AquaSolve. hydroxypropylmethylcellulose acetate succinate. Physical and chemical properties handbook

AquaSolve hydroxypropylmethylcellulose acetate succinate Physical and chemical properties handbook

Table of Contents INTRODUCTION..................................... 4 CHEMISTRY......................................... 5 Origin Manufacturing Grades and Types PHYSICOCHEMICAL PROPERTIES...................... 6 Product Specifications Morphology Moisture Absorption Thermal Properties Glass Transition Temperature Thermal Decomposition Temperature Melt Viscosity Melt Viscosity with Various Plasticizers Viscosity in Various Solvents Solubility at Various ph Film Strength APPLICATIONS..................................... 12 Solid Dispersion for Bioavailability Enhancement Enteric Coating INCOMPATIBILITIES....15 STABILITY AND STORAGE CONDITIONS................ 15 PACKAGING AND SHIPPING...15 REGULATORY STATUS...15 TOXICOLOGY...15 REFERENCES...15 AquaSolve Hydroxypropylmethylcellulose Acetate Succinate / 3

Introduction AquaSolve hydroxypropylmethylcellulose acetate succinate (HPMCAS; known as hypromellose acetate succinate in pharmaceutical applications) is a mixture of acetic acid and monosuccinic acid esters of hydroxypropylmethyl cellulose in the form of a white to off-white powder or granules. It has a faint acetic acidlike odor and a barely detectable taste. AquaSolve HPMCAS is available in several grades varying in extent of substitution of acetyl and succinoyl groups and in particle size (fine or granular). AquaSolve HPMCAS can be used as a solid-dispersion carrier for bioavailability enhancement of poorly soluble compounds. It is insoluble in gastric fluid, but will swell and dissolve rapidly in the upper small intestine. AquaSolve HPMCAS is commonly used as an enteric film-coating agent for tablets, capsules and granules. For aqueous film-coating purposes, a dispersion of HPMCAS fine powder and plasticizer (such as triethyl citrate) in water is commonly used. AquaSolve HPMCAS is also used in preparation of sustained drug-release formulations. The release rate of the model drug from the matrix is ph dependent. Other formulation options include neutralized-solution/organic-solvent applications and dry-powder coating. AquaSolve HPMCAS has the following functions and properties: -- It is practically insoluble in water, ethanol and hexane. -- It may have a faint acetic acid-like odor. -- It is tasteless. -- It is physiologically inert. -- It is a preferred solid-dispersion carrier for bioavailability enhancement. -- It is an enteric coating polymer. These properties and functions make it suitable for use in many pharmaceutical applications. The polymer is available in three grades: L, M and H, based on the content of acetyl and succinoyl groups (wt%) in the HPMCAS molecule. Each grade is available in two different particle sizes, F (fine) and G (granular). This handbook describes basic chemical and physical properties of AquaSolve HPMCAS. The range of types produced and the typical uses for this versatile cellulosic enteric polymer are also discussed. 4 / AquaSolve Hydroxypropylmethylcellulose Acetate Succinate

Chemistry Figure 1 shows the structure of the HPMCAS molecule; it is visualized as a polymer chain composed of 2-hydroxypropoxy groups (-OCH 2 CH(CH 3 )OH), methoxy groups (-OCH 3 ), acetyl groups (-COCH 3 ), and succinoyl groups (-COCH 2 CH 2 COOH). CASRN: 71138-97-1 CAS Name: Cellulose, 2-hydroxypropyl methyl ether, acetate hydrogen butanedioate Figure 1 Structure of hydroxypropylmethylcellulose acetate succinate R = R 1 = RO O RO H OR O RO O RO C(O)CH 2 CH 2 CO 2 H CH 3 [CH 2 CH(CH 3 )O] m R 1 C(O)CH 3 H C(O)CH 3 CH 3 C(O)CH 2 CH 2 CO 2 H O OR n Manufacturing Acetic anhydride and succinic anhydride are reacted with hydroxypropylmethylcellulose (HPMC) under specifically controlled conditions to produce AquaSolve HPMCAS. The process begins with cellulose, a polymer chain composed of repeating β-1,4-anhydroglucose units. Each anhydroglucose unit contains three hydroxyl groups. The hydroxyl groups of HPMC used to make HPMCAS are substituted with specific levels of methoxyl and hydroxypropoxy groups. The degree of substitution (DS) of methoxyl on HPMC ranges from 1.78 to 2.02 while the molar substitution of hydroxypropoxy is 0.23 to 0.41. The methoxyl DS influences the amount of free hydroxyl groups available for further substitution. Because the hydroxypropoxy group by definition contains a hydroxyl substitution, the level of hydroxypropoxy substitution does not change the overall number of hydroxyl groups available for further substitution. When HPMC is reacted with defined quantities and ratios of acetic anhydride and succinic anhydride, HPMCAS is produced, containing various levels of acetyl and succinoyl esters. Grades and Types AquaSolve HPMCAS is produced in three substitution grades: L, M and H. The three grades are insoluble in acidic aqueous solutions. All three grades are soluble in dilute caustic solution, and to various degrees in acetone and methanol. Each grade is available in fine (F) and granular (G) particle sizes. The range of grades is listed in Table 1, according to the content of acetyl groups. The contents of the other major substituent groups are also listed in the table. Unless otherwise noted, all percentages in this text are percentages by weight. Origin AquaSolve HPMCAS is a synthetic polymer derived from cellulose, the most abundant polymer in nature. Highly purified cellulose pulp is reacted with methyl chloride and propylene oxide under alkaline conditions to produce hydroxypropylmethylcellulose (HPMC). The HPMC is then used in a chemical sequence to produce AquaSolve HPMCAS by reaction with acetic anhydride and succinic anhydride. Table 1 AquaSolve HPMCAS grades Grade Acetyl Content Succinoyl Content Methoxyl Content L 5 9% 14 18% 20 24% 5 9% M 7 11 10 14% 21 25% 5 9% H 10 14% 4 8% 22 26% 6 10% Hydroxypropoxy Content Figure 2 shows the available grades of AquaSolve AquaSolve Hydroxypropylmethylcellulose Acetate Succinate / 5

Physicochemical Properties HPMCAS plotted by range of acetyl and succinoyl substitution levels. Product Specifications Detailed product specifications are listed in Table 2. Figure 2 Available grades of AquaSolve HPMCAS Succinoyl Content (wt%) 30 28 26 24 22 20 18 16 14 12 10 8 6 4 2 Methoxyl range: 12-28% Hydroxypropoxy range: 4-28% L Grade M Grade H Grade 0 0 2 4 6 8 10 12 14 16 18 20 Acetyl Content (wt%) AquaSolve HPMCAS complies with National Formulary and Japanese Pharmaceutical Excipients specifications (shaded box) Table 2 Product specifications Appearance Identification Viscosity 1 LF and LG AquaSolve HPMCAS MF and MG HF and HG White to off-white powder (F) or granules (G) Conforms to U.S. National Formulary and Japanese Pharmacopoeia monographs 2.4 3.6 mpa s Loss on Drying 5% Residue on Ignition 0.20% Heavy Metals Arsenic Limit of Free Succinic and Acetic Acids < 10 ppm 2 ppm 1.0% Acetyl Content 5 9% 7 11% 10 14% Succinoyl Content 14 18% 10 14% 4 8% Methoxyl Content 20 24% 21 25% 22 26% Hydroxypropoxy Content Average Particle Size (Laser Diffraction) F Types D90 (Laser Diffraction) F Types 1 Measured for a 2% solution at 20 C. 5 9% 5 9% 6 10% 10 microns 20 microns Ashland can tailor certain chemical and physical properties of AquaSolve HPMCAS to meet users unique requirements. Users are encouraged to discuss their needs with their Ashland technical representative, or to call the toll-free number shown on the back cover of this booklet for product information. 6 / AquaSolve Hydroxypropylmethylcellulose Acetate Succinate

Morphology The fine grind grades of AquaSolve HPMCAS are rounded to elongated particles ranging from approximately 0.50 to 1.50 microns in diameter mixed with elongated to rounded fairly dense agglomerates ranging up to around 10.0 microns in diameter. The coarse grind grades of AquaSolve HPMCAS consist of large, fairly dense, rounded and slightly elongated agglomerates ranging up to approximately 1.60 mm in length. The fine elongated to round particles that form the agglomerates range up to around 30.0 microns in length. Representative samples of AquaSolve MF and MG HPMCAS are shown in Figures 3 and 4. Figure 4 SEM imagery for AquaSolve MG HPMCAS; for all G grades, particle size distribution is less than 1 mm Figure 3 SEM imagery for AquaSolve MF HPMCAS; for all F grades, D50 is near 5 μm and D90 is near 10 μm Moisture Absorption AquaSolve HPMCAS absorbs moisture from the air. The amount absorbed and the rate of absorption depend on the initial moisture content and on the relative humidity and temperature of the surrounding air. Figure 5 shows the effect of relative humidity on equilibrium moisture content of three grades of AquaSolve HPMCAS. Figure 5 Effect of relative humidity on equilibrium moisture content of AquaSolve HPMCAS at 25 C 10 Equilib brium mo oisture co ontent (% %) 8 6 4 2 AquaSolve L HPMCAS AquaSolve M HPMCAS AquaSolve H HPMCAS 0 0 25 50 75 Relative humidity (%) AquaSolve Hydroxypropylmethylcellulose Acetate Succinate / 7

Thermal Properties Glass Transition Temperature Glass transition temperatures (T g ) of polymers were tested using differential scanning calorimetry (DSC) under a nitrogen purge with a TA Instruments DSC2000 calorimeter on 5 mg samples. Each sample was heated at a rate of 20 C/minute from 20 C to 190 C and then cooled at the same rate back to 20 C. After cooling, samples were held isothermal for 5 minutes and then heated again at the same rate to 195 C. The glass transition temperature was identified as the half-height midpoint for the reheat data cycle. All three grades of HPMCAS have a T g near 120 C (Figure 6 and Table 3). Glass transition temperature helps to guide the lower end of hot-melt extrusion processing temperature. Typically, hot-melt extrusion is processed about 20 40 C above T g. Thermal Decomposition Temperature Thermal decomposition temperature (T d ) was measured by thermogravimetric analysis (TGA). TGA was performed on 10 mg samples in a TA Instruments TGA Q5000IR* thermogravimetric analyzer under N2 atmosphere. Nitrogen flow rate was 25 ml/min at normal air pressure with a heating rate of 10 C/min. Samples were heated to above 800 C until 5% weight loss, excluding moisture loss. All three grades of AquaSolve HPMCAS had decomposition temperatures in the range of 258 to 276 C (Figure 7 and Table 3). Thermal decomposition temperature defines the higher end of the extrusion temperature range. Figure 7 Thermal decomposition temperatures for each grade of AquaSolve HPMCAS Figure 6 Glass transition temperatures for each grade of AquaSolve HPMCAS 110 AquaSolve L HPMCAS AquaSolve M HPMCAS AquaSolve H HPMCAS 276 C Heat Flow (W/g) 0.0-0.2-0.4-0.6 AquaSolve L HPMCAS AquaSolve M HPMCAS AquaSolve H HPMCAS 119 C 120 C 122 C Weight (%) 90 80 70 258 C 267 C 0 200 300 400 Temperature ( C) Universal V4.7A TA Instruments -0.8-1.0 0 50 150 200 Temperature ( C) Exo Up Table 3 Glass transition and thermal decomposition temperatures of AquaSolve HPMCAS Universal V4.7A TA Instruments L Grade M Grade H Grade T g 119 120 122 T d 258 267 276 Melt Viscosity Melt viscosity information can help to identify the hotmelt extrusion processing temperature window. The influence of shear frequency (shear rate; see Figure 8) and temperature (see Figure 9) on melt viscosity were studied with a TA Instruments AR G2 stress-controlled rotational rheometer, with a 25 mm parallel-plate geometry. The isothermal frequency sweep test was conducted at 170 C with a frequency range from 0.1 rad/s to 600 rad/s and a strain in the linear viscoelastic region of the sample. All three grades of AquaSolve HPMCAS show shear thinning behavior at 170 C. 8 / AquaSolve Hydroxypropylmethylcellulose Acetate Succinate

Figure 8 Influence of shear frequency on melt viscosity of AquaSolve HPMCAS at 170 C 1,000,000 Viscos sity (Pa s),000 10,000000 1,000 AquaSolve L HPMCAS AquaSolve M HPMCAS AquaSolve H HPMCAS 01 0.1 1 10 0 Frequency (rad/s) The temperature-sweep test was performed from 150 C to 200 C with a heating rate of 2 C/min. The measurement frequency was set at 6.28 rad/s and the strain was within the linear viscoelastic region of each sample. All grades of AquaSolve HPMCAS had melt viscosities below,000 Pa s at these temperatures, which is the generally accepted upper viscosity limit for hot-melt extrusion. Viscosities of all three grades decreased with increasing temperature from 150 C to 200 C. The melt viscosity of the H grade is significantly lower compared with the M and L grades, especially at high temperatures. Melt Viscosity with Various Plasticizers Polymer and plasticizer mixtures were prepared by spray drying. Melt viscosity was evaluated using the same conditions as for the pure polymer. Results are shown in Figures 10 to 12 for each grade of AquaSolve HPMCAS. All plasticizers effectively reduced the melt viscosity to below,000 Pa s, making extrusion possible at lower temperatures (around 120 C) to improve processability. Figure 9 Melt viscosity of AquaSolve HPMCAS as a function of temperature (measured at frequency of 6.28 rad/s) Figure 10 Melt viscosity of AquaSolve L HPMCAS with various plasticizers at 10%,000 10,000,000 AquaSolve L HPMCAS With dibutyl sebacate 1,000,000 With diethyl phthalate With triethyl citrate Viscos sity (Pa s) 10,000000 AquaSolve L HPMCAS Viscosity (Pa s),000 With polysorbate 80 With Vitamin E TPGS With distilled acetylated monoglycerides AquaSolve M HPMCAS AquaSolve H HPMCAS 10,000 1,000 150 160 170 180 190 200 Temperature ( C) 1,000 120 130 140 150 160 170 180 190 200 Temperature ( C) AquaSolve Hydroxypropylmethylcellulose Acetate Succinate / 9

Figure 11 Melt viscosity of AquaSolve M HPMCAS with various plasticizers at 10% 10,000,000 y (Pa s) Viscosit 1,000,000 AquaSolve M HPMCAS With dibutyl sebacate With diethyl phthalate With triethyl citrate With polysorbate 80 With Vitamin E TPGS,000 With distilled acetylated monoglycerides 10,000 Viscosity in Various Solvents A lower solution viscosity is advantageous for spray drying and coating. The typical concentration of total solids for spray drying is less than 10%, and concentrations of 3% to 5% are common. For film coating, polymer concentration is generally less than 10% in solution. The viscosity of solutions of each grade of AquaSolve HPMCAS in various solvents was measured using a Brookfield viscometer. Results are shown in Figures 13 through 15. At 10% solids content, a viscosity less than 300 mpa s indicates good processability. Figure 13 Viscosity of AquaSolve L HPMCAS at 20 C in various solvents 1,000 120 130 140 150 160 170 180 190 200 Temperature ( C) Figure 12 Melt viscosity of AquaSolve H HPMCAS with various plasticizers at 10% 10,000,000 Viscosity (Pa s) 1,000,000 AquaSolve H HPMCAS With dibutyl sebacate With diethyl phthalate With triethyl citrate With polysorbate 80 With Vitamin E TPGS,000000 With distilled acetylated monoglycerides 10,000 Visc cosity (mpa s) 00 0 10 Acetone 2:1 Ethanol:Acetone 8:2 Ethanol:Water Methanol 2:1 Methylene chloride: Methanol 1 0 5 10 15 20 HPMCAS concentration (%) Figure 14 Viscosity of AquaSolve M HPMCAS at 20 C in various solvents 1,000 120 130 140 150 160 170 180 190 200 Temperature ( C) Visc cosity (mpa s) 0 10 Acetone 2:1 Ethanol:Acetone 8:2 Ethanol:Water Methanol 2:1 Methylene chloride: Methanol 1 0 5 10 15 20 HPMCAS concentration (%) 10 / AquaSolve Hydroxypropylmethylcellulose Acetate Succinate

Figure 15 Viscosity of AquaSolve H HPMCAS at 20 C in various solvents Figure 16 Disintegration time of films made from various grades of AquaSolve HPMCAS Vis scosity (mpa s) 0 10 Acetone 2:1 Ethanol:Acetone 8:2 Ethanol:Water Methanol 2:1 Methylene chloride: Methanol integration time (min) Disi 120 80 60 40 AquaSolve L HPMCAS AquaSolve M HPMCAS AquaSolve H HPMCAS 20 1 0 5 10 15 20 HPMCAS concentration (%) 0 5 5.5 6 6.5 7 7.5 8 ph of USP phosphate buffer Solubility at Various ph Polymer solubility at various ph was evaluated by disintegration of films in phosphate buffer solutions. Films were cast with acetone as the solvent to a thickness of 90 μm and cut into squares of 1.3 cm. Disintegration time was measured using a USP disintegration apparatus at 37 C following general USP disintegration guidelines. Results varied by grade and ph, as shown in Figure 16. Film Strength The films prepared for the dissolution testing were also used for film tensile strength evaluations. Films were cast to a thickness of 90 μm. An Instron Universal Tensile tester was used to perform the evaluations. Results are described in Table 4. Aquasolve L, M, and H grades of HPMCAS have similar film characteristics. Table 4 Film strength results Grade of AquaSolve HPMCAS Elongation (%) Modulus (MPa) Yield Stress (MPa) L 11 1574 35 M 19 1523 37 H 16 1494 40 AquaSolve Hydroxypropylmethylcellulose Acetate Succinate / 11

Applications HPMCAS has been used as an enteric filmcoating polymer for tablets and also for capsules. Its effectiveness as a solid-dispersion carrier for bioavailability enhancement has attracted the most attention in recent years. Numerous publications have indicated that HPMCAS is able to initiate and maintain supersaturation for drugs with a wide variety of structures and physical properties, and the efficacy advantage of HPMCAS is primarily due to the polymer s superiority as a precipitation inhibitor via the formation of colloidal species in aqueous media. 1,2 Solid Dispersion for Bioavailability Enhancement Acetyl and succinoyl substitution levels have a significant impact on the performance of HPMCAS as an amorphous solid-dispersion carrier. This effect is demonstrated in a case study in which the dissolution performance of solid dispersions prepared by spray drying using AquaSolve HPMCAS L, M and H grades and the poorly soluble compounds ezetimibe (EZE), itraconazole (ITZ) and felodipine (FEL) was evaluated. The acetyl to succinoyl ratios of the AquaSolve L, M and H HPMCAS grades were 0.48, 0.87 and 1.8, respectively. Spray-drying solutions were prepared by dissolving model compound and polymer into 2:1 (w/w) dichloromethane:methanol solution at 5% solids. Spray drying was performed on a GEA SD Micro* Spray-Dryer. The feed material was atomized using a 0.5 mm twofluid Schlick nozzle targeting an inlet temperature of 85 C, a process gas flow of 25 kg/hr, an atomizing gas pressure of 0.5 bar, and an atomizing-gas flow rate of 1.5 kg/hr. The liquid-feed rate was adjusted to maintain an outlet gas temperature of 55 C. After spray drying, the spray-dried dispersions were vacuum dried for 48 hours at 40 C under 25 in. Hg reduced pressure. The spray-dried powders were evaluated for the amorphous characteristics of the samples and the dissolution performance. All spray-dried solid dispersions were characterized as amorphous by X-ray powder diffraction (XRPD) performed on a Bruker D8 Focus diffractometer, using a copper tube element and a PSD LynxEye* detector. Dissolution experiments were performed using a Pion μdiss Profiler* dissolution apparatus. Spray-dried samples were added to 20 ml of fasted-state simulated intestinal fluid (FaSSIF) maintained at 37 C under a constant stirring speed of 300 rpm. A 2.0 mg model drug equivalent of each spray-dried powder was added to each vial and drug concentration was measured by in situ fiber optic probes at various time points. For the solid dispersions of all three model compounds, L grades consistently gave the fastest initial dissolution (Figures 17 through 19). The ability of the polymer to maintain supersaturation was highly dependent on the interaction between model drug and polymer. Figures 17 through 19 show the relative performance of AquaSolve HPMCAS with different substitution levels on solubilization enhancement of model drugs with varying solubility. Figure 17 Kinetic solubility results for spray-dried dispersions produced with itraconazole (ITZ) and each grade of AquaSolve HPMCAS at 25% drug load ion (μg/m ml) ncentrati Co 180 160 140 120 80 60 40 20 0 25% Itraconazole AquaSolve L HPMCAS 25% Itraconazole AquaSolve M HPMCAS 25% Itraconazole AquaSolve H HPMCAS Itraconazole API Solubility of itraconazole: < 1 mg/l 0 50 150 200 Time (minutes) 12 / AquaSolve Hydroxypropylmethylcellulose Acetate Succinate

Figure 18 Kinetic solubility results for spray-dried dispersions produced with ezetimibe (EZE) and each grade of AquaSolve HPMCAS at 50% drug load 120 Figure 19 Kinetic solubility results for spray-dried l) Con ncentratio on (µg/m 80 60 40 Solubility of 20 ezetimibe: 8.46 mg/l 0 50% Ezetimibe and AquaSolve L HPMCAS 50% Ezetimibe and AquaSolve M HPMCAS 50% Ezetimibe and AquaSolve H HPMCAS Ezetimibe API 0 50 150 200 Time (minutes) dispersions produced with felodipine (FEL) and each grade of AquaSolve HPMCAS at 40% drug load As indicated in Figure 17, the itraconazole solid dispersion 600 had a greater area under the dissolution curve (AUC) when formulated with AquaSolve L and M grades of HPMCAS. Itraconazole is a weakly basic compound that can form ionic interactions with the succinoyl groups of HPMCAS. The L and M grades have more readily available succinoyl groups and rendered solid dispersions with better dissolution performance. Both ezetimibe (weak acid) and felodipine (neutral) showed low AUCs with L grade solid dispersions and higher AUC in M- and H-grade solid dispersions (Figures 18 and 19). For both compounds, M-grade solid dispersions performed similarly with H-grade solid dispersions. AquaSolve M and H HPMCAS are more hydrophobic than L grade, as indicated by their higher acetyl to succinoyl ratios, and these two grades therefore have stronger intermolecular interactions with hydrophobic ezetimibe and felodipine and were able to maintain supersaturation for prolonged periods. It can be concluded from this case study that for basic compounds, like itraconazole, the L grade with more succinoyl groups can form ionic interactions and result in solid dispersions with better dissolution performance. For hydrophobic compounds such as ezetimibe and felodipine that are non-ionizable or acidic, the more hydrophobic H and M grades offer better performance due to their strong interactions with the compounds. In addition, the dissolution rate of the polymers has significant impact on the dissolution rate of the solid dispersions. l) centratio on (µg/ml Con 500 400 300 200 0 40% Felodipine and AquaSolve L HPMCAS 40% Felodipine and AquaSolve M HPMCAS 40% Felodipine and AquaSolve H HPMCAS Felodipine API Solubility of felodipine: 19.7 mg/l 0 50 150 200 Time (minutes) Enteric Coating This case study was performed on tablets containing omeprazole as the model drug. Omeprazole is a protonpump inhibitor that is unstable in acidic conditions, making an enteric coating necessary. An enteric coating dispersion formulation was prepared using a neutralization method by adding basic agents. The coating formulations are listed in Table 5 and were prepared as follows: triethyl citrate and sodium lauryl sulfate were added to water (at ambient conditions) and stirred for 5 min. AquaSolve HPMCAS and talc were added and stirred until uniformly distributed. Finally, monoethanolamine was added to the dispersion, ph was adjusted to ph 8 (target ph 7 9) with ammonium hydroxide and the mixture was stirred for 3 h at ambient conditions until no HPMCAS particles were left. The final step was filtration with a 20 mesh sieve. Alternatively, a 20 mesh screen can be placed at the end of the inlet tubing. The dispersion was gently stirred during the entire coating process to prevent the precipitation of talc. AquaSolve Hydroxypropylmethylcellulose Acetate Succinate / 13

Table 5 Omeprazole tablet coating formulations HPMCAS under the U.S. Pharmacopoeia testing methods Ingredient Percent by Weight HPMCAS (L, M or H) 58.1 Monoethanolamine 3.4 Triethyl citrate 14.8 Sodium lauryl sulfate 1.6 Talc 20.0 Ammonium hydroxide ~2.1 released (%) 80 60 AquaSolve L HPMCAS The formulations were coated on 300 mg tablets containing a 20 mg dose of omeprazole, using the parameters listed in Table 6. Table 6 Omeprazole tablet coating parameters Parameter Pan size Gun O Hara LabCoat II 15 inch Schlick 1.2 mm Pan load (kg) 3 Pan speed (rpm) 14 Bed temperature ( C) 45 50 Spray rate (g/min) 20 Inlet temperature ( C) 55 60 Outlet temperature ( C) 43 45 Air volume (cfm) 175 Atomizing air pressure (psi) 30 Pattern air pressure (psi) 30 Final solution viscosity of the coating was to 300 mpa s with a solids content of 15%. Tablets were coated to a 20% weight gain. Omeprazole dissolution analysis with high-performance liquid chromatography (HPLC) was made to ensure compliance with the British and U.S. pharmacopoeia standards for drug release, detailed in Table 7. The L grade of AquaSolve HPMCAS was tested using the U.S. Pharmacopoeia (USP) method <711>. The M and H grades were tested using the British Pharmacopoeia (BP) monograph for gastro-resistant omeprazole tablets. Results of the dissolution testing are shown in Figures 20 and 21. Ome eprazole 40 20 ph 1.2 ph 6.8 0 0 30 60 90 120 150 Time (min) Figure 21 Dissolution testing results for AquaSolve M and H HPMCAS under the British Pharmacopoeia testing methods razole re eleased (% %) Omep 80 60 40 20 AquaSolve M HPMCAS AquaSolve H HPMCAS ph 4.5 ph 6.8 0 0 15 30 45 60 75 90 Time (min) Table 7 Omeprazole tablet release criteria BP Method USP Method ph 4.5 ph 6.8 ph 1.2 ph 6.8 45 min 45 min 2 hr 30 min < 10% > 60% < 10% > 75% Figure 20 Dissolution testing results for AquaSolve L 14 / AquaSolve Hydroxypropylmethylcellulose Acetate Succinate

Incompatibilities AquaSolve HPMCAS is incompatible with strong acids or bases, oxidizing agents and sustained levels of elevated humidity. Stability and Storage Conditions AquaSolve HPMCAS should be stored in a wellclosed container, in a cool, dry place. In such storage conditions, HPMCAS is a stable material. HPMCAS is hygroscopic and can hydrolyze to acetic acid and succinic acid over prolonged periods of time. Hydrolysis is the main degradation pathway that is responsible for increasing amounts of free acids in storage, especially upon exposure to moisture. Packaging and Shipping The moisture content of AquaSolve HPMCAS does not exceed 5% by weight when the products are packed. Because of varying storage and shipping conditions, there is a possibility of some moisture pickup from the aspacked value. Although packaging has been designed to reduce moisture pick up, product should be stored under clean, dry conditions and used in rotation. The standard product packaging is 20 kg net weight sealed polyethylene bags, shipped in fiber drums. The type, lot number and drum number are stenciled on the outside of each drum. Read and understand the Safety Data Sheet (SDS) before using this product. Regulatory Status All AquaSolve HPMCAS grades conform to the monograph requirements of the current editions of the National Formulary and Japanese Pharmacopoeia. Please contact your Ashland representative for access to the Excipient Information Package (EIP) for further details. References 1. Friesen, D. T., R. Shanker, M. Crew, D. T. Smithey, W. J. Curatolo, and J. A. S. Nightingale. Hydroxypropyl Methylcellulose Acetate Succinate-based Spray-dried Dispersions: An Overview. Molecular Pharmaceutics. 5 (2008): 3 1019. 2. Curatolo, W., J. A. Nightingale and S. M. Herbig. Utility of Hydroxypropylmethylcellulose Acetate Succinate (HPMCAS) for Initiation and Maintenance of Drug Supersaturation in the GI Milieu. Pharmaceutical Research. 26 (2009): 1419 1431. 3. Hoshi, N., K. Ueno, H. Yano, K. Hirashima & H. Kitagawa. General Pharmacological Studies of Hydroxypropylmethylcellulose Acetate Succinate in Experimental Animals. Journal of Toxicological Sciences. 10(Suppl 2). (1985): 129 146. 4. Hoshi, N., H. Yano, K. Hirashima, H. Kitagawa & Y. Fukuda. Toxicological Studies of Hydroxypropylmethylcellulose Acetate Succinate Acute Toxicity in Rats and Rabbits, and Subchronic and Chronic Toxicities in Rats. Journal of Toxicological Sciences. 10(Suppl 2). (1985): 147 185. 5. Hoshi, N., K. Ueno, T. Igarashi, H. Kitagawa, T. Fujita, N. Ichikawa, Y. Kondo & M. Isoda. Teratological Studies of Hydroxypropylmethylcellulose Acetate Succinate in Rats. Journal of Toxicological Sciences. 10(Suppl 2). (1985): 203 226. 6. Cappon, G. D., T. L. Fleeman, M. S. Rocca, J. C. Cook & M. E. Hurtt. Embryo/Fetal Development Studies with Hydroxypropyl Methylcellulose Acetate Succinate (HPMCAS) in Rats and Rabbits. Birth Defects Research Part B: Developmental and Reproductive Technology. 68. (2003): 421 427. 7. Hoshi, N., K. Ueno, T. Igarashi, H. Kitagawa, T. Fujita, N. Ichikawa, Y. Kondo & M. Isoda. Teratological Study of Hydroxypropylmethylcellulose Acetate Succinate in Rabbits. Journal of Toxicological Sciences. 10(Suppl 2). (1985): 227 234. 8. Hoshi, N., K. Ueno, T. Igarashi, H. Kitagawa, T. Fujita, N. Ichikawa, Y. Kondo & M. Isoda. Studies of Hydroxypropylmethylcellulose Acetate Succinate on Fertility in Rats. Journal of Toxicological Sciences. 10(Suppl 2). (1985): 187 201. 9. Hoshi, N., K. Ueno, T. Igarashi, H. Kitagawa, T. Fujita, N. Ichikawa, Y. Kondo & M. Isoda. Effects on Offspring Induced by Oral Administration of Hydroxypropylmethylcellulose Acetate Succinate to the Female Rats in Peri- and Post-natal Periods. Journal of Toxicological Sciences. 10(Suppl 2). (1985): 235 255. Toxicology AquaSolve hypromellose acetate succinate (HPMCAS) is insoluble in water and this, combined with a molecular weight range between 10,000 and 500,000 daltons, indicates that it is not orally bioavailable. There were no adverse effects in several toxicological studies, including chronic or reproductive and developmental animal studies. 3 9 HPMCAS is an approved pharmaceutical excipient for oral dosage forms. The present Inactive Ingredient Database limit for HPMCAS is 560 mg per day. AquaSolve Hydroxypropylmethylcellulose Acetate Succinate / 15

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