Véronique Henner, Dr. Andreas Sauer veronique.henner@se-pfmd.com andreas.sauer@se-pfmd.com

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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