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A li i S di f L HPC d HPMCASApplication Studies of L-HPC and HPMCAS for Pharmaceutical Dosage Forms
U d t- Update -
Sakaé OBARA
Specialty Chemicals Research Center
Shin Ets Chemical Co LtdShin-Etsu Chemical Co., Ltd.
Niigata, JAPAN
ExcipientFest Americas 2012, San Juan, PR
Shin-Etsu Chemical Co., Ltd.Shin Etsu Chemical Co., Ltd.
L-HPC
1) Application to a Proton-Pump Inhibitor Formulation
2) Application to Orally-Disintegrating Tablets
HPMCAS
3) Effect of Succinoyl/Acetyl Substituion on Drug Dissolution from Solid Dispersion Prepared by Melt-Extrusion
Low-Substituted H d l C ll lHydroxypropyl Cellulose
L-HPC
Functions of L-HPC
• Disintegrant• Disintegrant
• Dry Binder
• Anti-Capping Agent
• Others
CH2OROR CH2OROR
OO
OO
2
ORORO
O
OO
2
OROR
R = HCH2CH(OH)CH3
CH2OR ORnCH2OR ORn
Manufacturing Process of L-HPC
NaOH Propylene oxide
Pulp Alkali cellulose Reaction
PrecipitationWashingDrying
Milling ProductMilling Product
L-HPC vs HPC
HPC (Soluble in water)L-HPC (Insoluble in water) HPC (Soluble in water)HPC (Soluble in water)L-HPC (Insoluble in water)L-HPC (Insoluble in water) HPC (Soluble in water)
Molar substitution = 3.5Molar substitution* = 0.2
( ) HPC (Soluble in water)
Molar substitution = 3.5
HPC (Soluble in water)
Molar substitution = 3.5Molar substitution* = 0.2
( )
Molar substitution* = 0.2
( )
CAS No : 9004-64-2
Glucose unitHydroxypropoxyl groupGlucose unitHydroxypropoxyl groupGlucose unitHydroxypropoxyl groupGlucose unitHydroxypropoxyl group
Grades of L-HPC
LH-11 LH-21 LH-31 LH-B1LH 11 LH 21 LH 31 LH B1
“Micronized”app. 20 m
L/D:3.6
“Fibrous”app. 50 m
L/D:5.0
“Regular”app. 40 m
L/D:3.8
“Non-Fibrous”app. 50 m
L/D:2.5L/D:2.5
Best for Best forAnti-Capping Pellet Extrusion
Development History
LH-11LH-11
LH-B11977
LH-212002
1980’s2011
LH-31NBDGradesLH-31 Grades
Variety of Grades
GradeParticle
appearanceDescription
Meanparticle
size (mm)
Bulkdensity(g/mL)
Tapdensity(g/mL)
Aspectratio
Angle ofrepose (°)
Hydroxy-propoxy
content (%)
Averagemolecular
weightTypical application
Di t i ( tiLH-11 Most fibrous 50 0.34 0.57 5.0 49 11 130,000
Direct compression (anti-capping)
LH-21 Moderately fibrous 40 0.40 0.65 3.8 45 11 120,000Regular grade (drymixing, wet granulation)
LH-22Moderately fibrous
/ lowhydroxypropoxyl
40 0.37 0.63 3.8 48 8 135,000Lower hydroxypropoxythan LH-21 (sometimesbetter disintegration)
LH-31 Micronized 20 0.30 0.59 3.6 49 11 100,000 Pellet extrusion, LayeringLH 31 , , y g
LH-32Micronized/ lowhydroxypropoxyl
20 0.21 0.49 3.6 53 8 115,000Pellet extrusion, layering(sometimes betterdisintegration than LH-31)
Fl id b d l ti
Particle identification
Chemical identification(Substituent level) 1 Hi h (11%)
NomenclatureLH- 2 1
LH-B1 Non fibrous 50 0.50 0.70 2.5 40 11 140,000Fluid-bed granulation,direct compression forhigh-load formulations
Particle identification1: Coarse2: Medium3: MicronizedB: High bulk density
1: High (11%)2: Low (8%)
Application to a
Proton-Pump Inhibitor
F l tiFormulation
(Drug-Layered Beads)(Drug-Layered Beads)
Lansoprazole (proton-pump inhibitor)
- Unstable under acidic conditions (Best stability at pH 9)
- Enteric coating is necessary.
- Interactive to excipients
- Stabilizer is necessary (CaCO3 was found to be the best)Stabilizer is necessary (CaCO3 was found to be the best).
Tabata et al Drug Dev Ind Pham 20 1661 (1994)Tabata et al., Drug Dev. Ind. Pham. 20, 1661 (1994)
Tabata et al., Drug Dev. Ind. Pham. 20, 1661 (1994)
Shimizu et al., Chem. Pharm. Bull., 51, 942-947 (2003)
LansoprazoleAPI LayerIntermediate Layer
HPMC LansoprazoleMgCO3
L-HPC (LH-32) Sucrose
HPMCL-HPC (LH-32)Talc
Sucrose HPC
Core(Sugar sphere)(Sugar sphere)
Acrylic polymers and other ingredients
Enteric LayerAcrylic polymers and other ingredients
Based on article by Shimizu et al., Chem. Pharm. Bull., 51, 942-947 (2003)
Tabata et al., Drug Dev. Ind. Pham. 20, 1661 (1994)
Benefits of L-HPC (LH-32)
in the Lansoprazole-Layered Beads
- Reduces friability, without delaying disintegration.
Mi i l I i i h API- Minimal Interaction with API.
Application of
L-HPC - NBD Grade - to
Orally Disintegrating Tablets
L-HPC NBD-GradesConventional grade
NBD-022 NBD-021 NBD-020 LH-21Hydroxypropoxy (%) 8 11 14 11D50 (m) 45 45 45 45
New grade
D90 (m) 100 100 100 135D90/D50 2.2 2.2 2.2 3.0Bulk density (g/mL) 0.32 0.32 0.32 0.39Angle of repose (°) 43 43 43 50
F t Q i k lli St d dHigher binding
St d d
The data is typical value and not specification
Feature Quick swelling Standardg gcapability
Standard
Typical applicationFor Orally
Disintegrating Tablets(ODT)
For DirectCompression (DC)
For Wet Granulation(WG)
The data is typical value and not specification.
Conventional L-HPC (LH-21)NBD GradeNBD Grade
NBD Grades: Compared to the Regular Grades
Flowability : Non Fibrous = Better
Compressibility: Better
Disintegration: Sameg
Wicking Test
LH-21
Super Disintegrant B
Super Disintegrant A
NBD-021
NBD-020
LH-22
0 10 20 30 40
NBD-022
Wicking Time (min)
10
12
14
e (m
in)
LH
Flat-faced Tablet 150 mg/T
Compression Pressure 70MPa
P ifi d W t + Pi t
2
4
6
8
Wic
king
Tim
e
NBD
Purified Water + Pigment
0
2
6 8 10 12 14 16
Hydroxypropoxy Content (%)
W
Suspension Viscosity1000
y (m
Pa-
s)
100
1000ty
(m
Pa-
s)
LH
100
ensi
on V
isco
sit
NBD
LH
10
100
ensi
on V
isco
sit
NBD
10
0 1 2 3 4 5 6
Aspect Ratio (L/D)
Susp
e
1
0 2 4 6 8 10 12 14 16
Hydroxypropoxy (%)
Susp
e
400
600
sity
(m
Pa-
s)
(10% L-HPC suspended in Water.)
Viscosity ∝ Mouth feel
0
200
L L L L N N Npens
ion
Vis
co Viscosity ∝ Mouth feel
(Shimizu et al. Chem. Pharm. Bull. , 2003 )
LH-11
LH-21
LH-B1
LH-22
NBD-022
NBD-021
NBD-020
Susp
Advantages of NBD-022Advantages of NBD-022
● Faster disintegration● Good flowability● Good mouth feelingGood mouth feeling● Good API dissolution● Excellent stability
→ Good For Orally Disintegrating Tablets (ODT)
Mannitol Tablets (DC Method)
Ingredient Weight Ratio
Mannitol (Granulated) 85
L-HPC (NBD-022, or LH-21) 15
Mg stearate 1
Tablet Weight 250 mg
Diameter 8 mm
VERGO® Rotary Tableting Machine (Kikusui Japan)VERGO® Rotary Tableting Machine (Kikusui, Japan)
Mannitol Tablets (DC Method)
20
30
on
Tim
e
60
70
(N)
NBD 022
10
20
Dis
inte
gra
tio
(se
c)
NBD-022
LH-21
30
40
50
Ha
rdn
es
s (
LH-21
NBD-022
0
0 20 40 60
T bl t H d (N)
US
P D
80e
0
10
20
Ta
ble
t
without L-HPC
Tablet Hardness (N)
40
60
gra
tio
n T
ime
c)
LH-21
0 5 10 15
Compression Force (kN)
0
20
40
Ora
l Dis
inte
g(s
e
NBD-022
0
0 20 40 60
Tablet hardness (N)
O
Wet Granulation by SprayingL-HPC Suspensionp
SpraySpray DryingDryingSpraySpray DryingDrying Main IngredientDryingy g
SuspendedSuspendedin waterin water
Dryingy g
SuspendedSuspendedin waterin water
Main Ingredient Powder
DD--MannitolMannitolLL--HPCHPC DD--MannitolMannitolLL--HPCHPC
6% L-HPC suspended i t
Equipment: Multiplex MP-01 (Powrex, Japan)Inlet Temperature :60ºCOutlet Temperature: 27-28ºCInlet Air Flow:0 45-0 6m3/min
in water
Inlet Air Flow:0.45 0.6m /minSpray Rate:12 g/minAtomizing Pressure: 150kPaPost Drying: Untill 45ºC-outlet
Tablets from Wet Granulation by SprayingL-HPC Suspension
(Mannitol / L HPC / Mg stearate = 100 / 6 /0 5)(Mannitol / L-HPC / Mg stearate = 100 / 6 /0.5)
100
120
N)
30
ec
)
40
60
80
et
ha
rdn
es
s (
N
20
rati
on
tim
e (
se
NBD-022
NBD-021
NBD-020
0
20
40
0 10 1
Ta
ble
0
10
Dis
inte
gr
L-HPC 5%系
0 5 10 15
Compression force (kN)
0
0 50 100
Tablet hardness (N)
Hypromellose Acetate Succinate NFHypromellose Acetate Succinate NF
H d l th l ll lHydroxypropylmethylcellulose Acetate Succinate JPE
HPMCAS
Shin-Etsu AQOAT®
HPMCAS
Cellulose, 2-hydroxypropyl methyl ether, acetate, hydrogen butanedioate
OR CH2OR
CAS registry number 71138-97-1
OR
O
OR O
O
O
CH2OR OR n
R = -H -COCH3
-CH3 - COCH2CH2COOHCH CH(CH )OH-CH2CH(CH3)OH
Structure
HPMC HPMCP HPMCAS
: Methyl
: Succinoyl
: Acetyl
yHydroxypropyl
: Phthalyl
Commercial APIs using HPMCAS
ATP sodium Fluoxetine HCl
Bisacodyl
Cefaclor
Ivacaftor
Kallidinogenase
Cefalexin
Diclofenac sodium
Nicardipine HCl
OmeprazoleDiclofenac sodium
Diltiazem HCl
D i HCl
Omeprazole
Pancreatin
S l lf idiDocaparmine HCl
Duloxetin HCl
Salazosulfapyridine
Telaprevir
Efonidipine HCl Vemurafenib
Compendial Status of HPMCASCompendial Status of HPMCAS
•Hypromellose Acetate Succinate NF
•Hydroxypropylmethylcellulose Acetate Succinate JPE
→ Hypromellose Acetate Succinate JPyp
(In Processing)
Effect of Succinoyl and Acetyl Substitutions in y y
HPMCAS on Dissolution Profile of Nifedipine
Solid-Dispersion Prepared by Melt ExtrusionSolid-Dispersion Prepared by Melt Extrusion
Preparation of HPMCAS Samples (Various Succinoyl/Acetyl Content)
CharacterizationChamical Analysis (NF-Monograph)Tg (DSC)Tg (DSC)Surface Tension of solution in pH 6.8 Phosphate Buffer by Ring MethodSolubility Parameter () calculated by Fedor’s method
Nifedipine – HPMCAS ( 1 : 2 ) Melt-Extrusion
C ill Rh t (C il h® T iki J )Capillary Rheometer (Capilograph®, Toyoseiki, Japan)
170-180ºC, 50 mm/min, 1 mm-d
Dissolution Test / pH 6.8 (100 rpm)
Characteristics of Prepared HPMCAS Samples
A B C D E F G H I
Viscosity mPa-s 3.15 3.00 3.10 3.14 2.74 3.01 3.12 2.83 2.92
AS-L AS-M AS-H
Sample ID
Grade
Methoxy % 22.3 22.5 22.6 22.7 23.1 23.1 23.5 23.6 23.8
Hydroxypropoxy % 6.7 7.2 7.0 6.9 7.2 7.1 7.2 7.4 7.2
Succinoyl % 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
Tg / DSC ºC 121 119 121 121 121 121 122 118 119
δ_Fedor 22.88 22.57 22.49 22.75 22.47 22.21 22.36 22.06 21.81
δ Fedor* 0 03 0 34 0 42 0 16 0 45 0 70 0 55 0 86 1 10δ_Fedor* 0.03 0.34 0.42 0.16 0.45 0.70 0.55 0.86 1.10
Surface Tension dyne/cm2 48.2 44.6 44.2 45.2 43.7 40.7 40.4 40.2 -
* Nifedipine = 22.91
Dissolution Profiles of Nifedipine
AS-L AS-M AS-H
100100)100
60
80
100
(mg
/L_1
00m
g/L
)
Sample G
Sample H
S l I
60
80
100
(mg
/L_
10
0m
g/L
)
S l F
60
80
d N
P (
mg
/L)
0
20
40
Dis
solv
ed N
P ( Sample I
0
20
40
Dis
so
lve
d N
P Sample F
Sample E
Sample D
0
20
40
Dis
so
lve
d
Sample CSample BSample A
0
0 20 40 60 80 100 120
Time (min)
0 20 40 60 80 100 120
Time (min)
0 20 40 60 80 100 120
Time (min)
*The original solubility of Nifedipine is 12 mg/L
Inhibition of Recrystallization vsSolubility Parameter and Surface Tension
40
n
40
L)
Solubility Parameter and Surface Tension
0
20
P a
t 3
0-1
0m
in/L
)
20
30
-10
min
(m
g/L
-20
0
ss
olv
ed
NP
(mg
-20
0
so
lve
d N
P a
t 3
-40
-0.25 0.25 0.75 1.25
Δδ_Fedor
Di
-40
35 40 45 50
Surface tension (dyne/cm2)
Dis
s
•Substitution level of succinoyl and acetyl groups in HPMCAS influenced the dissolution of Nifedipine.
Th ti f b tit ti t•There was an optimum range of substitution to achieve a good dissolution and maintaining super-saturation.
•Surface tension and solubility parameter were correlated to the substitution level and they may be
l d di l irelated to dissolution.