Typical excipients in a tablet formulation. Glidant SiO 2

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1 Development of a lubricant coated binder Dr. Reinhard Vollmer Technical Competence Center JRS Pharma, HQ Holzmühle GERMANY Typical excipients in a tablet formulation Binder Lubricant Disintegrant MCC Na stearylfumarate Na starch glycolate gy Glidant SiO 2 1

2 What happens when we combine these 4 excipients into 1? What happens when we combine these 4 excipients into 1? 1. Microcrystalline cellulose (MCC) 2. Colloidal silicon dioxide (CSD) 3. Sodium starch glycolate (SSG) 4. Sodium stearyl fumarate (SSF) 2

3 What happens when we combine these 4 excipients into 1? Result : An All-Rounder with properties of all 4 single components 3

4 MCC CSD SSF SSG Physical mixture All Rounder 4

5 All Rounder Powder characteristics Parameter All-Rounder Physical Mixture Bulk Density, g/l Angle of Repose, Flow, FloDex, g/sec 0.95 (6 mm) 0.0 (6 mm) Specific Surface Area, m 2 /g

6 Properties of the co-processed material Better flowability Less dust 6

7 Properties of the co-processed material Better flowability Less dust Higher hardness - less ejection forces Hardness 40 % Paracetamol 60 % All-Rounder 3,50 3,00 ile Strength [MPa] Tensi 2,50 2,00 1,50 1,00 0,50 0, Compression Force [kn] All-Rounder Physical mixture 7

8 Ejection 40 % Paracetamol 60 % All-Rounder Eje ection Force [N] Compression Force [kn] All-Rounder Physical mixture Dissolution 40 % Paracetamol 60 % All-Rounder 100 Diss solved Active [%] Time [min] All-Rounder Physical mixture 8

9 Properties of the co-processed material Better flowability Less dust Higher hardness - less ejection forces Modified lubrication properties Mixing time with the All-Rounder Particle Lubricant 9

10 Mixing time with the All-Rounder poor hardness Continuous film around the particle Mixing time with the All-Rounder Particle All-Rounder 10

11 Mixing time with the All-Rounder 40 % Paracetamol 60 % All-Rounder 100 let Hardness in % Tab All-Rounder Blending Time [min] Physical mixture with PRUV with Mgstearat Staying time with the All-Rounder 40 % Paracetamol 60 % All-Rounder let Hardness [%] Tab Staying Time [min] 40 days All-Rounder Physical mixture 11

12 Properties of the co-processed material Better flowability Less dust Higher hardness - less ejection forces Modified lubrication properties Better uniformity in low dosage formulations Low dosage formulations Uniformity with 5% Folic Acid Weight Uniformity [%] Content Uniformity [%] Hardness Uniformity [%] All-Rounder Physical Mixture

13 Low dosage formulations Uniformity with 1% Folic Acid Weight Uniformity [%] Content Uniformity [%] Hardness Uniformity [%] All-Rounder Physical Mixture Low dosage formulations Uniformity with 0.4% Folic Acid Weight Uniformity [%] Content Uniformity [%] Hardness Uniformity [%] All-Rounder Physical Mixture

14 Properties of the co-processed material Better flowability Less dust Higher hardness - less ejection forces Modified lubrication properties Better uniformity in low dosage formulations Sharp embossing / engraving Logo Physical mixture All-Rounder 14

15 Logo Iron oxide tablet t All-Rounder 97.0 % Ferrum salt 3.0 % Stability Conditions : All-Rounder in the original packaging Temperature 40 0 rel. humidity 75 % Loss on drying : Start 5.1 % 3 months 5.0 % 6 months 5.0 % 15

16 Stability All Rounder Placebo Tensile Strength [MPa] 8,00 7,50 7,00 6,50 6,00 5,50 5,00 4,50 4, ,50 3,00 2,50 2,00 1,50 1,00 0,50 0, Compaction force [kn] Start 3 Months 6 Months APIs from different BCS classes BCS Class Characteristics Remarks I II III IV High Solubility High Permeability Low Solubility High Permeability High Solubility Low Permeability Low Solubility Low Permeability Low Formulation Risk In Some Cases Problems with the Disintegration/Dissolution Usually Low Formulation Risk; Disintegration could be critical Critical Dissolution; Risk of Irreproducible Dissolution Results Low Bioavailability 16

17 APIs from different BCS classes BCS Class Characteristics API I II III IV High Solubility High Permeability Low Solubility High Permeability High Solubility Low Permeability Low Solubility Low Permeability Propranolol HCl, Diclofenac Sodium Atenolol Hydrochlorothiazide APIs from different BCS classes CH 3 CH 3 O OH N H H-Cl CH 3 H 3 C NH OH O O NH 2 Propranolol CH 2 COONa Atenolol Cl NH Cl H H N N S O O Cl NH 2 S O O Diclofenac Sodium Hydrochlorothiazide 17

18 BCS Class I CH 3 O OH N CH 3 H-Cl Propranolol Hydrochloride PROPRANOLOL HYDROCHLORIDE Fine, amorphous particles Poor flow Blending problems BCS Class I # Formulation 1 Formulation 2 PROSOLV EASYtab Physical Mixture mg % mg % Propranolol HCl PROSOLV EASYtab Microcrystalline Cellulose Colloidal Silicon Dioxide Sodium Starch Glycolate Sodium Stearyl Fumarate Total

19 8,00 Propranolol Hydrochlorid 550 Propranolol Hydrochlorid 7,00 Formulation 1 with PROSOLV EASYtab Formulation 2 with the Dry Blend 500 6, Tensile Strength S [MPa] 5,00 4,00 3,00 2,00 Compressibility Ejectio on Force [N] Ejection Force Formulation 1 with PROSOLV EASYtab 1, Formulation 2 with the Dry Blend 0, Compression Force [kn] Compression Force [kn] Propranolol Hydrochlorid Propranolol Hydrochlorid Formulation 1 with PROSOLV EASYtab Formulation 2 with the Dry Blend 90 Disintegration Time [sec] Disintegration DissolvedActivee [%] Dissolution Formulation 1 with PROSOLV EASYtab Formulation 2 with the Dry Blend ,00 0,50 1,00 1,50 2,00 2,50 3,00 3,50 4,00 4,50 5,00 Tensile Strength [MPa] Timet [min] BCS Class I Uniformity Relative Standard Deviation Formulation 1 Formulation 2 PROSOLV EASYtab Dry Blend Tablet Hardness Uniformity 2.38 % 3.85 % Tablet Weight Uniformity 016% % 0.54 API Content Uniformity 1.29 % 4.47 % 19

20 H N Cl H NH N 2 S S O O O O Hydrochlorothiazide HYDROCHLOROTHIAZIDE Crystalline Abrasive Low compressibility BCS Class IV # Formulation 1 Formulation 2 PROSOLV EASYtab Dry Blend mg % mg % Hydrochlorothiazide PROSOLV EASYtab Microcrystalline Cellulose Colloidal Silicon Dioxide Sodium Starch Glycolate Sodium Stearyl Fumarate Total

21 8,00 Hydrochlorothiazide Formulation 1 with PROSOLV EASYtab 300 Hydrochlorothiazide 7,00 Formulation 2 with the Dry Blend 250 6,00 Ejection Force Tensile Stren ngth [MPa] 5, ,00 3,00 Ejection Force [N] ,00 1,00 Compressibility 50 Formulation 1 with PROSOLV EASYtab Formulation 2 with the Dry Blend 0, Compression Force [kn] Compression Force[kN] Disintegration Time [sec] Hydrochlororthiazide Formulation 1 with PROSOLV EASYtab Formulation 2 with the Dry Blend Disintegration 0 0,00 1,00 2,00 3,00 4,00 5,00 6,00 7,00 Tensile Strength [MPa Dissolution Test of Hydrochlorothiazide with the Physical Mixture: 6 Randomly Selected Tablets, USP Test 110 Hydrochlorothiazide Active [%] Dissolved Formulation 2 with the Dry Blend Time [min] 21

22 Dissolution Test of Hydrochlorothiazide with PROSOLV EASYtab 6 Randomly Selected Tablets, USP Test 110 Hydrochlorothiazide e Ingredient [%] Dissolved Active Formulation 1 with PROSOLV EASYtab Time [min] Uniformity Relative Standard Deviation Formulation 1 Formulation 2 PROSOLV EASYtab Dry Blend Tablet Hardness Uniformity 1.88 % 4.33 % Tablet Weight Uniformity 0.26 % 0.41 % API Content Uniformity 1.00 % 3.93 % 22

23 Production trials The All-Rounder in a modern high speed tablet press. Production trials Why have we done the trials? Modern rotary presses can produce more than tablets / hour! = theory ( brochure ) In practice the output is much lower. why? 23

24 Limitation of modern rotary presses Active transport Gravity Flowability Different particle shape causes different flow properties physical mixture All-Rounder 24

25 The model substance 40 % Paracetamol 60 % All-Rounder vs 40 % Paracetamol 57.8% microcrystalline cellulose 1.2% silicon dioxide 0.7% sodium starch glycolate 0.3% sodium stearyl fumarate Parameter of the tablets Weight: Diameter: High: 300 mg 10 mm 3,9 mm Machine set up (All-Rounder) Tablets / h Main compression force 10 kn Fillomat Rounds / min 35 Filling way mm 8 25

26 Machine set up ( physical mixture ) Tablets / h Main compression force 10 kn 15 kn Fillomat Rounds / min Filling way mm 8 Only with new machine settings 26

27 Content t Uniformity it (P Paracetamol l) EASYtab physical mixture Assay n = 12 rel. Std. dev. Assay n = 12 rel. Std. dev ,9 % 0,8 % 96,6 % 2,5 % ,8 % 1,9 % 96,5 % 7,3 % ,1 % 2,4 % 93,4 % 6,8 % Consequences Campaign: tablets Speed of the tablet press: EASYtab: phys. mixture: tablets / hour tablets / hour EASYtab: phys. Mixture: / = 10 hours / = 30 hours 27

28 Consequences Campaign: tablets EASYtab: phys. Mixture: / = 10 hours / = 30 hours EASYtab: 10 hours * 270 = phys. Mixture: 30 hours * 270 = in 1 28

29 Many Thanks to : Dr. Edmont Stoyanov Tobias Götz Questions? 29