New Method For Synthesis Of Hydroxypropyl Methylcellulose Acetate Succinate And Its Characterization

Hydroxypropyl methylcellulose acetate succinate is an esterified product on thestructural unit or branched chain of hydroxypropyl methylcellulose, and there are ether bondsand ester bonds in the molecular structure. It is usually used in pharmaceutical enteric coating,because it has antacid properties and dissolves in intestine environment.In this work, we focused on the synthesis of hydroxypropyl methylcellulose acetatesuccinate in the acetic acid-sodium acetate system and acetone-pyridine system. Besides, wedeveloped a rapid and accurate headspace gas chromatography method to measure themethoxyl and hydroxypropoxyl contents in hydroxypropyl methylcellulose, as well as a newmethod with high performance liquid chromatography to determine the acetyl groups andsuccinyl groups in hydroxypropyl methylcellulose acetate succinate.Hydroxypropyl methylcellulose acetate succinate was successfully synthesized fromhydroxypropyl methylcellulose reacted with succinic anhydride and acetic anhydride in theacetic acid and sodium acetate system, or acetone and pyridine system. Various products withdifferent contents of succinyl groups and acetyl groups were prepared by varying reactioncondition, and the structure of the product was characterized. The results show that theacetone and pyridine system is much better than the acetic acid and sodium acetate system. Inthe acetone and pyridine system, there is no corrosion to equipment, the product is easy towash, and the solvent can be recycled. Beyond all the benefits, the product has a good storagestability. By varying the content of esterifying agent, we can get products with different ratioof acidic groups. Under the optimum condition, the obtained products have the molecularweight from5.39×104to5.41×104, number average molecular weight from4.97×104to5.13×104, and polydiversity from1.05to1.08. The product can dissolve well in acetone andmethanol, and form films on mould. The films have a good pH-sensitive, tensile and thermalstability. It can dissolve in the solution of pH from5.4to6.4so that it is suitable forpharmaceutical enteric coating.In order to measure the contents of groups in cellulose derivative, we demonstrated aheadspace gas chromatography method to measure the methoxyl and hydroxypropoxylcontents in hydroxypropyl methylcellulose with internal standard method. The procedureconsists of reaction of hydroxypropyl methyl cellulose with hydriodic acid in headspacesample vials by a modified Zeisel method and neutralizing the remaining hydroiodic acid withsodium hydroxide before the headspace gas chromatography performance, which can avoid the damage of the sample injection system and column. The reaction time, reactiontemperature and equilibration time of sample had effect on determination. Under the optimaldetermining condition, vial equilibration time of30min was enough for the vapor-liquidequilibrium at80°C, the reference standard curves showed a good linear relationship(methoxyl r=0.9997; hydroxypropoxyl r=0.9995; n=7). Compared with other methods basedon Zeisel reaction, the present method is simple, rapid, and has better precision. It is wellsuited for the quality control of hydroxypropyl methyl cellulose needed in pharmaceuticalmanufacture.The acetyl groups and succinyl groups were also determined by high performance liquidchromatography. The conditions for determination were as following: column is Dikma ODSC18platial (5um,250×4.6mm), eluting buffer is0.02mol/L pH=2.8KH2PO4, and the detectionwavelength was215nm. The relationship of determination for acetic acid and succinic acidwas good in the range of0.03-0.8mg/mL for product solution, and linear correlationcoefficients were0.9992and0.9993, respectively. The Relative Standard Deviation (RSD) ofdetermination results were3.04%and2.32%(n=6). The average recovery was99.3%and99.4%. The results obtained by the present method are accorded well with those obtained bychemical titration.