physical stability of spray dried solid dispersions of
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PHYSICAL STABILITY OF SPRAY DRIED SOLID DISPERSIONS OF AMORPHOUS TOLFENAMIC ACID AND
POLYVINYLPYRROLIDONE K-30
Pia Thybo
The Danish University of Pharmaceutical Sciences
Copenhagen, Denmark
GPEN October 2006 Side 2Pia Thybo
The Danish University of Pharmaceutical Sciences
Outline of Today’s Presentation
Introduction
• Spray drying method
• Amorphous versus crystalline material
• Stabilization - solid dispersions
Specific study
• Tolfenamic acid
• Methods
• Results (stability, dissolution)
Summery
GPEN October 2006 Side 3Pia Thybo
The Danish University of Pharmaceutical Sciences
Spray Drying
• Simple up-scaling. Unique ability to produce specific particle
size and volatile content regardless of dryer capacity
• Continuous reliable operation. Powder quality remains constant
throughout the dryer run time under constant operating
conditions
• Ability to handle heat sensitive, thermoplastic and/or
hygroscopic materials
GPEN October 2006 Side 4Pia Thybo
The Danish University of Pharmaceutical Sciences
Spray Drying - Continued
•Ability to handle solutions, suspensions, emulsions, pastes or
melts
• Ability to handle materials under cGMP and aseptic drying
conditions
• Ability to handle hazardous substances i.e. flammable solvents,
dust explosion hazards, toxic materials
• Wide choice of spray dryer designs allows product
specifications to be met by tailoring the design
GPEN October 2006 Side 5Pia Thybo
The Danish University of Pharmaceutical Sciences
Examples of Spray-Dryers
Laboratory scale Pilot scale Production scale
GPEN October 2006 Side 6Pia Thybo
The Danish University of Pharmaceutical Sciences
Applications in the Pharmaceutical IndustryFormation of micro-particles
Inhalable products
• Particle size
• Particle size distribution
Micro encapsulation
• Controlled Release formulations
• Masking of a bad taste
Polymorphism
• Solubility/dissolution
GPEN October 2006 Side 7Pia Thybo
The Danish University of Pharmaceutical Sciences
Key Elements in Spray Drying
Atomization
of liquid feed into a spray of droplets
Droplet-Gas Contact
mixing and flow pattern
Drying of Droplets
moisture / volatiles evaporation (~ 10 sec.)
Product Recovery
separation of particles from the gas
GPEN October 2006 Side 8Pia Thybo
The Danish University of Pharmaceutical Sciences
Atomization
Rotary atomizer
Two-fluid nozzle
Co-current mode
Two-fluid nozzle
fountain mode
Pressure nozzle
GPEN October 2006 Side 9Pia Thybo
The Danish University of Pharmaceutical Sciences
Droplet-Gas Contact
Ref.: Masters 2002
GPEN October 2006 Side 10Pia Thybo
The Danish University of Pharmaceutical Sciences
Dry particle
Drying – From Droplet to Particle
time
Drying rate
Constant rate period (Saturated surface)
Falling rate period (liquid/vapour diffusion)
Heating up
Ref.: Masters 2002
Formation of surface
GPEN October 2006 Side 11Pia Thybo
The Danish University of Pharmaceutical Sciences
Schematic picture of spray drying process
Feed
Heater
2 fluid nozzle
Feed flow Nozzle gas flow
Drying
chamber
Cyclone
Collection
vessel
Bag filter
Tin
(Tout)
Feed
flow rate
Nozzle gas
flow rate
Feed
concentration
Exhaust
air
GPEN October 2006 Side 12Pia Thybo
The Danish University of Pharmaceutical Sciences
Effect of Spray Drying Parameters
Particle size
Feed concentration, Atomization ratio (Atom. gas flow
rate/Feed flow rate), Outlet temperature, Particle
morphology, Nozzle type
Volatile content
Outlet temperature, Drying gas flow rate (residence
time), Particle morphology, Particle size
Particle morphology
Solvent and carrier choice, Outlet temperature,
Formulation
Yield
Particle size, Volatile content, Particle Morphology
GPEN October 2006 Side 13Pia Thybo
The Danish University of Pharmaceutical Sciences
Amorphous versus Crystalline- DefinitionCrystalline
…“the adjective, crystalline, implies an ideal crystal in
which the structural units, termed unit cells, are repeated
regularly and indefinitely in three dimensions in space”
Vippagunta et al, Advanced Drug Delivery Reviews, 48, 2001
Amorphous
”Similar to a crystalline solid an amorphous solid may
have short-range molecular order, but unlike a crystalline
solid, an amorphous solid have no long-range order of
molecular packing”
L. Yu., Advanced Drug Delivery Reviews, 48, 2001
GPEN October 2006 Side 14Pia Thybo
The Danish University of Pharmaceutical Sciences
Amorphous versus Crystalline
Positive
• Improved dissolution rate
• Bioavailability
Negative
• Stability
• More hygroscopic
GPEN October 2006 Side 15Pia Thybo
The Danish University of Pharmaceutical Sciences
Physical Stability
• The glass transition temperature (Tg) is often used to
predict stability
• As a rule of thumb Hancock et al. (1995) proposed that
the Tg of a pharmaceutical product should be at least 50 ºC
above the storage temperature
• Stabilization approaches are often necessary for
amorphous pharmaceutical drugs
GPEN October 2006 Side 16Pia Thybo
The Danish University of Pharmaceutical Sciences
Physical Stability – Moisture sorption• Absorbed water act as plasticizer, increasing molecular
mobility resulting in a reduced Tg
• Absorbed water can alter the hydrogen bonding between
molecules
Phase separation often accompanied with
re-crystallization
GPEN October 2006 Side 17Pia Thybo
The Danish University of Pharmaceutical Sciences
Stabilization - Solid Dispersions
Several studies have shown the potential of high Tg
polymers to inhibit/retard re-crystallization of amorphous
drugs
Mechanisms
• Anti-plasticizing effect
• Interactions between drug and polymer
• Enchanged solubility
GPEN October 2006 Side 19Pia Thybo
The Danish University of Pharmaceutical Sciences
Purpose
To increase the dissolution rate of Tolfenamic acid through
manipulation of solid state properties
The intension is to produce small amorphous particles prepared
by spray drying method
Stabilization of this high-energy amorphous form by addition of
crystal growth inhibiting compounds
GPEN October 2006 Side 20Pia Thybo
The Danish University of Pharmaceutical Sciences
The Drug – Tolfenamic Acid
• NSAID
• White and yellow polymorph
(conformational – geometry of amino group)
Hydrogen bonded dimers in crystal
• Comparable solubility
Solubility in water: ~ 50 µg/ml
Solubility in ethanol: ~10 mg/ml
• Solutions of both modifications are
colourless and have identical physical
properties
Yellow polymorph
White polymorph
GPEN October 2006 Side 21Pia Thybo
The Danish University of Pharmaceutical Sciences
Preliminary Experiments
Part 1: Composition of feed solution
• Screening of suitable excipients, primarily within the
water soluble polymers
• Selection of drug/polymer ratios
• Selection of solvent for feed solution
• Concentration
Choices:
• Formulation as solid dispersion with PVP as excipient
• Drug/polymer ratio: (1:1, 1:3, 1:5, 1:7)
• Ethanol as solvent
GPEN October 2006 Side 22Pia Thybo
The Danish University of Pharmaceutical Sciences
Preliminary Experiments
Part 2: Optimization of the spray drying process
(process parameters)
Feed
Heater
2 fluid
nozzle
1 mm
Feed flow
Nozzle gas flow
Drying
chamb
er
Cyclone
Collection
vessel
Bag
filter
115 º C
20 g/min
6 kg/hr
16 g/L
Exhaust air
80 kg/hr
GPEN October 2006 Side 23Pia Thybo
The Danish University of Pharmaceutical Sciences
Preparation & Characterization
Solution
Solid particles
Initial
characterization
TGAXRPD SEMDissolution
Stability
study
Spray drying
Drug content FTIR
GPEN October 2006 Side 24Pia Thybo
The Danish University of Pharmaceutical Sciences
Dissolution
Time(min)
0 10 20 30 40 50 60
% R
ele
ase
d
0
20
40
60
80
100
Spray dried TA
Physical mixture 1:1
SD 1:1
SD 1:3
SD 1:5
SD 1:7
TA as obtained from supplier
GPEN October 2006 Side 25Pia Thybo
The Danish University of Pharmaceutical Sciences
Morphology, Crystallinity & Stabilization
2θ (degrees)
5 10 15 20 25 30
2θ (degrees)
5 10 15 20 25 30
2θ (degrees)
5 10 15 20 25 30 5 10 15 20 25 30
2θ (degrees)
SD 1:1 12 weeks SD 1:1 24 weeks
GPEN October 2006 Side 26Pia Thybo
The Danish University of Pharmaceutical Sciences
Stability - Interaction
SD1:1 SD1:3 SD1:5 SD1:7
50.0 75.0 83.3 87.5
Weig
ht
loss
(%
)
2
4
6
8
10
12
14
16
Measured
Additive prediction
TA starting material
Physical mixture 1:1
Molar excess PVP prediction
% PVP
Measured after 12 weeks
storage – equilibrium reached
GPEN October 2006 Side 27Pia Thybo
The Danish University of Pharmaceutical Sciences
Main Conclusions from Study - Summery• Able to transform tolfenamic acid into its amorphous form
in solid dispersions
• All solid dispersions show higher dissolution rate when
compared to physical mixture and starting material
• The drug to polymer ratio is important from a stability
point of view
• Indication of intermolecular interaction in the solid
dispersions
GPEN October 2006 Side 28Pia Thybo
The Danish University of Pharmaceutical Sciences
More Interested……..
The presented data is included in a paper accepted for
publication in Pharmaceutical Development and Technology
(January 2007).
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