Evaluation of Hydroxyethyl Cellulose Grades as the Main ...

Diclofenac sodium tablets were successfully prepared via hot-melt extrusion (HME) and fused deposition modeling (FDM), using different molecular-weight (Mw) grades of hydroxyethyl cellulose (HEC) as the main excipient. Hydroxypropyl cellulose (HPC) was added to facilitate HME and to produce drug-loaded, uniform filaments. The effect of the HEC grades (90&#; kDa) on the processability of HME and FDM was assessed. Mechanical properties of the filaments were evaluated using the three-point bend (3PB) test. Breaking stress and distance were set in relation to the filament feedability to identify printer-specific thresholds that enable proper feeding. The study demonstrated that despite the HEC grade used, all formulations were at least printable. However, only the HEC L formulation was feedable, showing the highest breaking stress (29.40 ± 1.52 MPa) and distance (1.54 ± 0.08 mm). Tablet drug release showed that the release was Mw dependent up to a certain HEC Mw limit (720 kDa). Overall, the release was driven by anomalous transport due to drug diffusion and polymer erosion. The results indicate that despite being underused in FDM, HEC is a suitable main excipient for 3D-printed dosage forms. More research on underutilized polymers in FDM should be encouraged to increase the limited availability.

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1. Introduction

There is growing interest in the use of 3D printing as a manufacturing tool for drug delivery systems with unique properties for individualized therapy [1], such as tailored drug dissolution profiles [2] or multi-component dosage forms [3]. Over the last decade, several researchers successfully broadened the knowledge and usability of pharmaceutical 3D printing. They investigated the use of multiple drugs, different excipient additives, and the manufacturing process itself, to gain a better understanding for a pharmaceutical applicability [4,5].

Today, there are several 3D-printing techniques available, especially for pharmaceutical use [5]. The most common 3D-printing technique for fused deposition modeling (FDM) requires a drug-loaded filament as a feedstock. The filament mostly consists of thermoplastic polymers mixed with additional additives, including plasticizers, lubricants, or fillers, as well as excipients and the active pharmaceutical ingredient (API) [6]. During the printing process, the filament is fed and melted in a heated print head and the melt is deposited precisely through a small heated nozzle onto a building plate, in order to construct a computer-designed model layer by layer [2]. This technique enables the fabrication of dosage forms with highly accurate internal and external geometries and API distribution, which, in turn, allows for tailoring the exact drug release, offering opportunities for an individualized therapy [7].

The required filaments can be produced by hot-melt extrusion (HME), a widely used pharmaceutical manufacturing method [8]. During HME, the raw materials are melted and mixed by one or two rotating screws [7,9] as they are conveyed through a heated barrel to the extrusion die to form a continuous filament strand. For the preparation of filaments in the pharmaceutical field, twin-screw extruders are preferred over single-screw extruders due to the superior mixing capability [10]. HME is often used to produce molecular dispersions of poorly water-soluble APIs in polymeric matrices to improve their solubility [11]. It can further be used for taste masking [12,13] and the manufacturing of drug delivery systems with different release profiles [14,15,16].

In this context, different pharmaceutical-grade polymers have been investigated as excipients for HME, followed by FDM, which enables the extrusion of filaments that can be printed as immediate or modified release dosage forms [4]. Since oral dosage forms are the most commonly used route of administration, a recent study [17] investigated the role and use of polymers in additive manufacturing of solid oral dosage forms and identified about 70 potentially suitable pharmaceutical-grade polymers. However, only about 30 of them are currently used in various additive manufacturing techniques, with some of these polymers, such as polylactic acid or polyvinyl alcohol, being more frequently utilized compared to others [6,17]. Unfortunately, the available pharmaceutical-grade polymers often result in filaments that have insufficient mechanical properties [9], leading to different printing defects. While filaments that are too soft tend to deform between the feeding gears, brittle filaments break under the force of the gears or inside the bowden tube [17]. In addition, the polymers intended for FDM have to possess suitable thermal properties, including thermoplasticity [17]. Ideally, the polymers should also have a favorable processing window where glass transition temperature (Tg) or melting temperature (Tm) tend to be low, while the degradation temperature (Td) is preferably high to avoid degradation and allow for a sufficient range to optimize the printing results. However, there are many polymers, such as cellulose, xanthan, or starch, that do not possess these favorable thermal and mechanical properties [17] but can still offer advantages for the printed form when combined with favorable excipients or additives for 3D printing [18,19]. Since the number of polymers available for 3D printing is limited [9,20,21,22] and needs to be expanded to provide new opportunities for formulation development and potential personalization of therapies, further investigations on the usability of unused polymers are necessary, for example, by combining them with beneficial excipients or additives.

In addition to the frequently used polyethylene oxide, polyvinyl alcohol, or polyvinylpyrrolidone [17], cellulose ethers, such as hydroxypropyl cellulose (HPC) or hydroxypropyl methylcellulose, which serve as hydrophilic matrices [23], are often selected for 3D printing [4,6]. HPC, a non-ionic, semi-crystalline polymer with a low glass transition temperature and good plasticity, allows for processing at relatively low temperatures [24,25]. Depending on its molecular weight (Mw), the drug release differs, which makes its use appropriate for a controlled drug release [4,26]. Due to acceptable mechanical properties, HPC has also been processed without the need for further additives [27]. Additionally, low-Mw HPC grades have been shown to produce chemically stable formulations with poorly and highly water-soluble APIs after being hot-melt mixed [26], making HPC a versatile excipient, suitable for HME and the 3D printing of different drug delivery systems.

Another cellulose ether that is often used in the pharmaceutical and cosmetics industry, but not yet in 3D printing, is hydroxyethyl cellulose (HEC). HEC is a non-ionic and water-soluble polymer, mostly used as a thickening and gelling agent or coating material [28]. Due to its wide range of available Mw grades, which offers a potential to tailor drug release, HEC seems to be a promising excipient for drug delivery systems with controlled release profiles. Nevertheless, its thermoplastic characteristics are poor compared to other cellulose ethers, such as HPC [29], which might explain the lack of available studies for HEC in thermal manufacturing processes, such as FDM. To our best knowledge, HEC has only been used in a few studies where pharmaceutically driven HME or FDM were involved. Here, it was used as a suspending agent in 3D-printed dosage forms (5%w/w [30]) or as a release modifier in hot-melt extrudates (up to 36%w/w [31]) in relatively small amounts. For a further evaluation of the usability of HEC in FDM and to potentially increase the current number of available polymers, more investigations need to be conducted.

Therefore, we aimed to develop filaments with HEC as the main matrix former to produce dosage forms loaded with the BCS-II class active ingredient diclofenac sodium and to evaluate both the influence of HEC on filament extrusion and 3D printing in particular, along with the drug release properties. In this context, we would like to point out that the development of a gastro-resistant shell filament was not within the scope of our work. However, if the dosage form targets the small and large intestine, respectively, for drug release, a gastro-resistant shell is inevitable [32]. For the assessment of four different HEC grades (Mw from 90 kDa to kDa), we investigated the thermal behavior and solid-state with commonly used thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and x-ray diffraction (XRD). Furthermore, we determined mechanical properties (breaking stress and breaking distance) of the filaments and conducted 3D-printing experiments to determine feedability, printability, and printing parameters for the different formulations. Finally, the resulting dosage forms were further analyzed in terms of their drug release profile and mechanism.

Methyl Hydroxyethyl Cellulose, also known as Methylcellulose and colloquium, is an organic compound methyl hydroxyethyl cellulose uses in various cosmetic and medical applications, the primary one being as a thickening agent. In decorative applications, it's found most often as a component of toothpaste and cough syrups. The compound is tasteless and odorless, and in medicine, it is ingested by patients to relieve constipation, diarrhea, and hemorrhoids. Here are top uses methyl hydroxyethyl cellulose

1. Thickening agent

Methyl hydroxyethyl cellulose uses to thickener in cosmetic products such as shampoos and conditioners because it can form a film on hair strands. This film makes hair appear smooth and shiny. In addition, the material coats the hair strands to protect them from water damage. Because it is water-soluble, methyl hydroxyethyl cellulose does not cause build-up on hair strands after repeated use of the product containing it.

2. Medicine

You may have taken methyl hydroxyethyl cellulose without even knowing it. That's because this substance has been used in manufacturing pharmaceutical products for decades. It works as an excipient (a sense included with an active drug that binds together all ingredients). Furthermore, methyl hydroxyethyl cellulose can be used to coat pills and help slow down their release into the body.

3. Binding agent

Methyl hydroxyethyl cellulose is an excellent binding agent or adhesive because it forms a gel when mixed with water. The substance is often used in the manufacture of pills and capsules because it binds together different pill components to create uniform tablets that are easy to swallow.

4. Paper Production

Due to the low toxicity of the compound and its ability to improve the properties of paper while decreasing production costs, MHE has gained wide acceptance in the paper manufacturing industry. It can be used as a dry strength agent in paper production to increase tensile strength without increasing gram mage; it can also be used as a pigment binder in paper coatings and water retention agents in paper due to its good properties as a dispersing agent.

5. Dispersing Agent.

When mixed with other chemicals, this compound works as a dispersing agent because it absorbs water to form a gel while keeping the ingredients in suspension. This makes it useful in various applications, including household products like laundry detergent, foods like whipped cream, cosmetics like toothpaste, and pharmaceuticals like cough syrups or eye drops.

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6. Soil Stabilizers.

Methyl hydroxyethyl cellulose (MHEC) is used as a soil stabilizer to increase the yield of crops on marginal land and in areas where irrigation is not practical. The product can be mixed with water and applied to soil to improve moisture retention during dry periods or when rainfall is sparse. When incorporated into fertilizer formulas, MHEC allows nutrients to remain available to plants over more extended periods than untreated fertilizers.

7. Moisturizer and surfactant

Methyl hydroxyethyl cellulose (MHEC) is also used as a moisturizer and surfactant in cosmetics, baby lotions, shampoos, and bath oils. A surfactant is a wetting agent that lowers the surface tension of liquids and allows them to spread over a surface. It can be used as an emulsifier that keeps water-based and oil-based ingredients mixed in cosmetics.

8. Herbicide

Some farmers use Methylcellulose as an herbicide. When mixed with water and sprinkled on certain plants, it can help prevent growth or kill the plant entirely. The gel-like substance helps the herbicide stay in place without being washed away by water or carried away by the wind.

9. Concrete Mixes

Concrete mixes using Methylcellulose are commonly used for their smoothness and strength. Methylcellulose is used to coat the interior surface of concrete pipes, giving them a uniform thickness that reduces wear over time. This method also produces lines resistant to cracking when exposed to water, heat, or other harsh conditions.

10 Food Production

Methylcellulose is commonly used as an ingredient in the production of commercially-made ice cream due to its ability to stabilize the product. It serves as an alternative to gelatin and vegetable gum such as guar gum and locust bean gum. The chemical compound is also added to baked goods, salad dressings, and salad gums. It helps prevent sugar crystallization and increases the shelf life of food products by controlling moisture content.

11. Cement

Methylcellulose helps increase the efficiency of cement by prolonging water retention and hydration reactions. This helps reduce the amount of glue required during construction projects, ultimately lowering costs. The chemical compound can also be added to concrete mixes to improve their structural properties, such as flexural strength, compressive strength, and tensile strength.

 12. Oil drilling

Methyl hydroxyethyl cellulose uses is also used in oil drilling operations to thicken liquids used in the exploration process. This helps ensure that the fluid can be pumped through pipes without dripping or spilling, making them less effective at their intended function.

13. Cosmetics

Methyl hydroxyethyl cellulose is found in many cosmetic products, including hair sprays, shampoos, conditioners, toothpaste, and soaps. Like other uses for methyl hydroxyethyl cellulose, it's used to increase the viscosity of these products and make them easier to apply.

14. Paints and coatings

Methyl hydroxyethyl cellulose, also known as MHEC and Methylcellulose, is a thickening agent used in paints and coatings. The chemical compound can help prevent paint from sagging and dripping when it dries. The combination can also help provide the color with extra adhesion, making it helpful in constructing buildings. MHEC is commonly used as a thickening agent in decorative paints. Decorative paints are not as strong as structural paints, so they need thickening agents to help them adhere to walls and other surfaces without breaking apart or peeling away. MHEC provides water resistance to decorative paints, making it more difficult for walls to become damaged by exposure to water. It also helps make paint that has been applied easier to clean.

Wrapping Up

The most significant methyl hydroxyethyl cellulose uses include its use in the production of adhesives, cosmetics, paper and textiles, pharmaceuticals, paint, and a host of other industrial applications.

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