Dissolution control of direct compression tablets in different test media using novel pregelatinized starch, Swelstar TM MX-1 ASAHI KASEI CHEMICALS CORPORATION CEOLUS R&D DEPARTMENT 1
CONTENTS General Characteristics of SWELSTAR TM MX-1 Special Properties of SWELSTAR TM MX-1 Application Fields of SWELSTAR TM MX-1 Mechanism of Dissolution Control by SWELSTAR TM MX-1 Conclusions 2
General Characteristics of SWELSTAR TM MX-1 Developed by Asahi Kasei Chemicals and Sanwa Cornstarch. Produced by physical modification of potato starch. Performs as matrix agent to control sustained drug release. Applicable for CR of drugs with various water solubilities. Dissolution controllable tablets in different media. Conformable to USP/NF, EP and JPE [Pregelatinized Starch]. 3
Special Properties of SWELSTAR TM MX-1 Water soluble and insoluble elements - Resistant to alpha-amylase High swelling ability by rapid hydration - Gel matrix structure - Independent of ionic strength in test media Strong gel matrix structure having resistance to erosion - Resistant to digestive tract motions Controllable gel strength with addition of water soluble material - Dissolution control - Zero-order release profile Low reactivity - High storage stability 4
Powder Properties of SWELSTAR TM MX-1 Particle morphology a) Dry state (SEM) b) Wet state (OM *1 ) Typical properties of MX-1 Bulky density [g/cm 3.27 ] Repose angle [ ] 36 * 1 Optical microscope Av. particle diameter [μm] Water holding capacity [%] Swelling volume [cm 3 /g] Water soluble content [%] Viscosity [mpa s] 2% solution at 25 ºC 32 8 9 6-85 7 MX-1 consists of water soluble and insoluble substances. The insoluble part keeps the raw starch-like crystalline structure, contributing to its resistance to alpha-amylase. MX-1 forms gel matrix structure after swelling by rapid hydration. 5
Application Fields of SWELSTAR TM MX-1 Controlled release gel-matrix tablets Dissolution control of direct compression tablets - various drugs with different water solubilities - various media with different ph - different rotation speeds - storage stability of the drug release profile 6
Dissolution Control of Direct Compression Tablets Purpose of this study Generally, dissolution profile of direct compression (DC) tablets is faster than that of wet-granulation (WG) tablets. Therefore, it is not easy to adjust the dissolution profile of DC tablets to that of WG tablets in various test media required by the guideline for the bioequivalence tests of generic drugs. It was investigated whether it is possible to adjust the dissolution profile of DC tablets in different test media by using a small amount of MX-1 to the original dissolution profile of WG tablets. 7
Benefits of DC Method WG method Powder Granulation and drying granule Tableting Tablet DC method Powder Tableting Tablet DC method has no granulation and drying process, therefore it can give an effective cost reduction. 8
Experiment Procedure - Highly Water Soluble Drug - WG method SSA 1 MCC 2 Lactose 3 CS 4 HPC-L 5 7 wt% 1 wt% 15 wt% 5 wt%.75 wt%* (*Of total of above) 1 Sodium salicylic acid, Yoshitomi (Solubility in water: 125 mg/ml) 2 Microcrystalline cellulose, Ceolus PH-11, ASAHI KASEI 3 Pharmatose 2M, DMV-Fonterra 4 Corn starch, ST-C, Nippon Starch Chemical 5 Hydroxypropyl cellulose, Type L Granulation Drying High shear granulator VG-1 (Powrex Corporation), Load: 16g, Binder: 2g (6% HPC-L aq.), Impeller: 28rpm, Cross screw: 3rpm, Granulation time: 3min Fluidized bed granulator MP-1 (Powrex Corporation) Granule 141 μm Tableting Single press (MODEL-1321DW CREEP, AIKOH Engineering) 18 mg, φ8 mm, round-face (Tablet hardness: about 6N) Evaluation Dissolution test Rotating paddle (5, 1 rpm) method with 9 ml medium: Water, Artificial gastric buffer ph 1.2 (1st fluid in JP XIV) and Artificial intestinal buffer ph 6.8 (2nd fluid in JP XIV) 9
Experiment Procedure - Highly Water Soluble Drug - SSA 1 MCC 2 Lactose 3 SiO2 4 DC-1 method 7 wt% 2 wt% 1 wt%.5 wt%* (*Of above total) SSA 1 MCC 2 Lactose 3 MX-1 or HPC-L 5 SiO2 4 DC-2 method 7 wt% 18-2 wt% -7 wt% 3-12 wt%.5 wt%* (*Of above total) 1 Sodium salicylic acid, Yoshitomi 2 Microcrystalline cellulose, Ceolus UF-711, ASAHI KASEI 3 Super-Tab TM, DMV-Fonterra 4 Silica, Aerosil 2, Nippon Aerosil 5 Hydroxypropyl cellulose, Type L Mixing for 3 min in PE bag Tableting Single press (MODEL-1321DW CREEP, AIKOH Engineering) 18 mg, φ8 mm, round-face (Tablet hardness: about 6N) Evaluation Dissolution test Rotating paddle (5, 1 rpm) method with 9 ml medium, Water, Artificial gastric buffer ph 1.2 (1st fluid in JP XIV) and Artificial intestinal buffer ph 6.8 (2nd fluid in JP XIV) 1
Dissolution Profiles from WG Tablets and DC Tablets - Highly Water Soluble Drug - 1 ph Buffer 1.2 直打処方 DC-1 Tablets 1 DC-2 Method Tablets (MX-1) DC-1 Tablets 直打処方 溶出率 8 6 4 2 2 4 6 8 1 12 時間 湿打処方 WG Tablets 溶出率 8 6 4 2 1 2 4 6 8 1 12 時間 [min] DC-2 Tablets (HPC-L) 湿打処方 WG Tablets MX-1 3% MX-1 5% MX-1 6% DC-1 直打処方 Tablets Only 5% MX-1 demonstrates the same 6 sustained release profile of SSA from 4 DC tablets as the WG tablets, however HPC could not sustain release of SSA 2 even at 12%. 溶出率 8 2 4 6 8 1 12 時間 [min] WG Tablets 湿打処方 HPC-L 3% HPC-L 6% HPC-L 9% HPC-L 12% 11
The Influence of Different Test Media - Highly Water Soluble Drug - 1 ph Buffer Buffer ph 1.2 ph Buffer Buffer ph 6.8 1 8 8 6 4 2 DC-1 Tablets WG Tablets DC-2 Tablets (5% MX-1) DC-2 Tablets (12% HPC-L) 6 4 2 DC-1 Tablets WG Tablets DC-2 Tablets (5% MX-1) DC-2 Tablets (12% HPC-L) 2 4 6 8 1 12 2 4 6 8 1 12 Water 1 8 6 4 2 DC-1 Tablets WG Tablets DC-2 Tablets (5% MX-1) DC-2 Tablets (12% HPC-L) MX-1 could adjust the dissolution profile of DC tablets in different test media to that of WG tablets. 2 4 6 8 1 12 12
The Influence of Different Rotating Speeds - Highly Water Soluble Drug - DC-2 Tablets (5% MX-1) 溶出率 [%] 1 8 6 4 2 WG Tablets 1rpm 5rpm ph Buffer 1.2 湿打処方 /1rpm 湿打処方 /5rpm 1 8 6 4 2 1rpm 5rpm 2 4 6 8 1 12 2 4 6 8 1 12 時間 [min] MX-1 shows the same dissolution profile as WG tablets at both conditions of 5 rpm and 1 rpm. 溶出率 [%] 1 8 6 4 2 DC-2 Tablets (12% HPC-L) 1rpm 5rpm 湿打処方 /1rpm 湿打処方 /5rpm HPC-L 12% 5r HPC-L 12% 1 2 4 6 8 1 12 時間 [min] 13
Disintegration of Tablets - Highly Water Soluble Drug - 1 8 6 4 Water DC-1 Tablets WG Tablets DC-2 Tablets (5% MX-1) Disintegration Time [min] 7 25 12 2 DC-2 Tablets (12% HPC-L) 14 2 4 6 8 1 12 MX-1 could sustain release of SSA from DC tablets without delaying the disintegration time compared to WG tablets. 14
Experiment Procedure - Water Insoluble Drug - WG method Etz 1 Lactose 2 HPC-L 3 3 wt% 7 wt% 5 wt%* (*Of total of above) 1 Ethenzamide, Yoshitomi (Solubility in water:.97 mg/ml) 2 Pharmatose 2M, DMV-Fonterra 3 Hydroxypropyl cellulose, Type L Granulation High shear granulator VG-1 (Powrex Corporation), Load: 15g, Water: 14g, Impeller: 28rpm, Cross screw: 3rpm, Granulation time: 3min Drying Fluidized bed granulator MP-1 (Powrex Corporation) Granule Tableting Evaluation COMIL (Powrex Corporation), Screen: 1.14mmφ, Spacer: 25mm, Frequency: 4Hz, - 141μm Single press (MODEL-1321DW CREEP, AIKOH Engineering) 18 mg, φ8 mm, round-face (Tablet hardness: about 6N) -Dissolution test Rotating paddle (5 rpm) method with 9 ml medium, Water, Artificial gastric buffer ph 1.2 (1st fluid in JP XIV), Artificial intestinal buffer ph 6.8 (2nd fluid in JP XIV) and buffer ph 4. 15
Experiment Procedure - Water Insoluble Drug - DC-1 method DC-2 method Etz 1 Lactose 2 MCC 3 3 wt% 5 wt% 2 wt% Etz 1 Lactose 2 MCC 3 MX-1 or HPC-L 4 3 wt% 35-44 wt% 2 wt% 6-15 wt% 1 Ethenzamide, Yoshitomi 2 Super-Tab TM, DMV-Fonterra 3 Microcrystalline cellulose, Ceolus UF-711, ASAHI KASEI 4 Hydroxypropyl cellulose, Type L Mixing for 3 min in PE bag Tableting Single press (MODEL-1321DW CREEP, AIKOH Engineering) 18 mg, φ8 mm, round-face (Tablet hardness: about 6N) Evaluation -Dissolution test Rotating paddle (5 rpm) method with 9 ml medium, Artificial gastric buffer ph 1.2 (1st fluid in JP XIV) 16
Dissolution Profiles from WG Tablets and DC Tablets - Water Insoluble Drug - 1 DC-1 Tablets ph buffer 1.2 1 DC-2 Tablets Method (MX-1) 8 8 6 4 2 WG Tablets 3 6 9 12 15 18 6 4 2 1 3 6 9 12 15 18 DC-2 Tablets (HPC-L) MX 1:6% MX 1:8% Only 8% MX-1 demonstrates the same 6 sustained release profile of Etz from DC 4 tablets as the WG tablets, however HPC could not sustain the release of 2 Etz even at 15%. 8 3 6 9 12 15 18 HPC-L:1% HPC-L:15% 17
The Influence of Different Test Media on WG Tablets - Water Insoluble Drug - 1 8 6 4 2 WG (ph 1.2) WG (ph 6.8) WG (water) 3 6 9 12 15 18 WG Tablets The dissolution profiles of WG tablets in ph buffer 6.8 and water show the biggest difference. Dissolution tests of DC tablets with either 5% MX-1 or 5% HPC were performed in ph buffer 6.8 and water. 18
The Influence of Different Test Media on DC Tablets - Water Insoluble Drug - WG tablet DC tablets with either 5% MX-1 or 5% HPC-L Etz 1 Lactose 2 HPC-L 3 3 wt% 7 wt% 5 wt%* (*Of total of above) Etz 1 Lactose 4 MX-1 or HPC-L 3 3 wt% 7 wt% 5 wt%* (*Of total of above) 1 Ethenzamide, Yoshitomi 2 Pharmatose 2M, DMV-Fonterra 3 Hydroxypropyl cellulose, Type L 4 Super-Tab TM, DMV-Fonterra 1 8 6 4 2 WG Tablets DC Tablets (5% HPC-L) DC Tablets (5% MX-1) WG (ph 6.8) WG (water) 3 6 9 12 15 18 1 8 6 4 2 DC with 5% HPC (ph 6.8) DC with 5% HPC (water) 3 6 9 12 15 18 1 8 6 4 2 DC with 5% MX-1 (ph 6.8) DC with 5% MX-1 (water) 3 6 9 12 15 18 Both WG tablets and DC tablets which contain 5% HPC showed faster dissolution in ph buffer 6.8 than in water. To the contrary, DC tablets which contain MX-1 showed the reverse action. Therefore HPC was used in order to enhance the dissolution in ph buffer 6.8 together with a main matrix agent, MX-1. 19
The Influence of Different Test Media on DC Tablets - Water Insoluble Drug - WG tablet DC tablets with 5% MX-1 and 5% HPC-L Etz 1 Lactose 2 HPC-L 3 3 wt% 7 wt% 5 wt%* (*Of total of above) Etz 1 Lactose 4 MCC 5 MX-1 HPC-L 3 3 wt% 4 wt% 2 wt% 5 wt% 5 wt% 1 Ethenzamide, Yoshitomi 2 Pharmatose 2M, DMV-Fonterra 3 Hydroxypropyl cellulose, Type L 4 Super-Tab TM, DMV-Fonterra 5 Microcrystalline cellulose, Ceolus UF-711, ASAHI KASEI 1 8 ph buffer 6.8 1 8 Water 6 4 WG 6 4 WG 2 DC with 5% MX-1 + 5% HPC-L 3 6 9 12 15 18 2 DC with 5% MX-1 + 5% HPC-L 3 6 9 12 15 18 By using 5% MX-1 and 5% HPC, the dissolution profiles are closer to that of WG tablets, but not the same. It needs to be promoted in the later stage of the dissolution. 2
The Effect of PEG on Drug Release Profile - Water Insoluble Drug - DC tablets with 5% MX-1 and 5% HPC-L and 1% PEG Etz 1 Lactose 2 MCC 3 MX-1 HPC-L 4 PEG 5 3 wt% 3 wt% 2 wt% 5 wt% 5 wt% 1 wt% 1 Ethenzamide, Yoshitomi 2 Super-Tab TM, DMV-Fonterra 3 Microcrystalline cellulose, Ceolus UF-711, ASAHI KASEI 4 Hydroxypropyl cellulose, Type L 5 Polyethylene glycol, Macrogol 6, Sanyo 1 8 Buffer ph buffer ph 6.8 6.8 1 8 Water 6 4 2 5%MX-1+5%HPC 5%MX-1+5%HPC+1%PEG 6 4 2 5%MX-1+5%HPC 5%MX-1+5%HPC+1%PEG 3 6 9 12 15 18 3 6 9 12 15 18 By adding 1% PEG, the dissolution was restrained in the early stage and then it was promoted in the later stage. 21
Experiment Procedure - Water Insoluble Drug - DC-3 method Etz 1 Lactose 2 MCC 3 MX-1 HPC-L 4 PEG 5 3 wt% 3 or 33 wt% 2 wt% 5 wt% 5 wt% 7 or 1 wt% 1 Ethenzamide, Yoshitomi 2 Super-Tab TM, DMV-Fonterra 3 Microcrystalline cellulose, Ceolus UF-711, ASAHI KASEI 4 Hydroxypropyl cellulose, Type L 5 Polyethylene glycol, Macrogol 6, Sanyo Mixing for 3 min in PE bag.5% Mg-St 6 6 Magnesium Stearate, Taihei Chemical Industrial Co. Ltd. Tableting Rotary Press (Clean Press, Kikusui Seisakusho Ltd.), 12punches, 54rpm 18 mg, φ8 mm, round-face Evaluation -Dissolution test Rotating paddle (5 rpm) method with 9 ml media, Water, Artificial gastric buffer ph 1.2 (1st fluid in JP XIV), Artificial intestinal buffer ph 6.8 (2nd fluid in JP XIV) and Buffer ph 4. 22
Dissolution Profiles in Different Media - Water Insoluble Drug - 1 8 6 4 2 1 8 Water WG Tablets DC-1 Tablets DC-3 Tablets (7% PEG) DC-3 Tablets (1% PEG) 3 6 9 12 15 18 1 8 It was possible to adjust the dissolution profile of DC tablets in different test media by using 5% MX-1 in combination with 5% HPC and 7-1% PEG to that of WG tablets. MX-1 acted as a sustained-release matrix and PEG was used to specifically control the dissolution profile. HPC was effective to enhance the dissolution in ph buffer 6.8, in which the WG tablet shows faster dissolution than in the other media. 1 8 6 4 2 Buffer ph Buffer ph 1.2 6 4 2 Buffer ph Buffer ph 6.8 6 4 2 Buffer ph Buffer ph 4. 3 6 9 12 15 18 3 6 9 12 15 18 3 6 9 12 15 18 23
Disintegration of Tablets - Water Insoluble Drug - 1 8 6 4 2 Water 3 6 9 12 15 18 DC-1 Tablets WG Tablets DC-3 Tablets (7% PEG) DC-3 Tablets (1% PEG) Disintegration Time [min] 2 45 32 37 MX-1 could sustain release of Etz from DC tablets without delaying disintegration time compared to WG tablets. 24
Storage Stability of Drug Release under Accelerated Conditions - Water Insoluble Drug - Etz/Lactose/MCC/MX-1/HPC/PEG =3/33/2/5/5/7 Storage for 6 months under the condition of 4 C75%R.H. in sealed glass bottles 1 Water 1 ph Buffer Buffer ph 1.2 ph Buffer Buffer ph 6.8 Buffer ph Buffer ph 4. 4. 1 1 8 8 8 8 溶出率 [%] 6 4 溶出率 [%] 6 4 溶出率 [%] 6 4 溶出率 [%] 6 4 2 2 2 2 3 純水 4 75%RHオープン 6 9 12 15 18 3 6 9 12 15 18 1 時間 [min] 時間 [min] 3 6 9 12 15 18 時間 [min] 3 6 9 12 15 18 時間 [min] 8 WG Tablets-initial 湿打 -initial 直打 DC-3 -initial Tablets (7% 6 PEG)-initial 直打 -2week 直打 -1month 溶出率 [%] DC-3 Tablets (7% PEG)-2 weeks 4 DC-3 Tablets (7% PEG)-1 month 直打 DC-3-3month Tablets (7% 2 PEG)-3 months DC-3 Tablets (7% PEG)-6 months 直打 -6month 3 6 9 12 15 18 時間 [min] The release profiles of Etz from DC-3 tablets with 7% PEG hardly changed under accelerated conditions for 6 months. 25
Storage Stability of Drug Release under Accelerated Conditions - Water Insoluble Drug - Etz/Lactose/MCC/MX-1/HPC/PEG =3/3/2/5/5/1 Storage for 6 months under the condition of 4 C75%R.H. in sealed glass bottles 1 Water 1 ph Buffer Buffer ph 1.2 ph Buffer Buffer ph 6.8 ph Buffer Buffer ph 4. 1 1 8 8 8 8 溶出率 [%] 6 4 溶出率 [%] 6 4 溶出率 [%] 6 4 溶出率 [%] 6 4 2 2 2 2 3 6 9 12 15 18 純水 4 75%RH オープン 3 6 9 12 15 18 時間 [min] 1 時間 [min] 3 6 9 12 15 18 時間 [min] 3 6 9 12 15 18 時間 [min] 湿打 -initial 直打 -initial 直打 -2week 直打 -1month 直打 -3month 直打 -6month 溶出率 [%] 8 WG Tablets-initial DC-3 Tablets (7% PEG)-initial 6 DC-3 Tablets (7% PEG)-2 weeks 4 DC-3 Tablets (7% PEG)-1 month DC-3 Tablets (7% PEG)-3 months 2 DC-3 Tablets (7% PEG)-6 months 3 6 9 12 15 18 時間 [min] The release profiles of Etz from DC-3 tablets with 1% PEG hardly changed under accelerated conditions for 6 months. 26
How could SWELSTAR TM MX-1 Specifically Control the Dissolution Profile? In combination with PEG, MX-1 could restrain the dissolution of the DC tablets in the early stage and then promote dissolution in the later stage. The mechanism of the dissolution control by MX-1 and PEG was investigated. 27
Experiment Procedure - The Effect of PEG - APAP 1 MX-1 or HPMC 2 MCC 3 PEG 4 1 wt% 6 wt% 2-3 wt% -1 wt% 1 Acetaminophen, Yoshitomi (Solubility in water: 15.8 mg/ml) 2 Hydroxypropyl methylcellulose, Viscosity of 2% solution: 1mpa s 3 Microcrystalline cellulose, Ceolus KG-82, ASAHI 4 Polyethylene glycol, Macrogol 6, Sanyo Mixing for 3 min in PE bag Tableting Single press (MODEL-1321DW CREEP, AIKOH Engineering) 18 mg, φ8 mm, round-face, Compression force 6 kn Evaluation -Dissolution test Rotating basket (1 rpm) method with 9 ml medium Artificial intestinal buffer (2nd fluid in JP XIV), ph: 6.8, α-amylase 5 μg/l -Tablet weight & water absorbing capacity (WAC) Tablet being removed during dissolution test WAC= (TW wet TW dry ) / TW dry 1 TW wet : Tablet weight in wet state TW dry : Tablet weight after drying 28
Dissolution Profiles of Matrix Tablets - The Effect of PEG - 1 6% MX-1 6% HPMC 1 % Dissolution 8 Dissolution rate [%] 6 4 2 PEG(%) 5 1 2 4 6 8 1 Time (hr) % Dissolution Dissolution rate [%] 8 6 4 2 PEG(%) 1 2 4 6 8 1 Time (hr) In combination with 1% PEG, MX-1 restrained the dissolution of matrix tablets in the early stage and then promoted dissolution in the later stage, whereas HPMC showed no change of the dissolution with PEG. 29
Swelling and Erosion of Matrix Tablets during Drug Dissolution - The Effect of PEG - Tablet weight Wet weight in wet (mg) state [mg] 35 3 25 2 15 1 5 Tablet weight in wet state swelling MX-1 PEG % MX-1 PEG1% HPMC PEG % HPMC PEG1% erosion 1 2 3 4 5 6 7 8 9 Time(hr) [hr] Water Water absorbing capacity(%) [%] 35 3 25 2 15 1 5 Water absorbing capacity MX-1 PEG % MX-1 PEG1% HPMC PEG % HPMC PEG1% 1 2 3 4 5 6 7 8 9 Time Time(hr) [hr] Both MX-1 and HPMC swelled in the first 2 hours, and then eroded. Tablet weight in wet state showed that MX-1 experienced less erosion than HPMC especially without PEG. Addition of PEG increased water absorbing capacity and accelerated erosion for MX-1 after 5 hours. PEG did not affect swelling or erosion patterns of HPMC. 3
Assumed Mechanism: How could SWELSTAR TM MX-1 Specifically Control the Dissolution Profile with PEG? 6% MX-1 Matrix Tablet 1st stage Hydration of MX-1 particles was promoted, then strong gel layer was formed. Drug diffusion was restrained effectively. 2nd stage Excess water absorption decreases gel strength. Diffusion of drugs and erosion of gel layer were promoted remarkably. Water penetration was promoted by adding PEG Dissolution % Dissolution rate [%] 1 8 6 4 2 1st stage 2nd stage PEG: % PEG: 1 % 2 Time 4 [hr] 6 8 1 Time (hr) 1 6% HPMC Hydration of HPMC particles was not largely affected by promoting water penetration, because hydration rate was very high originally. Dissolution % Dissolution rate [%] 8 6 4 2 PEG: % PEG: 1 % Matrix Tablet 2 4 6 8 1 Time (hr) Time [hr] 31
Assumed Mechanism: How could SWELSTAR TM MX-1 Sustain Release of Drug without Delaying Disintegration Time? 5% MX-1 Gel Layer Water Penetration Tablet Swelling Disintegration It is assumed that tablets containing 5% MX-1 disintegrate into fragments, and each fragment forms gel layer ( ) on its surface, which sustains the release of drug. 32
CONCLUSIONS MX-1 can sustain the release of drugs from DC tablets at low doses without delaying disintegration time, and adjust the dissolution profile to the original dissolution profile of WG tablets in combination with other excipients such as PEG. MX-1 is a sustained-release excipient which is applicable to varying conditions such as drugs with different water solubilities, various media with different ph and different rotation speeds. Tablets containing MX-1 show stable drug release profiles under accelerated conditions. MX-1 can perform as an effective and useful sustained-release excipient to control dissolution profiles of DC tablets. 33
Thank you for your attention! 34