NISSO HPC - dalian-diligence.com

1 NISSO HPC for Pharmaceutical Applications Contents Introduction Features of NISSO HPC Major Application of NISSO HPC NISSO HPC Grades and Availability How to use based on Application and Features of NISSO HPC Powder Characteristics Application to Fluidized Bed Granulation Method Application to High Shear Granulation (Binder Solution Mix Method) Application to High Shear Granulation (Binder Dry Mix Method) Application to Direct Compression Method Application to Hydrophilic Matrix, Sustained Release Formulation Application to Solubility Enhancement of Poorly Soluble Drugs Grades and Specifications Packaging Safety Precautions - 2 - Suitable viscosity (molecular weight) can be chosen depending on application and formulation owing to availability of various grades of polymerization NISSO HPC rarely reacts with other substances owing to its chemically inert nature.

2 NISSO HPC is non-toxic and non-harmful to the human body. NISSO HPC is soluble in both water and major alcohol at room temperature. Binder for Wet Granulation Binder for Direct Compression / Dry Granulation Controlled Release Agent for Hydrophilic Matrix Formulation Agent for Film Coating on tablets Agent for Oral Film Drug Formulation Agent for Solubility Enhancement of Poorly Soluble Drugs NISSO HPC (hydroxypropyl cellulose) is a hydroxypropoxy ether obtained by reacting propylene oxide with cellulose. It is a water-soluble polymer which is solublized by introducing hydroxypropyl groups that hinder the hydrogen bonding of hydroxyl groups of cellulose. Manufacturing of NISSO HPC was started in 1967, and it was listed in the Japanese Pharmacopeia in 1971. Since then, NISSO HPC has become widely used as high performance excipient for pharmaceutical applications.

3 Introduction Features of NISSO HPC Major application of NISSO HPC R=H or [-CH2-CH(CH3)-0]mH n and m represent common integral numbers. - 3 - NISSO HPC Grade and Availability Grade SSL SL L M H Viscosity (mPa*s 2% aqueous solution at 20 C 150-400 1000 4000 Molecular Weight/GPC method - 40,000 - - 100,000 - - 140,000 - - 620,000 - - 910,000 - Particle Size Regular Powder (40mesh Pass) Fine Powder (100mesh Pass) Super Fine Powder (330mesh Pass) How to Use based on Application and Features of NISSO HPC Binder for Wet Granulation (Recommendation : HPC-L, HPC-SL, HPC-SSL) Low viscosity grade of HPC offers excellent granule and tablet properties when used as binder for wet granulation. When lower viscosity grade is selected, faster disintegration of tablet and drug release can be obtained without deterioration of tablet hardness and friability.)

4 Having good wettability, fine powder type is more suitable as a dry-mix binder for high shear mixer granulation method. Binder for Direct Compression / Dry Granulation (Recommendation : HPC-SSL-SFP) Super Fine powder, Special Low Viscosity Grade of NISSO HPC (HPC-SSL-SFP) offers excellent compression formability without hindering disintegration of tablet and drug release at lower usage amounts compared to existing grade of HPC or any other dry binders. Controlled Release Agent for Hydrophilic Matrix, Sustained Release (Recommendation : HPC-M, HPC-H) High viscosity grade of NISSO HPC offers excellent sustained release performance and suitable release profile when it used as controlled release agent for hydrophilic matrix formulation. Film Forming Agent (Recommendation : HPC-L, HPC-SL, HPC-SSL) Lower viscosity grades of NISSO HPC can be used for film forming, and improves flexibility, elongation and adhesion of film coatings.

5 Agent for Solubility Enhancement of Poorly Soluble drugs (Recommendation : HPC-SL, HPC-SSL) Lower viscosity grades of NISSO HPC can be used as inactive carrier of solid dispersion for solubility enhancement of poorly soluble drug. NISSO HPC maintains drug in an amorphous state by breaking crystalline structure thus improving solubility. - 4 - Powder Characteristics (reference value) Particle Size Distribution D10 (mm) D50 (mm) D90 (mm) SSL 30 85 185 SL 65 155 275 L 75 160 355 M 80 185 355 H 85 185 365 FP 35-50 80-110 150-200 SFP 8 20 50 SSL SL L M H Bulk density loose Bulk density tapped Compressibility (%) 32 24 22 16 17 Angle of repose( ) 46 43 45 43 44 Powder Characteristics (Regular Powder) SSL-SFP SL FP L FP M FP H FP Bulk density loose Bulk density tapped Compressibility (%) 46 33 28 23 25 Angle of repose( ) 53 47 42 44 43 Powder Characteristics (Fine Powder, SFP) - 5 - 020406080100120010203040506070 Time (min)Drug Released (%)

6 HPC-SSLHPC-SLHPC-L Evaluation of tablet properties and drug release of Ethenzamide tablet prepared by fluidized bed granulation method using HPC-L, SL and SSL was carried out. Comparison of Tablet Properties In the case of lower viscosity grade HPC, finer granule could be obtained, and disintegration of tablet could be shortened without deterioration of tablet hardness and friability. Tablet Formulation Application to Fluidized Bed Granulation Method Preparation of Tablet Ethenzamide, Lactose and Corn Starch were pre-mixed in PE bag for 3 minutes and added to the granulator (FL-LABO, FREUND Co., Ltd. 500g scales), followed by granulation with spraying 8% aqueous solution at spray speed of 5mL/min and drying. Powder for tablet was prepared by dry-mixing granules of 30 mesh pass and Magnesium Stearate for 30 seconds.

7 Laboratory scale rotary tablet press machine(VELA5, KIKUSUI SEISAKUSHO Ltd.) was used to compress tablet at 10kN of compression force. Tablet weight is 200mg and its diameter is 8mm. Measurement of Tablet Properties Tablet hardness of 10 tablets per lot was measured by Load-cell type tablet tester. Friability and disintegration time were measured according to JP16 method. Release of Ethenzamide was also measured according to JP16 method and concentration of Ethenzamide at each time point was determined by measurement of absorbance at 234nm with UV spectrophotometer. Ingredient wt% Ethenzamide 30 Lactose 49 Corn starch 21 HPC 3 HPC-SSL HPC-SL HPC-L Particle Size (D50) 117 138 176 Hardness (kgf) Friability (%) Disintegration time (min) Comparison of Drug Release The results showed drug release depended on viscosity of HPC.

8 Faster drug release could be obtained as by choosing lower viscosity grade of HPC. - 6 - Evaluation of tablet properties and drug release of Ethenzamide tablet prepared by High Shear Mixer granulation (binder solution mix method) with HPC-L, SL, SSL was carried out. Comparison of Tablet Properties Similar to the results with fluidized bed granulation method, high shear mixer granulation method (binder solution mix method) showed little difference in tablet properties based on different HPC viscosities. However, unlike fluidized bed results there is not a clear difference in disintegration time depending on HPC viscosity. It is thought that penetration of water into the granule takes more time with high shear granule than with fluidized bed granulation since heavy and high density granules tend to be prepared with high shear mixer.

9 Also, a clear difference in the drug release seen in fluidized bed granulation method was not observed with high shear mixer. Tablet Formulation Application to High Shear Mixer Granulation (Binder Solution Mix method) Preparation of Tablet Ethenzamide, Lactose and Corn Starch were pre-mixed in high shear mixer granulator (Type FS-GS5, Pawtec Co., 500g Scale) for one minute. Granulation was operated for 5 minutes with adding 8 % aqueous solution (adding time: 1 minute). The impeller and chopper were operated at constant speeds of 400 rpm and 1500 rpm respectively. The granules was dried at 80 C with airflow of for 20 minutes and milled using grated screen. Powder for tablet was prepared by dry-mixing granules of 30 mesh pass. This was followed by addition of Magnesium Stearate and further dry-mixing for 30 seconds.

10 Laboratory scale rotary tablet press machine (VELA5, KIKUSUI SEISAKUSHO Ltd.) was used to compress tablet at 15kN of compression force. Tablet weight is 200mg and its diameter is 8mm. Measurement of Tablet Properties Tablet hardness of 10 tablets per lot was measured by Load-cell type tablet tester. Friability and disintegration time was measured according to JP16 method. Release of Ethenzamide was also measured according to JP16 method and concentration of Ethenzamide at each time point was determined by measurement of absorbance at 234nm with UV spectrophotometer. (min)Drug Released (%)HPC-SSLHPC-SLHPC-LIngredient wt% Ethenzamide 30 Lactose 49 Corn starch 21 HPC 3 HPC-SSL HPC-SL HPC-L Particle Size (D50) 69 98 91 Hardness (kgf) Friability (%) Disintegration time (min) Comparison of Drug Release - 7 - In the case of high shear mixer granulation method, it is more beneficial to add binder as dry powder than to add binder as solution since preparation of the binder solution is not needed, and granulation is not affected by viscosity of binder solution.