Oral medicine administration is one of the most widely used ways because it is greater patient compliance, easier to administer, and more inexpensive. The oral route is difficult for older and paediatric patients since they have trouble swallowing and are afraid, they will choke. Drug delivery techniques have become safer and more advanced as a result of research on patient convenience and compliance. One product that has lately acquired public choice and appeal is fast dissolving medication delivery systems. This is because the product's quick disintegration or dissolve enables for self-administration even without the need for water or chewing. Fast-dissolving drug delivery devices were first created in the late 1970s to assist patients, particularly young and old, who had difficulty swallowing pills and capsules. The use of buccal medication delivery as a drug administration technique has increased recently. Bioadhesive mucosal dosage forms that have been developed include adhesive tablets, gels, ointments, patches, and, more recently, the use of polymeric films for buccal delivery, also known as mouth dissolving films. An undulating basement membrane effectively divides the stratified squamous epithelium covering the buccal cavity's surface from the underlying tissue, the lamina propria and submucosa. It's interesting to note that intestinal permeability is lower than buccal mucosa permeability, which is roughly 4-4,000 times higher than skin permeability. When administering chemicals with little skin penetration, buccal administration offers the best absorption medium. The main permeability barrier of the otiral mucosa is formed by intercellular material that comes from the so-called "membrane coating granules" at the top 200 ?m layer. These dosage forms have a two- to three-year shelf life, depending on the active therapeutic ingredient; nonetheless, they are very vulnerable to environmental dampness. An ideal quick dissolving delivery system should have high stability, transportability, ease of handling and administration, no specific packing material or processing requirements, no need for water during application, and a pleasant flavour. They are therefore perfect for patients who are bedridden, old, or have Parkinson's disease, mucositis, dysphagia, or vomiting. This cutting-edge medicine delivery technique may help meet the demands of the industry today. When rapidly dissolving films (RDF) were originally introduced to the market, they were marketed as dental strips and soap, along with breath fresheners. However, the pharmaceutical markets in the US and Europe are offering a range of dose forms for therapeutic uses. Pfizer, a major pharmaceutical company, invented the first oral strips (OS) called Listerine® pocket packsTM for mouth freshening reasons. Chloraseptic® Comfort Strips were the first therapeutic oral thin films (OTF) to treat sore throats; they included seven benzocaine Fast-dissolving buccal film is made from ingredients such as strip-forming polymers, plasticizers, active pharmaceutical ingredients, sweeteners, flavouring agents, saliva-stimulating agents, colouring agents, stabilising and thickening agents, permeation enhancers, and superdisintegrants. Regulators believe that all of the excipients used in the fast-dissolving film's composition ought to be approved for use in oral pharmaceutical dosage forms.[1

Figure no 1 : Stages in the development oral solid dosage forms

For ease of explanation, fast dissolve technologies can be divided into three primary kinds.

1. Systems lyophilized.
2. Systems based on compressed tablets.
3. OTF.

SPECIAL FEATURES OF FAST DISSOLVING FILM [2]

1. A film must have a sleek, appealing appearance.
2. Is available in many shapes and sizes
3. Unnoticeable.
4. It should be easy to insert into the oral cavity.
5. Must decompose rapidly in the absence of water.
6. Rapid discharge.

The stratified squamous epithelium makes up the oral mucosa's outermost layer. Beneath this is the deepest layer, the submucosa, lamina propria, and basement membrane. The epithelium shares features with the other stratified squamous epithelia in the body, such as a mitotic basal cell layer. Before this layer reaches the superficial layers, where cells are lost from the surface of the epithelium, it passes through a number of developing intermediate levels.

ADVANTAGES [4]

1. 1. Presented without the need for water, at any time, wherever.
   2. Its large surface area causes it to melt and dissolve quickly in the mouth.
   3. Dosage accuracy.
   4. You are able to avoid the stomach's acidic environment.
   5. Local as well as site-specific activities.
   6. Being lightweight and flexible makes it easier to handle and store the customer while in transit.
   7. For everyone, regardless of age, who experiences difficulties with swallowing, is ill, has a developmental or mental disorder, is resistant to therapy, or has issues consuming fluids.
   8. Helpful in situations requiring a quick start, such as motion sickness, severe pain, allergic reactions, or coughing.

DISADVANTAGES [5]

1. 1. Drugs that are not stable at buccal pH cannot be administered.
   2. Drugs cannot be given in larger than necessary dosages.
   3. Due to their harsh taste, several medications need to have their taste masks applied.
   4. Due to its fragile nature and the requirement to be kept dry and away from water, it needs particular packing.
   5. drugs that should not be taken this way because they irritate the mucosa.

IDEAL CHARACTERISTICS OF SUITABLE DRUG CANDIDATE [6]

1. 1. Mouth dissolving film should be thin, flexible, but strong to enable easy handling and administration, as well as a dependable manufacture and storage method. The films should not stick to surfaces, be portable, and be able to keep their flat shape without rolling.
   2. Simple administration for people who refuse or have mental disease or disability.
   3. Their flavour and texture must be pleasing.
   4. It is not necessary to have water.
   5. Everything ought to disintegrate as quickly as possible.
   6. The environment's temperature and humidity levels ought to have the biggest impacts on them.
   7. They must be able to offer pharmaceutical formulations that combine the advantages of liquid and solid forms.

CLASSIFICATION OF MOUTH DISSOLVING FILMS [7]

1. Mucoadhesive melt-away wafer:

A Mucoadhesive film is applied to the buccal and gingival mucosa, and it sticks to the mucosal surface. Two kinds of films are immunoadhesive.

1. Mucoadhesive melt-away strip: 

This kind of strip sticks to the mucosa, melts all by itself in a few minutes, and delivers medication continuously over time.

2. Sustained release mucoadhesive films:

These films stick to the mucosa and remain there for a few hours.

2. Flash release wafers:

These wafers dissolve for up to 60 seconds and then immediately release the drug into the oral cavity. The application site determines how the two parts of the flash release wafers are categorised.

A. Orodispersible film (ODF):

ODF is a minuscule strip that is about the size of a postage stamp.

1. 1. 2. Sublingual films:

These films are produced using the same methodology as ODFs. These films are positioned under the tongue as opposed to in the mouth.

STANDARD COMPOSITION OF MOUTH DISSOLVING FILMS

1. Active Pharmaceutical Ingredient-

The drug-loaded film's area should be between 1 and 20 cm2, depending on how much of the water-soluble polymers accelerate the film's dissolution. An array of APIS can be supplied by oral strip technology. This delivery system may consist of multiple substances. These could include erectile dysfunction drugs, antihistamines, anti-asthmatics, gastrointestinal problems, nausea, discomfort, CNS (e.g., anti-parkinson's disease), anxiety pills, cardiovascular drugs, sore throat and cough/cold remedies (antitussives, expectorants). Since it enhances the oral strip's consistency, dissolving ability and film texture, micronized API is typically beneficial. In these oral strip technologies, APIs are more promising but have a harsher taste. This makes the composition unpleasant, particularly in the case of kid-friendly compositions.

2. Film Forming Polymers-

For the creation of the oral soluble film, water soluble polymers are used, such as HPMC E-3, E-5, E-15, K-3, methyl cellulose A-3, A-6, and A6, carboxymethylcellulose, pullulan, maltodextrin, hydroxypropyl cellulose Cekol 30, polyvinyl alcohol, etc. They can be used separately or in combination to affect the desired aspects of the film. The peculiarities of the film-forming polymer:

1. It must have an extended shelf life.
2. It must possess good wetting properties.
3. It needs to have a decent spread ability property.
4. It must not encourage the growth of secondary infections in the oral mucosa or teeth.
5. The mouthfeel must be pleasant.
6. The polymer that is utilised must be nontoxic, nonirritating, and devoid of any impurities that may leak out. [8]

3. Plasticizers-

It improves the film flexibility by reducing its brittleness and boosts the strip property for oral film processing, making it an essential component of oral film. It also improves the polymer's flow and strengthens it. The plasticizer of choice will be determined by how effectively it combines with the polymer and the solvent used in the strip casting process. Plasticizers should normally be used at concentrations between 0 and 20% w/w of dry polymer weight. [8].

D. Strip Forming Polymers –

The polymers in the formulation can be used singly or in combination to achieve the required strip properties. The resultant film must be strong enough to withstand any damage during handling or transportation. The durability of the strip will depend on the type and amount of polymer used. There are several different types of polymers that can be used to make oral strips. On the other hand, a fast-dissolving strip dosage form should be able to instantaneously dissolve in the mouth and deliver the medication to the oral cavity.

When creating oral strips, pullulan, hydromellose, and gelatin are the polymers that are most frequently used. A dry oral strip should typically have at least 45% weight percent polymers. [8].

1. 1. 5. Saliva Stimulating Agent-

Saliva stimulaters are used to boost saliva production rates because saliva facilitates the fast disintegration of rapidly dissolving films. Saliva stimulating agents are employed singly or in mixtures ranging from 2 to 6% weight/weight of the film. [8].

1. 1. 6. Sweetening Agent-

The use of sweeteners in pharmaceutical and food preparations that are supposed to dissolve or disintegrate in the mouth has increased. Sweeteners, both natural and artificial, are used to improve the mouth-dissolving formulations' palatability. Water soluble natural sweeteners, such as xylose, ribose, glucose, sucrose, maltose, and stevioside, are among the approved sweeteners. Artificial sweeteners that dissolve in water: acesulfame-K, sodium or calcium saccharin salts, etc. Aspartame is a dipeptide-based sweetener. Agent that Stimulates Saliva: Because most salivary stimulants have an acidic character, they promote the production of saliva in the buccal cavity and facilitate the breakdown of ODFs. Saliva-stimulating agents that are frequently used include tartaric acid, lactic acid, ascorbic acid, malic acid, and citric acid.

1. 1. 7. Surfactant-

Surfactants are used as wetting, dispersion, or solubilizing agents to facilitate the fast dissolution of the film and immediate release of the active ingredient. Additionally, surfactants aid in the fast dissolution of buccal films by making poorly soluble medicines more soluble. As an example, consider tweens and spans, sodium lauryl sulphate, Polaxamer 407, benzalkonium chloride, and benzthonium chloride.

1. 1. 8. Flavor-

Flavours are used to mask the unpleasant or harsh taste of integrated pharmaceuticals. Its type and potency affect taste intensity. Any US FDA-approved flavour, such as mint, sour, or sweet, may be used. According to one study, the mix of mint, licorice, and sucralose flavours successfully masks the bitter taste of diclofenac sodium. To distinguish between distinct flavours, electronic tongues are used. masked agents (TMAs) [9].

1. 1. 1. Colouring Agent-

In oral strips, when specific formulation ingredients or drugs are present in an insoluble or suspension form, pigments such as titanium dioxide or FD&C-approved colouring additives are added at amounts no more than 1%w/w. [9]

MECHANISM OF FILM FORMATION

A thin, transparent film is formed on the skin as the solvent in the film-forming system evaporates. The volatile components of the vehicle are lost after formulation application to the skin, which results in a significant alteration in the film forming system's composition and the formation of residual film on the skin's surface. The drug's concentration on the skin's surface increases during this process to the point of saturation and possibly even beyond super saturation. Supersaturation improves drug flow through the skin by increasing the formulation's thermodynamic activity without weakening the skin's barrier, which lessens side effects and irritation. One can utilise the modified version of Fick's law of diffusion to demonstrate supersaturation. Fick's law of diffusion equation:

                  "J"=DKCv/h

Where

J is the drug permeation rate (flux) per unit skin area per unit time.

D is the drug's diffusion coefficient.

Cv= medication concentration h is the diffusion barrier's thickness

It is clear from this equation that there is a proportionality between the drug's concentration and the rate of skin penetration. To show supersaturation, one can apply the modified version of Fick's law of diffusion. This equation makes it very evident that the rate of skin penetration and the drug's concentration are proportionate. However, if the drug entirely dissolves in the car, this is accurate. The following equation characterises the modified form of Fick's law of diffusion: ? D/?h = J, where ? represents the drug's thermodynamic activity in the membrane and a denotes the drug's thermodynamic activity in the formulation. According to this formula, the saturation-related thermodynamic activity of the system is directly associated with the drug's flow. Conversely, as super saturation increases, thermodynamic instability increases. FFS rapidly creates supersaturated systems via the human epidermis in vitro when applied to the patch (EVRA®). By forming the skin, the film resolves the instability problem. As a result, the enhanced formulations showed a higher penetration than the conventional patch.  The ethinyl ethinyl estradiol distribution efficiency of the film-forming solutions is higher than that of the commercial patch. An enhancer was used to study estradiol. The ethinyl estradiol permeation of the formulation provided approximately seven times the amount of ethinyl estradiol as the film-forming solution of the commercial patch, regardless of whether enhancer was used. Considering this, these techniques exhibit potential in comparison to the drug permeation enhancement systems that are in use today. [10].

PREFORMULATION STUDIES:

Formulation scientists first identify the physical, chemical, and mechanical properties of innovative therapeutic substances in order to design stable, secure, and efficient dosage forms. We call this procedure preformulation. The preformulation stage should ideally begin early in the discovery process in order to have the required physical and chemical data available to help with the identification of new chemical entities that join the development process. This evaluation also considered possible interactions with various inert compounds intended to be utilised in the final dosage form. The following facts must be considered.

Drug - Excipient Compatibility Study-

Practically every dosage form used in medicine requires an excipient. A stable and effective solid dosage form formulation requires the careful selection of excipients, which are additives made to a solid dosage form to promote the drug's uniform release and bioavailability, aid in administration, and shield it from degradation. The mixture was put through a 40# sieve after the API and excipients were carefully combined in the ratios shown in the table below. The liquid was filled into transparent glass vials, which were then charged to the previously stated stress condition and sealed with grey rubber stoppers and aluminium seals. API should be maintained in the same manner as samples, which should always be kept on file. Samples were taken out for analysis within two days of the sampling date in accordance with the compatibility research design. For a maximum of one month, physical observation should be done once every week. FTIR and DSC investigations were performed to determine whether the excipients and the drug are compatible.

FTIR Study-

Evaluations of Drug-Excipient Interactions by DSC Ropinirole hydrochloride DSC thermograms and its physical mixing with polymers were done to investigate possible interactions between the medication and the polymer (Pullulan, HPMC, PVA). The selected heating rate is from 50°C to 300°C at a rate of 20°C per minute using a Differential Scanning Calorimeter (Shimadzu Corporation, Japan).

ANALYTICAL METHOD DEVELOPMENT

Calibration curve of API [11].

FORMULATION METHODS [12]

Solvent casting, which entails dissolving medication, polymers, and water-soluble excipients in de-ionized water, is the most widely used method for creating ODFs. To create a homogenous mixture, high shear forces generated by a shear processor are then employed. The prepared solution is then put onto a petri plate and the solvent is exposed to a high temperature to allow it to dry, producing high-quality films. The solvent casting method was successfully used to produce an orodispersible film of tianeptine sodium using different grades of Lycoat and HPMC. When employing the solvent casting technique, film-forming polymer is usually steeped in the appropriate solvent for a whole night. The type of API required for ODF dictates the optimal solvent based on the API's significant physico-chemical properties, such as melting point, shear sensitivity, and polymorphic form. The drug's compatibility with the solvent and other excipients is taken into account before a formulation is finalised. Air bubble entrapment during formulation may result in fewer uniform films being created. As a result, the mixture is assisted in deaerating by use of a vacuum pump. Another effective method for producing the mosapride orodispersible film formulation was solvent casting.The viscosity of the solution to be poured is an important part of the casting process. Concentrations of pullulan ranging from 2% to 8% result in low viscosity solutions that make film casting easy.

Figure no 3 : Solvent casting method

Figure no 4 : Solvent Casting Method-Flow Chart

2. Semi-solid casting method-

 Flow map of semi-solid casting method is given below.

3. Hot melt extrusion

A mixture of medication, polymer, and excipients is extruded at a high temperature using the hot melt extrusion technique to generate a homogenous mass that is then casted to create smooth films. The processing of thermolabile materials is one of this method's primary drawbacks, despite the fact that it doesn't require the use of solvents because extrusion requires a high temperature.

Figure no 5 : Hot Melt Extrusion

Figure no 6 : Hot Melt Extrusion Method-Flow Chart

1. Solid dispersion extrusion-

It was possible to effectively turn domperidone into a solid dispersion by combining beta-cyclodextrin, PEG 400, and HPMC E15. The films were then made using the solid dispersion extrusion technique.

Figure no 7 : Solid dispersion method

Figure no 8 : Solid Dispersion Extrusion- Flow Chart

2. Rolling method-

Fig shows the plot of the rolling method. The prepared solution needs to have specific rheological properties in order for it to roll onto the drum. [12]

Figure no 9 : Rolling method

Figure no 10 : Rolling Method- Flow Chart

3. Spray technique

The drug substance, polymers, and all other excipients are dissolved in the proper solvent to produce a transparent solution. Then, this clear solution is sprayed onto the proper surfaces, which include glass, Teflon sheets, non-siliconized Kraft paper, and polyethylene film.

Figure no 11 : Spray Technique- Flow Chart