INTRODUCTION Solid dispersion technology is a 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 physical stability, but are more difficult to process by melt extrusion with-out plasticization by adjuvants and/or the API. The thermal de-composition 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.

PLASTICIZER COMPATIBILITY AND THERMAL AND RHEOLOGICAL PROPERTIES OF POVIDONE AND COPOVIDONE POLYMERS FOR HOT-MELT EXTRUSION APPLICATION

Mohammed Rahman1, Seher Ozakan

2, James Lester

1, Ishrath Farzani

1, Vivian Bi

3, and Thomas Dürig

3

1Ashland Specialty Ingredients,Solubilization Center of Excellence, Columbia, MD 21045, USA;

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

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

EXPERIMENTAL METHODS Thermal Gravimetric Analysis TGA experiments were performed using TA Instruments Q500. Thermal decomposition of Plasdone

TM povidone and copovidone

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 different samples were held at fixed temperatures from 140–230 °C for 30 minutes. Differential Scanning Calorimetry DSC experiments were performed using a TA instruments DSC Q2000. Glass transition temperatures of the polymers was measured using a heat cool heat method where the samples were heated at 20°C/min to 100°C and held there for five min-utes. Next the samples was cooled at 50°C/min to 0°C before performing a modulated heating cycle ramping at 2°C/min. USP Testing Plasdone

TM povidone and copovidone 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 be-ing extruded. All polymers tested were within USP specifica-tions.

CONCLUSIONS All Plasdone povidone and copovidone polymers demon-strate thermal stability at temperatures below 180°C; con-

sequently, an upper limit of 180°C is recommended for

melt extruding these polymers. Plasdone S-630 copovi-done and Plasdone

K-12 povidone have ideal rheological

characteristics for melt extrusion. Plasdone K-29/32 povi-done will either require plasticization by API or other adju-vants in order to successfully melt extrude solid disper-sions below 180°C.

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

TM povidone and copovidone polymers.

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). Granular 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.

Table1: Tg of PlasdoneTM

povidone and copovidone polymers.

Product K-Value

(Kinematic Vis-

cosity)

Typical Weight

Ave. Mol. Wt.

Typical Glass

Transition

Temperature,

°C

PlasdoneTM K12 povidone 10.2 - 13.8 4,000 120

PlasdoneTM K17 povidone 15.5 – 17.5 10,000 140

PlasdoneTM K25 povidone 24 – 26 34,000 160

PlasdoneTM K29/32 povidone 29 – 32 58,000 164

PlasdoneTM K90povidone 85 - 95 1,300,000 174

PlasdoneTM S-630 copovidone 26 - 29 40,000 109

Figures 3 and 4 show TGA results for Plasdone S-630 copovidone that was heated to 170°C and 230°C respectively and held there for 30 minutes to measure the amount of degradation that occurs when the polymer is exposed to that temperature, the same test was per-formed at all the temperatures shown in Figure 5 (TGA results not shown). 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. Plasdone S-630 copovidone, isothermal @ 170°C for 30 minutes. Sample purged with air.

Figure 4. Plasdone S-630 copovidone, isothermal @ 230°C for 30 minutes. Sample purged with air.

All Plasdone povidone and copovidone polymers exhibit simi-lar degradation behavior; temperature ramps from ambient to 600°C show short-exposure degradation from 270–300°C and 30 minute isothermal holds show weight and color changes appearing at 190–200°C. Figure 6 illustrates the recom-mended melt extrusion processing window for neat Plasdone povidone and copovidone polymers; the polymer processing window is restricted between the Tg of the material and the on-set of degradation.

Figure 6. Tg and thermodegradation temperatures of Plasdone povidone and copovidone polymers.

Rheology The melt rheology of neat Plasdone povidone and copovidone poly-mers was characterized by:

Measuring viscosity as a function of shear rate at constant tem-perature

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 povidone and copovidone polymers at

various temperatures is shown in Figure 7, the ideal hot-melt extru-sion processing window for these polymers is between ~700 and 100,000 Pa.s while maintaining temperatures below the degradation point of 180°C.C.

Figure 7. Plasdone povidone and copovidone polymer melt rheology

Figure 9. Plasdone S630 copovidone melt rheology with increasing temperature.

Figure 5. Plas-done S-630 copovidone, af-ter exposure to various tempera-tures for 30 min-utes.

Figure 1. Plasdone K-29/32 povi-done Tg determination using heat/cool/heat method.

Figure 2. Plasdone S-630 copovi-done Tg determination using heat/cool/heat method.

Figure 10. Plasdone S630 copovidone melt rheology with increasing temperature.

Figure 8. Processing window for Plasdone K-29/32 povidone.

Plasticizer (10%) MDSC (HCH)

Tg Enthalpy

No Plasticizer 163.67 °C 0.1603 J/g°C

Dibutyl Sebacate 120.62 °C 0.1325 J/g°C

Diethyl Phthalate 117.58 °C 0.0983 J/g°C

Pluronic F-68 99.80 °C 0.0601 J/g°C

Pluronic F-127 112.70 °C 0.1054 J/g°C

Glycerol Monostearate

124.36 °C 0.1385 J/g°C

Polyethylene Glycol 140.18 °C 0.1378 J/g°C

Sodium Lauryl Sul-fate

131.24 °C 0.1211 J/g°C

Sodium Docusate 110.67 °C 0.0263 J/g°C

Triethyl Citrate 109.99 °C 0.0394 J/g°C

Triacetin 112.17 °C 0.0528 J/g°C

Tween 80 142.96 °C 0.0735 J/g°C

Vitamin E-TPGS 117.00 °C 0.0940 J/g°C

Plasticizer (10%) MDSC (HCH)

Tg Enthalpy

No Plasticizer 107.77 °C 0.1839 J/g°C

Dibutyl Sebacate 89.51 °C 0.0641 J/g°C

Diethyl Phthalate 99.53 °C 0.1511 J/g°C

Pluronic F-68 110.34 °C 0.2218 J/g°C

Pluronic F-127 117.51 °C 0.5494 J/g°C

Glycerol Monostearate

94.34 °C 0.1204 J/g°C

PEG 3350

95.54 °C 0.1248 J/g°C

Sodium Lauryl Sul-fate

82.65 °C 0.1220 J/g°C

Sodium Docusate 91.99 °C 0.0607 J/g°C

Triethyl Citrate 95.54 °C 0.1034 J/g°C

Triacetin 94.29 °C 0.1145 J/g°C

Tween 80 87.09 °C 0.1066 J/g°C

Vitamin E-TPGS 95.53 °C 0.1493 J/g°C

Table 2: Tg of Plasdone K-29/32 povidone with plasti-cizers.

Table 3: Tg of Plasdone S-630 copovidone with plasti-cizers.