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Modeling Phase Separation Risk During Spray Drying from Mixed Solvents Jonathan Cape, Ph.D. – Principal Scientist Jonathan Cape | Lonza Rapid Fire Presentation | 2020
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Modeling Phase Separation Risk During Spray Drying from Mixed
SolventsJonathan Cape | Lonza Rapid Fire Presentation | 2020
Jonathan Cape | Lonza Rapid Fire Presentation | 2020
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.
Learning
Objectives:
compositions
Apply modeling tools to a representative quaternary spray solution
system
Biography and Contact Information
Ph.D. in Biochemistry and Biophysics (2006) from Washington State
University
Research Interests:
• 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.
Jonathan Cape | Lonza Rapid Fire Presentation | 2020
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…
Bioavailability Enhancement with Amorphous Solid Dispersions
Stability • Physical
• Permeation
• Sustainment
Spray Drying is one of the more prevalent process approaches used
to produce ASDs
Jonathan Cape | Lonza Rapid Fire Presentation | 2020
Solvent Selection – a Key Decision Point in Spray Drying Process
Development
Solvent Selection has large
Jonathan Cape | Lonza Rapid Fire Presentation | 2020
Solubility Slump Solubility BUMP
0.0001
0.001
0.01
0.1
1
10
100
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
Mixed solvent systems can also become poor
solvents as lower volatility components are
enriched during drying (e.g. water)
Optimization Problem
• Least risk to physical state
Jonathan Cape | Lonza Rapid Fire Presentation | 2020
Drying Model with Phase State Calculation as a Risk Assessment Tool
for Solvent Selection
A “minimal” drying model for
a four-component system has
droplet during the drying
Flory Huggins calculation for
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
% C
% C
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
Jonathan Cape | Lonza Rapid Fire Presentation | 2020
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)
solubility boundary is
encountered at about
Jonathan Cape | Lonza Rapid Fire Presentation | 2020
Application of the Drying Model to Solvent Selection for the
Ritonavir / PVP-VA / Methanol / Water System
Experimentally, the onset
enthalpy peak occurs
Jonathan Cape | Lonza Rapid Fire Presentation | 2020
Drying Model with Phase State Calculation as a Risk Assessment Tool
for Solvent Selection
Recap of
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
Jonathan Cape | Lonza Rapid Fire Presentation | 2020
Jonathan Cape | Lonza Rapid Fire Presentation | 2020
Disclaimer and Forward-looking statements This presentation
(“Presentation”) is the property of Lonza AG and its affiliates
(“Lonza”) and any unauthorized use or interception of this
Presentation is illegal.
The information contained herein are believed to be correct.
However, no warranty is made, either expressed or implied,
regarding its accuracy or the results to be obtained from the use
of such information. Lonza disclaims any liability for the use of
this presentation and the use of the information contained herein
is at your own risk. All trademarks belong to Lonza or its
affiliates or to their respective third party owners and are only
being used for informational purposes. All copyrighted material has
been reproduced with permission
from their respective owners, all other materials ©2020 Lonza. All
rights reserved. Certain matters discussed in this Presentation may
constitute forward-looking statements. These statements are based
on current expectations and estimates of Lonza Group Ltd., although
Lonza Group Ltd. can give no assurance that these expectations and
estimates will be achieved. Investors are cautioned that all
forward-looking statements involve risks and uncertainty and are
qualified in their entirety. The actual results may differ
materially in the future from the forward-looking statements
included in this Presentation due to
various factors. Furthermore, except as otherwise required by law,
Lonza Group Ltd. disclaims any intention or obligation to update
the statements contained in this Presentation.
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