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HOT MELT EXTRUSION
AN EMERGING DRUG DELIVERY
TECHNOLOGY
Monika Vasant Pawar
M.Pharm- I
Guided By : Dr. S.S.Mahajan
1
HOT MELT EXTRUSION
Hot melt extrusion is a process of converting raw
material into a product of uniform shape and density by
forcing it through a die under controlled condition.
2
3
MATERIAL USED IN HME
API
Polymers
Additives
Relevant characteristics of API
Solubility
Melting temperature
Physical state
Lipophilicity
Thermal stability4
• Polymers :Selection by :
Thermoplastic behaviour
Suitable glass transition temperature (typically between 50-
180°c)
High thermal stability
No toxicity
Eg : Polyethylene glycol, Eudragit , Vinyl pyrollidone
• Additives :
Physical state
Plasticizing effect
Lubricant effect
Compatibility with API and polymer.5
PLASTICIZER
To improve processing condition,physical and mechanical
properties of final product.
To facilitate the extrusion and increase flexibility.
Plasticizer reduces the
Tg of the polymer
Processing temperature and increase the stability.
Shear forces
Eg :Diethyl phthalate,PEG 400,Glycerol,Methyl
paraben,Triacetin.6
HOT MELT EXTRUSION
Hot-melt extrusion (HME) is used for blending, melting,
extrusion and shaping in a single step process.
Extruders provide extensive mixing and agitation that
causes de-aggregation of the suspended particles in the
molten polymer resulting in a uniform dispersion.
7
PROCESS
In hot-melt extrusion, a blend of polymer and excipients in powder form is transferred by a rotating screw through the heated barrel in the extruder.
The molten mass is continuously pumped through the die at the end of the extruder and rapidly solidifying when exiting the machine.
The screw itself is divided into three parts; feeding, melting and metering. In the feeding section, the material is transported from the hopper into the barrel.
In the melting zone the polymer softens and melts, moving by circulation in a helical path.
8
In the metering zone, the pulsating flow is reduced
to ensure a uniform delivery rate through the die
cavity which is attached at the end of the barrel.
9
EXTRUDER
There are two types of extruders: single-screw and twin-screw
extruders.
Twin-screw extruders use two side-by-side screws either co-
rotating or counter-rotating .
There are several advantages of twin-screw extruders over
single-screw extruders such as easier material feeding and
dispersion capacities, less tendency to over-heat and shorter
transit times .
10
MONITORING PARAMETERS
Barrel temperatures:
The glass transition or
melting temperatures of
polymers and drug usually determines
the barrel temperature.
Feed rate and screw speed: The constant feeding rate and screw
speed throughout the process is
important as the combination of
these two factors establishes the
level of fill in extruder.
The motor load and melt
pressure: These parameters
depend on feed rate and screw
speed.
11
CHARACTERIZATION OF EXTRUDATES
Differential Scanning Calorimetry (DSC)-
Differential scanning calorimetry (DSC) has been widely used
to study the thermal properties of materials used in hot melt
extrusion.
DSC can be used for the quantitative detection of transitions
(melting point, glass transition) in which energy is required or
liberated (i.e. endothermic and exothermic phase
transformations).
The lack of a melting transition in the DSC scan of the hot-
melt extrudate indicates that the drug is present in an
amorphous rather than crystalline form.12
Thermo Gravimetric Analysis (TGA)
TGA is a measure of thermally induced weight loss of a
material as a function of applied temperature.
TGA is limited to studies involving either a weight gain
or loss, and is commonly used to study desolvation and
decomposition.
TGA can be used as a screening tool for the thermal
stability of materials used in hot-melt extrusion.
13
X-Ray Diffraction (XRD)
XRD is also used to characterize the crystalline properties of hot-
melt extruded dosage forms.
XRD is commonly used to determine the solid state of the drug
in an HME formulation immediately after processing and during
storage, and to assess the impact on dissolution and
bioavailabiliy.
Microscopy :
SEM is used to identify the microscopic structure of a dosage
form and allow characterization of difference of crystal growth in
the bulk and at the surface of a dosage form.
Drug recrystallization was lower in extrudates containing
polycarbophil & PVP compared to formulation without additives.14
Infrared Spectroscopy (IR)
IR can be used to detect changes in bonding between
functional groups due to structural changes or a lack of
crystal structure and also identify complex formation.
IR can be used to differentiate between peaks that are
sensitive to changes in crystallinity from those that are not.
Residence time
A high screw speed & powder flow rate reduce the mean
residence time.
Too high screw speed can result in insufficient exposure to
heating zones & insufficient melting and/or dissolving of the
drug substances as the residence time becomes too short.15
Atomic force microscopy :
AFM , a method which can study the surface microstructure of
hot melt extrudate, can be used to visualize phase separation
and/or non homogenicity of of HME samples.
Raman Spectroscopy :
To monitor the API concentration and the solid state of the
formulation during HME.
To identify interaction between drug and polymer based on
peak shift in the spectra.
To determine the residence time distribution.
To study drug distribution in a matrix.
16
SOLID DISPERSION
Solid dispersions is an approach to increase the solubility of the
API and increase bioavailability.
Eg :Lafutidine solid dispersion
Amphiphilic Soluplus used as a primary solubilizing agent,
with different concentrations of selected surfactants like PEG
400, Lutrol F127 (LF127 ), Lutrol F68 (LF68) were used to
investigate their influence on formulations processing via
HME.
Prepared amorphous glassy solid dispersion was found to be
thermodynamically and physicochemically stable17
TABLETS
Tablets of HME formulation can be formed by injection
molding of the hot thermoplastic material or via milling of the
cooled extrudate followed by mixing with excipient and
tableting.
A thermoplastic polymer is molten and injected into a specific
mold.
The molten polymer is solidified in the mold. A matrix tablet
is then achieved.
A tablet of desirable size and shape is easily obtained by
injection-molding.
Eg : Kaletra tablets18
IMPLANTS
By this method PLGA- or PLA- based implants are prepared.
To fabricate PLGA or PLA implants, an operating temperature
above their Tg has to be applied.
By contrast, too high temperature is not allowed, because
incorporating drugs can be thermally degraded.
A drug, peptide or protein, which is sensitive to organic
solvents or water, can be incorporated into the biodegradable
implants.
For example:1. Implanon ,Nexplanon
2.Haloperidol and Diclofenac sodium, have been loaded into
the biodegradable implants by hot-melt extrusion the drug
loading could be up to 40% 19
PELLETS
Hot-melt extrusion is capable of preparing pellets with a
compact structure that can resist rapid water penetration,
thereby enabling the production of pellets with modified
release.
The extruded strands are transferred to a spheronizer
where they are broken into short cylindrical rods and the
ends are thereafter rounded off when in contact with the
rotating friction plate.
Pellets are usually filled into hard capsules to produce
modified-release behaviour.
20
HME MARKETED PRODUCT
21
CONCLUSION
Today melt granulation technology represents an efficient
pathway for manufacture of various drug delivery systems.
This technique is applicable to improve the dissolution
characteristics of a poorly water-soluble drug by improving
the dissolution rate and bioavailability of the drug by
forming a solid dispersion or solid solution.
Melt granulation technique is less time consuming and
economic . 22
REFERENCES
Dennis Douromis ,Hot melt extrusion:Pharmaceutical
Application ,p:43-64.
Halle Pradeep D;*, Sakhare Ram S;, Dadage Ketan K;, Birajdar
Ganesh O; Raut Deepika B, A review on melt granulation
technique,Journal of Pharmacy and Phytotherapeutics,p:6-10.
Singhal S , Lohar V K, Arora V , Hot Melt Extrusion
Technique,p :1-20.
Pradip S Patel, Jignesh P Raval, Hemul V. Patel, Review
on the pharmaceutical applications of hot melt extruder,
Vol.3 Issue 2, April-June 2010
Michael M. Crowley and Feng Zhang, Pharmaceutical
Applications of Hot-Melt Extrusion: Part I ,p:1-18.
K.Kolter,M.Karl,A.Gryczke,Hot Melt Extrusion with BASF
pharma polymers,p:15-37.23
Hot melt extrusion,particle sciences drug development
services,2011,vol3,p:1-2.
Ankit patel, deepak sahu, ashok dashora, rahul garg, piyush
agraval, a review of hot melt extrusion technique , international
journal of innovative research in science, engineering and
technology ,vol. 2, issue 6, june 2013 ,p:1-5.
Ritesh fule, purnima amin,development and evaluation of
lafutidine solid dispersion via hot melt extrusion, asian journal
of pharmaceutical sciences 9 (2014), p:92-106.
Malin lindén, hot-melt extrusion of modified release pellets
,p:6-12.
Duangratana shuwisitkul , biodegradable implants with
different drug release profiles,p:27-34
M.Karl,S.Nalawade,A,Maschke,Suitability of pure and
plasticized polymers for HME,p:1-2.24
25