NISSO HPC for Pharmaceutical Applications

Transcription

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 Introduction 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 Since then, NISSO HPC has become widely used as high performance excipient for pharmaceutical applications. R=H or [-CH2-CH(CH3)-0]mH n and m represent common integral numbers. Features of NISSO HPC 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. 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. Major application of NISSO HPC 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 - 2 -

3 NISSO HPC Grade and Availability Grade SSL SL L M H Viscosity (mpa*s) 2% aqueous solution at Molecular Weight/GPC method - 40, , , , ,000 - Regular Powder (40mesh Pass) Particle Size 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. 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. 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 D 10 (mm) D 50 (mm) D 90 (mm) SSL SL L M H FP SFP Powder Characteristics (Regular Powder) SSL SL L M H Bulk density loose Bulk density tapped Compressibility (%) Angle of repose( ) Powder Characteristics (Fine Powder, SFP) SSL-SFP SL FP L FP M FP H FP Bulk density loose Bulk density tapped Compressibility (%) Angle of repose( )

5 Drug Released (%) Application to Fluidized Bed Granulation Method 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. Tablet Formulation Ingredient wt% Ethenzamide 30 Lactose 49 Corn starch 21 HPC 3 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. 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. Comparison of Tablet Properties HPC-SSL HPC-SL HPC-L Particle Size (D 50 ) Hardness (kgf) Friability (%) Disintegration time (min) 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. Comparison of Drug Release HPC-SSL HPC-SL HPC-L The results showed drug release depended on viscosity of HPC. Faster drug release could be obtained as by choosing lower viscosity grade of HPC Time (min) - 5 -

6 Drug Released (%) Application to High Shear Mixer Granulation (Binder Solution Mix method) 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. Tablet Formulation Ingredient wt% Ethenzamide 30 Lactose 49 Corn starch 21 HPC 3 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 with airflow of 0.4m 3 /min for 20 minutes and milled using 0.8mm 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. 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. Comparison of Tablet Properties HPC-SSL HPC-SL HPC-L Particle Size (D 50 ) Hardness (kgf) Friability (%) Disintegration time (min) Comparison of Drug Release HPC-SSL 40.0 HPC-SL HPC-L Time (min) 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. Also, a clear difference in the drug release seen in fluidized bed granulation method was not observed with high shear mixer

7 Application to High Shear Granulation (Binder Dry Mix Method) 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. In this study, Comparative evaluation of particle size distribution and properties of tablet prepared by high shear mixer granulation (binder dry mix method) using HPC-L Regular Powder and HPC-L Fine Powder as binder was carried out. Tablet Formulation Ingredient wt% Acetaminophen 30 Lactose 49 Corn starch 21 HPC 3 Preparation of Tablet Preparation Acetaminophen, Lactose and Corn Starch were pre-mixed in high shear mixer granulator (Type FS- GS-5, Fukae Pawtec Co., 500g Scale) for one minute. Granulation was operated for 3 minutes with adding distilled water (dropping 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 with airflow of 0.4m3/min for 20 minutes and milled using 0.8mm 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. 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. Comparison of Granulated powder and Tablet Properties HPC Grade liquid of granulation Particle Size(%) 500μ on μ μ μ μ μ μ μ 75μ pass Bulk density HPC-L Regular Powder HPC-L Fine Powder (g) (%) loose tapped Angle of repose ( ) Hardness (kgf) Friability (%) Disintegration time (min) The results showed generation of coarse particles could be suppressed more effectively by using HPC-L Fine Powder than HPC-L Regular Powder. Harder tablet hardness can be obtained by HPC-L Fine Powder than Regular Powder while tablet hardness increased in proportion to solution added for granulation in both case

8 Hardness (kgf) Application to Direct Compression Method Direct compression method has advantages in terms of process time and production cost over wet granulation method. In addition, it has merits such as applicable to water-sensitive drugs. High Performance Dry Binder HPC-SSL-SFP HPC-SSL-SFP was developed as a high performance dry binder which can provide both extremely higher compression formability and faster disintegration of tablet and drug release at low usage amount. 1.Evaluation by Single Punch Tablet Press Machine Comparative Evaluation of compression formability for Erythritol, which is a well-known poorly compressible excipient, was carried out by direct compression method using single punch tablet press machine. Tablet Formulation Ingredient wt% Erythritol HPC-SSL-SFP Other binders* Crospovidone Silica * Other binders HPC-SSL HPC-SL-FP HPC-L-FP Sucrose Stearate Preparation of Tablet / Measurement of Tablet Properties Powder for tablet was prepared by dry-mixing of materials without Sucrose Stearate in screw vial for 3 minutes. This was followed by addition of Sucrose Stearate and further dry-mixing for 30seconds. Single punch tablet press machine (Tomyx Press, Sansho Industry Co., Ltd.) was used to compress tablet at 10kN of compression force. Tablet weight and diameter were 200mg and 8mm respectively.tablet hardness of 10 tablets per lot was measured by Load-cell type tablet tester. Comparison of Tablet press result Addition of Binder (%) HPC-SSL-SFP HPC-SSL HPC-SL-FP HPC-L-FP The results showed HPC-SSL-SFP could provide more excellent compression formability than the other grades of HPC at lower usage amounts. Additionally, capping was observed in the case of the other grades of HPC added 3% and 5%. However, it was not observed in the case of HPC-SSL-SFP

9 Drug Released (%) 2. Comparison of Tablet Properties and drug release with various binders Evaluation of Tablet Properties and drug release of Acetaminophen tablet prepared by Direct compression method with HPC-SSL-SFP and various dry Binders was carried out. Tablet Formulation Ingredient wt% Acetaminophen Lactose Corn starch HPC-SSL-SFP *other binders HPC-SL-FP MCC PH-101 PVP-VA L-HPC Other binders* Silica Magnesium Stearate Preparation of Tablet Powder for tablet was prepared by dry-mixing of materials except Magnesium Stearate in PE bag for 3 minutes. This was followed by addition of Magnesium Stearate and further dry-mixing for 30 seconds. Laboratory scale rotary tablet press machine (VELA5, KIKUSUI SEISAKUSHO Ltd.) was used to compress tablet at 10kN of compression force. Tablet weight and diameter were 200mg and 8mm respectively. 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 JP method 16edition. Release rate of Acetaminophen was also measured according to JP method 16 edition and concentration of Acetaminophen at each time point was determined by measurement of absorbance at 243nm with UV spectrophotometer. Comparison of Tablet Properties Hardness Friability Disintegration time HPC-SSL-SFP 5% HPC-SSL-SFP 3% HPC-SL-FP 15% MCC PH % PVP-VA 15% L-HPC 15% HPC-SSL-SFP 5% HPC-SSL-SFP 3% HPC-SL-FP 15% MCC PH % PVP-VA 15% L-HPC 15% HPC-SSL-SFP 5% HPC-SSL-SFP 3% HPC-SL-FP 15% MCC PH % PVP-VA 15% L-HPC 15% Hardness (kgf) The results showed HPC-SSL-SFP could provide harder tablet hardness and less friability with much lower usage amount than the other dry binders, while also having fast disintegration time. Comparison of Drug Release Friability (%) Disintegration Time (min) HPC-SSL-SFP 3% HPC-SSL-SFP 5% HPC-SL-FP 15% MCC PH % PVP-VA 15% L-HPC 15% Time (min) Drug release rate of tablet containing 3% HPC-SSL-SFP was very close to the release rate of tablet using L-HPC which is disintegrator. Additionally, drug release rate of tablet using HPC-SSL-SFP was faster than MCC. This result is showing MCC may impact drug release due to its insoluble properties. In the case of HPC-SSL-SFP, faster drug release can be obtained since it is water-soluble and hydration and diffusion is faster when usage amount is low

10 Application to Hydrophilic Matrix, Sustained Release Formulation Hydrophilic matrix, sustained release is a formulation utilizing hydrophilic polymer as controlled release material as the material has a swelling and hydro-gelating nature in water. Release rate of drug is controlled by the amount of hydrophilic polymer, and it can be prepared by ordinary tablet preparation methods such as wet granulation, dry granulation and direct compression. Also, manufacturing process is more simple than sustained release coating. Therefore, this formulation is widely used in the world. Mechanism Tablet surface wets, and hydrophilic polymer begins hydrate, forming a gel layer. Drug near surface of the tablet is released. Gel Layer Water permeates into the tablet, increasing the thickness of the gel layer; soluble drugs diffuse through the gel layer. Outer Polymer layer becomes fully hydrated, eventually dissolving into the gastric fluids. Water continues to permeate toward the tablet core. Drug is released primarily by diffusion through the gel layer. Poorly soluble drug is released with disintegration. Evaluation of NISSO HPC for Hydrophilic Matrix, Sustained Release Formulation NISSO HPC is thought as an effective controlled release material. It is a hydrophilic polymer which swells and becomes a state of hydro-gel in water, which then releases drug slowly with dissolution and diffusion. Also, it is thought NISSO HPC rarely interacts in acid, alkali and other electrolytes since it is nonionic. In this study, comparison of tablet properties and drug release for high viscosity grade of HPC and HPMC was carried out both by direct compression and wet granulation methods using theophylline as model drug. Tablet Formulation Ingredient wt% Theophylline 50 Controlled Release Materials (water soluble polymer,hpc or HPMC) 30 Microcrystalline Cellulose 19 Silica 0.5 Magnesium Stearate 0.5 Controlled Release Materials Viscosity (mpa*s) Particle Size (D 50 ) HPC-M-FP HPC-H-FP HPMC HPMC * 2% aqueous solution at 20ºC

11 Drug Released (%) Drug Released (%) Preparation of Tablet 1. Direct Compression Method Powder for tablet was prepared by dry-mixing of materials except Magnesium Stearate in PE bag for 3 minutes. This was followed by addition of Magnesium Stearate and further dry-mixing for 30 seconds. Laboratory scale rotary tablet press machine was used to compress tablet at 10kN of compression force. Tablet weight was 200mg and its diameter was 8mm. 2. High Shear Granulation Method High Shear Granulation was carried out in high shear mixer granulator (FS-GS-5, FUKAE PAWTEC Co., 500g Scale). All powder except Silica and Magnesium Stearate were added to the granulator and dry mixing for 1 minute. Granulation was operated for 4 minutes with pouring 30g of distilled water. The impeller and chopper were operated at constant speeds of 400 rpm and 1500 rpm respectively. The granules were pre-dried and milled using 3mm grated screen followed by drying surface of granule at 52 C for 3min, and dried with fluidized bed system (FL-LABO, FREUND Co., Ltd.) at 80 C followed by milled using 1 mm grated screen. Powder for tablet was prepared by dry-mixing granules of 30 mesh pass and silica in PE bag for 3 minutes. This was followed by addition of Magnesium Stearate and further dry-mixing for 30 seconds. Tablet was prepared at 15kN of compression force by the same tablet machine as DC method. Tablet weight was 200mg and its diameter was 8mm. Measurement of Drug Release Release of theophylline was measured according to JP method (paddle method, Solvent: 900ml of deionized water, Paddle rotation speed: 100rpm) and concentration of theophylline at each time point was determined by measurement of absorbance at 271nm with UV spectrophotometer. Comparison of Drug Release Direct Compression High Shear Granulation HPC-M-FP HPMC 4000 HPC-H-FP HPMC HPMC 4000 HPC-H-FP HPMC Time (hours) Time (hours) In comparison of drug release from tablet prepared by direct compression method, the results showed drug release from tablet prepared with HPC-M-FP, the lowest viscosity, was faster than the other polymers used in this study. On the other hand, HPC-H-FP sustained drug release more than HPMC 4000, which is equivalent viscosity to HPC-H-FP, and showed equivalent release control performance to HPMC while its viscosity was much lower. In comparison of drug release from tablet prepared by high shear mixer granulation method, HPC-H-FP also sustained drug release more than HPMC 4000, and showed equivalent release control performance to HPMC while its viscosity was much lower

12 Material for Solubility Enhancement of Poorly Soluble These days, most new development drugs are poorly soluble, and solubility enhancement of such poorly soluble drugs is frequently required at a stage of formulation. Solubilization by surfactant, micronization by milling, or solid dispersion are examples of methods of solubility enhancement. Solid dispersion is a condition of drug in a state of fine crystal or amorphous dispersing into inactive carriers. As inactive carriers, water soluble polymers are commonly used. Evaluation of NISSO HPC for Solid dispersion NISSO HPC is thought as an effective inactive carrier for solid dispersion since it is a hydrophilic polymer and chemically inert. In this study, comparison of solubility for physical mixture and solid dispersion by hot melt mixing using Carbamazepine (CBZ, BCS Class Ⅱ), which is poorly-soluble drug, using low viscosity grade of HPC (HPC-SL, HPC-SSL) as inactive carrier polymer was carried out. Preparation of sample Physical Mixture (PM) : Prepared CBZ and HPC at the ratio of 10:90, 12.5:87.5, 25:75, 50:50 and mixed by tubular mixer for 30 minutes. Hot Melt Mixing (HMM):Mixed PM by Brabender hot melt mixer at 150, 150rpm for 10 minutes. Test method of thermal analysis Thermal analysis was carried out by Differential Scanning Calorimetry under the condition of heating rate of 10 /min and the cooling rate of 50 /min. Test method of drug release Measurement of drug release was carried out with gelatin capsule filled up with 250mg of sample according to US Pharmacopeia (Solvent: ph6.8 phosphate buffer solution, Temperature: 37.5, Paddle rotation speed: 50rpm) Comparison of DSC Measurement Physical Mixture (PM) Hot Melt Mixing (HMM) Endothermic peak from the crystal of CBZ was not observed in HMM while it was done in PM. This result is indicating that formation of solid dispersion which CBZ turned into the state of amorphous by HMM

13 Drug Released (%) Drug Released (%) Comparison of Drug Release Time (hours) CBZ:HPC-SL=10:90 PM CBZ:HPC-SL=10:90 HMM CBZ:HPC-SSL=10:90 PM CBZ:HPC-SSL=10:90 HMM Time (hours) CBZ:HPC-SL=25:75 PM CBZ:HPC-SL=25:75 HMM CBZ:HPC-SSL=25:75 PM CBZ:HPC-SSL=25:75 HMM In HMM of mixture ratio of both 10:90 and 25:75, it was observed that solubility was enhanced much more than the physical mixture. It is thought that the drug converted into an amorphous state by HMM. The results indicated that lower viscosity grades of HPC could be used as inactive carriers of solid dispersion for solubility enhancement of poorly soluble drugs

14 Specifications JP Test items Unit Specifications Grade SSL SL L M H (at 20,2% solution) mpa s ,000-4,000 Description Identification(1)~(3) ph Clarity of solution Chlorides % white to yellowish-white powder comformed 5.0~7.5 comformed not more than Sulfates % not more than Heavy metals ppm not more than 20 Arsenic ppm not more than 2 Loss on drying % Residue on ignition % Hydroxypropoxy groups % USP Fine powder:100mesh 99% pass SFP:330mesh 99% pass not more than 5.0 not more than ~77.5 Test items Unit Specifications Grade SSL SL L M H (at 20,2% solution) mpa s ,000-4,000 Appearance Identification ph Loss on drying % white to yellowish-white powder comformed 5.0~8.0 not more than 5.0 Residue on ignition % not more than 0.2 Lead % not more than Heavy metals % not more than Assay for Hydroxypropoxy groups % not more than 80.5 EP Test items Unit Specifications Grade SSL SL L M H (at 20,2% solution) mpa s ,000-4,000 Characters Identification(A.~F.) Appearance of solution ph Silica % white to yellowish-white powder comformed comformed 5.0~7.5 not more than 0.6 Chlorides % not more than 0.5 Heavy metals ppm not more than 20 Loss on drying % not more than 7.0 Sulphated ash % not more than 1.6 Hydroxypropoxy groups % 53.4~77.5 Packaging 10kg Carton Box Double Layer PE Bag 1kg Carton Box Double Layer PE Bag 500g Carton Box Double Layer PE Bag (SFP grade only)

15 Safety Precautions Hazardous Identification See English version of MSDS First Aid Measures Please see English version of MSDS Fire Fighting Measures See English version of MSDS Accidental Release Measures Sweep up, place in containers and hold for waste disposal. Stability, reactivity Flash point :Not applicable Powder explosiveness :65g/m 3 (regular powder), 50g/m 3 (Fine powder, SFP) (lower limit) Stability and reactivity :HPC is chemical stable, but it must be kept away from strong oxidixing agents. The data set out in this catalog is not a guarantee of performance or quality. Note that the contents of the catalog may be changed without prior notice. Before using this product, be sure to carry out tests and checks, and confirm that the product is suitable and safe for your intended application

16 NIPPON SODA CO., LTD. Head Office U.S/Canada Europe HP Pharma-Chemicals Business Group Shin-Ohtemachi Bldg., 2-1, 2-Chome, Ohtemachi Chiyoda-ku, Tokyo TEL: FAX: Nisso America Inc. Wall Street Plaza 88 Pine street,14 th Floor New york, NY10005 TEL: FAX: Nisso Chemical Europe, GmbH Berliner Allee 42, Duesseldorf, Germany TEL:+49-(0) FAX:+49-(0) NISSO HPC technical data For Pharmaceutical Applications version.1.0 April 1, 2013 Copyright 2013 Nippon Soda Co., Ltd.