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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
Co-processed Excipients
pro
cessed E
xcipientsfor developing new direct compressible excipients:
� High speed tablet press
� Poor compressibility of actives
� Avoid new chemical excipients
| Ulrich Marcher | ©MEGGLE 319.11.2012
Co-p
rocessed E
xcipients
Co-processing: Technology
Cellacto
se®
80
| Ulrich Marcher | ©MEGGLE 419.11.2012
Pharma Spray Tower at Meggle: H 21,4 m; Dmax 9,41 m. D; V 700 m3; 1,500kg/h Water evaporation
Co-processed Excipients
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
| Ulrich Marcher | ©MEGGLE 519.11.2012
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
� 75% α-Lactose Monohydrate [Ph.Eur./USP-NF/JP]
� 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
| Ulrich Marcher | ©MEGGLE 719.11.2012
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
| Ulrich Marcher | ©MEGGLE 819.11.2012
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
| Ulrich Marcher | ©MEGGLE 1019.11.2012
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
| Ulrich Marcher | ©MEGGLE 1119.11.2012
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
| Ulrich Marcher | ©MEGGLE 1219.11.2012
MicroceLac® 100
MicroceLac® 100
� 75% α-Lactose Monohydrate [Ph.Eur./USP-NF/JP]
� 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
| Ulrich Marcher | ©MEGGLE 1419.11.2012
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
| Ulrich Marcher | ©MEGGLE 1519.11.2012
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
| Ulrich Marcher | ©MEGGLE 1619.11.2012
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
| Ulrich Marcher | ©MEGGLE 1719.11.2012
StarLac®
Sta
rLac®StarLac®
� 85% α-Lactose Monohydrate [Ph.Eur./USP-NF/JP]
� 15% Corn Starch [Ph.Eur./USP-NF/JP]
spray-dried
1819.11.2012 | Ulrich Marcher | ©MEGGLE
d50 StarLac = 160µm, Hausner ratio =
1.19
� 15% Corn Starch [Ph.Eur./USP-NF/JP]
Comparison:StarLac® vs. Physical Admixture
Sta
rLac®
| Ulrich Marcher | ©MEGGLE 1919.11.2012
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®
| Ulrich Marcher | ©MEGGLE 2019.11.2012
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®
| Ulrich Marcher | ©MEGGLE 2119.11.2012
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®
| Ulrich Marcher | ©MEGGLE 2219.11.2012
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®
| Ulrich Marcher | ©MEGGLE 2319.11.2012
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®
| Ulrich Marcher | ©MEGGLE 2419.11.2012
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®
| Ulrich Marcher | ©MEGGLE 2519.11.2012
_________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
| Ulrich Marcher | ©MEGGLE 2619.11.2012
100
Flowability
Tablettose 70/80
Tablettose 100
FlowLac 100
Product Functionality
| Ulrich Marcher | ©MEGGLE 2719.11.2012
0 Compressibility
Disintegration
Price Index FlowLac 90
StarLac
Cellactose 80
MicroceLac100
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
| Ulrich Marcher | ©MEGGLE 2919.11.2012
� 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
19.11.2012 | Ulrich Marcher | ©MEGGLE
RetaLac®
RetaLac®
� 50% α-Lactose Monohydrate [Ph.Eur./USP-
NF/JP]
spray-agglomerated Reta
Lac®
| Ulrich Marcher | ©MEGGLE 3319.11.2012
� 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®
| Ulrich Marcher | ©MEGGLE 3419.11.2012
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
RetaLac lot L1021 A4020
RetaLac lot L1033 A4020
Physical admixture 1
Physical admixture 2
Physical admixture 3
Reta
Lac®
| Ulrich Marcher | ©MEGGLE 3519.11.2012
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®
| Ulrich Marcher | ©MEGGLE 3619.11.2012
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
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
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 %
Phosphate pH 7.40.1 M HCl
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®
Phosphate pH 7.40.1 M HCl
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
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®
| Ulrich Marcher | ©MEGGLE 4919.11.2012
� 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
| Ulrich Marcher | ©MEGGLE 5019.11.2012
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
| Ulrich Marcher | ©MEGGLE 5119.11.2012