Effervescent Tablet Preparation by Twin-Screw Melt Granulation with Sorbitol as a Melt Binder

Abstract

Methods: Effervescent granules containing citric acid and sodium bicarbonate were successfully prepared for the first time via TS-MG using a polyol (sorbitol) as a melt binder.

Results: Processing parameters, specifically granulation temperature and screw speed, were systematically varied to investigate their influence. The granulation efficiency, inversely related to the wt.% of fines, decreased in the following order across the tested conditions (granulation temperature–screw speed; ℃-rpm): 95-6 > 100-5 > 90-5 > 100-7 > 90-7. Granulation temperature had a minimal impact on the bulk and tapped densities of the uncalibrated granules, whereas increased screw speed led to higher densities, associated with a reduced proportion of fines. The tensile strength of the resulting effervescent tablets increased with granulation temperature and was generally higher for tablets derived from granules with higher granulation efficiency. The residence time within the TS-MG barrel decreased with increasing temperature and screw speed. Notably, the greatest effect of granulation temperature on tensile strength occurred between 90 and 95 °C, particularly under longer residence times. The disintegration time of the tablets was shortest for the 90 °C and 5 rpm condition, corresponding to the lowest tensile strength, while tablets across formulations showed consistent homogeneity as indicated by similar pH values post-disintegration.

Conclusions: These findings underscore sorbitol’s suitability as a melt binder and highlight the interplay between TS-MG parameters and the physical characteristics of effervescent granules and tablets.

Introduction

In 1767, the English chemist Joseph Priestley discovered how to carbonate water by dissolving carbon dioxide in it, laying the foundation for effervescent beverages and later medicinal uses [1]. This led to the development of effervescent tablets, which became common in the 19th century. Effervescent formulations contain acids or acid salts (e.g., citric acid) and carbonates or bicarbonates (e.g., sodium bicarbonate) that release carbon dioxide gas when dissolved in water through a neutralisation reaction. The resulting fizzing improves the taste, allows faster dissolution and absorption, and makes swallowing easier [2]. However, they require special packaging to prevent premature reactions and are more complex and costly to manufacture [2].

The preparation of effervescent granules can be achieved via dry granulation using roller compaction [3,4], wet granulation [5,6,7], or melt granulation [8,9,10] with high-shear mixer–granulator, fluid bed granulator, and hot melt extruder methods. Wet granulation involves the addition of a liquid solvent into the dry powder mixture [11]. The solvent method has disadvantages and limitations. It requires a time-/resource-consuming drying step. Since water-containing solvents as components of binding solutions initiate the neutralisation reaction, they are inapplicable for effervescent formulations [12]. The final moisture content of effervescent granules is also a critical parameter [13]. While this makes dry granulation a better option for the preparation of effervescent granules since it does not require the use of a binding solution and thus the additional drying step, it has its own disadvantages such as the necessity of a relatively higher weight fraction of excipients in order to obtain desirable granule and tablet mechanical properties [14,15,16,17].

Wet granulation with an organic solvent-based binding solution is the most commonly applied method for effervescent granulation [2], which leaves other methods such as melt granulation under-investigated. The major benefits of the melt granulation method for the preparation of effervescent granules includes the elimination of the need for liquid solvents, which is required in wet granulation sometimes with a residual amount of water, in which case melt granulation reduces the risk of premature neutralisation reaction before the product is used [12]. Additional benefits of melt granulation are that there is no need for a drying step, less equipment and time is required, and it is economically preferable [18]. Melt granulation is simpler than the traditionally used wet granulation method for the manufacturing of effervescent granules due to the avoidance of the use of binding solutions and the reduction of operations during the manufacturing process, reducing the number of critical parameters. In accordance with the Manufacturing Classification System (MCS), process simplification and the reduction of critical process parameters decrease the risk of deviation in target quality parameters and reduce the quality control load [19].

The temperature used during melt granulation is usually defined by the melting temperature range of the melt binder. The thermal stability of the drug and/or excipients sets the upper limit for processing temperature [14]. Based on this, APIs and excipients can be classified into four categories in the TS-MG formulation system, according to two factors: the thermal/chemical stability of the API (poor or good) and the drug–binder miscibility (poor or strong) [20]. Melt granulation can be carried out by various equipment, such as a fluidised bed processor [8,10], high-shear mixer [10], and twin-screw melt granulator (TS-MG) [9]. However, a major advantage of TS-MG includes it being a continuous process with controlled temperature and shear history, which is one of the main drivers behind the pharmaceutical industry’s interest in TS-MG due to the list of advantages continuous manufacturing offers over batch manufacturing [14]. Furthermore, TS-MG allows for the precise tracking of the time the components spend inside the TS-MG barrel (residence time) at the specified processing parameters with the introduction of a small amount of dye at the feed port [21].

The selection of an appropriate melt binder for melt granulation is crucial, especially for the preparation of effervescent granules due to the effervescent ingredients that have low degradation temperatures, such as citric acid (160–270 °C) and sodium bicarbonate (100–180 °C) [22]; a melt binder with a melting temperature range below 100 °C is recommended. Additionally, other properties of the melt binder, such as the following rheological properties; melt viscosity and degradation, solidification and crystallisation temperatures, influence the granulation process and affect the properties of the resultant effervescent granules and their respective effervescent tablets [23,24,25]. While polymers (such as polyvinylpyrrolidone (PVP) or its copolymers such as polyvinylpyrrolidone-vinyl acetate (PVPVA), poly (ethylene-co-vinyl acetate), various grades of polyethylene glycol (PEG), cellulose-esters and cellulose-acrylates, polyethylene oxides (PEOs) of varying molecular weights, poly-methacrylate derivatives, and poloxamers [26]) have been widely used as melt binders, sugar alcohols (polyols) possessing comparable processing temperatures (based on their melting temperature) offer advantages regarding tablet disintegration and dissolution, as well as tablet hardness. While polyols have been widely used in pharmaceutical formulations including for hot melt extrusion (HME) in oral dosage forms [27] such as erythritol [28,29], sorbitol [29,30], mannitol [31,32], and xylitol [29,31,32], they have been under-investigated for use in TS-MG, such as the co-processing of hydroxypropylcellulose with mannitol [33], and especially lacking in research regarding their application for effervescent granulation via TS-MG [34].

The aims of this work were to investigate the effect of sorbitol as a melt binder on the granulation efficiency and tablet properties (such as tensile strength, disintegration time, and homogeneity) as a function of screw speed and granulation temperature.

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Materials

Citric acid (Merck KGaA, Darmstadt, Germany) and sodium bicarbonate (Sisecam Soda Lukavac d.o.o., Lukavac, Bosnia and Herzegovina) were used as the effervescent ingredients. The polyols xylitol (Sigma; Thermo Fisher Scientific, Vantaa, Finland), sorbitol (Parteck® SI 200, Merck KGaA, Darmstadt, Germany), isomalt (galenIQ™ 721; Beneo-Palatinit GmbH, Südzucker AG, Obrigheim, Germany), mannitol (Pearlitol® 160C; Roquette Frères, Beinheim, France), and sucrose (Nordzucker AG, Kantvik, Finland) were considered as melt binder candidates. Sodium stearyl fumarate (PRUV®; JRS Pharma, Germany) was introduced as a water-soluble lubricant for the tableting of granulated formulations. Copper (II) oxide (particles less than 10 µm) was used as a dye to track the residence time of particles inside the TS-MG barrel.

Horváth, Z.M.; Kukuls, K.; Frolova, A.J.; Žogota, M.; Buczkowska, E.M.; Pētersone, L.; Mohylyuk, V. Effervescent Tablet Preparation by Twin-Screw Melt Granulation with Sorbitol as a Melt Binder. Pharmaceutics 2025, 17, 676. https://doi.org/10.3390/pharmaceutics17050676

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