A Seminar on

Films and Strips: formulation, manufacturing & evaluation

Keyur Vasava.

Contents Introduction Advantages and Disadvantages Types of films Formulation aspects of films Manufacturing method Factors affecting manufacturing of film/strip Evaluation Conclusion References

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Introduction
Pharmaceutical film or strip is the thin, flexible solid unit dosage form meant to use for either local or systemic action. They are either orodissolving or transdermal. They are made either fast dissolving or slow dissolving for sustain release. Mouth dissolving films, a new drug delivery system for the oral delivery of the drugs, was developed based on the technology of the transdermal patch. The delivery system consists of a very thin oral strip, which is simply placed on the patient s tongue or any oral mucosal tissue, instantly wet by saliva the film rapidly hydrates and adheres onto the site of application. Transdermal films are slow releasing for sustain release of medicament while oral dissolving films are use for both fast dissolving and slow release of drug in buccal cavity. Among these two oral dissolving films are widely used in market. Technology Catalysts forecasts the market for drug products in oral thin film formulations to be valued at $500 million in 2007 and could reach $2 billion by 2010. Rapidly dissolving dosage forms have acquired great importance in the pharmaceutical industry because of their unique properties. Rapidly dissolving dosage forms are also called quick-dissolving delivery systems; quick-disintegrating, orally disintegrating, mouth dissolve dosage forms; or melt-in-mouth dosage forms, Rapidfilm, fast dissolving film, oral disintegrating film (ODF), Oral thin film (OTF), and Rapid dissolving film (RDF). In less than one minute, these dosage forms disintegrate or dissolve in the salivary fluids of the oral cavity, releasing the drug and inactive ingredients. Most of the drug is swallowed with the saliva where subsequent absorption takes place in the gastrointestinal tract. The advantages of OST (oral soluble thin film) are the administration to paediatric and geriatric patient population where the difficulty of swallowing larger oral dosage forms is eliminated. This technology has been used for local action, rapid release products and for buccoadhesive systems that are retained for longer period in the oral cavity to release drug in controlled fashion. OST offers an alternate platform for molecules that undergo first pass metabolism and for delivery of peptides.

This dosage form has following distinct advantages over other formulations such as:

I. Oral soluble thin film:

General advantages: For patients, the main benefit of RDF is the ease of taking a product that tastes good, anywhere, anytime. RDF have many advantages over other dosage forms such as effervescent tablets, dry syrup, oral disintegrating tablet, chewing gum or chewable tablets which are commonly used to enhance patient compliance. 1. Availability of larger surface area that leads to rapid disintegrating and dissolution in the oral cavity.
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2. The disadvantage of most oral dissolving tablets (ODT) is that they are fragile and brittle which warrants special package for protection during storage and transportation. Since the films are flexible they are not as fragile as most of the ODTs. Hence, there is ease of transportation and during consumer handling and storage. 3. As compared to drops, syrup, gels, creams or lotions etc. formulations, precision in the administered dose is ensured from each of the strips. Patient related advantages 1. Convenient and easy to administer as it does not require water for administration yet it disintegrates and dissolves in mouth with in fraction of seconds. Therefore, a major benefit for people using RDF products for as needed conditions such as seasonal allergies, migraines, etc, is the ability to take the medication when they are not near a suitable drinking supply. 2. Improved compliance for patients suffering from Dysphagia (disorder of difficulty in swallowing). 3. Pleasant mouth feel and non grittiness. Medication as bitter pill has changed by excellent mouth feel property produced by use of sweeteners and flavors in RDF. 4. Ease of administration for paediatric, geriatric, travelling and institutionalized patients (especially for mentally challenged and psychiatric patients). Clinical advantages 1. Rapid disintegration of film results in quick dissolution and rapid absorption which provides rapid onset of action. 2. Bioavailability of drugs that are absorbed from mouth, pharynx and esophagus is increased. 3. Pregastric absorption of drugs avoids hepatic metabolism which reduces the dose. This in turn reduces adverse drug reactions (ADRs). 4. Combines benefits of liquid formulations with that of solid dosage form. Technical advantages 1. Provides good stability, accurate dosing, easy manufacturing, small packaging size and easy handling by patients. 2. Can be adaptable and amenable to existing processing and packaging machinery. 3. Excipients required are relatively safe, economic and easily available. 4. Compatible with taste masking techniques. Economic and business related advantages 1. 2. 3. 4. Unique product differentiation in market. Provides value added product line extension. Extended patent protection. Life-cycle management of existing products.

II.

Transdermal film:
1. Since the first pass effect can be avoided, there can be reduction in the dose which can lead to reduction in side effects associated with the molecule hence dose can be reduced. Sometimes due to adverse reaction, we have to terminate the therapy which is difficult in other sustain release formulation but can be applicable in transdermal film.

2.

Disadvantages:
I. Oral dissolving film: 1. Buccal delivery route has the low flux that in turn results in low drug bioavailability and the constant salivary secretion within the oral cavity makes it quite difficult for dosage forms to be retained for long periods of time. 2. Accidental swallowing of dosage forms and salivary scavenging is another limitation in buccal delivery systems. 3. Drugs which are very bitter or otherwise have unacceptable taste are difficult to formulate as OTF because they have to be first taste masked. 4. Drug should be stable in water because organic solvents are not preferred for oral dissolving film.

II.

Transdermal film
1. Highly organized stratum corneum is the big headache for several drugs to be penetrated in transdermal route. 2. Tolerance development is a big challenge to this technique.

III.

General disadvantages:
1. It is difficult to prove bioequivalence with the conventional tablets and capsules for certain drugs which are extensively absorbed through pregastric route. 2. OTFs generally accommodate only a small dose of drugs from 1mg to 20 mg. High dose cannot be incorporated into the strip. 3. This requires several physicochemical properties of drugs like short half life (for transdermal film), low dose, small molecular size etc.

A number of molecules can be incorporated into this delivery system. They may include cough/cold remedies (antitussives, expectorants), sore throat, penis erectile dysfunction drugs, antihistaminics, antiasthmatics, gastrointestinal disorders, nausea, pain and CNS (e.g.
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anti-parkinsons disease). Other applications comprise caffeine strips, snoring aid, multivitamins, sleeping aid etc.

Types of film/strip
There are mainly three types available. 1. Oral fast dissolving: It is made to dissolve in mouth in fraction of seconds. Most of available marketed preparations are mouth freshener strips. However there are few medicated preparations are also available. E.g. Benzocain containing wafers for sore throat. 2. Buccal slow release film: It releases drug for 4-5 hr for prolong action in buccal cavity either locally or systematically. E.g. Metronidazole buccal patch. 3. Transdermal patch: It includes sustain release films for prolong action. E.g. Papverin transdermal patches.

Formulation aspects
1. Orodissolving film:
Formulation of films involves characteristics such as taste masking, fast dissolving, physical appearance, mouth-feel etc. The excipients used in formulation of films are given below as per their categories. From the regulatory perspectives, all excipients used in the formulation of OS should be Generally Regarded as Safe (i.e. GRAS-listed) and should be approved for use in oral pharmaceutical dosage forms.

a. Active pharmaceutical ingredient:

The film technology has the potential for delivery of variety of APIs. However since the size of the dosage form has limitation, high dose molecules are difficult to be incorporated in film. Generally 5%w/w to 30%w/w of active pharmaceutical ingredients can be incorporated in the film. Multivitamins up to 10%w/w of dry film weight was incorporated in the film with dissolution time of less than 60sec. Water soluble APIs are present in the dissolved state in the films or in the solid solution form, the water insoluble drugs are dispersed uniformly in the strip. The distribution of water insoluble molecules in water miscible polymer becomes important from the large scale manufacture point of view. APIs can also be added as milled, micronized or in the form of nanocrystals, liposomes, niosomes or particles depending upon the ultimate release profile desired. Micronized API will improve the texture of the film and also for better dissolution and uniformity in the films.

Many APIs, have bitter taste. This makes the formulation unpalatable especially for paediatric preparations. Thus, taste needs to be masked. Various methods can be used to improve the palatability of the formulation. Among the techniques employed, the simplest method involves the mixing and co-processing of bitter tasting API with excipients with sweet taste. This is often termed as obscuration technique. Barrier technologies that can be used to mask the bitter taste include complexation, polymeric coating, conversion into microparticles/microcapsules, coated particles or coated granules. However, in the cases where the drug is encapsulated, the fast release of medicament will not be achieved. Depending on the material employed in encapsulation and the manufacturing technique, the rate of drug release varies. The taste masking product must not affect the bioavailability of the drug confirming the potential of the developed technology. E.g. MonosolRx technology utilizes particulate technology approach for preparation of taste masked product to be incorporated in the film. See Table-1 for examples.

b. Strip forming polymers:

A variety of polymers are available for preparation of film. The polymers can be used alone or in combination to obtain the desired strip properties. The film obtained should be tough enough so that there won't be any damage while handling or during transportation. The robustness of the strip depends on the type of polymer and the amount in the formulation. Fast dissolving strip dosage form should have the property to disintegrate in seconds when placed in mouth and deliver the drug to the oral cavity instantaneously. As the strip forming polymer (which forms the platform for the film) is the most essential and major component of the film, at least 45%w/w of polymer should generally be present based on the total weight of dry film. Various polymers available pullulan, PVA, gelatin, PVP, hypromellose are most commonly used for preparation of films. Pullulan is a natural polymer obtained from non-animal origin and does not require chemical modification. This polymer provides highly clear and homogenous films. It has low oxygen permeability and low water content which makes it most suitable for production of orodissolve film. Modified starches are also used for preparation of orodissolving. Due to low cost of this excipient it is used in combination of pullulan to decrease the overall cost of the product. About 50 to 80%w/w of pullulan can be replaced by starch in the production of orodissolving film without loss of required properties of Pullulan. Typically 60 to 65%w/w of water soluble polymer is preferred for preparation of film with desired properties.

Many times, mixtures of polymers are used to improve hydrophilicity, flexibility, mouth-feel and solubility characteristics of film. Polyvinyl pyrrolidone (PVP) films are brittle in nature and therefore copovidone is mixed with PVP for preparation of flexible fast disintegrating strips. Combination of microcrystalline cellulose and maltodextrin has been used to formulate film of piroxicam. In this case, microcrystalline cellulose is used to render the film non-sticky and smooth. Microcrystalline cellulose was also used to decrease the disintegration time and improve the dissolution of drug from the film. The polymer employed should be non-toxic, non-irritant and devoid of leachable impurities. It should have good wetting and spreadability property. The polymer should exhibit sufficient peel, shear and tensile strengths. The polymer should be readily available and should not be very expensive. Various polymers can be employed to modulate the disintegration property of the oral strip. This is especially used in case of slowly disintegrable oral bioadhesive strips or patches that need to be retained in intact form for longer duration in the oral cavity. The bioadhesive polymer used in such formulations imparts the adhesive property to the strip such that it adheres to buccal mucosa to deliver the drug for prolonged period. Bioadhesive polymer should ideally adhere quickly to the buccal mucosa and should have sufficient mechanical strength. They should have good shelf life and not cause secondary infections in the oral mucosa or dental regions. It would be ideal to have a polymer that would have local enzyme inhibition action along with penetration enhancing property. Mucoadhesive polymers include polycarbophil, cellulose derivatives like hydroxylpropyl methylcellulose, poly(acrylic acid) derivatives, sodium carboxymethyl cellulose, hydroxyl ethyl cellulose, hyaluronic acid, xanthan gum, locust bean gum, guar gum, carrageenan, sodium alginate, chitosan, poly (ethylene oxide), poly (ortho esters), poly (hydroxyl butyrate), poly (cyano acrylates), polyphosphazenes, poly (vinyl alcohol) etc. Second generation mucoadhesive polymers include thiolated polymers. Canker Cover is a tablet-like patch that is used in the treatment of canker sore. It adheres to the canker sores and lasts for 812 h. It forms a clear gel patch after application.

c. Plasticizers:
Plasticizer is a vital ingredient of the oral soluble formulation. It helps to improve the flexibility of the strip and reduces the brittleness of the strip. Plasticizer significantly improves the strip properties by reducing the glass transition temperature of the polymer. The selection of plasticizer will depend
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upon its compatibility with the polymer and also the type of solvent employed in the casting of strip. Glycerol, Propylene glycol, low molecular weight polyethylene glycols, phthalate derivatives like dimethyl, diethyl and dibutyl phthalate, Citrate derivatives such as tributyl, triethyl, acetyl citrate, triacetin and castor oil are some of the commonly used plasticizer excipients. Typically the plasticizers are used in the concentration of 020%w/w of dry polymer weight. However inappropriate use of plasticizer may lead to film cracking, splitting and peeling of the strip. It is also reported that the use of certain plasticizers may also affect the absorption rate of the drug. The Plasticizer employed should impart the permanent flexibility to the strip and it depends on the volatile nature plasticizer and the type of interaction with the polymer. It should be noted that the properties of plasticizer are important to decrease the glass transition temperature of polymer in the range of 4060 C for non aqueous solvent system and below 75 C for aqueous systems. Plasticizer should be compatible with drug as well as other excipients used for preparation of strip. It was observed that malic acid was found to be better plasticizer as compared to citric acid, oleic acid and tartaric acid as it did not crystallize out when the strips were dried. Amongst the different grades of polyethylene glycol (PEG); PEG 300 was found to be better plasticizer for gelatin as compared to higher molecular weight PEG. This is because lower molecular weight PEG formed visually superior films and had low water vapour permeation rate. When sugars like mannitol and sorbitol were tested as plasticizers for gelatin strips, sorbitol was found to be better as compared to mannitol since mannitol crystallizes out from the gelatin strip. Maltodextrin can also be plasticized and converted into films with incorporation of glycerine and propylene glycol as plasticizer in the concentration range of 1620%w/w. namely internal plasticization (involving chemical interaction) and external plasticizing effect. The latter mechanism is preferred, as it does not involve chemical interactive alterations in the product. E.g. of internal plasticization is where PEG 4000 was used as plasticizer for Phenobarbital where the drug release was reduced to considerable extent.

There are two mechanisms propagated of how the plasticization takes place

d. Sweetening agents:
Sweeteners have become the important part of the food products as well as pharmaceutical products intended to be disintegrated or dissolved in the oral cavity. The sweet taste in formulation is more important in case of paediatric population. Natural sweeteners as well as artificial sweeteners are used to improve the palatability of the mouth dissolving formulations.

 Generally sweeteners are used in the concentration of 3 to 6 %w/w either alone or in combination. The classical source of sweetener is sucrose, dextrose, fructose, glucose, liquid glucose and maltose. The sweetness of fructose is perceived rapidly in the mouth as compared to sucrose and dextrose. Fructose is sweeter than sorbitol and mannitol and thus used widely as a sweetener. Polyhydric alcohols such as sorbitol, mannitol, isomalt and maltitol can be used in combination as they additionally provide good mouth-feel and cooling sensation. Polyhydric alcohols are also less carcinogenic and do not have bitter after taste which is a vital aspect in formulating oral preparations. The sweetness property of most of the polyols is less than half of that of sucrose except xylitol and maltitol which have similar sweetness as that of sucrose (scale of 0.81.0). Natural sugars in such preparations need to be restricted in people who are on diet or in the case of diabetic patients. Due to this reason, the artificial sweeteners have gained more popularity in food and pharmaceutical preparations. Saccharin, cyclamate and aspartame are the first generation of the artificial sweeteners followed by acesulfame-K, sucralose, alitame and neotame which are second generation artificial sweeteners. E.g. strip of piroxicam, maltodextrin was employed as sweetening agent.

e. Flavoring agents:
Perception for the flavors changes from individual to individual depending upon the ethnicity and liking. Age plays a significant role in the taste likeliness. The geriatric population like mint or orange flavors while younger generation like flavors like fruit punch, raspberry etc. The selection of flavor is also dependant on the type of drug to be incorporated in the formulation. E.g. mint flavor is generally added in products used for gastric related ailments like indigestion. The acceptance of the oral disintegrating or dissolving formulation by an individual by and large depends on the initial flavor quality which is observed in first few seconds after the product has been consumed and the after taste of the formulation which lasts for at least about 10 min. Flavoring agents can be selected from synthetic flavor oils, oleo resins, extract derived from various parts of the plants like leaves, fruits and flowers. Flavors can be used alone or in the combination. Peppermint oil, cinnamon oil, spearmint oil, oil of nutmeg are examples of flavor oils while vanilla, cocoa, coffee, chocolate and citrus are fruity flavors. Apple, raspberry, cherry, pineapple are few examples of fruit essence type. The amount of flavor needed to mask the taste depends on the flavor type and its strength. Preferably up to 10%w/w flavors are added in the film formulations. Cooling agents like monomethyl succinate can be added to improve the flavor strength and to enhance the mouth-feel effect of the product.
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 Other cooling agents like WS3, WS23 and Utracoll II can also be used in conjunction with flavors.

f. Colouring agents: Pigments such as titanium dioxide or FD&C approved coloring agents are
incorporated (not exceeding concentration levels of 1%w/w) in OS when some of the formulation ingredients or drugs are present in insoluble or suspension form.

g. Saliva stimulating agent:

The purpose of using saliva stimulating agents is to increase the rate of production of saliva that would aid in the faster disintegration of the rapid dissolving strip formulations. Generally acids which are used in the preparation of food can be utilized as salivary stimulants. E.g. Citric acid, malic acid, lactic acid, ascorbic acid and tartaric acid. Citric acid being the most preferred amongst them. These agents are used alone or in combination between 2 to 6%w/w of weight of the strip. Other film ingredients such as sweeteners also act as salivary stimulants. Food grade sugars as well as synthetic sugars are useful salivary stimulants along with acidulents. Glucose, fructose, xylose, maltose, lactose are few examples of such sweeteners. The stimulation of salivation can be measured by comparing the amount of resting flow and stimulated flow at equal time under same conditions. The comparison between the salivary stimulation using citric acid and other sugars is given in. The stimulant action of sweeteners is dependent on the sweetness value. Fructose has the sweetness value of 1.1 as compared to 0.7 of glucose and 1.0 of sucrose. The artificial sweetener is preferred over natural sugars because lower concentration is required and multiple uses don't result in dental caries in individuals.

h. Stabilizing and thickening agents: The stabilizing and thickening agents are employed to improve the viscosity
and consistency of dispersion or solution of the strip preparation solution or suspension before casting. Natural gums like xanthan gum, locust bean gum, carrageenan and cellulosic derivatives can be used in the concentration up to 5%w/w as thickening agents and stabilizing agents. Other ingredients such as surfactants and emulsifying agents are also added in small amount to improve the strip properties.

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2. Transdermal film:
This formulation also includes the same basic ingredients for film formation like, film forming polymers, film stabilizers, thickening agents and plasticizers. It does not include organoleptic ingredients and saliva stimulating agents. Apart from these, it includes following ingredients.

a. Active pharmaceutical ingredient:

The drug should be potent with a daily dose of the order of few mg/day. Since the size of the dosage form has limitation, high dose molecules are difficult to be incorporated in film. Generally 5%w/w to 30%w/w of active pharmaceutical ingredients can be incorporated in the film however now upto 62.5% API may be incorporated. The half life (t1/2) should be short to avoid toxicity in case of sustain release formulation and drug must not induce cuteneous irritant or allergic response The tolerance to the drug must not develop under the near zero-order release profile of transdermal delivery. It should have molecular weight less than 1000 dalton for transdermal application. Depending on the material employed in encapsulation and the manufacturing technique, the rate of drug release varies. In this type of film both water soluble and organic solvent soluble drugs can be used. See the Table-1

b. Permeation Enhancer:
These are compounds which promote skin permeability by altering the skin as a barrier to the flux of a desired penetrant. Permeation enhancers are hypothesized to affect one or more of layers of skin to achieve penetration enhancement. A large number of compounds have been investigated for their ability to enhance stratum corneum permeability. These may conveniently be classified under the following main headings:

Solvents These compounds increase penetration possibly by swelling the polar pathway and/or by fluidizing lipid. Examples include water, alcohols methanol and ethanol; alkyl methyl sulfoxides dimethyl sulfoxide, alkyl homologs of methyl sulfoxide, dimethyl acetamide and dimethyl formamide; pyrrolidones 2-pyrrolidone, N-methyl, 2-pyrrolidone; laurocapram, miscellaneous solvents- propylene glycol, glycerol, silicone fluids, isopropyl palmitate. Surfactants These compounds are proposed to enhance polar pathway transport, especially of hydrophilic drugs. The ability of a surfactant to alter
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penetration is a function of the polar head group and the hydrocarbon chain length. These compounds are, however skin irritants, therefore, a balance between penetration enhancement and irritation has to be considered. Anionic surfactants can penetrate and interact strongly with the skin. Once these surfactants have penetrated the skin, they can induce large alterations. Cationic surfactants are reported more irritant than the anionic surfactants and they have not been widely studied as skin permeation enhancers. Of the three major classes of surfactants, the nonionics have long been recognized as those with the least potential for irritation. Examples of commonly used surfactants are: Anionic Surfactants Dioctyl sulphosuccinate, sodium lauryl sulphate, dedodecylmethyl sulphoxide, etc. Nonionic Surfactants Pluronic F127, Pluronic F68, etc. Bile salts Sodium taurocholate, sodium deoxycholate, sodium tauroglycocholate. Binary systems These system apparently open up the heterogeneous multivitaminate pathways as well as continuous pathways. E.g. propylene glycol-oleic acid and 1, 4-butane diol-linoleic acid.

c. Pressure sensitive adhesives:

This is a material that helps in maintaining an intimate contact between transdermal system and the skin surface. It should adhere with not more than applied finger pressure, be aggressively and permanently tachy, and exert a strong holding force. Additionally, it should be removable from the smooth surface without leaving a residue. Polyacrylates, polyisobutylene and silicon based adhesives are widely used in TDDS. The selection of an adhesive is based on numerous factors, including the patch design and drug formulation. For matrix systems with a peripheral adhesive, an incidental contact between the adhesive and the drug and penetration enhancer should not cause instability of the drug, penetration enhancer or the adhesive. In case of reservoir systems that include a face adhesive, the diffusing drug must not affect the adhesive. In case of drug-in-adhesive matrix systems, the selection will be based on the rate at which the drug and the penetration enhancer will diffuse through the

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adhesive. Ideally, adhesives should be physicochemically and biologically compatible and should not alter drug release

d. Backing layer: They are flexible and provide a good bond to the reservoir, prevent drug from
leaving the dosage form through the top, and accept printing. It is impermeable substance that protects the product during use on the skin e.g. metallic plastic laminate, plastic backing with absorbent pad and occlusive base plate (aluminium foil), adhesive foam pad (flexible polyurethane) with occlusive base plate (aluminium foil disc) etc.

e. Release Liner:

During storage the patch is covered by a protective liner that is removed and discharged immediately before the application of the patch to skin. It is therefore regarded as a part of the primary packaging material rather than a part of dosage form for delivering the drug. However, as the liner is in intimate contact with the delivery system, it should comply with specific requirements regarding chemical inertness and permeation to the drug, penetration enhancer and water. Typically, release liner is composed of a base layer which may be non-occlusive (e.g. paper fabric) or occlusive (e.g. polyethylene, polyvinylchloride) and a release coating layer made up of silicon or teflon. Other materials used for TDDS release liner include polyester foil and metalized laminates.

f. Solvents:

Various solvents such as chloroform, methanol, acetone, isopropanol and dichloromethane are used to prepare drug reservoir. In addition plasticizers such as dibutylpthalate, triethylcitrate, polyethylene glycol and propylene glycol are added to provide plasticity to the transdermal patch.

Manufacture and production of oral strips

Films can be prepared following technique: Solvent casting
Semi-solid casting Hot-melt extrusion Solid dispersion extrusion Rolling.

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From above methods mainly solvent casting and hot-melt extrusion methods are widely used for making films. Rolling technique is used in industries for commercial scale production. Fig. 1 . Extrusion technique: In the extrusion process the API and other ingredients are mixed in dry state, subjected to heating process and then extruded out in molten state. In this process, solvents are completely eliminated. The strips are further cooled and cut to the desired size. The high temperature used in this process may degrade thermolaabile APIs. Hence, generally the solvent cast method is employed for manufacture of strips. Solvent casting technique: It includes the preparation of the base material which involves the mixing of strip forming excipients and the API mixed together in a suitable solvent or solvent system. The selection of solvent essentially depends on the API to be incorporated into the strip. The solution is subjected to continuous mixing process in order to keep the viscosity and concentration unchanged. The solution or suspension may be kept under controlled temperature condition to achieve the desired viscosity of the material. Once this solution is prepared, the film casting process is performed wherein a strip of desired thickness is cast onto a moving inert substrate. The formed strip is then subjected to drying process to remove the solvent. Glass or Teflon plates are used as the inert base for casting the film. The critical step is the film casting and the drying process. Optimization of speed of casting and drying time are important from the commercial scale output. The thickness of wet strip cast and the physicochemical properties of the coating solution affect scale-up by limiting the drying speed of product and final thickness of the dried strip. In the continuous coating line the proper selection of dryers (for instance; bowtype or horizontal-nozzle, or hot-flue type dryer) and also the number of online dryers improves the processing times. High dosing accuracy essentially depends on micrometer accuracy of film casting and accuracy in cutting of the strip. Many a times, during the optimization trials in small scale, the strip is cut and weighed in a try to estimate the accurate dose per strip. Once the strips are dried, it is cut into suitable shape and size as per the required dosage and thickness of the formed strip and intended application. Many a times the strips are rolled and kept for certain duration before cutting. The medicated strip then is subjected to packaging. In the primary package, the strips are placed into individual lower packaging web. Packaging of strips is very

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important. The pack should be robust enough to give mechanical protection to the strip. Moisture barrier property is equally important aspect for the selection of pack. Aluminium foils are ideal and most preferred for packaging strips. Tamper proof packaging is achieved by using suitable lidding foil.

Fig. 1. Schematic representation of a typical film manufacturing unit by rolling technique. A Formation of medicated film takes place. The rollers can be adjusted to get the desired film thickness. After formation of film, it is dried. a Reservoir for the film forming materials, b deaerator and film applicator, c rollers. B The dried medicated film is slit and cut into little strips of desired size. C Strips are placed into lower packaging web. D Laser printer prints on upper packaging web. E Sealing head seals the strips into single dose sachets. F Introduction of tear-notch/slit/cut off to sachet. G Quality control conveyer to final packaging.

Factors affecting manufacturing of film

The physicochemical properties of the API like heat sensitivity, shear sensitivity, the polymorphic form of the API employed, compatibility of the API with solvent and other strip excipients are to be critically studied. The significant elements in this are liquid rheology, desired mass to be cast and content or dosage uniformity. Solvents used for the preparation of solution or suspension should ideally be selected from ICH Class 3 solvent list.
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Heating process may be included at this stage for the complete dissolution of materials. At this point the important thing to be considered is the air bubbles that may have entrapped during the solution preparation. Entrapped air may tend to produce uneven strips. Deaeration step is good to get a strip with uniform thickness. Vacuum assisted machines can be employed to remove the entrapped air. Many firms adopt bubble-free mixing using suitable type of specialized stirring systems. Another important aspect is the moisture present in the solution because moisture can cause changes in the mechanical properties of the strips such as tensile strength, flexibility, folding endurance, Young's modulus, elongation etc. Hence care should be exercised by using suitable humidity controls in the manufacturing production area.

Evaluation of film
The final product is then critically examined for tests stated below:

A. Thickness
The thickness of strip can be measured by micrometer screw gauge at different strategic locations. This is essential to ascertain uniformity in the thickness of the film as this is directly related to the accuracy of dose in the strip.

B. Dryness test/tack tests: About eight stages of film drying process have been identified and they are set-to-touch, dust-free, tack-free (surface dry), Dry-to-touch, dry-hard, drythrough (dry-to-handle), dry-to-recoat and dry print free. Although these tests are primarily used for paint films, most of the studies can be adapted intricately to evaluate pharmaceutical film as well. Tack is the tenacity with which the strip adheres to an accessory (a piece of paper) that has been pressed into contact with the strip. Instruments are also available for this study.

C. Tensile strength:

Tensile strength is the maximum stress applied to a point at which the strip
specimen breaks. It is calculated by the applied load at rupture divided by the cross-sectional area of the strip as given in the equation below:

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D. Percent elongation:

When stress is applied, a strip sample stretches and this is referred to as strain.
Strain is basically the deformation of strip divided by original dimension of the sample. Generally elongation of strip increases as the plasticizer content increase.

E. Tear resistance:

Tear resistance of plastic film or sheeting is a complex function of its ultimate

resistance to rupture. Basically very low rate of loading 51 mm (2 in.)/min is employed and is designed to measure the force to initiate tearing. The maximum stress or force (that is generally found near the onset of tearing) required to tear the specimen is recorded as the tear resistance value in Newtons (or pounds-force). F. Young's modulus: Young's modulus or elastic modulus is the measure of stiffness of strip. It is represented as the ratio of applied stress over strain in the region of elastic deformation as follows:

Hard and brittle strips demonstrate a high tensile strength and Young's modulus with small elongation.

G. Folding endurance: Folding endurance is determined by repeated folding of the strip at the same place till the strip breaks. The number of times the film is folded without breaking is computed as the folding endurance value.

H. Adhesion test: i. Peel Adhesion Test: Peel adhesion is the force required to remove an adhesive
coating from a test substrate. It is important in transdermal systems because the adhesives should provide adequate contact of the device with the skin and should not damage the skin on removal. Peel adhesion properties are affected by molecular weight of the adhesive polymer, the type and amount of additives, and polymer composition. It is measuring the force required to pull a single coated tape, applied to a substrate, at a 1800angle. Stick the adhesion layer to the platform and check the force to peel it. This is qualitative test to check the adhesion strength.

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No residue on the substrate indicates adhesive failure which is desirable for transdermal system. Remnants on the substrate indicate cohesive failure signifying a deficit of cohesive strength coating.

ii. Tack Property: Tack is the ability of a polymer to adhere to a substrate with little contact pressure. It is important for transdermal devices which are applied with finger pressure. Tack is dependent on the molecular weight and composition of polymer as well as the use of tackifying resins in the polymer. Test includes following: ii (a). Thumb Tack Test: This is the subjective test in which evaluation is done by pressing the thumb briefly into the adhesives. Experience is required for using this test. ii (b). Rolling Ball Tack Test: This test involves measurement of the distance that a stainless steel ball travels along an upward facing adhesive. The less tacky the adhesive, the farther the ball will travel.
22.50 slope Adhesive layer

7/16 ball

ii (c). Quick-stick (peel test) Test: The peel force required breaking the bond between an adhesive Backing film Adhesive film and substrate is measured by pulling the tape away 0 from the substrate at 90 at a speed of 12 inch/min. The force is recorded as the tack value and expressed in ounce (or grams) per inch width with higher values indicating increasing tack.

ii(d). Probe Tack Test (Polyken probe tester): All the following tests are quantitative. The tip of clean probe is brought into contact with adhesive. When bond is formed between probe and adhesive, The force required to pull the probe away from the adhesive at fixed rate is recorded as tack (Grams).

Polyken probe tester

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iii. Shear Strength Test: the measurement of the cohesive strength of an adhesive polymer. Shear strength or creep resistance is determined by measuring the time it takes to pull an adhesive coated tape off a stainless steel plate when a specified weight is hung from the tape which pulls the tape in a direction parallel to the plate.

I. Disintegration time:

The disintegration time limit of 30 s or less for orally disintegrating tablets

described in CDER guidance can be applied to fast dissolving oral strips. Although, no official guidance is available for oral fast disintegrating films/strips, this may be used as a qualitative guideline for quality control test or at development stage. Pharmacopoeial disintegrating test apparatus may be used for this study. Typical disintegration time for strips is 530 sec.

J. Dissolution test:
Dissolution testing can be performed using the standard basket or paddle apparatus described in any of the pharmacopoeia. The dissolution medium will essentially be selected as per the sink conditions and highest dose of the API. Many times the dissolution test can be difficult due to tendency of the strip to float onto the dissolution medium when the paddle apparatus is employed.

K. Diffusion test:
In vitro diffusion test: It is being performed for the transdermal films. To check the drug release amount and time using diffusion cells. In vivo diffusion test: It is being performed on rats. Patch is applied on shaved rat skin and the drug release is checked by suitable way as per the nature of drug.

L. Assay/drug content and content uniformity: This is determined by any standard assay method described for the particular API in any of the standard pharmacopoeia. Content uniformity is determined by estimating the API content in individual strip. Limit of content uniformity is 85115%. M. Moisture content: The prepared films are weighed individually and kept in a desiccators containing calcium chloride at room temperature for 24 h. The films are weighed again after a specified interval until they show a constant weight. The percent moisture content is calculated using following formula.

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% Moisture content = Initial weight Final weight X 100 Final weight

N. Moisture Uptake: Weighed films are kept in a desiccatoar at room temperature for 24 h. These are then taken out and exposed to 84% relative humidity using saturated solution of Potassium chloride in a desiccator until a constant weight is achieved. % moisture uptake is calculated as given below.

% moisture uptake = Final weight Initial weight X 100 Initial weight O. Flatness: A transdermal patch should possess a smooth surface and should not constrict with time. This can be demonstrated with flatness study. For flatness determination, one strip is cut from the centre and two from each side of patches. The length of each strip is measured and variation in length is measured by determining percent constriction. Zero percent constriction is equivalent to 100 percent flatness.

% constriction = I1 I2 X 100 I1

I2 = Final length of each strip I1 = Initial length of each strip

P. Organoleptic evaluation:
Since films are intended to disintegrate rapidly or reside for more duration of time in the oral cavity, the product needs to have acceptable organoleptic palatable characteristics. The product should possess the desired features of sweetness and flavor which is acceptable to a large mass of population. For evaluation of psychophysical evaluation of the product, special controlled human taste panels are used. In vitro methods of utilizing taste sensors, specially designed apparatus and drug release by modified pharmacopoeial methods are being used for this purpose. These in-vitro taste assessment apparatus and methodologies are well suited for high throughput taste screening of oral pharmaceutical formulations.

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Experiments using electronic tongue measurements have also been reported to distinguish between the sweetness levels in taste-masking formulation.

Conclusion
It is consumer-friendly alternative, many of the pharmaceutical companies are moving towards thin films. This technology option can also provide a good platform for patent non-infringing product development. Compared to some of the complicated and expensive process (like lyophilization) used to manufacture other dosage forms, the film is relatively easy to fabricate thus reducing the overall cost of the therapy.

References:
N.K.Jain, Controlled and Novel Drug Delivery, CBS PUBLISHERS & DISTRIBUTORS, New Delhi, page 61-71, 105-122 R.P. Dixit, S.P. Puthli, Oral strip technology: Overview and future potential, Journal of Controlled Release, vol. 139 ,2009, page 94107 R. P. Patel, G. Patel, A. Baria , Formulation and evaluation of transdermal patch of Aceclofenac, International Journal of Drug Delivery vol. 1,2009, page 41-51 G. Aggarwal, Development, Fabrication and Evaluation of Transdermal Drug Delivery System - A Review, pharmainfo.net, Vol. 7, Issue 5, 2009 A. Gupta, A.K. Mishra, V. Gupta, P. Bansal, R. Singh, A.K. Singh, review article: Recent Trends of Fast Dissolving Tablet - An Overview of Formulation Technology, International Journal of Pharmaceutical & Biological Archives, vol.1(1), page 1 10 P.D. Shah, Formulation development and evaluation of terbutaline sulphate quick dissolving oral film (thesis) Thin film drug delivery-www.wikipedia.org

Table-1 list of drugs can be used in film/strip.

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