In these slides, you will be introduced to the science and scale-up behind mesoporous silica technology, an emerging formulation option for poorly soluble drug delivery. Included in the slides: - A broad overview of mesoporous silica technology - An introduction to the unique stability advantages of mesoporous silica - Case studies of in vitro and in vivo performance of mesoporous silica formulations - How to scale-up from lab to production scale Watch the webinar here: https://bit.ly/2IoV8k7

1. Merck KGaA
Darmstadt, Germany
Dr Gudrun Birk and Dr Iris Duarte
Lab to Production Scale
Solubility enhancement, stability
and scalability of mesoporous
silica formulations

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

3. Welcome...
3
Dr. Gudrun Birk:
Head of Controlled
Release

4. Welcome...
Dr. Iris Duarte:
Scientific Project Lead
4
Dr. Gudrun Birk:
Head of Controlled
Release

5. Jet MillingSpray Drying Wet Impregnation Hot Melt Extrusion
 60 years of experience as a specialist integrated CDMO
 Broad competence in particle engineering technologies
 Service for loading studies readily available
 Production facility and scalability established
 Offers integrated pharmaceutical development services
Welcome...
5

6. 1
3
2
Introduction
Parteck® SLC 500
Excipient
Manufacturability
IV/IV Case Studies
Summary
4
5
6
6
Agenda
Q&A
6

7. 1
3
2
Introduction
Manufacturability
IV/IV Case Studies
Summary
4
5
7
7
Parteck® SLC 500
Excipient
Agenda
Q&A
6

8. Importance of bioavailability enhancement
Bioavailability enhancement helps to reduce the failure rate and R&D success.
A. Pandit, GlobalData 2009
Introduction
8

9. 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
Percentage
distribution of oral
immediate-release
drugs on the market
Percentage distribution of
a data set of 28,912
medicinal chemistry
compounds (NCEs)
Today
Tomorrow
New molecular entities are becoming less soluble
Solubility of New Chemical Entities
Introduction
Poor solubility
Good solubility
9

10. 10
Strategies to Solubility Enhancement
Introduction
 Type of dosage form
 Disintegration time
 Tissue targeting
 Protein binding
 Avoid the first
pass effect
 Reduce
enzymatic bio-
transformation
 Increase
circulation
lifetime
 Increase size
 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
Increase
absorption
Solubility Permeability Other
Influence
distribution
Reduce
metabolism
Postpone
elimination
10

11. 11
Strategies to Solubility Enhancement
Introduction
 Type of dosage form
 Disintegration time
 Tissue targeting
 Protein binding
 Avoid the first
pass effect
 Reduce
enzymatic bio-
transformation
 Increase
circulation
lifetime
 Increase size
 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
Increase
absorption
Solubility Permeability Other
Influence
distribution
Reduce
metabolism
Postpone
elimination
11

12. Introduction
Opportunities and Challenges in drug carrier applications
Stability
Nano-confinement and the
potential for improved stability
Manufacturability
Final implementation of the
carrier technology requires
 Loading in production scale
 Final dosage form
In-vitro / in-vivo correlation
First understanding of the
potential gained by in-vitro
studies
In-vivo trials are essential for
final confirmation
Mesoporous Silica
Inorganic drug carrier
Variety of loading methods
Solvent-based preferred
12

13. 3
2
Introduction
Manufacturability
IV/IV Case Studies
Summary
4
5
1
13
13
Parteck® SLC 500
Excipient
Agenda
Q&A
6

14. Mesoporous silica inorganic drug carrier
Chemical formula: SiO2
Pharmacopoeial monograph: Silicon Dioxide (USP) and Silica, colloidal hydrated (Ph Eur)
Micronized silica carrier
What is Parteck® SLC Excipient?
Typical values
Particle size 5 – 20 µm
Bulk density 0.32 g/mL
Surface area ~ 500 m2/g
Pore size ~ 6 nm (disordered)
14

15.  Stable porous structure
 High surface area
 Defined surface properties
 Adsorbs and releases drugs in a reproducible manner
 Physicochemical stability of API can be improved
 Safe and inert material (GRAS = Generally Recognized As Safe) *
* By the U.S Food and Drug Administration
ca.6 nm diameter
Sterically stabilized
amorphous!
15
Parteck® SLC Excipient: General Working Principle

16. 3
1
2
Introduction
Manufacturability
IV/IV Case Studies
Summary
4
5
16
16
Parteck® SLC 500
Excipient
Agenda
Q&A
6

17.  What formulation technologies do you currently employ in pre-clinical development? (e.g.
pre-clinical tox, etc.)
a) Simple parenteral formulations
b) Enabling parenteral formulations
c) Simple solid formulations
d) Enabling solid formulations
17
Question 1: Pre-clinical Formulation

18. API Fenofibrate
Fenofibrate is present in its amorphous state when loaded upon Parteck® SLC Excipient.
DSC
Crystalline API
Parteck® SLC
Excipient,
API load 30 %
In vitro – in vivo study
Wet Impregnation
 Acetone used as organic solvent
 Addition of the API solution to the silica powder
via solvent impregnation method
 Target drug load of 30 % was achieved,
homogeneously distributed
 Drug is amorphously stabilized
 Residual solvent below ICH limit (0.5 %)
 Lab-scale loading is accessible and requires no
extra capital investment
18

19. Dissolution profile
The initial dissolution performance of fenofibrate is improved by Parteck® SLC Excipient.
Dissolution procedure:
USP Apparatus 2 (Paddle Apparatus),
1000 mL SGFsp + 0.1 % SDS
75 rpm, 37 °C
n=3
In vitro – in vivo study
19

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
In vitro – in vivo study
PK study in pigs
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
20

21. In vitro – in vivo study
PK study in pigs
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
Plasmaconcentration(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
21

22.  Solid-state stability is a common problem in pharmaceutical development, have you
experienced any of these common stability hurdles?
a) Unreliable polymorphism
b) Unsuccessful solid-state conversion during formulation of amorphous solid dispersion
c) Long-term solid-state stability in amorphous solid dispersion
d) None of the above
22
Question 2: Stability

23.  A poor glass former is a compound that is fragile in the amorphous form. Poor glass formers therefore
have a high crystallization tendency (Baird, et al. J. Pharm. Sci. 2010)
 Poor glass formers have a higher risk of failure in commercial development: they are not easily
stabilized by polymer-based technologies due to molecular mobility in polymers.
 Mesoporous silica has the potential to improve stabilization of poor glass formers based on the
nanoconfinement of molecularly absorbed API in the small pores.
ca.6 nm diameter
23
Enhanced Stability with Mesoporous Silica

24. Mesoporous silica formulations for two extremely poor (class I) glass formers remain
amorphous for 3 months at ICH Q1 stability conditions (75% RH and 40C).
24
Steric StabilizationEnhanced Stability with Mesoporous Silica
Carbamazepine Loaded Silica Haloperidol Loaded Silica
(a)
(b)
(c)
(d)
(e)
Crystalline (a), fresh (b), 1 month (c), 2 month (d) and 3 month (e)

25. HME formulations recrystallized within one week under the same conditions.
Re-crystallization was also observed visually, and with DSC, dissolution, SEM and SS-NMR
Enhanced Stability with Mesoporous Silica
25
(a)
(b)
(c)
(d)
(e)
Crystalline (a), fresh (b), 1 month (c), 2 month (d) and 3 month (e)

26. 3
Introduction
Manufacturability
IV/IV Case Studies
Summary
2
4
5
1
26
26
Parteck® SLC 500
Excipient
Agenda
Q&A
6

27. Loading drugs into silica
Benchmarking technologies
TECHNOLOGIES
PARAMETER Solvent Methods
(e.g. wet impregnation)
Melt Methods
(e.g. hot melt extrusion)
Milling Methods
(e.g. jet milling)
Investment (e.g. equipment) ↓ ↓ ↓
Processing cost ↑ ↓ ↓
Scale-up + + +
Heat labile molecules + - -
Shear labile molecules + - -
Hydrogen bonding molecules + + +
27
A wide range of technologies have been successfully used to load drugs onto silica.

28. How it works:
Wet impregnation
Solution
Preparation
Wet
Impregnation
Drying Bulk Material
Solubilise
Crystalline API
Mesoporous Silica
+ H2OSolvent
Removal
 Amorphous
 Assay and degradants
 Homogeneity
 Residual solvent < ICH
 Improved dissolution
 High process yield
28

29. How it works:
Wet impregnation
Solution
Preparation
Wet
Impregnation
Drying Bulk Material
Solubilise
Crystalline API
Mesoporous Silica
+ H2OSolvent
Removal
 Solvent selection
 API solubility
 Temperature
 Solids content
 Amorphous
 Assay and degradants
 Homogeneity
 Residual solvent < ICH
 Improved dissolution
 High process yield
29

30. How it works:
Wet impregnation
Solution
Preparation
Wet
Impregnation
Drying Bulk Material
 Solvent selection
 API solubility
 Temperature
 Solids content
 Feed flow rate
 Droplet size
 Temperature
 Solvent to Silica ratio
 Solvent evaporation rate
 Agitation
 Amorphous
 Assay and degradants
 Homogeneity
 Residual solvent < ICH
 Improved dissolution
 High process yield
30
Solubilise
Crystalline API
Mesoporous Silica
+ H2OSolvent
Removal

31. How it works:
Wet impregnation
Solution
Preparation
Wet
Impregnation
Drying Bulk Material
 Solvent selection
 API solubility
 Temperature
 Solids content
 Feed flow rate
 Droplet size
 Temperature
 Solvent to Silica ratio
 Solvent evaporation rate
 Agitation
 Temperature
 Vacuum
 Nitrogen sweep
 Agitation
 Amorphous
 Assay and degradants
 Homogeneity
 Residual solvent < ICH
 Improved dissolution
 High process yield
31
Solubilise
Crystalline API
Mesoporous Silica
+ H2OSolvent
Removal

32. How it works:
Wet impregnation
Solution
Preparation
Wet
Impregnation
Drying Bulk Material
 Solvent selection
 API solubility
 Temperature
 Solids content
 Feed flow rate
 Droplet size
 Temperature
 Solvent to Silica ratio
 Solvent evaporation rate
 Agitation
 Temperature
 Vacuum
 Nitrogen sweep
 Agitation
Multiple loading
steps if needed
 Amorphous
 Assay and degradants
 Homogeneity
 Residual solvent < ICH
 Improved dissolution
 High process yield
32
Solubilise
Crystalline API
Mesoporous Silica
+ H2OSolvent
Removal

33. Manufacturability
Scale-up
Lab-scale:
 Simple lab equipment
which can be easily
adapted in scale size
Development-scale:
 Process is transferred to pilot-
scale without further need for
process development
Production-scale:
 Suitable equipment
available in different sizes
for scaling-up the process
Up to ~500 g loadings
Up to ~20 kg loadings
Up to ~500 kg loadings
33

34. Manufacturability
Scale-up
Lab-scale:
 Simple lab equipment
which can be easily
adapted in scale size
Development-scale:
 Process is transferred to pilot-
scale without further need for
process development
Production-scale:
 Suitable equipment
available in different sizes
for scaling-up the process
Up to ~500 g loadings
Up to ~20 kg loadings
Up to ~500 kg loadings
34
Process development and scale-up of the loading process was successfully
performed from laboratory to commercial scale for ibuprofen.

35.  Referring to the scale-up of silica loading, what are your current infrastructure capabilities?
a) Lab-scale loading
b) Development-scale loading
c) Production-scale loading
35
Question 3: Scale-up

36. Manufacturability
Scale-up
Parameter Lab-scale Development-scale Production-scale
Amount of silica charged (filling volume) ≤ 250 g (0.6 L, 30%) 13 kg (40 L, 40%) 100 kg (313 L, 50%)
Concentration of API solution (Ibuprofen) 25 wt.% 25 wt.% 25 wt.%
Feed flow rate (loading time) 2 g/min (6h) 62 g/min (6h) 476 g/min (6h)
Temperature 60ºC 60ºC 60ºC
Nitrogen sweep yes (low level) ~0.04 kg/h ~0.8 kg/h
Pressure - 0.2 bar - 0.1 bar - 0.2 bar
Agitation speed (tip speed) 50 rpm (0.4 m/s) 11 rpm (0.4 m/s) 6 rpm (0.4 m/s)
36
Process development – Wet impregnation
Critical: monitoring the acetone condensates throughout the loading step.

37. Manufacturability
Scale-up
Parameter Lab-scale Development-scale Production-scale
Temperature 60ºC 60ºC 60ºC
Nitrogen sweep yes (low level) ~0.04 kg/h ~0.8 kg/h
Pressure - 0.8 bar - 0.9 bar - 0.9 bar
Agitation speed (tip speed) 50 rpm (0.4 m/s) 11 rpm (0.4 m/s) 6 rpm (0.4 m/s)
Drying process time Until < ICH limit Until < ICH limit Until < ICH limit
37
Process development – Drying
IPC: the acetone content throughout drying is monitored by GC, until the ICH limit is
reached (i.e. < 5000 ppm).

38. Manufacturability
Lab scale
Loading process
Parameter 25 g loading 200 g loading
Concentration of API solution (Ibuprofen) 29.9 % 30.0 %
Mass of organic solvent (Acetone) 0.032 kg 0.27 kg
Mass API solution 0.04 kg 0.34 kg
Loading process time ~ 7:15 h:min ~ 8:45 h:min
Drying time ~ 14 h ~ 18 h
Yield 96.7 % 97.2 %
Small scale loading established in different sizes
38

39. Results: Lab Scale
API load / state
Sample API load
Residual solvent
(acetone)
25 g loading 29.4 ± 0.0 % 0.01 ± 0.00 %
200 g loading 29.9 ± 0.1 % 0.01 ± 0.01 %
25 g loading
Crystalline API
200 g loading
Consistent results - Fully amorphous samples achieved, solvent is fully removed
39

40. Results: Lab Scale
Dissolution performance
0
20
40
60
80
100
120
0 15 30 45 60 75 90 105 120
Dissolution[mg/L]
Time [min]
1000 mL SGFsp, pH 1.2, 75 rpm, 150 mg API
crystalline API Lab scale_25g Lab scale_200g
Dissolution performance is comparable for different small scale loadings
40

41. Loading successfully upscaled confirmed by consistent results
Manufacturability
Development scale
Loading process
Parameter 1 kg loading 13 kg loading
Concentration of API solution (Ibuprofen) 25.0 % 24.9 %
Weight of organic solvent (Acetone) 750.9 g 16.75 kg
Weight API solution 1001.6 g 22.3 kg
Loading process time ~ 6:01 h:min ~ 6:46 h:min
Drying time ~ 23 h ~ 36 h
Yield 89.4 % 94.9 %
41

42. 42
Results
API load / state
Key parameter are comparable to small scale loading
Sample API load
Residual solvent
(acetone)
Dev. Scale 1 kg (n=3) 30.8 ± 0.06 % 0.2 ± 0.0 %
Dev. Scale 13kg (bottom, n=3) 29.1 ± 0.7 % 0.06 ± 0.00 %
Dev. Scale 13kg (middle, n=8) 28.9 ± 0.7 % 0.05 ± 0.00 %
Dev. Scale 13kg (top, n=4) 29.0 ± 0.3 % 0.07 ± 0.03 %
° 2 Teta
Dev. Scale_13 kg-1
Crystalline API
Dev. scale_1kg-1
Dev. scale_1kg-2
Dev. scale_13kg-1
Dev. scale_13kg-1

43. 43
Results
Dissolution performance
Comparable and consistent dissolution performance achieved
0
20
40
60
80
100
120
0 15 30 45 60 75 90 105 120
Dissolution[mg/L]
Time [min]
1000 mL SGFsp, pH 1.2, 75 rpm, 150 mg
crystalline API Dev. Scale_1 kg_1 Dev. Scale_1 kg_2
Dev. Scale_13 kg_1 Dev. Scale_13 kg_2

44. Upscale of the loading to production size is successfully performed
Manufacturability
Production scale (100 kg)
Loading process
Parameter Trial 1
Concentration of API solution (Ibuprofen) 25.0 %
Mass of organic solvent (Acetone) 129 kg
Mass of API solution 172.0 kg
Loading process time ~ 6:07 h:min
Drying time ~ 36 h
Yield 87.3 %
44

45. Results: Production Scale
API load / state
Consistent loading results – comparable to small and development scale
Sample API load
Residual solvent
(acetone)
„Dead volume“ (n=1) 29.5 % 0.1 %
„Normal discharge“
(n=10)
29.6 ± 0.3 % 0.1 ± 0.0 %
„Scrapping“
(n=1)
29.7 % 0.1 %
Overall 29.6 ± 0.1 % 0.1 ± 0.0 %
Prod. Scale_1
° 2 Teta
Crystalline API
Prod. scale_1
Prod. scale_2
Prod. scale_3
Prod. scale_4
45

46. Results: Production Scale
Dissolution performance
Reliable dissolution performance meeting previous results
0
20
40
60
80
100
120
0 15 30 45 60 75 90 105 120
Dissolution[mg/L]
Time [min]
1000 mL SGFsp, pH 1.2, 75 rpm, 150 mg
crystalline API Lab scale Prod. scale_1
Prod. scale_2 Prod. scale_3 Prod. scale_4
46

47. Manufacturability
From loaded drug carrier to final dosage form
API loaded drug
carrier
Capsule Fast and easy formulation for early stages
Tablet Prefered final dosage form for late stage
47

48. Composition
 The API-loaded Parteck® SLC powder (drug load 30 %) was blended with the other components.
 Tablet production using a rotary tablet press (30 kN, 500 mg tablets, Ø 11 mm)
Manufacturability
Tablet formulation
Amount [mg] Amount [%] function
API-loaded Parteck® SLC
Excipient
125 25 Model API and carrier
Parteck® M 200 Excipient 100 20 Binder/diluent
MCC 255 51 Binder/diluent
Na-CMC 10 2 Superdisintegrant
Silicon dioxide 5 1 Flow regulator
Parteck® LUB MST Excipient 5 1 Lubricant
Total 500 100
48

49. Galenical properties
Tablet performance (rotary press)
Parameter Specification Results
Weight (average) [mg] 500 ± 25
503.7 (SD 5.8)
Min 491.7
Max 513.4
Hardness [N] > 100 125 ± 13.6
Disintegration [s] < 300 35 ± 3.7
Friability [%] < 1 0.02
The tablets show a very low friability, excellent hardness and fast disintegration.
Results
49

50. Dissolution performance
Tablets with API-loaded Parteck® SLC Excipient from production scale:
 show complete API release and are easy to manufacture
 are well suitable as final dosage forms
Results
0
20
40
60
80
100
0 30 60 90 120
Dissolution[%]
Time [min]
Tablet Capsule Size 0 Powder Ibuprofen crystalline
Dissolution procedure:
USP Apparatus 2 (Paddle Apparatus),
500/1000 mL SGFsp
75 rpm, 37 °C
n=3
Tests performed under sink conditions
50

51. 5
1
2
Introduction
Manufacturability
IV/IV Case Studies
4
3
Summary
51
51
Parteck® SLC 500
Excipient
Agenda
Q&A
6

52. 52
52
Mesoporous Silica: A valuable and accessible technology to enhance solubility
and stability of poorly soluble active pharmaceutical ingredients
Summary

53. 53
53
Mesoporous Silica: A valuable and accessible technology to enhance solubility
and stability of poorly soluble active pharmaceutical ingredients
Proof of Concept: Formulation enhancement has been demonstrated robustly
and reliably in both in vitro and in vivo studies
Summary

54. 54
54
Mesoporous Silica: A valuable and accessible technology to enhance solubility
and stability of poorly soluble active pharmaceutical ingredients
Proof of Concept: Formulation enhancement has been demonstrated robustly
and reliably in both in vitro and in vivo studies
Manufacturability: Scale-up from small (g) to production scale (100 kg)
has been demonstrated, ensuring consistent formulation performance in
final dosage forms.
Summary

55. Q&A
55

56. iduarte@hovione.comGudrun.birk@emdgroup.com
Special thanks goes out to our
partner Hovione for the great
collaboration.
Dr. Iris DuarteDr. Gudrun Birk
acknowledgements
The vibrant M and Parteck 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.
© 2019 Merck KGaA, Darmstadt, Germany and/or its affiliates. All Rights Reserved.
Thank you for your attention