Véronique Henner, Dr. Andreas Sauer [email protected] [email protected]
L-HPC / NBD: Five Reasons to use it!
Content
What is L-HPC? Characteristics of L-HPC Five reasons to use it SmartExTM: Co-processed Excipient by SE
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HPMC/MC HV Metolose®
Tylopur
HPMC/MC LV Pharmacoat®
/ Tylopur
HPMCAS Shin-Etsu AQOAT®
L-HPC
HPMCP
HPMC Metolose® SR
Tylopur SR
Shin-Etsu Product Portfolio
SmartExTM Tylopur Grades produced in Germany
Binder/Disintegrant
ODT
SE Product Portfolio
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What is L-HPC? Structure derived from Cellulose
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CAS 9004-64-2; R = H or CH2CH(CH3)OH
Derivatization of cellulose pulp
Pulp Alkali
cellulose
NaOH Propylene oxide
Reaction
Acid
+ Cellulose OH NaOH
Cellulose O CH CH2
OH
CH3 CH H2C
O
CH3
Precipitation Washing Drying Milling
Manufacturing Process
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What is L-HPC
HPC (Hydroxypropylcellulose) • Water-soluble binder • MS 3.1
L-HPC is Low subsituted Hydroxypropylcellulose • MS 0.2 • Insoluble in Water • Binder & Disintegrant
≠
Anhydroglucose unit
Hydroxypropoxy
Same CAS Number, but different
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Main Features of L-HPC
L-HPC is.. .. insoluble in water (swelling observed) .. a non ionic excipient (disintegrant/binder) .. listed in EP, NF, and JP
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Pharmaceutical Application of L-HPC in Solid Dosage
L-HPC in Granulation
L-HPC in Direct
Compression
L-HPC in Pellet Extrusion
L-HPC in Capsule Filling
Immediate Release Tablets Dispersing Aid Disintegrating Pellets
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Development of L-HPC
Non-ionic disintegrant developed by Shin-Etsu, constant progress
1977 2002 2011 2014
First approval in Japan
NBD (high flowability and compressibility) grades launched
SmartExTM launched (Direct Compression of ODT)
LH-B1 launched (non fibrous grade)
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1977 1986 1990
First approved in Japan
Listed in National Formulary (NF) XVII
Listed in Japanese Pharmacopeia (JP) XI
2016
Listed in European Pharmacopeia (E.P.) 8.7
Regulatory Status of L-HPC
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Grade Identifier
“Micronized”
app. 20 mm
“Fibrous”
app. 55 mm
“Regular”
app. 45 mm
L/D: 3.0
“Non-Fibrous”
app. 55 mm “narrower PSD”
app. 45 mm
L/D: 2.2
LH-11 LH-21 LH-31 LH-B1 NBD-021
LH- NBD-
21 021
Particle size 1: Coarse 2: Medium 3: Micronized B: High bulk density
Substituent level 0: Very High (14%), only NBD 1: High (11%) 2: Low (8%)
11 Major grades mentioned, total of 9 grades with different particle size and HPO content available
0.0
0.4
0.8
1.2
NB シリーズ LH-21 LH-B1 MCC PH- 101
MCC PH- 302
Spe
cific
Sur
face
Are
a
( m 2 /g
)
NBD
Specific Surface Area (BET)
0
4
8
12
16
20
NB-02 L-HPC 従来品 (LH-21)
L-HPC 従来品 (LH-B1)
MCC PH-101 cl-CMC-Na
Ela
stic
rec
over
y (%
)
NBD LH-21 LH-B1 MCC cl-CMC-Na
Elastic Recovery
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Why NBD?
L-HPC is insoluble in water. Swelling tendency of L-HPC quickly disintegrate the tablet. The swelling volume depend on particle size and hydroxypropoxy content.
acryl tube
(26mmf)
probe
(25mmf) Texture
Analyzer
test sample
filter paper
wire mesh
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Characteristic: Swelling
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Characteristic: Swelling
L-HPC doesn‘t has little free water compared to MCC 15
Characteristics: LOD/Water activity
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L-HPC / NBD
Aspirin only L-HPC cl-CMC-Na CMS-Na
cl-PVP CMC-Ca MCC Corn Starch
Aspirin Tablets (50˚C, 3 months), 20% excipient
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Excellent Stability
Excellent Stability
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L-HPC has no peroxide. Residual peroxide may cause interactions with APIs
Excellent Stability
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Tested formulation
20 70 10
Spray dried lactose Excipients API
1 NBD-021 10% (Internal added)
2 NBD-021 10% (External added)
3 cl-PVP 3.5% (External added)+ MCC 6.5%
4 cl-CMC Na 2% (External added) + MCC 8%
5 NBD-021 5% (Internal added) + MCC 5%
Paracetamol (API)
Other excipients
L-HPC® (Internal addition)
Wet granulation
(high shear mixer、fluid-
bed)
↑ Binder solution (HPMC)
Drying Mixing with
lubricant Tableting
↑
L-HPC® (External addition)
Tablet:12mm-d.
500mg, flat
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Good Hardness and Disintegration
1 2 3 4 5
Formulation NBD In NBD ExCl-PVP
+MCC
Cl-CMCNa
+MCC
NBD In
+MCC
Compression force kN 15 10 10 10 10 10
Tablet hardness N 106 59 85 85 111 72
Disintegration time S 48 41 66 41 42 51
Capping (12 tab) 0 0 0 0 0 0
Friability % 0.11 0.12 0.15 0.18 0.15 0.21
Dissolution property Quickest - Latest
Formulation 1 gave hard tablets with quick disintegration and quick dissolution, Formulation 4 gave harder tablets with quick disintegration, however showed the slowest dissolution
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Good Hardness and Disintegration
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Good Hardness and Disintegration Formulation w/w
Acetaminophen 10
Lactose 200M 80
L-HPC or MCC 101 10
MgSt* 1 * 0.5 parts RC, 0.5 parts tablet compression
Roller Compaction (Mini Freund)
Sieving (Quick Mill M-10, 1mm)
Tablet Compression (8mm, round, 200 mg)
• Harder Tablets with NBD-021 and LH-31 compared to MCC • Quickest disintegration wiht NBD-021
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Good Hardness and Disintegration
Filling + Pre-compression Compression Ejection
Stress-concentrated area Residual die-wall pressure
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Anti Capping Effect
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Anti Capping with LH-11
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Anti Capping with LH-11
LH-11: High fiber content
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• L-HPC NBD gives high tablet hardness
• low disintegration time over a wide hardness window
• NBD-021 higher hardness than LH-21 Just use one instead of two excipients
Simplifying Formulation
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Formulation w/w
Acetaminophen 20
Lactose (granulated) 75 or 55
Disintegrant or Binder 5 or 25
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Commercialized Products Product Name
Fosamax 10 mg
Kredex 12,5 mg
Cefpodoxime 100mg
Orelox
Iperten 20 mg
Risperdaloro 0,5 -1 mg
Lamictal
Augmentin 500/62,5 mg
Lanzor 15/30 mg
Plavix 300 mg, 75 mg
Duoplavin 75/75
Ogast 15/30 mg
Zykadia
Sta
bili
ty
Flowability
L-HPC NBD
MCC
Dis
inte
gra
tio
n P
rop
erti
es
Binding Properties
L-HPC NBD
MCC
Binder and super disintegrant combination
Super disintegrants
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Summary
Co-processed excipient by Shin-Etsu, manufactured by Freund corp
Pharmaceutical excipients used DMF #030193 Complies with EP Chapter
„co-processed excipient“ Two grades QD-50/100 ODT by easy DC process
D-Mannitol (JP/USP/EP)
L-HPC (JP/NF/EP)
PVA (JPE/EP)
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SmartExTM
SmartEXTM
Advantages of SmartEX™: Low Hygroscopicity
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Placebo tablets 200 mg, diam. 8mm
QD-50 less impacted by the tablet hardness
QD-50 and QD-100 showed good tablet hardness
Advantages of SmartEX™: Hardness and Disintegration
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Lowest Variation in Disintegration: • QD-50 • QD-100
Lowest Variation in Hardness: • QD-50 • QD-100 • Competitor C
Advantages of SmartEX™: Stability (40°C/75%rh)
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Five Reasons to use L-HPC
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Excellent Stability
Avoids Capping
High Tablet Hardness & Rapid Disintegration
Simplifying Formulation Savings
Listed in NF/JP, and EP
L-HPC / NBD
1
2
3
4
5
L-HPC Application Tool
Total 9 Grades of L-HPC / NBD
2 Grades of SmartExTM
Application tool by SE: Practical guide to select the appropriate L-HPC Grade
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