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Slide 1
Modeling Phase Separation Risk During Spray Drying from Mixed Solvents
Date
Jonathan Cape Ph.D.
Slide 2
Legal disclaimer
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Slide 3
Session Description and Objectives
Solvent Selection is a critical decision point in process development for spray dried amorphous
dispersions. Low organic solubility compounds often require the use of mixed solvents to increase
solubility, though their use can create phase separation risks during drying. A model is presented
that aids solvent selection by assessing the thermodynamic landscale for phase separation and
identifying low risk solvent compositions for processing.
Optimize process spray drying process throughput by choosing optimized
solvent compositions
Minimize phase separation risks by identifying high risk solvent compositions
Apply modeling tools to a representative quaternary spray solution system
Learning
Objectives:
Slide 4
Biography and Contact Information
Jonathan Cape
is a Principal Scientist
at Lonza in Bend,
OR, USA
email:
Ph.D. in Biochemistry and Biophysics (2006) from Washington State
University
Research Interests:
• NMR spectroscopic approaches to understand phase state and diffusivity
• Kinetic modeling of drug release mechanisms from MR dosage forms
• Analytical approaches to aid process understanding
Post-doctoral studies at WSU and Los Alamos National Laboratory.
Slide 5
Bioavailability Enhancement with Amorphous Solid Dispersions
Amorphous Solid Dispersions (ASDs) are a highly successful approach to improving the bioavailability of low aqueous solubility compounds
Development of successful ASD intermediates can be challenging
Amorphous dispersions
increase solubility…
…which increases the
absorption rate and
bioavailability
Absorption
↑ [Csat- API]
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Bioavailability Enhancement with Amorphous Solid Dispersions
Stability• Physical
• Chemical
Manufacture• Throughput
• Scale-up
• Cost
Performance• Dissolution
• Permeation
• Sustainment
Spray Drying is one of the more prevalent process approaches used to produce ASDs
10-6 sec
~1 sec
10-2 sec
ATOMIZATION & DRYINGTHE
PROCESS
30 microns
Nozzle
DRYING
GAS
DR
YIN
G C
HA
MB
ER
FEED
SOLUTION
Slide 7
Solvent Selection – a Key Decision Point in Spray Drying Process Development
Solvent Selection has large
impacts to process
throughput
Process throughput
becomes particularly
sensitive to solvent
properties as API solubility
decreases
Slide 8
Solubility Slump Solubility Slump
Mixed Solvents Systems Can Improve Process Throughput
0.0001
0.001
0.01
0.1
1
10
100
Mebendazole Ritonavir
So
lub
ilit
y,
mg
/mL
acetone solubility, mg/mL 95/5 or 90/10 acetone/water solub, mg/mL water solubility mg/mL
API Solubility in Acetone/Water Mixed Sovlents
Mixed solvents systems can improve starting
spray solution solubility and therefore improve
process throughput
Solubility behavior is highly API dependent
Mixed solvent systems can also become poor
solvents as lower volatility components are
enriched during drying (e.g. water)
Optimization Problem
• Best process throughput
(highest solubility, lowest ΔHv, highest P)
• Least risk to physical state
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Drying Model with Phase State Calculation as a Risk Assessment Tool for Solvent
Selection
A “minimal” drying model for
a four-component system has
been constructed in order to
track the composition of the
droplet during the drying
process. The drying
simulation is coupled to a
Flory Huggins calculation for
approximation of
thermodynamic phase state.
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Composition of Droplet During Drying
(80% Methanol, 20% Water Solvent System)
Composition of Droplet During Drying
(85% Methanol / 15% H2O Solvent System)
Application of the Drying Model to Solvent Selection for the Ritonavir / PVP-VA /
Methanol / Water System
0
10
20
30
40
50
60
70
80
90
0 0.2 0.4 0.6 0.8 1 1.2
% C
om
po
nen
t
Drying Time (s)
% Methanol % Water
0
10
20
30
40
50
60
70
80
90
0 0.2 0.4 0.6 0.8 1 1.2
% C
om
po
nen
t
Drying Time (s)
% Methanol % Water
5% increase in
solvent
water content
To what extent
does this
increase Φ
separation risk?
In order to test the utility of the model, we have applied it to a model system (RTV / PVPVA / MeOH / H2O), which
undergoes amorphous phase separation in certain MeOH/H2O solvent systems
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Application of the Drying Model to Solvent Selection for the Ritonavir / PVP-VA /
Methanol / Water System
In the case of the (RTV /
PVPVA / MeOH / H2O)
system we find that a
solubility boundary is
encountered at about
11.5% starting content of
water in the spray solvent
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Application of the Drying Model to Solvent Selection for the Ritonavir / PVP-VA /
Methanol / Water System
Experimentally, the onset
of phase separation may
occur somewhere around
this predicted solvent
content, with a broadening
of the Tg and a second
enthalpy peak occurs
starting around the 90/10
MeOH/H2O starting
solvent content.
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Drying Model with Phase State Calculation as a Risk Assessment Tool for Solvent
Selection
Recap of
Learning
Objectives:
Spray drying process throughput can be optimized by choosing a solvent that
exhibits optimal process characteristics (low ΔHvap, high P, low viscosity) and
solubility for the API / polymer system
Mixed solvent systems can improve solubility for low organic solubility APIs, but
can also lead to phase separation risks due to differential drying rates
Kinetic modeling of the drying process allows compositional trajectories to be
assessed, which can then be plotted against a quaternary phase diagram to
identify high risk solvent systems to avoid during process development
Slide 14
Questions