A li i S di fL HPC d HPMCAS Application Studies of L-HPC and HPMCAS for Pharmaceutical Dosage Forms Udt - Update - Sakaé OBARA Specialty Chemicals Research Center Shin Ets Chemical Co Ltd Shin-Etsu Chemical Co., Ltd. Niigata, JAPAN ExcipientFest Americas 2012, San Juan, PR Shin-Etsu Chemical Co., Ltd. Shin Etsu Chemical Co., Ltd.
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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
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)