1.SOLUBILITY
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Can be dissolved in water, its highest concentration is only determined by the viscosity, the solubility changes with the viscosity, the lower the viscosity, the greater the solubility.
2. NON-IONIC
The product is a non-ionic cellulose ether, and it is not a polyelectrolyte, so it is relatively stable in aqueous solution in the presence of metal salts or organic electrolytes, but excessive addition of electrolytes can cause gelation and precipitation
3. SURFACE ACTIVITY
Due to the active function of the aqueous solution, it can be used as a colloidal protective agent, emulsifier and dispersant
4. THERMAL GELS
When the product aqueous solution is heated to a certain temperature, it becomes opaque and the gel forms a precipitate. However, when it is continuously cooled, it returns to the original solution state. The temperature at which this gelation and precipitation occurs mainly depends on their lubricants and suspending agents. Protective colloid. Emulsifier, etc.
5. FILM FORMATION
Can form a transparent, tough and flexible film with good oil resistance and water resistance
6. MILDEW RESISTANCE
Has relatively good anti-fungal ability. Good viscosity stability during long-term storage.
Hydroxypropyl methylcellulose (Hypromellose, HPMC) is a well-known excipient used in the pharmaceutical and nutraceutical fields due to its versatile physicochemical properties. HPMC (derived from cellulose and obtained through etherification) varies in polymerization degree and viscosity, factors that both influence its functional applications. Usually, an increased polymerization degree implies a higher viscosity, depending also on the amount of polymer used. Hypromellose plays a crucial role in solid dosage forms, serving as a binder in the case of controlled-release tablets, a film-forming agent in the case of orodispersible films and mucoadhesive films, and a release modifier due to its presence in different polymerization degrees in the case of extended or modified release tablets. However, its compatibility with other excipients and the active ingredient must be carefully evaluated to prevent formulation challenges via several analytical methods such as differential scanned calorimetry (DSC), Fourier Transformed Infrared spectroscopy (FT-IR), X-Ray Particle Diffraction (XRPD), and Scanning Electron Microscopy (SEM). This review explores the physicochemical characteristics, and diverse applications of HPMC, emphasizing its significance in modern drug delivery systems.
Cellulose is a biodegradable polymer of natural origin composed of repeated units of glucose. It possesses adequate mechanical properties, biocompatibility, and is easily accessible, aspects that led to the polymer’s recognition in industries such as pharmaceuticals, food, textiles, the paper industry, and many more in recent years. Among its limitations, cellulose presents poor solubility in water and organic solvents, due to its hydrophilic nature and crystalline structure. By modifying the initial structure, well-known cellulose derivatives were created through the etherification of the hydroxyl groups: Methyl cellulose (MC), Ethyl cellulose (EC), Hydroxyethyl cellulose (HEC), Hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC), carboxymethyl cellulose (CMC), and sodium carboxymethyl cellulose (NaCMC). This improved the solubility profile, offering additional applications in the biomedical field. Among these, HPMC stands out as a tablet binder, film-coating, gelling, and encapsulating agent, making it one of the most versatile cellulose derivatives used in the pharmaceutical domain [1,2].
Hydroxypropyl methylcellulose (HPMC), a semi-synthetic cellulose ether, is one of the most commonly used cellulose derivatives. Its excellent film-forming properties, high stability, remarkable biocompatibility, and biodegradability make it commonly employed in the food industry, the pharmaceutical industry, and other industries [3]. Also known as hypromellose, HPMC has now been used in hydrophilic matrices for over 60 years [4].
Hydroxypropyl methylcellulose is derived from natural cellulose through etherification, where hydroxyl groups in the cellulose structure are replaced with hydroxypropyl and methyl groups. This alteration can improve cellulose solubility, viscosity, film-forming properties, and soothing effects [5].
HPMC has extensive applications in various pharmaceutical technologies, playing a crucial role in developing mucoadhesive formulations, ophthalmic preparations, and different types of controlled-release dosage forms. Due to its properties, large biocompatibility, and edible character, it can be used as a tablet binder, film-coating material, biological adhesive, gelling agent, as well as an encapsulation, suspending, and thickening agent [6].
The properties of HPMC are dependent on the degree of substitution and molecular weight [7]. The food industry utilizes HPMC as a thickener, emulsifier, and stabilizer in processed foods [8]. Additionally, it plays a crucial role in construction materials, such as tile adhesives and cement-based coatings, due to its ability to improve water retention and workability [9].
Previous studies have shown that HPMC is suitable for water-soluble drugs, loading large amounts of drugs, and is compatible with numerous active pharmaceutical ingredients (APIs) such as bupropion hydrochloride, diclofenac sodium, and acetaminophen [10]. HPMC’s biodegradability and non-toxic nature make it a sustainable and safe polymer, further expanding its applications in eco-friendly and biomedical materials as mentioned by multiple international regulatory bodies (United States Food and Drug Administration—US-FDA and European Chemicals Agency). Ongoing research continues to enhance its properties and develop new applications, solidifying its importance in various industrial and scientific fields. Collectively, these assessments reinforce the status of HPMC as a safe, multifunctional polymer across pharmaceutical, food, cosmetic, and industrial applications.
Considering that this review is concerned with different pharmaceutical, analytical, and medical aspects, the first step consisted of establishing the names of the chapters and the subchapters. As a result, the main keywords used were as follows: HPMC, Hypromellose, hydroxypropyl methylcellulose as film-forming agent, hydroxypropyl methylcellulose as coating agent, HPMC utility in the medical field, HPMC interactions with other excipients, and HPMC conditions for degradation. The databases used for collecting information for this review were PubMed, Google Scholar, and Web of Science.
Hypromellose (Hypromellosum—Ph. Eur. 11) (Figure 1) is a white, free-flowing, hygroscopic powder, and due to its lack of odour, and taste, as well as its edible character, it has been approved as a food additive by both the U.S. Food and Drug Administration agency and the European Union. The daily dosage accepted by the FDA for oral intake is 25 mg/kg [11,12]. In addition to its water-solubility, the non-ionic polymer is soluble in polar organic solvents and insoluble in pure chloroform or ethanol [13,14]. It is stable at pH values between 3 and 11 [15].
As previously mentioned, hydroxypropyl methylcellulose belongs to a group of semi-synthetic cellulose derivatives, whose hydroxyl groups have been partly substituted by ether-linked methoxy and hydroxypropyl side groups [16]. This addition disrupts cellulose’s crystalline structure, contributing to HPMC’s hydrophilic nature. Its unique character relies on the ability to hydrate, swell, and form a gel upon heating at 75–90 °C while being soluble in cold water [17,18].
For its synthesis, cellulose is first treated with an alkaline base such as NaOH. The etherification can be obtained through the chemical reaction with methyl chloride and propylene oxide, the latter resulting in chain extension [19,20,21]. The substitution of the glycosyl units occurs in positions 2, 3, or 6 with methyl or 2-hydroxypropyl as radicals [22]. Lismeri et al. attempted to produce HPMC from α-cellulose derived from cassava stems by using dimethyl sulphate for the methylation reaction [23]. Another method proposed by Yuan et al. suggests first methylating cellulose to obtain Methylcellulose (MC) and then synthesizing HPMC through hydroxypropylation [24]. Therefore, the polysaccharide-based polymer is available in a wide variety of substitution degrees, each differing in molecular weight, and presenting various features that directly impact the field of application [25]. For HPMC, the degree of substitution (DS) provides information on the number of methoxy groups substituted per repeated molecule, whereas molar substitution (MS) refers to the average hydroxypropyl molar content, the second-mentioned being the ability to undergo chain reactions, increasing the MS value. Depending on the character provided by the methoxy (hydrophobic) and the hydroxypropyl (hydrophilic) groups, the behaviour in aqueous media presents different particularities [26]. The ratio between the two substituents directly influences the compound’s solubility, swelling capacity, and thermal gelation temperature, dividing the field into subcategories [27]. A higher percentage of the methoxy substituent leads to an increase in hydrophobic interactions and, ultimately, a lower hydration rate, swelling, and matrix gel strength, through the obstruction of the hydrophilic groups [10]. On the other hand, a study carried out by Perez-Robles et al. investigated the impact of DS and MS on the connection between temperature and the gelation process. It was shown that with the increase of the DS and MS values, gelation took place faster, and the viscosity of the produced gel was lower [28].
The European Pharmacopoeia 11th edition [29] classifies hypromellose into four categories based on the substitution content, as presented in Table 1, where the first two digits represent the average percentage of the methoxy groups (), while the last two stand for the hydroxypropyl substituent percentage (). As part of the Methocel® product line, Dow Chemical Company introduced the E, F, J, and K classification system, which dates back to the mid-20th century, but since , it has belonged to DuPont [21,30,31].
Table 1. Classification of HPMC types based on substitution grade.
The viscosity of polymer solutions arises from the hydration of polymer chains, where oxygen atoms form hydrogen bonds, resulting in irregular coils. As hydration continues, more water molecules get trapped within the expanded structure, further increasing viscosity [34]. An additional numerical suffix was introduced to indicate the viscosity of the polymer solution expressed in millipascal-seconds (mPa·s), which was strongly linked to the molecular weight of HPMC. The viscosity grade varies from 3 to 100,000 mPa·s and is measured in a 2% aqueous solution (w/w) at 20 °C. In addition to the numerical value, the letters “C” and “M” suggest a multiplication of 100 or , respectively. In the case of hydrophilic matrix tablets, HPMC with a higher viscosity grade is used for highly soluble drugs, while lower viscosity grades are chosen for drugs with low solubility. Based on the API’s desired release mechanism, the formation of the gel layer is of great importance [35]. The degree of polymerization (DP) is closely linked to the polymer’s viscosity grade. In normal conditions, the increase in the number of monomers in the chain and, consequently, the molecular weight is proportional to the rise in the viscosity of HPMC solutions, with the process being more visible for lower DPs [36,37].
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For labelling purposes, additional suffixes are also used for identifying the different characteristics of HPMC products, such as the following: “P” which identifies Methocel® Premium grade products, “LV” which is used for low viscosity products, “CR” refers to controlled release products, and “DC” denotes HPMC variations used for direct compression, while “G”, “S”, and “FG” stand for granular, surface treated, and food grade abbreviations [38].
Concerning the availability of the polymer, hypromellose is highly used and easily accessible worldwide through different trademarks: Methocel® (Dow Chemical Company, Midland, MI, USA), Metolose®, Pharmacoat® (Shin-Etsu Chemical Company, Tokyo, Japan), Benecel® (Ashland, Zwijndrecht, The Netherlands), and Mecellose and Anycoat (Lotte Fine Chemical, Ulsan, Republic of Korea). In terms of comparison, each subgrade provides distinct characteristics and therefore, different applications within the pharmaceutical field, as highlighted in Table 2. Recently, a new grade of HPMC was developed as a solution to poorly soluble drugs [32,39,40,41,42]. Affinisol (DuPont, Wilmington, DE, USA) presents improved solubility in organic solvents and can be used in thermally demanding technologies such as hot melt extrusion and spray-drying [27,43].
HPMC plays a crucial role as a multifunctional excipient in the pharmaceutical industry. It is commonly used as a binder in tablet formulations, ensuring structural integrity and durability in controlled-release dosage forms and enabling sustained drug release over time. Its film-forming properties make it an ideal choice for coating tablets, providing a protective barrier that enhances stability, masks taste, and facilitates swallowing. Additionally, it can be used in capsule manufacturing as a gelling agent. Its utilities in pharmaceutical technology will be further summarised, and the chosen main roles of the film-forming agent and coating agent will be detailed in the following chapters.
4.1. Binding Properties
Due to their excellent adhesive properties, binders are commonly used to produce solid dosage forms and enhance the mechanical strength of granules or tablets. They help hold the ingredients of a tablet together, ensuring integrity during manufacturing, storage, and transportation [52]. HPMC is considered a versatile binding agent as it is compatible with both soluble and insoluble drugs. The viscosity of a binder is a crucial parameter to consider during granulation, as it directly influences the strength of the resulting granules [53]. The lower viscosity grades of HPMC serve as both a binder and a disintegrant in tablets, pills, and granulations, whereas higher viscosity grades function solely as binders. Concentrations ranging from 2% to 5% w/w can be used as a binder in either wet or dry granulation processes, depending on the specific types and requirements [54].
For example, Fristiohady et al. conducted a study to evaluate the effectiveness of HPMC as a binder in tablet formulations with Cassia siamea extract, observing the effect of HPMC and examining the impact of varying HPMC concentrations (2%, 3%, and 4%) on the physical properties of the tablets. The tablets were evaluated in terms of weight, thickness, hardness, and disintegration time. All physical quality standards were met except for that of tablet hardness, which proved to be greater than expected. This may be attributed to the high concentrations of lubricants and particles interlocking and undergoing plastic deformation facilitated by the binder [55].
4.2. Film-Coating Material
Among cellulose derivatives, HPMC is a polysaccharide widely used for coating formulations due to its “film-forming, transparency, flexibility **, ** and stability properties” [56]. These attributes are responsible for forming tough and flexible films that protect fragile tablets from environmental factors (light, oxygen, pH, moisture) and resist abrasion. Moreover, the resulting film masks the unpleasant taste or smell of the drug and improves the appearance of the tablet [57]. Taste masking has become a potential tool in the pharmaceutical industry to improve patient compliance and the marketing success of a product.
To optimize production efficiency and reduce coating time, the lowest possible viscosity grade of the polymer is generally preferred, as it allows for a higher solid content in the coating solution with a lesser amount of water. The apparent viscosity of an aqueous HPMC solution is directly related to the molecular weight of the HPMC polymer, with a reduction in molecular weight leading to diminished physical properties of the film coat [58]. The higherviscosity grades of HPMC provide films with good tensile strength, but their films have poor adhesion to the core surface and can easily peel off the tablet surface [59]. Generally, HPMC is used in concentrations of 2–20% w/w in film-forming solutions for coating tablets [54].
In another study, Iswandana et al. studied the film-coating capacity of HPMC by formulating and developing film-coated tablets containing Momordica charantia. The tablets were prepared by wet granulation using carboxymethyl cellulose as a binder and then coated with HPMC 5%. The purpose of the study was to improve the physical appearance and mask the unpleasant taste of a bitter melon. The results complied with the criteria of a good physical appearance and lower bitterness levels [60]. In another study provided by Abbaspour et al., HPMC was used as a film-coating agent. The study aimed to design and evaluate a moisture-resistant film formulation based on HPMC and microcrystalline cellulose and compare it with Sepifilm® as a commercial gastro-soluble composition for the film coating of moisture-sensitive solid dosage forms (aspirin). The formulations were assessed in terms of mechanical strength, moisture permeability, and morphological properties. It was concluded that HPMC films could be applied as a moisture-resistant film coating, providing acceptable stability for aspirin tablets [61].
4.3. Biological Adhesive
Hydroxypropyl methylcellulose plays an important role in the field of mucoadhesive drug delivery systems, finding applications across numerous therapeutic domains. HPMC is extensively used in controlled-release formulations due to its thickening, gelling, and swelling properties, forming clear, stable, and odourless hydrogels. Moreover, it enhances contact with the mucous membrane and facilitates slow drug release, achieving the purpose of the treatment [62]. Its bioadhesive properties are attributed to the presence of the hydroxyl functional groups in HPMC molecules that can form hydrogen bonds with water and other polymers. This facilitates the absorption of large quantities of water, followed by swelling as a result of their hydrophilic nature. Furthermore, hydrogen bonding interactions between polymer chains and the mucin glycoproteins produced by epithelial tissues contribute to the mucoadhesive strength of HPMC [16,63]. As a mucoadhesive excipient, HPMC can be strategically utilized on the mucosal linings of the oral cavity and gastrointestinal tract, effectively exhibiting its strong mucoadhesive properties [64].
Another research group led by Peh et al. have investigated the suitability of SCMC (sodium carboxymethyl cellulose) and HPMC K4M films as drug delivery systems for buccal delivery. The mechanical properties and in vitro/in vivo bioadhesive strength capacity were evaluated, with HPMC films showing greater in vivo bioadhesion, although their in vitro bioadhesive strength was lower than that of the SCMC films. The authors concluded that HPMC films might be preferred over SCMC films as drug carriers for buccal delivery due to their superior toughness, elasticity, bioadhesiveness in vivo, and a more controlled swelling behaviour in the oral cavity [65]. Araujo et al. developed a microemulsion gel obtained from hydroxypropyl methylcellulose films for the transdermal administration of Zidovudine. They observed that the addition of HPMC 1.2% to the film formulation caused an increase in viscosity, ensuring that the gel remains at the site of application for a prolonged time, enabling a transdermal permeation of the active ingredient [66].
4.4. Gelling Agent
Hydroxypropyl methylcellulose can also be used as a gelling agent in the production of cosmetics and medicines since it can produce a clear gel, dissolve easily in water, and has low toxicity. Additionally, HPMC forms a neutral, clear, and colourless gel that remains stable within a pH range of 3–11, offering strong resistance to microbial growth and enhancing film strength upon drying on the skin. The results of previous research indicated that HPMC bases had a good drug release rate and wide spreadability [67,68]. As a gelling agent, HPMC showed the most optimal physical stability in gel preparations compared to Carbopol. Its advantages include good skin dispersion, a cooling effect, no clogging of skin pores, and easy water-washing. Nevertheless, it is utilised in the pharmaceutical industry because it exhibits good stability under different conditions. Even when exposed to heat and humid conditions, HPMC gels maintain their homogeneity, pH, clarity, texture profile, and rheological properties without significant changes [69].
The studies showed that HPMC is mostly used as a gelling agent in concentrations ranging from 1% to 4%. Tanwar et al. have developed topical gel formulations with Diclofenac sodium using different gelling agents (HPMC K4M, Carbopol 934, carboxymethylcellulose sodium salt medium viscosity 200–400 cPs, and sodium alginate) at various concentrations. They used 1%, 1.5%, and 2% HPMC and concluded that a high polymer concentration increases viscosity, which leads to a consequent decrease in drug release [70]. Daood et al. have used 1%, 2%, and 3% HPMC for the preparation of a metronidazole topical gel, while Nursal et al. have developed an emulgel with 1–4% HPMC concentrations. All formulations showed acceptable physical properties concerning colour, homogeneity, consistency, spreadability, and pH value [71,72].
4.5. Encapsulation Material
Hypromellose, a widely accepted cellulose-derived material, has demonstrated its versatility as a polymer with easily adjustable solution properties, making it suitable for producing hard two-piece capsules using standard manufacturing equipment [73]. HPMC capsules have presented an attractive alternative to gelatine capsules in recent years as a result of their promising properties. The main limitation of hard capsules resulted from an exchange of moisture between the capsule shell and the fill. Their usefulness is related to their capacity to protect the contents in the presence of moisture. The moisture content of gelatine capsules may vary between 13% and 16% according to the weight of water, compared to HPMC capsules, where they can remain stable from 2% to 6% [74,75]. Variations in moisture content may influence the properties of capsules, such as stability, crystallinity, or efficiency. Yang et al. have proven that HPMC capsules, in comparison to gelatine capsules, can more effectively protect high, moderate, and low hygroscopic contents from outside moisture absorption, showing weaker moisture sorption [76]. Moreover, hypromellose capsules require unique manufacturing methods because hypromellose solutions do not naturally undergo a self-solution-gel transition without the use of process aids, leading to variability in the quality properties [77]. Some of their advantages are as follows:
4.6. Suspending Agent
The higher viscosity grades of HPMC can be used as suspending agents and suspension-type liquid formulations in concentrations of 0.2–1.5% w/w. Their effect is satisfactory, being that it easily spreads, and the flocculation grain is smooth [80,81]. Although it can be used for this purpose, studies conducted by Tagliari et al. and Murthy et al. showed inferior results compared to other suspending agents, such as sodium carboxymethylcellulose or methylcellulose, in terms of the instability index, sedimentation velocity, and resuspendability of the suspensions [82,83].
4.7. Thickening Agent
The incorporation of HPMC into liquid systems enhances viscosity due to increased intermolecular friction among the solvated HPMC chains. Increasing viscosity helps keep colloidal dispersions stable because it delays particle aggregation. As a result, HPMC is used as a thickener and stabiliser in the pharmaceutical industry. The increase of the polymer’s average molecular weight at a certain temperature leads to a higher viscosity [21]. By exceeding a certain molecular weight, the chains tend to entangle, forming gels. In a study conducted by Stolic-Jovanović et al., HPMC was used as a thickening agent at a concentration of 1% [84]. As a thickening agent, HPMC is used and commonly employed in ocular drug delivery systems. El-Kamel developed and evaluated a gel-forming solution to improve the bioavailability and decrease the side effects of timolol. For this purpose, the rheological behaviour of various agents was studied, with HPMC 80–120 cP 2% exhibiting a high viscosity [85].
4.8. Controlled-Release Polymer
Hydroxypropyl methylcellulose is a commonly used release-controlling polymer in hydrophilic matrix tablets. The principle of the polymer’s controlled-release property is that, upon contact with a dissolution medium, the polymer found on the tablet’s surface rapidly hydrates, forming a gel layer. The gel layer acts as a physical barrier, protecting the tablet core and controlling the drug release from the matrix. Drug release usually occurs by two routes: a diffusion of molecules through the gel layer and a gradual degradation of the polymer matrix at the interface with the dissolution medium [86]. Several researchers reported that molecules that are highly soluble in water follow a diffusion release mechanism, whereas poorly water-soluble molecules are mainly released by an erosion mechanism [14]. The release rate is correlated to the porosity and tortuosity of the pores or channel networks, both of which are attributed to the polymer’s swellability. Variables such as particle size, viscosity, and concentration of HPMC can also influence drug release from the matrix. An increase in HPMC particle size generally leads to higher drug release rates from matrix tablets, while higher viscosity grades often result in slower release rates [87]. The variety of HPMC grades with different substitution degrees and viscosities makes it a versatile matrix for the controlled release of a wide range of drugs with varying solubilities and doses [88].
Pani et Nath studied the controlled release of nateglinide from HPMC-coated tablets using a 32-randomized full factorial design. They obtained an optimal formulation containing HPMC K15M 5% and K100M 15%, which showed promising statistical results (the maximum value of the similarity factor and minimum value of the difference factor) and the desired stability during accelerated stability tests. The projected release of nateglinide from the controlled-release tablets was 26.63% w/w at 1 h, 33.30% at 2 h, 39.97% at 3 h, 46.64% at 4 h, 59.98% at 6 h, 73.32% at 8 h, 86.66% at 10 h, and 100% at 12 h. This sequence of values was taken as the reference release profile for comparison with the test formulation. The optimal formulation presented the most similar results to the theoretical drug release profile [89]. Ohara et al. carried out a study to analyse the release mechanism of indomethacin, a poorly water-soluble drug, from matrix systems composed of ethyl cellulose (EC) and hydroxypropyl methylcellulose HPMC, TC-5EW in a 1:1 (w/w) ratio. The results revealed that the drug dissolution mechanism was influenced by the structural characteristics of the polymeric matrices, which were, instead, affected by the preparation method and the pH of the dissolution medium. As the pH of the dissolution medium was lowered, the dissolution rates markedly decreased. At pH 3.5, roughly 80% of the HPMC diffused out within 6 h; yet, only about 20% of indomethacin (IND) was released. This is attributable to the hydrophobic affinity between ethyl cellulose and IND: in acidic conditions, once HPMC departs from the solid-dispersion granules, IND remains adsorbed onto the ethyl cellulose matrix instead of entering the bulk dissolution medium, and it is released only gradually thereafter. It was implied that the hydrophobic interaction between indomethacin and ethyl cellulose occurred in the lower pH region and strongly delayed the dissolution of IND [90].
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