Re-imagining yourODT Formulation

Introducing a New Lactose Product

SuperTab® 50ODT

Mara van Haandel, MScInnovation Manager, DFE PharmaDDF Berlin, 12 March 2019

Spray-dried Granulated

Anhydrous

Moving from standard offerings to innovative solutions,

while maintaining the same focus on product consistency

DFE Pharma Direct Compression Portfolio: Evolution of lactose grades

•Standard offering

•Compactable, spherical morphology enhancing flowability

SuperTab® 11SD

•Enhanced compactabilityby reducing the primary particle size

SuperTab® 14SD •Rapid disintegration due

to microporous structure

•Enhanced mouthfeel

SuperTab® 50ODT

•Standard offering

•Highly compactable

SuperTab® 21AN

•Improved flowability by fines reduction

SuperTab® 22AN

•Agglomerated anhydrous

•Increased compactability and reduced disintegration time

SuperTab® 24AN

•Agglomerated anhydrous and lactitol

•Excellent flow, excellent compactibility, soluble

SuperTab® 40LL

•Great all-round product with good compactabilitycombined with good flowability and disintegration properties

SuperTab® 30GR

ODTs differ from traditional tablets in that they are designed to be dissolved on the tongue rather than swallowed as a whole. The regulatory condition to meet the ODT requirement:

- disintegrate in less than 30 seconds for US ODT products

- less than 3 minutes for European ODT products.

Main challenge of orally disintegrating tablet

ODT’s are a novel way for product line extensions and a new manner helping to deliver medication to pediatrics and geriatric patients, or to those who suffer from Dysphagia.

Challenges:• Tablet should dissolve fast• Tablet should have a pleasant mouthfeel• Tablet should have robust tablets (high hardness and low friability)

Good

Mouthfeel

FastDisintegration

Low

Friability

Pleasant mouthfeelMildly sweet -disaccharide

Robust tablet hardnessLow friability ensuring consistent performance

Fast dissolving speed Fast disintegration due to macropores by design

SuperTab® 50 ODT : Re-imagine your ODT formulation

New future possibilities

- ODT market is growing - Product Line extension - Increased comfort of taking medication- Proceed in pursuit of excipient excellence

Key users criteria

SuperTab® 50 ODT

Friability

Tablet tensile strenght

Source: Invivo Friesland Campina global sensory development Wageningen - CATA RATA method

Global Sensory FrieslandCampina

Sensory is…

As perceived by the senses

The awareness through the senses

Sensory testing: using people as “measuring device”

The five senses

Interaction between product properties, sensory properties and consumer behavior

Sensory: product perception & measurement by ensuring quality and objectivity

7

We use people as a “measuring device”

Screening:

Only the best tasters are selected

- Basic taste test

- Ranking tests

- Odour & Flavour recognition test

Training:

Dedicated panelists are extensively trained on tablets

- Generate attributes

- Determine definitions

- Ranking & scaling of products on attributes

Monitoring:

Panelists are continuously monitored on:

- Reproducibility

- In line with each other

- Distinguish between products on all attributes

Procedure for tablet production and sensory evaluation

Tablet production:• Formulation: 95.5 wt% of filler, 4 wt% superdisintegrant, 0.5 wt% lubricant. • Blending process: Turbula blender 90 rpm 8+2 min.• Compression process: Tablets (250 mg, 9 mm flat bevelet) were produced at 50 N

tablet hardness

The 50ODT panel : • #14 trained people• Age: 20-60 years old • Randomly tested (single

blind)

Sensory evaluation: 1. Attribute generation & reduction (only keeping the

relevant attributes for the panel and the requester)2. Training the panel on the attributes; focusing on

definitions 3. Practicing the scale for the RATA attributes (Rate all

that apply)4. Practice test & check quality of results 5. Final (short) training session based on practice test

results6. Official CATA/RATA test for project

a. Taste one product and evaluate the attribute listb. Neutralize: cracker + waterc. Taste next product etc.

Test set-up

Testing method: a combination of CATA (Check All That Apply) and RATA(Rate All That Apply). The RATA method is used when possible for attributes that require more differentiation in the results.

RATA: CATA:

Taste and mouthfeel attributes

Attribute Taste/Mouthfeel Description CATA/RATA

Sweet Dextro Taste Grape sugar CATA: No | Yes

Chalky Taste Taste like chalk CATA: No | Yes

Sweet Taste Overall sweet taste RATA: Not | a little bit | a bit | average | very | extremely

Paper/cardboard/ mouldy Taste Paper taste RATA: Not | a little bit | a bit | average | very | extremely

Soft/creamy Mouthfeel Granules present during melting

CATA: No | Yes

Powdery Mouthfeel Sandy texture of tablet during melting

CATA: No | Yes

Dissolves into paste Mouthfeel Product dissolves at once instead of melting gradually

CATA: No | Yes

Melts immediately Mouthfeel Product starts melting/ dissolving immediately when in mouth

CATA: No | Yes

Crumbling at end Mouthfeel Tablet becomes granules at the end

CATA: No | Yes

Dissolving speed Mouthfeel The speed of dissolving Rata: Extremely fast | very fast | fast | normal | slow | very slow

Amount of effort needed Mouthfeel Effort to dissolve RATA: From little effort needed till a lot of effort needed

The outcome of Sensory testings

High dissolving

Very sweet

High dissolving speed; Directly starts to melt; Powdery; Dry; Paper

Directly starts to melt; Powdery; Dry

Very low in sweetness; Paper; Melts in phases; Crumbly; Powdery; Dry

Very low dissolving speed; Crumbly

Very sweet; Dextro sweet; Fruity; High dissolving speed; Dircetlystarts to melt; Dissolves into paste; Velvet

Very sweet; Dextrosweet; Directly starts to melt

Observations (axes F1 and F2: 61,39%)

F1 (37,98%)

F2

(23,

41%

)

CompA

CompB

CompC

CompD

SuperTab® 50ODT

Disintegration In-vivo vs In-vitro

Co-processed SuperTab® 50 ODT Mannitol

Dissolving speed

In-vitro: Measured in 800ml water Invivo: Measured Real environment

Co-processed

High

Medium

Low

SuperTab® 50 ODT supports faster disintegration due tomacropores by design

• SuperTab® 50 ODT shows a rapid disintegration resulting from spray drying.

• A 100% inert, stable, soluble and palatable excipient

• Lactose based ODT excipient allowing steering capability by adding a superdisintegrant finding the balance best fitting the formulation.

Co-processed SuperTab® 50 ODT Mannitol

Dissolving speed

Source: Invivo Friesland Campina global sensory development Wageningen

High

Medium

Low

0

10

20

30

40

50

60

70

80

90

100

1 10 100 1000

Cu

mu

lati

ve u

nd

ers

ize

(%

)

Particle size (um)

SuperTab 50 ODT

SuperTab® 50 ODT enhances mouthfeel due to macroporous by design

• SuperTab® 50 ODT was found to have a mildly sweet taste as it is a disaccharide excipient.

• Modification by spray drying offers porosity which enhances a good mouthfeel defined by its ease of use in the mouth and fast dissolving time

• Powdery/ grittiness is prevented due to primary particle size of less than 35 µm*

Not A little bit A bit Average Very ExtremelyEffort needed (Amount of effort needed to dissolve)

Dissolving speed (dissolves quickly)

Not A little bit A bit Average Very Extremely

Testing method : RATA –Rate All That Apply CATA –Check All That Apply

Immediately starts melting

Melts gradually

Powdery

Crumbly

Aimed: Performance of lactose as alternative excipient versus mannitol in ODT.

* E. Imai, 1995, Oral perception of grittiness: effect of particle size and concentration of the dispersed particles; Beckett, 2008, Industrial Chocolate Manufacture and use

SuperTab® 50 ODT enables robust tablet hardness at a given compaction force

Find the right balance between hardness and disintegration

Robust tablet hardness

Typically ODT’s are tableted soft (at a lowcompaction force). SuperTab® 50 ODT has a lowfriability (<0.5%w/w) ensuring consistentperformance on tablet hardness over time. Thiscombined with a good tensile strength at a givencompaction force.

Friability

Tablet tensile strenght

SuperTab® 50 ODT : A monohydrate lactose modified by spray drying

Microscopy (SEM):lactose monohydrate modified by spray drying

Parameter Spec

<45um(airjet sieve)

Max 20%

<106um(airjet sieve)

30-60%

<250um(airjet sieve)

>90%

0

10

20

30

40

50

60

70

80

90

100

1 10 100 1000

Cu

mu

lati

ve u

nd

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(%

)

Particle size (um)

SuperTab 50 ODT

Parameter Typical

Bulk Density 0.64

Tapped density 0.73

HR 1.14

Car’s index 12%

FFC 22

x10 55

x50 130

x90 220

Main techniques used in preparation of orally disintegrating tablets (ODT) :• Freeze drying (lyophilization) • DC of spray dried /co-processed excipients

SuperTab® 50 ODT produced on our spray dryer in Borculo

Product Information

• A 100% lactose based ODT excipient to re-imagine ODT formulations

• Packed in 25kg boxes

• Re-test: 18 months

SuperTab® 50 ODT Reimagine your ODT

Good

Mouthfeel

FastDisintegration

Low

Friability

SuperTab® 50 ODT provides

• Pleasant mouthfeel by it’s ease of use, dissolving speed and disscharide

• 100% natural, inert and soluble• Robust tablet hardness, due to low friability • Unlike polyols, lactose does not decrease small intestinal

transit time*

Targetting:

Pediatric and geriatric patients

Key users criteria