Preparation and Property Determination of Hydroxypropyl Methyl Cellulose Phthalate

Abstract: Objective: To prepare enteric coating material hydroxypropylmethylcellulose titanate (HPMCP), and analyze its structure and properties. Methods: Infrared spectroscopy, ultraviolet spectrophotometry and chemical analysis were used to characterize, and the solubility, pH sensitivity and dissolution of HPMCP in organic solvents and artificial intestinal juice were tested. Results: The content of phthaloyl group in HPMCP was closely related to the amount of phthalic anhydride added in the preparation process; mixed solvents such as acetone/ethanol/water were good solvents for HPMCP; HPMCP was buffered at pH 5.1-5.4 Quickly dissolve in liquid. Conclusion: HPMCP has better coating process and higher bioavailability.

Key words: hydroxypropyl methylcellulose phthalate; enteric coating; structure; performance; preparation

Hydroxypropylmethylcellulose phthalate (HPMCP) is obtained by esterification of hydroxypropylmethylcellulose (HPMC) with phthalic anhydride. Soluble film coating material, with good film-forming properties, fast dissolution, stable physical and chemical properties, etc. In addition to being widely used in various enteric-coated preparations (granules, tablets, capsules), it can also be used as a polymer carrier to prepare drug microcapsules, microspheres, and sustained-release or controlled-release preparations of drugs. For this reason, specially synthesized HPMCP, and analyzed its performance.

1. Experimental part

1.1 Instruments and reagents

EQUINOX55 infrared instrument (Germany Bruker). Hydroxypropylmethylcellulose (HPMC, KIMA CHEMICAL CO., LTD); the reagents used are of analytical grade.

1.2 Methods and Results

1.2.1 Preparation of HPMCP

Disperse a certain amount of HPMC and phthalic anhydride in glacial acetic acid, using sodium acetate as a catalyst, at 60°C. React at 85°C for 3 h, precipitate, filter, fully wash with water, and dry to obtain pure HPMCP.

1.2.2 Infrared spectrum measurement

Use an infrared instrument to test the samples in the wavenumber range of 4000-350cm-1. The characteristic absorption peak of the carbonyl group at 1732 cm-1 is confirmed by the absorption peak at 1068 cm-1 in the fingerprint area (attributed to the C-O-C stretching vibration peak), indicating that the product contains hydroxyl groups and phthalic anhydride after the reaction Formed ester bond; 3 weak absorption peaks between 1500 and 1650 cm-1, which are characteristic absorption peaks of benzene ring. Therefore, it was judged that the synthesized product was the target product HPMCP.

1.2.3 Dissolution experiment

Take an appropriate amount of HPMCP and dissolve them in several conventional organic solvents. The synthesized HPMCP can be well dissolved in acetone, ethanol/dichloromethane, acetone/ethanol/water, acetone/ethanol, and no agglomeration phenomenon occurs during the dissolution process. Therefore, choosing these solvents in the coating process will have better manufacturability.

1.2.4 Determination of esterification rate

Fix the mass ratio of HPMC, HAc, and NaAc to 100:500:60, change the feeding ratio of phthalic anhydride to 100, 110, 120, 130, 140, 150, and 160, and measure the content of phthalic anhydride , and then determine the amount of free phthalic acid. Separate the aqueous layer by liquid extraction first, and use O. 1 mol L. 1 NaOH standard solution neutralizes and titrates the free acid to obtain the free acid content, and calculates the combined phthalic acid content, that is, the esterification rate. The esterification rate of the product initially increases with the increase of the phthalic anhydride feed ratio, and when the phthalic anhydride feed ratio increases to a certain critical value, the product esterification rate tends to a stable value. This value is determined by the balance of raw material concentration and system viscosity.

1.2.5 Determination of pH sensitive point

Appropriate amount of sample is made into sample solution with acetone-absolute ethanol-deionized water (2:1:1). Appropriate amounts were spread on film-forming glass plates, and dried naturally for 48 h to obtain dry free films. Take an appropriate amount of dry free membranes, place them separately in a series of buffer solutions with pH 5-5.5, shake at a constant temperature at 37°C for 2 hours, and 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. HPMC solution is very stable at pH 3-1l, but when it reacts with phthalic anhydride, the product has pH sensitivity after introducing carboxyl functional groups. The content of free carboxyl groups in the product can be adjusted by changing the ratio of raw materials to obtain HPMCPs with different pH sensitivities. When the esterification rate of HPMCP is 28.04%, 29.36%, 29.42%, 29.5%, 29.54%, the pH sensitivity values are 5.1, 5.2, 5.2, 5.3, 5.4, this range of pH sensitive value can meet the requirements of insoluble in gastric juice (pH1.5-3.5) and soluble in intestinal juice (pH4.7-6.7), therefore, HPMCP has a higher of bioavailability.

1.2.6 Solubility of free membrane

The standard curve of HPMCP in artificial intestinal juice is: Y=0.0313X-0.0079 (r=0.9999), the absorbance of HPMCP has a good linear relationship with the concentration, and the dissolution limit can be reached within the first 25 minutes. The dissolution rate is fast.

2. Discussion

In this paper, the target product HPMCP was successfully synthesized, and acetone, ethanol/dichloromethane, acetone/ethanol/water, acetone/ethanol and so on were good solvents. Most of the commercially available pharmaceutical polymer materials are in the form of granules and powders, which are easy to agglomerate into agglomerates in the 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 continued diffusion of the solvent into the particles. Inside, the coating process is not good. In this paper, HPMCP can be dispersed well without agglomeration when it is put into solvent, so it has better coating performance. The pH sensitivity of HPMCP is 5.1-5.4, and it has high bioavailability in artificial intestinal juice.