BRI Horizontal Poster Template
Conditions
16
Pressurized Testing Apparatus
14
Above solubility temperature
Below solubility temperature Sight glass Liquid T temperature
Highpressure stainlesssteel vessel
Stir bar
BREC-0446-037
Batch
Results
12 10
Methanol
Solids loading (wt%)
9/1 MeOH/Water
Solvent (w/w%)
Acetone
Spray-dryer scale
9/1 Acetone/Water
SDD total batch size (g)
BREC-0446-075
30
20
THF/water/methanol
90/10 methanol/water
Methanol
2500
191
288
Sheath gas pressure (psi)
-
60
60
Solution flow rate (g/min)
170
135
135
Solution temperature (°C)
RT
127
133
2
Drying-gas inlet temperature (°C)
120
125
119
0
Drying-gas outlet temperature (°C)
45
49
46
1850
1871
1810
98
86
71
50 100 Temperature (C°)
150
Drying-gas flow rate (g/min) Yield (%)
Bulk Powder Properties for Development SDDs
Hot-Process Spray-Drying Process Schematic SOLUTION TANK
Mobile Minor Spray Dryer
IN-LINE HEAT EXCHANGER Residence time < 15 s
API crystals as a suspension at ambient temperature
P >Pboil
T >Tboil
Bulk Powder Properties Batch
BREC-0446-037
BREC-0446-065A
BREC-046-075
THF/water/methanol
90/10 methanol/water
Methanol
Bulk density (g/cc)
0.23
0.18
0.30
Tap density (g/cc)
0.41
0.34
0.59
D(10) (µm)
7
4
3
D(50) (µm)
18
15
12
D(90) (µm)
38
37
28
D [3,2] (µm)
12
7
5
Solvent system
D [4,3] (µm) Span
FLASH NOZZLE
9
D [4,3] (µm)
29
20
18
14
1.80
2.18
2.10
0.009
API RS: 0.63% Methanol SDD RS: 0.64% 90:10 methanol/water SDD RS: 0.66%
0.005
0.004
0.003
6.00
7.00
8.00
9.00
10.00
11.00
12.00
13.00
14.00
15.00
16.00
17.00
18.00
19.00 Minutes
20.00
21.00
22.00
23.00
24.00
25.00
26.00
27.00
28.00
29.00
30.00
31.00
300 290 280 270
Methanol SDD 90:10 methanol/water SDD Crystalline API
260 250 240 230 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 10 0 4
10
20
2-Theta - Scale
Authors: C. Bloom*, J. Baumann*, S. Parks*, Z. Martin*, S. Bone*, C. Lindemann† *Bend Research Inc., 64550 Research Road, Bend, OR 97701 USA • Phone: 1-800-706-8655 † Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301 USA
5.00
6.00
7.00
30
8.00
9.00
10.00
11.00
12.00
13.00
14.00
15.00
16.00
17.00
10
20
30
2Θ Scale (°)
mDSC Analysis: Single Tg
18.00
19.00
20.00 Minutes
21.00
22.00
23.00
24.00
25.00
26.00
27.00
28.00
29.00
30.00
31.00
32.00
33.00
34.00
35.00
Microcentrifuge Dissolution Results For SDD Demonstration Batch and API 50% IB
SDD 30% 20%
API
10%
-30
0
30 Time (min)
60
90
1000 μgA/mL dose in GB (pH 4.5 citrate buffer), diluted to 500 µgA/mL dose in IB (0.5% bile salts in PBS, pH 6.5)
Tablet Demonstration Batch Using a Dry Granulation Process The SDD demonstration batch was used to manufacture immediate-release tablets equivalent to previous batches. Nonsink Dissolution Test Results for Demonstration Batch and Original SDD Tablets 100%
Hot-process demonstration batch tablets Previous Tablet Original tablets
Hot Process FPN Tablet
Roller compaction and milling of intragranular blend
Blending of extragranular excipients
Compression of final blend
Tablet coating with Opadry cosmetic coating
Compaction and compression parameters were adjusted to achieve the desired ribbon and tablet characteristics.
5.0
Original demonstration batch FPN
4.0
Hot-process Hot Process FPN demonstration Compression batch compression
3.0 2.0 1.0
50
100 150 200 Compression Stress (MPa)
250
75%
50%
25%
0% -30
0
30
60
Time (min)
Tablet Cores
Coated Tablets
1000 μgA/mL dose in GB (pH 4.5 citrate buffer), diluted to 500 µgA/mL dose in IB (0.5% bile salts in PBS, pH 6.5)
Yellow shaded areas denote the target tensile strength of 2 MPa and the corresponding compression stress required to achieve it.
32.00
PXRD Data: No Crystals in SDDs y
Methanol (20 wt%)
-0.002
0%
0 5.00
90/10 Methanol/Water (30 wt%)
API 4
0.0
0.001
0.000
THF/Methanol/Water (10 wt%)
0.002 0.000
0
0.002
SEM Images of Development Batches: No Crystals or Fusing
0.006 0.004
20 10
Hot Process FPN Hot-process demonstration batch
0.006
Atomization occurs
SDD
120 110 100 90 80
6.0
0.007
Pnozzle < Pboil
0.010 0.008
40%
Blending of intragranular excipients including lubricant
0.008
HIGH-PRESSURE PUMP
0.012
GB
0.010
Pnozzle > Pboil
0.016 0.014
170 160 150 140 130
50 40 30
SEM Image: No Crystals
0.011
DRYING CHAMBER
190 180
70 60
94.2
D [3,2] (µm)
Purity: No Significant Increase In Related Substances (RS)
Flash-Nozzle Atomization
Flash atomizer
210 200
Flash atomizer (380-µm ID, 50-mm length)
SK 80-16
250
0
Atomizer
0.020 0.018
122
400
4
5639
Mobile Minor with 6-foot extension
Nozzle pressure (psi)
6
Mobile Minor with 6-foot extension
Dry yield (%)
10
Atomizer
8
90/10 methanol/water
SDD total batch size (g)
0.024 0.022
240 230 220
30
API RS: 0.43% SDD RS: 0.53%
0.028 0.026
260 250
BREC-0446-078
Spray-dryer scale
BREC-0446-065A
300 290 280 270
[API] (Dose Dissolved)
API Concentration vs Solubility Temperature
0.032
AU
Conditions
Solvent (w/w%)
Results
0.034
0.030
Solids loading (wt%)
Spray-Drying Conditions for Development SDDs
PXRD Data: No Crystals
Lin (Cps)
Hot-Process Solubility Screening
20
© Bend Research Inc. 2013
Spray-Drying Summary Batch
SDD Process Development and Test-Batch Manufacture and Characterization
Purity: No Significant Increase in RS
[API] (Dose Dissolved)
Solubility of the compound and PVP-VA were evaluated in methanol, acetone, and solvent/water mixtures as a function of temperature up to 130°C. The solubility experiments were performed in sealed stainlesssteel vessels with viewing windows and pressure-relief valves. Based on the solubility data, appropriate solution and temperature conditions were selected. Development lots of SDD were manufactured on a laboratory-scale spray dryer with a 150-kg/hr drying-gas flow-rate capacity. A suspension feedstock was used with transient heating via an inline heat exchanger to completely dissolve the crystalline drug immediately before atomization using a specially designed nozzle. The SDDs were tested for purity, performance, and physical state by high-performance liquid chromatography (HPLC), scanning electron micrography (SEM), powder x-ray diffraction (PXRD), modulated differential scanning calorimetry (mDSC), Karl Fischer titration (KF), headspace gaschromatography (GC), and nonsink dissolution methods. Tablets were manufactured using a dry granulation process.
Based on the test-batch results, a 5.6-kg demonstration batch of SDD was manufactured using a 30-wt%-solids feedstock at a 94% yield.
Tensile Strength (MPa)
Methods
Based on the solubility determination, a feedstock containing 30-wt% solids was selected with a 130°C in-line heating step. This “hot process” resulted in complete dissolution of crystalline drug, producing amorphous SDDs that had purity and performance profiles and powder properties that were equivalent to SDDs prepared using the original process.
AU
A tablet formulation based on a spray-dried dispersion (SDD) of a low-solubility oncology compound in vinylpyrrolidone-vinyl acetate copolymer (PVP-VA) has been developed to increase solubility and reduce variability of exposure. Initial SDD preclinical and clinical supplies were spray-dried at 10-wt% solids in a ternary tetrahydrofuran (THF)/methanol/ water solution due to solubility limitations in preferred solvent systems. The purpose of this body of work was (1) to identify a solvent system and spray-drying process to increase throughput and eliminate the use of THF and (2) to manufacture SDD intermediate and tablets with performance and stability equivalent to the initial materials.
SDD Demonstration Batch
Results and Discussion
Lin (Cps)
Introduction
Concentration (wt %)
Poster W5256
Heated Spray-Drying Process and Formulation Development For A Spray-Dried Dispersion
Conclusions An improved process and solvent system was developed to increase spray-drying throughput and eliminate THF. The improved process employs a transiently heated methanol/water system and a more-concentrated 30-wt%-solids feedstock for more efficient manufacture. The resulting SDD can be manufactured using the original tablet formulation and process, and the process is appropriate for further scale-up. SDDs and tablets were subsequently manufactured for clinical trials using this process and solvent systems.
90
16
Pressurized Testing Apparatus
14
Above solubility temperature
Below solubility temperature Sight glass Liquid T temperature
Highpressure stainlesssteel vessel
Stir bar
BREC-0446-037
Batch
Results
12 10
Methanol
Solids loading (wt%)
9/1 MeOH/Water
Solvent (w/w%)
Acetone
Spray-dryer scale
9/1 Acetone/Water
SDD total batch size (g)
BREC-0446-075
30
20
THF/water/methanol
90/10 methanol/water
Methanol
2500
191
288
Sheath gas pressure (psi)
-
60
60
Solution flow rate (g/min)
170
135
135
Solution temperature (°C)
RT
127
133
2
Drying-gas inlet temperature (°C)
120
125
119
0
Drying-gas outlet temperature (°C)
45
49
46
1850
1871
1810
98
86
71
50 100 Temperature (C°)
150
Drying-gas flow rate (g/min) Yield (%)
Bulk Powder Properties for Development SDDs
Hot-Process Spray-Drying Process Schematic SOLUTION TANK
Mobile Minor Spray Dryer
IN-LINE HEAT EXCHANGER Residence time < 15 s
API crystals as a suspension at ambient temperature
P >Pboil
T >Tboil
Bulk Powder Properties Batch
BREC-0446-037
BREC-0446-065A
BREC-046-075
THF/water/methanol
90/10 methanol/water
Methanol
Bulk density (g/cc)
0.23
0.18
0.30
Tap density (g/cc)
0.41
0.34
0.59
D(10) (µm)
7
4
3
D(50) (µm)
18
15
12
D(90) (µm)
38
37
28
D [3,2] (µm)
12
7
5
Solvent system
D [4,3] (µm) Span
FLASH NOZZLE
9
D [4,3] (µm)
29
20
18
14
1.80
2.18
2.10
0.009
API RS: 0.63% Methanol SDD RS: 0.64% 90:10 methanol/water SDD RS: 0.66%
0.005
0.004
0.003
6.00
7.00
8.00
9.00
10.00
11.00
12.00
13.00
14.00
15.00
16.00
17.00
18.00
19.00 Minutes
20.00
21.00
22.00
23.00
24.00
25.00
26.00
27.00
28.00
29.00
30.00
31.00
300 290 280 270
Methanol SDD 90:10 methanol/water SDD Crystalline API
260 250 240 230 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 10 0 4
10
20
2-Theta - Scale
Authors: C. Bloom*, J. Baumann*, S. Parks*, Z. Martin*, S. Bone*, C. Lindemann† *Bend Research Inc., 64550 Research Road, Bend, OR 97701 USA • Phone: 1-800-706-8655 † Array BioPharma Inc., 3200 Walnut Street, Boulder, CO 80301 USA
5.00
6.00
7.00
30
8.00
9.00
10.00
11.00
12.00
13.00
14.00
15.00
16.00
17.00
10
20
30
2Θ Scale (°)
mDSC Analysis: Single Tg
18.00
19.00
20.00 Minutes
21.00
22.00
23.00
24.00
25.00
26.00
27.00
28.00
29.00
30.00
31.00
32.00
33.00
34.00
35.00
Microcentrifuge Dissolution Results For SDD Demonstration Batch and API 50% IB
SDD 30% 20%
API
10%
-30
0
30 Time (min)
60
90
1000 μgA/mL dose in GB (pH 4.5 citrate buffer), diluted to 500 µgA/mL dose in IB (0.5% bile salts in PBS, pH 6.5)
Tablet Demonstration Batch Using a Dry Granulation Process The SDD demonstration batch was used to manufacture immediate-release tablets equivalent to previous batches. Nonsink Dissolution Test Results for Demonstration Batch and Original SDD Tablets 100%
Hot-process demonstration batch tablets Previous Tablet Original tablets
Hot Process FPN Tablet
Roller compaction and milling of intragranular blend
Blending of extragranular excipients
Compression of final blend
Tablet coating with Opadry cosmetic coating
Compaction and compression parameters were adjusted to achieve the desired ribbon and tablet characteristics.
5.0
Original demonstration batch FPN
4.0
Hot-process Hot Process FPN demonstration Compression batch compression
3.0 2.0 1.0
50
100 150 200 Compression Stress (MPa)
250
75%
50%
25%
0% -30
0
30
60
Time (min)
Tablet Cores
Coated Tablets
1000 μgA/mL dose in GB (pH 4.5 citrate buffer), diluted to 500 µgA/mL dose in IB (0.5% bile salts in PBS, pH 6.5)
Yellow shaded areas denote the target tensile strength of 2 MPa and the corresponding compression stress required to achieve it.
32.00
PXRD Data: No Crystals in SDDs y
Methanol (20 wt%)
-0.002
0%
0 5.00
90/10 Methanol/Water (30 wt%)
API 4
0.0
0.001
0.000
THF/Methanol/Water (10 wt%)
0.002 0.000
0
0.002
SEM Images of Development Batches: No Crystals or Fusing
0.006 0.004
20 10
Hot Process FPN Hot-process demonstration batch
0.006
Atomization occurs
SDD
120 110 100 90 80
6.0
0.007
Pnozzle < Pboil
0.010 0.008
40%
Blending of intragranular excipients including lubricant
0.008
HIGH-PRESSURE PUMP
0.012
GB
0.010
Pnozzle > Pboil
0.016 0.014
170 160 150 140 130
50 40 30
SEM Image: No Crystals
0.011
DRYING CHAMBER
190 180
70 60
94.2
D [3,2] (µm)
Purity: No Significant Increase In Related Substances (RS)
Flash-Nozzle Atomization
Flash atomizer
210 200
Flash atomizer (380-µm ID, 50-mm length)
SK 80-16
250
0
Atomizer
0.020 0.018
122
400
4
5639
Mobile Minor with 6-foot extension
Nozzle pressure (psi)
6
Mobile Minor with 6-foot extension
Dry yield (%)
10
Atomizer
8
90/10 methanol/water
SDD total batch size (g)
0.024 0.022
240 230 220
30
API RS: 0.43% SDD RS: 0.53%
0.028 0.026
260 250
BREC-0446-078
Spray-dryer scale
BREC-0446-065A
300 290 280 270
[API] (Dose Dissolved)
API Concentration vs Solubility Temperature
0.032
AU
Conditions
Solvent (w/w%)
Results
0.034
0.030
Solids loading (wt%)
Spray-Drying Conditions for Development SDDs
PXRD Data: No Crystals
Lin (Cps)
Hot-Process Solubility Screening
20
© Bend Research Inc. 2013
Spray-Drying Summary Batch
SDD Process Development and Test-Batch Manufacture and Characterization
Purity: No Significant Increase in RS
[API] (Dose Dissolved)
Solubility of the compound and PVP-VA were evaluated in methanol, acetone, and solvent/water mixtures as a function of temperature up to 130°C. The solubility experiments were performed in sealed stainlesssteel vessels with viewing windows and pressure-relief valves. Based on the solubility data, appropriate solution and temperature conditions were selected. Development lots of SDD were manufactured on a laboratory-scale spray dryer with a 150-kg/hr drying-gas flow-rate capacity. A suspension feedstock was used with transient heating via an inline heat exchanger to completely dissolve the crystalline drug immediately before atomization using a specially designed nozzle. The SDDs were tested for purity, performance, and physical state by high-performance liquid chromatography (HPLC), scanning electron micrography (SEM), powder x-ray diffraction (PXRD), modulated differential scanning calorimetry (mDSC), Karl Fischer titration (KF), headspace gaschromatography (GC), and nonsink dissolution methods. Tablets were manufactured using a dry granulation process.
Based on the test-batch results, a 5.6-kg demonstration batch of SDD was manufactured using a 30-wt%-solids feedstock at a 94% yield.
Tensile Strength (MPa)
Methods
Based on the solubility determination, a feedstock containing 30-wt% solids was selected with a 130°C in-line heating step. This “hot process” resulted in complete dissolution of crystalline drug, producing amorphous SDDs that had purity and performance profiles and powder properties that were equivalent to SDDs prepared using the original process.
AU
A tablet formulation based on a spray-dried dispersion (SDD) of a low-solubility oncology compound in vinylpyrrolidone-vinyl acetate copolymer (PVP-VA) has been developed to increase solubility and reduce variability of exposure. Initial SDD preclinical and clinical supplies were spray-dried at 10-wt% solids in a ternary tetrahydrofuran (THF)/methanol/ water solution due to solubility limitations in preferred solvent systems. The purpose of this body of work was (1) to identify a solvent system and spray-drying process to increase throughput and eliminate the use of THF and (2) to manufacture SDD intermediate and tablets with performance and stability equivalent to the initial materials.
SDD Demonstration Batch
Results and Discussion
Lin (Cps)
Introduction
Concentration (wt %)
Poster W5256
Heated Spray-Drying Process and Formulation Development For A Spray-Dried Dispersion
Conclusions An improved process and solvent system was developed to increase spray-drying throughput and eliminate THF. The improved process employs a transiently heated methanol/water system and a more-concentrated 30-wt%-solids feedstock for more efficient manufacture. The resulting SDD can be manufactured using the original tablet formulation and process, and the process is appropriate for further scale-up. SDDs and tablets were subsequently manufactured for clinical trials using this process and solvent systems.
90
