The Role of Polymer Excipients in Hot Melt Extrusion – A ... · 5/17/2018 2 Hot-Melt Extrusion...
Transcript of The Role of Polymer Excipients in Hot Melt Extrusion – A ... · 5/17/2018 2 Hot-Melt Extrusion...
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The Role of Polymer Excipients in Hot Melt Extrusion – A Continuous Manufacturing Process
Nigel LangleyExcipientFest May 1, 2018
Principle of HME
Hot-Melt Extrusion – A Continuous Manufacturing Process
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Hot-Melt Extrusion Technology
A poorly soluble crystalline API and an amorphous polymer are transferred into a solid dispersion with thermal and mechanicalenergy
Hot Melt Extrusion is one key technology for the preparation of solid dispersions
Extruder
∆EHot Melt Extrusion
Solid dispersionAPI in polymer
poorly soluble crystalline API
Amorphouspolymersolvent
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Biopharmaceutical Classification System BCS
The BCS classifies APIs by their solubility and permeability for cell membranes. There is a trend for recent API candidates to fall in the low solubility class II (or IV).
Source: G.L. Amidon, H. Lennermäs, V.P. Shah, J.R. Crison, Pharm. Res. 12 (1995), 413-420
High Solubility Low Solubility
High Permeability Class I Class II
Low Permeability Class III Class IV
Relevant Types of Solid Dispersions
Drug:dissolved
crystalline amorphous molecularly
Polymer: amorphous amorphous amorphous
Thermo-dynamic almost stable unstable stable (drug belowstabilitysolubility)
(kinetically controlled) saturation
Solid Solutions and Solid Dispersions
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Relevant Polymer Characteristics
Targeted release profileLong term
stability
Hygros-copicity
Physico-chemical
properties of active
Thermo-stability of
drug & polymer
Solution &solubilizingcapability
Melt viscosity
Drug + Polymer
Glass transition tempera-
ture
Parameters to Consider
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Basic Requirements for Polymers
Thermoplastic behavior
Suitable Tg
High thermal stability
Low hygroscopicity
No toxicity
High or no solubilization capability
deformability is essential
50 – 180°C
50 – 180°C
prevents crystallization
application of large amounts
thermodynamically stable formulation
Polymer Properties
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Polymers for Different Release Profiles
EntericIR
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SR
Kollidon® VA 64 Kollidon® K17, K30, K90
Kollicoat® IR Soluplus®
Kolliphor P 188 / 407HPMCHPCEudragit® EPEGPolyvinyl alcohol
Kollicoat® MAE 100- 55Kollicoat MAE 100 PEudragit® L 100-55 HPMCAPHPMCAS
Kollidon® SR Polyvinyl acetate Ethyl celluloseEudragit® RS
Polymers for Hot Melt Extrusion
Matrix polymers for solid dispersions
Kollidon® 12 PF, 17 PF(Povidone)
**
NO
n
**
N
n
O O O
m
Kollidon® VA 64(Copovidone)
Kollicoat® IR,Kollicoat®
Protect
OHO
OO
*
*
N
O
O
Oo o
o
Soluplus® Kollicoat® MAE 100P
Kollidon® SR(PVAc)
**
O O
n
OHO
m
**
O O
n
Hydrophilicity / Polarity
Lipophilicity / Hydrophobicity
(enteric release)
(modified release)
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dried polymer film
Preparation of filmswith 10% to 50% drug content
Observation of film stability drug must not recrystallize
Goal:stable solid solution with 50% drug load
Active in solvent
Polymer in solvent
1:1
Film Test for Solid Solution Capacity
Solvent Screening Procedure
> 50< 25
> 5033 - 5033 - 50
< 25< 25< 25
< 25< 25
< 25< 25
> 5033 - 5025 – 33
> 50< 25< 25
> 50< 25< 25
33 - 5025 – 33< 25
33 - 5025 – 3325 – 33
> 5033 - 5025 – 33
Polymer
Drug content[% dissolved in polymer]
Fenofibrate Carbamazepine Itraconazole
Kollidon VA 64 25 – 33 33 - 50 > 50
Soluplus 33 - 50 33 - 50 > 50
Kollidon 12 PF 25 – 33 25 – 33 33 - 50
Kollidon 17 PF < 25 25 – 33 33 - 50
Kollidon 30* < 25 < 25 > 50
Kollidon 90 F** < 25 < 25 > 50
Kollidon SR 25 – 33 33 - 50 > 50
Kollicoat MAE 100P* < 25 > 50 n.d.
Kollicoat IR* < 25 < 25 n.d.
Kollicoat Protect* < 25 < 25 n.d.
Lutrol F 127 < 25 < 25 < 25
* with 10 % PEG 1500 ** with 20 % PEG 1500
Solid Solution Capacity
API Drug load – model drugs
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Glass Transition Temperatures of matrix polymersTe
mpe
ratu
re [
°C]
70
90
149 156
39
114 118130
186
101
0
20
40
60
80
100
120
140
160
180
200
Soluplus Kollidon12PF
Kollidon90F
KollicoatMAE
HPC
152
Usually, extrusion requires temperatures of min. 20 - 30 °C > Tg
Polymers for HME
**
N
n
O O O
m
Soluplus®
Innovative matrix andsolubilizer in one
taylored for HME use
increases solubilityand bioavailability
Solid Dispersions / Solid Solutions
Matrix Formers Solubilizers
Plasticizers
SoluplusKollidon VA 64Kollidon VA 64 FineKollidon 12 PFKollidon 17 PFKollidon 25 / 30Kollidon 90Kollidon SRKollicoat IRKollicoat ProtectKollicoat MAE 100P
Kolliphor P 188 Kolliphor P 188 micro
Kolliphor P 407Kolliphor P 407 micro
Kollisolv GTAKolliwax GMS IKolliwax SAKollisolv PEG E 300 Kollisolv PEG E 400Kollisolv PEG 1450
Kolliphor HS 15Kolliphor RH 40Kolliphor EL/ ELPKolliphor PS 20 Kolliphor PS 60Kolliphor PS 80Kolliphor SLS / FineKolliphor P 188Kolliphor P 407Soluplus
Kollidon® VA 64
Established matrixformer especially in hot melt extrusion
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Melt Viscosity as a Function of Temperature
Shear stress controlled rotational rheometer (Rheometrics SR5), plate to plategeometry, angular frequency: 16 rad/s
100
10
1000
10000
100000
1000000
120 140 220 240160 180 200
Temperature [°C]
Vis
cosi
ty*
[Pa*
s]Kollidon VA 64 SoluplusKollidon 12 PFKollidon 17 PFKollidon 30Kollidon 90 F Kollidon SRKollicoat MAE 100PKollicoat IRKollicoat Protect
Optimal melt viscosity range for HME
Melt Viscosities
Influence of Plasticizers on Extrusion Temperatures
The addition of 10% plasticizer significantly decreases processing temperatures
Pure Polymer
+ 10 %Kolliphor® P 188
Temperature [°C]
Kollidon® VA 64
Kollidon® 12 PF
Soluplus®
Kollidon® 17 PF
Kollicoat® IR
Kollidon® SR
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Appearance of polymer extrudates at specific extrusion temperatures
Kollidon® VA 64(160 °C)
Soluplus® (145 °C)
Kollidon® 12 PF (100 °C)
Kollidon® 17 PF(175 °C)
Kollicoat® Protect(160 °C)
Kollicoat® IR(160 °C)
Kolliphor™ P407(60 °C)
Kollidon® SR(180 °C)
0,00
0,10
0,20
0,30
0,40
0,50
0,60
0,70
0,80
0,90
1.000 10.000 100.000 1.000.000 10.000.000
w(l
og
(M))
M/Da
Kollidon VA 64 LOT 76964875L0extruded 160°C
Kollidon VA 64 LOT 76964875L0
Kollidon® VA 64 extrudates prepared at different temperatures
Kollidon® VA 64 can be extruded up to 220°C without degradation
160 °C 180 °C
220 °C 240 °C
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Soluplus® - The Solid Solution
Soluplus® combines the benefits of asolid solution and an excellent solubilizer
PEG 6000/ vinylcaprolactam/ vinyl acetate grafted copolymer 13/57/30
Tg: ~ 70 °C
soluble in water, acetone, ethanol
Soluplus®
Saturation solubility in phosphate buffer pH 7.0 [g/100 ml]
Soluplus® strongly increases the solubility for APIs with different chemical structures
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
~0.
001
~0.
001
~0.
001
~0.
0001
~0.
0001
~0.
0001
~0.
001
Soluplus® Pure API
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
10% solubilizer solution, saturation solubility detected after 72h stirring
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Soluplus®
Saturation solubility in phosphate buffer pH 7.0 [g/100 ml]
With 4 out of 10 APIs Soluplus® shows the highest solubilization capacity!
10% solubilizer solution, saturation solubility detected after 72h stirring
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
Soluplus® Kolliphor® PS 80
Kolliphor® P 407
Kolliphor® RH40
Kolliphor® HS15
Extrusion parameters• 120 – 260°C• 1 kg/h
At extrusion temperatures up to 160°C nearly colourless extrudates
Thermostability
Soluplus® Thermal Stability
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Polymer Stability During Extrusion - Soluplus®
No change in chemical and physicochemical parameters up to 180 °C
Test parameter PowderExtrudate Extrudate
[extruded at 140°C] [extruded at 180°C]
Identification (IR)
pH-value
Ester value [mg KOH/g]
Vinyl acetate [ppm]
Vinyl caprolactame [ppm]
Caprolactame [g/100g]
Ethylenglykole [ppm]
Acetic acid / Acetate [ppm]
Peroxide [ppm]
Molecular weight Mw [g/Mol]
conf.
4.1
197
<2
<10
0.3
<100
365
<20
118,000
conforms
3.9
196
<2
<10
0.3
60
399
<20
119,000
conforms
3.9
196
<2
<10
0.3
63
396
<20
116,000
Analytical Results
Extrusion lead to amorphous extrudates (XRD) in all cases
Extrusion Studies
Extrusion parameters
16mm ThermoFisher Polylab, 40D
200 rpm
1 kg/h
mean residence time ~1 min
PolymerItraconazole
(15 %API)Fenofibrate (20 %API)
Carbamazepine (15 %API)
Soluplus® 150 100 140
Extrusion temperature [°C]
Hot-Melt Extrusion Process Conditions
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Soluplus® Extrudates with Fenofibrate - Appearance dependent on drug load
The transparency of extrudates decreases with increasing Fenofibrate load
25% 30% 35% 40% 45% 50%
Soluplus® + Fenofibrate
Dissolution – Extrudates with 15% Itraconazole
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Different matrix polymers give different dissolution profiles for Itraconazole
USP apparatus 2, 50rpm, 700 ml HCL (0.1molar), granulated extrudates, 100mg API (n=3, mean±sd)0
20
40
60
80
100
0 30 60 90 120
t [min]
drug
rel
ease
[%]
SoluplusKollidon VA 64Kollidon 12 PFHPC
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5 15 25 45 5535
2 theta [°]
inte
nsity
[a.u
.]
crystalline itraconazole
solid solution itraconazole
Solid solution Soluplus & itraconazole (85/15)
XRD
No crystalline active
Soluplus® Amorphous Extrudate
Soluplus® Bioavailability Enhancement of Itraconazole
A Soluplus® solid solution significantly increases the bioavailability of Itraconazole
Itraconazole –Soluplus®
extrudate
Sempera®
Itraconazolecrystalline
Plasma level [ng/mL]
0
150
300
450
600
750
0 10 20 30 40 50 60 70 80Time [hours]
Bioavailability = area under the curve (AUC)
Bioavailability of Soluplus® extrudate: 26-fold compared to crystalline drug2.3-fold compared to Sempera®
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Strategy for Formulation Development
Keep the formulation (and process) as simple as possible
Choose the appropriate polymer
+
+
For improved processability
For improved drug contentand prevention of crystallization in gastric and intestinal fluid
Active + Polymer
Plasticizer
Solubilizer
Hot-Melt Extrusion Manufacturing Process
Melt extrusion is an excellent process to formulate poorly soluble drugs and to improvebioavailability
Advantages vs spray drying – continuous process
Choice of an appropriate polymer is crucial for the formulation and the process
Most important polymer features are
- Tg and melt viscosity
- Solubilization capacity
- Dissolution
- Stability
- Toxicity/regulatory status
Polymers show very different extrusion behavior and suitability
Interactions between the various ingredients strongly influence the formulation
Soluplus® is a highly promising excipient designed for solid solutions and hot-melt extrusion
SummarySummary