Solubility enhancement of poorly soluble API using ... · PDF fileSolubility enhancement of...
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Solubility enhancement of poorly soluble API using
cellulose derivatives
28th April 2014Shilpa Mistry
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Class up to improve drug solubility
BCS :Biopharmaceutics Classification system*1
More than 60%of candidate drug
Class Ⅱa/ IIb Class Ⅰ
Class Ⅳ Class Ⅲ
0.1mg/mSolubility
90%(10-6)
Abs
orpt
ion
(Per
mia
bilit
y)
Need to Improve
Formulation Change
(hard technique)
Chemical Change(relatively easy)
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Solid dispersion
30
10
20
30
0 5 10 15Time (min)
Am
ount
dis
solv
ed (m
g/ m
L)
Solid Dispersion
Physical mixture
Drug (Crystal) solubility
Physical mixture Solid dispersion
Drug (Crystal) Drug (Molecule) Carrier (Polymer)
Drug crystal amorphous(molecule)
Solubility Low High
Stability Stable Unstable (recrystallization)
Drug & polymer miscibility Stable in the process
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Approach to Improve drug solubilityPhysical modifications
-Micronization-Complexation (Surfactants, CyD, etc.)-Polymorphs-Solid dispersion (amorphous)
Chemical modification-Soluble prodrugs-Salts
Requirements of a good solid dispersion:Superstation release profile (3hrs), high API content, Good stability.
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Solid dispersion➤ Approach to Improve Drug Solubility
First paperSekiguch and Obi, Chem. Pharm. Bull. 1961Eutectic mixture(Sulfathiazole-Ascorbic acid, acetoamide, nicotineamide, urea…)
Chiou and Riegelman, J. Pharm. Sci. 1969Solid dispersion(Griseofulvin-PEG6000)
First commercial product-SepamitNifedipine Solid Solution by Kanebo since 1981
Few products on the market : because ofstability issuesmanufacturing issuesother opportunities for delivery of insoluble compounds
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Preparation of solid dispersions
Powder
・Hot melt extrusion
Drug Polymer
Solvent
・Spray Dry
DrugPolymer
・Co-precipitation
Spray dryer
Fluidized bedCore: lactose etc.
Capsule orTablet
・Spray Coating
Using poor solvent
Powder
Injection moulded tablets
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Preparation of Solid dispersion
• Solvent method– Spray drug-polymer
solution• Co-soluble process
– Miscible to solvent• Hot Melt Extrusion
– Heat and shear drug-polymer mixture
• Co-melt process– Thermal misible
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Particle morphology –Solid dispersion
x1000
x1000x1000
x250 x250
Spray Drying
Spray Drying (lactose) Melt Extrusion (milled)
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Carrier substances for solid dispersion
PolyvinylpyrrolidonePolyethylene glycolsCellulose derivatives-HPMC, HPC, HPMCP, HPMCAS…PolyacrylatesUreaSugar
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Structure
Enteric coating agent (cellulose derivatives)HPMC HPMCAS
: MethylHydroxypropyl : Succinoyl …hydrophilic
(anionic dissociation)
: Acetyl …hydrophobic
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HPMCAS : Shin-Etsu AQOAT®
OOR
OR
OR
O
H
HH H
H
H
H
H
CH2OR
CH2OR
HORH O
O
➤ Enteric coating agent➤ Sustained release coating
Multi functional substituent➢ hydrophobic➢ H-bonding
Amorphous polymer chain network
CAS; 71138-97-1, listed in JPE, USP/NF
R= -H, -CH3, -COCH3,-COCH2CH2COOH-CH2CH(OH)CH3,
-CH2CH(CH3)OCOCH3,-CH2CH(CH3)OCOCH2CH2COOH
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Grades of HPMCAS pH dependent solubility
Acetyl(%)
Succinoyl(%)
AS-LG/LF 8 15AS-MG/MF 9 11AS-HG/HF 12 7
0
20
40
60
80
100
4.5 5.0 5.5 6.0 6.5 7.0
pH
% d
isso
lved
at 3
0 m
in.
AS-MF MG
AS-HF HG
AS-LF LG
Vitamin B2 tablet
G: Granular grade (HME and SDD)F: Fine grade (Aqueous & dry coating)
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Glass transition temperaturesHPMC AQOAT (HPMCAS) HPMCP
Tg: 165˚C(P-606)
Tg:120˚C (AS-L)130˚C (AS-M)
135˚C (AS-H)
Tg: 145˚C(HP-55)
: MeO or HPO: Phthalyl
: Succinoyl
: Acetyl
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Screening study Preparation API and polymer were dissolved in a mixed solvent
(Ethanol:Dichloromethane = 1:1w/w) and then sprayed onto Teflon sheet and grounded.
PolymersHypromellose acetate succinate
(HPMCAS: Shin-Etsu AQOAT® AS-MF, Shin-Etsu Chem.)
Hypromellose phthalate (HPMCP: HP-55, Shin-Etsu Chem.)
Hypromellose (HPMC: Pharmacoat® 606, Shin-Etsu Chem.)Polyvinylpyrrolidone (PVP: Kollidon® K30, Sigma)
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Screening study (solvent method)Nifedipine Griseofulvin Dipyridamole Carbamazepine
Mw: 346 Mw: 352 Mw: 504 Mw: 236
water solubility:0.0063mg/mL
water solubility:0.0096mg/mL
water solubility:0.004mg/mL
water solubility:0.224mg/mL
solubility at pH6.8:0.0060mg/mL
solubility at pH6.8:
0.0084mg/mL
solubility at pH6.8:
0.0037mg/mL
solubility at pH6.8:
0.163mg/mL
solubility at pH1.2:
0.0061mg/mL
solubility at pH1.2:
0.0011mg/mL
solubility at pH1.2:>2.5mg/mL
solubility at pH1.2:0.192mg/mL
NP GRF DIP CBZ
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0
20
40
60
80
100
0 30 60 90 120Time (min)
Dis
solv
ed N
P (μ
g/m
L_)
HPMCASHPMCHPMCPPVP
0
20
40
60
80
100
0 30 60 90 120Time (min)
Dis
solv
ed G
RF
(mg/
L)
HPMCASHPMCHPMCPPVP
0
20
40
60
80
100
0 30 60 90 120Time (min)
Dis
solv
ed D
IP(m
g/L)
HPMCASHPMCHPMCPPVP
Screening study (solvent method)Dissolution test (pH6.8)
HPMCAS solid dispersion improved drug dissolution
GRF crystalNP crystal
DIP crystal
0
100
200
300
400
500
0 30 60 90 120Time (min)
Dis
solv
ed C
MZ
(mg/
L)HPMCASHPMCHPMCPPVP
CBZ crystal
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Screening study (solvent method)Inhibition effect of recrystallization of dissolved NP
(pH6.8), NP:carrier 1:1
0
20
40
60
80
100
0 30 60 90 120 150 180Time (min)
Dis
solv
ed N
P (μ
g/m
L_10
0μg/
mL)
HPMCASHPMCPHPMCPVPNP Crystalline
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Screening study (solvent method)Stability (Storage condition: 50˚C in the closed bottle)
Assay by HPLC(%)
Dissolution of NP at 10min. (pH6.8)
(mg/L_50mg/L)
initial 18 months initial 18 months
NP 100 - 8 8
HPMCAS 95.6 96.9 47 49HPMC 100 98.7 43 46
HPMCP 93.1 93.1 40 45PVP 93.2 88.4 34 12
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Screening study (solvent method)Hygroscopicity
Equi
libriu
m m
oist
ure
cont
ent (
%)
0
5
10
15
20
25
30
0 20 40 60 80 100Relative humidity (%)
PVP
HPMCHPMCP
HPMCAS
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Large scale spray drying Formulation:HPMCAS-LG: Felodipine 3:1 Solvent, Acetone
Preparation solution:Felodipine was dissolved in acetone and the HPMCAS was added slowly and mixed for one hour.
Equipment: GEA Niro 12.5CC pilot plantEquipped with 4 pneumatic hammers, HEPA filters & Cyclone to collect the primary powder fraction. Including the controlled room
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Process parameters
Test Number Trial Temp(0C) Nozzle
Solid content Pressure
Feed Rate
Particle Size LOD Quantity
Bulk density (g/ml)
Inlet Outlet (mm) (%) (bar) (kg/hr) D50 (um) (%) (kg) Lose Tap
1 68 50 0.71 5 55 25 14 3.2 0.50 0.21 0.36
2 64 49 0.71 5 18 15 27 2.7 0.50 0.20 0.26
3 66 49 0.78 10 16 23 49 3.52 0.60 0.19 0.25
4 68 49 0.98 10 13 25 50 2.79 0.65 0.19 0.27
5 49 38 0.98 10 13 25 47 3.43 0.65 0.19 0.27
6 70 41 1.18 10 9 45 71 3.98 0.90 0.20 0.28
7 100 44 1.18 10 60 100 44 3.28 1.00 0.20 0.30
8 60 41 1.18 12.4 12 45 115 4.54 1.20 0.19 0.28
9 65 35 1.18 12.4 32 69 94 5.32 0.80 0.20 0.29
10 101 42 1.18 12.4 68 128 61 3.4 1.30 0.24 0.34
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Post Drying
Before After
Test Number Particle Size LOD Quantity Mesh size Temperature Air flow Time LOD after
D50 (um) (%) (kg) (µm) (°C) (min) (%)
1 14 3.2 0.50 65 50 60 10 0.82
2 27 2.7 0.50 65 50 70 15 0.92
3 49 3.52 0.60 65 50 50 20 0.79
4 50 2.79 0.65 65 50 50 20 0.80
5 47 3.43 0.65
6 71 3.98 0.90 65 50 38 20 1.33
7 44 3.28 1.00 65 50 50 20 0.80
8 115 4.54 1.20 65 50 90 30 0.72
9 94 5.32 0.80 65 50 50 30 1.06
10 61 3.4 1.30 65 50 37 30 1.41
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X-ray diffraction
0 20 40 60 80 100 120
Inte
nsity
(cps
)
2θ (°)
felodipine crystal
No.1 No.2
No.4 No.6 No.10
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14µm
26µm
94-110µm
49-53µm
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Summary
Particle size has a large effect on your release profile and need to take are that when scaling up to production.
With the larger particle size the flow improves therefore can avoid granulation step.
Post drying is essential to remove the residual solvents. Increasing our solid content to 12.4% gave the best results
which results to shorter processing times and good yield.
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0 10 20 30 402θ (°)
Inte
nsity
(c
sp)
Crystalline
HPMC
HPMCAS
HPMCP
PVP
HPMCAS
Screening study (solvent method)XRD solid dispersion (API: carrier = 1:2)
NP
0 10 20 30 402θ (°)
Inte
nsity
(c
ps)
Crystallin
HPMC
HPMCAS
HPMCP
PVP
0 10 20 30 402θ (°)
Crystalline
HPMC
HPMCAS
HPMCP
PVP
DIP
GRF* (GRF:carrier 1:4)
0 10 20 30 402θ (°)
Inte
nsity
(c
ps)
Crystalline
HPMC
HPMC
HPMCP
PVP
Amorphous solid dispersion
CBZ
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0
50
100
150
200
250
Pulp HPMC HPMCAS HPMCP PVPVA
Tg/T
deco
mp. (
C)
TdecompTg
TgN.D.
155
115130
210 200 195
101
230
Operation window for melt extrusionHPMCAS shows the wider operation window among cellulose derivatives
HPMCAS
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DSC and TGA measurement
Glass Transition temperatures were appeared in cellulose derivatives (HPMC & HPMCAS)
Thermal plasticity (HPMC & HPMCAS) Similar thermal decomposition temperature
Thermodynamic properties of HPMCAS
-0.5
-0.4
-0.3
-0.2
-0.1
0
0.1
0 50 100 150 200Temp(ºC)
DSC
(mca
l/s)
PulpHPMCHPMCAS
0
20
40
60
80
100
0 100 200 300 400 500
Temp (ºC)W
eigh
t Los
s (%
)
PulpHPMCHPMCAS
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HME- Feasibility studies
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• Labo Scale– Apparatus: MiniLab (Haarke Thermo)– Sample: 5g (Drug-polymer[1:2] mixture)– Condition: 170°C, 20rpm[screw]– Milled after extrusion
• Formulation:NP/AQOAT (AS-L,M,H) 1/2NP/KollidoneVA64* 1/2 & 1/6
*: Kollidone VA64 (BASF; PVPVA copolymer)
• Evaluation– Drug crystallinity– Improvement of drug dissolution
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Improvement of Drug Dissolution
0
20
40
60
80
100
0 20 40 60 80 100 120Time (min)
Dis
solv
ed N
P
(mg/
L_10
0mg/
L)
NP/AS-LF 1/2NP/AS-MF 1/2NP/AS-HF 1/2NP/Kollidone VA64 1/2NP/Kollidone VA64 1/6NP/KollidoneVA64 1/2(160℃)
Drug crystal (intact)
Improvement (sustained high drug release): HPMCAS > Kollidone VA64
NP Dissolution in pH 6.8
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Design of experiments- optimum process parameters
Temperatures (Degrees)
Torque (%) Speed(rpm) Feeder(kg/hr) Pressure(bar)
Melt Temperature ( Degrees) Initial
Zone 2
Zone 3
Zone 4
Zone 5
Zone 6
Zone 7
Zone 8 Die
1 16 150 0.15 3 130 20 50 90 100 130 130 130 130 130
2 17 200 0.15 3 131 20 50 90 100 130 130 130 130 130
3 18 200 0.15 10 121 20 50 90 100 120 120 120 120 120
4 22 200 0.30 13 122 20 50 90 100 120 120 120 120 120
5 22 200 0.30 17 111 20 60 100 110 110 110 110 110 109
6 24 300 0.50 20 112 20 60 100 110 110 110 110 110 109
7 24 300 0.50 22 102 20 60 100 100 100 100 100 100 100
8 27 300 0.60 28 103 20 60 100 100 100 100 100 100 100
Formulation:Shin-Etsu Aqoat HPMCAS-MG: Ibuprofen 2:1
Pharma 11 Thermo Scientific, Germany)
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Extrudates
Extruded pellets
During processing the measured extruder torque was 25%.
Our general recommendation is to use extrusion temperature for HPMCAS is 150ºC but in the presence of 33% ibuprofen it could be readily processed at 100ºC.
This suggests that ibuprofen acted as a plasticiser and allowed processing at a reduced temperature.
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Injection moulding & Results
Mini Jet (Thermo Scientific, UK)120°C of the injection piston and 30°C of the mould
Pressure: 400 bar over 5 seconds and post pressure: 300 bar 2 sec
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Hotmelt Extrusion (Pure HPMCAS, Haake MiniLab)
grade lot viscosityAS-MF 8053095 cP MeO HPO Ac Suc Succinic acid Acetic acid
Temp. (℃) roter (rpm)2.76 1.3 23.0 7.2 9.3 11.4 0.03 0.04 0.07
160 100 2.66 1.3 22.9 7.1 9.4 11.1 0.44 0.10 0.53200 2.60 1.1 23.1 7.2 9.3 10.8 0.68 0.12 0.80300 2.60 1.1 23.0 7.1 9.4 10.7 0.85 0.14 1.00
180 100 2.62 1.2 23.0 7.3 9.2 10.8 0.72 0.11 0.82200 2.59 1.1 23.0 7.2 9.3 10.8 0.77 0.12 0.89300 2.59 1.1 23.1 7.2 9.3 10.9 0.88 0.12 1.00
200 100 2.50 1.1 23.0 7.2 9.2 10.4 1.19 0.16 1.35200 2.46 1.0 23.0 7.2 9.3 10.5 1.09 0.15 1.23300 2.50 1.2 23.0 7.2 9.1 10.1 1.13 0.16 1.29
Totalacid (%)
before HME
free acid (%)Substituent (%)Loss onDrying
Cleavage of Succinic Groups
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Stability for Melt ExtrusionDiscussion: -Cleavage of Succinoyl Groups → Free acid increase
(dissolution pH shifts to higher)-Color Change (more yellowish)
-Slight Reduction in Molecular weight at 200˚C→Possibility of interaction between API and free acid
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Storage stability (NP solid dispersion)
36
NP content of solid dispersionAssay by
HPLC Storage period (18M)
(%) Initial 40˚C, 75%RH 50˚C, closed bottleNP 100 - -
AQOAT 95.6 98.0 96.9HPMC 100 96.8 98.7
HPMCP 93.1 93.8 93.1PVP 93.2 93.3 88.4
Eudragit L 94.8 96.2 94.8
In most cases, drug content remain the same level. (Stable)
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Storage stability (NP solid dispersion)E
quili
briu
m m
oist
ure
cont
ent (
%)
0
5
10
15
20
25
30
0 20 40 60 80 100Relative humidity (%)
PVP
HPMC
HPMCP
HPMCAS
Equilibrium moisture content (25˚C)
AQOAT is lower hygroscopic. PVP is highly hygroscopic. → absorb moisture →recrystallize
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AQOAT-NP solid dispersion pellet
0
20
40
60
80
100
0 60 120 180 240Time (min)
Diss
olut
ion
amou
nt o
f NP
(μg/
mL
)
CH2Cl2・EthanolMethanol
Aceton
NP only
Core beads : Nonpareil® -101Spray solution :
9% AS-M/NP (2:1) solution**Solvent : CH2Cl2/EtOH,
MeOH, AcetoneLayering amount : 10% NP
rotary fluidized bed granulator
core
Solid dispersion layer
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ConclusionAQOAT could be useful as carrier of solid dispersion.
Benefit:Amorphous SD with small carrier ratioGreat improvement of drug dissolution (enteric) Inhibition of recrystallizationGood stability
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HME Cleaner
How to use the cleaner:
The cleaner consist of Hypromellose and water soluble plasticizer which is commonly used in pharmaceutical applications.
Samples are available in 4kg bags
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Examples of HME Cleaner The cleaner consist of Hypromellose and water soluble plasticizer which is commonly used in pharmaceutical applications.
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42Shah et al. J. Pharm. Sci. 102 (3), 2013
m.p. 272.1ºC
Solubility
Aqueous < 0.1 mg/mL
Organic Solvents (mg/mL)
DMSO > 50
MeOH 4.57
AcCN 1.40
CH2Cl2 1.95
Acetone < 6
Vemurafenib
(For Melanoma)
“Microprecipitated Bulk Powder” (MBP) Method
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43Shah et al. J. Pharm. Sci. 102 (3), 2013
Ionic polymer Crystalline API
Drug + polymer
dissolve in solvent
Cold dilute acid / base
Solvent removal
Aqueous washDrying
Coprecipitation Process for Preparation of MBPVemurafenibHPMCAS, HPMCP, Eudragit L 100-55
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44Shah et al. J. Pharm. Sci. 102 (3), 2013
Dissolution Profiles of Vemurafenib
USP Apparatus 2 (b) with 0.09% HTAB
MBP with HPMCAS
MBP with Eudragit L100-55
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Quality by Design (HPMCAS)
45
Substitution level: Acetyl / SuccinoylMethoxy / Hydroxypropoxy
Viscosity: (Molecular weight)
Impurities: Free acetic acidFree succinic acidResidual salt (sodium acetate)Moisture
Factors that may affect to performance
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46
Acetyl / Succinoyl - Affect to API dissolution.- May affect to stability of API- Subject to hydrolysis- Recommended to set up a range
Methoxy / Hydroxypropoxy- May affect to API dissolution
Viscosity (Molecular weight)- May affect to API dissolution
Factors that may affect to performance
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47
Effect of Succinoyl / Acetyl Groups
*The original solubility of Nifedipine is 12 mg/L
AS-LG AS-MG AS-HG
0
20
40
60
80
100
0 20 40 60 80 100 120Time (min)
Dis
solv
ed N
P (m
g/L_
100m
g/L)
Sample GSample HSample I
0
20
40
60
80
100
0 20 40 60 80 100 120
Time (min)
Dis
solv
ed N
P (m
g/L_
100m
g/L)
Sample FSample ESample D
0
20
40
60
80
100
0 20 40 60 80 100 120
Time (min)
Dis
solv
ed N
P (m
g/L)
Sample CSample BSample A
Sample ID A B C D E F G H ISuccinoyl, % 18.1 15.0 14.0 14.2 11.4 9.9 8.0 7.7 4.1
Acetyl, % 5.7 7.9 8.4 7.5 9.1 10.6 10.7 11.6 13.9
AS-LG AS-MG AS-HG
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48
-Acetic acid / Succinic acid-Sodium acetate-Moisture
- May affect stability of API.- Gradually increases during storage.
(Except sodium acetate)
Shin-Etsu is open to communicate customers to discuss QbD strategy such as Extreme samples, Variability Data, and Custom
Specifications.
Impurities within HPMCAS
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Recent approval of solid dispersion using Shin-Etsu AQOAT (HPMCAS)
Approved on Mft Brand API DiseaseMay, 2011 Vertex INCIVEK Telaprevir Hepatitis CAug, 2011 Roche ZELBORAF Vemuratenib MelanomaJan, 2012 Vertex KALYDECO Ivacaftor Systic FibrosisNov, 2013 Merck NOXAFIL TAB Posaconazole Immune deficiency