The Overall Review on Formulation, Evaluation and Different Types of Manufacturing of Oral Disintegrating Films

Oral administration is the most popular route because of the ease of ingestion, pain avoidance, versatility (to accommodate various types of drug candidates), and most importantly, patient compliance^.1 Also, solid oral delivery systems do not require sterile conditions and are thus less expensive to manufacture^.2 Several novel technologies for oral delivery have recently become available to address the physicochemical and pharmacokinetic characteristics of drugs while improving patient compliance.³The pharmaceutical sector is becoming increasingly interested in fast drug delivery systems. Without the use of water or chewing, these systems melt or disintegrate in about a minute. Recently, thin films that dissolve or disintegrate quickly in the buccal cavity have been proposed.⁴ Oral disintegrating films are new dose forms that dissolve or disintegrate in the mouth. The transdermal patch platform inspired the idea of films that dissolve in the mouth.⁵ Fast dissolving drug delivery systems were first created in the late 1970s as a substitute for tablets, capsules, and syrups for juvenile and geriatric patients who have difficulty ingesting standard oral solid dosage forms, as well as for travelling patients who do not have access to water.⁶ To satisfy this demand, orally dissolving tablets (ODTs) have arisen. Despite short dissolution or disintegration times, some patients' fears of swallowing solid dosage forms (tablets, capsules) and the risk of asphyxiation persist.⁷ In these situations, oral disintegrating film (ODF) drug delivery systems are a better option.⁸When placed on the tongue, orally disintegrating films (ODFs) quickly hydrate by soaking in saliva after disintegration and/or dissolution, releasing the active pharmacological drug from the dosage form.⁹ ODFs are formulations that are frequently made with hydrophilic polymers to allow for fast disintegration when exposed to saliva.¹⁰ A typical ODF is usually looking like postal stamp and having equal to the size of a postal stamp.¹¹ In market place, the introduction of ODT was strongly associated with counselling of patients about the appropriate administration by giving instruction like ‘‘do not chew/do not swallow’ ’oral disintegrating/dissolving films or strips can be defined as follows: “These are drug delivery systems that they are quickly releasing the drug by dissolving or adhering in the mucosa with saliva within a few seconds due to it contains water-soluble polymers when it placed in the mouth cavity or on the tongue”.¹²

Anatomy of oral cavity:

The structure and anatomy of oral cavity is studied for understanding the environment provided for delivering drugs.¹³ The oral mucosa allows direct access of drug to the systemic circulation and avoids first pass metabolism. The epithelium of the oral cavity is quite similar to that of the skin, with slight differences with regard to keratinization, protective and lubricant mucous which is spread across its surface.¹⁴ The permeability of oral mucosa is 4–1000 times greater than that of the skin. The oral cavity is divided into two regions: outer being the oral vestibule bounded by the lips and cheeks; the hard and soft palates, the floor of the mouth and tonsils.¹⁵ Oral drug delivery has been known for decades as the most widely utilized route of administration among all the routes that have been explored for the systemic delivery of drugs via various pharmaceutical products of different dosage forms.¹⁶

Advantages:

Rapid onset of action with increased bioavailability due to bypassing hepatic first pass effect and stability.¹⁷ Convenient for dysphasic patients having difficulty in swallowing tablets and capsules.¹⁸

Limitations:

1. Only administrated those drugs who are pharmacological effective at less dose.
2. Hygroscopic in nature so it can easily absorb the moisture.
3. Special packaging is required for long time preservation.¹⁹
4. A combination of more than one drug is very challenging in the ODF because they effect the dissolving and disintegration time of filming. Difficulty to distribute a uniform dose in every film.
5. Thermolabile drug are not easily load in the film because they cannot dry in hot oven or hot plate so they required alternative method of drying.²⁰

Formulation:

ODFs are thin, fast-dissolving films with a surface area ranging from 5 to 20 cm² in which the drug is integrated as a matrix using a hydrophilic polymer. Plasticizers, colourants, sweeteners, flavour masking agents, and other excipients can be added up to 15 mg of active pharmaceutical component.²¹

Ingredient Amount

1. Drug (API) 5-30%

2. Water soluble polymer 45%

3. Plasticizer 0-20%

4. Saliva stimulating agent 2-6%

5. Surfactant Q.S.

6. Sweetening agent 3-6%

7. Flavours, colours, fillers Q.S.²²

Active pharmaceutical ingredient:

The film composition contains 5-30% w/w of the active pharmaceutical ingredient. This technology is capable of delivering a diverse set of APIs.²³ A number of drugs can be used as oral disintegrating film including anti-histamines, anti-diarrheal, anti-depressants, vasodilators, anti-asthmatics, anti-emetic medicines, and so on.²⁴

Film Forming Polymers:

Polymers that dissolve in water are utilized as film formers. They help films disintegrate quickly, provide a good mouthfeel, and offer strong mechanical strength.²⁵ The strip's toughness depends on the polymer type and amount used. Water-soluble polymeric films bind to the buccal mucosa and rapidly deliver medication into the bloodstream.²⁶ Pullulan, gelatin, and Hypromellose are commonly used for film preparation. Typically, dry films contain 45% polymer by weight. This can be increased to 60–65% w/w to achieve desired film properties. The polymer used in thin strip formulations should have specific qualities.²⁷

Plasticizers:

A plasticizer improves the spreadability, flexibility, elongation, and tensile strength of polymers by lowering their glass transition temperature. Common plasticizers include glycerol, propylene glycol, PEG, dimethyl, and castor oil.²⁸

Sweetening agents:

Natural and artificial sweeteners are employed to increase the palatability of oral dissolving formulations.²⁹ Sweetening chemicals are designed to crumble or disperse in the tongue. ODFs are made with both artificial and natural sweeteners. Sweeteners and flavours are also said to have a modest impact on film elasticity.³⁰

Surfactants:

Surfactants are employed as a wetting, solubilizing, or dispersing agent to breakdown the film quickly and release the active ingredient.³¹ Commonly employed are poloxamer 407, benzethonium chloride, sodium lauryl sulfate, tweens, etc. poloxamer 407 is mostly used in formulations.³²

Saliva stimulating agent:

Saliva stimulating agents are used to enhance the rate at which saliva is produced, which helps in the faster dissolution of film formulations.³³ Salivary stimulants are typically acidic and help accelerate the disintegration of ODFs by enhancing saliva secretion in the buccal cavity. Commonly used salivary stimulants include citric acid, malic acid, tartaric acid, ascorbic acid, and lactic acid.³⁴

Flavoring agents:

Flavors help mask the bitter and unpleasant taste of the API. Selection depends on taste, preference, and user age. Children prefer fruit punch and raspberry, while older adults favor orange, lemon, and mint. Cooling agents can enhance the flavor.³⁵

Colouring agents:

Pigments serve as coloring substances. Titanium dioxide or approved by FD&C.Coloring substances are dissolved (not surpassing concentration levels of 1% w/w) in ODF.³⁶   Formulation when certain ingredients or medications within the formulation are found in an insoluble or suspension form.³⁷

Manufacturing Methods³⁸

The ODF can be made using one or a combination of the following procedures:

A. Solvent casting method

B. Hot-melt extrusion

C. Semisolid casting

D. Solid dispersion extrusion

E. Rolling

F. Spray technique

G. Printing method

Solvent Casting Method:

This method is used because no special equipment is necessary and it is easy and straightforward, for preparing ODF. The API and excipient mixture are cast onto a surface, dried, and cut into the desired size. The API, polymer, and plasticizer suspension must be degassed to achieve a homogeneous film thickness and thickness.³⁹ After that, the suspension is vacuumed to eliminate any trapped air bubbles before being transferred to a petri dish or Teflon plate and dried. There are some parameters like the temperature of the drying process must be kept under control.⁴⁰ If a thermosensitive API is included in the formulation, a low temperature should be employed to get the desired viscosity.⁴¹The ODF produced via the solvent casting method may have poor production levels, environmental issues, and instability brought on by uncontrollable factors, including Moisture absorption or loss, Polymer chain relaxation, Polymer-Plasticizer interaction during storage.⁴²

Hot-Melt Extrusion (HME)

HME has been employed in the pharmaceutical industry since the early 1980s. It is commonly utilised in drug delivery systems such as prolonged release tablets, granules, transmucosal, and transdermal. HME (Hot Melt Extrusion) is a continuous processing method used in pharmaceuticals.⁴³ A desired medication release profile can be established using API-polymer mixtures. Films prepared through this method have better content uniformity. There are fewer steps involved in the time-consuming processing and drying processes.⁴⁴  The vigorous blending and stirring generated by the rotating screw lead to deaggregation  of suspended particles leading to more consistent distribution and the procedure is ongoing and effective In hot melt extrusion method, firstly the drug is mixed with carriers without any use of solvent, in solid form.⁴⁵ Then the extruder consisting of heaters are used to melt the mixture. Finally, the melted mixture is given the shape of films with the help of dies.⁴⁶

ADVANTAGES:

• There are fewer operational units.
• Scale-up capabilities
• Efficacy of solubility augmentation for poorly soluble APIs
• No need for solvent or water
• Compressibility characteristics of the API may not be important
• Intense mixing and agitation result in a more uniform dispersion of fine particles.⁴⁷

DISADVANTAGES:

• Limited number of available polymers
• Flow characteristics of polymer are crucial for processing
• Costly and requiring sophisticated equipment
• Stability difficulties emerge in medication or polymer due to thermal process.⁴⁸

Semi Solid Casting Method                                    

Semi-solid casting is a new technology that combines the benefits of casting and forging to create complex-shade components. Although this approach is comparable to the solvent casting method above, it requires two major polymers, hydrophilic and hydrophobic polymers.⁴⁹To begin, make a solution with a water-soluble film-forming polymer. After that, a solution containing an acid-insoluble polymer, such as cellulose acetate phthalate or cellulose acetate butyrate, in ammonium or sodium hydroxide, is mixed with the gel mass of the solution. ⁵⁰A 1:4 solution ratio of soluble film-forming polymer to acid insoluble polymer is required. The gel mass is ultimately cast using a heat-controlling chemical. The film has a thickness of 0.015–0.05 inches.⁵¹

Solid Dispersion Extrusion

Solid dispersion in water soluble carriers has attracted a lot of attention in order to improve the dissolution rate and bioavailability of hydrophobic drugs, as illustrated below.⁵² An appropriate dispersion can be made into a solid dispersion without the need for a liquid solvent. This approach involves dissolving one or more APIs in a suitable solvent and incorporating them into polyols such as melted PEG.⁵³

Rolling Method

To use the rolling method, first make a suspension using water, a film-forming polymer, a water-alcohol mixture, and other excipients (except APIs) while processing rheological characteristics.⁵⁴ After that, the prepared suspension flowed through the metering roller. The amount of suspension in the roller is controlled by a metering pump and a control valve, and it moves indefinitely to the mixers.⁵⁵Through the metering pump, the API is now added to the suspension mixture. The film thickness is established by the metering roller, and it is applied by the applicator roller.Finally, the film is created, and the backing roller is used to transport it.⁵⁶ After that, the film is dried using a controlled bottom drying method in the absence of external air and film on the surface of the film.⁵⁷

Spray technique

To make a clear solution, the drug ingredient, polymers, and other excipients are dissolved in a suitable solvent. This clear solution is then sprayed onto a suitable surface, such as glass, non-siliconized Kraft paper, polyethylene film, or Teflon Sheet.⁵⁸

Printing Method

The above methods, such as hot-melt extrusion and solvent casting, require the drug and polymer to be mixed and formed into a film.⁵⁹ As a result, the mechanical properties of the films produced by both methods change depending on the physicochemical properties of the APIs and are limited by production speed. In the event of unstable APIs, mixing and drying may be problematic.This technology offers an option by writing APIs on the film layer's substrate.⁶⁰

Printing method is divided in two methods are

• Inkjet printing
• Flexographic printing
• Inkjet printing can accurately distribute powerful or low-dose APIs, but it is not appropriate for high film production.⁶¹

Flexographic printing is an "offset rotary printing method" in which API-staining ink is applied to a roller, which is then transferred to a printing cylinder, which prints the drug-free film.⁶²

• 3D printing technology has just been invented, and it has the potential to play an essential role in future development.⁶³

Packaging of Thin Film

In pharmaceutical industries, the selection of packaging has an important role in preserving the intrigrity of drugs and exceptions. In the case of thin film, special care is required during storage, in-process, and manufacturing. Because the film is made of hydro flick polymers, it easily absorbs moisture.⁶⁴ The film should be packed in an airtight container or pouch so they do not absorb the moisture and the films are not degraded. In response to the last dissent, aluminium foil is widely used as a packaging material. But nowadays, various types of material are used for packaging of thin films like plastic pouches, blister cards, foils, and papers.⁶⁵

1) Plastic Pouch

The flexible pouches are commonly used for single strips, but sometimes they are used for two or three strips packed in one pouch. The plastic pouch has lots of benefits, like low packaging cost, easy filling, easy to handle, and light weight. But plastic pouches are not environmentally friendly. It pollutes the environment.⁶⁶

2) Plastic box

Plastic boxes are used for the packaging of multiple films in one packet. Ten to fifteen films should be packed into one box. It reduces the packaging cost and is environmentally friendly. However, they shouldn't adhere to one another.⁶⁷

3) Blister

It consists of two components. First one is blister who have cavity for holding the strips and second one is lid stock that shield the blister. The lid stock is made from plastic and cavity are made from plastic.⁶⁸

Evolution Parameters of Film:

Weight variation:

The ODFs were weighed on an analytical scale, and the average weight for each film was computed. It is preferable for films to have a uniform weight. It's critical to check that a film has the appropriate number of excipients and API.⁶⁹

Thickness of film:

The thickness of a film is measured with a calibrated digital micrometre, and then a mean average is determined. Three readings from each batch are usually taken, and an average is calculated.⁷⁰

Folding endurance:

Another approach for determining a film's mechanical qualities is folding endurance. It's calculated by repeatedly folding a film at the same location until it breaks. The "folding endurance value" refers to how many times the film can be folded without breaking.⁷¹

Tensile strength:

The highest stress applied to a place where the strip specimen breaks is called tensile strength. The purpose of this test is to determine the mechanical strength of films. The applied load at rupture is divided by the strip’s cross-sectional area, as shown in the following equation:⁷²

Tensile strength = Load at failure × 100/film thickness × film width

Percent Elongation

When a film sample is stressed, it stretches, which is referred to as strain. Strain is defined as the deformation of a film divided by the sample's original dimension. In general, as the plasticizer content increases, film elongation increases.⁷³

The following formula is used to calculate it:

% Elongation = Increase in length× 100/ Initial length of film 

 Drug content uniformity:

The content uniformity test ensures that each film includes the same quantity of drug material as the previous one, with little fluctuation across films within the same film. Three portions were clipped from the whole film, each measuring 4 cm2 (2 cm × 2 cm) and tested for drug content. The mean and standard deviation measurements were used to determine content uniformity.⁷⁴

 Surface pH of film:

The pH of ODF's surface was measured to see whether there were any potential adverse effects. Because an acidic or alkaline pH might irritate the oral mucosa, it was decided that the surface pH should be kept as near to neutral as feasible. A mixed pH electrode was employed for this. With the assistance of water, the oral strip was gently moistened. The pH was determined by placing the electrode on the oral film's surface. The trials were carried out three times, and the average results were given.⁷⁵

Disintegration time:

The disintegration time was determined as the amount of time needed for ODF to totally break down, leaving no visible solid remnant on the screen. The disintegration time was determined as the amount of time needed for ODF to totally break down, leaving no visible solid remnant on the screen. The disintegration period often varies with formulation and ranges from 5 to 30 seconds depending on the film's composition.⁷⁶

In-vitro dissolution test:

Dissolution studies on films are carried out using standard official basket or paddle apparatus. Throughout dissolution, sink conditions should be preserved. Film may occasionally float over the medium during this process, making it challenging to do the test correctly. Since the paddle approach is more likely to induce this issue, the basket equipment is typically selected.⁷⁷ 6.8 pH phosphate buffer media are employed. The rotation speed is often regulated to 50 rpm while the temperature is kept at 37± 0.5°C. At certain intervals, dissolved drug sample samples are collected and subjected to UV spectrophotometer analysis. Dissolution tests continue to have significant accuracy and test failure issues despite their widespread use.⁷⁸

Swelling property:

Studies on film swelling are carried out with stimulated saliva solution. Each film sample is weighed and set inside a stainless-steel wire mesh that has been pre-weighted. A 15ml medium in a plastic container is added to the mesh containing the film sample. But until a steady weight was noticed, the film's weight increased at predetermined intervals. The degree of swelling was calculated by using following formula⁷⁹

Degree of swelling = final weight(w_t) – initial weight (w₀)/initial weight (w₀)

w_t = weight of film at time interval t; w₀= weight of film at time 0.

Stability Testing

Stability measurement is done by storing the of oral strip were stored under controlled conditions of 25ºC/60% RH as well as 40°C/75% RH over a period of 12 months in stability chamber according to the ICH guideline. The thickness, morphological characteristics, tensile strength, water content, and dissolving behaviour of the material are all evaluated over the storage time.⁸⁰

SEM analysis

Scanning electron microscopy (SEM) was used to examine the morphology of the oral strip at a specific magnification. The distinction between the upper and lower sides of the films is discussed in the study. It aids in figuring out how the API is distributed.⁸¹

 CONCLUSION:

Oral disintegrating films (ODFs) represent a promising and patient-friendly drug delivery system that combines convenience, rapid onset of action, and improved compliance, particularly among pediatric, geriatric, and dysphagic populations. Advances in formulation techniques, film-forming polymers, and incorporation of a wide range of active pharmaceutical ingredients have broadened their applicability in both prescription and over-the-counter medications. Despite challenges in achieving optimal drug loading, stability, and taste masking, continuous research and technological innovations are paving the way for more efficient and commercially viable ODF products.

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