Co-Processed Lactose- based excipients for Direct Compressionnovachemie.com/clientes/Co-Processed Lactose for DC.pdf · Co-Processed Lactose-based excipients for Direct Compression

Co-Processed Lactose-based excipients forDirect Compression

Ulrich MarcherMeggle GmbH & Co. KG, Germany

Co-processed Excipients

Definition:“ two or more

by an appropriate process”

Aim:

pro

cessed E

xcipients

Aim:

� Formation of excipients with

compared to the simple physical mixtures of their

components

� To obtain a product with related to the

ratio of its functionality / price.

| Ulrich Marcher | ©MEGGLE 219.11.2012

Co-p

rocessed E

xcipients


pro

cessed E

xcipientsfor developing new direct compressible excipients:

� High speed tablet press

� Poor compressibility of actives

� Avoid new chemical excipients


Co-p

rocessed E

xcipients

Co-processing: Technology

Cellacto

se®

80


Pharma Spray Tower at Meggle: H 21,4 m; Dmax 9,41 m. D; V 700 m3; 1,500kg/h Water evaporation


pro

cessed E

xcipients

Cellactose® 80GranuLac® 70 PrismaLac® 40DuraLac® HTablettose® 70 FlowLac® 90 InhaLac® 70 InhaLac® 400

anhydrousagglomerated

Direct Compression

Tabletting PowderPreparations

Dry Powder Inhalation

Granulation

spray-dried sieved milledco-processedmilled sieved


Co-p

rocessed E

xcipients

MicroceLac® 100GranuLac® 140 CapsuLac® 60Tablettose® 80 FlowLac® 100

StarLac®GranuLac® 200 SacheLac® 80Tablettose® 100

RetaLac®GranuLac® 230 SpheroLac® 100

SorboLac® 400

Cellactose® 80GranuLac® 70 PrismaLac® 40DuraLac® HTablettose® 70 FlowLac® 90 InhaLac® 70 InhaLac® 400

InhaLac® 170

InhaLac® 230

InhaLac® 250

Lactose in co-processed Excipients (DC)

� 75% α-Lactose Monohydrate [Ph.Eur./USP-NF/JP]

Cellactose® 80spray-dried

Cellacto

se®

80


� 25% Powdered Cellulose [Ph.Eur./USP-NF/JP]

| Ulrich Marcher | ©MEGGLE 6

d50 ≈ 180 µm, Hausner ratio = 1.24

Cellactose 80: Compaction profile

Cellacto

se®

80

150

200

250

Ha

rdn

ess

[N

]

Cellactose 80

75% Tablettose 80 + 25% MCC 102

Tablettose 80


0

50

100

0 50 100 150 200 250 300

Ha

rdn

ess

[N

]

Compaction Pressure [MPa]

Cellactose® 80:High loaded Vitamin C tablets

100

120

140

Formulation:

Vitamin C 98% DC 69%

Compritol 888 (1%)

Tablet press: comprex I

Tablet: d=12mm, w=500mg Cellacto

se®

80


0

20

40

60

80

100

0 5 10 15 20 25 30 35

Ta

ble

t H

ard

ne

ss [

N]

Compression force [kN] (comprex I, 12mm punch)

Adherence Capacity

Turbula mixer30 min.

Different ExcipientsMicronized Glibenclamide

Separation of nonadheredparticles by

Air jet sieving

Assay

Cellacto

se®

80

| Ulrich Marcher | ©MEGGLE 9

Schmidt and Rubensdörfer, 1994, Evaluation of Ludipress as a „Multipurpose Excipient“ for DC Part I: Powder Characteristics and Tabletting

Properties, Drug dev. ind. Pharm. 20(18); 2899-2925

Assay

Adherence Capacity: Results

80

ad

hered

[%

]

Cellacto

se®

80


Avicel PH 200

Ludipress

Karion Instant

Cellactose 80

0

20

40

60

80

1,75 3,5 5 10

Glib

en

cla

mid

ead

hered

Glibenclamide content before blending

Cellactose® 80:Disintegration properties

Cellacto

se®

80

1000

1500

2000

2500

Dis

inte

gra

tio

n ti

me

[s]

Cellactose 80


0

500

1000

0 50 100 150 200 250

Dis

inte

gra

tio

n ti

me

[s]

Tablet hardness [N]

For very hard compressed Cellactose® 80tablets, an addition of 2-3% superdisintegrantcan reduce the disintegration timesignificantly.

Meggle Lactose – Cellactose® 80

� Ideal Diluent / Binder Combination

� Spherical form → Good Flowability

� High Adherence Capacity (micronized API)

� High Dosage Formulations (up to 75 % API)

� Application:

Cellacto

se®

80

– Chewable tablets (pleasant mouthfeel)

– Difficult to compress formulations (e.g. oblong tablets)

– Suitable alternative to undergo MCC/Lactose in patents


MicroceLac® 100

MicroceLac® 100


� 25% Microcrystalline Cellulose [Ph.Eur./USP-NF/JP]

spray-dried

Micro

ceLac®

100

1319.11.2012 | Ulrich Marcher | ©MEGGLE

d50 MicroceLac® = 150µm, Hausner ratio =

1.22

MicroceLac® 100: Compaction Profile

Micro

ceLac®

100

200

250

300

350H

ard

ne

ss [

N]

Microcelac 100

75% Tablettose 80 + 25% MCC 102

Tablettose 80


0

50

100

150

0 50 100 150 200 250 300

Ha

rdn

ess

[N

]

Compaction pressure [MPa]

MicroceLac® 100: Improving Content Uniformity

Micro

ceLac®

100

V-type mixer

MicroceLac® 100 Physical Admixture

Micronized Glibenclamide 5%

Sample taken at prescribed (2, 5, 10, 15, 20 and 30 min.)

time and defined points


By courtesy of Prof. Sunada, Meijo University, Nagoya

Assay

MicroceLac® 100: Improving Content Uniformity

8

10

12

glib

encla

mid

e [

%] 8

10

12

glib

encla

mid

e[%

]

Formulation 15% Glibencl. /

Formulation 25% Glibencl. /

Micro

ceLac®

100


0

2

4

6

0 10 20 30 40time [min]

glib

encla

mid

e [

%]

0

2

4

6

8

0 10 20 30 40

time [min]

glib

encla

mid

e[%

]

Demixing

Glibenclamide 5,00 %

Tablettose 80 71,25 %

Avicel PH 101 23,75 %

Glibenclamide 5,00 %

MicroceLac 100 95,00 %

Meggle Lactose – MicroceLac® 100

� Ideal Diluent / Binder Combination

� Spherical Form → Good Flowability

� High and Consistent Tablet Hardness

� Helps solving Content Uniformity problems

� Very Low to High Dose Formulations Micro

ceLac®

100

� Application:

– DC tableting

– Formulations with poorly flowable, micronized APIs


StarLac®

Sta

rLac®StarLac®


� 15% Corn Starch [Ph.Eur./USP-NF/JP]

spray-dried


d50 StarLac = 160µm, Hausner ratio =

1.19

� 15% Corn Starch [Ph.Eur./USP-NF/JP]

Comparison:StarLac® vs. Physical Admixture

Sta

rLac®


StarLac®

� 15% Corn Starch

� 85% α-Lactose monohydrate

Physical Admixture

� 15% Corn Starch

� 85% spray dried Lactose

Magnification x 85 Magnification x 85

StarLac®:Disintegration

300

400

500

600

Dis

inte

gra

tio

n T

ime

[s]

Starlac

Flowlac

Sta

rLac®


0

100

200

300

0 100 200 300

Dis

inte

gra

tio

n T

ime

[s]

Tablet Hardness [N]

16 mm tablets, flat, height 4 mm, Exacta 21 tablet press, 0.6 % Mg stearate

Comparison:StarLac® vs. Physical Admixture

Flowability:

29

30

31

32

33

34

35

36

37

38

0 20 40 60 80

An

gle

of

rep

ose [

°]

Content of ascorbic acid [%]

StarLac

Physical

blend Sta

rLac®


0

20

40

60

80

100

0 5 10 15 20 25

Dis

so

luti

on

[%

]

Time [min]

StarLac

Physical blend

Dissolution (30 % Vitamin C):up to 40% faster for tablets with StarLac®

StarLac®:Compression-Hardness Profile

100

120

140

160

180

Ha

rdn

ess

[N]

StarLac

Tablettose 70

Sta

rLac®


0

20

40

60

80

0 50 100 150 200 250 300

Ha

rdn

ess

[N]

Compression Force [MPa]

StarLac®:Influence of Mg-Stearate

01' 44''

02' 01''

02' 18''

02' 36''

02' 53''

Dis

inte

gra

tio

n t

ime

[s]

Phys. Mixture + MgS 0,5%

Phys. Mixture + MgS 0,1%

StarLac + MgS 0,5%

StarLac + MgS 0,1%

Sta

rLac®


00' 00''

00' 17''

00' 35''

00' 52''

01' 09''

01' 26''

01' 44''

0 20 40 60 80 100 120 140 160 180

Dis

inte

gra

tio

n t

ime

[s]

Tablet hardness [N]

StarLac + MgS 0,1%

StarLac®:Orodispersable Formulation I

Ascorbic acid 250.0 mg 20.83 %StarLac 888.8 mg 74.07 %Sodium bicarbonate 36.0 mg 3.00 %Orange flavour 12.0 mg 1.00 %Aspartam 3.6 mg 0.30 %Acesulfam K 3.6 mg 0.30 %Magnesium stearate 6.0 mg 0.50 %

Sta

rLac®


Magnesium stearate 6.0 mg 0.50 %____________1200.0 mg

Weight SD: 0.14 % Tablet thickness: 3.52 mm

Tablet density: 1.344 Tablet hardness: 54.6 N

Hardness SD: 14.37 % Compression: 30.6 kN

StarLac®:Orodispersable Formulation II

Acetylcysteine 200.0 mg 16.67 %StarLac 953.2 mg 79.43 %Orange flavour 24.0 mg 2.00 %Aspartame 7.2 mg 0,60 %Acesulfam K 7.2 mg 0.60 %Magnesium stearate 8.4 mg 0.70 %

_________

Sta

rLac®


_________1200.0 mg

Weight SD: 0.11 % Tablet thickness: 4.91 mm

Tablet density: 1.216 Tablet hardness: 51.6 N

Hardness SD: 14.22 % Compression: 16.5 kN

Meggle Lactose – StarLac®

� Spherical form → excellent flowablility

� Fast, hardness-independent disintegration

� Minimal influence of hydrophobic lubricant (Mg-stearate)

� Low to mid-dose dosage formulation (up to 20%)

� Application:

Sta

rLac®

– DC Tableting with fast release

– ODT`s


100

Flowability

Tablettose 70/80

Tablettose 100

FlowLac 100

Product Functionality


0 Compressibility

Disintegration

Price Index FlowLac 90

StarLac

Cellactose 80

MicroceLac100

RetaLac®:A new DC excipient for

SR formulations

Reservoir systems� Membrane controlled (constant or non-constant activity)

� Membrane –matrix combination

Common dosage form: Multi unit-coated beads, Multi-unit coated minitablet, Monolithic coated tablet

Osmotic pump systems� Elementary osmotic pump

Enteric Coating

Common oral extended-release Systems


� Microporous osmotic pump

� Layered osmotic pump (e.g. Push-PullR, Push-StickR)

Common dosage form: Coated monolithic tablet, Coated layered tablet

(erosion/diffusion or swelling/erosion controlled)

� Hydrophobic Homogenous (dissolved drugs)

Heterogenous (dispersed drugs)

Common dosage form: Monolithic tablet, Multi-unit minitablets, Layered tablet,

Compression coated tablet

API Release Mechanisms

Two competing dissolution mechanism:

� API diffusion

30| Ulrich Marcher | ©MEGGLE

API Release Mechanisms

Two competing dissolution mechanism:

� API diffusion

– Fickian diffusional API release

31| Ulrich Marcher | ©MEGGLE

Administration of SR tablet

Hydrating, formation of gellayer, water penetration, Expansion of gel layer

API release controlled bydiffussion

Hydrophilic matrix system:API release

32

Completed hydration, API release controlled by

Erosion

Erosion of tablet


RetaLac®

RetaLac®

� 50% α-Lactose Monohydrate [Ph.Eur./USP-

NF/JP]

spray-agglomerated Reta

Lac®


� 50% HPMC, Type 2208, 4000 mPas (2% w/v at

20 °C); [Ph.Eur./USP-NF/JP]

RetaLac – Functional performance - Flowability

25

30

35

40

45

Flo

w r

ate

[m

l/s]

Flowability

RetaLac versus an

Admixture Comprising Tablettose 80 & HPMC K4M DC

RetalacRetalacRetalacAdmixture 1Admixture 2Admixture 3

Reta

Lac®


0

5

10

15

20

25

0 5 10 15

Flo

w r

ate

[m

l/s]

Aperture [mm]

Admixture 3

RetaLac – Functional performance

2,5

3,0

3,5

4,0

4,5

5,0

Ten

sile s

tren

gth

[M

Pa]

Tensile Strength as a Function of Compression PressureRetaLac versus an Admixture Comprising Tablettose 80 & Hypromellose K4

RetaLac lot L1004 A4020



Physical admixture 1



Reta

Lac®


0,0

0,5

1,0

1,5

2,0

2,5

0 100 200 300 400 500

Ten

sile s

tren

gth

[M

Pa]

Compaction pressure [MPa]

Wetgranulation vs. Direct Compression

IngredientDirect compression Wet granulation

% mg % mg

Metformin HCl 50 500 50 500

RetaLac 49.5 495

Lactose monohydrate, 200 mesh 24.5 247.5

Hypromellose 24.5 247.5

Reta

Lac®


Hypromellose 24.5 247.5

Magnesium stearate 0.5 5 0.5 5

Total 100 1000 100 1000

Direct compression Wet granulation

Compaction force (kN) 27 29

Tablet hardness (N) 45 54

Dissolution profile See graph

50

60

70

80

90

100

Metf

orm

ind

isso

lved

Metformin Dissolved as a Function of TimeDissolution in 0.05 M pH 6.8 Phosphate Buffer

Wet Granulation vs. Direct Compression

Reta

Lac®

37

0

10

20

30

40

50

0 1 2 3 4 5 6 7 8

% M

etf

orm

in

time (h)

RetaLac: DC

Admixture: WG

RetaLac®

Reta

Lac®


Materials and Methods

APISolubility

(25°C)Absorbance

λStructure

Theophylline 7.4 mg/L 271 nm

Acetaminophen(Paracetamol)

14.0 g/L 244 nm

Reta

Lac®

39

(Paracetamol)

Diprophylline 330 g/L 274 nm

API [%] 5.0 10.0 20.0 30.0 40.0 50.0 60.0

RetaLac [%] 84.5 89.5 79.5 69.5 59.5 49.5 39.5

Mg stearate [%] 0.5 0.5 0.5 0.5 0.5 0.5 0.5

RetaLac®

Reta

Lac®


100

125

150

dru

g r

ele

ased

, m

g

60 % Theophylline

50

40

30

20

10

5

100

125

150

dru

g r

ele

ased

, m

g

60 % Theophylline

50

40

30

20

10

5

Drug Release: Theophylline

Reta

Lac®

Phosphate pH 7.40.1 M HCl

0

25

50

75

0 2 4 6 8

dru

g r

ele

ased

, m

g

Time [h]

0

25

50

75

0 2 4 6 8

dru

g r

ele

ased

, m

g

Time [h]

41

Absolute Drug Release: Paracetamol

Reta

Lac®

75

100

125

150

dru

g r

ele

ased

, m

g

60 % Paracetamol

50 %

40 %

30 %

20 %

10 %

75

100

125

150

dru

g r

ele

ased

, m

g

60 % Paracetamol

50 %

40 %

30 %

20 %

10 %


42

0

25

50

75

0 2 4 6 8d

ru

g r

ele

ased

, m

g

Time [h]

0

25

50

75

0 2 4 6 8

dru

g r

ele

ased

, m

g

Time [h]

100

150

200

dru

g r

ele

ased

, m

g

60 % Diprophylline

50

40

30

20

10

5100

150

200

dru

g r

ele

ased

, m

g

60 % Diprophylline

50

40

30

20

10

Absolute Drug Release: Diprophylline

Reta

Lac®


0

50

100

0 2 4 6 8d

ru

g r

ele

ased

, m

g

Time [h]

5

0

50

100

0 2 4 6 8

dru

g r

ele

ased

, m

g

Time [h]

5

43

RetaLac®

Reta

Lac®


Tablet Surface Area, Height

Area of the top is πr2

Area of the bottom is πr2

Area of the side is 2πrh

Surface area = 2πr2 + 2πrh

Volume V= πr2hr

Cylinder

h

Reta

Lac®

45

Ratio vs. is smaller for a larger (h)

h Height (h)

(r=1)

Volume (V) Surface area

(A)

A/V

1 π 4π 4

10 10π 22π 2.2

100 100π 202π 2.02

Tablet Height

Reta

Lac®

50

75

100

dru

g r

ele

as

ed

, %

1.5 mm

2.3

3.2

4.2

50

75

100

dru

g r

ele

as

ed

, %

1.5 mm

2.3

3.2

4.2

46

0

25

0 2 4 6 8

time, h

dru

g r

ele

as

ed

, %

0

25

0 2 4 6 8

time, h

dru

g r

ele

as

ed

, %

Effects of the initial tablet height (indicated in the diagrams) on theophylline release from RetaLac®

-based tablets in different buffer systems (drug loading: 50%, initial tablet diameter: 11.3mm).

0.1 M HCl phosphate buffer pH 7.4

75

100

dru

g r

ele

ase

d,

%

D=6 mm

D=16 mm

75

100

dru

g r

ele

ase

d,

%

D=6 mm

D=16 mm

Tablet Diameter

Reta

Lac®

0

25

50

0 2 4 6 8

dru

g r

ele

ase

d,

%

time, h

0

25

50

0 2 4 6 8

dru

g r

ele

ase

d,

%

time, h

47

Effects of the initial tablet diameter (indicated in the diagrams) on theophylline release from RetaLac®

-based tablets in different buffer systems (drug loading: 10%, initial tablet height: 2.4mm).

0.1 M HCl phosphate buffer pH 7.4

Reta

Lac®

Agitation in cold water

Wettability of HPMC vs. RetaLac®

50% HPMC 4000mPas & 50% Lactose monohydrate

48

Physical admixture Co-processed RetaLac®

No dispersion after 10 min. Immediate dispersion(see also: http://www.meggle-pharma.de/de/produkte-und-leistungen/produkte/produktuebersicht/retalac-coprocessed-)

RetaLac®:Characteristics

� Enables direct compression of sustained release formulations

� Superior compressibility to physical mixture, minimizes friability

� Structured surface, good flowability

� Defined and adjustable release profiles

� Reduced process steps (two-in-one system)

Improves wettability of HPMC

Reta

Lac®


� Improves wettability of HPMC

� Applications:

– Direct compression of modified release formulations (up to 60% API)

– Facilitates preparation of dispersions containing HPMC/Lactose

Starting materials (α–Lactose Monohydrate and Powdered Cellulose, MCC, Starch, HPMC) are

monographed according to Ph.Eur, USP-NF, JP.

Regulatory Status

pro

cessed E

xcipients


Co-p

rocessed E

xcipients

Meggle Contacts

www.meggle-pharma.com

Sales Contact: Ruth Leinenbach

E-mail: [email protected]

Tel.: +55 11 2893 4831

Fax: +55 11 991 464 850

Technical Contact: Ulrich Marcher

E-Mail: [email protected]

Tel.: +49 80 71 73 480

Fax: +49 80 71 73 320


Questions?


Co-Processed Lactose- based excipients for Direct Compressionnovachemie.com/clientes/Co-Processed Lactose for DC.pdf · Co-Processed Lactose-based excipients for Direct Compression

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