HPMC (Hydroxypropylmethylcellulose , E464) is a chemical compound, a water-soluble non-ionic cellulose ether, a semi-crystalline polymer with very low glass transition amorphous polymer domains along with crystalline domains and obtained by chemical reaction of the hydroxyl groups at the 2, 3 and/or 6 positions of the cellulose glucose residues.

It is a cellulose derivative obtained by replacing some of the hydroxyl groups in natural cellulose with hydroxypropyl groups. This modification gives hydroxypropyl cellulose unique properties, such as solubility in both water and certain organic solvents. It is widely used in the food, pharmaceutical, and cosmetic industries as a thickening agent, stabilizer, binder, and film-former. Its ability to form gels, improve viscosity, and stabilize emulsions makes it a versatile ingredient in various applications.

Chemical Composition and Structure

Hydroxypropyl cellulose is produced through the reaction of cellulose with propylene oxide, which replaces the hydroxyl groups (-OH) in cellulose with hydroxypropyl groups (-CH₂CHOHCH₃). This structure gives hydroxypropyl cellulose good solubility in water and a greater ability to form viscous solutions, making it ideal for enhancing the texture and stability of products.

Physical Properties

It typically appears as a white or granular powder, odorless and tasteless. It is soluble in both hot and cold water, as well as in certain organic solvents. Its ability to absorb water allows it to form viscous solutions and gels, making it useful as a thickening, binding, and stabilizing agent in numerous 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.

The name defines the structure of the molecule:

• Hydroxypropyl refers to a group derived from propylene, a three-carbon alkene, with an attached hydroxyl (-OH) group.
• Cellulose refers to a type of polysaccharide that is the main component of plant cell walls. Cellulose is a large molecule consisting of many smaller glucose units linked together.

Production Process

Hydroxypropyl cellulose is produced by reacting cellulose with propylene oxide under alkaline conditions. This chemical process replaces the hydroxyl groups in cellulose with hydroxypropyl groups, enhancing its solubility and gel-forming capabilities. The resulting material is purified and dried for use in powder or granular form. 

The synthesis process takes place in several stages:

• Cellulose purification. The first step in the synthesis of HPC is the purification of cellulose, derived from plant sources. This involves the removal of impurities such as lignin, hemicellulose and other components.
• Alkaline treatment. Purified cellulose is treated with an alkali, sodium hydroxide. This process, known as mercerization, increases the reactivity of cellulose by breaking down its crystalline structure.
• Reaction to propylene oxide. The alkali-treated cellulose is reacted with propylene oxide. This introduces hydroxypropyl groups (-CH2CHOHCH3) on the cellulose molecule. The degree of substitution, or the average number of hydroxypropyl groups connected to each unit of glucose in cellulose, can be controlled by adjusting the reaction conditions.
• Neutralization and washing. After the reaction, the mixture is neutralized, usually with an acid such as hydrochloric acid. The product is then washed to remove unreacted reagents and by-products.
• Drying and grinding process. The wet mass is then dried and ground into a fine powder to produce the final product, hydroxypropylcellulose.
• Quality control. The final product is then tested to ensure it meets the required specifications. This may involve testing for parameters such as degree of replacement, viscosity, and moisture content.

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.

What it is used for and where

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 (2), in capsules to control drug release (3) as a thickening agent, coating polymer, bioadhesive, in solid dispersion to improve solubility, binder in the granulation process and in modified release formulations (4) and has excellent mucoadhesive properties suggesting its use in oral mucosal delivery systems including tablets and mucoadhesive films (5).

Food

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

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

E463 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 E463 may be associated with high risks of cardiovascular diseases (CVD) (5).

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___________________________________________________________

(1) Rashid R, Kim DW, Din FU, Mustapha O, Yousaf AM, Park JH, Kim JO, Yong CS, Choi HG. Effect of hydroxypropylcellulose and Tween 80 on physicochemical properties and bioavailability of ezetimibe-loaded solid dispersion. Carbohydr Polym. 2015 Oct 5;130:26-31. doi: 10.1016/j.carbpol.2015.04.071.

(2) Jones DS, Rafferty GP, Andrews GP. Design of binary polymeric platforms containing ɩ-carrageenan and hydroxypropylcellulose for use in cataract surgery. Carbohydr Polym. 2016 Dec 10;154:296-304. doi: 10.1016/j.carbpol.2016.06.042.

(3) Tang B, Shan J, Yuan T, Xiao Y, Liang J, Fan Y, Zhang X. Hydroxypropylcellulose enhanced high viscosity endoscopic mucosal dissection intraoperative chitosan thermosensitive hydrogel. Carbohydr Polym. 2019 Apr 1;209:198-206. doi: 10.1016/j.carbpol.2018.12.103.

(4) Yang J, Dong Y, Wang J, Chen C, Zhu Y, Wu Y, Zhang P, Chen T, Zhou W, Wu P, Thanh NTK, Ngoc Quyên Trân, Chen J, Chen S. Hydroxypropylcellulose Coating to Improve Graft-to-Bone Healing for Anterior Cruciate Ligament Reconstruction. ACS Biomater Sci Eng. 2019 Apr 8;5(4):1793-1803. doi: 10.1021/acsbiomaterials.8b01145.

Abstract. An anterior cruciate ligament (ACL) injury is one of the most common injuries in sports, and ACL reconstruction with an artificial ligament is a good treatment for quick recovery. However, current artificial ligaments made of polyethylene terephthalate (PET) are still associated with some problems due to the hydrophobic nature and low biological induction activity of PET. Many efforts have been used to improve the biocompatibility of PET in recent years, and our previous work has shown that surface modification is an effective strategy. Here, a hydroxypropylcellulose (HPC) coating was applied on the surface of a PET artificial ligament order to improve its biocompatibility. The effects of the HPC coating on PET artificial ligament graft-bone healing was investigated in vitro using bone marrow stromal cells (BMSCs), fibroblasts, and RSC-364 cells as well as in vivo in a beagle dog model of ACL reconstruction. HPC was coated successfully on the PET and significantly promoted cell growth, adhesion, and capability of osteogenic differentiation compared to the PET graft without HPC coating. In vivo, the HPC coating significantly enhanced ligament tissue regeneration. Moreover, higher expression of some bone-formation- and ligament-tissue-regeneration-contributing proteins and cell factors, such as COL1, BMP-7, COL3, OCN, RUNX2, TGF-β1, and VEGF, was observed on the HPC-coated PET artificial ligament in comparison with the pure PET artificial ligament. In conclusion, HPC coating can significantly improve the cytocompatibility and graft-to-bone healing of a PET artificial ligament for ACL reconstruction.

(5) 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.