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
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Enhancing Solubility and Stability of Poorly Soluble Drugs with Mesoporous Silica
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.
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
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
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
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)
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
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
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
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