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Challenges in the Analysis of Spray Dried Formulations: Dissolution
Dr Adele PattersonSenior Research Investigator II
Bristol-Myers Squibb
8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
Acknowledgements
Ana FerreiraClare Rawlinson-Malone
Zoe Gault
Other BMS colleagues in DPST and ABD at Moreton UK and New Brunswick USA
28th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
Outline
• What is driving the interest in amorphous materials in the pharmaceutical industry?
• Polymer Selection
• Understanding dissolution behaviour of amorphous materials
Advantages
Mechanistic Understanding – Why & How?
• Development of in-vitro dissolution methods
Challenges / Limitations
What can we change?
8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
Why Are We Interested?
Solid
Cs
0x
x
Solid
Cs
0x
x
Solid
Cs
0x
x
Biopharmaceutic Classification Systema
a Amidon, Lennernas et al. (1995) Pharmaceutical Research b L. Benet et al, (2006) Bulletin Technique Gattefosse . .
HIGH LOW
Co-crystals
35-70% of APIs b
Class II
Amorphous
Size reduce
Salt or Solvate
Colloid systemsSolid Dispersions
Wetting and
Porosity
Dissolution of Amorphous Dispersion:“Spring and Parachute” model
Guzmán et al, J. Pharm.Sci. 2007, 96(10) 2686-27025
POLYMER SELECTION
How Do You Select a Polymer?
• Primary Function = Maintain Physical Stability of the API
• Dissolution Rate / Sustainment
Solubility Considerations
Water Uptake
Interactions with API
Chemical Stability
8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
Target Material Profile (TMP)
What Are the ASD Critical Parameters?
8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
TMPBackbone
Functional Groups
Substitution
Mol Weight Dist ASD
Powder Properties
Drug Loading in
ASD
ASD Loading in
Tablet
MECHANISTIC UNDERSTANDING
In vivo performance model
Free drug
Particles dissolve
kdis(must be
rapid) kabs
Bile-salt micelles
Colloids
Drug Species
Intestinalbilayer
Crystalline drug
Rapid absorption
:.:.
:.:. :.:.:.:.
:.:.:. :.:.
:. :.:.:.:.:.:.:.
:.:.
:. :.:.:.:.:.:.:.
:.:.
:. :.:.:.:.:.:.:.
:.:.
:. :.:.:.:.:.:.:.
:.:.
:. :.:.:.:.:.:.:.:.
:.:. :.:.:.:.
:.:.:.
Granules
Particles
10
Rapiddisintegration
is critical
Bioperformanceis function of dispersion
8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
SDD dissolution mechanistic models
11
Seconds Polymer Gel
Drug Nanostructures
Dry SDD Particle
Minutes
Polymer Chains
Minutes to Hours
Dispersion Hydrates Resulting in nano-scale
Phase Separation
Dispersion hydrates with limited phase separation. As drug
diffuses from particle boundary layer, polymer becomes soluble.
SDD particles erodes. Drug diffuses from particle into solution.
kdiff
Hypothesis: 1.Dissolution fast most of the time: k relatively size and loading independent. 2.Situation is better for nanoaggregateformation.
Hypothesis: 1.Dissolution is a function of loading and particle size (surface area)2.Situation is worst for nanoaggregateformation3.Sink and non-sink dissolution behavior may be very different.
Drug with low solubility in hydrated polymer
Drug with high solubility in hydrated polymer
Seconds Polymer Gel
Drug Nanostructures
Dry SDD Particle
Minutes
Polymer Chains
Minutes to Hours
Dispersion Hydrates Resulting in nano-scale
Phase Separation
Dispersion hydrates with limited phase separation. As drug
diffuses from particle boundary layer, polymer becomes soluble.
SDD particles erodes. Drug diffuses from particle into solution.
kdiff
Hypothesis: 1.Dissolution fast most of the time: k relatively size and loading independent. 2.Situation is better for nanoaggregateformation.
Hypothesis: 1.Dissolution is a function of loading and particle size (surface area)2.Situation is worst for nanoaggregateformation3.Sink and non-sink dissolution behavior may be very different.
Drug with low solubility in hydrated polymer
Drug with high solubility in hydrated polymer
Chapter 9 in Amorphous Solid Dispersions – Theory and Practice, Eds. Navnit Shah et al., Springer 2014
Dissolution Methods
12BMS Confidential & Proprietary
Dissolution Methods
8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
Research methods
Non Sink
Low Volume
Powder
Complex Media
Specialist Equipment
QC Release methods
Sink
≥ 500 mLs
Tablets
USP Media
USP Equipment
Formulation Development
Sink
≥ 500 mLs
Tablet
Wide Range of
Media
USP Equipment
Build Mechanistic Understanding
Support for SDD UnderstandingDissolution Methodology - Sink Method
SDD syringe dissn method – rate of dissolution – Media: 2% NaTc/POPC in PBS pH 5.8 Dose: 75µg API/ml
138th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
14
Support for SDD UnderstandingDissolution Methodology – non sink methods
8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
Chord Length (μm)
Co
un
ts
Fibre Optics
Sapphire Window
Rotating Optics
Beam Splitter
Focussed Beam Reflectance Measurement
8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
Dry SDD particleParticle erosion rate-limiting step
Drug Y - UV
Drug Y - FBRM
Colloidal nano speciesrate-limiting step
Drug X - UV
Drug X - FBRM
Drug YDrug ADrug B Drug ZDrug X
?
Drug C
8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
Dissolution Methods
17BMS Confidential & Proprietary 8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
Research methods
Non Sink
Low Volume
Powder
Complex Media
Specialist Equipment
QC Release methods
Sink
≥ 500 mLs
Tablets
USP Media
USP Equipment
Formulation Development
Sink
≥ 500 mLs
Tablet
Wide Range of
Media
USP Equipment
Monitor Product Performance against Specification
Dissolution Methods
18BMS Confidential & Proprietary 8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
Research methods
Non Sink
Low Volume
Powder
Complex Media
Specialist Equipment
QC Release methods
Sink
≥ 500 mLs
Tablets
USP Media
USP Equipment
Formulation Development
Sink or Non Sink
≥ 500 mLs
Tablet
Wide Range of
Media
USP Equipment
Identify & Discriminate for Critical
Performance Parameter
(CPP)
Evidence of Recrystallization
METHOD DEVELOPMENT
Method Development
• Physical Parameters
Apparatus
Rotation Speed
Media Volume
Detection Method
• Media Selection
pH
Buffer Ionic strength
Surfactant Class / Concentration
8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
Affect Sink Conditions for your API and the
Polymer
Media Ranking: Sink Solubility of SDD
Dissolution
Media
Sink
Solubility
pH 1.0
pH 4.5
pH 6.0 > 0.25 mg / mL
pH 6.8 > 0.10 mg / mL
pH 1.0 CTAB < 0.10 mg / mL
pH 4.5 CTAB
pH 6.0 CTAB
pH 6.8 CTAB
pH 1.0 SLS
pH 4.5 SLS
pH 6.0 SLS
pH 6.8 SLS
pH 1.0 Tween
pH 4.5 Tween
pH 6.0 Tween
pH 6.8 Tween
pH 1.0 CHAPS
pH 4.5 CHAPS
pH 6.0 CHAPS
pH 6.8 CHAPS
0 2 4 6 80
20
40
60
80
100
120
0
2
4
6
8
10
12
Pol
ymer
Sol
ubili
ty (
% D
isso
lved
)
pH
AP
I Sol
ubili
ty (
mg/
mL)
pH Dependant Solubility of SDD Components
API Polymer
Media Ranking: Sink Solubility of SDD
Dissolution
Media
Sink
Solubility
pH 1.0
pH 4.5
pH 6.0 > 0.25 mg / mL
pH 6.8 > 0.10 mg / mL
pH 1.0 CTAB < 0.10 mg / mL
pH 4.5 CTAB
pH 6.0 CTAB
pH 6.8 CTAB
pH 1.0 SLS
pH 4.5 SLS
pH 6.0 SLS
pH 6.8 SLS
pH 1.0 Tween
pH 4.5 Tween
pH 6.0 Tween
pH 6.8 Tween
pH 1.0 CHAPS
pH 4.5 CHAPS
pH 6.0 CHAPS
pH 6.8 CHAPS
0 2 4 6 80
20
40
60
80
100
120
0
2
4
6
8
10
12
Pol
ymer
Sol
ubili
ty (
% D
isso
lved
)
pH
AP
I Sol
ubili
ty (
mg/
mL)
pH Dependant Solubility of SDD Components
API Polymer
Media Ranking: Sink Solubility of SDD
AU
-0.010
0.000
0.010
0.020
0.030
0.040
0.050
0.060
0.070
0.080
0.090
Minutes0.20 0.40 0.60 0.80 1.00 1.20 1.40 1.60 1.80 2.00 2.20 2.40 2.60 2.80 3.00 3.20 3.40 3.60 3.80 4.00 4.20 4.40
pH 4.5 Tween pH 6.8 SLS
pH 1.0 no surfpH 6.0 CTAB
Dissolution
Media
Sink
Solubility
HPLC Peak
Shape
pH 1.0
pH 4.5
pH 6.0
pH 6.8
pH 1.0 CTAB
pH 4.5 CTAB
pH 6.0 CTAB
pH 6.8 CTAB
pH 1.0 SLS
pH 4.5 SLS
pH 6.0 SLS
pH 6.8 SLS
pH 1.0 Tween
pH 4.5 Tween
pH 6.0 Tween
pH 6.8 Tween
pH 1.0 CHAPS
pH 4.5 CHAPS
pH 6.0 CHAPS
pH 6.8 CHAPS
Media Ranking: Sink Solubility of SDD
CTAB
Dissolution
Media
Sink
Solubility
HPLC Peak
Shape
Solution
Appearance
Media
Ranking
pH 1.0
pH 4.5
pH 6.0
pH 6.8
pH 1.0 CTAB
pH 4.5 CTAB
pH 6.0 CTAB
pH 6.8 CTAB
pH 1.0 SLS
pH 4.5 SLS
pH 6.0 SLS
pH 6.8 SLS
pH 1.0 Tween
pH 4.5 Tween
pH 6.0 Tween
pH 6.8 Tween
pH 1.0 CHAPS
pH 4.5 CHAPS
pH 6.0 CHAPS
pH 6.8 CHAPS
0
10
20
30
40
50
60
70
80
90
100
0 20 40 60 80 100 120
% D
isso
lved
Mins
1 % Brij PSD2 1 % CTAB PSD2
1 % SDS PSD2 1 % CHAPS PSD2
Non-ionisable drug / ~ 50% Ionised polymer / Variable surfactant
Dissolution: Effect of Surfactant Class
0
10
20
30
40
50
60
70
80
90
100
0 10 20 30 40 50 60 70 80
Dis
so (
%)
Time (mins)
HCl & SDS -1% HCl & CTAB -1%
+vely drug / Un-Ionised polymer / Charged surfactant
Dissolution: Effect of Media pH
-10
10
30
50
70
90
110
0 10 20 30 40 50 60 70 80
Dis
so (
%)
Time (mins)
HCl & SDS -1% pH 6.0 & SDS -1%
0
20
40
60
80
100
120
0 20 40 60 80 100 120 140
% D
isso
lved
(%
)
Time (mins)
pH 5.25 pH 5.4
pH 5.5 pH 5.6
pH 5.7 pH 5.8
Ionisable drug / Ionisable polymer / -velyCharged surfactant
Non-ionisable drug / ionisable polymer / non-ionisable surfactant
27
0
20
40
60
80
100
120
0 10 20 30 45 60 90 120
% D
isso
lved
Time (Mins)
pH 5.25 pH 5.4pH 5.5 pH 5.6pH 5.7 pH 5.8
8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
Dissolution: Effect of Surfactant Grade
0
20
40
60
80
100
120
0 20 40 60 80 100 120 140
% D
isso
lved
(%
)
Time (mins)
pH 5.25 pH 5.4
pH 5.5 pH 5.6
pH 5.7 pH 5.8
0
10
20
30
40
50
60
70
80
90
100
0 20 40 60 80 100 120
% D
isso
lved
(%
)
Time (mins)
Effect of Surfactant Concentration on Dissolution
0% Brij 0.05% Brij 0.10% Brij
0.15% Brij 0.20% Brij 0.40% Brij
0.60% Brij 0.80% Brij 1.00% Brij
8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
Dissolution: Effect of Surfactant Concentration
-4.5
-4
-3.5
-3
-2.5
-2
-1.5
0 1 2 3 4 5 6 7 8 9 10
Lo
g k
ob
s(h
-1)
pH
The log kobs-pH profile for degradation at 40C.
• API / Polymer Trace level impurities Chemical structure Intermolecular interactions
• Water Free / bound in polymer Uptake
• Amorphous materials are inherently less stable
Chemical Stability
29
O
OR
OR
CH2OR1
O
OR2
OR
CH2OR
O
n
O
R1 = -H R2 = -COCH3
-CH3 -COCH2CH2COOH-CH2CH(CH3)OH
HPMC-AS
8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
• API / Polymer Trace level impurities Chemical structure Intermolecular interactions
• Water Free / bound in polymer Uptake
• Amorphous materials are inherently less stable
Chemical Stability
30
Inc in Degradant after 3 wks
SDI with HPMC-AS Grade
L M H
40/75 (Open) 0.7 0.5 0.4
50/75 (Open) 2.6 2.0 1.3
Acetyl Levels 5 - 9% 7 - 11% 10 - 14%
Succinyl Levels 14 - 18% 10 - 14% 4 - 8%
8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
• API / Polymer Trace level impurities Chemical structure Intermolecular interactions
• Water Free / bound in polymer Uptake
• Amorphous materials are inherently less stable
Chemical Stability
31
Patterson et al. (2015) Int J of Pharmaceutics 478, 348-360
𝑙𝑛𝑘 = 𝑙𝑛𝐴 −𝐸𝑎𝑅𝑇
+ 𝐵 %𝑅𝐻 + 𝐶 %𝑆𝐴
R2 = 0.9905, RMSEC = 0.0161
𝑙𝑛𝑘 = 𝑙𝑛𝐴 −𝐸𝑎𝑅𝑇
+ 𝐵 %𝑅𝐻
R2 = 0.9827, RMSEC = 0.0290
8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
Summary
Knowledge / Understanding
8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
Thank you for your attention
8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
Backup Slides
Particle erosion model of SDD dissolution
35
Relative impact of SDD powder properties vs polymer chemistry
25% drug 75% HPMCAS
Central composite design 16 SDD lots + 6 re-sprays + 4 confirmation lots Total = 26 lots
8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
0 2 4 6 8 10 12 14 16 18 200
20
40
60
80
100
120
140
Time (min)
% D
isso
lved
(pH
5.8
) -
corr
ecte
d fo
r po
tenc
y an
d st
artin
g do
se v
aria
tion
Run 1Run 2
Run 3
Run 4
Run 5Run 6
Run 7
Run 8Run 9
Run 10
Run 11Run 12
Run 13
Run 14
Run 15Run 16
Confirmation 13
Confirmation 14Confirmation 9
Confirmation 5
Respray 1Respray 5
Respray 14
Respray 9
Respray 13Respray 6
Sink conditions: 300µg/ml SDD in pH 5.8 PBS with 2% bile salts
SDD in-vitro dissolution
36
First order model used to determine dissolution rate
)1( kteQQ
with Q ∞ = 100 % 0 10 20 30 40 50 60 70 80 90 1000
50
100
Dissolution @ pH 5.8
Dis
solu
tion
pred
icte
d by
mod
el
R2 = 0.993
Run 1
0 2 4 6 8 10 12 14 16 18 200
50
100
Time (min)
% D
isso
lved
(pH
5.8
)
Run 1
Data
Unweighted fit95% Confidence Limits
0 10 20 30 40 50 60 70 80 90 1000
50
100
Dissolution @ pH 5.8
Dis
solu
tion
pred
icte
d by
mod
elR2 = 0.993
Run 1
0 2 4 6 8 10 12 14 16 18 200
50
100
Time (min)
% D
isso
lved
(pH
5.8
)
Run 1
Data
Unweighted fit95% Confidence Limits
8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
Relative impact of powder properties and polymer:Interactive effects
37Succinoyl content Bulk Vol Particle Size (D90)
Succinylcontent
Bulk Vol
Particle SIze
2-way: Dissn rate is more sensitive to bulk vol (and to a lesser extent particle size) at high succinoyl content3-way: None observed
Succinoylcontent B
ulk Vol
Particle S
ize (D90)
Target Product Profile
388th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
0
20
40
60
80
100
120
140
160
180
200
0 50 100 150 200 250
Time (min)
Co
nc
en
tra
tio
n (
ug
/mL
)
0
20
40
60
80
100
120
140
160
180
200
0 50 100 150 200 250
Co
ncen
trati
on (u
g/m
L)
Time (min)
0
20
40
60
80
100
120
140
160
180
200
0 50 100 150 200 250
Co
ncen
trati
on (u
g/m
L)
Time (min)
ML H
0
50
100
150
200
0 30 60 90 120
[Dru
g] (µ
g/m
L)
Time (min)
40%A HPMCAS SDD
25%A HPMCAS SDD
40%A PVPVA SDD
25%A PVPVA SDD
40% API:HPMC-AS SDD
25% API:HPMC-AS SDD
40% API:PVP-VA SDD25% API:PVP-VA SDD
Effect of Formulation Choices on Dissolution of Amorphous Dispersion:
39
Not just fast dissolution
Sustainment in solution
8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
BRI Test Ref: BREC0249-041
G
Add 1.8 mL MFDS
Allow to StandUndisturbedat 37°C
CA
E
Sample 50 µLDilute Into250 µL Organic Solvent
MicrocentrifugeTube ContainingDispersion
B
F
Cap + Resuspendon Vortex for~30 Seconds
Cap + ContinuouslyMix on Vortex for60 Seconds
D
Centrifuge at13,000 RPM for1 Minute or 80,000 RPMfor 20 min (Free Drug)
Repeat Steps C-G for Sampling of Timepoints
* After 90 minutes, the supernatant was completely removed & replaced with fresh MFDS
Support for SDD UnderstandingDissolution Methodology – non sink methods
8th Annual Global Drug Delivery & Formulation Summit: Berlin Mar 2017
[AP
I]
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