Az SZTE Kutatóegyetemi Kiválósági Központ tudásbázisának kiszélesítése és hosszú távú szakmai fenntarthatóságának megalapozása a kiváló tudományos utánpótlás biztosításával”
Gyógyszertudományok Doktori Iskola Ph.D. kurzus (GYTKDIE16)
„Introduction to melt extrusion and application of quality by design principles”
2012. 03. 27. – 03. 30.
„Solid dispersions: Types, production, characterization”
Prof. Dr. Peter Kleinebudde
TÁMOP‐4.2.2/B‐10/1‐2010‐0012 projekt
InsJtute of PharmaceuJcs and BiopharmaceuJcs Heinrich‐Heine‐University
Düsseldorf, Germany
PharmaceuJcal Solid State
PSSRC
Research ClusterPeter Kleinebudde
Introduc.on to melt extrusion and applica.on of quality by design principles
Szeged, March 26‐30, 2012
PharmaceuJcal Solid State
PSSRC
Research ClusterContent
• Solid dispersions: Types, producJon, characterizaJon
• IntroducJon to melt extrusion: Equipment, process, materials, properJes of extrudates, downstream processing, applicaJons
• PAT applicaJons for melt extrusion and mulJvariate analysis of spectral data
• Tools for risk analysis in the context of melt extrusion
• Approaches to develop a design and a control space
3
PharmaceuJcal Solid State
PSSRC
Research ClusterExtrusion
4 Melt extrusion and QbD principles I
Applica.on of pressure to a mass un.l it flows through an orifice with defined diameter.
Two dimensions of the extrudate
are defined, only the length can
vary.
PharmaceuJcal Solid State
PSSRC
Research ClusterExtrusion techniques
5 Melt extrusion and QbD principles I
Extrusion
wet-extrusion
solid lipid extrusion melt-extrusion
cutting spheronisation
milling
PharmaceuJcal Solid State
PSSRC
Research ClusterExtrusion techniques
6 Melt extrusion and QbD principles I
Wet extrusion
• pure liquids or polymeric binders dissolved in
– water – alcohols etc.
• room temperature
• solidificaJon by drying
PharmaceuJcal Solid State
PSSRC
Research ClusterExtrusion techniques
7 Melt extrusion and QbD principles I
Melt extrusion
• meltable binders
– lipids, sugars, macogol – polymers
• hydrophilic
• hydrophobic
• temperature above the melJng point or glass transiJon temperature of the binder
• solidificaJon by cooling
Solid lipid extrusion
• thermo‐mechanical plasJcisaJon
• plasJcally deforming binders – lipids
– macrogols
• room temperature up to some K below the melJng point of the binder
• solidificaJon not necessary
PharmaceuJcal Solid State
PSSRC
Research ClusterCourtesy of BASF
Con.nuous Process
No Water or Solvents
StraighJorward, Reliable Process – Novel composi.ons Excipients
approved by FDA
PharmaceuJcal Solid State
PSSRC
Research ClusterMelt extrusion
• Equipment & Processing
• Materials & FormulaJon
• Downstream processing
• ApplicaJons: Case studies
9
PharmaceuJcal Solid State
PSSRC
Research ClusterMelt extrusion equipment
Extruder
o Feeding hopper o Barrel
o Screw (single or twin) o Screw driving unit o HeaJng/Cooling device o Die
Monitoring tools o Temperature gauges o Screw speed controller o Extrusion torque monitor o Pressure gauges
o Viscosity monitor
Downstream auxiliary equipment— for collecJon and shaping of extrudates (films, tablets, pellets, etc.)
11
PharmaceuJcal Solid State
PSSRC
Research ClusterScrew extruder
Temperature sensor
Powder feeder
heated barrel
Pressure sensor screws
Die plate
degassing
PharmaceuJcal Solid State
PSSRC
Research ClusterScrew extruder
PharmaceuJcal Solid State
PSSRC
Research ClusterThe channel depth is the distance from the screw roots to the inner barrel surface, the flight clearance is the distance between the screw flight and the inner barrel surface, the channel width is the distance between two neighboring flights, the helix angle is the angle between the flight and the direcJon perpendicular to the screw axis.
Breitenbach 2002
Screw geometry
PharmaceuJcal Solid State
PSSRC
Research ClusterLeistritz Coperion
Screw elements
PharmaceuJcal Solid State
PSSRC
Research ClusterScrew elements: flow resistance
Kohlgrüber, Wiedmann: Co‐
RotaGng Twin‐
Screw Extruders
PharmaceuJcal Solid State
PSSRC
Research ClusterConveying elements
Kohlgrüber, Wiedmann: Co‐
RotaGng Twin‐
Screw Extruders
PharmaceuJcal Solid State
PSSRC
Research ClusterKneading elements
Kohlgrüber, Wiedmann: Co‐
RotaGng Twin‐
Screw Extruders
PharmaceuJcal Solid State
PSSRC
Research ClusterKneading elements
Kohlgrüber, Wiedmann: Co‐
RotaGng Twin‐
Screw Extruders
PharmaceuJcal Solid State
PSSRC
Research ClusterScrew extruders
• Single screw
• Twin screw
– Co‐rotaJng – Counter‐rotaJng
• MulJple screws
Fa. Entex
Fa. Brabender
PharmaceuJcal Solid State
PSSRC
Research ClusterPharmaceuJcal Solid State
PSSRC
Research ClusterTwin‐screw extruders
• screw diameter
• screw length
• type and sequence of elements
Leistritz
feeding densification
kneading
extrusion
PharmaceuJcal Solid State
PSSRC
Research ClusterLiO‐off barrel
Prism Euro LAB digital 16 mm twin‐screw extruder
Courtesy: Thermo Fisher Scien.fic
PharmaceuJcal Solid State
PSSRC
Research ClusterLeistritz Extruder Corporation, Somerville, New Jersey
PharmaceuJcal Solid State
PSSRC
Research ClusterPharmaceuJcal Solid State
PSSRC
Research ClusterExtrusion dies
Ronden Die Melt Die
T1 T2 T3
T1 T2
PharmaceuJcal Solid State
PSSRC
Research ClusterModificaJon of the extrusion die
27 Improvement of Bioavailability of Poorly Soluble Drugs
Figure: Temperatures of the standard extrusion die
Figure: Temperatures of the modified extrusion die Figure: Schematic drawing of the
extrusion die (1 heating device; 2 additional heating device; 3 cooling device; 4 extrusion screw; T1, T2, T3 additional temperature sensors)
PharmaceuJcal Solid State
PSSRC
Research ClusterTwin screw extruder: process
Feed rate(s)
Barrel temps.
Temperature- profile
Screw speed Vacuum
Residence time Filling degree Viscosity Die pressure Die temperature Torque
Power consumption
PharmaceuJcal Solid State
PSSRC
Research ClusterMelt extrusion: Process
30
T. Geilen, ThermoFisher
PharmaceuJcal Solid State
PSSRC
Research ClusterMelt extrusion: Residence Jme distribuJon
31
T. Geilen, ThermoFisher
PharmaceuJcal Solid State
PSSRC
Research ClusterMelt extrusion: Residence Jme distribuJon
32
Throughput is important Screw speed is less important
T. Geilen, ThermoFisher
PharmaceuJcal Solid State
PSSRC
Research Cluster AcJve pharmaceuJcal ingredients
Lipid and polymeric carriers
PlasJcizers & processing aids
Bioadhesive agents
Drug release modifiers
Super‐disintegrants
AnJoxidants and anJstaJc agents
PharmaceuJcal Solid State
PSSRC
Research ClusterSolid dispersions: Carrier materials
hydrophilic lipophilic
Small molecules Sugars, sugar alcohols, urea,
cyclodextrins, surfactants Lipids: fats, waxes, paraffins etc., surfactants
Polymers Macrogols, polyox, cellulose ethers, povidone, copovidone, PEG‐PVA gran copolymer etc.
Cellulose ethers, PMMA derivaJves, silicones, PE etc.
35
PharmaceuJcal Solid State
PSSRC
Research ClusterChemical Name Trade Name Tg (°C) Tm (°C)
Polyethylene glycol Carbowax® ‐20 35‐65
Polyethylene oxide PolyOx™ ‐50 60‐80
Hydroxypropyl cellulose Klucel® 0
Ethyl Cellulose Ethocel® 133
Hydroxypropyl Methyl Cellulose Methocel® 160‐170
Poly(dimethylaminoethyl methacrylate‐co‐methacrylic
esters) Eudragit® E 50
Ammonio methacrylate
copolymer Eudragit® RS/RL PO 64
Poly(vinyl pyrrolidone) Kollidon®
Poly(vinyl acetate) Sentry® Plus 35‐40
PharmaceuJcal Solid State
PSSRC
Research ClusterPlas.cizer Type Examples
Citrate esters triethyl citrate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate
Fary acid esters butyl stearate, glycerol monostearate, stearyl alcohol Sebacate esters dibutyl sebacate
Phthalate esters diethyl phthalate, dibutyl phthalate, dioctyl phosphate Glycol derivaJves Polyethylene glycol, propylene glycol
Others triaceJn, mineral oil, castor oil, Vitamin E TPGS Increase the workability, flexibility, and distensibility of a polymer lowering the melt viscosity, glass transiGon temperature and elasJc modulus of a polymeric film
PharmaceuJcal Solid State
PSSRC
Research Cluster Hydroxypropyl cellulose
Hydroxy propyl methyl cellulose
Carbopol
Poly vinyl pyrrolidone
Carboxy methyl cellulose
Poly(vinyl alcohol)
Poly(isobutylene)
Xantham gum
Chitosan
Polycarbophil
Poly(acrylic acid)
PharmaceuJcal Solid State
PSSRC
Research ClusterMelt extrusion: Advantages
Melt extrusion is a potenJal conJnuous process
No organic solvents or water are needed
Less labor and equipment demands
Shorter and more efficient processing Jmes
Favorable product cost
Can produce solid soluJons or dispersions which may lead to improved solubility and bioavailability
Product life cycle management
39
Melt extrusion and QbD principles I
PharmaceuJcal Solid State
PSSRC
Research ClusterCooling, milling
Micro GL27‐28D, Leistritz, Germany
Conveying belt 130, Brabender, Germany
ZM 200, Retsch, Germany
PharmaceuJcal Solid State
PSSRC
Research ClusterConJnuous ProducJon
42
PharmaceuJcal Solid State
PSSRC
Research ClusterCourtesy: Thermo Fisher Scien.fic
Pharma 24 PelleJzer Varicut
TF 207 Pharma Chill Roll 24 mm
PharmaceuJcal Solid State
PSSRC
Research ClusterMelt extrusion: ApplicaJons
47
PharmaceuJcal Solid State
PSSRC
Research ClusterDosage forms
Solid oral dosage forms
– Granules, Microgranules – Tablets
– Capsules – Oral film strips
Other dosage forms
– Pressure sensiJve adhesives
• Transdermal
• Stoma products
– Vaginal rings
– Implants
PharmaceuJcal Solid State
PSSRC
Research ClusterAn illustra.on of Implanon®
implantable contracep.on An illustra.on of Kaletra Meltrex
Tablets
An illustra.on of NuvaRing®
PharmaceuJcal Solid State
PSSRC
Research ClusterPrototype Transmucosal (“Patch”) applied in‐vivo (placebo)
Die‐cut Prototype Denture Adhesive Film for maxillary (upper) denture
US Patent No. 6,375,963, M. Repka, L. Repka, J. McGinity, April 23, 2002
PharmaceuJcal Solid State
PSSRC
Research ClusterSource: LTS
Films/ wafers
PharmaceuJcal Solid State
PSSRC
Research ClusterFilm extrusion I
Repka et al. 2003
PharmaceuJcal Solid State
PSSRC
Research ClusterFilm extrusion I
• Killion extruder
• 125‐130 °C
• 70 rpm
• 6 inch flex lip die
• 340‐360 μm film thickness
• Sustained‐release
bioadhesive films for use in topical treatment of
candidiasis in the oral cavity
PharmaceuJcal Solid State
PSSRC
Research ClusterFilm extrusion I
PharmaceuJcal Solid State
PSSRC
Research ClusterFilm extrusion II
Repka et al. 2005
PharmaceuJcal Solid State
PSSRC
Research ClusterFilm extrusion II
Tumuluri et al. 2008
CASE STUDIES
CASE I
GLASSY SOLID SOLUTIONS
PharmaceuJcal Solid State
PSSRC
Research ClusterHot melt extrusion
Chokshi et al. 2005
PharmaceuJcal Solid State
PSSRC
Research ClusterHot melt extrusion
Foster et al., 2001
PharmaceuJcal Solid State
PSSRC
Research ClusterHME: Celecoxib
PharmaceuJcal Solid State
PSSRC
Research ClusterCEL/aPMMA 1:1 (w/w)
Celecoxib
PharmaceuJcal Solid State
PSSRC
Research ClusterCEL/aPMMA 1:1 (w/w)
Albers et al. 2009
PharmaceuJcal Solid State
PSSRC
Research ClusterCEL/aPMMA 1:1 (w/w): SEM Extrudates
opaque transparent
before dissoluJon
aner 2 min dissoluJon
PharmaceuJcal Solid State
PSSRC
Research ClusterDSC: Celecoxib extrudates
PharmaceuJcal Solid State
PSSRC
Research ClusterLoading of extrudates
PharmaceuJcal Solid State
PSSRC
Research ClusterCEL/aPMMA 1:1 (w/w)
PharmaceuJcal Solid State
PSSRC
Research ClusterCEL/PEG‐PVA 1:1 (w/w)
PharmaceuJcal Solid State
PSSRC
Research ClusterCEL/aPMMA 1:1 (w/w)
PharmaceuJcal Solid State
PSSRC
Research ClusterCEL/aPMMA 1:1 (w/w)
PharmaceuJcal Solid State
PSSRC
Research ClusterCEL/aPMMA 1:1 (w/w)
200 mg CEL, 40 mg HPMC
PharmaceuJcal Solid State
PSSRC
Research ClusterMelt Extrusion
PharmaceuJcal Solid State
PSSRC
Research ClusterSolubility parameter distance
bold: glassy solid soluJons
PharmaceuJcal Solid State
PSSRC
Research ClusterDifferenJal Scanning Calorimetry
API: Tm, Tg, enthalpy
PharmaceuJcal Solid State
PSSRC
Research ClusterDifferenJal Scanning Calorimetry
HPMC: API and carrier miscible
PharmaceuJcal Solid State
PSSRC
Research ClusterDSC parameter distance
bold: glassy solid soluJon
CASE II
POLYMER MIXTURES
PharmaceuJcal Solid State
PSSRC
Research ClusterFormulaJons
79 Melt extrusion and QbD principles I
Kalivoda et al. 2012
PharmaceuJcal Solid State
PSSRC
Research ClusterProcess prameters
80
Melt extrusion and QbD principles I
PharmaceuJcal Solid State
PSSRC
Research ClusterMelt extrusion and QbD principles I 81
PharmaceuJcal Solid State
PSSRC
Research ClusterComparison with physical mixtures
82
Melt extrusion and QbD principles I
CASE III
ELECTROSTATIC INTERACTIONS
PharmaceuJcal Solid State
PSSRC
Research ClusterElectrostaJc interacJons
84 Melt extrusion and QbD principles I
Kindermann et al. 2011
PharmaceuJcal Solid State
PSSRC
Research ClusterElectrostaJc interacJons
85 Melt extrusion and QbD principles I
Kindermann et al. 2011
PharmaceuJcal Solid State
PSSRC
Research ClusterElectrostaJc interacJons
86 Melt extrusion and QbD principles I
Kindermann et al. 2011
FT‐IR Raman
salt formaJon confirmed
PharmaceuJcal Solid State
PSSRC
Research ClusterElectrostaJc interacJons
87 Melt extrusion and QbD principles I
Kindermann et al. 2011
addiJon of NaCl 50 mg drug
PharmaceuJcal Solid State
PSSRC
Research ClusterElectrostaJc interacJons
88 Melt extrusion and QbD principles I
Kindermann et al. 2011
addiJon of NaCl
500 mg drug
CASE V
CYCLODEXTRIN AS CARRIER
PharmaceuJcal Solid State
PSSRC
Research ClusterComponents
90 Melt extrusion and QbD principles I
Indomethacin 1:1 mixture HP‐ß‐CD
PharmaceuJcal Solid State
PSSRC
Research ClusterDissoluJon
91 Melt extrusion and QbD principles I
Yano & Kleinebudde 2010
Wet extrudate Melt extrudate Physical mixture
Pure indomethacin
PharmaceuJcal Solid State
PSSRC
Research ClusterSolid state
92 Melt extrusion and QbD principles I
Yano & Kleinebudde 2010
f = melt extrudate
CASE VI
SOLID CRYSTAL SUSPENSIONS
PharmaceuJcal Solid State
PSSRC
Research ClusterSolid state characterisJcs
94
Thommes et al. 2011
PharmaceuJcal Solid State
PSSRC
Research ClusterDissoluJon
95
Thommes et al. 2011
PharmaceuJcal Solid State
PSSRC
Research ClusterDissoluJon: storage stability
96
Thommes et al. 2011
PharmaceuJcal Solid State
PSSRC
Research ClusterWerability
97
Thommes et al. 2011
pure griseofulvin crystalline suspension containing
50% griseofulvin in mannitol
PharmaceuJcal Solid State
PSSRC
Research ClusterSolid crystal suspension
• The preparaJon of crystalline mixtures by hot melt extrusion has the potenJal to be an effecJve way to increase the dissoluJon rate of poorly soluble drugs.
• The use of mannitol as a matrix forming agent with a low molecular weight showed a fast drug release for three poorly soluble drugs.
• The magnitude of enhancement of the dissoluJon rate is comparable to that sought with other types of solid dispersions.
• The “solid crystal suspension” appears to be a general approach suitable for drugs that are difficult to stabilize in the amorphous form.
98
Melt extrusion and QbD principles I
PharmaceuJcal Solid State
PSSRC
Research ClusterReferences
PharmaceuJcal Solid State
PSSRC
Research ClusterDüsseldorf
NASA, 2004
