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eye on dictate the pH-solubility behavior of the polymer (Figure 1). The L grade dissolves at pH 5.5, the M grade at pH 6.0, and the H grade at pH 6.8. Particle size is denoted F for fine and G for granular. Although the use of HME is increasing, there are few commercially available products that entail extruded HPMCAS solid dispersions. Resear- chers are thus seeking to better under- stand the utility of existing HPMCAS grades [2] and to develop grades of HPMCAS that are especially suited for HME applications [3]. The goal of the study described here was to gain a fundamental under- standing of the functional performance and physicochemical stability of HPM- CAS used in HME to help researchers select the optimal processing tempera- ture for various formulations. Methods The study investigated the func- tionality and stability of three grades of HPMCAS: L (acetyl content 5.0 to 9.0 percent (%), succinoyl content 14.0% to 18.0%) M (acetyl content 7.0% to 11.0%, succinoyl content 10% to 14%), and H (acetyl content 10.0% to 14.0%, succinoyl content 4.0% to 8.0%). How temperature and HME processing conditions affected the physicochemical properties of the three grades and the API-polymer extrudates was also assessed. Determining melt rheology. The rheological properties of the HPM- CAS polymers before and after extru- sion were studied using an AR-G2 controlled-stress rotational rheometer (TA Instruments, New Castle, DE) equipped with a 25-millimeter (mm) parallel-plate geometry. Dynamic fre- quency sweep experiments were con- ducted at 170°C and at a frequency range of 0.1 to 600 radians per second (rad/s). Dynamic temperature sweep was determined using a temperature range of 150° to 200°C, a ramp rate of 2°C per minute, and a fixed frequency of 6.28 rad/s (1 Hertz). Profiling pH-solubility. A quartz crystal microbalance was used to mea- sure the pH-solubility profiles of the HPMCAS polymers before and after extrusion. Two milliliters (ml) of 1% (by weight) HPMCAS solution was spin-coated at 3,000 rpm onto a gold- surfaced sensor for 60 seconds. Measurements were taken at 37°C. The coated sensor baseline was first established in a pH 4.5 buffer. A new buffer was introduced every 10 min- utes until the film was mostly dis- solved off the surface. Determining substitution. To deter- mine substitution of the HPMCAS, high-performance liquid chromatogra- phy (HPLC)—as described in the monograph for hypromellose acetate succinate in USP38/NF33—was used. HPLC of the polymer grades and their corresponding HME samples was per- formed using a 1200 Series Quaternary LC system (Agilent, Santa Clara, CA) Tablets & Capsules January 2016 43 Quyen Schwing, Marvin Davis, Divya Tewari, and Thomas Durig Ashland Specialty Ingredients This edition of the column assesses the functionality and stability of HPMCAS when used in hot-melt extrusion. The majority of today's new chemi- cal entities are poorly water-soluble. One widely used means of overcom- ing that problem is to develop solid dispersions by mixing—at the molecu- lar level—the drug candidate into a polymer matrix [1]. Spray drying and hot-melt extrusion (HME) are the most common technologies used to manufacture these amorphous solid dispersions. With spray drying, an organic solvent dissolves the API and polymer, followed by rapid removal of the solvent. With HME, an API-poly- mer blend is extruded at high tempera- ture and high shear to create a solid dispersion. HME is preferred because it can operate continuously and offers economic advantages. Hypromellose acetate succinate (HPMCAS)—a mixture of acetic acid and monosuccinic acid esters of hydroxypropyl methylcellulose (HPMC)—has demonstrated the abil- ity to improve solubility. The physico- chemical properties and functions of HPMCAS, such as amphiphilicity, solubility in various organic solvents, and suitable melt viscosity, make it an ideal polymer for manufacturing amorphous solid dispersions either by spray drying or HME. AquaSolve HPMCAS (Ashland Specialty Ingredients, Wilmington, DE) is available in several grades that vary in the extent of substitutions of acetyl and succinoyl groups and parti- cle size [1]. Acetyl and succinoyl sub- stitutions on the HPMC backbone Figure 1 Chemical structure of HPMCAS excipients ..