QbD Approach to Formulation of Hydrophilic Matrix Using Sample Kit of Hypromellose [Metolose SR] DVA Symposium Mexico City Anisul Quadir Ph.D, MBA SE Tylose USA, Inc. (A Shin-Etsu Chemical Group Co.) Totowa, NJ 1
Production of Cellulose Derivatives Pulp (Pure Cellulose) Reagents (CH 3 Cl etc.) NaOH Alkali Cellulose Reactor
Cellulose -CH 3 Methylcellulose -CH 3 -CH-CH-CH 3 OH -CH-CH-CH 3 OH METOLOSE Hypromellose PHARMACOAT Acid Depolymerization -COCHCH 2 COOH -COCH 3 Low-substituted - -COOH Hypromellose Acetate Succinate (HPMCAS) Hydroxypropylcellulose Hypromellose Phthalate HPMCP L-HPC Shin-EtsuAQOAT
Structure of Hypromellose (HPMC) Hypromellose (a.k.a. Hydroxypropyl Methylcellulose) O OR OR O CH2OR O CH2OR O OR OR n R = -H, -CH 3, -CH 2 CH(CH 3 )OH 4
Commercial and Regulatory Status of HPMC - Used in pharmaceuticals, foods, cosmetics, and other industries for long time. - Multiple sources available - Generally Recognized as Safe (GRAS) - Harmonized monograph in USP, PhEur, and JP 5
Characteristics of HPMC - Water Soluble (However, temperature dependent) - Thermal gelation 6
Compendial Specifications of HPMC Substitution Type 2208 2906 2910 Methoxy (%) 19.0 24.0 27.0 30.0 28.0 30.0 Hydroxypropoxy (%) 4.0 12.0 4.0 7.5 7.0 12.0 80 120 % of Labeled Viscosity (< 600 mpa s) Viscosity 75 140 % of Labeled Viscosity ( > = 600 mpa s) 2 % aqueous solution, 20 C ph 5.0 8.0 Loss on Drying NMT 5.0 % Residue on Ignition NMT 1.5 % 7
Substitution Grades of HPMC and MC (Specification Range) Substitution Type (Methylcellulose) 2208 2906 2910 Methoxy (%) 26.0 33.0 19.0 24.0 27.0 30.0 28.0 30.0 Hydroxypropoxy (%) - 4.0 12.0 4.0 7.5 7.0 12.0 Commercial Nomenclature (SE) (Dow) SM 90SH 65SH 60SH A K F E 8
Substitution Grades of HPMC and MC (Typical value) Substitution Type (Methylcellulose) 2208 2906 2910 Methoxy (%) 30 22 29 29 Hydroxypropoxy (%) - 8 5 9 Commercial Nomenclature (SE) (Dow) SM 90SH 65SH 60SH A K F E 9
Substitution Grades of HPMC and MC (Molecular Substitution) Substitution Type (Methylcellulose) 2208 2906 2910 Methoxy (MS) 1.8 1.4 1.8 1.9 Hydroxypropoxy (MS) - 0.20 0.12 0.25 Commercial Nomenclature (SE) (Dow) SM 90SH 65SH 60SH A K F E 10
Glucose ring CH 3 - CH 3 CH(OH)CH 2 - MC (Methylcellulose) HPMC (Hypromellose) 11
Substitution Grades vs Charactristics Substitution Type (Methylcellulose) 2208 2906 2910 SM 90SH 65SH 60SH MeO (%), Typical 30 22 29 29 HPO (%), Typical 0 9 5 9 Thermal Gelation Temperature 55 C 70-85 C 60-75 C 55-75 C MeO = Methoxy HPO = Hydroxypropoxy 12
Thermal Gelation HEAT SM 65SH
Extended Release Tablet Using HPMC Hydrophillic Matirix Tablet API + Metolose Hydration Gel Layer Formation Erosion/Diffusion USP Specification
Substitution Grades vs Charactristics Substitution Type (Methylcellulose) 2208 2906 2910 SM 90SH 65SH 60SH MeO (%), Typical 30 22 29 29 HPO (%), Typical 0 9 5 9 Dissolving Temp. < 20 C < 40 C < 35 C < 40 C Hydration at 37 C Very slow Fast Slow Fast 15
Swelling Properties Apparatus : water Formulation for swelling test : HPMC or MC 100 mg Aluminum oxide 400 mg Detector Tablet Filter Test conditions : Compression 1.0 ton/punch Tablet size 15 mm, flat Purified water at 37 C
Swelling (%) Effect of HPO Content on Swelling 20 SM-4000 (HPO = 0 %) Very Slow Hydration 10 0 0 Time (sec) 100 65SH-4000 (HPO = 5 %) Slow Hydration 60SH-4000 (HPO = 9 %) Fast Hydration 90SH-4000 (HPO = 8 %) Fast Hydration
Matrix Tablet using HPMC Quick Hydration Slow Hydration (Initial Burst) 18
% Release Substitution Grade vs Drug Release 100 SM-4000 Paracetamol :HPMC = 68:32 80 (Disintegrated) MC HPMC 2208 60 40 65SH-4000 60SH-4000 90SH-4000 Stable 20 0 0 2 4 6 8 Time(hr)
Gel Strength Penetration time of a glass rod Glass rod: 15 g, 6 mm 10% conc. 5 cm
Penetrating time (sec) Gel Strength 400-mPa s grades 90SH type 40 40 30 30 20 20 10 10 0 HPO = 60SH 9 % 90SH 8 % 65SH 5 % SM 0 % 0 100 400 4000 mpa s
Viscosity vs Molecular Weight 1000000 Weight-average molecular weight Mw = 33400 log h + 3800 (log h) 3 Weight-Average Molecular Weight 100000 10000 Methylcellulose Hypromellose 2208 Hypromellose 2910 Hypromellose 2906 1 10 100 1000 10000 100000 Ubbelohde Viscosity (mm 2 /s) Viscosity (mpa-s) 22
Viscosity Grade vs Drug Release 100 80 90SH-100SR Dissolved (%) 60 40 20 90SH-4000SR 90SH-100,000SR Theophylline 90SH-SR Mg-stearate Total 90 part 10 part 0.5 part 480 mg / Tab 0 0 2 4 6 8 10 12 Time (hr)
Viscosity is related to: Molecular weight Dissolving rate Hydration Thermal gelation temperature 24
Swelling (%) Effect of Mw and Particle Size on Swelling 20 10 90SH-100000 (Coarse Particle) 90SH-100000SR (Smaller Particle) 90SH-4000 (Lower Viscosity) 0 0 Time (sec) 100
Effect of particle size 120 µm 72 µm 59 µm 52 µm Theophylline 90SH-100,000SR Mg-stearate Total 90 part 10 part 0.6 part 480 mg / Tab
Specifications of Metolose SR 90SH- 100SR 90SH- 4000SR Grade 90SH- 15000SR 90SH- 100000SR Labeled Viscosity 100 mpa s 4000 mpa s 15000 mpa s 100000 mpa s Viscosity spec (mpa s) 80 120 3000 5600 11250 21000 Methoxy 22.0 24.0 % Hydroxypropoxy 8.5 10.5 % ph 5.0 8.0 Loss on Drying NMT 5.0 % Residue on Ignition NMT 1.5 % Particle Size (mm) D 10 D 50 D 80 20 40 50 80 100 160 75000 140000 27
Compendial Specifications of HPMC 28
Commercial Specifications of Metolose SR 29
QbD Support Share information on lot-to-lot variability Sample kit having high/low levels in some factors 30
QbD Sample Kit (Metolose 90SH-4000SR) Sample Code Description MeO % HPO % Viscosity mpa s Particle Size (D 50 ), mm ST Standard 23.2 9.2 3940 69 HS High Substitution 22.8 10.7 4070 63 LS Low Substitution 23.5 8.1 3580 71 HV High Viscosity 23.2 9.5 5320 75 LV Low Viscosity 23.2 9.5 3100 68 CP Coarse Particle 23.2 9.3 3730 83 FP Fine Particle 23.2 9.2 3570 60 31
QbD Kit is Available for all 4 Viscosity Grades. 32
Robustness Study Hydrophillic Drug Metformin HCl 10 mg Lactose 374 HPMC (Metolose 90SH-100000SR) 96 Total 480 mg Single-Punch Tablet Press (Sankyo-Piotech) 10 kn Flat-Faced Tablet, 11 mm-d Dissolution Test: Paddle Method 50 rpm Purified water 900 ml UV Detection 33
% Dissolved Dissolution vs Viscosity 100 80 60 40 20 0 100000LV (Vis=72800) 100000ST (Vis=103000) 100000HV (Vis=130000) 0 2 4 6 8 10 12 Tme (hrs) 34
% Dissolved Dissolution vs Particle Size 100 80 60 40 20 0 100000FP (D50=58.9) 100000ST (D50=63.3) 100000CP (D50=73.4) 0 2 4 6 8 10 12 Time (hrs) 35
% Dissolved Dissolution vs HPO Content 100 80 60 40 20 100000LS (HPO=7.9) 100000ST (HPO=9.5) 100000HS (HPO=10.6) 0 0 2 4 6 8 10 12 Time (hrs) 36
Robustness Study Hydrophobic Drug Dipyridamole 3 mg Lactose 381 HPMC (Metolose SR) 96 Total 480 mg Single-Punch Tablet Press (Sankyo-Piotech) 10 kn Flat-Faced Tablet, 11 mm-d Dissolution Test: Paddle Method 50 rpm Purified water 900 ml UV Detection 37
% Dissolution Dissolution vs Viscosity 100 90 80 70 60 50 40 30 20 10 0 4000 LV (Vis=3040) 4000 ST (Vis=4100) 4000 HV (Vis=5470) 0 2 4 6 8 10 12 14 16 18 Time (Hrs.) 38
% Dissolution % Dissolution % Dissolution % Dissolution Effect of Viscosity Grade 90SH-100 SR 90SH-4000 SR 100 90 80 70 100 LV (Vis=89.4) 100 ST (Vis=98.2) 100 HV (Vis=117) 100 90 80 70 4000 LV (Vis=3040) 4000 ST (Vis=4100) 4000 HV (Vis=5470) 60 60 50 50 40 40 30 30 20 20 10 10 0 0 2 4 6 8 10 12 14 16 18 Time (Hrs.) 0 0 2 4 6 8 10 12 14 16 18 Time (Hrs.) 90SH-15000SR 90SH-100000 SR 100 90 80 70 60 15000 LV (Vis=9600) 15000 ST (Vis=17000) 15000 HV (Vis=24000) 100 90 80 70 60 100000 LV (Vis=72800) 100000 ST (Vis=103000) 100000 HV (Vis=133000) 50 50 40 30 20 10 0 0 2 4 6 8 10 12 14 16 18 Time (Hrs.) 40 30 20 10 0 0 2 4 6 8 10 12 14 16 18 Time (Hrs.) 39
% Dissolution Dissolution vs HPO Content 100 90 80 70 60 50 40 30 20 10 0 4000 LS (HPO=8.1) 4000 St (HPO=9.4) 4000 HS (HPO=10.7) 0 2 4 6 8 10 12 14 16 18 Time (Hrs.) 40
% Dissolution % Dissolution Effect of HPO Content / Viscosity 90SH-100 SR 90SH-4000 SR 100 90 80 70 60 50 40 30 20 10 0 100 LS (HPO=8.1) 100 ST (HPO=9.5) 100 HS (HPO=10.9) 0 2 4 6 8 10 12 14 16 18 100 90 80 70 60 50 40 30 20 10 0 4000 LS (HPO=8.1) 4000 St (HPO=9.4) 4000 HS (HPO=10.7) 0 2 4 6 8 10 12 14 16 18 Time((Hrs.) Time (Hrs.) 41
% Dissolution Dissolution vs Particle Size 100 90 80 70 60 50 40 30 20 10 0 4000 FP (PS=60.2) 4000 ST (PS=67.5) 4000 CP (PS=83.4) 0 2 4 6 8 10 12 14 16 18 Time (Hrs.) 42
Summary Hydrophillic Drug (Mainly by Diffusion) Relatively less affected by properties of HPMC Hydrophobic Drug (Mainly by Erosion) More affected by viscosity and HPO content QbD Sample Kit is useful to test robustness of Hydrophillic Matrix Tablet formulation. 43
L-HPC Low-Substituted Hydroxypropyl Cellulose Understanding the Mechanistic Study of L-HPC as Super Disintegrant
L-HPC is not HPC. L-HPC (Insoluble in water) Molar substitution* = 0.2 HPC (Soluble in water) Molar substitution = 3.5 Dual function excipient of binder and disintegrant. CAS No : 9004-64-2 Water-soluble binder. Glucose unit Hydroxypropoxyl group
Variety of Grades Grade Particle appearance Aspect ratio Mean Particle Size (µm) Bulk density (g/ml) Tap density (g/ml) Angle of repose ( ) Hydroxypropoxy (%) Molecular weight Degree of polymerization Typical application LH-11 Most fibrous 5 55 0.33 0.56 49 11 130,000 730 Direct compression (anti-capping) LH-21 Moderately fibrous Moderately 3.8 45 0.38 LH-22 fibrous/low 3.8 45 0.36 0.63 48 8 135,000 780 hydroxypropoxy LH-31 Micronized 3.6 20 0.28 0.59 49 11 100,000 560 0.63 45 11 120,000 680 Regular grade (drymixing, Wet granulation) Lower hydroxypropoxy Than LH-21 (sometimes better disintegration) Pellet extrusion, layering LH-32 LH-B1 Nomenclature Particle identification Micronized/low hydroxypropoxy Non fibrous 1: Coarse 2: Medium size 3: Micronized B: High bulk density 3.6 20 2.5 55 0.48 0.69 40 LH-21 0.21 0.55 53 Chemical identification (hydroxypropoxy level) 1: High (11 %) 2: Low (8 %) 8 115,000 660 11 140,000 790 Pellet extrusion, layering (sometimes better disintegration than LH-31) Fluidized-bed Granulation, direct compression for highload formulations
Mechanisms of Tablet Disintegration Swelling type Wicking type Fine particles of disintegrant, superior in swelling, faster dissolution. Better wettability, quicker water penetration into core, faster disintegration. L-HPC LH-21,LH-B1 LH-22 Suitable application Wet granulation (internal addition) Direct compression (external addition) Function Faster dissolution Faster disintegration
Benefits of L-HPC Superior in swelling function Dissolution improvement Better compatibility with various APIs Anti-capping
% swelling % swelling ph Dependency of Swelling 180 180 160 140 120 Purified water ph 1.2 ph 6.8 160 140 120 ph 6.8 ph 1.2 100 100 Purified water 80 80 60 60 40 20 0 L-HPC (LH-21) 0 50 100 150 200 Time (sec) 40 20 0 Croscarmellose sodium 0 50 100 150 200 Time (sec) Composition: Excipients:Alumina = 4:1 Tablet size: 500 mg/t, 15 mm-d Compression force: 10 kn
Disintegration time (min) Disintegration time (min) Disintegration time (sec) Tablet Disintegration 25 Vitamin C 1.5 Aspirin 400 Emcompress (Gissinger and Stamm, 1980) 20 15 CMS-Na 1 CMS-Na L-HPC 350 300 250 200 L-HPC cl-pvp 10 5 cl-cmc-na L-HPC CMC-Ca cl-pvp 0.5 cl-pvp cl-cmc-na CMC-Ca 150 100 50 CMS-Na 0 0 1 2 3 4 5 6 7 8 0 0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 0 0 0.5 1 1.5 2 2.5 cl-cmc-na Percentage of Disintegrant Percentage of Disintegrant Percentage of Disintegrant
Stability of Aspirin Tablets (50 C, 3 months) Aspirin only L-HPC cl-cmc-na CMS-Na cl-pvp CMC-Ca MCC Corn Starch Excipient: 20 %
Stability of VC Tablets (50 C, 2 months) Ascorbic acid only L-HPC CMS-Na MCC Corn Starch Excipient: 20 %
Loss on Drying Ascorbic acid 0.3 % L-HPC 2.4 MCC 2.5 CMS-Na 4.0 Corn Starch 12.9
Moisture Content vs. Water Activity 80 Sample ERH Water Activity as Equilibrium Moisture content (%) 70 60 50 40 30 20 10 MCC L-HPC 0 0 5 10 15 Moisture (Loss on Drying %) Journal of the Society of Powder Technology, Japan, Vol.11, p50 (1993).
Shin-Etsu Pharmaceutical Excipients Product Metolose (HPMC, MC) Metolose SR (HPMC) Pharmacoat (HPMC) HPMCP Shin-Etsu AQOAT (HPMCAS) L-HPC HME Cleaner SmartEx TM Function Thickening Agent Sustained-Release Film Coating, Binder Enteric Coating Enteric Coating, Solubility Enhancement Disintegrant, Binder Purge Compound based on HPMC Co-Processed Compound for ODT / IR