Characterization of Hydroxypropylmethylcellulose Acetate Succinate

Abstract: Objective: To synthesize a new type of enteric coating material, hydroxypropylmethylcellulose acetate succinate (HPMCAS), and analyze its structural characteristics and properties. Methods: Infrared spectroscopy, ultraviolet spectroscopy, thermogravimetric analysis and chemical analysis were used to characterize, test the solubility, viscosity, tensile strength and ultimate elongation of HPMCAS in organic solvents, and compare with Japan's hydroxypropyl methyl acetate Base cellulose succinate sample AS-LG for comparison. Results: The content of acidic succinyl and acetyl groups in HPMCAS is closely related to the amount of acid anhydride added; mixed solvents such as dichloromethane-ethanol are good solvents for HPMCAS; Rapid weight loss. Conclusion: Its physical and chemical properties are close to those of Japanese sample AS-LG.

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

Hydroxypropyl methylcellulose acetate succinate (HPMCAS) is a mixed ester of acetic acid and succinic acid of hydroxypropyl methylcellulose (HPMC), which is obtained by esterifying HPMC with acetic anhydride and succinic anhydride. Excellent enteric coating 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 has its own characteristics for increasing the small intestine absorption of drugs. It is an urgent development and application in my country. Variety of accessories.

There are few types of enteric-coated excipients in China. At present, the main applications are enteric-coated acrylic resins II and III, and cellulose acetate phthalate. In this experiment, the physical and chemical analysis of the synthesized HPMCAS enteric coating material was carried out, mainly to investigate the influence of the self-made HPMCAS structure and the content of acidic succinyl and acetyl groups on the viscosity, solubility and mechanical properties of the free film. samples were compared.

1. Experimental materials

HPMC (self-made sample); acetic acid, sodium acetate, succinic anhydride, acetic anhydride, etc. are commercially available analytically pure.

The synthesis process of HPMCAS is as follows: a certain amount of HPMC, succinic anhydride, acetic anhydride and other materials are dispersed in acetic acid medium, reacted in stages at 60-95 °C for 2-5 h in the presence of sodium acetate, after precipitation and filtration , fully washed with water, and dried to obtain pure HPMCAS. It is a water-insoluble cellulose mixed ether diester, with three groups of methoxy, acetyl and succinyl attached to the alcoholic hydroxyl group or hydroxypropoxyl hydroxyl group on the glucose residue.

2. Method

2.1 Infrared Spectral Analysis

The Broker EQuINOX55 infrared instrument (Germany) tested the samples in the wavenumber range of 4000-350 cm-1.

2.2 UV spectrum analysis

WFF800-D2 ultraviolet spectrophotometer (Beijing Second Optical Instrument Factory).

2.3 Dissolution experiment

Take samples 1, 2, 3 (three products with different processes) and Japanese sample AS-LG in appropriate amounts, and place them in several organic solvents commonly used in laboratories to investigate the dissolution behavior of the substances.

2.4 Chemical quantitative analysis

The test of acidic succinyl group content is to neutralize and titrate the carboxyl group on the acidic succinyl group of HPMCAS with 0.1 mol L-1NaOH standard solution, and the acidic succinyl group content is obtained by calculation; the test of acetyl group content is to use 0.5 mol ·The NaOH standard solution of L-1 neutralizes the carboxyl group on the acidic succinyl group, hydrolyzes the two ester bonds in HPMCAS, and then neutralizes the hydrolyzed product, and calculates the acetyl group content according to the titration result.

2.5 Thermogravimetric analysis

Use TA company (USA) Q600SDT DSC-TG coupler. Under the protection of nitrogen, 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.

2.6 Preparation of free membrane

Take appropriate amount of samples 1, 2, 3 and Japanese sample AS-LG, and make a 5% solution with dichloromethane-absolute ethanol (1:1) respectively. Take an appropriate amount and spread it on a 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.

2.7 Viscosity test

Using NDJ-79 type viscosity tester. 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, and 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.

2.8 Mechanical property test

The dried free film was cut into 10 mm × 50 mm size for later use. The tensile strength and elongation at break of the free film were measured using an electronic universal testing machine (wD4005, Changchun Institute of Precision Instruments, Chinese Academy of Sciences), according to ISO6239-1986, with a tensile speed of 5 mm·min-1.

3. Results and Discussion

3.1 Spectral analysis results

The absorption range of carboxylate (-COO-) and carboxylic acid (-COOH) groups is from 1 710 to 1 780 cm-1, and a strong sharp absorption peak can be found at the wave number of 1 744 cm-1; at 1 057, the absorption peak at 1158 cm-1 was confirmed to be the C-O-C stretching vibration peak, and in the rolling spectrum of hydroxypropyl methylcellulose, there is no characteristic absorption peak of carbonyl at 1 730-1 750 cm-1 , indicating that the structure of HPMCAS contains the ester bond formed by the reaction of hydroxyl and anhydride; the absorption peak at wave number 1 456 cm-1 is the bending vibration peak of -CH3; the absorption peak at 2 938 cm-1 is the stretching vibration peak of -CH3 ; 3 468 cm-1 is the absorption peak of -OH. This qualitatively shows that the target product HPMCAS has been prepared.

3.2 Dissolution

From the dissolution of the product in various conventional organic solvents, acetone, ethanol-dichloromethane, acetone-ethanol-water are good solvents for HPMCAS, and have a wide range of selectivity to solvents. As a coating material, HPMCAS is dissolved in an organic solvent to make a coating solution. A good solvent can be selected to make HPMCAS dissolve better and facilitate coating. In addition, most of the pharmaceutical polymer materials sold in the market are in the form of granular or powdery, which are easy to agglomerate 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 solvent continues to diffuse into the particle interior. The HPMCAS dissolution process can be wetted and dispersed with absolute ethanol first, and then added with dichloromethane to dissolve it. It can be seen from the HPMCAS ultraviolet spectrum that one COOH and one COOR will produce π-π transitions, and the maximum ultraviolet absorption wavelength of sample 1 in ethanol-dichloromethane is 230 nm.

3.3 Gene content assay results

It can be seen from the test results of acidic succinyl group and acetyl group content of the product that the content of acidic succinyl group and acetyl group in HPMCAS is related to the amount of succinic anhydride and acetic anhydride added in the reaction, and the two anhydrides compete with each other.

3.4 Thermogravimetric analysis results

It can be seen from the thermogravimetric curve of sample 1 that the product is stable to heat before 200°C, and the product begins to lose weight rapidly from 272.84°C. The mass loss of HPMCAS at 109.97℃ is 2.70%. This part of mass loss is contributed by the moisture in HPMCAS, which can be used to determine the moisture content of the sample. In the range of 110-406 ℃, the mass loss is mainly contributed by the degradation of HPMCAS, in addition, it also includes the loss of strongly bound water and the oxygen functional group formed by oxidative polymerization of HPMCAS after heating. After exceeding 406 °C, the sample carbonizes to a constant weight. The thermogravimetric curves of sample 2 and sample 3 show that the product is stable to heat before 200°C, and starts to lose weight rapidly from 271.51°C and 258.96°C respectively. The thermal weight loss curves of the above three samples indicate that the product is stable to heat before 200°C, and begins to lose weight rapidly at around 270°C. The higher the content of succinyl group, the more stable the product is. It has higher stability than hydroxypropyl methylcellulose phthalate (152 ℃) and cellulose acetate phthalate (124 ℃).

3.5 Film-forming properties

HPMCAS has good film-forming property, and the obtained film is transparent, flexible and not easy to be brittle. Take an appropriate amount of dry free membranes and place them in a series of buffer solutions within the range of pH 5-7, and the temperature is controlled at (37±0.5)°C. After shaking at constant temperature for 2 h, the dissolution of the free membrane was observed. The sensitive pH point of the membrane is judged based on the loss of integrity of the membrane and the turbidity of the solution. The free film of sample 1 can be dissolved in the buffer solution of pH 5.5; the dissolution of sample 2 is incomplete; Get soluble products in a wide pH range to meet different needs.

3.6 Viscosity results

From the concentration-viscosity curve of HPMCAS, it can be seen that the viscosity of HPMCAS increases significantly with the increase of concentration, and with the increase of succinyl content and the decrease of acetyl content, the viscosity of the product also increases correspondingly. The reason may be that as the content of polar succinyl group increases and the content of acetyl group decreases, intramolecular hydrogen bonds increase, and the interaction force between macromolecules increases, which reduces the flexibility of the chain. According to the polymer solution theory, the molecular chain The flexibility of the chain has a great influence on the viscosity, the flexibility of the chain is good, the potential barrier of internal rotation is low, the chain segment of the flow unit is short, and the holes required for flow are small; on the contrary, the chain segment length is large, the molecular volume is large, and the flow unit Larger holes are required. Therefore, the more flexible the molecular chain, the lower the viscosity. In addition, the volume of acidic succinyl group in HPMCAS is larger than that of acetyl group, the steric hindrance is large, the internal rotation is difficult, and the flexibility is relatively poor, and the viscosity of the product is also increased accordingly. The viscosity range of HPMCAS is similar to that of the Japanese sample AS-LG.

The tensile mechanical properties of HPMCAS free film are related to the relative molecular weight of raw material HPMC, the content of HPMCAS group in the product, and the control of synthesis and film-forming process conditions. It can be seen from the tensile mechanical properties of HPMCAS free film that its tensile strength exceeds 40 Mpa, its quality is good, its elongation is also between 8% and 10%, and it has certain toughness. With the decrease of succinyl group content and the increase of acetyl group content, the tensile strength and elongation at break of the product will change to a certain extent, and its value is related to factors such as the molecular weight of raw materials, the control of synthesis process conditions, and the group content. With the decrease of polar group-acidic succinyl group content, the density of hydrogen bonds formed between macromolecules decreased, and the elongation at break showed a downward trend. It can also be seen from the tensile mechanical properties of the HPMCAS free film that the tensile mechanical properties of the self-made HPMCAS free film sample 1 are close to the Japanese product AS-LG.

4.Conclusion

HPMCAS is a cellulose mixed ether diester, containing methoxy, hydroxypropoxy, acetyl and acidic succinyl groups, and is an enteric coating material with excellent performance. The study established a quantitative test method for groups in HPMCAS, and conducted a preliminary analysis of its structure. Experiments show that the cellulose derivative has good film-forming properties, and the tensile strength of its free film without plasticizers reaches 40-45 MPa. Elongation reaches 8% to 10%, in acetone, ethanol-dichloromethane, acetone. Ethanol. It can be well dissolved in water and other solvents. 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 the Et sample AS-LG. It can replace HPMC and HPMCP as enteric coating materials in medicine.