Hydroxypropyl methylcellulose production technology and market development status

Abstract : The present situation of production technology, application technology and market development of hydroxypropyl methylcellulose (HPMC) at home and abroad is reviewed. At present, developed countries such as Europe and the United States more adopt the gas-phase process to produce HPMC, which has high single-batch output, short reaction time, and low labor intensity; domestic production is mainly based on the liquid-phase process, and the reactor is usually below 15m, which is labor-intensive, but Low pressure requirements for equipment and low risk. The HPMC market in Europe and the United States is relatively mature, and the consumption of carboxymethyl cellulose (CMC) and HPMC each accounts for 50%. Flat CMC. Due to the early production of HPMC in Europe and the United States, the application technology is relatively rich; domestic HPMC application technology has just started, but with the acceleration of domestic urbanization and the improvement of people's living standards, construction, food and medicine will be the fastest growing areas of HPMC application. With the development of technology and the expansion of the market, in the next 10 years, large enterprises or multinational companies like Dow Chemical Company and Hercules Company will appear in China, and will lead the development of domestic cellulose ether enterprises to form A hundred flowers bloom and a hundred schools of thought contend.

Key words:hydroxypropyl methylcellulose; production technology; application technology; market

Hydroxypropylmethylcellulose (HPMC) is a cellulose mixed ether variety whose output, dosage and quality have been increasing rapidly in recent years. The non-ionic cellulose mixed ether made, HPMC molecular structure is [C6H702(OH)3-m-n(OCH3)(OCH2CHOHCH3)]. Due to the different proportions of methoxyl and hydroxypropyl content in HPMC, different viscosity, and different uniformity of product substitution, it becomes different varieties and different grades of products with different performances. HPMC has good dispersing, emulsifying, thickening, bonding, water-retaining and gel-retaining properties, soluble in water, and also soluble in ethanol and acetone below 70%. HPMC with a special structure can also be directly soluble in ethanol. HPMC can be widely used as film coating, slow-release agent and binder of pharmaceutical preparations, and can also be widely used in petrochemical, building materials, ceramics, textiles, food, daily chemical products by virtue of its thickening, dispersion, emulsification and film-forming properties , synthetic resins, medicine, coatings and electronics and many other fields.

Due to its superior comprehensive performance and wide application range, the output of HPMC in my country is close to 100,000 tons per year, and it is still rising. Due to the differences in technology and equipment among enterprises, the performance and quality are not the same. In the application process, the HPMC industry has highlighted problems such as the urgent need for standardization and the lack of in-depth research.

This article reviews the development status of hydroxypropyl methylcellulose production technology, application technology and market at home and abroad, including HPMC production technology, equipment development, HPMC product application technology and market status.

1. Hydroxypropyl methylcellulose production technology

As the cellulose non-ionic ether with the largest amount, the most varieties and the widest application fields, with the continuous expansion of the market application range and the continuous improvement of product quality requirements in the application field, the production technology and process of HPMC have also experienced a long and difficult process. Tortuous process. The diversity, complexity and endless pursuit of quality in the production and application of HPMC also show the development history of China's cellulose ether industry from the side.

1.1 Production technology of hydroxypropyl methylcellulose abroad

Cellulose ether was first reported in 1905 and was prepared by Suida by reacting alkali-swollen cellulose with dimethyl sulfate, but cellulose ether could not be completely separated at that time. In 1912, the first patent related to the preparation of cellulose ethers appeared. In 1927, hydroxypropyl methylcellulose was successfully synthesized and separated. In 1938, Dow Chemical Co. of the United States realized the industrial production of methyl cellulose and created the well-known trademark "Methocel". Large-scale industrial production of hydroxypropyl methylcellulose was carried out in the United States in 1948, and the production process reached maturity in 1960-1970. At present, the more advanced HPMC production companies in the world mainly include Dow Chemical Company of the United States, Hercules Co., and Clariant Co. of Germany. Shinetsu Chemical Co. of Japan and Samsung Fine Chemical Co. of South Korea imported technology and equipment from Dow Chemical Company of the United States and Loedige Co. of Germany.

The production process of HPMC can be divided into two categories: gas phase method and liquid phase method. At present, developed countries such as Europe, America and Japan are more adopting the gas phase process, using wood pulp as raw material (cotton pulp is used in the production of high-viscosity products), alkalization and etherification are carried out in the same reaction equipment, and the main reaction is horizontal reaction The kettle has a central horizontal stirring shaft and a side rotary flying knife specially designed for the production of cellulose ether, which can obtain a good mixing effect. The reaction process adopts advanced automatic control means, which can precisely control the temperature and pressure. After the reaction is completed, excess chloromethane and by-product dimethyl ether enter the recovery system in gaseous form and are recovered and reused separately. Refining and purification treatment is carried out in a continuous rotary filter press. Crushing is carried out in a high-efficiency finished product pulverizer, while drying to remove excess water. Auxiliary processes such as mixed packaging are also completed under the automatic control system.

The gas-phase process has the following advantages: compact equipment, high single-batch output; lower reaction temperature and shorter reaction time than liquid-phase method; more precise reaction control than liquid-phase method; no complicated solvent recovery system; low labor cost , The labor intensity is small.

However, this process also has the following disadvantages: large investment in equipment and automatic control, high technical content, and high investment and construction costs; due to the high degree of automation, the requirements for the quality of operators are particularly high, and once a failure occurs, major accidents are prone to occur, usually One problem can lead to the shutdown of the entire line.

1.2 Development and status quo of domestic hydroxypropyl methylcellulose production technology and process

At present, the domestic production of HPMC is mainly based on the liquid phase process. This process was promoted based on the research results of the research units represented by Wuxi Chemical Research and Design Institute Co., Ltd. in the 1970s. Initially, it was a gas phase etherification reaction. , because the equipment in our country is not suitable, the liquid-phase etherification reaction was developed later. Up to now, the liquid-phase etherification reaction process route with high liquor ratio is still the production of cellulose ethers such as Shandong Heda, Shandong Ruitai, and Shandong Yiteng. The HPMC production process adopted by the enterprise.

Domestic HPMC production generally uses refined cotton as raw material (some manufacturers have also begun to try to use wood pulp), and use domestic pulverizers to crush or directly use refined cotton for alkalization, and etherification uses binary mixed organic solvents in a vertical reactor react. The refining and purification treatment adopts a discontinuous process, that is, the organic solvent is removed in the reactor, and then the crude product is purified by washing and dehydrating several times through a scrubber and a centrifuge. Finished product processing adopts batch type, granulation is carried out under elevated temperature (some manufacturers do not perform granulation), drying and crushing are carried out in a conventional way, most of the special treatment is only to delay the hydration time of the product (fast dissolution) There is no anti-mildew and compounding treatment, and the packaging is manual.

The liquid-phase process has the following advantages: the internal pressure of the equipment is small during the reaction process, the requirements for the pressure-bearing capacity of the equipment are low, and the risk is small; after the cellulose is soaked in the lye, the alkali cellulose that is fully swollen and alkalized is obtained, and the alkali The liquid has better osmotic swelling to cellulose; the etherification reactor is smaller, and alkali cellulose can swell evenly, so the product quality is easy to control, and products with relatively uniform substitution degree and viscosity can be obtained, and the variety is easy to replace.

However, this process also has the following disadvantages: the reactor usually cannot be too large (below 15m³), and the production capacity is also small due to statistical limitations. The labor intensity is high; because there is no anti-mildew and compounding treatment, the viscosity stability of the product and the production cost are affected; the packaging is manual, which is labor-intensive and labor-intensive; the degree of automation of the reaction control is lower than that of the gas-phase method. Therefore, the accuracy of the control is relatively low; compared with the gas phase process, a complex solvent recovery system is required.

With the improvement of domestic HPMC production technology, some enterprises have made great progress in the slurry method of large kettles through continuous independent innovation, and have their own technical characteristics. Shandong Heda Co., Ltd. adopts the original "one-step" HPMC production process, which not only has the characteristics of reasonable production process, accurate and reliable operation control parameters, and full and reasonable use of raw materials, but also produces products with uniform substitution degree and complete reaction. , the solution has good transparency, and at the same time ensures the stable IoJ of product quality. In addition, the HPMC production lines of some enterprises, including Heda, have completed automatic transformation, using the distributed control system (DCS) to realize automatic control. Materials, including liquid and solid raw materials, can be accurately metered and added using the DCS system. During the reaction process The temperature and pressure control of the company also realizes DCS automatic control and remote monitoring, and has obvious improvements in the feasibility, reliability, stability and safety of product production compared with traditional production methods. It not only saves manpower and reduces labor intensity, but also improves the operating environment on site.

Shanghai Huiguang Fine Chemical Co., Ltd. is the first in China to introduce a flexible production line of large-scale HPMC reaction and purification equipment with international leading level, and imported equipment from Germany. The reactor is a 25m³ horizontal equipment, and the alkalization and etherification reactions are in the same equipment. In the middle, adopt DCS central control system. Through digestion and absorption of international advanced technology, the current HPMC product models and specifications are complete, and the production capacity has also been greatly improved. Huzhou Zhanwang Pharmaceutical Chemical Co., Ltd. has many years of experience in the production of pharmaceutical supplements. It boldly adopts German equipment such as crushing and desolvation washing, and has established a production management system and quality assurance system that are compatible with the production of pharmaceutical supplements. All kinds of software in production refer to pharmaceutical production. Good Management Practices (GMP) require implementation, and hardware is implementing GMP specifications.

2. Current status of hydroxypropyl methylcellulose market

In 2011, the total production capacity of cellulose ether in the world has exceeded 1 million tons per year. According to the global and domestic usage of building materials, pharmaceuticals, food and daily chemicals from 2009 to 2011, the global and domestic market demand for building materials, pharmaceuticals, food and daily chemicals MC/HPMC from 2009 to 2011 is calculated .

After years of development, the HPMC market in developed countries has become increasingly mature, while the market in developing countries is still in the growth stage, which will be the main driving force for the growth of global HPMC consumption in the future. In 2011, the global demand for MC/HPMC was 288,000 tons, and the consumption was 256,500 tons. Among them, the consumption of building materials was the largest at 165,000 tons, followed by daily chemical grades and pharmaceutical grades. The consumption was 32,000 tons and 28,000 tons respectively, the consumption of food grade reached 26,500 tons, and the consumption of other products was relatively small.

3. Bottleneck problem in the development of my country's hydroxypropyl methylcellulose industry

3.1 Lack of proprietary technology for the study of structure-activity relationship of hydroxypropyl methylcellulose

HPMC has a wide range of applications, and its application effect is directly related to its performance, and its performance depends on the basic chemical structure of HPMC. Although HPMC is the general name of hydroxypropyl methylcellulose, due to the raw materials, formula and production process The difference will lead to its physical and chemical indicators (methoxyl substitution degree (DS), hydroxypropoxyl molar substitution degree (MS), group distribution, product viscosity, ash content, moisture, light transmittance, gel temperature, water insoluble material, pH value, false specific gravity and fineness, etc.), resulting in differences in the application effects of products of various enterprises, resulting in unstable effects of HPMC in the application process, which is of great significance to some application fields, such as polymer polymerization, medicine and electronics. serious negative impact.

At present, most domestic cellulose manufacturers have relatively old and inconsistent test methods for HPMC structure. How to accurately and quickly determine the content of HPMC substituents has always been concerned. The chemical titration technology has been used for a long time, and the test is time-consuming, cumbersome, and there are many human factors. Domestic companies such as Kehong, Heda, Yiteng, Huzhou Zhanwang and Luzhou North have adopted gas chromatography technology to test the group content. Practice has proved that the method is accurate, time-saving, convenient and repeatable. The test method is described and standardized in the "Quality Standards for Cellulose Ether of Dry-Mixed Mortar in China".

In addition, for the study of the structure of cellulose ether, the determination of DS and MS is not enough. For decades, scientists from various countries have been exploring the distribution of substituents in the 2, 3, and 6 positions of the glucose unit and in the entire polymer chain of different products.

Research in this area has already been reported abroad. For example, YasuyukiTezuka et al. used 1H-NMR and 13C-NMR methods to study the structure of HPMC and HPC. Since these cellulose ethers are insoluble in conventional organic solvents, they are first acetylated and then analyzed by 13C-NMR to analyze and characterize the structure of HPMC by analyzing the structure of acetylated derivatives. The study concluded that: in the initial stage of the etherification reaction, the hydroxyl group at the C2 position reacts with propylene oxide the fastest, while the hydroxyl group at the C6 position is gradually consumed until its degree of substitution reaches the level of the C2 position. stage level. The C3 hydroxyl group has the slowest reaction rate with propylene oxide, that is, O-2>0-6>0.3. In addition, this method only obtains the distribution of substituents on the 2, 3, and 6 positions of the glucose unit, and the information on the distribution of substituents on the polymer chain cannot be obtained.

Both high performance liquid chromatography (HPLC) and gel liquid chromatography (GLC) can separate and quantify the hydrolysis products of cellulose derivatives. Brownell and Purves used paper chromatography to separate hydrolysates. However, some ethers were not well separated by this method, especially those with different numbers of oxyethylene groups at the same position. Croon

and Lindberg used the fractional elution of the hydrolyzate on a carbon-Serry column to separate the products well. A low rate is a prerequisite for good separation, so this method is very time consuming. Lott and Brobst used gas-liquid chromatography to analyze the hydrolyzate of hydroxyethyl starch sugar. However, due to the overlapping of many monomers, the interpretation of the chromatogram is very difficult. Olle Ramnas and Olof Samuelson et al. have adopted a new method for the analysis of nonionic cellulose ethers. First, the sample was hydrolyzed in sulfuric acid, and then the hydrolyzed products were separated by gas-liquid spectroscopy, and then the components were separated on an ion-exchange column. Finally, mass spectrometry was used to study the amount of each component of the hydrolyzate, and the distribution information of substituents at C2, C3, and C6 positions was obtained.

In 1988, two groups of scientists, Tanaka and Hillenkamp respectively proposed the use of matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS), which led to the development of laser desorption ionization mass spectrometry (LDI-MS) in the analysis of biological macromolecules. Both MALDI-MS and ESI-MS are the most studied and widely used soft ionization techniques in recent years. MALDI is usually combined with time-of-flight mass spectrometry (TOF-MS). Laser analysis technology, through the interaction between laser beam and solid sample molecules to produce molecular ions and fragments with structural information, can be used to study macromolecules with complex structures and not easy to gasify. Electrospray mass spectrometry (ESI-MS) is an ionization technique using a strong electrostatic field, which was first successfully used in the analysis of proteins in the 1980s. In recent years, many foreign researchers have applied these technologies to the structural molecules of cellulose ether.

Adden et al. randomly hydrolyzed HPMC and HEMC into oligomers with a degree of polymerization (DP) of 1 to 5, and after appropriate treatment, used MALDI-TOF-MS to quantitatively analyze the methyl and hydroxyalkyl groups of the sample along the polymer chain. Distribution. The key to the method is the treatment of the sample. Taking HPMC as an example, the sample needs to undergo perdeuteromethylation (MeI—d3), partial acidolysis (trifluoroacetic acid), reductive amination (n-propylamine) before mass spectrometry analysis, and finally Further complete methylation (MeI) yields O-alkyl, N-alkylated oligosaccharides.

Reasons for complete deuterium methylation: 1) Protection of free hydroxyl groups. Because the polarity of the free hydroxyl group is very different from that of the substituent. 2) To prevent the occurrence of side reactions during hydrolysis. Because the existence of free hydroxyl groups will promote the occurrence of side reactions, these side reactions will reduce the difference of glycosidic bonds with different stabilities, and affect the subsequent partial random hydrolysis. In addition, the aminoquaternization of the sample can increase the signal intensity by 10 times, making the spectrum clear and having a good signal-to-noise ratio.

With the development of various soft ion techniques and mass spectrometry techniques, MS has become a powerful technique for studying the structure of biological macromolecules (such as proteins, nucleic acids, and polysaccharides), oligosaccharide sequences, and bonding positions. However, there are still many unknowns about the fragmentation mechanism of fragment ions in mass spectrometry, and further research and exploration by scientists is still needed. In addition, the sample pretreatment process for mass spectrometry analysis is cumbersome and complex with high requirements, which is a great challenge to the existing laboratory conditions.

3.2 Research on HPMC application technology is weak

The molecular polymerization degree of HPMC is the same as its raw material refined cotton, and in the process of alkalization and etherification, due to the difference in equipment and material shape, stirring form and process, the product has extremely obvious inhomogeneity. As a typical cellulose nonionic mixed ether, its group content is on different macromolecular chains, and the distribution ratio of methoxyl and hydroxypropoxyl groups has a relatively large distribution ratio on each glucose ring position of c. Dispersion and randomness make it difficult to guarantee the quality stability of products forever. At the same time, under the same physical and chemical indicators, product uniformity determines its application indicators, and the most important factors affecting product quality uniformity are the performance of a single production equipment, the theme layout of equipment, and process conditions. Every link in the production process has an impact on the uniformity of product quality, the most important being the alkalization and etherification reactions. The diversity of product physical and chemical indicators leads to the variability of performance. It is a systematic project to study the influence of performance on the application effect and the specific formula and process of the application process.

Since hydroxypropyl methylcellulose was produced earlier in developed countries such as Europe and the United States, rich experience has been gained in researching the application technology of HPMC and broadening the application field of HPMC.

Now Japan's Shin-Etsu, Dow Wolfe, and Ashland Crossron are aware of the huge market for medical and food cellulose in the future, and they have increased their investment in this field through increased production or mergers. Dow Wolfe recently announced that it will strengthen its focus on the formulation, ingredients and demand of the Chinese pharmaceutical preparation market, and its applied research is also working hard to get closer to the market. Among the 10 professional technologies of excipient products, Dow Wolfe owns five of them, and pharmaceutical excipients have become the core business of Dow Wolfe. Dow Chemical Wolff Cellulose Division and Colorcon of the United States established a sustained and controlled release formulation alliance in 2007, with more than 1,200 employees in 9 cities, 15 asset institutions and 6 GMP companies , with a large number of applied research professionals serving clients in approximately 160 countries. Ashland has production bases in Beijing, Tianjin, Shanghai, Nanjing, Changzhou, Kunshan and Jiangmen in China, and has invested in three technology research centers in Shanghai and Nanjing. Recently, Ashland Cross Dragon technical experts introduced that Ashland BenecelⅢ HPMC is applied to fried food, which can minimize the intake of fat during frying, reduce the total fat content of fried food, and improve the quality of fried products. Improve the taste, prolong the oil change period of frying, increase the yield of fried products and reduce the cost of oil.

In addition, the application of pharmaceutical grade HPMC in preparations has shown a wide range of uses, such as film coating materials, solid preparation binders or mixed binders, sustained-release preparation pore-making materials, hydrophilic gels, and also used as Increase drug dissolution. At present, it is mainly used in the fields of film coating agents, VC granules and vegetable capsules. HPMC hollow capsules are a capsule product with higher safety than gelatin hollow capsules in terms of raw material control, finished product quality control, and production process control, and are currently favored by more and more people in the international market , has become the preferred capsule for high-end health care products and medicines, and its sales in the international market reach 20 billion capsules per year, with an annual growth rate of 20% to 30%.

Foreign HPMC manufacturers in the field of building materials mainly include Dow Chemical, Shin-Etsu of Japan, Bayer and Klein of Germany, Samsung of South Korea, Hercules of Belgium and Kuraray of Japan. Their technical application and service levels are significantly higher than many domestic levels. The dry mix mortar industry in Europe is doing well and there is a lot of investment in research and development in the field of new technologies to meet the ever-increasing technical demands, thereby improving its market position.

China's hydroxypropyl methylcellulose started relatively late. In the 1970s, the production process research began, and in the 80s and 90s of the last century, it was mass-produced, and it developed rapidly in the first 10 years of this century. Therefore, Compared with developed countries such as Europe, America and Japan, domestic HPMC application technology is in its infancy. At present, the problems mainly focus on the relatively narrow application field, the imperfect technology and method, and the disconnection between the application effect and the product production process.

The main application fields of HPMC in China also involve construction, coatings, food, medicine, ceramics, daily chemical products, polymer polymerization, etc. However, the quality of HPMC products for pharmaceutical grade and polymer polymerization is generally inferior to that of foreign countries, and many key technologies are still in the hands of developed countries such as Europe, America and Japan. However, through application research comparisons and process equipment transformation, the gap between domestic products and them has gradually narrowed. Individual product indicators have been surpassed.

With the continuous breakthroughs in the quality of domestic products, the application research continues to increase. In the food industry, HPMC has begun to be used in non-dairy cream, fruit juice and other industries. It has shown excellent performance as a suspending agent thickener and emulsion stabilizer. . HPMC plays a role in preventing the conversion of water phase and oil phase in non-dairy cream and improving product stability, and the addition amount is 0.1% to 0.2%. American Weiyi occupies about 57% of the domestic non-dairy cream market with high-quality products, and the rest of the market share is occupied by other domestic manufacturers.

HPMC has been used in the field of foreign building materials for decades, and there is no absolute substitute product. There is a large demand in the international market, but due to the production capacity and comprehensive advantages of foreign companies, most foreign manufacturers, especially European and American manufacturers, still mainly use the products of foreign companies. In recent years, due to the obvious cost-effective advantages of domestically produced HPMC, with the increase of application research, the formulation of national industry standards, and the continuous improvement of product quality, it can almost completely replace imported products and is widely used in the field of domestic building materials. Therefore, it is necessary to do a good job in the modification research and supporting technology research of HPMC in the future, and cultivate multi-directional advantages to meet the needs of domestic and foreign market development.

4. Conclusion

The progress of HPMC production and technology is endless, the requirements for product quality are also increasing, and the variety is increasing, and some manufacturers are also pursuing product diversification, that is, HPMC-based manufacturers also increase other cellulose Ether production to meet the development needs of the market and application process. There are also many such domestic enterprises, such as Shandong Ruitai, Luzhou North, Shandong Heda, Shandong Yiteng and Everbright Technology, etc. are all producing 2 to 6 kinds of cellulose ethers at the same time. The increase in varieties and the diversification of technologies and processes have also increased the impetus for the technological progress of enterprises.

As a non-ionic cellulose ether, hydroxypropyl methylcellulose has better properties than ionic cellulose ethers in terms of thickening, emulsification, film formation, protective colloid, moisture retention, adhesion, and anti-allergy. It is widely used in oilfield mining, latex paint, polymer polymerization, building materials, daily chemicals, food, pharmaceuticals, papermaking, textile printing and dyeing and other industries. With the acceleration of the domestic urbanization process, the demand for products is bound to increase year by year. There are vast rural areas in China, and the growth rate of downstream products will increase, and product quality will be improved to resist fierce competition in the market. The demand will increase, but the requirements for HPMC product quality and cost performance will also be higher. In the future, product quality and brand will become the focus of competition. Breaking through technical barriers and ensuring product stability will be the key to sustainable market development in the future.

Compared with foreign countries, my country's cellulose ether industry is not small in scale, but it lacks leading enterprises that can play a decisive role in industry development and market changes. To a certain extent, it also lacks industry research and development and investment in technology upgrading. Foreign companies mainly occupy the high-end market, have professional market research support, and have considerable advantages in formulating sales strategies. Taking application technology as the forerunner, set foot in the fields that have not been applied before, and occupy the market. Domestic companies mainly focus on the low-end market, or focus on capturing the application fields of foreign companies, lacking long-term strategies, or because of insufficient strength, unable to occupy the market, and just follow the market to do some small-scale development. Therefore, domestic cellulose ether enterprises should strive to increase investment in research and development, pay attention to market development and personnel training, and realize the transformation and upgrading of enterprises and healthy development as soon as possible.

HPMC products have shown strong vitality since their birth. With the advancement of technology and the development of new fields, HPMC will be applied to a wider range of fields. Judging from the current development trend, the next few years will definitely bring about the integration of industry resources, and enterprises will use their respective advantages to become more and more specialized, forming their own enterprise advantages, product advantages, brand advantages and cost advantages. After vicious competition such as homogenization and price suppression, enterprises will become more and more rational and specialized, and through integration, they will have their own characteristics and core advantages. With the development of technology and the continuous expansion and deepening of the application market, in the next 10 years, there will be several large enterprises or multinational companies like Dow Chemical Company and Hercules in China, and will lead the domestic cellulose ether enterprises. To move forward and form a situation where a hundred flowers bloom and a hundred schools of thought contend.