Access the interactive recording: https://bit.ly/2SApPJr Abstract: Historically, polymeric solid dispersions have been the technology of choice for amorphous formulation. However, this approach may have some downfalls when considering the ability to stabilize compounds in the amorphous form, 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, we will present recent data demonstrating the potential of mesoporous silica for superior amorphous stabilization of poor glass formers.

1. The life science business of Merck operates
as MilliporeSigma in the U.S. and Canada.
Amorphous Stability:
Mesoporous silica for poor glass formers
Daniel Joseph Price

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

3. Agenda
1
2
Introduction to Mesoporous
Silica
3
4
Mesoporous Silica for Poor
Glass Formers
Summary and Conclusions
Stability in Amorphous
Formulations

4. Mesoporous Silica:
Introduction

5. 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
5
Poorly soluble drugs are on the increase
Poor solubility can lead to low and variable absorption

6. 6
Crystal Lattice
Energy
Solvation
Energy
Crystalline
Solid
The solubility of a crystalline
solid is a function of the
strength of the crystal lattice
and the affinity of the drug
for the solvent.
Solid in
Solution
Amorphous
Solid
Without the crystal lattice, the energetics for
solvation of the amorphous form are more
favourable. Solubility is significantly enhanced
compared to the crystalline form
Mesoporous silica stabilizes the amorphous form to improve
absorption of poorly soluble APIs
However….
This form must be
stabilised to avoid re-
crystallisation (both in
solution and in the solid-
state)
Solubility can be increased using the amorphous form

7. 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)*
7
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

8. Solubilise
+Parteck® SLC
+ H2O
ca.6nm diameter
✓ Improved Solubility
✓ Faster Dissolution
✓ Improved Absorption
+ precipitation
inhibitor to prevent
recrystallisation
Sterically stabilized
Amorphous!
8
Solvent
Removal
Mesoporous silica stabilizes the amorphous form via pore
adsorption and nanoconfinement

9. Suspension methodImpregnation method
Overhead stirrer
Canulla
(API solution)
Silica powder
Vacuum
nitrogen
API solution
+ Silica powder
 Stirring
 Evaporation
9
Lab-scale loading of mesoporous
silica can be achieved without any
specialized equipment
Lab-scale loading is accessible and cost-effective
Lab-scale loading is accessible and requires no extra capital investment

10. 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
10
A full slide-deck on the scale-up of mesoporous silica loading is available on request
Loading is feasible from lab to production-scale

11. DSC
Crystalline API
Parteck® SLC
Excipient,
API load 30 %
 Solvent: Acetone
 Method: Impregnation
 Drug load: 30%
 Drug Form: Amorphous
 Residual solvent below ICH limit (0.5 %)
11
Loading of fenofibrate onto mesoporous silica results in the
amorphous form

12. In vitro-in vivo correlation demonstrates the positive effect of loading
fenofibrate onto Parteck® SLC
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
12
Formulation of fenofibrate with mesoporous silica enhances in vivo
bioavailability

13. Stability in Amorphous
Formulations

14. Glass forming ability (GFA) is a predictor of amorphous stability
14
“The ease of vitrification of a liquid upon cooling” (Avramov et al. 2003)
GFA I GFA II GFA III
Baird et al. Poor Glass Former
Moderate Glass
Former
Good Glass
Former
Usage in marketed
amorphous drugs
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
Why does physical instability of GFA-1 glass formers lead to failure in
development?

15. The most common amorphous formulations are polymeric
amorphous solid dispersions
15
Ditzinger, F. and Price, DJ. JPP. 2019
Polymer
Drug
Melt and Extrude
Spray-dry
Spray-dried
dispersion
(SDD)
Hot Melt
Extrusion
(HME)
Poor glass formers have a higher risk of phase separation and
re-crystallization in polymeric amorphous solid dispersions
Re-crystallization
Phase Separation
Amorphous Dispersion

16. Mesoporous Silica for Poor
Glass Formers

17. 17
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

18. 18
• 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.

19. Mesoporous silica is able to consistently stabilize high drug loads of
poor glass formers in the amorphous form
19
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.

20. Macroscopic changes in HME extrudates were observed after only
one-week under accelerated conditions
20
Macroscopic Changes in HME were observed after just one week under ICH
Q1 stability conditions
Price, DJ. And Ditzinger, F. Pharmaceutics. 2019.

21. 21
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)

22. SEM provides evidence for microscopic phase separation in HME (2)
22
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.

23. Mesoporous silica remains amorphous for the duration of the
study, while HME re-crystallizes (1)
23
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.

24. 24
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)

25. Solid-state instability in HME results in inconsistent and decreasing
dissolution performance (1)
25
2-fold supersaturation.
Precipitation based on the lack of a
precipitation inhibitor in the formulation.
No degradation in the profile
2-fold supersaturation
Polymer acts as a precipitation inhibitor
and sustains supersaturation.
Deviation towards the crystalline API after
accelerated stability,
Haloperidol Silica Haloperidol HME
Price, DJ. And Ditzinger, F. Pharmaceutics. 2019.

26. 26
Carbamazepine Silica Carbamazepine HME
Silica-based formulations were able to effectively stabilize the
selected poor glass formers
Price, DJ. And Ditzinger, F. Pharmaceutics. 2019.
Solid-state instability in HME results in inconsistent and decreasing
dissolution performance (2)

27. Our work was recently published in Pharmaceutics

28. Summary

29. Extend the formulation tool box to poor glass formers with
Parteck® SLC mesoporous silica!
29
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.
Mesoporous Silica has potential advantages in the stabilization of
compounds in the amorphous form due to steric confinement and a
reduction in molecular mobility4
5
Parteck® SLC was successfully used to stabilize two poor glass formers
in the amorphous form under accelerated conditions

30. References
1. Benet et al. JPharmSci. 2013;102(1):34-42
2. Baird et al. JPharmSci. 2010; 99(9):3787-3806.
3. Wyttenbach and Kuentz. EJPB. 2017;112:204-208.
4. Ditzinger, F. and Price, DJ. JPP. 2019;11:577-592.
5. Cordeiro et al. MolPharm. 2017;14:3164-3177.
Additional Resources:
6. Liu et al. AJPS. 2016;11(6):751-759.
7. Laine et al. IJP. 2016;512(1):118-125.
8. McCarthy et al. Expert Opin. Drug Deliv. 2016; 68(5):93-108.
9. O’Shea et al. JPP. 2017;68(5):634-645.
10. O’Shea et al. JPP. 2017;69(10):1284-1292.
11. Schultz et al. EJPB. 2018:125:13-20.
12. Ditzinger et al. JPP. 2019;89: 120-145.
13. Price et al. EJPS. 2019;132:1421-1456.
14. Price et al. EJPS. 2020;141:105-113.

31. Technical Product Manager
Daniel-joseph.price@milliporesigma.com
Thank you for listening, any questions?
Daniel Joseph Price