the same as the specification limits.

20. Peroxides in ready-to-use ODT systems
Composition of RTU ODT excipient systems:
 A: Mannitol, croscarmellose sodium
 B: Lactose, starch
 C: Mannitol, crospovidone, povidone, polyvinyl acetate
 D: Mannitol, xylitol, MCC, crospovidone, calcium
dihydrogen phosphate dihydrate
 E: Mannitol, xylitol, MCC, crospovidone, Mg Al Silicate
 F: Mannitol, fructose, MCC, silicon dioxide,
crospovidone
 G: Mannitol, starch
Oxidation
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Look for low levels of peroxides to improve API stability

22. Compression Force
How can compression force affect API stability?
Temperature rise Shear force breaks up
large molecules
Shear force breaks up
coated API particles
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23. Compression Force
Effect on coated API particles
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API
F
API
API
F
API Stability
Sustained
release
Taste
Masking

24. Compression Force
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Old formulation
Filler/binder Mannitol C
Compression
force
18 kN
Tablet hardness 40 N
DC Case Study: Enhanced stability of Vit. D3 by reduced compression force

25. Compression Force
DC Case Study: Enhanced stability of Vit. D3 by reduced compression force
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Old formulation New formulation
Filler/binder Mannitol C Mannitol B
Compression
force
18 kN 2 kN
Tablet hardness 40 N 55 N
Using the right excipient can help maximize hardness with minimizing
compression force

26. Compression Force
Evaluation of different excipients for direct compression
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Sorbitol and spray-dried mannitol deliver superior compressibility

27. Compression Force
Particle Engineering creates compressibility
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Large surface areas show great compressibility

29. What is most suitable for sensitive APIs:
Wet granulation?
Roller compaction?
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Direct
compression!

30. Granulation Process
Limitations in direct compression
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1
2
3
Content Uniformity
Compressibility
Flow

31. Granulation Process
Statistical mixture vs ordered mixture
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Common
knowledge:
Homogenous
mixtures only
possible for
similar particle
sizes

32. Granulation Process
Statistical mixture vs ordered mixture
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33. Spray-dried Mannitol A
+ 1% Ascorbic Acid < 10µm
Spray-dried Mannitol B
+ 1% Ascorbic Acid < 10µm
Granulation Process
Statistical mixture vs ordered mixture
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Large structured surface enables ordered mixtures by adsorption of the API

35. Case study 1
Direct compression with low dose actives
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Avicel is a registered trademark of FMC Corporation, Delaware, USA.
Compritol is a registered trademark of Gattefossé SAS, Saint-Priest, France.
A low dose water-sensitive active should be directly compressed

36. Webinar API stability in solid dose - How can excipients support you?36
40.000 Tab/h 80.000 Tab/h
Tablet weight 120.1 mg (rel.sd.: 0.6%) 118.8 (rel.sd.: 0.9%)
Hardness 178 N (rel.sd. 4.1%) 173 N (rel.sd: 4.1%)
Disintegration 3'25'' 3'22''
Structured surface enables perfect content uniformity;
good flow leads to constant perfomance
Case study 1
Direct compression with low dose actives

37. Webinar API stability in solid dose - How can excipients support you?37
Case study 1
How can we explain that?

39. Highlight traditionally difficult unstable API: Atorvastatin
Atorvastatin is known to be:
 Heat sensitive
 Moisture sensitive
 Oxidation sensitive
 Light sensitive
 Acid sensitive
 Unstable in amorphous form
Case study 2
API Stability
39 Webinar API stability in solid dose - How can excipients support you?

40. Use Mannitol in direct compression together with alkalizer
Case study 2
How to solve stability issues of Atorvastatin?
40 Webinar API stability in solid dose - How can excipients support you?
 Heat sensitive
 Moisture sensitive
 Oxidation sensitive
 Light sensitive
 Acid sensitive
 Unstable in amorphous form
 Omit wet granulation
 Direct compression
 Low compression force
 Keep out peroxides
 Add alkalizer (Meglumine
Parteck® MgDC Excipient, CaCO3)

41. API stability in solid dose – How can excipients support you?
Key takeaways
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43. Dr. Leo Ohrem
hans-leonhard.ohrem@emdgroup.com
The vibrant M is a trademark of Merck KGaA, Darmstadt, Germany or its affiliates. All other
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is available via publicly accessible resources.
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