Thermal and Rheological Evaluation of Pharmaceutical Excipients for Hot Melt Extrusion

Thermal and Rheological Evaluation of Pharmaceutical Excipients for Hot Melt Extrusion Karen Coppens, Mark Hall, Pam Larsen, Shawn Mitchell, P. Nguyen, Mike Read, Uma Shrestha, Parvinder Walia The Dow Chemical Company, Midland, MI 48674 Introduction Hot melt extrusion (HME) is becoming a more broadly practiced technology in the pharmaceutical industry. A thorough understanding of the thermal and rheological properties of the polymeric excipients used is an important consideration during the selection of the excipient and processing conditions. The purpose of this study is to report the fundamental thermal and rheological properties of hypromellose (HPMC), ethylcellulose (EC), and polyethylene oxide (PEO). s The excipients studied were manufactured by The Dow Chemical Company (Midland, MI) and are listed in Table 1. 1,2 Table 1. s studied. Descriptor Mn a ETHOCEL * Standard 10 Prem. EC STD 10 9,700 METHOCEL * E5 Premium LV HPMC E5 11,000 METHOCEL E4M Prem. HPMC E4M 62,000 METHOCEL K3 Prem. LV HPMC K3 8,700 METHOCEL K15M Prem. HPMC K15M 88,000 METHOCEL K4M Prem. HPMC K4M 82,000 METHOCEL K Prem. LV HPMC K 46,000 METHOCEL KM Prem HPMC KM 125,000 POLYOX WSR N-10 NF PEO N-10,000 POLYOX WSR N-750 NF PEO N-750 300,000 POLYOX WSR N-12K NF PEO N-12K 1,000,000 POLYOX WSR 301 NF PEO 301 4,000,000 a Number average molecular weight Other ingredients included propylene glycol (PG) (The Dow Chemical Company, Midland, MI) and acetaminophen (APAP) (Spectrum Chemical & Laboratory Products, Gardena, CA). Methods Thermal Analyses Thermal analyses were performed using a model Q differential scanning calorimeter and model Q500 thermogravimetric analyzer (TA Instruments, New Castle, DE). Typical conditions for differential scanning calorimetry (DSC) analysis were 0 C to 250 C at 10 C/min. This was followed by rapid quenching to a temperature below 0 C and subsequent analysis from this temperature to 250 C at 10 C/min. Thermal gravimetric analysis (TGA) was performed from room temperature to 500 C at 10 C/min. All analyses were performed in air. Torque Rheometry Torque rheometry studies were performed using a Haake TYP 557-9301 mixing bowl (Thermo Electron Corp., Boston, MA) with 50 60 cm 3 capacity. A typical experiment used 60 g of material. The test material was added as fast as possible to the bowl with the rotors turning at 10 rpm. When the total amount of sample was added, the chamber was sealed, and a 10-kg load was applied. The rotor speed was then increased to 60 rpm. Torque and melt temperature data were recorded for the 10-min duration of the experiment. Slit Die Rheology The slit die rheology studies were performed on a Haake Rheocord System 90 single-screw extrusion system (Thermo Electron Corp., Boston, MA). The material was melted and forwarded using a 0.75- inch diameter, 28:1 L/D, single-screw, Rheomex extruder attachment controlled by three heating/cooling zones. The pressure profiles were recorded using a series of three flush-mounted Dynisco pressure transducers (Dynisco, Franklin, MA) in a 1-inch wide by 0.075-inch high rectangular die. The polymer melt temperature was measured with a hand-held thermocouple in the material exiting the die. Results and Discussion Thermal Analyses The thermal data generated for the polymers studied are documented in Table 2. Glass transition temperatures (Tg) as measured during both the first and second heating cycle are reported. For purpose of HME processing, the Tg during the first heating cycle is of more interest. * Trademark of The Dow Chemical Company 2

Table 2. Thermal data summary. Tg First Heat Tg Sec. Heat Cryst. Melt at 2% Wt. Loss at 5% Wt. Loss EC STD 10 133 130 183 260 >300 HPMC E5 178 138, a >280 205 HPMC E4M 168 157 a >325 HPMC K3 173 150, a >250 197 HPMC K15M 209 191 a >280 HPMC K4M 205 186 a >280 HPMC K 205 184 a >290 HPMC KM 202 186 a >310 PEO N-10 <0 <0 66 319 350 PEO N-750 <0 <0 70 325 >350 PEO N-12K <0 <0 70 330 >360 PEO 301 <0 <0 70 306 >350 a Not reported Hypromellose TGA data typically exhibited a small weight loss at temperatures less than 110 C. This was attributed to evaporation of absorbed water (typically less than 3 wt %). Accordingly, no 2% weight loss data are reported for these polymers. The temperature at 5% weight loss is reported as a guideline to identify the maximum stability temperature of the various products. PEO resins indicated a broad processing window, between the crystalline melting point of approximately 70 C and temperatures in excess of 350 C. EC showed a modest processing window, between the Tg of 130 C and maximum stability temperature of ~300 C. Hypromellose showed a narrower processing window. The Tg of these polymers ranged from 169 to 209 C while the stability temperature ranged from 250 to 325 C, depending upon substitution type. Torque Rheometry Torque rheometry was used to identify initial processing temperatures for extrusion. The advantage of this approach is that small quantities of material were used and there is very limited risk of damage to the processing equipment. Further, small samples of melt-mixed product are generated which can be used for additional studies. Typical torque rheometry output is shown in Figure 1. A summary of torque rheometry data for the polymers studied is in Table 3. Processing temperature is the temperature setpoint of the equipment, maximum melt temperature is the peak melt temperature observed, and average torque is the plateau torque value. These data demonstrated that processing temperature affects the mechanical energy required for melt processing. The data for PEO N-750 and EC STD 10 both indicated that higher mechanical energy was required at lower processing temperatures. Other PEO observations were consistent with the molecular weight of these polymers. Higher molecular weight polymers generated higher torque and maximum melt temperatures when processed at the same temperature setting. The results for HPMC E5 and E4M indicate that melt processing of neat hypromellose will be very challenging. Careful selection of processing additives is anticipated to be required for successful melt processing of HPMC. Figure 1. Torque rheometry of PEO 301 at C. Torque (mg) 8000 7000 6000 5000 4000 3000 2000 Torque Melt Temperature 175 150 125 0 Table 3. Torque rheometry data summary. Proc. Max. Melt Av. Torque (mg) Observations EC STD 10 150 175 850 Melt has strong metal adhesion, brittle when cool EC STD 10 170 193 550 Melt has strong metal adhesion, brittle when cool HPMC E5 a 190 193 2 Dark brown in color, very stiff and glassy HPMC E4M a 190 192 3600 Dark brown in color PEO N-750 145 4400 Off white in color, nicely melted, no metal adhesion PEO N-750 110 151 4 Gray in color, no metal adhesion PEO 301 151 6 Off white in color, no metal adhesion a These experiments terminated after 5 minutes. Slit Die Rheology Slit die rheology was performed to generate melt viscosity data as a function of shear rate for the polymers studied. Further, the impact of processing temperature on these parameters is included. These data are in Table 4. The effect of melt temperature on melt rheology for PEO N-10 is shown in Figure 2. As expected, the melt viscosity decreased as the processing temperature increased. Interest- Melt Temperature 3

ingly, there was only a small change in viscosity until the processing temperature exceeded 150 C. Table 4. Melt rheology data summary for neat polymers. Processing Temperature Apparent Viscosity at s -1 Shear Rate (poise) EC STD 10 160 3,185 EC STD 10 170 2,615 PEO N-10 130 4,220 PEO N-10 150 4,140 PEO N-10 170 2,600 PEO N-750 130 16,540 PEO N-750 150 13,760 PEO N-750 170 14,620 PEO 301 130 14,900 PEO 301 150 13,660 PEO 301 170 12,000 Figure 2. Melt rheology of PEO N-10 at various temperatures. Apparent Viscosity (poise) 00 0 130 C 150 C 170 C 10 Apparent Shear Rate (s -1 ) Polymer molecular weight was expected to have a large impact on melt viscosity. Figure 3 contains melt rheology data for PEO 301, N-750, and N-10 processed at 130 C. Figure 3. Melt rheology of various PEOs at 130 C. Apparent Viscosity (poise) 00 0 PEO 301, 130 C PEO N-750, 130 C PEO N-10, 130 C 10 Apparent Shear Rate (s -1 ) Surprisingly, PEO 301 and PEO N-750 have very similar melt viscosity at this temperature. The data in Table 4 for these polymers offer further support of this observation at all temperatures studied. Only PEO N-10 exhibits the anticipated effect of molecular weight on melt viscosity. Plasticizers are commonly added to modify the melt processing of polymers. The primary effects are a decrease in the Tg and melt viscosity. For example, the effect of water addition to PEO 301 in torque rheometry is shown in Figures 4 and 5. Both torque and melt temperature decreased as higher levels of water were added to the polymer, indicating reduced melt viscosity. Figure 4. Torque rheometry of PEO 301 with addition of water ( C). Torque (mg) 8000 7000 6000 5000 4000 3000 2000 0 5% water 20% water 35% water PEO 301 Figure 5. Melt temperature of PEO 301 with addition of water ( C). Melt Temperature 160 150 140 130 120 110 90 80 5% water 20% water 35% water PEO 301 70 These results suggest that less mechanical energy is required to process plasticized materials and that the polymers can likely be processed at lower temperatures. This expectation was verified using the slit die rheometer. Melt rheology data for EC STD 10 plasticized with propylene glycol are shown in Figure 6. Addition of 5% propylene glycol to EC STD 10 reduced melt viscosity as well as the temperature at which the material could be processed. Figure 6 shows that a 5% addition of propylene glycol reduced the viscosity by ~60% at 160 C. Further, the processing temperature could be reduced to 150 C and the melt viscosity was still ~40% lower than the neat polymer at 160 C. The addition of a model drug was also found to affect melt viscosity. Figure 7 contains data generated with PEO N-750 at various levels of acetaminophen (APAP) and melt processed at 170 C. 4

Figure 6. Effect of propylene glycol on melt viscosity of EC STD 10. Viscosity (Poise) 00 0 EC STD 10 at 170 C EC STD 10 at 160 C EC STD 10 + 5% PG at 160 C EC STD 10 + 5% PG at 150 C 10 Shear Rate (s -1 ) Figure 7. Effect of APAP addition on PEO N-750 melt viscosity. 00 Conclusions Each of the polymers studied can be used in hot melt extrusion. PEO resins have the broadest processing window, followed by EC and HPMC. The addition of suitable plasticizers can be used to broaden the processing window of any of these materials. Drugs may act as plasticizers during melt processing. References 1. Mn values for METHOCEL cellulose ethers obtained from: Keary, C.M., Characterization of METHOCEL Cellulose Ethers by Aqueous SEC with Multiple Detectors, Carbohydrate Polymers, 45 (2001), 293-303. 2. Mn values for POLYOX resins obtained from: POLYOX Water-Soluble Resins NF in Pharmaceutical Applications, The Dow Chemical Company, Form No. 326-00013-0802 AMS. Viscosity (poise) 0 25% APAP, 75% PEO N-750 at 170 C 50% APAP, 50% PEO N-750 at 170 C PEO N-750 at 170 C Power (PEO N-750 at 170 C) 10 Shear Rate (s -1 ) For more information, complete literature, and product samples, you can reach a Dow representative by calling the following phone numbers. From the United States and Canada call 1-800-447-4369 From Mexico call 95-800-447-4369 In Europe FAX + 31/20.691.6418 call + 31/20.691.6268 Or you can contact us on the Internet at ETHOCEL@DOW.COM Notice: No freedom from any patent owned by Seller or others is to be inferred. Because use conditions and applicable laws may differ from one location to another and may change with time, Customer is responsible for determining whether products and the information in this document are appropriate for Customer s use and for ensuring that Customer s workplace and disposal practices are in compliance with applicable laws and other government enactments. Seller assumes no obligation or liability for the information in this document. NO WARRANTIES ARE GIVEN; ALL IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE ARE EXPRESSLY EXCLUDED. Printed in U.S.A. *Trademark of The Dow Chemical Company Form No. 198-02128 Published January 2005