LubriTose™ Mannitol -...

LubriTose™ Mannitol Michael Crowley,

Director of R&D, Excipients

2 | Taste & Nutrition

Introduction

• Michael Crowley • Director of R&D Excipients

158 St. Highway 320

Norwich, NY 13815 PH – 315-802-5970 [email protected]


Science & Technology Expertise 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

A robust foundation of technical expertise made up of integrated disciplines embedded in science, research and technology.


Excipient Technologies

• Portfolio • Lubricated Compression

Aid

• Fast Disintegrating

• Orally Dissolving

• Co-processed systems

• All monograph compliant

materials

• Free flowing, highly

compressible with low dusting

properties

Tabletting

Systems

• Portfolio (SheffCoat) • Immediate Release

• Moisture Barrier

• Enteric

• Natural

• Higher efficiency coatings

• Alternative and cost effective

• Custom formulation

development

• Matching of existing coating

• Tablet functionality testing

Film Coatings

• Portfolio • Anhydrous Lactose

• Crystalline Monohydrate

• Spray Dried Monohydrate

• Inhalation Lactose

• Original patent for Anhydrous

• 25 different off-the-shelf

grades

• Custom particle size

engineering capabilities

• Batch to batch consistency

• Dual manufacturing sites

• Animal Rennet Free

Lactose

• Portfolio • Mono & Diglyceride

• Acetylated Monoglyceride

• Polysorbates

• Tablet hardness maintained

• Low ejection forces

• Dispersing Agent

Glycerides Flavors

• Portfolio • Flavor Modulator

Technology (fmt™)

• Crystals

• Liquid & Powder

• Best in class flavor library with

DMF’s

• Bitterness masking of APIs

• Experience in supplying

nutraceutical and pharma

customers


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


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


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™ SD

LubriTose™ AN

LubriTose™ MCC

LubriTose™ Family

LubriTose™ Mannitol


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%


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


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


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.


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.


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.


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: FormaTM 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.


Powder SEMs


SD Mannitol

200x 1000x 5000x


Tablet SEMs


Tablet SEMs


SD Mannitol

200x 1000x 5000x


LubriTose™ Mannitol Lubrication Evaluation

Ejection force - LubriTose AN vs Lactose/Magnesium Stearate

5

7

9

11

13

15

17

19

21

600 800 1000 1200 1400 1600

Compression Force (lbs)

Eje

cti

on

Fo

rce (

lbs)

Lubritose AN DT 1% mag stear.

Note: 1% Mg. Stearate not typical but used to provide

excellent lubrication for comparative purposes


Lubritose Mannitol Compression Evaluation

0

50

100

150

200

250

300

350

0 5 10 15 20 25

Compression Comparison Compression Force vs Breaking Force

Mannitol 1 + Avicel Mannitol 2 + Avicel


Lubritose Mannitol Compression Evaluation

0

50

100

150

200

250

300

350

0 5 10 15 20 25

Compression Comparison Compression Force vs Breaking Force

Lubritose Mannitol Mannitol 1 + Avicel Mannitol 2 + Avicel


Tablet Weight Uniformity

Lubritose™

Mannitol

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

SD Mannitol:

Avicel PH102 (1:1)


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

SD mannitol 2:

Avicel PH102 (1:1)


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


Tablet Stability SD Mannitol 1


Tablet Stability – SD Mannitol 2


Tablet Stability – LubriTose™ Mannitol


LubriTose™ Mannitol Study Objective - Recap

Tablet lubrication comparison

Compressibility comparison

Tablet weight variability testing

Tablet stability testing


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%


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


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


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


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!

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