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