Emerging Perspectives in the Formulation of Lyophilized Orally Disintegrating Tablets: From Lyoc to Self-Nanoemulsifying Lyophilized Tablets (SNELTs) and Beyond into Hybrid Platforms

Abstract

Four decades have elapsed since orally disintegrating tablets (ODTs) were first formulated as the emulsion/type Lyoc tablet, a porous mass intended to rapidly disperse in saliva. Following the lyophilization process, new formulations of ODTs were designed, intending to make a simpler and more reproducible formulationZydis, LBL-Flash, Quicksolv, and, more recently, Zydis Ultra. Lyophilization is widely recognized as an effective technique for the development of ODTs, due to its ability to produce highly porous structures that enable rapid disintegration and improved patient compliance. However, its advantages should be considered in relation to other manufacturing methods, as each technology presents specific trade-offs in terms of cost, scalability, mechanical strength, drug loading capacity, and process robustness. In line with the modern sustainable and green pharmacy trend, new raw materials have gained attention as excipients for lyophilized ODTs; these materials include certain plant derivatives, but also performant excipients with newly discovered functionalities. At present, a new generation of ODTs is available in the form of Self-Nanoemulsifying Lyophilized Tablets (SNELTs), which bring the advantages of Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) into ODTs via the lyophilization method. The technique is mostly applicable to low-solubility drugs formulated as nanoemulsions, which are absorbed onto solid carriers and further lyophilized, forming the final ODT. Despite its limitations (expensive, time-consuming, and high product friability), lyophilization is being continuously developed nowadays, in combination with other techniques (3D printing, mucoadhesion, or electrospinning), building hybrid platforms for the modern ODTs of the future.

Introduction

In 1985, the French company L. Lafon formulated the first oral lyophilisates, with model drugs phloroglucinol and paracetamol, publishing the patent by the name Lyoc (1986) [1,2]. This product consisted of a porous mass obtained from an oil-in-water emulsion with rapid dispersion in saliva (within seconds), without the need for water [1,2,3]. Regardless of the complexity of the formulation, the elaborate and long lyophilization process, and the sensitivity of the final product, this design gained attention from the pharmaceutical world. Rapid release of the drugs, the possibility of bioavailability increase, and the advantages for certain categories of patients (elderly, children) led to the emergence of a new dosage form: orodispersible tablets or orally disintegrating tablets (ODTs) [4,5].

Consequently, the French Pharmacopoeia included a monograph for oral lyophilisates, and, later on, the European Pharmacopoeia included the orodispersible tablets as a sub-chapter in the monograph entitled Tablets [4,5,6]. The compendial definition is ‘uncoated tablets intended to be placed in the mouth, where they disperse rapidly before being swallowed’, with the disintegration condition as follows: ‘orodispersible tablets disintegrate within 3 min’ [6]. The FDA condition, however, limits the ODT disintegration time to ‘approximately 30 s or less’, when based on the United States Pharmacopeia (USP) disintegration test method or alternative [7].

Following the lyophilization process, new formulations of orally disintegrating tablets were designed, intending to make a simpler and more reproducible formulation than the emulsion/type Lyoc tablet. Thus, in 1986, the Scherer company (now a Catalent division) patented the Zydis formulation, consisting of a freeze-dried viscous suspension, with the possibility of implementing the technology on a larger industrial scale [8,9]. Other formulations with varying compositions, but still using lyophilization as the production method, were designed: Pharmafreeze, Quicksolv, LBL-Flash, etc. [10,11,12]. Given their advantages, in the following years, the pharmaceutical companies put ODTs in the spotlight, researching and finding ways to manufacture them by conventional methods while at the same time keeping their optimal characteristics. This was not an easy task, given the ideal desired features for ODTs: (a) disintegrates in the mouth within seconds; (b) allows formulation with high doses of drugs; (c) can be taste-masked and has no residual taste; (d) has minimum or zero grittiness upon dispersion in saliva; (e) has adequate hardness, which allows transportation and manipulation without breakage; (f) is not sensitive to environmental conditions (temperature, humidity); and (g) can be manufactured with conventional equipment and low costs [13,14,15].

Given the many advantages of ODTs, there are certain patient categories targeted for benefiting from this dosage form: patients suffering from acute or chronic pain; neurological patients (Parkinson’s disease, epilepsy, psychotic patients, sleep disorders, etc.); patients with allergies; immunotherapy; motion sickness; and also generally age categories such as geriatric and pediatric patients [14,15,16]. Consequently, the therapeutic classes of drugs that have been approached and widely formulated as ODTs are the ones which need rapid therapeutic effect: analgesics (paracetamol) [17,18]; NSAIDs (ibuprofen [19,20], piroxicam [21,22], nimesulide [23], rofecoxib [24,25], and valdecoxib [26]); neuroleptics (olanzapine [27], risperidone [28]); antihistaminic drugs (loratadine [29,30], cetirizine [31], desloratadine [32], and bilastine [33]); 5-HT3 inhibitors (ondansetron [34]); and 5-HT-1 agonists as anti-migraine drugs (sumatriptan [35], zolmitriptan [36]). The majority of these drugs have the advantage of being active in low doses, which mainly overcomes the formulation impediment of taste masking.

Other technologies emerged besides freeze-drying, and were used in obtaining orodispersible tablets, but none comply with all the targeted ideal features. Direct compression with or without effervescent systems has been implemented with success, using processed polyols as fillers (mannitol, sorbitol, and lactitol) and superdisintegrants, in order to achieve fast disintegration (sodium starch glycolate, sodium crosscarmellose, and crosspovidone) [37,38]. Orasolv and then Durasolv orodispersible tablets met most of the preferred characteristics; nevertheless, due to the direct compression method, their disintegration time lies in the range of 30–50 s [39,40]. Other particular methods have been tested in terms of obtaining different types of ODTs over time, such as wet granulation in a fluid bed with processed fillers, molding (wet compression), melt granulation, and sublimation [15,17,41,42].

Lyophilization (freeze-drying) is a special technique involving the evaporation of ice at low pressures and temperatures by the use of special equipment (lyophilizers). Applied to the manufacturing of ODTs, this leads to highly porous structures, also called oral lyophilisates, through the sublimation of water from the frozen drug–polymer matrix, resulting in remarkably rapid disintegration due to the capillary action inside the sponge-like structure. Conversely, in a tableting process, structural integrity is attained through direct compression of the powder to form the bonds between the particles [43,44].

The mixture to be freeze-dried has to be formulated as a thick suspension with a pasty consistency, so that after evaporation, a porous mass results, that will quickly absorb water and disintegrate.

Compared to all the other methods of obtaining ODTs, lyophilization imparts excellent qualities to the final product: the disintegration time is less than 15 s, the mouthfeel of oral lyophilisates is more pleasant than that of compressed ODTs, which, regardless of the new fillers with higher degree of fineness and potent superdisintegrants used in the formulations, have more grittiness and longer disintegration times, due to a decrease in tablet porosity during compression. Also, the mass and content uniformity are usually more reproducible in the lyophilization method, since it involves pouring of a viscous product (liquid, paste) into blister pack shells, compared to the homogeneity issues that can impact the direct compression method (Table 1) [45,46]. Numerous studies indicate higher performance regarding the dissolution and bioavailability of the incorporated drugs compared to other methods. However, the highly porous structure of lyophilized ODTs also increases their sensitivity to environmental moisture during storage and transportation. Therefore, these formulations generally require protective moisture-resistant packaging systems, such as peel-off or Alu-Alu blister packs, in order to maintain their physical stability and rapid disintegration properties. Additional preventive strategies include the incorporation of moisture-protective excipients, optimization of residual moisture content after lyophilization, and storage under controlled temperature and humidity conditions.

Table 1. Advantages vs. limitations of the lyophilization method for ODT preparation [45,46].

From a formulation perspective, the use of carefully selected cryoprotectants and bulking agents (e.g., sugars such as trehalose or mannitol) can significantly improve cake structure, prevent collapse, and enhance the stability of both the active pharmaceutical ingredient and the final orally disintegrating tablet (ODT) [13,14,15,16]. In addition, the development of multifunctional excipients, including co-processed and plant-derived materials, contributes to improved mechanical strength, faster disintegration, and better process robustness. [16,46].

From a process standpoint, the optimization of freezing protocols (controlled nucleation, annealing steps) and primary/secondary drying parameters can markedly reduce drying time while improving batch uniformity and product quality. Advances in freeze-dryer design, including improved heat transfer systems and real-time process monitoring via Process Analytical Technology (PAT) tools, also enhance reproducibility and scalability. Furthermore, continuous manufacturing approaches and cycle optimization strategies are increasingly being explored to reduce production costs and improve industrial feasibility [43,44,45,46].

Finally, emerging technological solutions, as well as hybrid systems combining lyophilization with alternative techniques, are being investigated to overcome inherent limitations of conventional freeze-drying. Taken together, these strategies indicate that while lyophilization has intrinsic constraints, many of them can be mitigated through integrated formulation and process innovations, thereby supporting its continued relevance in the development of high-performance ODT systems.

4. Excipients in the Formulation of Freeze-Dried ODTs: From Past to Present

The main categories of excipients used in the formulation of lyophilized ODTs are [4,5,50,51]:

Matrix formers provide the cohesion of the matrix, increase tablet strength and decrease tablet friability;
Bulking agents (porosity enhancers) build the ‘skeleton’ of the lyophilisate, increase porosity, accelerate disintegration and also improve palatability;
Cryoprotectants protect the sensitive drugs in the freezing steps;
Collapse protectants maintain matrix porosity during the primary drying step;
Palatability enhancers (sweeteners, flavors).

One important direction in the formulation of freeze-dried ODTs focuses on new ingredients that are meant to overcome the limitations of traditional excipients (gelatin or high concentrations of saccharides), in order to improve stability, disintegration speed, and compatibility for diabetic patients. Also, the need for sustainable raw materials has opened new directions for using plant derivatives as binders or disintegrants in the formulation of ODTs, obtained first through compression methods, and over the latest years being translated and implemented also into the lyophilization method as well.

The most researched categories have been the matrix formers and bulking agents, since they make up the majority of the tablet mass. Table 4 displays examples of the traditional and emerging excipients as matrix formers/bulking agents in the lyophilization method for ODTs.

Table 4. Traditional and emerging excipients used as matrix formers/bulking agents in freeze-dried ODTs.

A new line of research has been focusing in the past years on zero-saccharide ODT formulation, by replacing the saccharide/polyols with amino acids [62]. The following section summarizes ‘old and new’ main excipients used in freeze-dried ODT formulation.

4.1. Gelatin

Gelatin is a scleroprotein extracted from animal tissues containing collagen (pig, calf, fish) by acid hydrolysis (type A) or alkaline hydrolysis (type B). Commercial grades are usually a mixture of both types; this is why the name ‘gelatin’ covers a range of products having different properties. The jellification capacity of gelatin is expressed as Bloom strength, varying from 100 to 200 in pharmaceutical applications [63].

In ODTs prepared by lyophilization, gelatin is a good matrix former and mostly used, as reported by the literature, being still considered the ‘golden standard’ [50,51,64,65] (Table 5). For the preparation of the pasty, mixture gelatin is dissolved in water usually in a concentration of 2–5% and is mixed with other fillers (cellulose derivatives, polyols, etc.). It has been demonstrated that increasing gelatin concentration leads to a higher network strength upon lyophilization, which leads consequently to longer disintegration times and higher hardness (expressed as fracturability, measured in Newtons) [64].

Higher gelatin concentrations (14%) result in a disintegration time within 1 min, whereas concentrations of 20–22% gelatin lead to disintegration times that exceed 3 min [66]. The gelatin concentration will be chosen depending on the other ingredients used in the formulation (gums, cellulose derivatives), but generally a concentration below 1% tends to form friable ODTs, with very low hardness [67]. Because of its animal origin, there are ethical issues regarding gelatin use in pharmaceuticals; therefore, in hard capsules, where gelatin is the shell former, it has been replaced with hydroxypropyl methyl cellulose. In freeze-dried ODTs, the latest trends tend to replace it with methylcellulose (Methocel), certain grades of polyvidone (Kollicoat) and polyethylene oxide [68].

4.2. Xanthan Gum

Xanthan gum is a natural polysaccharide, obtained via the fermentation of glucose by the bacterium Xanthomonas campestris, with multiple applications mainly as a viscosity enhancer in the formulation of oral or topical pharmaceutical dosage forms [63]. In the lyophilization process of ODTs, it has been used from the beginning in the formulation of Lyoc tablets, playing the role of main matrix former, providing porosity and improved strength, compared to gelatin [1,2]. Xanthan gum is a good suspending agent and viscosity modulator, preventing particle sedimentation in the suspension-type formulations before freezing and insuring dose uniformity [21,43,69,70].

4.3. Hydroxypropyl Methyl Cellulose (HPMC)

Hydroxypropyl methyl cellulose has been used as a binder for oral lyophilisates as an alternative to gelatin. The low viscosity grades of HPMC used with success are HPMC E5 (in ODTs) and HPMC E15 (mainly in ODFs), with a viscosity of 5 mPa.s and 15 mPa.s (Methocel E15), respectively [71,72,73,74,75]. HPMC K4 M is a medium viscosity grade of hydroxypropyl methyl cellulose (4000 cPs at a concentration of 2%) and has a lower gelation temperature compared to the grades with higher viscosity [63]. It is a good matrix former for ODFs in combination with glycerin as a plasticizer [76]. In the freeze-drying process of ODTs, HPMC is mixed with polyols and saccharides, in order to optimize the tablet strength and shorten the disintegration time. It has been reported to make solid dispersions with low-soluble drugs, due to the formation of an amorphous mixture. Solid dispersions of HPMC/tenoxicam in different ratios have been reported to increase drug solubility upon lyophilization up to eight fold (for the tenoxicam/HPMC 1:2 ratio) [77].

4.4. Methylcellulose

Methylcellulose is widely used in the formulation of oral or topical dosage forms [63]. In ODTs, it acts as a matrix former, with good results in regards of tablet strength, while maintaining short disintegration times. The low viscosity grades can be used in the lyophilization process in concentrations of 2%, providing high porosity and uniform particle size dispersion [78,79,80]. In the investigation of cellulose derivative polymers in formulating lyophilized dry emulsions (LDEs), one of the studies had hydrochlorothiazide as a model drug. Methylcellulose was used as an emulsifier-binder for the obtaining of an oil-in-water LDE, in combination with maltodextrin, with good results [54].

4.5. Mannitol

Mannitol has been used in the lyophilization of ODTs for its excellent filler properties, serving as bulking agent/porosity excipient. It has good water solubility and a sweetening capacity of 50% of that of saccharose. An excellent advantage of mannitol in ODTs is its mouthfeel, leaving a cooling sensation, due to its negative heat of dissolution [81,82,83,84]. Unlike sorbitol, it is not hygroscopic, and is also chemically inert and stable in heating conditions [85]. In orodispersible tablets, it is used in concentrations between 10 and 80%, with increasing fracturability. In this matter, mannitol has proven to be more effective than sucrose or sorbitol, which are lyophilized tablets with the same respective polyol concentrations displaying higher hardness [64].

4.6. Maltodextrin

Maltodextrin is a non-sweet saccharide mixture of polymers that consists of D-glucose units, prepared by controlled starch hydrolysis [63]. It has been used in tablet technology as binder in wet granulation or filler-binder in direct compression. The grades that have a high dextrose equivalent number (DE) are used in the composition of chewable tablets or lozenges [70,86,87]. In ODTs, it acts as matrix former mixed with cellulose polymers [88], with an increase in maltodextrin concentration resulting in tablets with higher strength [89]. Also, research studies showed that maltodextrin formulations with a high DE value (DE38) showed a faster disintegration time compared to the ones with a lower DE (DE12 or DE24) [54].

4.7. Tamarind Seed Gum

Tamarind seed gum (also known as tamarind) is a natural, nonionic water-soluble gum, extracted from the endosperm of the tamarind seed, which contains polysaccharides such as xyloglucan. Primarily used as a thickener in food, in the past years, its use has expanded in cosmetics (creams, lotions) and in pharmaceutical formulations, due to its viscous and adhesive properties, as a binder for tablets (through direct compression and wet granulation). It is biodegradable, non-toxic, and non-irritant; also, it is considered a green ingredient, being obtained from the waste products in the tamarind fruit pulp industry [90,91]. Certain treatments, such as carboxymethylation, enhance its solubility, and its carboxymethylated grade has been used successfully to manufacture ODFs by the 2D-printing technique [91].

A study on lyophilized ODTs containing sodium diclofenac was reported with crude and modified tamarind seed gum as matrix formers, comparative with bulking agents as mannitol/sorbitol/xylitol. It was concluded that crude tamarind gum as a matrix former (~45%) can withstand the lyophilization method and results in ODTs with acceptable properties (in vitro and in vivo disintegration time of approx. 90 s and complete drug release in the first 10 min). An interesting observation was the behavior of bulking agents, with the tablets having different disintegration times depending on the polyol used. In this regard, tamarind/mannitol combination showed best ODT characteristics, whereas the tablets with the combination tamarind/sorbitol and tamarind/xylitol displayed disintegration times over 3 min [90].

This gum is still being studied to make a transition from oromucosal dosage forms to orodispersible tablets.

4.8. Powdered Plant Seed Mucilages (Ocimum sp., Plantago ovata, Senna tora)

Ocimum gratissimum, Ocimum sanctum and Ocimum basilicum seeds have found application as pharmaceutical excipients. The seeds can be processed by various treatments (milling, swelling/incubation) and the mucilage can be used as a binder in tablet formulation [92,93,94]. Recently, they have been reported as a good disintegrating agent in ODTs prepared by wet granulation followed by compression [94,95]. Ocimum sanctum seeds powder is considered a natural superdisintegrant through wicking action, which was tested in ODTs with nimesulide prepared by direct compression, with good results [96]. Another study published by Nayakal et al. uses Ocimum basilicum defatted seed powder as disintegrant in direct compression method for obtaining clopidogrel ODTs, in proportions of 3, 6 and 9% with good results for all formulations, with disintegration times less than 1 min in all cases (32 s for the 9% proportion), and 99% drug release after 10 min) [97]. These studies encourage the use of Ocimum sp. seed powder also in lyophilization, given that lyophilization is already a drying technique used for obtaining powdered mucilage, and would maintain its porosity over the freezing/drying states; moreover, its near-instantaneous dissolution upon contact with saliva makes it recommendable as compared to other semi-synthetic or synthetic superdisintegrants.

Plantago ovata and Senna tora (previously known as Cassia tora) mucilage powder are other plant derivative superdisintegrants used successfully in the formulation of ODTs by direct compression, with perspectives to be used also in the lyophilization method [92,93,98].

4.9. Pregelatinized Hydroxypropyl Pea Starch

Pea starch is extracted from various pea varieties (Pisum sativum), by removing protein and fibers. The pregelatinized hydroxypropyl grade is physically and chemically processed by the etherification of starch with propylene oxide, followed by mechanically processing in water and drying. Thus, the addition of hydroxypropyl groups makes it stable upon cooling without the phenomenon of gelation, which occurs to the other starch grades [99,100]. The pharmaceutical grade Lycoat RS720 contains 35% amylose and 65% amylopectin, is soluble in cold water and forms good mechanical strength, as well as flexible films. In the pharmaceutical field, it has been proposed as an alternative to gelatin capsule shells, in hard and soft capsules, and as a binder in wet granulation, as a natural replacement of synthetic binders [99].

In orally disintegrating tablets, it has been shown to increase tablet strength and provide a short disintegration time. A study published by Mahajan and Kelkar reported a concentration of 1% Lycoat RS720 as a good matrix former in combination with mannitol (0.5%) in lyophilized tadalafil ODTs, with good results for disintegration time (16.6 ± 0.8 s in vitro, 23 ± 2.5 s in vivo), drug release (more than 70% of tadalafil dissolved within 60 s) and stability over 3 months [101]. Also, compared to other starch derivatives, it has little tendency to absorb moisture, thus maintaining tablet integrity.

4.10. Polyethylene Oxide (Polyox™ Grades)

Polyethylene oxide (PEO) is a nonionic homopolymer of ethylene oxide and is represented by the formula (OCH2CH2)n, in which n represents the average number of oxyethylene groups. Since its discovery in the 1950s, polyethylene oxide (Polyox™) grades have been used various areas such as agriculture, paper industry, electrode and battery technologies, but they only began to be integrated as pharmaceutical excipients in the 1980s [102,103].

Due to its high molecular mass, as well as nonionic and hydrophilic properties, PEO has been used in the past decades in the formulation of solid dosage forms, especially as modified release systems, such as osmotic pump delivery tablets, gastroretentive dosage forms, and controlled release matrix formulations. The hydrogel layer forming upon hydration of polyethylene oxide provides drug release with various models. In the past years, Polyox grades have been included in the formulation of mucoadhesive dosage forms (buccal films, wafers) and ophthalmic hydrogels (combined with high viscosity grades of HPMC) [102,103,104]. Also, hydrogels containing polyethylene oxide have been prepared in combination with other hydrophilic polymers (carbopol, carrageenan, sodium alginate) to promote chronic wound healing [105].

In the freeze-drying process, Polyox has demonstrated good bulking properties, stabilizing the matrix during the sublimation stage and preventing the collapse of the tablet structure. In orodispersible dosage forms, it has the advantage of high hydrophilicity, fast water absorption and rapid disintegration in the oral cavity. ODFs containing quetiapine formulated with various grades of Polyox (in concentrations of 1–4%, with an optimum of 2%) have demonstrated good properties of tensile strength, a disintegration time less than 30 s, drug release over 80% and good stability [68]. ODFs with apixaban have been formulated for patients with dysphagia, based on a combination of Polyox (20%) and HPMC K4M and prepared via solvent casting technique; the films showed disintegration times less than 30 s, good tensile strength properties, good stability over a 6 months period and bioequivalence parameters compared to the original apixaban-marketed formulation [106]. In ODTs, low-viscosity Polyox grades (Polyon N10) were proven suitable as binders in 10% concentration, in combination with mannitol, resulting in robust ODTs with disintegration times below 40 s [107].

4.11. Side-Stream Lactose

This is a sustainable type of lactose obtained from byproducts from the dairy industry, like whey permeate and lactose mother liquor, and is nowadays increasingly valorized for pharmaceutical tablet manufacturing and nutrient-rich growth media. It has been proposed to be used as an excipient in spray-drying and freeze-drying, but also for direct compression mixed with other excipients such as microcrystalline cellulose [108].

4.12. Polyvinyl Alcohol

Polyvinyl alcohol (PVA) has been proposed as an alternative binder to gelatin in lyophilized ODTs and was found to be suitable for both low-dose and high-dose drugs. Vanbillemont et al. tested the characteristics of paracetamol high-dose ODTs and concluded that the optimal proportion is 2.76% PVA. Also, for low-dose ODTs containing hydrochlorothiazide, a proportion of 2.96% PVA was found to have minimum probability of failure, according to the experimental design [43].

4.13. Co-Processed Microcrystalline Cellulose Grades

Microcrystalline cellulose is an excellent excipient for direct compression, acting as a filler-binder, but it can also be used as a binder in other techniques such as wet granulation, dry granulation, extrusion, pelletization. It also possesses lubricant properties and acts as a disintegrant in tablets through wicking action [63,109]. Depending on their particle size, microcrystalline cellulose grades differ in their flowability, moisture uptake and are recommended for different manufacturing technologies. The Avicel CE15 grade is a co-processed excipient composed of microcrystalline cellulose (85%) and guar gum (15%), specially designed for buccal dosage forms (e.g., chewable tablets) to improve palatability [63].

In ODTs, it has been explored for direct compression formulations or dry granulation (slugging), in combination with other microcrystalline cellulose grades [110,111,112,113,114]. Also, Avicel CE15 has been used in combination with mannitol in the lyophilization process, with the obtained ODTs showing good porosity and short disintegration times (<10 s) [115].

Avicel HFE102 is a co-processed grade of co-spray dried microcrystalline cellulose (90%) and mannitol (10%), with a small particle size of approx. 100 µm [110,111]. It has better flowability, compaction and disintegration properties compared to traditional microcrystalline cellulose grades; at the same time, it displays less sensitivity to lubrication with stearates. It has been recommended for its good sensory attributes, to be used in chewable tablets, but recent studies have shown good applications also in ODTs [112].

4.14. Gellan Gum

Gellan gum is a natural anionic polysaccharide, produced through fermentation by the Sphingomonas spp. bacteria, which were isolated as Sphingomonas elodea in the U.S.A. from the lily plants that grew in the ponds. It was first approved as a food additive in Japan in 1988, being subsequently introduced as a pharmaceutical excipient and additive. It is a water-soluble, off-white powder, with a chemical composition of repeating units of D-glucose (~60%), L-rhamnose (~20%) and D-glucuronic acid (~20%) units. Its aqueous solutions are viscous at low concentrations, forming clear thermoreversible gels, which are less pH-dependent compared to other colloids [116,117,118]. In the pharmaceutical field, it has been used as a binder in modified release tablets, also in nanotechnology (drug-loaded gellan beads), ocular drug delivery and the formulation of hydrogels and thin films [118,119].

In orodispersible tablets, gellan gum has been implemented recently as a matrix former and as a binder with taste masking properties. One example of published study involves the preparation of atomoxetine ODTs by wet granulation, with various proportions of gellan gum (19–38%). Best results regarding in vitro disintegration time and drug release were recorded for the lowest concentrations of gellan gum, which also contributes to tablet disintegration, due to its swelling properties [120,121].

For the ODTs prepared by lyophilization, gellan gum has been used as a matrix former for drug-loaded nanoparticles, in order to prepare the dispersion to be freeze-dried [60]. Proportions of 15–45% of gellan gum were used in combination with mannitol in formulating freeze-dried ODTs with silymarin, with a notable in vitro disintegration time below 30 s. Increasing gellan gum ratio leads to higher tablet resistance, but with longer disintegration times [122].

4.15. Guar Gum

Guar gum is a natural polysaccharide derived from Cyanopsis tetragonolobus sp., highly used in pharmaceutical formulations for its viscosity properties [63]. Guar gum has been used successfully in the formulation of fast melt films prepared by various methods, including freeze-drying, due to its characteristics of rapid disintegration [123]. In orodispersible tablets, it has been used as a tablet matrix, making porous structures that disintegrate rapidly. However, a limit proportion should be used due to its swelling behavior, given that high concentrations (more than 8%), lead to a thick gel layer surrounding the tablet that may delay disintegration [124].

Modified guar gum (esterification through nucleophilic substitution with 2-Dodecen-1-yl succinic anhydride) modulates its swelling capacity and improves its dispersity in water, thus making it more adequate for rapid dispersion. The modified grade was formulated in ODTs with the model drug metoclopramide, with the tablets showing good pharmaco-technical and release pattern characteristics (more than 95% in the first 5 min) [125].

4.16. Amino Acids

Amino acids are a new class of excipients that are explored currently in the formulation of zero saccharide/polyols oral lyophilisates, with the aim of replacing the conventional matrix formers and to optimize the parameters of the lyophilization cycles. However, amino acids vary in their behavior and properties: the low glass transition temperature of some amino acids leads to the collapse of the matrix upon lyophilization, while other amino acids lack proper wettability, which is needed for providing short disintegration time [62,126].

A combination of proline and serine was reported by Al Husban et al., improving the qualities of lyophilized ODTs by choosing an adequate ratio of the two amino acids (45:55 proline/serine), for good wettability and adequate hardness [45]. Recently, lyophilized ODTs were formulated with alanine and serine with good results for high serine concentrations; combining it with alanine also increases the wettability of the ODTs [126]. Another study reports a combination of three amino acids (L-arginine, L-lysine, L-histidine 1.%, respectively) for obtaining freeze-dried ODTs with the antipsychotic drug lurasidone, with the aim of increasing drug solubility and absorption through the buccal epithelium (Table 5) [62]. The amino acids, especially L-histidine, prevented drug aggregation during freeze-drying and increased content uniformity. Also, it was observed that the presence of the amino acids L-arginine and L-lysine increases the hardness of the ODTs, while L-histidine and L-arginine accelerated transmucosal absorption [62].

4.17. Chitosan Grades and Chitin

Chitosan is a natural cationic, biodegradable polysaccharide extensively used in the past decades in the formulation of various dosage forms, due to its unique properties. In ODT formulations, its disintegrating, mucoadhesive and dissolution-enhancing characteristics have recommended chitosan as a multi-functioning excipient [127]. Medium molecular weight chitosan has been tried as superdisintergant, working by capillary action in the formulation of orodispersible tablets [128].

ODTs with meloxicam prepared by the wet granulation method with 7% chitosan as disintegrant displayed acceptable properties only at certain compression forces (10.8–11 kN) [128,129]. A combination of chitosan and alginate (1:1) was used as a disintegrating system in ODTs containing the highly water-soluble drug metoclopramide, prepared by the compression method. An interesting point was the addition of chitin (5–10%), which enhanced porosity and decreased tablet disintegration time [130,131]. Chitosan demonstrated good disintegrating properties at low concentrations (3.5–7%), being studied in ODTs with aspirin prepared by direct compression. These low concentrations are relevant, since it prevents jellification, which delays tablet disintegration [129].

Recently, chitosan nanoparticles have been implemented for the SNELT formulation of low-soluble drugs, such as rosuvastatine, which is a BCS class II drug (low solubility, high permeability). The drug was loaded into phospholipid nanoparticles coated with chitosan (chitosomes), which were further formulated for lyophilization, with the addition of matrix former excipients [132] (Table 5). The resulting ODTs had very short in vitro and in vivo disintegrating time and overall enhanced pharmacokinetic parameters compared to the non-loaded rosuvastatine lyophilized ODTs (Table 5) [132].

4.18. Eudragit E Grades

Eudragit E grades are cationic copolymers based on dimethylaminoethyl methacrylates and neutral methacrylates (such as buthyl and methyl methacrylate), which are soluble in biological fluid below pH = 5, and are therefore used for immediate release coatings of microparticles, tablets, minitablets, in order to achieve taste masking, protection from moisture and light or the bioavailability-enhancing characteristic of low-soluble drugs in the gastric juice. It is available in three grades: Eudragit E100 (granules), Eudragit EPO (powder) and Eudragit E 12.5 (organic solution). Eudragit E100 and EPO grades have been used in orally disintegrating tablets for coating the drug particles with the purpose of taste masking, because they are not soluble in the pH of saliva, thus keeping the coated units intact [133,134].

Granulation of the Eudragit E100 powder with tramadol in the proportion of 1:1, followed by the mass extrusion method was used to obtain taste-masked granules which were further compressed [135]. The EPO coating suspension (35% optimal amount) has been used for taste masking clindamycin hydrochloride beads for the preparation of ODTs via direct compression, using a fluid bed system. The taste masking efficiency was demonstrated by maintaining coating integrity, with good results [136].

Eudragit EPO has also been used in the lyophilization method. In a study reported by Bhoyar et al., trimetazidine hydrochloride particles were coated with Eudragit EPO by a physical mixture in an optimal proportion of 1:3, respectively, followed by lyophilization to obtain ODTs. The coating efficiency was tested by drug release in salivary fluid, demonstrating the capacity of taste masking of the prepared granules (Table 5) [137].

Excerpt from Table 5. Examples of formulation studies for lyophilized ODTs.

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Popa, E.G.; Mititelu Tartau, L.; Panainte, A.D.; Păduraru, L.; Crețeanu, A. Emerging Perspectives in the Formulation of Lyophilized Orally Disintegrating Tablets: From Lyoc to Self-Nanoemulsifying Lyophilized Tablets (SNELTs) and Beyond into Hybrid Platforms. Pharmaceutics 2026, 18, 615. https://doi.org/10.3390/pharmaceutics18050615