Advances and Perspectives in Orodispersible Tablets: Natural and Synthetic Superdisintegrants for Enhanced Drug Delivery.

Orodispersible Tablet:

Orodispersible tablets (ODTs) are innovative solid oral dosage forms that can rapidly break down or dissolve in the mouth—usually within seconds to three minutes—without needing water. They aim to enhance treatment adherence among patients, especially those from pediatric, geriatric, and dysphagic groups for whom standard tablets or capsules are hard to swallow. These tablets use superdisintegrants and customized formulations to guarantee rapid disintegration and immediate drug release, leading to a faster onset of the therapeutic effect.¹

Fig:1 representing the oral cavity's quick breakdown and the delivery of orodispersible tablets.

KEY FEATURES AND BENEFITS

• With ODTs, a rapid disintegration occurs in the mouth without water, which boosts convenience and patient acceptability.²
• They are especially advantageous for patients with swallowing difficulties or those needing medication delivery in emergencies.³
• Enhanced adherence by patients is accomplished via taste masking of bitter active pharmaceutical ingredients (APIs) and simplifying administration.⁴
• Due to pre-gastric absorption pathways and partial avoidance of first-pass metabolism, these tablets may increase certain medications' bioavailability and speed up their start of effect.⁵
• ODTs are acknowledged and characterized by reputable sources like the USP and European Pharmacopoeia, affirming their endorsement in regulated markets.⁶

IDEAL PROPERTIES OF ORODISPERSIBLE TABLETS:^7–10

The ideal characteristics of orodispersible tablets (ODTs) guarantee quick disintegration in the mouth, convenience for patients, and maximum therapeutic effects. The following are the essential characteristics as per the highest-rated pharmaceutical journals and pharmacopoeial standards:

• Disintegration without water: ODTs must break down or dissolve within seconds to a maximum of three minutes in the mouth, without the need for water to take them.
• Pleasant taste and mouthfeel: They ought to possess a pleasing mouthfeel and sufficient taste masking, and should leave little or no residue after being taken orally.
• Mechanical strength: ODTs must possess adequate mechanical strength to endure handling and packaging, while still ensuring rapid disintegration.
• Stability: The tablets need to be stable in changing environmental conditions, particularly with respect to humidity and temperature, and should ensure drug stability in saliva and water.
• Rapid onset of action: Due to pre-gastric absorption in the oral cavity, pharynx, or esophagus, ideal ODTs provide rapid drug release and absorption, frequently resulting in a quicker therapeutic onset.
• High drug loading: Able to house clinically pertinent drug doses, usually drugs that necessitate lesser doses.
• Simple and cost-effective manufacturing: They should be manufacturable using simple, economical processing techniques, compatible with existing tablet-making machinery.?
• Portability and convenience: ODTs ought to be easily transportable, safe to handle, and convenient for patients, particularly those who are mobile or have limited access to water.
• Low sensitivity to moisture: Effective under normal conditions of storage and transport, optimal ODTs exhibit low sensitivity to moisture.

DRUG SELECTION CRITERIA OF ODTs:^{11, 12}

• Capable of saturating the oral mucosa.
• Possess the capability to diffuse and partition into the upper GIT epithelium.
• BCS class-II drugs are promising candidates for ODTs.
• Non-ionized at least partially at the oral cavity's pH.
• Molecular weight is less than 500 Dalton.
• Drugs with low doses are mostly under 50 mg.
• Should exhibit good stability in saliva and water.
• Those with reduced bioavailability are suitable for ODTs.
• Drugs that have a short half-life and require frequent dosing are not appropriate for ODTs.
• Drugs with a very bitter taste and undesirable odor are unsuitable for ODTs.

ADVANTAGES AND DISADVANTAGES OF ORODISPERSIBLE TABLET’S, MOA, EXCIPIENTS USED IN ODTs FORMULATIONS:^13–22

Advantages:

• Enhanced adherence to treatment among patients, particularly those with dysphagia, older adults, and children, due to the rapid disintegration of ODTs in the absence of water.
• No need of water.
• Quick dissolution and uptake of the medication, along with enhanced bioavailability.
• Oral bioavailability of the drug may be increased through its pregastric absorption, leading to a reduction in the required dosage.
• Good chemical stability similar to that of conventional oral solid dosage forms.
• Decreased first pass metabolism.
• Direct compression methods lead to cost-effective manufacturing.

Disadvantages:

• Hygroscopic Nature: ODTs are extremely prone to absorbing moisture from the surroundings since they frequently contain hydrophilic excipients. Tablet integrity, disintegration, and shelf life may be jeopardized as a result, necessitating extremely dry storage conditions, which presents an additional difficulty for both patients and pharmacists.
• Low drug loading capacity: ODTs can only include modest to moderate medication dosages. This restricts the range of drugs that can be manufactured in this manner because ODTs are not appropriate for drugs that need high dosages.
• Unpleasant taste or mouthfeel: ODTs can cause mucosal irritation, an unpleasant aftertaste, or a gritty feeling if they are not properly prepared. This is because of taste-masking failures or exposed active components. Particularly in young and elderly populations, this may result in non-compliance from patients.

• Mechanical fragility: ODTs are often more brittle due to their quick disintegration design, which makes them susceptible to breaking or chipping during handling, shipping, packing, and even when taken out of blister packs.
• Specialized packaging requirements: Because of its delicate and hygroscopic nature, it requires advanced, moisture-resistant packaging, which can raise manufacturing, shipping, and storage costs and provide difficulties for healthcare systems as well as manufacturers.
• Limited suitability for some ingredients: Not every medication can be made into an ODT. Poor prospects for this technology include medications with short half-lives, large dose requirements, high levels of bitterness, or significant moisture sensitivity.
• Inappropriate for certain patients: Saliva must be adequate for ODTs to dissolve. These pills may be problematic for patients with xerostomia (dry mouth syndrome), reduced salivary flow, or anticholinergic medicine.             

MECHANISM OF ACTION OF ORODISPERSIBLE TABLET:

Fig:2 Mechanism of action of orodispersibe tablet.

EXCIPIENTS USED IN THE FORMULATION OF ORODISPERSIBLE TABLETS:

Certain excipients are needed for the fast-dissolving tablet's composition, they are:

SUPERDISINTEGRANTS:

Superdisintegrants are unique excipients included in tablet formulations to promote quick fragmentation of tablets into smaller pieces in water, which leads to a marked decrease in disintegration time and an increase in dissolution rate. In orally disintegrating tablets (ODTs) and other fast-release dosage forms, this property is essential for ensuring that drugs are released and absorbed quickly, resulting in a faster onset of action.^{23, 24}                                                 

Basic mechanism of superdisintegrants:

Fig:3 Mechanism of superdisintegrants.

There are two types of superdisintegrants, they are:^23–28

1. Natural superdisintegrants.

2. Synthetic superdisintegrants.

1.Natural superdisintegrants: Excipients derived from renewable resources, known as natural superdisintegrants, facilitate the quick disintegration of tablets by means of processes such gel formation, wicking, and swelling. In contrast to synthetic disintegrants, they offer developers safe and environmentally favorable alternatives, especially for fast-dissolving and oral disintegrating tablets.

Biological sources like plants, algae, or naturally occurring polymers are the source of natural superdisintegrants. They are used into tablet formulations to hasten the disintegration of tablets upon coming into touch with gastrointestinal or salivary fluids. These materials are prized for being affordable substitutes for synthetic superdisintegrants that are biodegradable, non-toxic, and biocompatible.

SOME COMMON NATURAL SUPERDISINTEGRANTRANTS AND ITS SOURCES:

Advantages of natural superdisintegrants:

• Materials that are abundant in nature and biodegradable lessen reliance on artificial chemicals.
• Biocompatible, non-toxic, and non-irritating—perfect for formulas intended for children and the elderly.
• Provide environmentally friendly production methods that are in line with contemporary "green pharmacy" ideas.
• The disintegration performance is either the same as or better than that of synthetic agents.

Disadvantages of natural superdisintegrants:^{24, 29–31}

• Microbial contamination and stability: Natural materials are organic in nature, therefore exposure to moisture and temperature changes can cause microbial growth, deterioration, or chemical instability. This raises the cost and complexity of manufacturing by requiring extra sterilization or preservation procedures.
• Moisture sensitivity and aging: Natural polysaccharides' hydrophilic properties allow them to absorb moisture from the atmosphere, which gradually changes how well they disintegrate, especially in humid environments.
• Allergenic or irritant potential: Because of their high fiber or protein content, some plant-based superdisintegrants, such those made from psyllium husk (Plantago ovata), might irritate or trigger hypersensitivity responses in vulnerable people.
• Limited flow and compressibility: Compared to synthetic excipients, natural excipients frequently have poorer flowability and compressibility, which reduces tablet production efficiency and may result in weight variance or friability issues.
• Anionic interactions with cationic drugs: Anionic groups found in certain natural superdisintegrants can interact with cationic APIs to decrease medication release or stability while being stored.

2.Synthetic superdisintegrants: Chemically altered polymers known as synthetic superdisintegrants are made to speed up the breakdown and disintegration of tablets. Even in rigorous industrial settings, they offer superior homogeneity, stability, and repeatability in contrast to natural agents. These substances ensure quick drug release with low concentration in formulations primarily through swelling, wicking, and strain recovery processes.³²

SOME COMMON SYNTHETIC SUPERDISINTEGRANTS AND THEIR FEATURES ARE GIVEN BELOW:^{33, 34}

Advantages and disadvantages of synthetic superdisintegrants:^35–37

• Superior purity and repeatability in contrast to materials derived from plants.
• Superior flow and mechanical qualities for mass manufacturing.
• Effective across a broad range of moisture and pH levels.
• Smaller amounts (1–10%) are needed to produce quick disintegration.

Disavantages of synthetic superdisintegrants:

• Chemical residues and possible toxicity.
• Environmental Issues and Non-Biodegradability.
• High Cost of Manufacturing.
• Inadequate Biocompatibility.
• Problems with Stability and Sensitivity to Moisture.

Sugar based excipients: Sugar-based excipients are used as bulking agents and to cover flavor. The majority of the dugs have a disagreeable or bitter flavor. It is also a fundamental criterion for ODT design that the medication not have an unpleasant taste.  Therefore, in most situations, flavor masking is required. sorbitol, Mainly utilized include mannitol, xylitol, dextrose, fructose, etc. A pleasant mouthfeel and effective flavor masking are provided by aqueous solubility and sweetness. However, not every sugar-based compound dissolves quickly and has high compactibility or compressibility. However, methods for creating fast-dissolving tablets are being developed that utilize sugar-based excipients. Other frequently used additives include lubricants, plasticizers, binders, colors, flavors, water-soluble diluents, and antistatic agents.

Antiadherents: In order to keep powder (granules) from sticking to tablet punches, antiadherents are employed to lessen their adherence to the punch faces. They also aid in preventing pills from adhering. Magnesium stearate is most frequently utilized.

Binders: The components of a tablet are held together by binder. Binders offer low active dosage tablets volume and ensure that the required mechanical strength can be produced in tablets and granules.

Fillers or diluents: The size of a pill or capsule is completed by fillers, which makes production feasible and user-friendly. The fillers enable the finished product to have the appropriate volume for the treatment of patients by raising the bulk volume.

Flavours: Flavors can be added to cover up bad-tasting active substances and increase the patient's chance of finishing a prescription. Flavors might be artificial or natural, like fruit extract. For example, to enhance:

• An unpleasant product -mint, cherry or anise can be used.
• A salty product- peach, apricot or liquorice can be used.
• A sour product- raspberry or liquorice can be used.
• A product that is too sweet - vanilla can be used.

Colours: Colours are added to a formulation to make it seem better. Consistency in colour is crucial since it makes identifying a drug simple.

Lubricants: Lubricants prevent components from clumping together and sticking to the tablet punches or capsule filling machine. Additionally, lubricants guarantee that there is minimal friction between the solid and die wall during tablet generation and ejection. The most often used lubricants in tablets or hard gelatin capsules include common minerals like talc or silica and fats like vegetable stearin, magnesium stearate, or stearic acid.

Glidants: Glidants are used to increase powder flow by decreasing the cohesiveness and friction between particles. Because they cannot lessen die wall friction, they are employed in conjunction with lubricants. Fumed silica, talc, and magnesium carbonate are a few examples.

Preservatives: Typical preservatives included in pharmaceutical formulations include

• Antioxidants like vitamin A, vitamin E, vitamin C, retinyl palmitate, and selenium.

• The amino acids cysteine and methionine.
• Citric acid and sodium citrate.
• Synthetic preservatives like the parabens: methyl paraben and propyl paraben.

Sweeteners: In liquids like cough syrup or chewable pills like antacids, sweeteners are added to make the components more appealing. Therefore, using cough syrup excessively is occasionally linked to tooth decay. Bad scents or tastes can be covered up with sugar.

Sublimating agents: It was investigated to employ sublimating substances such as thymol, menthol, and camphor. The disintegration time (about 30 sec) was further reduced with the addition of camphor, although the percentage of friability increased.

TECHNILQUES USED FOR THE PREPARATION OF ORODISPERSIBLE TABLETS (ODTs):^38–44

Specialized methods are needed to prepare orodispersible tablets (ODTs) so that they dissolve quickly in the mouth without sacrificing stability or strength. The drug's physicochemical parameters and the intended tablet features determine which of several traditional and cutting-edge methods are used.
Every technique has different benefits and drawbacks in terms of price, scalability, and manufacturing simplicity.

1.Direct compression method.

2.Lyophilization(freeze-drying).

3.Sublimation process.

4.Other novel techniques.

• Spray drying.
• Hot met extrusion (HME)
• Molding method

1.Direct compression method: The most popular and economically feasible method for producing ODTs is direct compression. Using this technique, a combination including the medication, superdisintegrants, diluents, and other excipients is directly compressed. It is simple, affordable, and appropriate for medications that are sensitive to moisture and heat.
Direct compression has several benefits, including simplicity, fast throughput, and reduced production costs. However, careful excipient selection and compression force optimization are necessary to strike a compromise between tablet porosity and mechanical strength.

Advantages: Fewer processing stages, appropriate for heat-sensitive pharmaceuticals, and faster manufacture.

Disadvantages: Low mechanical strength when using too much disintegrant; requires flowable particles.

2.Lyophilization (Freeze-drying): Lyophilization includes preparing a liquid or semi-solid solution containing the medicine and excipients, filling it into premade blisters or molds, freezing it, and drying it under vacuum to sublimate the solvent. The resultant pill is very porous and dissolves quickly in the mouth. While this technology yields ODTs with fast disintegration rates (typically under 10 seconds), it has disadvantages such as high manufacturing costs, low mechanical strength, and the necessity for specific packaging to minimize breakage and moisture uptake.

Advantages: More rapid dissolution than other available solid products.

Disadvantages: Expensive, fragile tablets, and poor humidity stability.

3.Sublimation process: The sublimation procedure involves adding a volatile chemical like camphor, menthol, or ammonium bicarbonate to the tablet formulation. When heated, the volatile component transforms into a porous matrix, allowing for better water penetration and faster tablet breakdown. This approach enhances ODT porosity and disintegration while maintaining tablet hardness. Proper temperature control is crucial to prevent deterioration of active medicinal ingredients during manufacturing.

Advantages:

• creates pills that dissolve and disintegrate in the mouth incredibly quickly due to their highly porous composition.
• The pill is perfect for people who have trouble swallowing since it enhances wetness and saliva penetration.

Disadvantages:

• Because of their high porosity, the manufactured tablets are mechanically fragile and easily shatter when handled, packaged, or transported.
• Increased matrix mass can compromise mechanical stability, making high-dose formulations unsuitable.

4.Other novel techniques:

Spray drying: By atomizing a medication solution into a heated drying chamber, spray drying causes the solvent to evaporate quickly and a fine, dry powder to develop. This powder has outstanding disintegration qualities and may be compacted straight into ODTs. The method works well for medications that are sensitive to heat and allows particle engineering to increase bioavailability and solubility.

Advantages:

• Rapid and continuous process: efficiently transforms liquid input into dry powder in a single step, making it suitable for large-scale production.
• Improve bioavailability.
• Precise particle control.
• Taste masking and encapsulation.
• Improve shelf life.

Disadvantages:

• High energy consumption.
• High equipment and operational cost.
• Solvent handling risk.
• Limited for heat sensitive APIs.
• Bulk density limitations.

Hot melt extrusion (HME): In hot melt extrusion, a mixture of thermoplastic and pharmaceutical polymers is melted, then formed into tablets using an extruder. Improving medication solubility and attaining sustained or instantaneous release characteristics are benefits of this technique. Fast-dissolving matrices may now be created thanks to recent developments in HME, even if they are less prevalent for ODTs. The drug's physicochemical makeup, the intended disintegration time, the cost of manufacture, and the viability of scaling up all influence the process used to prepare ODTs. For certain applications, sophisticated procedures like lyophilization and hot melt extrusion provide better performance than traditional methods like direct compression, which are preferred for their ease of use. Having a solid grasp of each technique enables formulation scientists to create efficient, patient-focused ODTs.

Advantages:

• Solvent free process.
• Rapid and continuous process.
• Uniform drug distribution.
• Improve mechanical and physical strength.
• Eco friendly and scalable.
• Enhance stability.

Disadvantages:

• High energy and equipment cost.
• Limited polymer compatibility.
• Requires precise process optimization.
• Limited use for moisture requiring APIs.

Molding method: The molding procedure entails moistening, dissolving, or dispersing the medication and excipients with a solvent (typically hydroalcoholic) to create a wet mass. This is then molded into tablets under low pressure and dried to remove the solvent, resulting in highly porous and rapidly disintegrating tablets.

Types of molding:

• Compression molding: The wet mixture is gently compressed—not as heavily as with direct compression—until tablets are created.
• Heat molding: use heat to make the mixture solid.
• No-vacuun lyophilization: forming solid tablets under ambient circumstances by use of solvent evaporation.

Advantages:

• Quick disintegration.
• Pleasant mouthfeel.
• Enhanced Acceptability by Patients.
• Suitable for Innovative Drug Delivery.

Disadvantages:

• Complicated Drying Procedure.
• Inadequate Stability in Humidity.
• High Cost of Production.
• Special Tools are Required.
• Less adequate for APIs That are sensitive to water.

DRUGS TO BE IN CORPORATED IN ODTs:^{3, 9, 13, 34, 41, 44–50}

As long as the material is utilized as an active ingredient in a pharmaceutical, there are no specific restrictions.

1. Anthelmintics: Albendazole, Bephenium Hydroxynaphthoate, Cambendazole, Dichlorophen, Iverrnectin, Mebendazole, Oxarnniquine, Oxfendazole, Oxantel Embonate, Praziquantel, Pyrantel Embonate, Thiabendazole. Anti-Arrhythmic Agents: Amiodarone, Disopyramide, Flecainide Acetate, Quinidine sulphate.
2. Anti-bacterial: Benethamine Penicillin, Cinoxacin, Ciprofloxacin, Clarithromycin, Clofazimine, Cloxacillin, Demeclocycline, Doxycycline, Erythromycin, Ethionamide, Imipenem, Nalidixic Acid, Nitrofurantoin, Rifampicin, Spiramycin, Sulphabenzamide, Sulphadoxine, Sulphamerazine, Sulphacetamide, Sulphadiazine, Sulphafurazole, Sulphamethoxazole, Sulphapyridine, Tetracycline, Trimethoprim.
3. Anti-coagulants: Dicoumarol, Dipyridamole, Nicoumalone, Phenindione.
4. Antidepressants: Amoxapine, Ciclazindol, Maprotiline, Mianserin, Nortriptyline, Trazodone, Trimipramine Maleate., Acetohexamide, Chlorpropamide, Glibenclamide, Gliclazide, Glipizide, Tolazamide, Tolbutamide. Anti-Epileptics: Beclamide, Carbamazepine, Clonazepam, Ethotoin, Methoin, Methsuximide, Methylphenobarbitone, Oxcarbazepine,valproic acid.
5. Anti-Hypertensive: Amlodipine, Carvedilol, Benidipine, Darodipine, Dilitazem, Diazoxide, Felodipine, Guanabenz Acetate, Indoramin, Isradipine, Minoxidii, Nicardipine, Nifedipine, Nimodipine, Phenoxybenzamine, Prazosin, Reserpine, Terazosin, Metoprolol tartrate.
6. Anti-Fungal: Amphotericin, Butoconazole Nitrate, Clotrimazole, Econazole Nitrate, Fluconazole, Fiucytosine, Griseofulvin, Itraconazole, Ketoconazole, Miconazole, Natamycin, Nystatin, Sulconazole Nitrate, Terbinafine, Terconazole, Tioconazole, Undecanoic Acid.
7. Anti-Gout: Sulphinpyrazone, Allopurinoc, probenecid. Anti-Malarial: Amodiaquine, Chloroquine, Chlorproguanil, Halofantrine, Mefloquine, Proguanil, Pyrimethamine, Quinine Sulphate.
8. Anti-Migraine: Dihydroergotamine Ergotamine Tartrate, Methysergide Maleate, Pizotifen Maleate.
9. Anti-Muscarinic: Atropine, Benzhexol, Biperiden, Ethopropazine, Hyoscine Butyl Bromide, Hyoscyarnine, Mepenzolate Bromide, Orphenadrine, Oxyphencylcimine, Tropicamide.
10. Anti-Protozoal: Benznidazole, Clioquinol, Deco quinate, Diiodohydroxyquinoline, Diloxanide Furoate, Dinitolmide, Furzolidone, Metronidazole, Nimorazole, Nitrofurazone, Omidazole, Tinidazole.
11. Anti-Thyroid: Carbimazole, Propylthiouracil, Anxiolytic, Sedatives.
12. Corticosteroids: Beclomethasone, Betamethasone, Budesonide, Cortisone Acetate, Desoxymethasone, Dexamethasone, Fludrocortisone Acetate, Flunisolide, Flucortolone, Fluticasone Propionatu, Hydrocortisone, Methylprednisolone, Prednisolone, Prednisone, Triamcinolone.
13. Diuretics: Acetazolarnide, Amiloride, Bendrofluazide, Bumetanide, Chlorothiazide, Chlorthalidone, Ethacrynic Acid.
14. Histamine H, -Receptor Antagonists: Acrivastine, Astemizole, Cinnarizine, Cyclizine, Cyproheptadine, Dimenhydrinate, Flunarizine, Loratadine, Meclozine, Oxatomide, Terfenadine, Triprolidine.

LIST OF SOME MARKETED ORODISPERSIBLE TABLETS USING SYNTHETIC SUPERDISINTEGRANTS:^{13, 17, 42, 45, 46, 49}

LIST OF SOME MARKETED ORODISPERSIBLE TABLETS USING NATURAL SUPERDISINTEGRANTS:

1. MARKET ORODISPERSIBLE TABLETS IN INDIA USING SYNTHETIC SUPERDISINTEGRANTS:¹³

2. MARKET ORODISPERSIBLE TABLETS IN INDIA USING NATURAL SUPERDISINTEGRANTS:

C. INDIAN MANUFACTURERS AND ODT TECHNOLOGY PROVIDERS:

PATENTED TECHNOLOGIES OF ODTs:

MOST PREFERED DOSAGE FORMS BY PATIENTS:^{2, 51–53}

Tablet dosage forms are the most popular and extensively utilized by people of all ages, including in India and other significant markets, according to several international research. Among tablets, orodispersible tablets (ODTs) and regular tablets are particularly well-liked by children, the elderly, and patients who have trouble swallowing.

Fig:4 participants preference (%) vs types of dosage forms.

Fig:5 participants preference (%) vs types of routes of administration