Compendium of the most significant studies with reference to properties, effects.

Shmuel K, Dalia M, Tair L, Yaakov N. Low pH Hypromellose (Taffix) nasal powder spray could reduce SARS-CoV-2 infection rate post mass-gathering event at a highly endemic community: an observational prospective open label user survey. Expert Rev Anti Infect Ther. 2021 Oct;19(10):1325-1330. doi: 10.1080/14787210.2021.1908127.

Abstract. Objectives: Bney Brak city tops Israel's COVID-19 infection rate and mortality. Before the Jewish New Year (two-day gathering) SARS-CoV-2 PCR positivity rates were 17.6% and reached 28.1% two weeks later Taffix - an innovative nasal powder creates a protective gel over the nasal mucosa blocking viruses from infecting nasal cells, was tested for efficacy in preventing SARS CoV2 infection.Methods: In a prospective users survey, 243 members of an ultra-orthodox community that participated in two days prayers were followed for 14 days following this 'superspread' event. Eighty-three used Taffix throughout holiday's prayers and the following two weeks (ITT). Eighty-one used it regularly (PP). Two used it rarely if at all. The remaining 160 did not use Taffix.Results: After 14 days, 0/81 (0%) of (PP) Tafffix users, 2/83 (2.4%) of (ITT) Taffix users and 16/160 (10%) nonusers were infected. Odds ratio for infection among Taffix users was 0.22, a reduction of 78% (95%CI 1%-95%). No side effects reported.Conclusion: Taffix could be an additional tool against COVID19 spread, in addition to recommended safety measures. This is the first time that a prevention measure of SARS-CoV-2, beyond the use of masks, has proved effective.

Sauer A, Warashina S, Mishra SM, Lesser I, Kirchhöfer K. Downstream processing of spray-dried ASD with hypromellose acetate succinate - Roller compaction and subsequent compression into high ASD load tablets. Int J Pharm X. 2021 Oct 14;3:100099. doi: 10.1016/j.ijpx.2021.100099.

Abstract. Despite wide commercial application of hypromellose acetate succinate (HPMCAS) in spray-dried amorphous solid dispersion (ASD) drug products, little information is available in the references on downstream processing of spray-dried dispersions with HPMCAS. Poor flow and high dilution factor are a challenge in formulating spray-dried ASDs into tablets, leaving little space for other excipients facilitating binding and disintegration. Direct compression is not possible due to the poor powder flow of spray-dried ASDs. Moisture has to be avoided due to the plasticizing properties of water on the ASD, resulting in reduced stability of the amorphous state. Thus, dry granulation by roller compaction and subsequent tablet compression is the preferred downstream process. We report the investigation of downstream processing by roller compaction and tablet compression of a high load formulation with 75% of spray-dried amorphous solid dispersion (Nifedipine:HPMCAS 1:2). A head to head comparison of microcrystalline cellulose/croscarmellose (MCC/cl-NaCMC) as binder/disintegrant vs. MCC and low-substituted hydroxypropyl cellulose (L-HPC) as excipient for binding and disintegration showed improved re-workability of the formulation with MCC/L-HPC after roller compaction. Upon transfer to the rotary press, a 45% higher tensile strength of tablets is observed after dry granulation with MCC/L-HPC. © 2021 The Author(s).

Ueda K, Iwai T, Sunazuka Y, Chen Z, Kato N, Higashi K, Moribe K. Effect of molecular weight of hypromellose on mucin diffusion and oral absorption behavior of fenofibrate nanocrystal. Int J Pharm. 2019 Jun 10;564:39-47. doi: 10.1016/j.ijpharm.2019.04.033.

Bagchi B, Salvadores Fernandez C, Bhatti M, Ciric L, Lovat L, Tiwari MK. Copper nanowire embedded hypromellose: An antibacterial nanocomposite film. J Colloid Interface Sci. 2021 Sep 25;608(Pt 1):30-39. doi: 10.1016/j.jcis.2021.09.130.

Grdešič P, Paudel A, German Ilić I. High-Molecular-Weight Hypromellose from Three Different Suppliers: Effects of Compression Speed, Tableting Equipment, and Moisture on the Compaction. AAPS PharmSciTech. 2020 Jul 22;21(6):203. doi: 10.1208/s12249-020-01688-y.

Abstract. Use of higher tableting speeds is gaining increasing importance for pharmaceutical industry. There is a profound lack of new studies of mechanical properties of hypromellose, and none of them evaluate different suppliers. Thus, the objective of this study was to investigate flow and compaction properties of different grades of hypromellose (type 2208) from three different suppliers, with particular focus on the effect of the compression speed. The flow properties were determined using flow time, shear cell, Carr index, and constant B from initial part of Heckel profile. Compaction properties were quantified using "out-of-die" Heckel, Walker, and Kuentz-Leuenberger models; two tensile strength profiles (tabletability and compactibility); and elastic recovery. Compaction was performed by both an instrumented single-punch press and a high-speed rotary press simulator. Due to larger, rounder, and smoother particles, both Methocel™ DC grades together with Benecel™ K4M showed better flow properties compared with other materials, with Metolose® K100M having the worst flow. Overall, Benecel™ K100M and Metolose® K100M showed the best compaction properties, closely followed by Metolose® K4M. Heckel analysis showed the highest compressibility of Benecel™ K100M, followed by both Methocel™ DC grades. Kuentz-Leuenberger model showed to have no practical superiority in comparison with Heckel model in the compression pressure range used. Results of strain rate sensitivity showed that Methocel™ K4M DC was the least susceptible to change of tableting speed, followed by Methocel™ K100M DC and both grades of Benecel™, and in contrast, both grades of Metolose® were the most sensitive. Effect of moisture on compaction was also studied.

Ishizuka Y, Ueda K, Okada H, Takeda J, Karashima M, Yazawa K, Higashi K, Kawakami K, Ikeda Y, Moribe K. Effect of Drug-Polymer Interactions through Hypromellose Acetate Succinate Substituents on the Physical Stability on Solid Dispersions Studied by Fourier-Transform Infrared and Solid-State Nuclear Magnetic Resonance. Mol Pharm. 2019 Jun 3;16(6):2785-2794. doi: 10.1021/acs.molpharmaceut.9b00301.

Abstract. The present study evaluated the specific intermolecular interactions between carbamazepine (CBZ) and substituents of hypromellose acetate succinate (HPMC-AS), as well as the mechanism of inhibition of recrystallization of solid dispersions (SDs) using Fourier-transform infrared (FTIR) and solid-state nuclear magnetic resonance (NMR) spectroscopy. CBZ and HPMC derivatives, including HPMC, hypromellose acetate (HPMC-A), and hypromellose succinate (HPMC-S), were spray-dried to prepare CBZ/polymer spray-dried samples (SPDs). CBZ/HPMC SPD and CBZ/HPMC-A SPD recrystallized within 10 days at 60 °C and 0% relative humidity, whereas CBZ/HPMC-S SPD maintained its amorphous state for a longer period. FTIR and solid-state NMR measurements using 13C cross polarization (CP), 1H single-pulse, and 1H-15N CP-based heteronuclear single quantum correlation filter experiment with very fast magic angle spinning (MAS) at 70 kHz identified molecular interactions in CBZ/polymer SPDs. Although the HPMC backbone and substituents did not interact notably with CBZ and disrupt CBZ-CBZ intermolecular interactions (formed in the amorphous CBZ), acetate and succinate substituents on HPMC-A and HPMC-S disrupted CBZ-CBZ intermolecular interactions through formation of CBZ/polymer interactions. The acetate substituent formed a hydrogen bond with the NH2 group of CBZ, whereas the succinate substituent formed molecular interactions with both the C═O and NH2 groups of CBZ. Formation of relatively strong molecular interactions between CBZ and the succinate substituent followed by disruption of CBZ-CBZ intermolecular interactions effectively stabilized the amorphous state of CBZ in CBZ/HPMC-S SPD. The correlation between CBZ-polymer interactions and ability of polymers to effectively inhibit CBZ recrystallization is reflected in various commercial HPMC-AS. For example, HPMC-AS LF grade, containing higher amounts of the succinate group, was found to effectively inhibit the recrystallization of CBZ through strong molecular interactions as compared with the HPMC-AS HF grade. The present study demonstrated that a detailed investigation of molecular interactions between the drug and the polymer using FTIR and solid-state NMR spectroscopy could contribute to a suitable selection of the SD carrier.

Zarmpi P, Flanagan T, Meehan E, Mann J, Fotaki N. Biopharmaceutical Understanding of Excipient Variability on Drug Apparent Solubility Based on Drug Physicochemical Properties: Case Study-Hypromellose (HPMC). AAPS J. 2020 Feb 18;22(2):49. doi: 10.1208/s12248-019-0411-1.

Abstract. Identification of the biopharmaceutical risks of excipients and excipient variability on oral drug performance can be beneficial for the development of robust oral drug formulations. The current study investigated the impact of Hypromellose (HPMC) presence and varying viscosity type, when used as a binder in immediate release formulations, on the apparent solubility of drugs with wide range of physicochemical properties (drug ionization, drug lipophilicity, drug aqueous solubility). The role of physiological conditions on the impact of excipients on drug apparent solubility was assessed with the use of pharmacopoeia (compendial) and biorelevant media. Presence of HPMC affected drug solubility according to the physicochemical properties of studied compounds. The possible combined effects of polymer adsorption (drug shielding effect) or the formation of a polymeric viscous layer around drug particles may have retarded drug dissolution leading to reduced apparent solubility of highly soluble and/or highly ionized compounds and were pronounced mainly at early time points. Increase in the apparent solubility of poorly soluble low ionized drugs containing a neutral amine group was observed which may relate to enhanced drug solubilization or reduced drug precipitation. The use of multivariate data analysis confirmed the importance of drug physicochemical properties on the impact of excipients on drug apparent solubility and revealed that changes in HPMC material properties or amount may not be critical for oral drug performance when HPMC is used as a binder. The construction of a roadmap combining drug, excipient, and medium characteristics allowed the identification of the cases where HPMC presence may present risks in oral drug performance and bioavailability.

Mašková E, Naiserová M, Kubová K, Mašek J, Pavloková S, Urbanová M, Brus J, Vysloužil J, Vetchý D. Highly Soluble Drugs Directly Granulated by Water Dispersions of Insoluble Eudragit® Polymers as a Part of Hypromellose K100M Matrix Systems. Biomed Res Int. 2019 Mar 5;2019:8043415. doi: 10.1155/2019/8043415.

Abstract. The aim of the present study was to investigate the suitability of insoluble Eudragit® water dispersions (NE, NM, RL, and RS) for direct high-shear granulation of very soluble levetiracetam in order to decrease its burst effect from HPMC K100M matrices. The process characteristics, ss-NMR analysis, in vitro dissolution behavior, drug release mechanism and kinetics, texture profile analysis of the gel layer, and PCA analysis were explored. An application of water dispersions directly on levetiracetam was feasible only in a multistep process. All prepared formulations exhibited a 12-hour sustained release profile characterized by a reduced burst effect in a concentration-dependent manner. No effect on swelling extent of HPMC K100M was observed in the presence of Eudragit®. Contrary, higher rigidity of formed gel layer was observed using combination of HPMC and Eudragit®. Not only the type and concentration of Eudragit®, but also the presence of the surfactant in water dispersions played a key role in the dissolution characteristics. The dissolution profile close to zero-order kinetic was achieved from the sample containing levetiracetam directly granulated by the water dispersion of Eudragit® NE (5% of solid polymer per tablet) with a relatively high amount of surfactant nonoxynol 100 (1.5%). The initial burst release of drug was reduced to 8.04% in 30 min (a 64.2% decrease) while the total amount of the released drug was retained (97.02%).

Ohyagi N, Ueda K, Higashi K, Yamamoto K, Kawakami K, Moribe K. Synergetic Role of Hypromellose and Methacrylic Acid Copolymer in the Dissolution Improvement of Amorphous Solid Dispersions. J Pharm Sci. 2017 Apr;106(4):1042-1050. doi: 10.1016/j.xphs.2016.12.005. 

Nižić L, Potaś J, Winnicka K, Szekalska M, Erak I, Gretić M, Jug M, Hafner A. Development, characterisation and nasal deposition of melatonin-loaded pectin/hypromellose microspheres. Eur J Pharm Sci. 2020 Jan 1;141:105115. doi: 10.1016/j.ejps.2019.105115.

Ueda K, Hate SS, Taylor LS. Impact of Hypromellose Acetate Succinate Grade on Drug Amorphous Solubility and In Vitro Membrane Transport. J Pharm Sci. 2020 Aug;109(8):2464-2473. doi: 10.1016/j.xphs.2020.04.014.

Li Y, Zhong M, Xie F, Sun Y, Zhang S, Qi B. The effect of pH on the stabilization and digestive characteristics of soybean lipophilic protein oil-in-water emulsions with hypromellose. Food Chem. 2020 Mar 30;309:125579. doi: 10.1016/j.foodchem.2019.125579.

Wang Q, Yu DG, Zhang LL, Liu XK, Deng YC, Zhao M. Electrospun hypromellose-based hydrophilic composites for rapid dissolution of poorly water-soluble drug. Carbohydr Polym. 2017 Oct 15;174:617-625. doi: 10.1016/j.carbpol.2017.06.075.

Ipromellose (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

Ipromellose 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.