Transcript Crystalline Drug Nanosuspension Manufacture

Issues Associated with the
Manufacture of Large Scale
Crystalline Nanosuspensions
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History
Manufacture of crystalline nanosuspensions at Alderley Park
• Small volume crystalline drug nanosuspensions manufactured at AP using Fritsch P7
Planetary Micromill with zirconia milling pots & zirconia beads.
• Fritsch P7 Mill limited to relatively small volume manufacture.
~ 32ml
• Dynomill was acquired to manufacture large volume crystalline nanosuspensions –used
stainless steel mill chamber and high density/highly cross-linked polystyrene milling
beads (zirconia chambers available but very expensive)
• Can process litres of suspension
• Suppliers of polystyrene milling beads DOW (had an exclusivity agreement with ELAN).
AZ obtained beads from NORSTONE.
• Mid 2010 NORSTONE signed exclusivity agreement with “?” – would not supply beads
to AZ in future – alternative bead required.
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History
• A feasibility study was carried out at Sodertalje to identify an
alternative.
• Trials used glass beads as it was perceived there might be issues
with zirconia (heavy metal) for clinical manufactures.
• Sodertalje investigated soda lime & borosilicate beads of different
sizes from suppliers such as:- Sigmund-Lindner, Sigma, Mo-Sci,
Retsch-VWR & Christian Berner.
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Glass Beads Before and After Milling Run in Dynomill
Sigmund-Lindner
Sigma
Retsch
Christian Berner
Mo-Sci
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Alternative Beads Selected Based on Performance versus Polystyrene Beads
Manuf./Supplier
Type1
Size
[µm]
pH
bef/aft
AZ
PS
400-600
6.0/
6.1
Sigmund
Lindner
SL
250-500
6.6/
11.5
Sigmund
Lindner
SL
400-600
4.4/
11.0
Sigmund
Lindner
BS
500-750
4.3/
10.3
Sigma
SL
150-212
4.6/
10.8
Sigma
SL
425-600
5.5/
10.4
MO-SCI
BS
180-212
5.4/
7.6
MO-SCI
SL
400-600
4.7/
11.5
Retsch/VWR
SL
250-500
10.42/
11.5
Retsch/VWR
SL
500-750
5.7/
11.5
Christian
Berner
SL
300-700
4.2/
11.2
Milling
efficiency
Milling
Abrasion
observations
(SEM)
Better than or equal to control
Much worse than control
Slightly worse
than control
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2009
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Metals
[AU] (EDS)
Residuals
[weight%]
Crystalline Drug Nanosuspension Manufacture
• Initially a nanosuspension was prepared by bead milling (using Fritsch
P7 Planetary Mill & zirconia milling media) as limited exposure had been
observed with a microsuspension formulation.
M.E. Commonly use 3 prototype drug formulations dependant on the physical properties of the drug
• Initial nanosuspension was manufactured at 200mg/ml drug load in
vehicle PVP/Aerosol OT and had mean particle size <200nm.
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Structures of Stabilizing Surfactants
Polyvinylpyrrolidone (ex BASF)
(non-ionic)
Dioctyl sodium sulfosuccinate (Aerosol OT ex Cytec)
(anionic)
DPPE-PEG2000 (Dipalmitoylphosphatidylethanolamine poly(ethylene glycol) 2000 (ex Genzyme)
(anionic)
Hydroxypropylmethylcellulose (ex Dow)
(non-ionic)
Polyoxyethylene
(20) sorbitan monooleate (Tween 80)
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(non-ionic)
FOR
INTERNAL USE ONLY
Crystalline Drug Nanosuspension Manufacture
• MTD and DRF studies required the manufacture of several
litres of nanosuspension – Dynomill manufacture.
• Bead milled drug in Dynomill at 200mg/ml using vehicle
PVP/Aot with MO-SCI soda-lime glass beads
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Crystalline Drug Nanosuspension Manufacture
Knew from feasibility study - Soda-lime glass beads would cause
suspension pH to rise > pH9, and also metal and colloidal glass
contamination.
Measured pH of suspension was ~pH9.1
Analysis showed the metal levels were below acceptable limits.
Measured Levels in suspension:
Limits by EMEA:
Fe:
42 ppm
1300 ppm
Ni:
7 ppm
25 ppm
Cr:
10 ppm
25 ppm
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Crystalline Drug Nanosuspension Manufacture
pH Adjustment:
Attempted to manually adjust pH to pH6.9 by addition of 1M HCl – but reduced pH to ~pH2
which resulted in coagulation of the nanosuspension
A nano suspension at pH 6.9 (from Fritsch mill) was manually pH adjusted to pH 9.1 and
then successfully re- adjusted to pH 6.9 using 0.1 M acetic acid (weak acid).
This nanosuspension remained as free flowing particles no visible evidence of
aggregation
However after addition of HCl adjusting pH to ~ 2, the nanosuspension coagulated.
What would happen when dosed orally?
Nanosuspension also coagulatedProprietary
whenand
diluted
in Simulated Gastric Fluid
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Crystalline Drug Nanosuspension Manufacture
Preparation of nanosuspension at 200mg/ml in PVP/Aot in Acetate Buffer at
pH4.6 – was successful
d10 74nm
D50 168nm
d90 503nm
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Crystalline Drug Nanosuspension Manufacture
Preparation of nanosuspension in DPPE-PEG2000
200mg/ml
A 200mg/ml suspension in 4% DPPE-PEG2000 milled on the
Fritsch mill produced a suspension with a similar overall size
profile to that obtained with PVP/Aot:
d50= 144nm d90= 644nm
When diluted into SGF the DPPE-PEG2000 nanosuspension
DID NOT COAGULATE but remained as free-flowing individual
particles.
However problems as to the suitability of this vehicle due to
possibility of anaphylactic shock in dogs (due to peroxide
content) also doubts about whether DPPE-PEG2000 can be
taken forward into FTiM studies.
d10 69nm
d50 144nm d90 644nm
Formulation was therefore deemed not suitable for use in the dog tox study and study postponed.
Mouse study went ahead as only required small volumes which could be manufactured using the Fritsch mill
Dog PK study was set up to assess whether there was any advantage in dosing a nanosuspension compared to a
microsuspension
Although there was variability in exposure, the results indicated the dog MTD could commence with a microsuspension,
whilst further work progressed on the nanosuspension formulation
However tox observed with microsuspension.
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Flocculation/Coagulation Testing of Drug Microsuspensions in PVP/Aot
Carried out Flocculation/Coagulation testing of microsuspension formulations
Diluted microsuspension manufactured in PVP/Aot and manufactured in HPMC/Tween80
in SGF and in SGF adjusted to pH4.5 (mimic mouse)
Microsuspension (200mg/ml) in PVP/Aot
Vehicle
Diluted 1:3 in SGF adjusted to pH4.5
Diluted 1:3 in SGF (pH1.2)
Dilute in SGF
Dilute in SGF/pH4.5
HPMC/Tween80
√
√
PVP/Aot
X
√
√ = no coagulation
X = coagulation
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PVP/Aot is not a good stabiliser
system
for this compound
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SUMMARY
Nanosuspension manufactures using SL glass beads will result in high pH suspensions unless buffered
PVP/Aot
The PVP/Aot vehicle makes suspensions at 200mg/ml in the Fritsch Mill using zirconia media that are chemically and
physically stable.
The suspensions in PVP/Aot coagulate spontaneously when diluted into SGF (1:3 dilution) or when pH reduced to ~pH2
A nanosuspension can be prepared at 200mg/ml in PVP/Aot/acetate buffer(pH4.6) – but the suspension coagulated when
diluted into SGF or pH reduced to ~2
DPPE-PEG2000
A nanosuspension could be prepared at 200mg/ml drug load in 4% DPPE-PEG2000 which does not coagulate when diluted in SGF
Issues found with milling with glass beads – pH rise, some glass and metal contamination (albeit below
recommended limits).
Could be an issue for compounds unstable at high pH – but it is possible to manufacture in vehicle/buffer
Accidentally found out that the nanosuspension in PVP/Aot coagulated at gastric pH.
Also found out microsuspension in PVP/Aot coagulated at gastric pH indicating that PVP/Aot not a good
stabilizer for this compound
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Recommendations
Future reference:- Important to choose optimum stabiliser system for
nanosuspension manufacture
M.E. do not routinely carry out flocculation/coagulation testing on suspensions –
maybe we should?
If it had not accidentally been found that the nanosuspension coagulated at
gastric pH the nanosuspension would have been dosed, probably would have
coagulated in the stomach, producing low exposures and variable results
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