LubriTose Mannitol Michael Crowley, Director of R&D, Excipients

LubriTose Mannitol Michael Crowley, Director of R&D, Excipients

Introduction Michael Crowley Director of R&D Excipients 158 St. Highway 320 Norwich, NY 13815 PH 315-802-5970 Michael.Crowley@Kerry.com 2 Taste & Nutrition

3 Taste & Nutrition

Science & Technology Expertise A robust foundation of technical expertise made up of integrated disciplines embedded in science, research and technology. Over 800 R&D Scientists 250+ w/ PhD s & MSc degrees Global infrastructure that is aligned through common information system architecture Expertise across a range of technical disciplines 4 Taste & Nutrition

Excipient Technologies Lactose Flavors Tabletting Systems Film Coatings Glycerides Portfolio Anhydrous Lactose Crystalline Monohydrate Spray Dried Monohydrate Inhalation Lactose Portfolio Flavor Modulator Technology (fmt ) Crystals Liquid & Powder Portfolio Lubricated Compression Aid Fast Disintegrating Orally Dissolving Portfolio (SheffCoat) Immediate Release Moisture Barrier Enteric Natural Portfolio Mono & Diglyceride Acetylated Monoglyceride Polysorbates Original patent for Anhydrous 25 different off-the-shelf grades Custom particle size engineering capabilities Batch to batch consistency Dual manufacturing sites Best in class flavor library with DMF s Bitterness masking of APIs Experience in supplying nutraceutical and pharma customers Co-processed systems All monograph compliant materials Free flowing, highly compressible with low dusting properties Higher efficiency coatings Alternative and cost effective Custom formulation development Matching of existing coating Tablet functionality testing Tablet hardness maintained Low ejection forces Dispersing Agent Animal Rennet Free 5 Taste & Nutrition

Kerry Lactose Over 70 year experience producing lactose Highlights Kerry (Sheffield) brands Anhydrous and crystalline Anhydrous DT brand Anhydrous DTHV brand Three manufacturing facilities Foremost Farms brands Spray dried and crystalline Fast Flo 316 brand Pharmaceutical Film Coatings SheffCoat brand SheffCel brand HPMC 6 Taste & Nutrition

Kerry Co-Processing Technology Technologies Co-spray drying Fluid bed agglomeration Hot melt extrusion Particle coating Functional co-processing philosophy Not just ingredient combination for ease of purchase or blending Manufacturing or process improvement Stability improvements Challenging API s Functional synergies 7 Taste & Nutrition

LubriTose Kerry developed Self Lubricating Excipients- LubriTose Coated with glyceryl monostearate Ejection forces similar as when using magnesium stearate Ease of use (no over blending and less dust) LubriTose Family LubriTose SD LubriTose AN LubriTose MCC LubriTose Mannitol 8 Taste & Nutrition

LubriTose LubriTose SD Spray dried Lactose 96% Glyceryl monostearate 4% LubriTose AN Anhydrous Lactose 96% Glyceryl monostearate 4% LubriTose MCC Microcrystalline cellulose 98% Glyceryl monostearate 2% LubriTose Mannitol Spray dried mannitol 96% Glyceryl monostearate 4% 9 Taste & Nutrition

LubriTose Mannitol Study Objective Objective: To compared LubriTose Mannitol to Spray Dried Mannitol and determine if there are benefits with LubriTose Mannitol Tablet lubrication comparison Compressibility comparison Tablet weight variability testing Tablet stability testing 10 Taste & Nutrition

Acknowledgment Study completed by St. John Fisher College Study lead: Vivek S. Dave, P.D. Assistant Professor (Pharmaceutical Sciences) St. John Fisher College Wegmans School of Pharmacy Rochester, NY 11 Taste & Nutrition

Materials LubriTose Mannitol Physical blends: SD Mannitol (brand 1)/MCC/Magnesium stearate SD Mannitol (brand 2)/MCC/Magnesium stearate NOTE: The LubriTose Mannitol samples were compressed neat, i.e. without adding anything. The other samples, i.e. the spray-dried mannitol could not be compacted successfully in their pure form due to extensive capping and lamination issues. For these materials, binary mixtures (1:1) with Avicel PH102 were prepared and lubricated with Mg-stearate (0.5% w/w, 2 minute blending). These mixtures were then compressed into compacts. 12 Taste & Nutrition

Methods Tablet Ejection Force Comparison Tablet ejection Tablet ejections were not measured during the SJF study. However, Kerry has performed extensive testing on the other LubriTose grades using an instrumented press. We have compared ejection forces for the LubriTose products to physical blends of the corresponding excipients with magnesium stearate. A curve of LubriTose AN is included. This is a simulated worst case scenario as anhydrous lactose would stick easily without proper lubrication. We would expect similar results when using LubriTose Mannitol. 13 Taste & Nutrition

Methods Compression Evaluations Tablet manufacture The tablets (compacts) of the samples were prepared on an instrumented, 10- station, single-layer, rotary tablet press (Model: Piccola B-506, SMI Inc., Lebanon, NJ) using 10mm, standard-concave, B tooling (SMI Inc., Lebanon, NJ). The target compact weight was set at 500 mg. The compacts were prepared at a constant tableting speed of 20RPM. The compacts were prepared at different compression forces ranging from 5-25KN, in 5 KN increments. Tablet compression The compacts were prepared at different compression forces ranging from 5-25KN, in 5 KN increments. The breaking force (diametrical crushing strength) of the prepared compacts was tested using the method specified in the USP38 NF33, general chapter <1217> on tablet breaking force. Briefly, 10 randomly selected tablets from each batch were tested using an automatic hardness tester (Model: VK200, Varian, Inc., Cary, NC). The compact breaking force is reported in Kp units. 14 Taste & Nutrition

Methods Weight and Stability Tablet weight evaluation The weight variation of the prepared compacts was evaluated using the method specified in the USP 38 NF 33, general chapter <905> on the uniformity of dosage units. Tablets (n=10) were randomly selected from each batch, and individually weighted on an electronic balance, and the weight recorded. Stability studies All samples (neat powders and the prepared compacts) were subjected to stability testing for a period of one month. The standard stability conditions, i.e. 25 C/60%RH, and 40 C/75% RH were used to assess the influence of temperature and humidity on the samples. The powder samples, and the prepared compacts were placed in open, 6 inch plastic weighing boats (for maximum exposure) in the stability chambers (Model: Forma TM 3911, Thermo Scientific, Rochester, NY). The powder and the compact samples were pulled out on day 10, day 20, and day 30). These samples were evaluated using the methods above, and compared to the day 0 samples. 15 Taste & Nutrition

Powder SEMs LubriTose Mannitol SD Mannitol 200x 1000x 5000x 16 Taste & Nutrition

Tablet SEMs 17 Taste & Nutrition

Tablet SEMs LubriTose Mannitol SD Mannitol 200x 1000x 5000x 18 Taste & Nutrition

Ejection Force (lbs) LubriTose Mannitol Lubrication Evaluation 21 Ejection force - LubriTose AN vs Lactose/Magnesium Stearate 19 17 15 13 11 9 7 5 600 800 1000 1200 1400 1600 Compression Force (lbs) Lubritose AN DT 1% mag stear. Note: 1% Mg. Stearate not typical but used to provide excellent lubrication for comparative purposes 19 Taste & Nutrition

Lubritose Mannitol Compression Evaluation 350 Compression Comparison Compression Force vs Breaking Force 300 250 200 150 100 50 0 0 5 10 15 20 25 Mannitol 1 + Avicel Mannitol 2 + Avicel 20 Taste & Nutrition

Lubritose Mannitol Compression Evaluation 350 Compression Comparison Compression Force vs Breaking Force 300 250 200 150 100 50 0 0 5 10 15 20 25 Lubritose Mannitol Mannitol 1 + Avicel Mannitol 2 + Avicel 21 Taste & Nutrition

Tablet Weight Uniformity Lubritose Mannitol SD Mannitol: Avicel PH102 (1:1) SD mannitol 2: Avicel PH102 (1:1) Condition Compression force (KN) 10 15 20 25 Day 0 501.8 ± 1.32 499.8 ± 1.32 502.6 ± 1.26 502.9 ± 1.60 25 C/60% RH Day 10 502.2 ± 0.63 501.0 ± 1.63 502.4 ± 1.07 502.2 ± 1.03 Day 20 502.0 ± 1.25 500.4 ± 1.43 502.1 ± 1.91 501.7 ± 0.82 40 C/75% RH Day 10 502.4 ± 0.84 501.1 ± 0.88 502.3 ± 0.82 501.9 ± 0.99 Day 20 500.7 ± 2.06 500.7 ± 0.95 501.9 ± 0.88 502.2 ± 1.23 Condition Compression force (KN) 10 15 20 25 Day 0 505.8 ± 2.44 504.3 ± 2.31 502.1 ± 3.31 500.2 ± 2.62 25 C/60% RH Day 10 505.7 ± 3.20 506.7 ± 2.45 501.1 ± 3.45 503.5 ± 2.32 Day 20 506.5 ± 2.99 506.9 ± 2.18 501.1 ± 3.03 502.8 ± 1.55 40 C/75% RH Day 10 506.4 ± 2.80 506.6 ± 3.66 503.3 ± 2.36 501.5 ± 2.22 Day 20 504.4 ± 4.06 504.8 ± 2.94 502.6 ± 2.27 499.2 ± 4.73 Condition Compression force (KN) 10 15 20 25 Day 0 499.2 ± 4.69 501.0 ± 2.21 503.1 ± 4.31 504.6 ± 2.80 25 C/60% RH Day 10 500.0 ± 5.40 503.6 ± 2.37 506.6 ± 2.32 509.2 ± 2.62 Day 20 502.1 ± 4.70 502.9 ± 2.38 505.4 ± 3.06 512.3 ± 2.83 40 C/75% RH Day 10 500.1 ± 4.53 503.4 ± 2.67 505.3 ± 2.21 509.6 ± 2.76 Day 20 498.4 ± 4.17 501.0 ± 2.36 503.4 ± 3.57 507.5 ± 5.32 22 Taste & Nutrition

Tablet Stability SD Mannitol 1 23 Taste & Nutrition

Tablet Stability SD Mannitol 2 24 Taste & Nutrition

Tablet Stability LubriTose Mannitol 25 Taste & Nutrition

LubriTose Mannitol Study Objective - Recap Tablet lubrication comparison Compressibility comparison Tablet weight variability testing Tablet stability testing 26 Taste & Nutrition

Study Conclusions - Lubrication No tablet sticking was observed across all compression forces Low ejection forces across all compression forces Similar to physical blend with magnesium stearate at 1% 27 Taste & Nutrition

Study Conclusions Compression Comparison Able to achieved tablet breaking strength of 300kN Tablet capping was observed with SD Mannitol alone Required addition of MCC to SD Mannitol in order to eliminate capping and achieve breaking strength of 300kN Tablets were less porous than those with SD Mannitol 28 Taste & Nutrition

Study Conclusions Tablet Weight Variability Tablet weight variability was low across all compression forces tested (10kN -25kN) LubriTose Mannitol variability was ~+/- 1 mg for 500mg tablets SD Mannitol was ~ +/- 3 mg, with a high of 5.4 mg 29 Taste & Nutrition

Study Conclusions Stability Testing Tablets were produced and stored under accelerated stability conditions Breaking strength of tablets was measured after storage (0, 10, and 20 days) With LubriTose Mannitol, breaking strength dropped from ~300kN to ~250kN With SD Mannitol/MCC, strength dropped dramatically, from ~300kN to ~75kN 30 Taste & Nutrition

Notes and Next Steps Notes: Samples available from at least three commercial lots Fully commercialized process and DMF available Product currently used in market Next Steps: Perform studies of LubriTose Mannitol with some model APIs Evaluate LubriTose Mannitol at various use levels Thank you for your attention! 31 Taste & Nutrition