EF13 April 30, Hall A #3, Jian-Xin Li (DFE Pharma)ipecamericas.org/sites/default/files/EF13April30HallA3Jian-XinLi... · ICH Q7A Guidelines (API) Pharmacopoeial standards: USP/ NF

ExcipientFest Americas 2013 April 30th

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SuperTab® 24ANA New Generation of Directly Compressible

Lactose

Jian-Xin Li, Ph.D.

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What is so special about excipients?

DFE Pharma ExcipientFest 20132

All medicines depend on excipients to stabilize and deliver their active ingredients

The quality and effectiveness of the medicine depends greatly on how the excipient performs

Performance of active ingredients and excipients togetherdetermines healthcare benefits for the patient


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A century long heritage


With roots in dairy producing companies

Our heritage

1900 – HMS (Dutch Milk Sugar Factory) founded

1926 – Six Dutch dairy producers form DMV

1946 – First lactose plant built in Kapuni NZ

1960 – DOMO starts producing pharmaceutical grade lactose

1985 – Start inhalation grade lactose by DOMO in Borculo

2003 – Superdisintegrants acquired from Avebe

2006 – DMV-Fonterra Excipients created from DMV & LNZ

2010 – DOMO-pharma integrated

2011 – Acquisition Brahmar Cellulose India

2011 – Launch new corporate brand name DFE Pharma

2013 – Global launch of MCC by DFE Pharma

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DFE Pharma – a joint venture between 2 leading global dairy cooperatives

Sales Marketing QA R&D F&A Operations

50% 50%


HR


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International dairy cooperative

Registered head office in

Amersfoort (the Netherlands)

Turnover € 9.6 billion

19,000 employees

14,400 member dairy farms

International dairy cooperative

Registered head office in

Auckland (New Zealand)

Turnover NZ$ 19,8 billion

Up to 17,300 employees

Up to 10,600 share holders

Our parent companies


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Responsiveness with global presence

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Offices, production facilities & global distributor network


Sales Office Japan

Sales Office

Singapore

Production New Zealand

3 Production The Netherlands

Sales Office

US

Production Germany

Global distributor network

Main Office

Germany

Sales Office

India

Production India


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We want to grow from a lactose supplier to an excipient expert.

DFE Pharma Strategy

Our ambition

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Lactose supplier

Wide range supplier Excipient expert



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DFE Pharma production facilities

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FoxholThe Netherlands

BorculoThe Netherlands

Nörten HardenbergGermany

KapuniNew Zealand

VeghelThe Netherlands

CuddaloreIndia


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Quality is guaranteed

Production:cGMP production standardsICH Q7A Guidelines (API)Pharmacopoeial standards: USP/ NF ,Ph. Eur., JPEDrug Master FilesISO 9001:2008 certified production facilities, FDA inspected

Shelf life guaranteed:MCC: 4 yearsMilled & sieved lactose: 3 yearsDirect compression lactose: 2-3 years (vary by grade)Starches: 2-4 yearsSuperdisintegrants: 5 years



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Directly Compressible Excipients

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Good flowability

High compactability

Good recompactability for dry granulation

Good blending properties

No (drug) segregation

Physical and chemical stability

Chemical compatibility

DC Excipients for Tablet ProductionMost important requirements for DC filler/binders

12 DFE Pharma ExcipientFest 2013


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DCP

Lactose

MCC

Starch

…

Choices for Excipients??


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Direct compression lactose

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The best DC lactose for your application

Spray-dried lactose (SD)Excellent flowImprovement of compactionLow dose formulationsLow tablet weight variation Anhydrous lactose (AN)

Roller compactionMoisture sensitive drugsHigh dose formulations

Granulated lactose (GR)Low dose applicationsQuick disintegrationCapsule and sachet filing



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Direct compression lactoseSummary of production routes

Crystals of pharmaceutical grade -lactose monohydrate

Spray-drying Roller drying Granulated

Lactopress® Spray Dried 250SuperTab® 11SD or 14 SD

Lactopress® Anhdyrous 250SuperTab® 21AN or 22 AN

Lactopress® GranulatedSuperTab® 30GR


AN=anhydrous, GR=granulated, SD=Spray Dried

SuperTab® 24AN“A New Generation of Directly

Compressible Lactose”


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Introduction SuperTab® 24AN

– Description

– Production process & product properties

Application studies

– Study 1: Mixing potential & Content Uniformity

– Study 2: Quick disintegration with high compaction

– Study 3: High speed tableting properties

Summary

SuperTab® 24ANOverview


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Combines the key properties of granulated and anhydrous lactose

– High powder flowability (granulation)

– Quick disintegration time (granulation)

– Excellent mixing properties (granulation)

– High compactability (granulation of anhydrous material)

– Low moisture content below 1.0 % H2O (anhydrous material)

Product is an anhydrous lactose according to Pharmacopeia

SuperTab® 24ANDescription



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SuperTab® 24ANProcess flow

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Patented: EP1851344 (B1), US2009/0081308


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SuperTab® 24ANProduct properties

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Property: SuperTab® 24AN SuperTab ® 21AN

H2O content – KF (%) 0.5 0.1

ratio 75/25 80/20

Bulk density (g/cm³) 0.490 0.700

Tapped density (g/cm³) 0.600 0.870

Flodex (mm) 6 20

PSD* % <75m ~ 20 (nmt 30) ~ 19

PSD* % <150 m ~ 65 (55-80) ~ 50

PSD* % <250 m ~ 92 (nlt 80) ~ 83

* By Rotap sieve analysis



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SuperTab® 24ANProduct Properties - visualization

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Light Microscope

SEM


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SuperTab® 24ANProduct Properties – PSD (laser diffraction)

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0

10

20

30

40

50

60

70

80

90

100

Ve

rte

ilun

gss

um

me

Q3

/ %

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

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1.0

1.1

1.2

1.3

1.4

Ve

rte

ilun

gsd

ich

te q

3*

1 5 10 50 100 500Partikelgröße / µm

Messung

2011-05-23 15:25:44.5980 1304 H

2011-05-23 15:20:40.4700 1304 H

x10= 34 µm

x50= 128 µm

x90= 273 µm



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SuperTab® 24ANProduct properties - flow

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AN=anhydrous, GR=granulated, SD=Spray DriedExcellent flow: comparable to granulated/spray-dried lactose


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SuperTab® 24ANProduct properties – low moisture uptake

< 0.7% of water uptake up to 90% RH when measured by Dynamic Vapour Sorption (DVS)



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Application study 1:Mixing potential & Content Uniformity


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Goal: comparison of mixing properties/potential vs. regular anhydrous lactose

Formulation – 2% Propranolol HCl, 97.5% Lactose , 0.5% Magnesium Stearate – 500 g formulations

Experimental conditions:– Mix API & Lactose for 2, 5, 8 minutes (Turbula 62 rpm)– Add lubricant & mix for 2 min– Compress on rotary Tablet Press (250 mg tablets, 9 mm, fbe

tooling)– Test tablets on content uniformity

SuperTab® 24ANStudy outline



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SuperTab® 24AN gave excellent content uniformity (RSD 3%) after only 2 minutes; a similar result for regular anhydrous grade is obtained after only 8 minutes mixing time.

SuperTab® 24ANMixing properties

80%

84%

88%

92%

96%

100%

104%

108%

112%

116%

120%

0 1 2 3 4 5 6 7 8 9

Dru

g la

be

l co

nte

nt (

%)

Mixing time (min)

SuperTab® 24AN

Regular anhydrous lactose


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Goal: comparison of content uniformity over long tableting duration: SuperTab® 24AN vs. regular anhydrous lactose

Formulation – 2% Paracetamol, 97.5% Lactose, 0.5% Magnesium Stearate

Experimental conditions:– Premix API & 10 % Lactose for 5 min, screen through 500m sieve– Add remaining lactose and & mix for 10 min (Turbula 62 rpm)– Add lubricant and mix for 2 min– Compress on rotary Tablet Press (250 mg tablets, 9 mm, flat

beveled tooling)– Test tablets on content uniformity




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SuperTab® 24ANContent Uniformity

SuperTab® 24AN gave excellent content uniformity over the entire tabletting duration

SuperTab 22AN

4,25

4,50

4,75

5,00

5,25

5,50

5,75

0 5 10 15 20 25 30 35 40

Tabletting Duration /min

Sin

gle

Tab

let a

ssay

/mg

92% - 105% LS

SuperTab 24AN

4,25

4,5

4,75

5

5,25

5,5

5,75

0 5 10 15 20 25 30 35

Tabletting Duration / min

Sin

gle

Ta

ble

t ass

ay

/mg

98% - 105% LS


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Application study 2:Quick disintegration combined with high compaction



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Goal: Comparison of placebo tablets on the tablet properties (disintegration & tablet crushing strength)

Formulation:– 95.5% lactose, 4% Primellose® (Croscarmellose Sodium), 0.5% Magnesium

Stearate

– 500 g formulations

Experimental conditions– Mix Lactose & disintegrant for 8 minutes (Turbula, 62 rpm), add Lubricant and mix

for further 2 minutes

– Compress on a R&D rotary tablet press (Rotab T, Luxner)

– 250 mg tablets, 9 mm, flat beveled tooling

– Test tablets on Tablet Crushing Strength (TCS), Disintegration Time (DT)



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SuperTab® 24AN25% more compactable vs. regular anhydrous lactose

AN=anhydrous, GR=granulated, SD=Spray Dried250mg tablets, 9mm flat bevel edged tooling, RoTab rotary tablet machine



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Quicker disintegration at higher tablet hardness

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SuperTab® 24AN

AN=anhydrous, GR=granulated, SD=Spray Dried 2% and 4% Primojel for 30GR and 11SD respectively

250mg tablets, 9mm flat bevel edged tooling, RoTab rotary tablet machineDFE Pharma ExcipientFest 2013

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Application study 3:High speed tableting properties



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Goal: investigation tableting properties on a high speed tableting machine with a low dose formulation

Formulation:– 0.1% APAP (d50 = 19 m), 99.4% lactose, 0.5% Magnesium Stearate

– 20 kg blends

Experimental conditions: – Premix API & 10 % Lactose (2 min), Premix + Lactose (8 min), Lubrication (2

min) – drum mixer

– Bosch Manesty Xpress 325*, 1300 tpm

– 800 mg tablets, 12,6 mm concaved tooling (precomp. 1.8 kN, maincomp. 5.9

kN)

* Turret speed equal to XPress700 = 1.1 million tablets/h



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High consistency of tablet crushing strength & thickness during tablet run

SuperTab® 24ANHigh speed tableting properties

0,0

20,0

40,0

60,0

80,0

100,0

120,0

140,0

160,0

180,0

200,0

1 2 4 6 10

Tabletting Time /min

Ta

ble

t Cru

shin

g S

tre

ng

th /N

6,5

6,55

6,6

6,65

6,7

6,75

6,8

6,85

6,9

6,95

7

Ta

ble

t Th

ickn

ess

/mm



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SuperTab® 24ANHigh speed tableting properties

Consistent uniformity (range 108-116% label, RSD ~ 2.3%) >> no segregation during tablet run

90

95

100

105

110

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120

125

130

0 2 4 6 8 10

Tabletting Time / min

% D

rug

La

be

l


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Agglomerated anhydrous lactose (complies with Pharmacopeia for anhydrous lactose)

Combines the key properties of granulated and anhydrous lactose – High powder flow / excellent mixing properties

– Superior compaction on high speed machine

– Short disintegration time @ high tablet hardness

– Low moisture content, below 1.0 % H2O (anhydrous material)

May provide a solution for:– content uniformity issues in DC (incl. low dose drugs) & transfer WG formulations to DC

(cost & time)

– improving drug dissolution, due to quicker disintegration times

– formulating hygroscopic drugs

– roller compaction

– Medium/high dose drugs

– Bilayer tablets

SuperTab® 24ANSummary



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Major drivers: life cycle management– Improve patient compliance– Improve therapeutic outcomes– Decrease adverse reactions– Motivation by regulatory agencies

Distinct layers of active formulations– Chemical incompatibility– Different release profile/rates– Core for osmotic pump

More complicated than single layer tablets

Bilayer or Multi-layer FDC Tablets


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Better flowing formulation is selected as first layer– First layer determines fill and weight control of second layer

Select more re-compactable material as first layer– First layer undergoes 2 compressions

Increase success in compression and layer adhesion– Layers with similar compaction/relaxation properties– Layers with similar expansion (thermal or moisture driven)

Optimization of compaction pressure and tableting speed– Strength of interface adhesion

Considerations guiding excipient selection for bilayer tablets



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Effect of materials on the strength of bilayer tablets

Kottala et al., AAPS PharmSciTech, Vol. 13, No. 4, December 2012DOI: 10.1208/s12249-012-9845-9

Total tablet weight 500 mg with each individual layer being 250 mg.


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Bilayer tablets made with brittle materials (lactose) in both layers are strongest.

For lactose–lactose tablets, an increase in adhesion between layers was observed, due to the formation of solid bridges upon storage.

More significant fracture is induced when MCC is the bottom layer (MCC 1st) than when it is compressed as the top layer (lactose 1st).

Interface was weakest for the compacts made with plastic materials (MCC) in both layers.

Lactose is good for bilayer tablets

42 Kottala et al., AAPS PharmSciTech, Vol. 13, No. 4, December 2012DFE Pharma ExcipientFest 2013


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Documents

EF13 April 30, Hall A #3, Jian-Xin Li (DFE Pharma)ipecamericas.org/sites/default/files/EF13April30HallA3Jian-XinLi... · ICH Q7A Guidelines (API) Pharmacopoeial standards: USP/ NF