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Excipient FestPorto RicoMay 2010
MEGGLE Excipients & Technology, Wasserburg Germany
Dr. Franz Karl Penz
Location
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Meggle headquarters, WasserburgGermany
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Founded: 1887 as a small dairy
Company Name: since 2002 MEGGLE AG
Head Office: Wasserburg a. Inn, Germany
Employees: about 2000
Turnover 2008: 750 mn Euro (consolidated)
123 Years of MEGGLE
Josef Anton Meggle
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MEGGLE AG – Holding
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MEGGLE Holding
Molkerei MEGGLEWasserburgGmbH & Co. KG100 %
MEGGLEEastern EuropeGmbH100 %
MEGGLEInternationalGmbH100 %
Food Industry
Animal Feed
Pharmaceut. Excipients
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MEGGLE Japan Ltd.
Founded in 1977 and situated in Tokyo.Sales of Functional Products, mostly Lactose.
MEGGLE USA Inc.
Founded in January 2009 and situated inWhite Plains, NY.Sales of pharmaceutical FunctionalProducts in North America.Own Production of pharmaceutical Lactosein USA, Minneapolis (La Sueur), MN at the beginning of 2011.
FormulaB LLC
Centre of Excellence for the pharmaceutical Industry in the Ukrainian town of Odessa.Founded in 2005, it offers research, development and design of solid dosage formulations.
Representative Office MEGGLE Shanghai
Founded in 2002 and situated in Shanghai. High demand for pharmaceutical Lactose inthe Chinese market.
MEGGLE Singapore Ltd.
Founded in 2003 and situated in Singapore.Sales of pharmaceutical Functional Products inSouth East Asia.
MEGGLE International (Pharma)
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History
Lactose for pharmaceutical use
1950 In the middle of the fifties MEGGLE decided to adopt the standards of the pharmacopeias for Lactose
1970 Tablettose® In the middle of the seventies the first agglomerated Lactose grade for Direct Compression (DC) was developed
1980 FlowLac ® In the beginning of the eighties spray-dried Lactose was introduced
Cellactose® At the end of the eighties we created ourfirst co-processed excipient
1990 RetaLac® In the nineties until now extension of DC-range
2000 InhaLac® Introduction of products for Dry-Powder-Inhaler
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Lactose Production
Production > 30,000 tons
Countries worldwide > 110
Agents worldwide > 50
Products > 20
Latest development RetaLac®
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Co-processing, a versatile pathway to modify excipients:
Lactose excipients from fast disintegrating to modified release
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Lactose excipients from fast disintegrating to modified release
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Granulation Process
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Dry Compaction Wet GranulationDirect Compression
Mixing and blending of API and adjuvants
Compression
Mixing and blending of API and adjuvants
Mixing and blending of API and adjuvants
Compression into slugs
Milling and sieving of slugs
Mixing of granules with adjuvants
Preparation of binder
Massing of binding solution with powder mixture
Wet screening of damp mass
Drying of wet granules
Risifting of dry granules and blending with adjuvants
Compression
Compression
Direct Compression of TabletsAdvantages
n Economy
n Avoidance of heat, moisture and compression
n Minimal variability compared to wet granulation– Viscosity of binder solution, wetting and drying parameters.
n Fewer long-term problems– Dissolution profile, chemical stability
n Optimisation of tablet disintegration– Individual drug particle released from tablet mass
instead of adherence (glued) onto larger agglomerates in wet granulation, which would reduce surface area for dissolution.
n Lower microbial level– Direct compressed tablets have lower microbial level compared
to those produced by wet granulation.
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Direct Compression of TabletsLimitations
n Choice of DC-Excipients
– blending, compactability, flowability, lubricant, stability
n No flaws in raw materials
– constant quality
n No satisfying colouring, dust
n Poor reworkability
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Reasons for developing new co-processed Excipients with improved Functionalities
n Rising technical standards
– High speed machines
n Poor compressiblity of actives
– Synergic functionality needed
n Demands of the customer
– Mask unfavourable properties
n High costs of development and toxicologic testing
– Risk with new chemical entities
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Co-p
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ssed E
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Definition & Aim
“Combining two or more established excipients
by an appropriate process”
n Formation of excipients with superior properties compared to the simple physical mixtures of their components
n To obtain a product with added value related to the ratio of its functionality vs. price.
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Methods of Preparation
n Chemical Modification MC, HPMC, Lactitol
n Physical Modification Sorbitol, Dextrates,
Compressible Sugars
n Sieving, Blending α-Lactose monohydrate, Lactitol
n Cristallisation Di-Pac®, ß-Lactose
n Spray-drying α-Lactose monohydrate, Karion instant®
n Agglomeration Tablettose®, RetaLac®
n Dehydration Anhydrous Lactose
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Modifie
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Co-processed Excipients for DC
Advantose ® FS-95 Fructose+ Starch SPI Polyols
Avicel ® CE-15 MCC +Guar Gum FMC
Di-Pac ® Sucrose+ Maltodextrin American Sugar
Emdex ® Dextrose+ Maltose JRS
Ludipress® α-Lactose monohydrate + BASF
PVP + PVP CL
Lycatab C ® Pregelatinized Starch Roquette
Pearlitol ® Mannitol Roquette
Plasdone ® Vinyl acetate + Vinyl pyrrolidone ISP
Pharmatose ® DCL 40 ß-Lactose anhydrous + Lactitol DMV
StarLac® α-Lactose monohydrate + Starch Roquette/Meggle
Xylitab® 200 Xylitol+ Na CMC Danisco
Prosolv SMCC® MCC+ Silicon Dioxide JRS
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Lactose in co-processed Excipients for DC
Lactose together with:
n Cellulose derivatives
– Powder cellulose Cellactose 80®
– MCC MicroceLac 100®
– HPMC (new) RetaLac®
n Lactitol Pharmatose® DCL 40
n PVP, PVP CL Ludipress®, Ludipress® LCE
n Starch StarLac®
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Lactose in co-processed Excipients (DC)
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Co-processed Excipients
Cellactose® 80
Lactose in co-processed Excipients (DC)
n 75% α-Lactose Monohydrate [Ph.Eur./USP-NF/JP]
n 25% Powdered Cellulose [Ph.Eur./USP-NF/JP]
spray-dried
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d50 ≈ 180 µm, Hausner ratio = 1.24
Cella
ctose
®80
Cellactose® 80
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Compaction Profile
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Compaction force [MPa]
0
50
100
150
200
250
0 50 100 150 200 250 300
Har
dnes
s [N
]
Tablettose 80+25% Vivacel 102
Tablettose 80
Cellactose 80
Cella
ctose
®80
Compaction Profile:Tablets with Extractum Hippocastani
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C Cellactose 80®
H Extr. Hippocast.AZ Physical mixture:
A Avicel®Z Zepharox®
(spray-dr. Lact.)
Cella
ctose
®80
By courtesy of Prof. Armstrong, University of Wales College of Cardiff
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High Dilution Potential
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0
20
40
60
80
100
120
140
0 5 10 15 20 25 30 35
Compression force [kN] (comprex I)
Hard
ness [
N]
Vitamin C 98% DC 345,0 [69%]
Cellactose® 80 150,0 [30%]
Compritol 888 5,0 [1%]
500,0
Punch: 12mm
Cella
ctose
®80
Adherence Capacity I
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Dry Compaction CarrierMicronized Glibenclamide
Premixing Mixing Turbula 30 min
Sampling
Separation of nonadhered particles by air jet sieving
Assay
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
Cella
ctose
®80
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Adherence Capacity II
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Cella
ctose
®80
Characteristics
n High adherence capacity
n High (up to 75%) dosage formulations
n Spherical form, good flowability
n Strong hardness depending disintegration
n Good mouthfeel
n Avoiding incompatibilities with MCC (Furosemide)
n Applications:
– Difficult to compress formulations as herbal extracts or inorganic salts
– Suitable alternative to undergo MCC/Lactose in patents
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Cella
ctose
®80
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Lactose in co-processed Excipients (DC)
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Co-processed Excipients
MicroceLac® 100
Lactose in co-processed Excipients (DC)
MicroceLac® 100
n 75% α-Lactose Monohydrate [Ph.Eur./USP-NF/JP]
n 25% Microcrystalline Cellulose
[Ph.Eur./USP-NF/JP]
spray-dried
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d50 MicroceLac® = 150µm, Hausner ratio = 1.22
Mic
roce
Lac®
100
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Improving Content Uniformity I
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By courtesy of Prof. Sunada, Meijo University, Nagoya
V-type mixer MicroceLac® 100 Physical Blend
Micronized Glibenclamide 5%
Sample taken at prescribed (2, 5, 10, 15, 20 and 30 min.) time and defined points
Assay
Mic
roce
Lac®
100
Improving Content Uniformity II
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0
2
4
6
8
10
12
0 10 20 30 40time [min]
glib
encl
amid
e [%
]
0
2
4
6
8
10
12
0 10 20 30 40
time [min]
glib
encl
amid
e[%
]
Formulation 15% Glibenclamide / Physical Blend
Formulation 25% Glibenclamide / MicroceLac® 100
Demixing!
Mic
roce
Lac®
100
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Tablet Hardness
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Michoel, A., Rombaut, P., Verhoye, A., 2002. Comparative evaluative of co-processed lactose and microcrystalline cellulose with their physical mixtures in the formulation of folic acid tablets. Pharm. Dev. Technol., 7(1), 79-87.
MicroceLac® 100 produced the hardest tablets with/without API
M3 - 75% α lactose monohydrate + 25% Avicel PH102M2 - 75% spray-dried lactose + 25% Avicel PH102
M1 - 75% anhydrous β lactose + 25% Avicel PH102M0 - MicroceLac® 100
Mic
roce
Lac®
100
Characteristics
n Improving content uniformity
n High and consistant tablet hardness
n Sperical form, good flowability
n Very low to high (up to 80%) dosage formulations
n Hard and smooth tablet surface (saving coating material)
n Improving rheology
n Applications:
– Conventional tabletting
– Formulations with poor flowable, micronized APIs
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Mic
roce
Lac®
100
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Lactose in co-processed Excipients (DC)
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Co-processed Excipients
RetaLac®
Lactose in co-processed Excipients (DC)
RetaLac®
n 50% α-Lactose Monohydrate[Ph.Eur./USP-NF/JP]
n 50% HPMC [Ph.Eur./USP-NF/JP]
spray-agglomerate
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Reta
Lac®
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Compaction Profile and Drug Release
Tabletting behaviour and dissolution ofTheophylline (98 mg) in a tablet formulationin the presence of 0.5% of Mg-stearate,using 8 mm punches (weight 400mg).
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Reta
Lac®
Characteristics
n Enables direct compression of sustained release formulations
n Superior compressibility to physical mixture, minimizes friability
n Structured surface, good flowability
n Low/medium (up to 50%) dosage formulation
n Improves wettability of HPMC
n Applications:
– Direct compression of sustained release formulations
– Facilitates preparation of dispersions containing HPMC/Lactose
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Reta
Lac®
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Lactose in co-processed Excipients (DC)
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Co-processed Excipients
Pharmatose® DCL 40 Pharm
ato
se®
DC
L40
Lactose in co-processed Excipients (DC)
Pharmatose® DCL 40
n 95% Anhydrous ß-Lactose
[Ph.Eur./USP-NF/JP]
n 5% Lactitol
[Ph.Eur./USP-NF/JP]
blend
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Pharm
ato
se®
DCL
40
Source: technical brochure DFE
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Compaction Profile
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Pharm
ato
se®
DCL
40
Compaction profile of various co-processed materials, open symbols lubricated with Mg-stearate 1% and unlubricated (closed symbols): , Cellactose; , Ludipress; , Pharmatose DCL 40.
Pharm. Powder Compaction Technology, ed. G. Alderborn and C. Nyström Vol. 71; pp. 485
Characteristics
n High dilution potential
n High tablet strength, low friability
n Spherical form, good flowability, narrow PSD
n Not sensitive to level of lubriction
n Low moisture uptake (<1% at 20oC / 80% RH)
n Sweet taste, impacts a cooling sensation
n Applications:
– Conventional tablets, chewable tablets, high dosage formulations
Source: technical brochure DFE
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Pharm
ato
se®
DCL
40
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Lactose in co-processed Excipients (DC)
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Co-processed Excipients
Ludipress® LCE
Ludipress®
Ludip
ress
®
Lactose in co-processed Excipients (DC)
Ludipress ® LCE
n 96,5 % α-Lactose Monohydrate
[Ph.Eur./USP-NF/JP]
n 3,5% PVP (Kollidon K30) [Ph.Eur./USP-NF/JP]
Ludipress ®
n Additional 3,5% (Kollidon CL)
spray-dried
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Ludip
ress
®
Source: technical brochure BASF
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Characteristics
n Superior compression characteristics, to a simple physical mixture of its constituents
n Fast release despite excellent hardness and low friability
n Excellent flowability
n Reduced process steps (three-in-one system)
n Applications:
– Conventional low dosage formulations
– Effervescent tablets (L. LCE)
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Ludip
ress
®LC
E /
Ludip
ress
®
Lactose in co-processed Excipients (DC)
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Co-processed Excipients
StarLac®
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Lactose in co-processed Excipients (DC)
StarLac®
n 85% α-Lactose Monohydrate [Ph.Eur./USP-NF/JP]
n 15% extra white Corn Starch [Ph.Eur./USP-NF/JP]
spray-dried
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d50 StarLac = 160µm, Hausner ratio = 1.19
Sta
rLac®
Disintegration
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Sta
rLac®
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Disintegration: Influence of Lubricants I
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Sta
rLac®
Disintegration: Influence of Lubricants II
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Sta
rLac®
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Dissolution and Flowability
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Sta
rLac®
Physical blendStarLac®
Tablets with 30% Vitamin C, DC grade
29
31
33
35
37
39
0 10 20 30 40 50 60 70 80
Content of Ascor bic Acid [ %]
0
20
40
60
80
100
0 5 10 15 20 25
Time [min]
Dis
solu
tion
[%]
An
gle
of
rep
ose
[°]
Flowability
Dissolution
Up to 40 % faster, probably due to
„wicking“
Characteristics
n Fast, hardness independent disintegration
n Minimal influence of lubricant
n Spherical form, excellent flowability
n Low-dose to mid-dose (up to 20%) dosage formulations
n Applications:
– Homeopathic formulations
– ODT
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Sta
rLac®
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Comperative Product Functionality
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3,0++++(+)++++(+)StarLac®
5,75+++++
++++++(+)Ludipress ®
Ludipress ® LCE
1++++++++++Pharmatose®
DCL 40
1,3Concentration dependent
++++++(+)RetaLac®
1,5++++++++++MicroceLac® 100
3,5+(+)++++++++Cellactose® 80
LOD [<%]DisintegrationCompressibilityFlowabilityDilution potential
Product
Thank you for your attention.
Visit us at our booth.
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