E464 (Hydroxypropylmethylcellulose, HPMC) is a chemical compound, a chemically modified cellulose derivative. It is widely used in the food, pharmaceutical, and cosmetic industries as a thickening agent, emulsifier, stabilizer, and coating agent. Due to its ability to form gels and improve viscosity, HPMC is valued for enhancing the texture and stability of various formulations.

Chemical Composition and Structure

Hydroxypropylmethylcellulose is produced by replacing some of the hydroxyl groups in natural cellulose with methoxyl (-OCH₃) and hydroxypropyl (-CH₂CHOHCH₃) groups. This chemical modification gives HPMC enhanced solubility in both cold water and some organic solvents, and its properties vary depending on the degree of methoxyl and hydroxypropyl substitution.

The name describes the structure of the molecule:

• Hydroxypropyl. This term refers to an organic functional group that contains a hydroxy group (OH) attached to a propyl group (a chain of three carbon atoms).
• Methylcellulose. This is a derivative of cellulose, a polysaccharide that is the main component of plant cell walls. Methylcellulose is cellulose that has been chemically modified to replace some of the hydroxy groups in cellulose with methyl groups (-CH₃).

Description of the raw materials used in its production:

• Cellulose is the main component used in the production of hydroxypropyl methyl cellulose. It is a polysaccharide found in the cell walls of plants and is mainly obtained from natural sources such as wood, sugar cane or cotton.
• Propylene oxide is a reagent used in the synthesis of hydroxypropyl methyl cellulose. It is a chemical that reacts with cellulose to introduce hydroxypropyl groups into the polymer structure.
• Methylether is another reagent used to introduce methyl groups into cellulose during the synthesis of hydroxypropyl methyl cellulose.

Production Process

Hydroxypropyl methylcellulose is produced by treating cellulose with sodium methoxide and propylene oxide. This process replaces the hydroxyl groups in cellulose with methoxyl and hydroxypropyl groups. After the reaction, the product is purified and converted into powder form for use in various industrial applications.

The synthesis process takes place in different steps:

• Preparation of Starting Materials. The synthesis of HPMC begins with the preparation of the necessary starting materials. This includes cellulose, propylene oxide, and methyl chloride.
• Etherification Reaction. The cellulose is then reacted with propylene oxide and methyl chloride in the presence of a strong base. This process is known as etherification and produces Hydroxypropyl Methylcellulose.
• Purification. The final step in the synthesis process is purification. This involves removing any unreacted starting materials and byproducts from the reaction mixture to obtain the pure HPMC.

Physical Properties

It is soluble in cold water and forms gels when heated, making it useful for a variety of applications. HPMC solutions are generally viscous, which makes it an effective thickener in many formulations. 

It appears in the form of tasteless and odorless white powder, non-ionic, non-toxic cellulose ether produced from high molecular weight cellulose, soluble in water and some organic solvents. Powder fineness: 80 mesh pass rate is more than 98.5%; 70 mesh pass rate more than 100%. It decomposes into carbon monoxide, carbon dioxide.

What it is used for

Usually used in the presence of cellulose as an emulsifier, dispersant, binder, filler, stabilizer, suspending agent or thickener. However, its real name should be Hydroxypropylmethyl cellulose or Hydroxypropylmethyl cellulose, as established, in order to avoid double names as established by the Codex Alimentarius Commission (1).

It has good water solubility in both instantaneous mode (it decomposes rapidly in cold water and increases viscosity after 2 minutes) and slow mode (it agglomerates in cold water and then increases viscosity). As a natural polymeric material, it contains methylcellulose (MC).

Advantages

• It has interesting water retention properties as it can reduce water loss.
• It is resistant to enzymes providing optimum viscosity stability during long term storage due to its bacterial invasion characteristics of fungi.
• It can form a flexible and transparent film to form a barrier for oil.
• It has non-ionic substitution: compatible with other additives and coexist stably when dissolved in water.
• It is an excellent lubricant suitable for improving the performance of cement and ceramic products, so it can improve the dispensing force of concrete pump.
• Thermal gelation: if the temperature of the product rises to a certain point, it will produce gel. If the temperature of the product decreases, the gel disappears.

How to use

• In a container of 85° water, hypromellose is gradually added, which floats to the surface at first, but then turns into a uniform slurry that is cooled under stirring until it becomes transparent. About 2/3 of the total water should be heated to more than 85°, add the cellulose to get a hot water swell, then add the remaining amount of cold water, stir and cool to get a uniform solution.   The surface-treated product can be added directly to the cold water to dissolve with stirring. For rapid dissolution, the surface amount can be adjusted for the dissolution time. The product will dissolve quickly to form a solution.

Applications

It has a variety of applications: synthetic resins, cosmetics, food, medicine, leather, paper, ceramics, petrochemicals. 

• Textile industry: Can create an oil-resistant coating.
• Building industry: wall putty, mortar, concrete additives, coat, gypsum plaster, crack filler

It is used medically in ophthalmology for dry eye, in capsules to control drug release as a thickening agent, coating polymer, bioadhesive, in solid dispersion to improve solubility, binder in the granulation process and in modified release formulations and has excellent mucoadhesive properties suggesting its use in oral mucosal delivery systems including tablets and mucoadhesive films.

Food

Labeled as E464 in the European food additives list as a thickener and stabilizer.

Pharmaceutical

• Controlled Release. HPMC can be used to control the release of a drug, allowing it to be released slowly over time. This can help to maintain a steady level of the drug in the body, reducing the need for frequent dosing.
• Thickening Agent. It is used as a thickening agent in ophthalmic solutions to prolong the residence time of the drug. It is also used in oral medications to increase viscosity.
• Coating Agent. HPMC is used as a coating agent in tablets. It helps to improve the appearance and make the tablet easier to swallow. It can also protect the drug from the environment and mask the taste.
• Stabilizer. It helps to stabilize solutions and emulsions, which can improve the shelf life and effectiveness of the drug.
• Bioavailability Enhancement. HPMC can enhance the bioavailability of drugs by increasing the time a drug is dissolved in the gastrointestinal tract.

Cosmetics

• Antistatic agent. Static electricity build-up has a direct influence on products and causes electrostatic adsorption. The antistatic ingredient reduces static build-up and surface resistivity on the surface of the skin and hair.
• Binder agent. Ingredient that is used in cosmetic, food and pharmaceutical products as an anti-caking agent with the function of making the product in which it is incorporated silky, compact and homogenous. The binder, either natural such as mucilage, gums and starches or chemical, may be in the form of a powder or liquid.
• Emulsion stabiliser. Emulsions are thermodynamically unstable. Emulsion stabilisers improve the formation and stability of single and double emulsions. as well as their shelf-life. It should be noted that in the structure-function relationship, the molar mass of the ingredient used plays an important role.
• Film-forming agent. It produces, upon application, a very thin continuous film with an optimal balance of cohesion, adhesion and stickiness on skin, hair or nails to counteract or limit damage from external phenomena such as chemicals, UV rays and pollution.
• Surfactant - Cleansing agent. Cosmetic products used to cleanse the skin utilise the surface-active action that produces a lowering of the surface tension of the stratum corneum, facilitating the removal of dirt and impurities. 
• Viscosity control agent. It controls and adapts viscosity to the required level for optimal chemical and physical stability of the product and dosage in gels, suspensions, emulsions, solutions. 

Safety in Use

E464 is considered safe for use in food and is approved by various international regulatory bodies such as the European Union and the Food and Drug Administration (FDA) in the United States. No significant side effects are associated with its use at the recommended levels.

Excessive intake of celluloses such as E464 may be associated with high risks of cardiovascular diseases (CVD).

The most relevant studies on this ingredient have been selected with a summary of their contents:

Hydroxypropylmethylcellulose studies

Where to buy:

• Molecular Formula: C₅₆H₁₀₈O₃₀
• Molecular Weight: 1261.4 g/mol
• CAS: 9004-65-3
• UNII 3NXW29V3WO
• EC Number: 220-971-6    926-742-3
• DSSTox Substance ID: 
• MDL number  MFCD00131360
• PubChem Substance ID  57503849
• NACRES  NA.21 
• InChiIn   1S// 
• ChI Key  PUSNGFYSTWMJSK-GSZQVNRLSA-N
• SMILES CC(COCC1C(C(C(C(O1)OC2C(OC(C(C2OCC(C)O)OCC(C)O)OCC(C)O)COCC(C)O)OCC(C)O)OCC(C)O)OCC(C)O)O.COCC1C(C(C(C(O1)OC2C(OC(C(C2OC)OC)OC)COC)OC)OC)OC
• IUPAC   (2R,3R,4S,5R,6R)-2,3,4-trimethoxy-6-(methoxymethyl)-5-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxyoxane;1-[[(2R,3R,4S,5R,6S)-3,4,5-tris(2-hydroxypropoxy)-6-[(2R,3R,4S,5R,6R)-4,5,6-tris(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)oxan-3-yl]oxyoxan-2-yl]methoxy]propan-2-ol
• ChEBI    

Synonyms: 

• HPMC
• Hydroxypropyl)methyl cellulose
• Hydroxypropylmethylcellulose
• Hypropyl methylcellulose
• Hypropyl mellose

References___________________________________________________________

144. The Committee did not support the proposal to introduce the dual name “hypromellose” for hydroxypropylmethyl cellulose (INS 464).

Capita L, Chalita MR, dos Santos-Neto LL. Prospective evaluation of hypromellose 2% for punctal occlusion in patients with dry eye. Cornea. 2015 Feb;34(2):188-92. doi: 10.1097/ICO.0000000000000325. 

Ghori MU, Ginting G, Smith AM, Conway BR. Simultaneous quantification of drug release and erosion from hypromellose hydrophilic matrices. Int J Pharm. 2014 Apr 25;465(1-2):405-12. doi: 10.1016/j.ijpharm.2014.02.028.

Chen L, Wang F. Development of sustained-release matrix tablets of BKP-01-041 (tilorone derivative) containing Hypromellose. Pharmazie. 2013 Oct;68(10):796-9.

Al-Tabakha MM. HPMC capsules: current status and future prospects. J Pharm Pharm Sci. 2010;13(3):428-42. doi: 10.18433/j3k881.

Mašková E, Kubová K, Raimi-Abraham BT, Vllasaliu D, Vohlídalová E, Turánek J, Mašek J. Hypromellose - A traditional pharmaceutical excipient with modern applications in oral and oromucosal drug delivery. J Control Release. 2020 Aug 10;324:695-727. doi: 10.1016/j.jconrel.2020.05.045.

 Sellem L, Srour B, Javaux G, Chazelas E, Chassaing B, Viennois E, Debras C, Salamé C, Druesne-Pecollo N, Esseddik Y, de Edelenyi FS, Agaësse C, De Sa A, Lutchia R, Louveau E, Huybrechts I, Pierre F, Coumoul X, Fezeu LK, Julia C, Kesse-Guyot E, Allès B, Galan P, Hercberg S, Deschasaux-Tanguy M, Touvier M. Food additive emulsifiers and risk of cardiovascular disease in the NutriNet-Santé cohort: prospective cohort study. BMJ. 2023 Sep 6;382:e076058. doi: 10.1136/bmj-2023-076058. PMID: 37673430; PMCID: PMC10480690.