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.