Watch the presentation of this webinar here: bit.ly39Rd5Xd Amorphous formulations provide unparalleled solubility advantages. However, physical stability of the molecule in the formulation is crucial for success. Join this webinar to learn the advantages and risks of amorphous formulations and strategies for ensuring stabilization of challenging compounds. Solubility is a major challenge in the development of oral solid dosage forms. Amorphous formulation with polymeric solid dispersions have been the technology of choice to enhance solubility. However, this approach may have some downfalls when considering the ability to successfully stabilize compounds, especially poor glass former compounds with high propensity to re-crystallize. This webinar will examine amorphous stability from a theoretical perspective in the context of polymeric solid dispersions and mesoporous silica formulations. Finally, recent data demonstrating the potential of mesoporous silica for superior amorphous stabilization of poor glass formers will be presented. In this webinar, you will learn • Why solubility is a critical consideration in development of oral medication • How the amorphous form can enhance solubility and increase absorption • Why some molecules are at risk of re-crystallization with typical polymeric amorphous technologies • How mesoporous silica can reduce the risk of re-crystallization of poor glass formers

1. The life science business of Merck KGaA,
Darmstadt, Germany operates as
MilliporeSigma in the U.S. and Canada.
Amorphous Formulation for
Bioavailability Enhancement
Challenges and Risks
Daniel Joseph Price
Strategic Marketing Manager, A&F
April 6th,2021

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

3. Agenda
A&F Overview
Solubility and Amorphous Formulations
Mesoporous Silica, the Basics
Mesoporous Silica for Poor Glass Formers
Summary

4. Agenda
A&F Overview
Solubility and Amorphous Formulations
Mesoporous Silica, the Basics
Mesoporous Silica for Poor Glass Formers
Summary

5. Overview
Amorphous Formulation for Bioavailability Enhancement Challenges and Risks
 Advanced Drug Delivery
 Solid Formulation
 Liquid Formulation
 mRNA
 API grade raw materials
 Chemiflex Critical Raw Material
Program
 cGMP/Non-GMP small molecules
 Antibody-Drug Conjugate
(ADC)
 cGMP small molecules-API
 Generics-API
 High potent API (HPAPI)
 Linker (activated PEG)
Contract Manufacturing Formulation API / Pharm Materials
Actives and Formulaton
5

6. Innovation Fields
Formulation Franchise
Amorphous Formulation for Bioavailability Enhancement Challenges and Risks
6

7. Agenda
A&F Overview
Solubility and Amorphous Formulations
Mesoporous Silica, the Basics
Mesoporous Silica for Poor Glass Formers
Summary

8. Poorly soluble drugs are on the increase
18
22
54
6
40
21
33
6 Class I
Class III
Class II
Class IV
New molecular entities (“NMEs”) are products containing active moieties that have not been approved by FDA previously.
Data adapted from Benet et al. JPharmSci. 2013;102(1):34-42
Distribution of oral
immediate-release drugs
on the market
NME percentages from
a data set of 28,912
medicinal chemistry
compounds
Today
Tomorrow
Good solubility
Poor solubility
Poor solubility can lead to low and variable absorption
Amorphous Formulation for Bioavailability Enhancement Challenges and Risks
8

9. Absorption is mainly related to solubility and permeability
• Type of dosage form
• Disintegration time
• Administration route
• Permeation enhancers
• API lipophilicity
• Efflux (P-gp)
• API stability
Speed up
liberation
Influence
distribution
Reduce
metabolism
Postpone
elimination
• Chemical approaches
• Physical approaches
• Tissue targeting
• Protein binding
• Avoid the first pass
effect
• Reduce enzymatic
bio-transformation
• Increase circulation
lifetime
• Increase size
Solubility Permeability Other
Increase
absorption
Amorphous Formulation for Bioavailability Enhancement Challenges and Risks
9

10. • Type of dosage form
• Disintegration time
• Administration route
• Permeation enhancers
• API lipophilicity
• Efflux (P-gp)
• API stability
Chemical
approaches
Physical
approaches
• Salt formation
• Prodrug formation
• Particle size reduction
• Complexation
• Drug carriers
• Solid form modification
• Solid dispersion
Speed up
liberation
Influence
distribution
Reduce
metabolism
Postpone
elimination
• Tissue targeting
• Protein binding
• Avoid the first pass
effect
• Reduce enzymatic
bio-transformation
• Increase circulation
lifetime
• Increase size
Permeability Other
Increase
absorption
Solubility
Solubility can be enhanced via chemical or physical
approaches
Amorphous Formulation for Bioavailability Enhancement Challenges and Risks
10

11. • Type of dosage form
• Disintegration time
• Administration route
• Permeation enhancers
• API lipophilicity
• Efflux (P-gp)
• API stability
Chemical
approaches
Physical
approaches
• Salt formation
• Prodrug formation
• Particle size reduction
• Complexation
• Drug carriers
• Solid form modification
• Solid dispersion
Speed up
liberation
Influence
distribution
Reduce
metabolism
Postpone
elimination
• Tissue targeting
• Protein binding
• Avoid the first pass
effect
• Reduce enzymatic
bio-transformation
• Increase circulation
lifetime
• Increase size
Permeability Other
Increase
absorption
Solubility
Solid state modification can substantially enhance drug
solubility
Amorphous Formulation for Bioavailability Enhancement Challenges and Risks
11

12. Crystal Lattice
Energy
Solvation
Energy
Crystalline
Solid
Solid in
Solution
Amorphous
Solid
Amorphous Formulation technologies stabilize the high
energy, more soluble solid state
Solubility can be increased using the amorphous form
Amorphous Formulation for Bioavailability Enhancement Challenges and Risks
12

13. The most common amorphous formulation are polymeric
amorphous solid dispersions
Ditzinger, F. and Price, DJ. JPP. 2019
Polymer
Drug
Melt and Extrude
Spray-dry
Spray-dried
dispersion
(SDD)
Hot Melt
Extrusion
(HME)
How can we predict if our drug will be unstable?
Amorphous Formulation for Bioavailability Enhancement Challenges and Risks
13

14. Propensity for re-crystallization can be determined with the
Glass Forming ability (GFA) classification system
“The ease of vitrification of a liquid upon cooling” (Avramov et al. 2003)
GFA I GFA II GFA III
Baird et al.
Recrystallization
after cooling of
the melt
Recrystallization
after reheating the
cooled melt
No
recrystallization
Usage in marketed
ASDs
6.25 % 18.75 % 75.00 %
Poor glass formers (GFA-I) have a higher propensity for re-crystallization.
They are more fragile in the amorphous form.
Baird, et al. J Pharm Sci. 2010 and Wyttenbach and Kuentz. EJPB. 2017
Amorphous Formulation for Bioavailability Enhancement Challenges and Risks
14

15. Agenda
A&F Overview
Solubility and Amorphous Formulations
Mesoporous Silica, the Basics
Mesoporous Silica for Poor Glass Formers
Summary

16. Mesoporous silica inorganic drug carrier
Chemical formula: SiO2
Pharmacopoeial monograph: Silicon Dioxide (USP) and Silica, colloidal hydrated (Ph Eur)
Regulatory status: Generally Regarded As Safe (GRAS)
Typical values
Particle size 5 – 20 µm
Bulk density 0.32 g/mL (0.56 g/mL**)
Surface area ~ 500 m2/g
Pore size ~ 6 nm (disordered)
* By the U.S Food and Drug Administration
** Parteck® SLC loaded with 30% Ibuprofen. Density is increased upon loading with API
Parteck® SLC is an inorganic silica carrier
Amorphous Formulation for Bioavailability Enhancement Challenges and Risks
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17. Solubilise
+Parteck SLC®
+ H2O
ca.6nm diameter
✓ Improved Solubility
✓ Increased Dissolution
✓ Improved Absorption
+ precipitation
inhibitor to prevent
recrystallisation
Sterically stabilized
Amorphous!
Solvent
Removal
Parteck® SLC is a porous SiO2 with up to 500 m2/g surface area
Parteck® SLC stabilizes the amorphous form via pore
adsorption and nanoconfinement
Amorphous Formulation for Bioavailability Enhancement Challenges and Risks
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18. Development scale
 1 / 13 kg loadings
 Suitable equipment for loading
and drying available in different
sizes
Small scale
 1 / 10 / 200 g loadings
 Simple lab equipment which
can be easily adapted in scale
size
Production scale
 100 kg loading
 Process is transferred to
production scale without
further need for process
development
Loading is feasible from lab to production-scale
Amorphous Formulation for Bioavailability Enhancement Challenges and Risks
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19. Fenofibrate is present in its amorphous state when loaded upon Parteck® SLC
Excipient.
DSC
Crystalline API
Parteck® SLC
Excipient,
API load 30 %
Wet Impregnation
 Loading solvent: acetone
 Method: wetness impregnation
 Drug load: 30%
 Amorphous
 Residual solvent below ICH limit (0.5 %)
 Lab-scale loading is accessible and requires no
extra capital investment
Loading of Fenofibrate onto Parteck® SLC Stabilizes the
Amorphous Form
Amorphous Formulation for Bioavailability Enhancement Challenges and Risks
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20. Sample Composition
Capsule
Fenofibrate loaded onto Parteck® SLC Excipient
Blended with HPMC-AS (12.5 %)
Filled in capsules
Suspension
Fenofibrate loaded onto Parteck® SLC Excipient
blended with 12.5 % HPMC-AS
suspended in water
Reference Crystalline Fenofibrate blended with 12.5 % HPMC-AS
Study Description
In-vitro dissolution test
Dissolution tests were carried out in 500 mL FaSSIF in USP type II
dissolution apparatus (n=3)
In-vivo studies
Bioavailability studies were conducted in fasted, male Landrace pigs
(12.5 – 16 kg, n=6)
Reference: J. P. O'Shea1 , A. Wieber2 , C. Saal2 , B. Griffin1 , V. Witt2 , K. Nagarsekar3 , E. Herbert3,
J. Dressman3, D. Lubda2: Mesoporous Silica for Improving Oral Bioavailability of Fenofibrate:
In Vivo Evaluation, AAPS Poster 2016
1University College Cork, 2Merck KGaA, Darmstadt, Germany, 3Goethe University1
A Biorelevant in vitro dissolution and in vivo PK study in
pigs was carried out: suspension and capsules
Amorphous Formulation for Bioavailability Enhancement Challenges and Risks
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21. Biorelevant dissolution provides a good prediction of relative bioavailability
PK study in pigs indicates a significant bioavailability enhancement of
Fenofibrate through Parteck® SLC Excipient also in vivo
0
500
1000
1500
2000
2500
3000
3500
4000
0 5 10 15 20 25
Plasma
concentration
(ng/ml)
Time (hrs)
Silica
Reference
Suspension
n = 6
Biorelevant in-vitro dissolution In-vivo bioavailability in fasted pigs
0
20
40
60
80
100
0 30 60 90 120
Dissolution
[%]
Time [min]
Reference Capsule
Silica Suspension
Silica Capsule
n = 3
Formulation of Fenofibrate with Parteck® SLC Enhances in
vivo bioavailability
Amorphous Formulation for Bioavailability Enhancement Challenges and Risks
21

22. Agenda
A&F Overview
Solubility and Amorphous Formulations
Mesoporous Silica, the Basics
Mesoporous Silica for Poor Glass Formers
Summary

23. Mesoporous silica is attractive from a physical chemistry
perspective for stabilization
GFA I GFA II GFA III
Baird et al.
Recrystallization
after cooling of
the melt
Recrystallization
after reheating
the cooled melt
No
recrystallization
Usage in
marketed ASDs
6.25 % 18.75 % 75.00 %
How can mesoporous silica be used to stabilize the previously impossible?
ca.6nm diameter
Sterically stabilized
Amorphous!
Amorphous Formulation for Bioavailability Enhancement Challenges and Risks
23

24. Dielectric spectroscopy has been used to study the effects of pore confinement
1 2a
Mesoporous silica has high potential for stabilization of poor glass formers!
Menthol mobility was probed by dielectric relaxation
spectroscopy, which allowed to identify two relaxation
processes in both pore sizes: a faster one associated with
mobility of neat-like menthol molecules (α-process),
and a slower, dominant one due to the hindered
mobility of menthol molecules adsorbed at the inner
pore walls (S-process).
• Menthol
• Tg: -60 °C
• Extremely poor glass former
• Stable amorphous with silica
• HME? SDD?
Molecular mobility is significantly hindered inside
mesoporous silica
Amorphous Formulation for Bioavailability Enhancement Challenges and Risks
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25. • Optimized pharma-grade polymer for HME
• Silica impregnation loading method
• Characterization with XRPD and non-sink FaSSIF dissolution
• ICH Q1 A (R2) accelerated stability conditions (40 °C and 75% RH)
Two model poorly soluble poor glass formers were
formulated with mesoporous silica and HME
Price, DJ. And Ditzinger, F. Pharmaceutics. 2019.
Amorphous Formulation for Bioavailability Enhancement Challenges and Risks
25

26. Mesoporous silica is able to consistently stabilize high drug
loads of poor glass formers in the amorphous form
Loading Content 30% 20% 15% 7.5%
Carbamazepine HME
Carbamazepine Silica
Haloperidol HME
Haloperidol Silica
Success of solid-state conversion after loading or extruding with silica or
HME, respectively at set loading concentrations.
Price, DJ. And Ditzinger, F. Pharmaceutics. 2019.
Amorphous Formulation for Bioavailability Enhancement Challenges and Risks
26

27. Macroscopic changes in HME extrudates were observed after
only one-week under accelerated conditions
Macroscopic Changes in HME were observed after just one week under ICH
Q1 stability conditions
Price, DJ. And Ditzinger, F. Pharmaceutics. 2019.
Amorphous Formulation for Bioavailability Enhancement Challenges and Risks
27

28. SEM confirmed that phase separation was occurring in the extrudates
SEM images: Haloperidol loaded silica
(a) and HME (b) showing particle size and
morphology at 0 days (top) and 7 days
stability (bottom)
Price, DJ. And Ditzinger, F. Pharmaceutics. 2019.
SEM provides evidence for microscopic phase separation
in HME (1)
Amorphous Formulation for Bioavailability Enhancement Challenges and Risks
28

29. SEM provides evidence for microscopic phase separation
in HME (2)
SEM confirmed that phase separation was occurring in the extrudates
SEM images: Carbamazepine loaded
silica (a) and HME (b) showing particle
size and morphology at 0 days (top) and
7 days stability (bottom)
Price, DJ. And Ditzinger, F. Pharmaceutics. 2019.
Amorphous Formulation for Bioavailability Enhancement Challenges and Risks
29

30. Mesoporous silica remains amorphous for the duration of the
study, while HME re-crystallizes (1)
Instability in HME formulations would result in failure of the formulation
Haloperidol Loaded Silica Haloperidol HME
(a)= crystalline, (b)-(e) = fresh, 30, 60 and 90 day ICH Q1
Price, DJ. And Ditzinger, F. Pharmaceutics. 2019.
Amorphous Formulation for Bioavailability Enhancement Challenges and Risks
30

31. Instability in HME formulations would result in failure of the formulation
Carbamazepine Loaded Silica Carbamazepine HME
(a)= crystalline, (b)-(e) = fresh, 30, 60 and 90 day ICH Q1
Price, DJ. And Ditzinger, F. Pharmaceutics. 2019.
Mesoporous silica remains amorphous for the duration of the
study, while HME re-crystallizes (2)
Amorphous Formulation for Bioavailability Enhancement Challenges and Risks
31

32. Amorphous Formulation for Bioavailability Enhancement Challenges and Risks
32

33. Agenda
A&F Overview
Solubility and Amorphous Formulations
Mesoporous Silica, the Basics
Mesoporous Silica for Poor Glass Formers
Summary

34. Mesoporous can be used as a best-in-class excipient to
stabilize even the most poorly stable glass formers
Amorphous Stability is a key issue for development of poorly soluble drug
formulations.
Glass Forming Ability is a key physicochemical parameter that can predict
long-term amorphous stability.
Poor Glass Formers are unstable in the amorphous form and are difficult
to formulate with traditional amorphous technology. Resulting in a
disproportionate amount of good glass formers in amorphous formulations.
Parteck SLC® mesoporous silica can successfully stabilize poor glass
formers in the amorphous form.
4
Amorphous Formulation for Bioavailability Enhancement Challenges and Risks
34
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information on trademarks is available via publicly accessible resources.
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