INTRODUCTION Solid dispersion technology is key enabling technology for bioavailability enhancement of poorly soluble compounds. Re-search in the past decade in solid dispersions and process tech-nology has established that stable solid dispersions can be pre-pared 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 re-crystallization. The preferred polymer must also be amenable to the process technology. In hot melt extrusion, thermal 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 extru-sion is performed at temperatures between 20–40°C above the Tg of the polymer. High Tg polymers are preferred for perform-ance stability, but are more difficult to process by melt extrusion without plasticization by adjuvants and/or the API. The thermal decomposition properties of the polymer (along with those of the API and any adjuvants) determine the upper process tempera-tures in melt extrusion. Rheological properties of the polymer melt are important for process start-up and steady-state process-ing, depending on the power of the extruder motor, melt viscosi-ties below 100,000 Pa.s and preferably below 10,000 Pa.s are desired for melt extrusion.

Thermal and Rheological Properties of PovidoneTM

and CopovidoneTM

Polymers for Hot Melt Extrusion Application

Mohammed Rahman1, Seher Ozakan

2, James Lester

1, Ishrath Farzani,

1Vivian Bi

3, and Thomas Dürig

3

1Ashland Specialty Ingredients, Columbia, MD 21045, USA;

2Ashland Specialty Ingredients, Wayne, NJ 07470, USA ;

3Ashland Specialty Ingredients, Wilmington, DE 19894-0001 USA

EXPERIMETAL METHODS Thermal Gravimetric Analysis TGA experiments were performed using TA Instruments Q500. Thermal decomposition of Plasdone 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 nitro-gen purges. Second different samples were held at fixed tem-peratures from 140-230 °C for 30 minutes. Viscosity Dynamic oscillatory flow tests were carried out in the linear vis-coelastic region using a strain-controlled ARES-G2 rheometer equipped with a temperature control chamber (TA instruments, DE). Granular samples were loaded on the 25mm 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 con-ducted for each sample under nitrogen and air purge.

CONCLUSIONS All Plasdone polymers show some degradation above 180°C; consequently, an upper limit of 180°C is recommended

for melt extruding these polymers. Plasdone S-630 and K-12 have ideal rheological characteristics for melt extrusion. The other grades will either require plasticization by API or other adjuvants in order to successfully melt extrude solid dispersion below 180°C.

RESULTS AND DISCUSSION Thermal Properties Figure 1 shows the glass transition temperature of various grades of Plasdone polymers.

Differential Scanning Calorimetry DSC experiments were performed using a TA instruments DSC Q2000. Glass transition temperatures of the polymers was meas-ured using a heat cool heat method where the samples were heated at 20°C/min to 100°C and held there for five minutes. Next the sam-ple was cooled at 50°C/min to 0°C before performing a modulated heating cycle ramping at 2°C/min. USP Testing The Plasdone polymers were processed on a Dynisco Laboratory Mixing Extruder at 180°C and tested to ensure that the polymers still met all USP requirements after being extruded. All polymers tested were within USP specifications.

Table1: Tg of PlasdoneTM

polymers.

Product K-Value

(Kinematic Vis-

cosity)

Typical Weight Ave.

Mol. Wt.

Typical Glass

Transition Tem-

perature, °C

PlasdoneTM K12 10.2 - 13.8 4,000 120

PlasdoneTM K17 15.5 – 17.5 10,000 140

PlasdoneTM K25 24 – 26 34,000 160

PlasdoneTM K29/32 29 – 32 58,000 164

PlasdoneTM K90 85 - 95 1,300,000 174

PlasdoneTM S630 26 - 29 40,000 106

Figures 3 and 4 show TGA results for Plasdone S630 that was heated to 170°C and 230°C respectively and held there for 30 min-utes to measure the amount of degradation that occurs when the polymer is exposed to that temperature. After heating the sample exposed to 170°C was colorless but the sample that was exposed to 230°C was a dark yellow color which is indicative of degradation.

Figure 3. PlasdoneTM

S-630, isothermal @ 170°C for 30 min-utes. Sample purged with air.

Figure 4. PlasdoneTM

S-630, isothermal @ 230°C for 30 min-utes. Sample purged with air.

All Plasdone polymers exhibit similar degradation behavior; temperature ramps from ambient to 600 °C show short-exposure degradation from 270-300 °C and 30 minute isother-mal holds show weight and color changes appearing at 190-200 °C. Figure 4 illustrates the recommended melt extrusion processing window for neat Plasdone polymers; the polymer processing window is restricted between the Tg of the material and the onset of degradation.

Figure 6. Tg and themodegradation temperatures of Plasdo-ne

TM polymers.

Rheology The melt rheology of neat Plasdone polymers was characterized by:

Measuring viscosity as a function of shear rate at constant temperature Measuring initial viscosity at different temperatures Measuring viscosity as a function of time at different tempera-tures to generate additional thermal stability information

The viscosity of Plasdone polymers at various temperatures is

shown in Figure 5, the ideal hot melt extrusion processing win-dow for these polymers is between ~700 and 100,000 Pa.s while maintaining temperatures below the degradation point of 180°C.

Figure 7. PlasdoneTM

polymer melt rheology

10

100

1000

10000

100000

1000000

10000000

100000000

0.1 1 10 100 1000

* (P

a.s)

Frequency (rad/s)

Plasdone K12 at 130°C

Plasdone K17 at 180°C

Plasdone K25 at 190°C

Plasdone S630 at 170°C

Plasdone K29/32 at 190°C

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100

1000

10000

100000

0.1 1 10 100 1000

* (P

a.s)

Frequency (rad/s)

Plasdone S630 at 150°C

Plasdone S630 at 170°C

Plasdone S630 at 200°C

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1000000

10000000

100000000

0.1 1 10 100

* (P

a.s)

Frequency (rad/s)

Plasdone K12 at 130°C

Plasdone K12 at 150°C

Plasdone K12 at 170°C

Figure 8. PlasdoneTM

polymers shear rate vs. viscosity at fixed temperature.

Figure 9. PlasdoneTM

S630shear rate vs. viscosity at various temperatures.

Figure 10. PlasdoneTM

K-12 shear rate vs. viscosity at various temperatures.

Figure 11. PlasdoneTM

S630 melt rheology with increas-ing temperature.

Figure 5. Plas-done

TM S-630,

after exposure to various tempera-tures for 30 min-utes.

Figure 1. PlasdoneTM

K-29/32 Tg determination using heat/cool/heat methond.

Figure 2. PlasdoneTM

S630 Tg determination using heat/cool/heat methond.

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0.1 1 10 100 1000

* (P

a.s)

Frequency (rad/s)

Plasdone K25 at 190°C

Plasdone K25 at 210°C

Figure 10. PlasdoneTM

K-17 shear rate vs. viscosity at various temperatures.