Views: 0 Author: Site Editor Publish Time: 2023-05-16 Origin: Site
Abstract: The enteric drug excipient hydroxypropylmethylcellulose trimellitate (HPMCT) was synthesized. Characterized by infrared spectroscopy, ultraviolet spectrophotometry and high performance liquid chromatography, the solubility characteristics of HPMCT in organic solvents, pH sensitivity and solubility in pH-6.86 buffer solution were tested, and HPMCT was tested. The coating process and release rate of coated tablets were studied. The results show that ethanol/dichloromethane, acetone/ethanol/water, acetone/ethanol, ethanol/water, etc. are all good solvents for HPMCT, and no agglomeration occurs in the initial stage of the dissolution process. The coating is made by the suspension coating method, which can be made into a dense, smooth and metallic coating film without the need for an enhancer, and has good coating process performance; according to the different esterification rates, the prepared The HPMCTpH sensitive value ranges from 3.8 to 4.0. The coated tablet does not disintegrate in the pH environment of gastric juice, and the release rate reaches 92.60% within 20 minutes in the buffer solution of pH = 6.86, which meets the requirements as Requirements for enteric coating materials.
Key words:hydroxypropyl methylcellulose trimellitate; enteric coating; pH sensitivity
pH-sensitive film coating materials are functional drug excipients that release drugs according to the pH range of different parts of the human body, which can significantly improve the bioavailability and targeting of drugs. Enteric coating material means that it does not dissolve in gastric juice, but only dissolves in intestinal juice, so that the drug can be released in intestinal juice and avoid irritation to the stomach. The hydroxypropyl methylcellulose trimellitate (HPMCT) synthesized in this paper is a kind of excellent performance obtained by esterifying hydroxypropyl methylcellulose (HPMC) with trimellitic anhydride. pH sensitive enteric coating material. The substance has the characteristics of good film-forming property, fast dissolution rate and stable physical and chemical properties. At present, foreign units have carried out research on HPMCT, and there are sporadic public reports, but domestic research on its synthesis and performance is still blank.
1.1 Instruments and materials
Hydroxypropyl methylcellulose HPMC, provided by KIMA CHEMICAL CO., LTD. Its performance index: the mass fraction of hydroxypropoxyl is 29.0%, the mass fraction of methoxyl is 11.5%, and the viscosity of aqueous solution with mass fraction of 2% is 8 mPa·S. Glacial acetic acid, sodium acetate, and trimellitic anhydride were of analytical grade, provided by Beijing Chemical Reagent Company.
1.2 Synthesis of HPMCT
Disperse a certain amount of HPMC, trimellitic anhydride and other materials in acetic acid medium, and react in stages at 80°C-95°C for 2-5 hours in the presence of sodium acetate, after precipitation, filtration, full washing, and drying, Get HPMCT. According to different reaction conditions, the esterification rate was 23.08%. 24.30%, 29.87% and 31.82%.
1.3 Experimental instruments and methods
Bruker EQUINOX55 infrared spectrometer was used to test the samples in the range of 4 000-350 cm-1;
Free film preparation: the sample was prepared into a solution of suitable viscosity with V (acetone): V (absolute ethanol) = 1:1 as the solvent, and the solution was spread on a film-forming glass plate, and dried naturally for 48 hours to obtain a dry free film. membrane.
Determination of pH sensitivity value: take appropriate amount of dry free membrane, place them in a series of buffer solutions with pH value in the range of 3.5-4.5, and control the temperature at (37±0.5)℃. After shaking at constant temperature for 2 h, the dissolution of the free membrane was observed. The pH sensitivity of the membrane was determined based on the loss of integrity of the membrane and the turbidity of the solution.
Preparation of buffer solution: Weigh 3.388 g of dry potassium dihydrogen phosphate (KH2PO4) and 3.533 g of disodium hydrogen phosphate (Na2HPO4), dissolve them in deionized water and dilute to 1 L in a volumetric flask to obtain pH = 6.86 standard buffer solution, the pH value of the buffer solution is the same as that of artificial intestinal juice.
Determination of dissolution rate: Using UV757CRT ultraviolet-visible spectrophotometer, first dissolve a certain amount of sample in the above buffer solution, take solutions of different concentrations to measure the absorbance, and draw the standard curve of the relationship between absorbance and concentration. The sample was made into a film, weighed, put into the above buffer solution, and absorbed 5 ml at regular intervals. The absorbance of the solution was measured at the maximum absorption wavelength, and 5 mL of the above buffer solution was added to the original solution.
Preparation of coated tablets: using a micro fluidized bed coating machine. Make HPMCT a solution with a mass fraction of 3% in a solvent of V (acetone): V (absolute ethanol): V (deionized water) 2:1:1, add a certain proportion of talc powder and dark green starch, made into a coating solution, and the coating solution was suspended and dried on a fluidized bed to make enteric-coated tablets on pravastatin sodium, and the coating quality increased by about 9%.
Determination of release rate: using ZRS-8G intelligent dissolution tester. According to the release test method [Chinese Pharmacopoeia 2005 edition two appendix XD second method (1)], the first method device of dissolution test method (Appendix XC) was adopted, with 750 ml, 0.1 mol/L hydrochloric acid as solvent, The speed is 100 r·min-1, and the operation is in accordance with the law. Immediately after 120 min, 250 ml was added to the above acid solution. 0.2 mol/L sodium phosphate solution at 37°C, continue to dissolve for 30 min, take 5 ml of the solution, and use the filtrate as the test solution. Another appropriate amount of pravastatin sodium reference substance was taken, accurately weighed, and made into 10 μL/ml with water. solution as a control solution. Take 10 μL each of the test solution and the control solution, inject it into a high-performance liquid chromatograph, record the chromatogram, and calculate the release amount of each tablet by the peak area according to the external standard method.
2. Results and Discussion
2.1 Infrared spectral analysis
Compared with HPMC, the combined product has a strong absorption peak at 1 744 cm-1, which should be the characteristic absorption peak of carbonyl. Confirmed with the absorption peak at 1 057 cm-1 in the fingerprint area (attributable to the C-0 stretching vibration peak), it shows that the product contains an ester bond formed after the reaction between hydroxyl and anhydride; it appears at 1 600-1 450 cm-1 The characteristic absorption peak of the benzene ring is shown, because it is connected with the strong electron-withdrawing group carboxyl, and the intensity of this band is obviously weakened. These results indicated that the synthesized product was the target product HPMCT.
2.2 Solubility of HPMCT
Generally, commercially available pharmaceutical polymer materials are easy to coalesce into agglomerates in solvents, and the polymers on the surface of the agglomerates in contact with the solvent dissolve first. The surface viscosity increases, which is not conducive to the continued diffusion of the solvent into the interior of the particles, and the coating process is not good.
The synthesized HPMCT can be well dissolved in ethanol/dichloromethane, acetone/ethanol/water, acetone/ethanol, ethanol/water, and no agglomeration occurs during the dissolution process. Therefore, choosing these solvents in the coating process will have better manufacturability. In addition, because the solvent system of acetone/ethanol/water is not completely composed of organic substances, it also contains water, so the coating process is more environmentally friendly and safe.
2.3 pH sensitivity of HPMCT
The so-called pH sensitivity means that the polymer can be dissolved in a solution not lower than a certain pH value, and the critical pH value is called the pH sensitivity value of the polymer, and this property is called pH sensitivity. HPMC is very stable in solutions with pH in the range of 3.0 to 11.0. However, when it reacts with trimellitic anhydride, the carboxyl functional group is introduced into the product, which has pH sensitivity. This is because the introduced carboxyl-COOH can be ionized in the solution, and the ionization balance depends on the pH value of the solution and the ionization constant of HPMCT itself.
The pH sensitivity value is an important index reflecting the bioavailability of the membrane, which determines the availability of the drug sustained-release and controlled-release system. It was determined that the esterification rates synthesized in this paper were 23.08%, 24.30%, 29.87% and 31.82%, and the pH sensitivity values of HPMCT were 3.8, 3.9, 4.0 and 4, respectively. .0. This pH range can meet the requirement of being insoluble in gastric juice (pH 1.5-3.5) but soluble in intestinal juice (pH 4.7-6.7). It has the necessary conditions to be used as an enteric-coated material.
2.4 Dissolution rate of free film
The dissolution rate of enteric-coated film in intestinal juice is one of the key factors affecting the bioavailability of drugs. The dissolution rate of the synthesized HPMCT free membrane in buffer solution was measured.
The absorbance of HPMCT solution has a good linear relationship with its concentration. Therefore, the A-f relationship curve can be used as a working curve for determining its dissolution within a certain period of time. HPMCT can reach the dissolution limit in the buffer solution within about 35 rain, and the dissolution rate is very fast. According to the previous analysis, the pH sensitive value of HPMCT is 3.8-4.0, which is much lower than the pH value of the buffer solution. Therefore, the carboxyl group in its molecular structure can be rapidly ionized, and HPMCT can be quickly dissolved.
2.5 Preparation of coating film
It can be seen from the solubility test that HPMCT has a variety of good solvents. When coating it, V (acetone): V (absolute ethanol): V (deionized water)-2:1: The mixed solvent of 1 is the coating solvent, because compared with the traditional system composed entirely of organic solvents, the organic solution-water mixed system partly reduces the amount of organic solvents, and reduces the toxicity and volatility.
Due to the high viscosity and good film-forming properties of HPMCT, no plasticizer was added to the HPMCT coated tablets, and a 3% coating solution was prepared to obtain dense, smooth and metallic coated tablets.
2.6 Release degree of coating film
Dissolution rate refers to the speed and degree of oral drug release from sustained-release preparations, controlled-release preparations or enteric-coated preparations in specified solvents. To a certain extent, it can reflect the differences in dosage form, particle size, prescription composition, types and properties of excipients, production technology, etc., and has been widely recognized and valued by people. Determination of release of solid dosage forms
The process of dissolution is called dissolution test, which is an in vitro test method that simulates the disintegration and dissolution of oral solid preparations in the gastrointestinal tract. In the experiment, the release rate of the coated tablets with HPMCT as the coating material and pravastatin sodium as the drug core was measured. The coated tablets did not disintegrate in the buffer solution, but dissolved in the buffer solution.
The release rate of HPMCT reached 92.60% in 20 minutes, and the release condition was good, which met the requirements of enteric coating materials.
The target product HPMCT was successfully synthesized. Ethanol/dichloromethane, acetone/ethanol/water, acetone/ethanol, ethanol/water, etc. are all good solvents, and HPMCT does not agglomerate in the early stage of the dissolution process; the coating is made by suspension coating method, no plasticizer is needed , can make dense, smooth, metallic luster coating film. It shows that HPMCT has good coating process performance; the pH sensitivity range of several HPMCTs synthesized in this paper is 3.8-4.0, and the coated tablet does not disintegrate in the pH environment of gastric juice, and the pH value of the coated tablet is 6 .86 buffer solution can reach 92.60% release within 20 minutes, and the release is good, which meets the requirements of enteric coating materials.