1. INTRODUCTION
Solid dispersion technology is a key enabling technology for
bioavailability enhancement of poorly soluble compounds.
Research in the past decade in solid dispersions and process
technology has established that stable solid dispersions can be
prepared at commercial scale through hot-melt extrusion. Polymer
selection is critical in producing a successful amorphous solid
dispersion that facilitates dissolution and prevents the API
recrystallization. In hot-melt extrusion, thermal degradation
properties and melt rheology must be considered when selecting a
formula. The glass transition temperature, Tg, of the polymers
defines the lower end of the processing temperature window;
typically extrusion is performed at temperatures between 20–40°C
above the Tg of the polymer. High Tg polymers are preferred for
physical stability but more difficult to process by melt extrusion
without plasticization by adjuvants and/or the API. The thermal
degradation properties of the polymer (along with those of the API
and any adjuvants) determine the upper process temperatures in
melt extrusion. Rheological properties of the polymer melt are
important for start-up and steady-state processing; depending on
the power of the extruder motor, melt viscosities below 100,000
Pa·s and preferably below 10,000 Pa·s are desired for hot melt
extrusion.
THERMAL AND RHEOLOGICAL PROPERTIES OF KLUCELTM
HYDROXYPROPYLCELLULOSE POLYMERS FOR
HOT-MELT EXTRUSION APPLICATIONS
Mohammed Rahman1
, Elanor Pinto3
, Seher Ozakan2
, Kimberly Gaughan3
, A. Sosnowik3
James Lester1
, James Brady3
, Ishrath Farzana1
, Robert Sulouff3
,
Vivian Bi3
and Thomas Dürig3
1
Ashland Specialty Ingredients,Solubilization Center of Excellence, Columbia, MD 21045, USA; 2
Ashland Specialty Ingredients, Wayne, NJ 07470, USA ; 3
Ashland Specialty Ingredients, Wilmington, DE 19808 USA
EXPERIMENTAL METHODS
Thermal Gravimetric Analysis
TGA experiments were performed using a TA Instruments Q500.
Thermal decomposition of Klucel hydroxypropylcellulose (HPC)
polymers was characterized by TGA using two methods; first, the
sample was heated from ambient to 600°C at different heating
rates under air and nitrogen purges. Second, samples were
isothermally heated from 140 to 230°C for long term 30 minute
heat exposure and short term 5 minute heat exposure.
Viscosity
Dynamic oscillatory flow tests were carried out in the linear
viscoelastic region using a strain-controlled ARES-G2 rheometer
equipped with a temperature control chamber (TA instruments).
Powder samples were loaded on the 25 mm stainless steel parallel
plate set up with the help of a melt ring. Samples were not dried
before testing. Dynamic strain sweep, frequency sweep,
temperature sweep and time sweep tests were conducted for each
sample under nitrogen and air purge.
Capillary Rheometry
Capillary viscosity experiments were performed using a bench top
Rosand RH2200 capillary rheometer with a twin bore configuration.
Test materials are placed inside barrels with select dies. During a
measurement, two pistons are inserted into the barrels and driven
downwards to extrude test materials through the dies. At the
bottoms of the barrels and near the die entrances, two pressure
transducers measure the pressure drop across the entire die
length with respect to the ambient pressure.
CONCLUSIONS
Higher molecular weight Klucel HPCs are less resistant to
thermal degradation and discoloration than lower molecular
weight HPCs. Although Klucel HPCs may yellow or brown at
relatively low temperatures, Klucel HPCs extruded at
temperatures above discoloration temperatures still meet select
USP compendial testing such as identification by FTIR,
moisture content, viscosity, pH and terminal methyl content.
Dynamic oscillatory flow testing suggests that all Klucel HPC
polymers can be extruded without the addition of plasticizer;
however, only lower molecular weight Klucel HPCs can be
extruded below discoloration temperatures without the addition
of plasticizer. Melt rheology data below 200o
C suggests that
water content could have a significant impact on Klucel HPC
melt behavior. Low molecular weight Klucel HPC polymers
have ideal rheological and thermal degradation characteristics
for hot melt extrusion without plasticization.
RESULTS AND DISCUSSION
Thermal Degradation & Discoloration by TGA
Table 1 describes the various grades of Klucel HPC polymers, their
respective molecular weights and aqueous solution viscosities.
Figures 1 and 2 illustrate the TGA results for Klucel ELF HPC that
was isothermally heated for long term 30 minute isothermal heat
exposure at 120°C and 180°C, respectively. Figure 3 shows the
resulting color change of long term 30 minute isothermal heat
exposure of Klucel ELF HPC between 100°C and 180°C. Klucel
ELF HPC shows slight yellow discoloration at 140°C and browning at
150°C. Figures 4 through 12 show similar experiments performed
with Klucel LF, JF, and HF HPC. Klucel LF HPC shows a similar
temperature induced discoloration profile as Klucel ELF HPC. Klucel
JF HPC shows slight yellow discoloration at 160°C and browning by
180°C. Klucel HF HPC shows slight yellow discoloration at 190°C
and browning by 200°C. Table 2 shows the temperature induced
discoloration profile of Klucel HPCs after long term 30 minute
isothermal heat exposure. The overall TGA results of all Klucel
HPCs show a 2-3% moisture loss in the first 5-10 minutes of
isothermal heating followed by a second less appreciable weight loss
(less than 1%) after 10-30 minutes of isothermal heating. The
second less appreciable weight loss in isothermal heating is less
significant at higher temperatures than lower temperatures,
suggesting heat induced degradation. The overall results suggest
that higher molecular weight HPCs are less resistant to isothermal
degradation and discoloration than lower molecular weight HPCs.
Short term 5 minute heat exposure experiments for Klucel HPCs
show similar results to the long term 30 minute heat exposure
experiments (results not shown.)
USP Testing
Klucel HPC polymers were processed on a Dynisco®
Laboratory
Mixing Extruder at 180°C and tested to ensure that the polymers still
met specific USP requirements after being extruded.
Fourier Transform Infrared Spectroscopy (FTIR)
The infrared spectra were collected employing a Golden Gate diamond
ATR accessory mounted in a Nicolet Magna 760 FTIR spectrometer.
Quantitative parameters were used for spectrum collection – 4cm-1
resolution, 150 co-added scans (3 minute 45 second collection time),
0.4747 mirror velocity, one level of zero filling and a DTGS detector.
Table 1: Klucel HPC Polymers
Klucel HPC
Grade
Typical Weight Avg. Mol.
Wt.
Solution Viscosity (wt/wt%)
(cP)
ELF 40,000 *
EF 80,000 200-600 (10%)
LF 95,000 75-150 (5%)
JF 140,000 150-400 (5%)
GF 370,000 150-400 (2%)
MF 850,000 4000-6500 (2%)
HF 1,150,000 1500-3000 (1%)
Rheology
The melt rheology of neat Klucel HPC polymers was characterized
by measuring the melt flow index by capillary rheometry at
constant temperature (Figure 15), measuring viscosity at various
temperatures (Figure 16), measuring viscosity as a function of
shear rate at constant temperature (Figure 17), and measuring
viscosity as a function of shear rate at various temperatures
(Figures 18-20).
As shown in Figure 16, the melt viscosity profile of Klucel HPC
polymers suggests that the ideal hot-melt extrusion processing
window for these polymers is between ~700 and 100,000 Pa·s
while processing below discoloration and degradation
temperatures. The temperature sweep data suggests that all
Klucel HPC polymers can be extruded below 200o
C; however, the
melt viscosity of Klucel HPC polymers does not show a linear
correlation with Klucel HPC molecular weight, suggesting that
moisture content may be playing a significant role in Klucel HPC
melt viscosity. The temperature dependent shear rate versus
viscosity data suggests that all Klucel HPC polymers demonstrate
classic psuedoplastic behavior wherein increasing shear rate
decreases melt viscosity. Increasing temperature of Klucel ELF
and HF HPCs significantly reduces melt viscosity but increasing
temperature of Klucel MF HPC does not significantly reduce the
melt viscosity, suggesting that temperature dependent melt
viscosity may not be molecular weight dependent.
Figure 16. Klucel HPC temperature
sweep.
Figure 17. Klucel HPC shear rate
vs. viscosity at 200o
C.
Figure 1. Klucel ELF HPC, 120°C, N2
purged 30 minute isothermal TGA
-2.8%
-0.1%
-0.5
0.0
0.5
1.0
1.5
2.0
[]Deriv.Weight(%/min)––––––
92
94
96
98
100
102
Weight(%)
0 5 10 15 20 25 30 35 40
Time (min)
Sample: X35319-4G Klucel HPC ELF
Size: 14.8220 mg
Method: Ramp-Iso 20-120°C
Comment: Lot # 13930
TGA
File: J:...QTGA ISO X35319-4G N2.120
Operator: Q5000 IR 0466
Run Date: 01-Jun-2012 14:16
Instrument: TGA Q5000 V3.13 Build 261
Universal V4.7A TA Instruments
Figure 2. Klucel ELF HPC, 180°C, N2
purged 30 minute isothermal TGA
-3.0%
-0.9%
-0.5
0.0
0.5
1.0
1.5
2.0
[]Deriv.Weight(%/min)––––––
92
94
96
98
100
102
Weight(%)
0 5 10 15 20 25 30 35 40
Time (min)
Sample: X35319-4G Klucel HPC ELF
Size: 16.3320 mg
Method: Ramp-Iso 20-180°C
Comment: Lot # 13930
TGA
File: J:...QTGA ISO X35319-4G N2.180
Operator: Q5000 IR 0466
Run Date: 04-Jun-2012 08:37
Instrument: TGA Q5000 V3.13 Build 261
Universal V4.7A TA Instruments
Figure 15. Effect of Klucel HPC MW
on Melt Flow Index at 150o
C
Figure 18. Klucel ELF HPC
temperature dependent shear rate
vs. viscosity.
Figure 19. Klucel LF HPC tempera-
ture dependent shear rate vs. vis-
cosity.
Figure 20. Klucel MF HPC
temperature dependent shear rate
vs. viscosity.
Figure 12. Klucel HF HPC, 210°C, N2
purged 30 minute isothermal TGA
-3.6%
-0.8%
-0.5
0.0
0.5
1.0
1.5
2.0
[]Deriv.Weight(%/min)––––––
92
94
96
98
100
102
Weight(%)
0 5 10 15 20 25 30 35 40 45
Time (min)
Sample: X35320-60-1 Klucel HPC HF
Size: 14.9890 mg
Method: Ramp-Iso 20-210°C
Comment: Lot # 15052
TGA
File: J:...QTGA ISO X35320-60-1 N2.210
Operator: Q5000 IR 0466
Run Date: 04-Jun-2012 17:10
Instrument: TGA Q5000 V3.13 Build 261
Universal V4.7A TA Instruments
Figure 11. Klucel HF HPC, 180°C, N2
purged 30 minute isothermal TGA
-3.5%
-0.4%
-0.5
0.0
0.5
1.0
1.5
2.0
[]Deriv.Weight(%/min)––––––
92
94
96
98
100
102
Weight(%)
0 5 10 15 20 25 30 35 40 45
Time (min)
Sample: X35320-60-1 Klucel HPC HF
Size: 15.0100 mg
Method: Ramp-Iso 20-180°C
Comment: Lot # 15052
TGA
File: J:...QTGA ISO X35320-60-1 N2.180
Operator: Q5000 IR 0466
Run Date: 04-Jun-2012 18:35
Instrument: TGA Q5000 V3.13 Build 261
Universal V4.7A TA Instruments
Figure 3. Klucel ELF HPC, 30 minute
exposure to various temperatures.
Figure 4. Klucel LF HPC, 30 minute
exposure to various temperatures.
Figure 10. Klucel HF HPC, 30 minute
exposure to various temperatures.
Figure 9. Klucel JF HPC, 30 minute
exposure to various temperatures.
-3.9%
-0.5%
-0.5
0.0
0.5
1.0
1.5
2.0
[]Deriv.Weight(%/min)––––––
90
92
94
96
98
100
102
Weight(%)
0 10 20 30 40 50
Time (min)
Sample: X35319-4C Klucel JF
Size: 15.2100 mg
Method: Ramp-Iso 20-190°C
Comment: Lot # 14521
TGA
File: J:...QTGA ISO X35319-4C N2.190
Operator: Q5000 IR 0466
Run Date: 21-Jun-2012 18:14
Instrument: TGA Q5000 V3.13 Build 261
Universal V4.7A TA Instruments
Figure 8. Klucel JF HPC, 190°C, N2
purged 30 minute isothermal TGA
-3.5%
-0.1%
-0.5
0.0
0.5
1.0
1.5
2.0
[]Deriv.Weight(%/min)––––––
90
92
94
96
98
100
102
Weight(%)
0 10 20 30 40 50
Time (min)
Sample: X35319-4C Klucel JF
Size: 15.3340 mg
Method: Ramp-Iso 20-130°C
Comment: Lot # 14521
TGA
File: J:...QTGA ISO X35319-4C N2.130
Operator: Q5000 IR 0466
Run Date: 21-Jun-2012 14:05
Instrument: TGA Q5000 V3.13 Build 261
Universal V4.7A TA Instruments
Figure 7. Klucel JF HPC, 130°C, N2
purged 30 minute isothermal TGA
Figure 5. Klucel LF HPC, 130°C, N2
purged 30 minute isothermal TGA
-2.5%
-0.1%
-0.5
0.0
0.5
1.0
1.5
2.0
[]Deriv.Weight(%/min)––––––
90
92
94
96
98
100
102
Weight(%)
0 10 20 30 40 50
Time (min)
Sample: X35319-4E Klucel LF
Size: 14.8920 mg
Method: Ramp-Iso 20-130°C
Comment: Lot # 14587
TGA
File: J:...QTGA ISO X35319-4E N2.130
Operator: Q5000 IR 0466
Run Date: 27-Jun-2012 13:49
Instrument: TGA Q5000 V3.13 Build 261
Universal V4.7A TA Instruments
-2.6%
-0.5%
-0.5
0.0
0.5
1.0
1.5
2.0
[]Deriv.Weight(%/min)––––––
90
92
94
96
98
100
102
Weight(%)
0 10 20 30 40 50
Time (min)
Sample: X35319-4E Klucel LF
Size: 14.6040 mg
Method: Ramp-Iso 20-170°C
Comment: Lot # 14587
TGA
File: J:...QTGA ISO X35319-4E N2.170
Operator: Q5000 IR 0466
Run Date: 27-Jun-2012 13:07
Instrument: TGA Q5000 V3.13 Build 261
Universal V4.7A TA Instruments
Figure 6. Klucel LF HPC, 170°C, N2
purged 30 minute isothermal TGA
Figure 14. Infrared spectra comparing
Klucel MF HPC reference and Klucel
MF HPC extruded at 230°C
Figure 13. Infrared spectra comparing
Klucel MF HPC reference and Klucel
MF HPC extruded at 200°C
Select Compendial Testing
Klucel ELF and HF HPC were processed on the Dynisco LME at
180°C and the resulting extrudates were found to be within USP
compendia specification for FTIR, moisture, viscosity, pH, and
terminal methyl content. Klucel MF and HF HPC were also
processed on the Dynisco LME at 200°C and 230°C and the
resulting extrudate showed no significant change compared to the
respective reference FTIR spectrum, as shown if Figures 13 and
14.
Table 2: Klucel HPC Heat Induced Discoloration Profile
Klucel HPC Grade Yellowing
Temperature (o
C)
Browning
Temperature (o
C)
ELF 140 150
EF 140 160
LF 140 170
JF 160 180
GF 180 210
MF 190 210
HF 190 210