Hydroxypropylmethylcellulose

(2014) used hydroxypropylmethylcellulose along with sodium dodecyl sulfate and found that the concentration of sodium dodecyl sulfate at critical micelle concentration is desired for the association of polymer and surfactant (Silva et al., 2011).

From: Dosage Form Design Considerations, 2018

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Oral controlled and sustained drug delivery systems

Gaganjot Kaur, ... Jitender Madan, in Drug Targeting and Stimuli Sensitive Drug Delivery Systems, 2018

15.3.1.4 Hydroxypropyl methylcellulose

Hydroxypropyl methylcellulose (HPMC) or hypromellose refers to soluble methylcellulose ethers. HPMC is used as a thickening agent, binder, film former, and hydrophilic matrix material. HPMC polymers for fabricating hydrophilic matrix systems are available in various viscosity grades ranging from 4000–100,000 mPa s. HPMC is a popular matrix material in oral controlled delivery systems and HPMC matrices show sustained release pattern by two mechanisms, i.e., diffusion and erosion of the gel layer. The viscosity of the polymer affects the diffusion pathway. HPMC can be employed as a matrix for controlling the release of both hydrophilic and hydrophobic drugs. It is being used in buccal adhesive tablets of pentazocine, gastroretentive systems, and colon delivery systems (Al-Tabakha, 2010; Caraballo, 2010).

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Polymer Properties and Characterization

J. Brady, ... J.-X. Li, in Developing Solid Oral Dosage Forms (Second Edition), 2017

7.3.1.2 Hydroxypropyl methylcellulose

Hydroxypropyl methylcellulose (HPMC or hypromellose) is a partly O-methylated and O-(2-hydroxypropylated) cellulose ether derivative (Fig. 7.44).

Figure 7.44. Typical structure for hydroxypropyl methylcellulose. This is an example of a mixed derivatized cellulosic containing both hydroxypropyl and methoxyl functionality. The specific system shown has a hydroxypropyl DS of 0.25 (~9.6 wt.%) and methoxyl DS of 1.5 (~23 wt.%). Due to the lower content of bound hydrophobic functionality relative to HPC shown in Fig. 7.38, this material will generally display better water solubility at higher temperatures.

HPMC is also widely used in solid oral dosage forms as a binder, a film coating, and a controlled-release matrix.66,67 It is often the polymer of choice in the preparation of hydrophilic matrix tablets because of its rapid formation of a uniform, strong, and viscous gel layer, which protects the matrix from disintegration and controls the rate of drug release. It is commercially available in several types with different DS and MS; here the added hydroxypropyl group introduces a secondary hydroxyl group that can also be etherified during the preparation of HPMC, giving rise to additional chain extension. Currently, the USP/NF and other compendia provide definitions for different substitution types of HPMC using a four-digit number: for example, hypromellose 2208, hypromellose 2906, and hypromellose 2910, respectively, where the first two digits refer to the approximate percentage content of the more methoxy group (OCH3), and the second two digits refer to the approximate percentage content of the more hydroxypropoxy group (OCH2CH(OH)CH3). Such variations in the ratios of methoxy and hydroxypropoxyl substitutions and molecular weight affect their properties such as organic solubility, thermal gelation temperature in aqueous solution, swelling, diffusion, and drug-release rate. In practice, hypromellose 2208 (also known as K chemistry or grade) and hypromellose 2910 (also known as E chemistry or grade) are the most widely used types of HPMC in modified-release formulations. These two types of HPMC are commercially available in many different viscosity grades corresponding to average molecular weights from 80,000 to 1,200,000 Da (Table 7.9).

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3D printing: Bioinspired materials for drug delivery

Georgia Kimbell, Mohammad A. Azad, in Bioinspired and Biomimetic Materials for Drug Delivery, 2021

Hydroxypropyl methylcellulose

HPMC is another bioinspired polymer derived from cellulose. It has been the favored choice for extended-release trials as the gel barrier it creates on contact with aqueous liquids, similar to HPC, can be utilized to prolong drug release [33]. This requires no additional tablet design elements to be in place, as the polymer itself extends release time. Increasing the concentration of HPMC in a tablet corresponds directly to a decrease in the rate of drug release [34-36]. This presents itself as a lag phase in dissolution due to swelling when the tablet takes up the surrounding dissolution medium [37, 38]. HPMC tablets tend to dissolve in dissolution medium, rather than disintegrate, due to HPMC’s swellability (Fig. 15.8) [34]. As HPMC is highly hydrophilic, Cui et al. showed that increasing concentrations of HPMC K100LV decreased surface flatness and had pronounced shrinkage after drying, due to the swelling effects of the polymer [38]. HPMC’s ability to control the drug release times has also proven successful in the development of polypills containing multiple drugs requiring different release times [35]. For example, Khaled et al. created a polypill made from HPMC capable of releasing five different drugs with different desired release time profiles [39].

Fig. 15.8. Dissolution of HPMC tablets[34].

HPMC can be used with traditional FDM printing, and it is possible to produce HPMC filament via HME [34]. A plasticizer or gel may be required to aid in extrusion [8]. However, interactions between a plasticizer and the drug should be considered, as the plasticizer can interfere with the drug and cause unwanted crystallization if the capsule is stored for too long [9]. Zhang et al. demonstrated that their HPMC filaments produced by HME displayed high stiffness and toughness, though they had rough surfaces, which made printing difficult, in addition to their high melt viscosities. A mixture of HPMC and Kollidon CL-F, a disintegrant, reduced the friction by smoothing any roughness [7]. Larger molecular weight and higher viscosity HPMC grades also exhibit a rougher printing path and require higher temperatures to extrude properly. Higher melt viscosity can also result in more weight variation [36]. Prasad et al. prepared a drug-loaded filament of HPMC via HME and showed that the HPMC filament and tablets behave as an amorphous polymer [9]. Maroni et al. created hollow HPMC capsules by FDM. They exhibited more variability of thickness than similarly produced polyvinyl alcohol (PVA) tablets [37].

It is also possible to create HPMC tablets using PAM the other type of extrusion-based printing. Khaled et al. have created bilayer tablets composed of HPMC using PAM. With lower viscosity HPMC and less binder, the tablets were shown to have greater variability in weight, and experienced more friability than traditionally made tablets, although they were still within an acceptable range [34]. Sustained-release gastric floating tablets composed of HPMC have also been produced by this method [40,41]. Li et al. used polyvinylpyrrolidone (PVP), an alternative to a water binder [42]. Avicel and lactose have been used as fillers to enhance paste flowability and deposition as well [41].

Fina et al. created drug release tablets via SLS printing [43]. A coating was required for successful printing. Higher laser scanning speeds resulted in more porous, low weight tablets, and provides a shorter dissolution time [43]. Alomari et al. created oral dispersible films using a modified thermal ink-jet (TIJ) printer and HPMC-based substrate for dosing multidrug combinations [44]. Niese et al. also created an oral dispersible film with HPMC as the matrix and showed that mechanical properties, as well as drug content, were preserved after 3 months in storage [45].

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Cellulose

R. Ergun, ... B. Huebner-Keese, in Encyclopedia of Food and Health, 2016

Effects on Lipid Metabolism

HPMC modulates plasma lipoprotein profiles and hepatic lipid levels. HPMC is not absorbed by the body, but its presence in the intestinal lumen increases fecal fat, sterol, and bile acid excretion and as a result changes hepatic lipid metabolism. It has been suggested that HPMC may be facilitating fat excretion in a biased manner with preferential fecal excretion of both trans and saturated fats in hamsters fed with fast-food diets.

In preliminary studies, maturing hamsters on a high-fat diet put on significantly less body weight when they were supplemented with HPMC than the control animals, due primarily to the reduced deposition of abdominal fat tissue and fat accumulations in their livers and skeletal muscles. In obese mice, 4% and 8% HPMC supplementation in a high-fat diet led to significant weight loss. Also reductions in plasma cholesterol, glucose, and insulin levels were seen, which are strongly correlated with reduced leptin concentrations. Moreover, an increase in the fecal secretion of total bile acids, sterols, and fats indicated altered fat absorption when HPMC is incorporated in the diet. The data indicate that HPMC not only reduces body weight but also normalizes the metabolic abnormalities associated with obesity. The data suggest as well that the effect of HPMC on glucose and lipid homeostasis in mice is mediated through improvement in leptin sensitivity resulting from reduced fat absorption. HEMC was shown to be similarly effective in improving the lipid metabolism under high-fat diet condition.

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Material Attributes and Their Impact on Wet Granulation Process Performance

Praveen Hiremath, ... Vivek Agrahari, in Handbook of Pharmaceutical Wet Granulation, 2019

2.5.4 Hydroxylpropyl Methylcellulose (HPMC)

HPMC is a water soluble nonionic cellulosic polymer in which some of the hydroxyl groups are substituted with methoxy and hydroxypropyl groups (Zarmpi et al., 2017). As a binder, HPMC is used at the concentration of 2%–5% w/w, however, it has been commonly used as tablet film coating polymer. The polymer chain length, size and degree of branching determine the viscosity of the polymer in solution. In general, a tablet film coating requires low viscosity polymers. Using low viscosity polymers, the solid content in the coating formulation can be increased with a lesser amount of water, which can increase coating speed and efficiency. HPMC has many of the desired coating polymer properties. It provides aqueous soluble films; easy processing because of its nontacky nature; a transparent, tough, and flexible film that protects fragile tablets; improved appearance; and resistance to abrasion. The lower viscosity HPMC, however, produced film with lower tensile strength. The higher viscosity grades of HPMC provide film with good tensile strength, but their films have poor adhesion to the core surface and can easily peel off the tablet surface. When used alone, HPMC has the tendency to bridge or fill the debossed tablet surfaces. Therefore, a mixture of HPMC with other polymers or plasticizers is used to improve its binding to the tablet surface and eliminate bridging or filling problems.

Different grades of HPMC are available according to their particle size distribution, viscosity, molecular weights, and substitution of methoxy and hydroxypropyl groups. Because water penetration affects drug release and dissolution, not only the hydroxypropyl group and the degree of substitution but also the substitution pattern affects the release and dissolution (Zarmpi et al., 2017). Heterogeneity in the substitution pattern alters the release of the polymer because of hydrophobic interactions between the substituent, and a subsequent drug release alteration (Viriden, Larsson, & Wittgren, 2010; Zhou et al., 2014). Variation in substitution pattern causes batch-to-batch variability (Dahl, Calderwood, Bormeth, Trimble, & Piepmeier, 1990). On aqueous solutions interaction, HPMC hydrates and forms a viscous gel layer that thickened when more water penetrated. These characteristics of HPMC affect its functionality. The MW and chain length has a significant effect on the viscosity of HPMC aqueous solutions and affects drug release and dissolution (Zarmpi et al., 2017). The hydrogen-bonding between oxygen atoms in ether groups of HPMC and water molecules leads to extension of the polymer and formation of a coil-shaped structure (Zarmpi et al., 2017). Coiled structures tend to form more hydrogen-bonds, entrap water, and form entanglements with other coiled molecules resulting in increased resistance to flow. Therefore, HPMC with high MW tends to swell faster and forms viscous layers.

Particle size of HPMC affects drug release and dissolution through its impact on tablet hardness and water penetration. HPMC of smaller particle size formed stronger tablets because of increased surface area and interparticle cohesiveness, whereas HPMC of larger particles enhanced the dissolution because they do not fully occupy the space around each particle, leaving voids for water penetration (Mohamed et al., 2015). Drug release was caused by disintegration, diffusion, and a combination of diffusion and erosion for large, medium, and small particle sizes of HPMC, respectively. These effects were attributed to the proximity of polymer particles and the differences in the porosity of the formed hydrogel. Faster dissolution observed with higher HPMC particle sizes because of their porous arrangement, was counterbalanced via high concentrations because more polymer chains were present leaving no spaces for water penetration. The drug release rate from HPMC matrices was influenced by the drug/HPMC ratio, drug solubility, compression force, and viscosity grade of the HPMC. Lower viscosity grade HPMCs are more sensitive to the effect of compression force and tend to provide erosion-based release, compared to higher viscosity grade HPMCs for predominantly diffusion-based drug release (Hiremath & Saha, 2008a, 2008b). Mechanical properties of HPMC also affect its functionality. According to Rowe, dense granules are expected when the spreading coefficient of binder over substrate was positive, while negative spreading coefficient led to the formation of porous granules (Rowe, 1990). Hydroxypropyl cellulose (HPC) is also one of the widely used binders (Parikh, 2010). HPC is nonionic, water-soluble, and pH insensitive cellulose ether polymer. The high level of substitutions makes HPC more thermoplastic and less hygroscopic than other water soluble cellulose ethers. Although, HPC has a good film formation property and excellent plasticity, it is not commonly used as an aqueous film coating polymer compared to HPMC because of its strong binding force. Various MW grades of HPC are available; however, low MW grades are typically used as binders. To overcome the above bridging or filling issues of HPMC, the combination of HPMC and HPC are used. HPC provides better film adhesion; however, the cost of HPC is much higher than HPMC.

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Binders in Wet Granulation

Thomas DürigKapish Karan, in Handbook of Pharmaceutical Wet Granulation, 2019

2.3 Hypromellose

HPMC is a partly O-methylated and O-2-hydroxypropylated cellulose ether. Manufactured by reacting alkali cellulose with methyl chloride and propylene oxide, this polymer is available in various substitution ratios and MW grades. HPMC is widely used in solid dosage forms as a binder, a film coating agent, and a controlled release matrix.

The binder properties of HPMC are comparable to MC, with the exception that it is somewhat more hydrophilic. As a binder, primarily low viscosity grades with substitution type 2910 (28%–30% methoxy groups by weight and 4%–12% hydroxypropyl groups by weight, often described as the E-grade) are used (Table 1). Concentrations of 2%–5% (w/w) can be used as a binder in either wet or dry addition processes, but is less efficient in the latter form (Skinner & Harcum, 1998).

HPMC type 2910 has a cloud-point of about 65°C, which necessitates higher water temperatures for solution preparation. To prepare an aqueous solution, HPMC is first hydrated in the required amount of hot water (> 65°C) with vigorous stirring, followed by addition of cold water to make up the volume. Hydroalcoholic solutions, with a minimum of 10% v/v water, or mixtures of other water-miscible solvents such as glycerin also can be used to solvate HPMC. HPMC is listed in the USP/NF, pH.Eur., JP, and the FCC.

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Alternative Technologies to Improve Solubility and Stability of Poorly Water-Soluble Drugs

Walter F. da Silva Júnior, ... Ádley A.N. de Lima, in Multifunctional Systems for Combined Delivery, Biosensing and Diagnostics, 2017

4.1.3 Hydroxypropyl Methylcellulose

Hydroxypropyl methylcellulose (HPMC) is mixed alkyl hydroalkyl cellulose ether containing methoxy and hydroxypropyl groups. It is prepared by reacting alkali treated cellulose first with methyl chloride to introduce methoxy groups and then with propylene oxide to introduce propylene glycol ether groups. Among the cellulose derivatives, HPMC has been extensively employed because of its ease of use, wide availability, superior film-forming capability, good biocompatibility and biodegradability. It is usually used in the pharmaceutical industry as a drug delivery matrix (film or gel) and in the food industry as a film former, emulsifier, stabilizer, or thickening agent. HPMC is a nonionic and water-soluble polymer (Rogers, 2009); this is of great importance as a carrier in drug release systems, including SDs (Lima et al., 2015) (Fig. 15.4).

Figure 15.4. Chemical structure of the major polymers used in the solid dispersions.

(A) Chemical structure of hydroxypropylmethylcellulose; (B) chemical structure of polyvinylpyrrolidone (PVP K-30), and (C) chemical structure of polyethylene glycol 6000 (PEG 6000).

Adapted from PubChem.
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3D printing as an emerging tool in pharmaceutical product development

Kuldeep Rajpoot, ... Rakesh K. Tekade, in The Future of Pharmaceutical Product Development and Research, 2020

2.3.5 HPMC

The plasticized HPMC-derived fabricated solid foams showed a great aptitude in the engineering of porous systems using inkjet printing. However, plasticized HPMC foams generally exhibit not only a superior absorption capacity but also a fast penetration effect for various solvents owing to greater porosity as well as open-cell pore structure than nonplasticized additive-free foams (Iftimi et al., 2019). Three different concentrations of the HPMC K100LV polymer has been used as a hydrophilic matrix in the semisolid extrusion 3D printing for the fabrication of personalized medicines (Cui et al., 2019). 3D extrusion-based printing method was employed for the fabrication of gastro-floating tablets using HPMC K4M and HPMC E15 as hydrophilic matrices. These fabricated gastro-floating tablets showed more than 8 h floating effect (Li et al., 2018). In another study, 3D printed filaments were synthesized by incorporating HPMC and diltiazem drugs. Further, results revealed stable extrusion of both diltiazem as well as HPMC at printing temperatures (Kadry et al., 2018).

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Fabrication of cellulosic composite scaffolds for cartilage tissue engineering

A.G. Nandgaonkar, ... L.A. Lucia, in Nanocomposites for Musculoskeletal Tissue Regeneration, 2016

9.5.3 Chemically modified cellulose–based hydrogels

Hydroxypropylmethylcellulose (HPMC) is a precursor of cellulose and is modified with small amounts of propylene glycol ether groups attached to the anhydroglucose terminus of the cellulose. It is a self-hardening hydrogel having silane grafted along the hydroxypropyl methylcellulose grafted with silanol group (Si-HPMC) chains (Fatimi et al., 2008). Vinatier et al. (2005) were among the first to mention its use as a potential cartilage tissue material. They have done singular research on injectable and self-setting hydrogels of Si-HPMC for cartilage TE. The cross-linking and the self-hardening of the hydrogels depend upon the pH of the environment and also on the silanol condensation from the silane grafted onto the cellulose backbone. The chondrocytes isolated from rabbit AC and two human chondrocytic cell lines maintain a chondrocyte-specific phenotype and express type II collagen and aggrecan. Although the hydrogel showed its potential for cartilage regeneration, its actual pH as an injectable hydrogel during the time of injection will differ from the physiological pH of the implant site (Vinatier et al., 2005). A later study by Vinatier et al. (2007) showed that the Si-HPMC encouraged the maintenance and recovery of human nasal chondrocytic phenotypes. After 3 weeks of in vivo culturing of cells in nude mice, the hydrogel was able to form a cartilaginous tissue, an appreciable result that demonstrates a feasible approach for cartilage TE (Vinatier et al., 2007). Extended work with injectable self-setting cellulose-based Si-HPMCs has been carried out to repair AC defects of rabbits in which Si-HPMC-containing autologous rabbit nasal chondrocytes are used. An analysis of the postoperative recovery of the articular cavity within 6 weeks revealed no signs of inflammation and found that the site has a structurally organized tissue resembling hyaline-like cartilage (Vinatier et al., 2009). This innovative hydrogel could be used as a transplantation hydrogel for in vivo cartilage TE.

The same research group extended their work on adipose tissue stem cells (ATSC) with Si-HPMC in the presence of a chondrogenic culture medium and under hypoxia (5% O2). The ATSC underwent a chondrogenic differentiation and favored type II collagen and aggrecan mRNA expression. An in vivo experiment was carried out in which an ATSC/Si-HPMC system was injected into subcutaneous pockets in nude mice. After 21 days of culture, ATSC was able to form a cartilaginous tissue when implanted with Si-HPMC hydrogel (Merceron et al., 2010). Again, the same group carried out further research exploring oxygen tension to determine its effect on the regenerative potential of mesenchymal stem cell (MSC) for cartilage repair. MSC from human and rabbit adipose stromal cells that was injected in Si-HPMC hydrogel and later preconditioned formed a cartilaginous tissue regardless of the oxygen tension. In a 3-D in vitro culture, 5% O2 enhances the chondrogenic differentiation; however, it does not enhance its in vivo chondrogenesis. This confirms the potential of Si-HPMC in cartilage repair when used with preconditioned appropriate cells (Portron et al., 2013).

Chondrocytes cell culture studies were carried out on two and three dimensional Si-HPMC scaffolds incorporated with two GAG-like marine exopolysaccharides (HE800 and GY785, with hyaluronic acid as control). The incorporation of exopolysaccharides significantly improved gelation time and the mechanical properties (10.25 KPa) which were similar to native cartilage and with a better dispersion of cells on the surface of these hydrogels in a 2-D culture. Although in a 3-D culture, the chondrocyte cells dispersed in the environment, leading to cluster formation. This happened because of the small pore sizes in the course of the preparation of the scaffold; however, the scaffold showed higher mechanical properties compared with the Si-HPMC scaffold alone (Rederstorff et al., 2011). Therefore, from the latter work, it can be deduced that an ideal scaffold should have an open porous structure to help cells to infiltrate and migrate within the scaffold and allow for adequate mechanical strength.

One particular cellulose derivative, CMC, had been modified by converting a large percentage of the native carboxylic groups (50%) into amidic groups and trying to mimic the hyaluronan macromolecule which is an essential component of AC. The resultant modified polysaccharide was further cross-linked to obtain hydrogels containing NH2 groups. The hydrogels showed a viscous–elastic solid-like behavior as verified by rheological characterization and can serve as potential filler for cartilage defects (Leone et al., 2008a). In later studies on the same hydrogels, the thixotropic (flow) behavior showed that the hydrogels can recover their original shape after removing a mechanical stressor, a finding that proves their potential to be injectable. This hydrogel was further analyzed by in vitro studies of normal human articular chondrocytes obtained from the human knee. The results showed that the hydrogels with chondrocytes showed increased production of ECM components rich in collagen and proteoglycans. This hydrogel also compared well with hyaluronan hydrogels as a substitute. An in vivo study carried out on adult male rabbit for 50 days showed from the results of histological sectioning that the amidated carboxymethylcellulose (CMCA)-treated defect had a layer of mixed fibrocartilaginous and hyaline-like tissue with a regular and smooth surface. The chondrocytes showed cluster and columnar formations in the new hyaline cartilage as seen in Fig. 9.3(c). The hydrogels showed similar behavior compared to hyaline hydrogels (Leone et al., 2008b).

Figure 9.3. Histological section of the chondral defects of a male rabbit after 50 days of in vivo studies. (a) Control defect with no hydrogels; (b) amidated carboxymethylcellulose (CMCA) hydrogels showed a mixed layer of fibrocartilaginous and hyaline-like tissue. (c) Chondrocytes showing cluster and columnar formations in new hyaline-like matrix (magnification: 5×).

Reprinted with kind permission from Springer Science and Business Media (Leone, G., Fini, M., Torricelli, P., Giardino, R., Barbucci, R., 2008b. An amidated carboxymethylcellulose hydrogel for cartilage regeneration. Journal of Materials Science: Materials in Medicine 19 (8), 2873–2880).
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Introduction

Reynir Eyjolfsson, in Design and Manufacture of Pharmaceutical Tablets, 2015

1.3.12 Methocel K100LV Premium

Hypromellose 2208. Slow-release control agent used in 10–80% concentration. White, yellowish white, or grayish white powder. Practically insoluble in hot water and in ethanol. It dissolves in cold water giving a colloidal solution. Hygroscopic after drying. pH 5.5–8.0 in 2% aqueous solution. Viscosity 80–120 mPa s in 2% solution in water at 20°C. Bulk density 0.34 g/ml. LOD NMT 5.0%, 105°C. Sieve test (slow-release grade): through 40 mesh (425 μm) NLT 99.0%, through 100 mesh (150 μm) NLT 90.0%, and through 230 mesh (63 μm) 50.0–80.0%.

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