Name: Hypromellose Acetate Succinate
CAS No: Cellulose, 2-hydroxypropylmethyl ether, acetate hydrogen butanedioate [71138-97-1]
USP-NF: Hypromellose Acetate Succinate
Aqoat; Aqoat AS-HF/HG; Aqoat AS-LF/LG; Aqoat AS-MF/MG; cellulose, 2-hydroxypropyl methyl ether, acetate succinate; HPMCAS.
Cellulose, 2-hydroxypropylmethyl ether, acetate hydrogen butanedioate [71138-97-1]
The USP32–NF27 describes hypromellose acetate succinate as a mixture of acetic acid and monosuccinic acid esters of hydroxypropylmethyl cellulose. It is available in several grades, which vary in extent of substitution, mainly of acetyl and succinoyl groups, and in particle size (fine or granular). When dried at 1058C for one hour, it contains 12.0–28.0% of methoxy groups; 4.0–23.0% of hydroxypropoxy groups; 2.0–16.0% of acetyl groups; and 4.0–28.0% of succinoyl groups. The molecular weight of hypromellose acetate succinate is approximately 55 000–93 000 Da, measured by gel permeation chromatography using polyethylene oxide as a relative reference standard.
Hypromellose acetate succinate is commonly used in oral pharmaceutical formulations as a film coating, as well as an enteric coating material for tablets or granules.(1–3) It is a solubility enhancing agent via solid dispersion. Hypromellose acetate succinate is insoluble in gastric fluid but will swell and dissolve rapidly in the upper intestine. For aqueous film-coating purposes, a dispersion of hypromellose acetate succinate fine powder and triethyl citrate (as a plasticizer) in water is commonly utilized.(4,5) Organic solvents can also be used as vehicles for applying this polymer as a film coating. Hypromellose acetate succinate may be used alone or in combination with other soluble or insoluble binders in the preparation of granules with sustained drug-release properties; the release rate is pH-dependent. Dispersions of poorly soluble drugs with hypromellose acetate succinate are prepared using techniques such as mechanical grinding, solvent evaporation, and melt extrusion.(6–10)
Hypromellose acetate succinate is a white to off-white powder or granules. It has a faint acetic acid-like odor and a barely detectable taste. Hypromellose acetate succinate is available in several grades, according to the pH at which the polymer dissolves (low, L; medium, M; and high, H) and its predominant particle size (cohesive fine powder, F; or free-flowing granules, G).
See Table I.
Density (bulk) 0.2–0.3 g/cm3 for Aqoat MF; 0.2–0.5 g/cm3 for Aqoat MG. Density (tapped) 0.3–0.5 g/cm3 for Aqoat MF; 0.3–0.6 g/cm3 for Aqoat MG. Density (true) 1.27–1.30 g/cm3 for Aqoat. Equilibrium moisture content 2–3% w/w at ambient temperature and humidity (258C, 40% RH). See also Figure 1. Glass transition temperature 11328C (differential scanning calorimetry; dried sample) Particle size distribution 10% <1 mm; 50% <5 mm; 90% <10 mm for Aqoat MF. 10% <200 mm; 50% <800 mm; 90% <1000 mm for Aqoat MG. Solubility Practically insoluble in ethanol (95%), hexane, unbuffered water, and xylene. On the addition of acetone, or a mixture of ethanol (95%) and dichloromethane (1 : 1), a clear or turbid viscous solution is produced. Hypromellose acetate succinate also forms a clear or turbid solution in buffers of pH greater than 4.5 with the rank order of solubility for the various grades (see Section 8) increasing with the ratio of acetyl over succinoyl substitution. The exact pH value at which the polymer starts to swell and dissolve depends on the buffer type and ionic strength, although the rank order for the different grades is independent of the buffer used. No solvent has been found to completely dissolve hypromellose acetate succinate polymer; the resulting clear or turbid solutions significantly scatter light in both static and dynamic light scattering experiments, indicating that the polymer may exist as colloids or aggregates. The data is collated from the Shin-Etsu Chemical Co. Ltd and the research work of the authors (R Chen, BC Hancock, and RM Shanker). Viscosity (dynamic) see Figure 2.
Hypromellose acetate succinate should be stored in a well-closed container, in a cool, dry place. In such storage conditions, hypromellose acetate succinate is a stable material. Hypromellose acetate succinate is hygroscopic. It is hydrolyzed to acetic acid and succinic acid, and the hypromellose polymer starts to form if dissolved in 1 mol/L sodium hydroxide for more than two hours.(11) The hydrolysis is the main degradation pathway that is responsible for increasing amounts of free acids in storage, especially upon exposure to moisture.
Hypromellose acetate succinate is incompatible with strong acids or bases, oxidizing agents, and sustained levels of elevated humidity.
Hypromellose acetate succinate is produced by the esterification of hypromellose with acetic anhydride and succinic anhydride, in a reaction medium of a carboxylic acid, such as acetic acid, and using an alkali carboxylate, such as sodium acetate, as catalyst.(12) The fibrous reaction product is precipitated out by adding a large volume of water to the reaction medium. Purification is achieved by thorough washing with water. The granular grade of hypromellose acetate succinate that is so obtained can be pulverized to a fine powder if required.
The safety and pharmacological profiles of hypromellose acetate succinate are similar to those of other ether and ester derivatives of cellulose.(13–17) All nonclinical studies reported in the literature identify no target organs for toxicity by hypromellose acetate succinate.(18,19) It has also been reported that hypromellose acetate succinate does not alter fertility in rats, does not produce any developmental anomalies in rats and rabbits, and does not alter perinatal and postnatal development in rats when assessed up to 2500 mg/kg body-weight.
Observe normal precautions appropriate to the circumstances and quantity of material handled. Hypromellose acetate succinate dust may be irritant to the eyes. Excessive dust generation should be avoided to minimize the risks of explosions. Avoid contact with open flame, heat, or sparks. Avoid contact with acids, peroxides, and other oxidizing materials. Eye protection is recommended.
Included in the FDA Inactive Ingredients Database for use in oral preparations (capsules, and delayed-action preparations). Hypromellose acetate succinate has been approved for use in commercial pharmaceutical products in the USA and in Japan.
Carboxymethyl cellulose; cellulose acetate; cellulose acetate phthalate; cellulose, microcrystalline; ethylcellulose; hypromellose; hypromellose phthalate; hydroxyethyl cellulose; hydroxypropyl cellulose; methylcellulose.
A specification for hypromellose acetate succinate is included in the Japanese Pharmaceutical Excipients (JPE).(24) A new accurate and robust analytical method based on liquid chromatography has been developed for the analysis of free organic acids, and acetyl and succinoyl substitutions in hypromellose acetate succinate.(11) It provides efficient separation and sensitive quantitation of free acetic and succinic acids. Another new analytical method based on liquid chromatography has also been developed for the analysis of methoxyl and 2-hydroxypropoxyl substitutions in hypromellose acetate succinate.(25)