In-process rheometry as a PAT tool for hot melt extrusion.
Summary (2 min read)
Introduction
- Hot Melt Extrusion (HME) is a continuous manufacturing process which is increasingly being used to generate amorphous solid dispersions or solutions of poorly soluble Active Pharmaceutical Ingredients (APIs) in polymer matrices 1, 2 .
- There exists a drive within the pharmaceutical industry to adopt real-time measurements for continuous processes to enhance process understanding and product quality, as part of a wider Quality by Design (QbD) approach.
- These basic process measurements give little direct indication of the consistency or rheology of the extrudate.
- Measurement of the pressure drop across this die at a range of flow rates allows calculation of rheological properties such as viscosity.
- A range of in-line rheological techniques have been reported for polymer extrusion to enhance process control or process understanding.
Thermal Analysis
- Thermo-gravimetric analysis (TGA) was carried out using a Q500 TGA (TA Instruments, UK) to determine the moisture content and the decomposition temperature of the base materials.
- All measurements were carried out in duplicate and the data were analyzed using Universal Analysis 2000 v.4.3A software (TA Instruments, UK).
- Samples of the polymer, drug, polymer:drug physical mixtures and extrudates were enclosed in an aluminum pan and sealed with a pin-holed lid allowing evaporation of moisture.
- A heat/cool/heat cycle was carried out for all the samples at rates of 10°C/min.
- The melting point was recorded at the top of the peak during the first heating stage, while the glass transition temperature (Tg) was calculated at onset, inflection and endpoint of the transition during the reheating step.
Rheological Analysis
- Off-line rheological testing was carried out using a Physica MCR 501 rotational rheometer (Anton Paar, Austria) with parallel plate geometry of diameter 25mm.
- The gap between the two plates was set to 1 mm for all tests.
- Frequency sweeps were performed at a constant strain of 3%, this value having been determined to be within the linear viscoelastic range by preceding strain amplitude tests.
Hot Melt Extrusion
- Extrusion was performed using a co-rotating twin screw pharmaceutical grade extruder (Pharmalab, Thermo Scientific, UK) with screw diameter 16mm and a screw length to diameter ratio of 40:1.
- The extruder was fitted with a rheological slit die (in-house design, University of Bradford) consisting of a temperature controlled adaptor and slit-die block.
- At each set temperature, the three pressure transducers used in the rheological die were calibrated to minimize any temperature-related signal drift.
- The powder blend or the polymer alone was fed into the extruder at each specified feed rate using a gravimetric twin-screw feeder.
- A linear fit was then applied and pressure drop along the slit length (ΔP) and predicted pressure at the exit of the die (P exit ) were calculated.
Results and Discussion
- DSC thermograms of the pure API, polymer and physical mixtures are shown in Figure 2 .
- This plasticisation can affect the melt processing behaviour of the polymer during melt extrusion, resulting in a viscosity reduction.
- For each material, a shear thinning effect was observed, in agreement with the off-line rheometry results previously shown in Figure 3 .
- Shear and complex viscosities measured during extrusion and using oscillatory rheometry are compared at 140°C for 20% w/w API in Figure 8 .
- These measurements displayed a clear discrimination between drug loadings not only in magnitude of exit pressure drop but also in the rate of increase with shear rate.
Conclusions
- An instrumented slit die rheometer designed to fit a pharmaceutical grade twin screw extruder has been developed and used to monitor hot melt extrusion of a development API within a copolymer matrix.
- Results showed that the compound displayed shear thinning behavior in the mixtures tested and that shear viscosity decreased with increase in API loading, reflecting miscibility of the API within the polymer matrix.
- Viscosity and die exit pressure were found to be heavily dependent upon.
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Cites background from "In-process rheometry as a PAT tool ..."
...Rheology regards the study of the material flow and deformation behaviour and may be measured by applying an external force (shear-induced deformation) to a sample [3]....
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13 citations
References
227 citations
"In-process rheometry as a PAT tool ..." refers methods in this paper
...Other workers have also used oscillatory rheometry as a preformulation tool [23,24]....
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204 citations
"In-process rheometry as a PAT tool ..." refers methods in this paper
...The application of HME for manufacture of pharmaceuticals has been widely reported including pellets [3], sustained release tablets [4,5] implants [6], and transdermal films [7]....
[...]
149 citations
"In-process rheometry as a PAT tool ..." refers background in this paper
...Hot Melt Extrusion (HME) is a continuous manufacturing process which is increasingly being used to generate amorphous solid dispersions or solutions of poorly soluble Active Pharmaceutical Ingredients (APIs) in polymer matrices [1,2]....
[...]
139 citations
"In-process rheometry as a PAT tool ..." refers background in this paper
...A number of comprehensive reviews of the pharmaceutical HME process are available [1,8,9]....
[...]
132 citations
"In-process rheometry as a PAT tool ..." refers methods in this paper
...The application of HME for manufacture of pharmaceuticals has been widely reported including pellets [3], sustained release tablets [4,5] implants [6], and transdermal films [7]....
[...]
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Frequently Asked Questions (13)
Q2. What is the effect of temperature on the viscosity of polymer molecules?
Increasing temperature provides the polymer molecules with greater mobility allowing them to flow more freely whereas plasticizers act to reduce the internal resistance of the polymer melt by effectively lubricating the flow of polymeric chains.
Q3. What can be used to give an indication of specific energy input to the melt?
Motor torque and material throughput can also be recorded and used to give an indication of specific energy input to the melt, which is related to the temperature, material properties and degree of filling in the extruder screw channels.
Q4. How long was the rheological die allowed to stabilize?
At each set throughput, the process was allowed a 15 minute stabilization period before pressure measurements were recorded, for a representative period of around 10 minutes.
Q5. What is the use of a slit die rheometer?
In-line rheological slit dies have also been used in twin screw extrusion, both for monitoring reactive extrusion processes such as cross-linking of polyethylene 29 and for incorporation of additives such as the flame retardant magnesium hydroxide into a polyethylene 30 .
Q6. How many Hz were used to measure the pressure of the slit die?
Three pressure transducers (Dynisco PT435) with a full scale deflection of 10.3 MPa were flush mounted at the surface of the slit and monitored at a frequency of 1
Q7. How can rheology be measured in a die?
Real-time assessment of rheology within the extrusion process can be achieved by measurement of pressure drop inside an instrumented extruder die.
Q8. What is the effect of the API loading on the die?
Results showed that the compound displayed shear thinning behavior in the mixtures tested and that shear viscosity decreased with increase in API loading, reflecting miscibility of the API within the polymer matrix.
Q9. How much shear strain was observed at 40 % w/w API?
The plasticization effect of the API was also clearly observed, with shear viscosity decreasing from 1150 Pa.s at 20 % w/w API to 233 Pa.s at 40 % w/w API at an apparent shear strain rate of 15 s -1 .
Q10. What can be used as a quality control indicator?
Such measurements can be used as a quality control indicator, using statistical process control and trending analysis to detect deviations from the desired set point.
Q11. How many studies have been reported on the use of rheology?
Rheology has been used to characterize pharmaceutical solid dispersions and solutions, although only a relatively small number of studies have been reported.
Q12. What is the effect of high temperature and mixing on the flow properties of the polymer?
It appears likely that this exposure to high temperature and mixing had an effect on the consistency of the flow properties of the compound, increasing the level of plasticization and mixing.
Q13. What was the result of the rheological analysis of the API?
This indicated that the API was readily miscible within the polymer matrix in the molten state, and that the API had a plasticising effect.