DVA Symposium Mexico City Anisul Quadir Ph.D, MBA SE Tylose USA, Inc. (A Shin-Etsu Chemical Group Co.) Totowa, NJ

Transcription

1 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

2 Production of Cellulose Derivatives Pulp (Pure Cellulose) Reagents (CH 3 Cl etc.) NaOH Alkali Cellulose Reactor

3 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

4 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

5 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

6 Characteristics of HPMC - Water Soluble (However, temperature dependent) - Thermal gelation 6

7 Compendial Specifications of HPMC Substitution Type Methoxy (%) Hydroxypropoxy (%) % of Labeled Viscosity (< 600 mpa s) Viscosity % of Labeled Viscosity ( > = 600 mpa s) 2 % aqueous solution, 20 C ph Loss on Drying NMT 5.0 % Residue on Ignition NMT 1.5 % 7

8 Substitution Grades of HPMC and MC (Specification Range) Substitution Type (Methylcellulose) Methoxy (%) Hydroxypropoxy (%) Commercial Nomenclature (SE) (Dow) SM 90SH 65SH 60SH A K F E 8

9 Substitution Grades of HPMC and MC (Typical value) Substitution Type (Methylcellulose) Methoxy (%) Hydroxypropoxy (%) Commercial Nomenclature (SE) (Dow) SM 90SH 65SH 60SH A K F E 9

10 Substitution Grades of HPMC and MC (Molecular Substitution) Substitution Type (Methylcellulose) Methoxy (MS) Hydroxypropoxy (MS) Commercial Nomenclature (SE) (Dow) SM 90SH 65SH 60SH A K F E 10

11 Glucose ring CH 3 - CH 3 CH(OH)CH 2 - MC (Methylcellulose) HPMC (Hypromellose) 11

12 Substitution Grades vs Charactristics Substitution Type (Methylcellulose) SM 90SH 65SH 60SH MeO (%), Typical HPO (%), Typical Thermal Gelation Temperature 55 C C C C MeO = Methoxy HPO = Hydroxypropoxy 12

13 Thermal Gelation HEAT SM 65SH

14 Extended Release Tablet Using HPMC Hydrophillic Matirix Tablet API + Metolose Hydration Gel Layer Formation Erosion/Diffusion USP Specification

15 Substitution Grades vs Charactristics Substitution Type (Methylcellulose) SM 90SH 65SH 60SH MeO (%), Typical HPO (%), Typical Dissolving Temp. < 20 C < 40 C < 35 C < 40 C Hydration at 37 C Very slow Fast Slow Fast 15

16 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

17 Swelling (%) Effect of HPO Content on Swelling 20 SM-4000 (HPO = 0 %) Very Slow Hydration Time (sec) SH-4000 (HPO = 5 %) Slow Hydration 60SH-4000 (HPO = 9 %) Fast Hydration 90SH-4000 (HPO = 8 %) Fast Hydration

18 Matrix Tablet using HPMC Quick Hydration Slow Hydration (Initial Burst) 18

19 % Release Substitution Grade vs Drug Release 100 SM-4000 Paracetamol :HPMC = 68:32 80 (Disintegrated) MC HPMC SH SH SH-4000 Stable Time(hr)

20 Gel Strength Penetration time of a glass rod Glass rod: 15 g, 6 mm 10% conc. 5 cm

21 Penetrating time (sec) Gel Strength 400-mPa s grades 90SH type HPO = 60SH 9 % 90SH 8 % 65SH 5 % SM 0 % mpa s

22 Viscosity vs Molecular Weight Weight-average molecular weight Mw = log h (log h) 3 Weight-Average Molecular Weight Methylcellulose Hypromellose 2208 Hypromellose 2910 Hypromellose Ubbelohde Viscosity (mm 2 /s) Viscosity (mpa-s) 22

23 Viscosity Grade vs Drug Release SH-100SR Dissolved (%) SH-4000SR 90SH-100,000SR Theophylline 90SH-SR Mg-stearate Total 90 part 10 part 0.5 part 480 mg / Tab Time (hr)

24 Viscosity is related to: Molecular weight Dissolving rate Hydration Thermal gelation temperature 24

25 Swelling (%) Effect of Mw and Particle Size on Swelling SH (Coarse Particle) 90SH SR (Smaller Particle) 90SH-4000 (Lower Viscosity) 0 0 Time (sec) 100

26 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

27 Specifications of Metolose SR 90SH- 100SR 90SH- 4000SR Grade 90SH SR 90SH SR Labeled Viscosity 100 mpa s 4000 mpa s mpa s mpa s Viscosity spec (mpa s) Methoxy % Hydroxypropoxy % ph Loss on Drying NMT 5.0 % Residue on Ignition NMT 1.5 % Particle Size (mm) D 10 D 50 D

28 Compendial Specifications of HPMC 28

29 Commercial Specifications of Metolose SR 29

30 QbD Support Share information on lot-to-lot variability Sample kit having high/low levels in some factors 30

31 QbD Sample Kit (Metolose 90SH-4000SR) Sample Code Description MeO % HPO % Viscosity mpa s Particle Size (D 50 ), mm ST Standard HS High Substitution LS Low Substitution HV High Viscosity LV Low Viscosity CP Coarse Particle FP Fine Particle

32 QbD Kit is Available for all 4 Viscosity Grades. 32

33 Robustness Study Hydrophillic Drug Metformin HCl 10 mg Lactose 374 HPMC (Metolose 90SH 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 33

34 % Dissolved Dissolution vs Viscosity LV (Vis=72800) ST (Vis=103000) HV (Vis=130000) Tme (hrs) 34

35 % Dissolved Dissolution vs Particle Size FP (D50=58.9) ST (D50=63.3) CP (D50=73.4) Time (hrs) 35

36 % Dissolved Dissolution vs HPO Content LS (HPO=7.9) ST (HPO=9.5) HS (HPO=10.6) Time (hrs) 36

37 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

38 % Dissolution Dissolution vs Viscosity LV (Vis=3040) 4000 ST (Vis=4100) 4000 HV (Vis=5470) Time (Hrs.) 38

39 % Dissolution % Dissolution % Dissolution % Dissolution Effect of Viscosity Grade 90SH-100 SR 90SH-4000 SR LV (Vis=89.4) 100 ST (Vis=98.2) 100 HV (Vis=117) LV (Vis=3040) 4000 ST (Vis=4100) 4000 HV (Vis=5470) Time (Hrs.) Time (Hrs.) 90SH-15000SR 90SH SR LV (Vis=9600) ST (Vis=17000) HV (Vis=24000) LV (Vis=72800) ST (Vis=103000) HV (Vis=133000) Time (Hrs.) Time (Hrs.) 39

40 % Dissolution Dissolution vs HPO Content LS (HPO=8.1) 4000 St (HPO=9.4) 4000 HS (HPO=10.7) Time (Hrs.) 40

41 % Dissolution % Dissolution Effect of HPO Content / Viscosity 90SH-100 SR 90SH-4000 SR LS (HPO=8.1) 100 ST (HPO=9.5) 100 HS (HPO=10.9) LS (HPO=8.1) 4000 St (HPO=9.4) 4000 HS (HPO=10.7) Time((Hrs.) Time (Hrs.) 41

42 % Dissolution Dissolution vs Particle Size FP (PS=60.2) 4000 ST (PS=67.5) 4000 CP (PS=83.4) Time (Hrs.) 42

43 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

44 L-HPC Low-Substituted Hydroxypropyl Cellulose Understanding the Mechanistic Study of L-HPC as Super Disintegrant

45 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 : Water-soluble binder. Glucose unit Hydroxypropoxyl group

46 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 , Direct compression (anti-capping) LH-21 Moderately fibrous Moderately LH-22 fibrous/low , hydroxypropoxy LH-31 Micronized , , 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 LH Chemical identification (hydroxypropoxy level) 1: High (11 %) 2: Low (8 %) 8 115, , Pellet extrusion, layering (sometimes better disintegration than LH-31) Fluidized-bed Granulation, direct compression for highload formulations

47 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

48 Benefits of L-HPC Superior in swelling function Dissolution improvement Better compatibility with various APIs Anti-capping

49 % swelling % swelling ph Dependency of Swelling Purified water ph 1.2 ph ph 6.8 ph Purified water L-HPC (LH-21) Time (sec) Croscarmellose sodium Time (sec) Composition: Excipients:Alumina = 4:1 Tablet size: 500 mg/t, 15 mm-d Compression force: 10 kn

50 Disintegration time (min) Disintegration time (min) Disintegration time (sec) Tablet Disintegration 25 Vitamin C 1.5 Aspirin 400 Emcompress (Gissinger and Stamm, 1980) CMS-Na 1 CMS-Na L-HPC L-HPC cl-pvp 10 5 cl-cmc-na L-HPC CMC-Ca cl-pvp 0.5 cl-pvp cl-cmc-na CMC-Ca CMS-Na cl-cmc-na Percentage of Disintegrant Percentage of Disintegrant Percentage of Disintegrant

51 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 %

52 Stability of VC Tablets (50 C, 2 months) Ascorbic acid only L-HPC CMS-Na MCC Corn Starch Excipient: 20 %

53 Loss on Drying Ascorbic acid 0.3 % L-HPC 2.4 MCC 2.5 CMS-Na 4.0 Corn Starch 12.9

54 Moisture Content vs. Water Activity 80 Sample ERH Water Activity as Equilibrium Moisture content (%) MCC L-HPC Moisture (Loss on Drying %) Journal of the Society of Powder Technology, Japan, Vol.11, p50 (1993).

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56 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