Preparation of a kind of hydroxypropyl methylcellulose composite film

Abstract: With hydroxypropyl methylcellulose-pullulan as the main component and K-carrageenan as the gelling agent, the effects of different compositions on the properties of the composite membrane were studied to determine the best formulation. Based on the single factor experiment, the formulation of the composite membrane was optimized and designed by the response surface method, and the optimal preparation process was determined as follows: the content of pullulan was 9.533%, the content of hydroxypropyl methylcellulose was 6.000%, and the amount of K-carrageenan was 2 .315%, glycerin content 7.903%. Under this condition, after experimental testing, the elongation at break of the obtained composite film was 56.35%±1.48%, the tensile strength was (2.68±0.39) MPa, and the gel strength was (785.48 ±10.32)g/cm², light transmittance is 46.73%±3.87%. The experimental verification results are close to the theoretical values, and the results obtained by response surface optimization have certain guiding significance for the actual production and in-depth research of composite membranes.

Key words:hydroxypropyl methylcellulose, polysaccharide, composite film, plant soft capsule, response surface method

Soft capsules are a packaging method of capsules. They have various shapes and are made by sealing liquid medicine or liquid medicine through soft capsule materials. They are widely used in health food and medicine. So far, there are more than 3,600 varieties of soft capsules. Gelatin soft capsules are the most widely used in the soft capsule market. Gelatin is favored by the masses because of its unique physical and chemical properties and relatively high nutritional value. However, the unique structural characteristics of gelatin molecules make it have some disadvantages in application. For example, as an animal source preparation, there may be a risk of virus transmission or it may not be easily accepted by vegetarians and some special cultures; Hardening occurs, absorbs moisture in the air and softens, and is prone to cross-linking and curing reactions when encountering aldehyde-containing substances; it cannot be used for hydrophilic or hygroscopic drugs. Therefore, it is imperative to develop plant soft capsules with controllable quality. Plant soft capsules can not only meet the needs of special groups of people, conform to the trend of nature and safety, but also have the advantages of wide adaptability, high temperature resistance, high stability, no adhesion, no risk of cross-linking, and long shelf life. A new type of soft capsule material with good development prospects.

Compared with gelatin capsules, capsules made of hydroxypropyl methylcellulose (HPMC) have less impact on drug disintegration and dissolution, and have higher drug compliance. Therefore, HPMC is considered to be a new type of capsule material for plant soft capsules that can replace gelatin. HPMC plant capsule Vcaps is a non-gelatin capsule developed by Pfizer of the United States, and then HPMC plant capsules such as Licaps liquid-filled capsules and Quali-V were born one after another. Although HPMC capsules have similar solubility, disintegration and bioavailability to gelatin capsules, and have some advantages that gelatin capsules do not have, they are still not widely used at present. One of the main reasons is the high price of the product. Compared with gelatin, the raw material cost of HPMC is higher. In addition, its slow gelation speed leads to long production cycle and long disintegration time of soft capsules. Bilbao-sainz etc. added nanoscale MCC (Microcrystalline cellulose) and MCC-lipids into HPMC to improve the mechanical properties and waterproof performance of HPMC. Ugurlu et al. found that pectin/HPMC has a good effect on the dissolution, disintegration and drug release properties of the large intestine-targeted delivery carrier. Byun et al. studied the film-forming properties and water resistance properties of the whole plant soft capsule shellac-HPMC. Studies by Levina et al. have shown that the release performance of HPMC capsules varies with different excipients. HPMC has the potential to replace gelatin, which can better meet people's dietary requirements and market needs, and will have a strong development prospect in the field of soft capsules.

This experiment uses the Design Expen 10 software, selects the BoxBehnken central combination program, uses the response surface method, and explores the effects of hydroxypropyl methylcellulose and pullulan on the gel properties during the gelation process by changing the type and ratio of additives. Influence and influence on the mechanical properties of film formation, in order to better guide production and application in the market.

1. Materials and methods

1.1 Materials and Instruments

Hydroxypropyl methylcellulose, analytically pure, KIMA CHEMICAL CO., LTD; glycerin, potassium citrate, and pullulan were all analytically pure, Sinopharm Chemical Reagent Co., Ltd.; K-carrageenan food grade, Lvxin Fujian Food Co., Ltd.

UV-8000 scanning ultraviolet-visible spectrophotometer, Shanghai Yuanxi Instrument Co., Ltd.; DHG-9036A electric heating constant temperature blast drying oven, Shanghai Jinghong Experimental Equipment Co., Ltd.; DR-6000A electronic universal tensile testing machine, Yangzhou De Rui Instrument Equipment Co., Ltd.; MS7-H550-Pro magnetic stirrer, Dalong Xingchuang Experimental Instrument (Beijing) Co., Ltd.; HWCL-5 type heat-collecting constant temperature magnetic stirring bath, Zhengzhou Great Wall Technology Industry and Trade Co., Ltd.; WD— Type 1 gel strength tester Quanzhou Wanda Experimental Instrument Equipment Co., Ltd.

1.2 Experimental method

1.2.1 Preparation of hydroxypropyl methylcellulose composite membrane

Process route: Composite membrane basic material → add distilled water and mix well → stir under temperature control → add plasticizer, gelling agent, coagulant → fully stir → static glue defoaming → lay film → dry → remove film → save for later use.

Key points of operation: Weigh a certain amount of film-forming agent: hydroxypropyl methylcellulose and a certain amount of film-forming agent pullulan, mix well, put the mixed material in distilled water at 80°C and stir to dissolve. Then add a certain amount of K-carrageenan (gelling agent), a certain amount of glycerin (plasticizer) and potassium citrate (coagulant) respectively, and stir in a heat-collecting constant temperature magnetic stirring bath at 80°C for 4 h. Stop the stirring but do not stop the heating, keep the glue at 80°C for 2 h, and then degas and remove bubbles under a vacuum of 0.1 MPa until there are no bubbles in the glue. Pour the glue solution into a glass plate groove coated with release oil (specification: 10 cm×10 cm×0.05 cm). Use the casting method until the glass plate tank is completely covered by the glue, dry in a 35°C oven for 4 hours, then remove the film and store it in a desiccator for later use, and the humidity of the desiccator is controlled at about 65%.

1.2.2 Single factor experiment of hydroxypropyl methylcellulose composite membrane

Fixed pullulan content (the content mentioned in the text is mass concentration) 8.00%, K-carrageenan content 2.00%, glycerin content 7.00%, potassium citrate content 0.15%, explore different hydroxypropyl methylcellulose The effect of content (6.00%, 7.00%, 8.00%, 9.00%, 10.00%) on the gel strength of the glue and on the mechanical strength and light transmittance of the film.

Fixed hydroxypropyl methylcellulose content 8.00%, K-carrageenan content 2.00%, glycerin content 7.00%, potassium citrate content 0.15%, explore different pullulan content (6 .00%, 7.00%, 8.00%, 9.00%, 10.00%) on the gel strength of the glue and on the mechanical strength and light transmittance of the film.

The fixed pullulan content was 8.00%, the content of hydroxypropyl methylcellulose was 8.00%, the content of K-carrageenan was 2.00%, and the content of potassium citrate was 0.15%. .00%, 6.00%, 7.00%, 8.00%, 9.00%) on the gel strength of the glue and on the mechanical strength and light transmittance of the film.

Fixed pullulan content 8.00%, hydroxypropyl methylcellulose content 8.00%, glycerin content 7.00%, potassium citrate content 0.15%, explore different K-carrageenan content (1. 50%, 1.75%, 2.00%, 2.25%, 2.50%) on the gel strength of the glue and on the mechanical strength and light transmittance of the film.

1.2.3 Design of response surface experiments

Taking the elongation at break, tensile strength, light transmittance and gel strength of the hydroxypropyl methylcellulose composite film as the single factor change index, through the single factor experiment, the hydroxypropyl methylcellulose content, pullulan content, glycerin content and K-carrageenan content as influencing factors. Determine the best parameters of four factors and three levels, carry out response surface analysis, formulate the independent variable factor code and level table of response surface experiment, among other ingredients of composite membrane: potassium citrate 0.15%.

1.2.4 Performance characterization and determination of hydroxypropyl methylcellulose composite membrane

1.2.4.1 Determination of elongation at break and tensile strength

According to the national standard GB/T 1040.1-2018, use an electronic universal tensile testing machine to measure the elongation at break and tensile strength of the composite film, in which the initial clamp distance is set to 40 mm, and the tensile speed is set to 10mm/s , and cut the film into square strips with a length × width of 80 mm × 10 mm.

1.2.4.2 Determination of light transmittance

Use a scanning ultraviolet spectrophotometer to measure the light transmittance of the composite film, cut the composite film into a square of 30 mm × 30 mm, and put it in a film sample holder, and measure the light transmittance of the sample at a wavelength of 600 nm. The transparency of the composite film is represented by the light transmittance, and an empty film sample holder is used as a blank control.

1.2.4.3 Determination of gel strength

According to the national standard GB 28304-2012, pour 40 mL of glue solution into three 50 mL beakers respectively, and let it stand for 24 hours in a room with a temperature of 25 °C and a humidity of 65%, and use a gel strength tester to measure the gel strength , the gels in the three beakers were measured and the average value was taken.

1.3 Data processing

All the experimental data in this paper are obtained by repeating the operation three times and taking the average value. Based on the results of the one-factor tests using Design Expert 10 software, the BoxBehnken central combination procedure was selected. According to different factors, the significant difference in the performance characteristics of the composite membrane is analyzed, and the reliability of the composite membrane is determined through a mathematical model, and the optimal formulation process of the composite membrane is determined by this.

2. Results and Analysis

2.1 Single factor experiment

2.1.1 Effect of hydroxypropyl methylcellulose on the properties of composite membranes

The effect of the content of hydroxypropyl methylcellulose on the properties of the composite film was studied. The experimental results show that when the content of hydroxypropyl methylcellulose is controlled at 6.00% to 10.00%, the elongation at break, light transmittance With the increase of hydroxypropyl methylcellulose content, it decreases, while the tensile strength increases continuously, and the gel strength first increases and then decreases. When the content is 8.00%, the gel strength reaches the maximum value, which is 670.00g%2Fcm². This is mainly due to the increase of its concentration, the increase of intermolecular friction, interaction and retardation, and the decrease of fluidity, so that its elongation at break and light transmittance have been reduced, while its intermolecular friction, interaction and retardation increased, making its tensile strength show an increasing trend.

2.1.2 Effect of pullulan on the properties of composite membranes

The effect of the content of pullulan on the properties of the composite film was studied. The experimental results showed that when the content of pullulan was controlled at 6.00% to 10.00%, the elongation at break, light transmittance and gel strength all decreased with each other. With the increase of the content of pullulan polysaccharides, they all showed a trend of first increasing and then decreasing, while the tensile strength showed a decreasing trend. This is mainly due to the fact that pullulan is one of the main components in this composite film. With the increase of its content, the molecular weight of pullulan contained in unit volume increases gradually, which makes the composite film compact and continuous. However, with the increase of the pullulan content, the viscosity of the glue is also increasing, which also increases the thickness of the film, resulting in the tensile strength %0A, light transmittance and gelation of the composite film. There is a downward trend in strength.

2.1.3 Effect of glycerol on the properties of composite membranes

The effect of glycerin content on the properties of composite films was studied. The experimental results show that when the glycerin content is controlled at 5.00% to 9.00%, the elongation at break and tensile strength decrease with the increase of glycerin content, while The light transmittance and gel strength show a trend of increasing first and then decreasing, which is mainly due to the fact that glycerol is a small molecule hydrophilic plasticizer, and each small molecule has three hydroxyl groups, which are easy to insert into hydroxypropyl methylcellulose. In the molecular chain jointly formed by the protein and pullulan, the number of hydroxyl groups per unit volume increases, and the number of bound water molecules also increases, which further weakens the interaction between molecules, effectively extends the structure of the membrane and gives it flexibility. sex. The increase of glycerol content will increase the content of water molecules in the composite film, which also makes the composite film have a certain degree of plasticity.

2.1.4 Effect of K-carrageenan on the properties of composite membranes

The effect of K-carrageenan content on the properties of composite membranes was studied. The experimental results show that when the K-carrageenan content is controlled at 1.50% to 2.50%, with the increase of its content, the elongation at break and gel strength Both showed a trend of first increasing and then decreasing, while the tensile strength and light transmittance showed a continuous increasing trend. The reason why elongation at break and gel strength first showed an increasing trend was mainly because the number of hydrogen bonds in the molecular structure increased with the increase of carrageenan content; while elongation at break and gel strength The trend of reduction is mainly due to the self-polymerization of carrageenan itself, which leads to the enhancement of the brittleness of the composite film. Therefore, when the content of carrageenan exceeds 2.25%, the polymer starts to change from plasticity to brittleness, which makes it tend to decrease. . The trend of increasing tensile strength is mainly due to the increase of K-carrageenan content, resulting in the increase of hydrogen bonds in the polymer.

Since this composite film will be applied to soft capsules, considering the main properties of the soft capsule film, the greater the better, except the elongation at break and tensile strength, the gel strength is also an important indicator. The larger the thickness, the better the toughness of the composite membrane. Based on the single factor experimental results, the light transmittance varies between 25% and 50% with the change of various influencing factors. In this light transmittance range, although the compatibility of the glue changes, the overall change is not large. Therefore, considering the changing trends of the three indicators of elongation at break, tensile strength and gel strength of the composite film, the content of hydroxypropyl methylcellulose is 6.00%, 8.00%, and 10.00%: the content of pullulan 6.00%, 8.00%, 10.00%; glycerol content 5.00%, 7.00%, 9.00%; K-carrageenan content 2.00%, 2.25%, 2.50% for response surface analysis, In order to determine the best preparation process of hydroxypropyl methylcellulose composite membrane.

2.2 Response surface method to optimize the process formula of hydroxypropyl methylcellulose composite membrane

2.2.1 Experimental design and results

According to the principle of Box-Benhken central combination experiment design, the elongation at break (Y1), tensile strength (Y2), gel strength (Y3) and light transmittance (Y4) were used as the response values, and A hydroxypropyl methyl fiber was selected. Factors, B pullulan, c glycerol content, D K-carrageenan as formulation variables, according to the Box-Benhken central combination program, design four factors and three levels of response surface analysis experiments.

2.2.2 Analysis of variance of regression equation of elongation at break

According to the determined four factors as the variables of the response value, the elongation at break is the response value, and the design expert 10 software is used to fit the model of the response surface. The model simulated by the software is as follows: elongation at break Y1=23.97-8.75A+8.09B+2.45C+6.40D-5.92AB+2.77AC-1.66AD-1.00BC+5.92BD-1.25CD+6.53A²+5.21B²+2.25C²-1.89D²

The validity of the equation was tested by the analysis of variance of the numerical model of the elongation at break of the composite film. It can be seen that the regression of the model is significant (P<0.0001), and the P value of the lack of fit item is 0.2168>O. 05, indicating that the lack of fit item is not significant, that is, the quadratic multiple regression equation is in good agreement with the actual situation, and the error in the experimental process is small, so the quadratic multiple regression equation can be used to predict the experimental results.

It can also be seen that A, B, C, and D in the first-order terms of the equation, the interaction terms AB and BD, and the second-order terms A2 and B2 have a significant impact on the response value (P<0.05). According to the analysis of variance, the following results can be obtained: FA=80.13, FB=68.51, FC=6.28, FD=42.87, these four results represent the degree of influence of each factor on the elongation at break, the results show that: The cellulose content had the greatest effect, and the glycerol content had the least effect.

From the comprehensive analysis of the elongation at break R², it can be seen that the corrected R² is 0.9566, and the R² is 0.9060, indicating that the mathematical model fits well with the actual experimental results. The difference between the predicted R² of 0.7573 and R² is less than 0.2, indicating that the The model is more predictive. The signal-to-noise ratio is 17.533>>4, which proves that the mathematical model is reliable. Therefore, a mathematical model can be used to analyze the change law of the expected response value.

2.2.3 Analysis of variance of tensile strength regression equation

According to the determined four factors as the variables of the response value, the tensile strength is the response value, and the design expen 10 software is used to fit the model of the response surface, and the model simulated by the software is as follows: tensile strength Y2=3.39-0.047A-0.20B+0.67C-1.35D-0.26AB+0.16AC+0.18AD+0.069BC-0.13BD-0.12CD-0.36A²-0.26B²+0.15C²+0.69D².

In order to test the validity of the equation, the numerical model of the tensile strength of the composite membrane was analyzed by variance. The results show that the regression of the model is significant (P<0.0001), and the P value of the lack of fit item is 0.6041> 0.05, which shows that the lack of fit item is not significant, which also shows that the quadratic multiple regression equation is in good agreement with the actual situation, and the error in the experimental process is small. Therefore, the quadratic multiple regression equation can be used to replace the actual point of the experiment. Make predictions about the experimental results.

It can also be seen that C and D in the first-order term of the equation, and the second-order term D2 have a significant impact on the response value (JP<0.05). According to the analysis of variance, the following results can be obtained: FA=0.19, FB=3.25, Fc=37.36, FD=152.60, these four results represent the degree of influence of each factor on the tensile strength, the results show that: K-carrageenan content influence maximum, with the least effect of hydroxypropyl methylcellulose content.

Correct R² to 0. 9517, R² is 0.8953, indicating that the mathematical model fits well with the actual experimental results, and the difference between the predicted R² of 0.7504 and R² is less than 0.2, indicating that the predictability of the model is better. The signal-to-noise ratio is 14.962>>4, which proves that the mathematical model is reliable. Therefore, a mathematical model can be used to analyze the change law of the expected response value.

2.2.4 Gel strength regression equation analysis of variance

Gel strength was the response value according to the variables identified as the response values for the four factors.