Performance Characterization of Hydroxypropyl Methyl Cellulose Acetate Phthalate

Abstract: Objective: To synthesize a new type of enteric coating material, hydroxypropyl methylcellulose acetate phthalate (HPMCAP), and analyze its structural characteristics and properties. Methods: Infrared spectroscopy, thermogravimetric analysis and chemical analysis were used for characterization, and the dissolution, viscosity, tensile strength and ultimate elongation of HPMCAP in organic solvents were tested, and compared with Japanese hydroxypropylmethylcellulose acetate Succinate samples AS-LG were compared. Results: The content of phthaloyl and acetyl groups in HPMCAP is closely related to the amount of acid anhydride added; mixed solvents such as dichloromethane/ethanol are good solvents for HPMCAP; Then lose weight quickly. Conclusion: Its physical and chemical properties are close to those of Japanese sample AS-LG.

Key words:hydroxypropylmethylcellulose acetate phthalate; enteric coating material; structure; performance; characterization

Hydroxypropylmethylcellulose phthalate (HPMCAP) is an enteric coating with excellent performance obtained by esterifying hydroxypropylmethylcellulose (HPMC) with acetic anhydride and phthalic anhydride. Material. In addition to being used for enteric coating, it can also be used as a polymer carrier to prepare drug microcapsules, microspheres and drug slow-release or controlled-release preparations. As an enteric coating material, it is characterized by good film-forming properties and does not require plasticizers; it has good solubility in the upper part of the small intestine (duodenum), and is ideal for increasing the small intestinal absorption of drugs compared with some currently used enteric coating materials. Domestic enteric-coated excipients mainly include enteric-coated acrylic resins II and III, cellulose acetate phthalate, etc. The physical and chemical analysis of the HPMCAP enteric coating material synthesized in the laboratory is now carried out, mainly investigating the structure and the influence of the content of phthaloyl and acetyl groups on the viscosity, solubility and mechanical properties of the free film, and compared with Japan's hydroxypropyl acetate Methylcellulose succinate (AS-LG) for comparison.

1. Experimental part

1.1 Instruments and materials

Bruker EQUINOX55 infrared instrument (Germany) measures the wave number range of 4000 ~ 350 cm-1; Q600SDT DSC/TG combined instrument (TA company, the United States); NDJ-79 viscosity tester. HPMCAP (self-made), on the basis of the literature, the preparation method was improved. Disperse a certain amount of HPMC, phthalic anhydride, acetic anhydride, etc. in acetic acid medium, react in stages at 60C ~ 95℃ for 2-5 h in the presence of sodium acetate, settling, filtering, fully washing, Dry to obtain pure HPMCAP. It is a water-insoluble cellulose mixed ether diester, with methoxy, acetyl, and phthaloyl groups connected to the alcoholic hydroxyl group or hydroxypropoxyl hydroxyl group on the glucose residue. 3 groups.

1.2 Experimental method

Three samples and an appropriate amount of AS-LC samples were taken, and they were respectively placed in several organic solvents commonly used in laboratories to compare their dissolution behavior.

The phthalyl content test is to use 0.1 mol.L-1NaOH standard solution to neutralize and titrate the carboxyl group on the HPMCAP phthalyl group, and calculate the phthalyl content. The test of the acetyl group content is to use 0.5 mol.L-1 NaOH standard solution to neutralize the carboxyl group on the phthaloyl group, hydrolyze the two ester bonds in HPMCAP, and then neutralize the hydrolyzate, and calculate it according to the titration results.

Under the protection of nitrogen atmosphere, the temperature was raised from room temperature to 450°C at a rate of 10°C·min-1, and the flow rate was 10 ml*min-1 for thermogravimetric analysis.

Take 3 samples and an appropriate amount of sample AS-LG, and make a 5% solution with dichloromethane-absolute ethanol (1:1). Take an appropriate amount and spread it on the film-forming glass plate, control the thickness of the film with the amount of solution, dry it naturally for 12 h, and put it in a vacuum desiccator for 3 h to obtain a dry free film. Take an appropriate amount of dry free membranes and place them in a series of buffer solutions with a pH range of 5-7, and control the temperature at 37°C + 0.5°C. After shaking at a constant temperature for 2 hours, observe the dissolution of the free membranes. The sensitive pH point of the membrane is judged based on the loss of integrity of the membrane and the turbidity of the solution. Cut the dry free film into a size of 10mmx50mm for later use. The tensile strength and elongation at break of the films were measured with an electronic universal testing machine (WD4005, Changchun Institute of Precision Instruments, Chinese Academy of Sciences). According to IS06239-1986, the tensile speed is 5mm.min-1.

Accurately weigh the absolute-dry sample (accurate to 0.001 g) after drying in a heat aging oven at 105°C for 2 h, transfer it into a ground bottle with a stopper, add a mixed solvent of acetone-ethanol-water (2:2:1) as a solvent, Stir with an electromagnetic stirrer at room temperature to make it dissolve evenly, measure the viscosity after 10 h, and control the temperature of the sample with a constant temperature bath.

1.3 Results

A strong and sharp absorption peak can be found at 1732 cm-1, which is the carbonyl absorption peak; the absorption peaks at 1068 cm-1 and 1130 cm-1 are confirmed to be C-0-C stretching vibration peaks, due to the In the standard IR spectrum, there is no characteristic absorption peak of carbonyl at 1730-1750 cm-1, indicating that HPMCAP contains ester bonds formed after the reaction of hydroxyl and anhydride; there are 3 weak absorptions between 1500 cm-1 and 1650 cm-1 , is the characteristic absorption peak of benzene ring; while the absorption peak at 1469 cm-1 is the bending vibration peak of - CH3; the absorption peak at 2935 cm-1 is the stretching vibration peak of - CH3; the absorption peak. This qualitatively shows that the target product HPMCAP was prepared.

Dissolution experiments in various conventional organic solvents. It can be seen that acetone, ethanol/dichloromethane (1:1), acetone/ethanol/water (2:2:1) and ethanol/water (8:2) are good solvents for HPMCAP, which is beneficial for coating. In addition, most commercially available pharmaceutical polymer materials are in the form of granular or powdery materials, which are easy to coalesce into agglomerates in a good solvent. The polymer on the surface of the agglomerate in contact with the solvent dissolves first, making the surface viscosity increase, which is not conducive to the formation of solvents. continue to diffuse into the particle interior. The HPMCAP dissolution process can be wetted and dispersed with absolute ethanol first, and then added with dichloromethane to make it dissolve quickly. It can be seen that the content of phthaloyl and acetyl groups in HPMCAP is related to the amount of phthalic anhydride and acetic anhydride added in the reaction, and the substitution degrees of the two anhydrides compete with each other.

The product is thermally stable below 150°C, and starts to lose weight rapidly from 260.42°C. The mass loss of HPMCAP at 79. .29℃ is 1. 13%, this part of mass loss is contributed by the free moisture in HPMCAP, which can be used to determine the moisture content of the sample. In the range of 110℃~404℃, the mass loss is mainly contributed by the degradation of HPMCAP, which also includes the loss of strongly bound water and the loss of gas functional groups generated by oxidative polymerization of HPM-CAP after heating. After exceeding 404 °C, the sample is carbonized to a constant weight. The thermogravimetric curve of sample 2.3 shows that the product is stable to heat when it is lower than 150°C, sample 2 begins to lose weight rapidly from 247.28°C and sample 3 from 263.34°C. The thermal weight loss curve of the sample shows that the product is stable to heat when it is lower than 150%, and begins to lose weight rapidly at around 260°C. The higher the phthaloyl content in HPMCAP, the more stable the product. Compared with the thermogravimetric analysis of hydroxypropyl methylcellulose phthalate (152°C) and cellulose acetate phthalate (124°C), it has higher stability.

HPMCAP has good film-forming property, and the obtained film is transparent, flexible and not easy to be brittle. Sample 1 free film can be dissolved in pH5.5 phosphate mixed salt buffer solution; sample 2 dissolves incompletely; Prepare products that are soluble in a wide pH range to meet different needs.

With the increase of the concentration, the viscosity increased significantly, and with the increase of the phthaloyl content and the decrease of the acetyl content, the viscosity of the product also increased correspondingly. probably intramolecular hydrogen bonding

increase, the interaction force between macromolecules is enhanced, and the flexibility of the chain is reduced. In addition, in HPMCAP, the volume of phthaloyl group is larger than that of acetyl group, the steric hindrance is large, the internal rotation is difficult, the flexibility is relatively poor, and the viscosity of the product is correspondingly increased. The viscosity range of HPMCAP is similar to that of Japanese sample AS-LG.

The mechanical tensile properties of the HPMCAP free film are related to the molecular weight of the raw material HPMC, the group content in the product HPMCAP and the condition control in the process of synthesis and film formation. Its tensile strength exceeds 40 MPa, its quality is good, its elongation is also 8% ~ 10%, and it has certain toughness. As the content of phthaloyl group decreases and the content of acetyl group increases, the tensile strength and elongation at break of the product are related to factors such as the molecular weight of raw materials, the control of conditions in the synthesis process, and the group content. The reduction of phthaloyl content, the formation of macromolecular

The hydrogen bond density decreased, and the elongation at break showed a downward trend. In addition, the tensile mechanical properties of the self-made HPMCAP free film sample 1 are close to those of the Japanese product AS-LG.

2. Discussion

In this paper, a quantitative test method for the HPMCAP group was preliminarily established, and its structure was initially analyzed and characterized. The results show that the cellulose derivative has good film-forming property, without plasticizer, the tensile strength of the free film reaches 40-45 MPa, and the elongation at break is 8%-10%. In solvents such as acetone, ethanol/dichloromethane, acetone/ethanol/water, etc., HPMCAP is easy to dissolve, and the viscosity range of the solution and the mechanical properties of the free film indicate that its physical and chemical properties are similar to those of Japan's AS-LG, and can replace HPMC, HPMCP is used as an enteric coating material in medicine.