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Research and development costs for a single new pharmaceutical that is introduced to the market are estimated to cost between $1 billion and $2 billion. Due to the high cost of development and the need to quickly access various technologies, it is more cost-effective (clinically and financially) to enhance current pharmaceuticals for potency, selectivity, drug metabolism, and dosing convenience before they reach the market. Orally dissolving tablets have been developed as a result. Pharmaceutical companies have created oral disintegrating tablets that dissolve or disintegrate in the mouth within a few seconds of being placed there in order to maximize the safety and efficacy of the medicine molecule. Because patients with weak physiological (patients with mental illnesses) and physical capacities can easily administer it to geriatrics, children, and patients with these conditions (patients suffering from dysphagia), as well as traveling patients who may not have easy access to water and where swallowing conventional solid oral-dosage forms presents difficulties, it has grown in popularity among a wide population. These tablets can be prepared in many ways like direct compression, freeze drying, sublimation, molding, and spray drying by using single or combinations of superdisintegrants or subliming agents.
School of Pharmacy, College of Medicine and Health Sciences, Mizan-Tepi University, Ethiopia
*Address all correspondence to: fikaduejeta@gmail.com
1. Introduction
To maximize the safety and effectiveness of the medication molecule, pharmaceutical companies have developed oral disintegrating tablets that dissolve or disintegrate in the mouth after a few seconds of being placed there. It has gained popularity among a large population because it can be administered with ease to patients with weak physiological (patients with mental illnesses) and physical capacities, geriatrics, children, and patients with these conditions (patients suffering from dysphagia), as well as traveling patients who might not have easy access to water and where swallowing conventional solid oral-dosage forms presents difficulties [1, 2].
The European Pharmacopoeia states that Orally Disintegrating Tablets (ODTs) are uncoated tablets that are intended to be placed in the mouth and then dispersed rapidly before being swallowed. The European Pharmacopeia specifies a limit of 3 minutes for the in vitro disintegration in water. A fast-dissolving drug delivery system is a novel drug delivery system that aims to improve the safety and efficacy of the drug molecule by formulating a dosage form that quickly dissolves in the mouth [3, 4]. Because it may be provided with ease to elderly patients, children, people with mental illness, people who have trouble swallowing, people who are traveling, and people who might not have access to water at all; it has gained popularity among the general population [5].
Liquid formulations for routinely used pediatric drugs, as well as for patients in an acute setting or with adherence issues, have been created by manufacturers. They are not without flaws, are frequently unstable, and have short shelf lives. Accurate dosage measurement and administration are also a challenge [6, 7]. As a result, both the pharmaceutical business and academics have recently become interested in the development of orally disintegrating tablets. Actually, ODTs are becoming more and more popular among patients, particularly those who are young and old and wish to have access to their prescriptions whenever they need it. Patients value these drugs’ discretion and ease of use because they can be taken without water and start working right away [8]. As long as dispersion is rapid, bioavailability of the drug can be significantly greater than those observed from conventional tablet dosage forms [9].
1.1 Pharmacokinetic and pharmacodynamics consideration
As drug dissolves in saliva, it bypasses enterohepatic circulation and prevents first-pass metabolism by undergoing pre-gastric absorption. This improves bioavailability of the drug and reduces dosing frequency and dose-related untoward effects [10]. Orally disintegrating formulations are bioequivalent to the typical capsules now in use, with the added benefit of not requiring liquids. This allows for the management of emergent pain as soon as possible, regardless of the location or situation in which it occurs. The safety evaluation revealed that both orally disintegrating tablets and capsules were well tolerated, with no reported side effects. The similar maximum plasma concentrations (Cmax) achieved by both preparations are consistent with the lack of changes in safety parameters between the two formulations. Finally, from a practical standpoint, the availability of a bioequivalent tablet that can be eaten without liquids adds value because emergent pain can be addressed right away, regardless of where it occurs. This type of galenic formulation may also be beneficial for people who have difficulty swallowing or who have restricted mobility. It may also be of interest to institutionalized patients, as caregivers’ jobs are made easier.
For example, salbutamol sulfate exhibits site-specific absorption in the stomach and upper parts of the small intestine [11]. Drug absorption requires molecules to be in solution at the absorption site. Conventional tablets may pass through the absorption site until they disintegrate and dissolve, resulting in reduced bioavailability. Because they appear as a solution at the absorption site, orally disintegrating tablets may increase the chances of being absorbed [12]. This may improve drug bioavailability, particularly for medicines with limited absorption sites in the small intestine [11, 13, 14].
Although albuterol and other ß2 agonists were formerly provided orally to provide a longer duration of action, this strategy is being phased out in favor of ß2 agonists that have a longer duration of action when administered via inhalation. Short-acting bronchodilators are the first line of treatment for COPD patients who have symptoms that come and go [15]. Drugs with very short half-lives need to be given at frequent dosing intervals to maintain therapeutic efficacy [16]. When the drug concentration is high and the enzyme is subjected to first-pass hepatic biotransformation [17], saturation occurs. As a result, the rate procedure is reduced to zero orders. As all of the enzyme molecules become complex with the drug, bioavailability may improve, and free drug may escape metabolism [11]. Drug bioavailability may be enhanced through oral cavity absorption as well as pregastric absorption of saliva-containing dispersed medicines that move down into the stomach. Furthermore, when compared to traditional tablets, the amount of medication susceptible to first-pass metabolism is reduced [5].
ODTs are frequently prepared for immediate release, but they can also be formulated for prolonged or controlled release. Rapid disintegration is an ODT feature as a result, during formulation at least one superdisintegrant is needed. But some scholars have used combinations of different superdisintegrants like crospovidone and starch glycolate [18], combinations of superdisintegrants, and subliming agents like ammonium bicarbonate [19].
Crospovidone is a water-insoluble tablet disintegrant and dissolution agent used at 2–8% concentration in tablets prepared by direct-compression methods [20]. This may vary depending on methods of manufacturing, types of excipients, and nature of active ingredients under investigation [21]. The superior disintegrant capability of crospovidone can be attributed to its rapid capillary action, faster hydration rate, and little tendency of gel formation. Crospovidone’s high and rapid water absorption ability has a negative influence on wetting time. Due to its porous particle shape, it causes enormous wicking forces, further expanding and dissolving the tablet into finer particles. Crospovidone increased the crushing strength of tablets in a synergistic manner. This is due to its plastic character and binding capability, in addition to being an efficient disintegration agent; it acts as a highly compressible material in the dry state, hence increasing its concentration from 2–8% considerably enhanced the crushing strength of tablets. Ammonium bicarbonate is chemically inert and when subjected to high temperature and pressure, sublime due to its volatile nature resulting in highly porous structure in the tablets. It is utilized as a porosity-forming agent in tablets at a concentration of 2.5–20%. The solid, crystalline nature of ammonium bicarbonate accounts for its superiority. After sublimation, the leftover fractions of liquid volatile components in tablets solidify and serve as binders, but ammonium bicarbonate in residual concentration does not undergo this transformation and does not alter the mechanical characteristics of tablets [22, 23].
Excipient compatibility is responsible for mechanical strength, while high porosity is the key factor controlling quick disintegration of ODTs. Binder/disintegrant systems with dual benefits have solved both objectives in part. Mannitol has nice flavor and sweetening properties. Microcrystalline cellulose, on the other hand, has better mechanical characteristics for ODTs than mannitol. More than only good binding qualities in an excipient is required for the production of orally disintegrating tablets [24]. Amalgamation of cellulose and polyol-based excipients such as mannitol provides us with a clear criterion for developing directly compressed ODTs [23, 25]. The hardness of ODT is usually preferable between 4 and 8 kg in order to withstand handling during manufacturing, packaging, and transportation [26]. The hardness of tablets depends on the amount and types of binding agent present [27]. Therefore the change in hardness values of different ODTs observed in different amount and type of binding agents [28]. The hardness values for all tested tablets increase as the Microcrystalline cellulose to Mannitol ratio increases [23]. Occasionally sweetening agents like Aspartame (artificial sweetener) noncarcinogenic and can be consumed by diabetes patients, and; flavoring agents like vanillin can be used to mask unpleasant tastes and flavors of the active ingredients even though these are weak in taste masking. Much more intense sweeteners compared with sucrose with acceptable daily intake of 50 mg/kg. Vanilla flavor is a natural flavor that supplements and complements the sweetening agent [29]. There are many taste-masking techniques that have been reported in addition to adding flavors and sweeteners, coating drug particles with inert agents [30], inclusion complexes [31], microencapsulation [32], solid dispersions [26], molecular complexes of drug with other chemicals and prodrug by using ion exchange resins [33].
The Orally disintegrating tablets could be prepared using various techniques such as direct compression, lyophilization, sublimation, tablet molding, and spray drying [34, 35].
3.1 Direct compression
Direct compression is a simple, cost-effective solution to produce robust tablets that retain the appropriate disintegration properties. It also provides better stability of active pharmaceutical ingredients, fast dissolution, simple validation, and low microbial contamination. Moreover, ODDTs manufactured via direct compression tend to have a much higher drug-loading capacity and the final mass of these ODTs easily exceeds that of other formulation techniques. On the other hand, tablets produced via direct compression have much higher physical resistance but take longer to disintegrate [36]. The basic principle of direct compression involves combining disintegrants, or effervescent agents, and hydrophilic ingredients. Superdisintegrants incorporated in optimum concentrations are often used to achieve rapid disintegration of ODDTs, as well as a good mouth feel [37]. Crospovidone is the disintegrants of choice for fastest disintegration, shortest wetting time, enhanced rate of drug dissolution, and robust tablets. This is because it swells without forming gels which can slow tablet disintegration or dissolution. But, other superdisintegrants form gels when fully hydrated, particularly when a high amount is used some formulations to achieve desired tablet disintegration or drug dissolution [38].
3.2 Freeze drying
Freeze drying (lyophilization) is a process of removing water from a substance at lower temperatures under controlled conditions through sublimation [36]. This method has the advantage of allowing pharmaceutical compounds to be processed at lower temperatures, reducing sensitivity to thermal impacts, and allowing the solid to be kept in a dry environment with fewer stability issues. Because the resulting structures are relatively porous, lyophilization yields products that disintegrate more quickly than other solid dosage forms. Furthermore, the freeze-drying procedure causes the bulking agents in a formulation to have a glassy amorphous structure, which improves their disintegration capabilities. This approach produces ODTs with low mechanical strength that requires special packaging [26].
3.3 Sublimation
This method entails adding volatile chemicals such as ammonium bicarbonate, urea, naphthalene, and camphor to the other tablet ingredients before compressing them to make ODTs. Sublimation removes the volatile material trapped within the compressed tablets, resulting in the creation of pores within the formulation [22, 23, 39]. A high porosity while used for the enhancing disintegration rate of ODTs is undesirable for tablet mechanical strength [40]. Because many ODTs are porous, if the processing parameters are not optimal, the tablets can become more friable, regardless of hardness adjustments. Co-processed excipients must be employed to make mechanically hard ODTs without sacrificing disintegration time [23, 41].
3.4 Spray drying
Spray drying offers a quick and affordable method for getting rid of solvents and creating highly porous, fine powders that dissolve quickly. Rapid evaporation of the processing solvent during spray drying might result in the production of very porous, fine powder. Rapidly disintegrating pills can be made by spray drying [42]. This method uses a particulate support matrix, which is made by spray drying an aqueous composition comprising the support matrix and other ingredients into a highly porous and fine powder. The active components are subsequently added and the pills are crushed [43]. Hydrolyzed and nonhydrolyzed gelatins are used as supporting agents, mannitol is used as a bulking agent, sodium starch glycolate or croscarmellose sodium is used as a disintegrating agent, and an acidic and/or alkali material (e.g., sodium bicarbonate) is used to improve disintegration and dissolution [44].
3.5 Molding
This method creates solid dispersions known as ODDTs. Molded tablets are mainly manufactured from soluble components such as xylitol, lactose, glucose, sorbitol, sucrose, and mannitol. The powder mixture is wet with a hydroalcoholic solvent before being molded into tablets at a lower pressure than traditional tablet compression. The solvent is subsequently removed by air drying. Compressed tablets are much more compact than molded tablets. Their porous nature facilitates dissolution [44]. Unfortunately, the mechanical strength of molded tablets is often low. Erosion and breaking of the molded tablets occur frequently during tablet handling and when blister pockets are opened, posing potential stability issues.
4. Compatibility studies of formulation ingredients
The presence of polymorphic solids, which have different chemical and physical properties with biopharmaceutical effects in the dissolution rates and/or bioavailability as well as added excipients interactions either physically or chemically would be expected.. Therefore the physical characterization of the solid state of a drug has become an extremely important area in pharmaceutics and has been the subject of many studies involving different analytical methods.
Fourier transform infrared analysis will be performed to detect any changes in chemical constitution of the drug after combining it with the excipients. Fourier transform infrared analysis will be performed to detect any interaction between the drug and ammonium bicarbonate and crospovidone. The compatibility between the drug and excipients used in many formulations is being studied using Fourier transform infrared spectroscopy (FTIR) at room temperature. Samples of drug and excipients and physical mixtures of both are commonly grinded and mixed thoroughly with KBr. at a 1:5 sample/KBr ratio. The KBr discs were prepared by compressing the powders at a pressure of 5 T for 5 min in a hydraulic press. The scanning range was 400 to 4000 cm−1and the resolution was 8 cm−1.
4.2 Powder X-ray diffraction
X-ray powder diffraction (XRD) is a rapid analytical technique primarily used for phase identification of a crystalline material and is a unique method in determination of crystallinity of a compound. XRD will be performed to detect any crystallinity between the drug and ammonium bicarbonate and crospovidone. The powder X-ray diffraction patterns were measured using an X-ray diffractometer with Cu anode material. The diffraction pattern was measured with a voltage of 40kV and a current of 15 mA in the area of 0° <2Theta <100°.
4.3 Differential scanning calorimetry (DSC)
DSC is one of many types of thermal analysis techniques useful for characterizing pharmaceutical solids. Calorimetry is quite useful to measure chemical reactions such as cross-linking or curing reactions, oxidation processes, and thermal decomposition. Chemical reactions and the kinetics of these reactions under either inert or reactive atmospheres can be quantified nicely. DSC will be performed to detect any thermal decomposition between the drug and excipients. The thermal behavior can be estimated using differential scanning calorimetry by using Indium as a standard to calibrate the differential scanning calorimetry (DSC) temperature and enthalpy scale. The samples are hermetically sealed in aluminum pans and heated at a constant rate of 10°C/min, over a scanning temperature range of 0–400°C. An inert atmosphere was maintained by purging with nitrogen at a flow rate of 100 mL/min.
The DSC graphs of salbutamol sulfate and salbutamol sulfate and crospovidone physical mixture are presented in Figure 1A and B, respectively The DSC curve of the pure drug showed a sharp endothermic melting peak with the onset of about 210°C reaching maximum at 288°C. The DSC curve of salbutamol sulfate and crospovidone physical mixture showed a sharp endothermic melting peak with the onset of about 210°C reaching maximum at 283° C due to polymorphs (R) – salbutamol; as salbutamol sulfate exists in racemate forms S and R [45]. Besides, the small difference in the decomposition temperature could be associated with the different crystal morphology of the polymorphs [46, 47]. The thermogram of the corresponding physical mixture showed small endothermic peak indicating that amorphous form existed in the physical mixture which is in agreement with PXRD results. These might explain the faster dissolution of the drug in the physical mixture [26]. Thermogravimetric analysis (TGA) has been performed for the blends, and the weight loss due to the volatilization of the degradation products has been monitored as a function of temperature [48] as shown in Figure 1A and B, respectively [49]. Temperature at the maximum rate of weight loss (Tmax) improvement of salbutamol sulfate is ascribed to the compatibility of salbutamol sulfate and crospovidone in blends.
Figure 1.
The differential scanning calorimetric thermograms and thermogravimetric analysis of salbutamol (A) and salbutamol and crospovidone physical mixture (B).
5. Stability studies of orally disintegrating tablets
The chemical and physical properties of the active substance and pharmaceutical excipients, the dosage form and its composition, the manufacturing process, the nature of the container-closure system, and the properties of the packaging materials are all factors that affect the stability of finished pharmaceutical products. In a stability study, the impact of changes in temperature, time, humidity, light intensity, and partial vapor pressure on the product in issue is evaluated. The effective or mean kinetic temperature, rather than the recorded mean temperature, better depicts the actual situation; a product held for one month at 20°C and one month at 40°C will differ from one kept for two months at 30°C. Furthermore, storage circumstances are frequently such that the temperature is higher than the country’s average climatic data would indicate as shown in Tables 1 and 2 [50].
Long-term storage conditions are determined by the climatic condition under which the finished pharmaceutical products (FPP) is intended to be marketed.
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Written By
Fikadu Ejeta
Submitted: 26 November 2021Reviewed: 09 January 2023Published: 12 February 2023
Open access peer-reviewed chapter
