CHALLENGES IN FORMULATION DEVELOPMENT OF FAST DISSOLVING ... · CHALLENGES IN FORMULATION...

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Indo American Journal of Pharmaceutical Research, 2013 ISSN NO: 2231-6876

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INDO AMERICAN

JOURNAL OF

PHARMACEUTICAL

RESEARCH

CHALLENGES IN FORMULATION DEVELOPMENT OF FAST DISSOLVING ORAL FILMS

Yuvraj G. Jadhav, Upendra C. Galgatte*, Pravin D. Chaudhari

*P. E. Society’s Modern College of Pharmacy, Nigdi, Pune – 411 044, Maharashtra, India

Corresponding author

Upendra C. Galgatte

Department of Pharmaceutics,

P. E. S’s Modern College of Pharmacy,

Nigdi, Pune – 44. Mobile no: +91 9890755938

FAX no: 020 27661314

Email address: [email protected]

Copy right © 2013 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical

Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ARTICLE INFO ABSTRACT

Article history

Received 19/08/2013

Available online

31/08/2013

Keywords Co-administration,

Drying time,

Insolubility,

Mouth dissolving film,

Taste masking

A number of pharmaceutical dosage forms are available in the market. But, every

dosage form has shown some drawbacks like chocking problem of tablets and painful

parenteral dosage forms. Fast dissolving oral film has many advantages related to

disintegration, dissolution and bioavailability over these existing dosage forms. In

addition to this, film avoids first pass metabolism due to pre-gastric absorption and fast

onset of action. As these are light in weight, transportation and handling is easy.

Patient compliance is high in all age groups patients especially paediatrics and

geriatrics. But, this film dosage form has come across some obstacles during its

formulation and development. So, there is need to address such challenges which may

help in future to explore the particular area in research and that may help in overall

formulation and development and large scale manufacturing. These challenges are directly related to patient compliance. These include insolubility of drug, taste masking

of bitter and obnoxious drug, reduction in drying time of film, high dose incorporation,

co-administration of drugs, stability against temperature and humidity, dose uniformity

and need of special packaging. Hence, preference should be given to them in

formulation and development. The present review describes challenges as well as

possible solutions to overcome them for formulation and development of fast

dissolving oral film.

Please cite this Article in press as Upendra C. Galgatte et.al. Challenges in formulation development of fast dissolving oral films. Indo American

Journal of Pharm Research.2013:3(8).

http://www.iajpr.com/index.php/en/

mailto:[email protected]

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Vol 3, Issue 8, 2013 Upendra C. Galgatte et al. ISSN NO: 2231-6876

INTRODUCTION

The oral route is highly acceptable route by patients. Due to patient acceptance, there are about 60% of oral solid dosage forms

available. Because of dysphasia patients, lower bioavailability and high onset of time, researchers changed their path from solid

dosage forms to liquid orals and parenterals. Unfortunately, liquid orals and parenterals also possess some drawbacks like drawback

concerned to accurate dosing of liquid orals and painful parenterals drug delivery. These systems show a patient incompliance due to

these drawbacks [1, 4].

Therefore, there is a demand of formulating the novel oral dosage form which will overcome these above drawbacks concerned with

bioavailability, onset of action and patient compliance. So, the fast dissolving tablets were formulated by using super- disintegrating

agents and hydrophilic ingredients. But, fast dissolving tablets have a difficulty to carry, store, handle (fragility, friability) and

expensive lyophilisation process. So, fast dissolving oral film is prepared which is the most advanced form of oral solid dosage forms

[1, 3].

Fast dissolving oral film consists of a thin strip of rectangular or square shaped which can be generally placed on tongue of patient or

any oro-mucosal tissue and get instantly wet by saliva. Then, the film rapidly hydrates and releases API within some minutes. It gives

quick absorption and instant bioavailability of drugs due to high blood flow and permeability of oral mucosa. Oral Films are useful in

patients such as paediatric, geriatrics, bedridden, emetic patients, diarrhoea and sudden episodes of allergic attacks [1, 2].

After dissolution of oral film in saliva, it moves down towards pharynx and region before stomach and simultaneously it also shows

absorption in these regions. This absorption is pre-gastric absorption i.e. absorption in the region before stomach. Due to pre-gastric

absorption, first pass metabolism is avoided which results in increase in bioavailability as compared to other dosage forms.

Objectives

This review tries to explain the obstacles which formulators usually face during formulation development of fast dissolving oral films.

In addition to this, review also elaborates remedies to overcome these challenges which will help in formulation of poorly water

soluble or bitter drug fast dissolving oral film. These remedies will enhance production of this dosage form in minimum time.

Figure 1: Flow Chart for the Development of Fast Dissolving Oral Film

Requirement of drug candidate into film formulation [2]

A large number of drugs can be formulated into mouth dissolving films. The main requirement of drug to be used in oral film is its

lipophilic nature. Lipophilic drug is highly permeable which is quickly absorbed in the oral mucosa. So, BCS class I (high solubility,

high permeability) or BCS class II (low solubility, high permeability) drugs can be used in oral film due to their high permeable

nature. Following are some of drug categories to be used for treatment of paediatrics and geriatrics populations in oral film

formulation.

Paediatrics (antitussives, expectorants, antiemetic & anti-asthmatic):

Paediatrics populations are very delicate as compared to younger and geriatrics population. Dosage form administered to paediatrics

should be taste masked. Because, they are fond of sweet taste and refuse to take bitter or obnoxious drug in. In case of oral film,

chocking problem does not appear which may appear in tablet dosage form. Because, film is chewed in oral cavity instead of

swallowing and paediatrics like to take chewing gums and chocolates. So, film dosage form is the best for paediatrics.

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Geriatrics (antiepileptic, expectrorants, antiparkinsonism therapy, antimigaine)

Geriatrics populations are generally suffered from many disorders like epilepsy, cough, Parkinsonism and migraine. Tablet and

capsule are difficult to swallow for them in case of dysphasic conditions. So, oral film is the best alternative dosage form for geriatrics

in these disorders.

Table 1: List of drugs used in formulation of oral film [1]

Sr. No. Category of drugs Examples

1 Anti-emetics Ondansetron, granisetron, palonosetron, dronabinol, aprepitant, ramosetron,

metopimazine, nabilone, tropisetron,metoclopramide, prochlorperazine,

trimethobenzamide, dimenhydrinate, prochlorperazine and dolasetron.

2 Selective serotonin

reuptake inhibitors

Fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram and alaproclate

3 5HT3 antagonists Alosetron, ondansetron, granisetron, palonosetron, ramosetron and tropisetron.

4 Anti-migraines Almotriptan, dihydroergotamine mesylate, eletriptan,frovatriptan, naratriptan,

rizatriptan, sumatriptan and zolmitriptan.

5 Anti-epileptics Carbamazepine, clonazepam, diazepam, divalproex sodium, fosphenyloin,

gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenyloin, pregabalin,

primidone, tiagabine, topiramate, valproate sodium, vigabatrin and zonisamide.

6 Dopamine D1 and D2

antagonists

Amisulpride, bromperidol, cabergoline, domperidone, fenoldopam,

haloperidol, metoclopramide, metopimazine,

pergolide mesylate, prochlorperazine, quetiapine, ropinirole hydrochloride,

sulpiride, tiapride and zotepine.

7 Statins Atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin,

rosuvastatin and simvastatin

8 Nootropics Almitrine dimesylate and raubasine, cevimeline hydrochloride, codergocrine

mesylate, donepezil, galantamine, ginkgo biloba extract (EGb 761),

memantine, nicergoline, piracetam.

Special features of mouth dissolving films [2, 6]

1. Mouth dissolving films are thin elegant film.

2. Films are available in various sizes and shapes.

3. Film shows an excellent mucoadhesion. So, film is not detached from mouth cavity while administration.

4. It shows fast disintegration within 1 minute.

5. Drug is rapidly released from dosage form due to its fast disintegration and gives quick onset of action.

Advantages of fast dissolving oral film [2- 4]

1. Water is not needed for administration of oral film. Film uses saliva in oral cavity for disintegration and dissolution.

2. Risk of chocking never appears after administration of film.

3. Dosage form improves patient compliance.

4. It shows rapid disintegrating and dissolution in oral cavity.

5. Flexible and portable nature provides ease in transportation, handling and storage.

6. Film avoids first pass metabolism due to pre- gastric absorption.

7. It reduces side effects associated with drug.

8. Film dosage form is generally useful for patient suffering from diseases like motion sickness, repeated emesis and mental

disorders.

CHALLENGES IN FORMULATING FAST DISSOLVING ORAL FILM

Technology catalysts give an idea of the market for drug products of oral thin film formulation which is valued at $ 500 million in

2007 and will be reached to $ 2 billion in future. Now a day, oral film is an alternative in the market due to patient’s preference to

tablets and capsules. Oral thin film technology is still in the beginning stages and will be the first preference of patient in future. Since

2003, North America is having more than 80 oral thin films brands but, the market remained limited when compared to oral dissolving

tablets. In US market, the OTC films of pain management and motion sickness are commercialized. Now, prescription oral films have

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been approved in three major countries i.e. US, EU and Japan. These approved films have a potential to dominate over other dosage

forms of same drugs. It seems that value of oral film market will grow significantly [1].

Today, huge literature is available on formulation, development and evaluation of oral fast dissolving or fast disintegrating tablets and

films. However, formulator comes across with some challenges while development of such dosage forms. There is need to address

such challenges which may help in future to explore the particular area in research and that may help in overall formulation and

development. These challenges are directly related to patient compliance. Hence, preference should be given to them in formulation

and development.

Table 2: Commercial Fast Dissolving Oral Films [3, 4]

Sr. no. Product Manufacturer Drug

1 Listerine Pfizer Cool mint Pfizer Cool mint

2 Triaminic Novartis Dextromethorphan HBr

3 Ondansetron Rapidfilm® Labtec GmbH Ondansetron

4 Donezepil Rapidfilm® - Donezepil

5 Theraflu Novartis Dextromethorphan HBr

6 Gas-X Novartis Simethicone

7 Sudafed Pfizer Phenylephrine HCl

8 Benadryl Pfizer Diphenhydramine HCl

9 Chloraseptic Prestige Benzocaine Menthol

10 Orajel Del Menthol / Pectin

11 Zolmitriptan RapidFilm® Labtec Zolmitriptan

12 Olanzapine RapidFilm® Labtec Olanzapine

Table 3: General composition of film formulation [1, 5]

Sr. No. Contents Composition Role of contents

1 Drug 5 to 30 % w/w API

2 Water soluble polymers 45 % w/w Film forming capability

3 Plasticizers 0-20 % w/w It improves the flexibility and

reduces the brittleness of the

film.

4 Sweetening agents 3 to 6 % w/w Tasking masking agent.

5 Saliva stimulating agent 2 to 6 % w/w Production of saliva to faster

disintegration.

7 Fillers, colours, flavours, etc q. s. It imparts attractiveness to film.

Following are some of the challenges in formulating fast dissolving oral film and trying to elaborate and solve these problems.

1) Insolubility of drug

2) Taste masking of bitter and obnoxious drug

3) Reduction in drying time of film

4) High dose incorporation in film

5) Co-administration of drugs

6) Stability of film against humidity and temperature

7) Need special packaging

8) Dose uniformity

1. Insolubility of drug:

Solubility plays a rate limiting parameter to get desired concentration of drug of orally administered formulation in systemic

circulation [7]. Problem of solubility is a main challenge for formulation of oral film of BCS class II drugs having low solubility and

high permeability. It is the most important preference of a drug candidate to be selected for formulation of oral film.

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In case of oral film, solubility plays an important role in two stages i.e. solubility of drug in solvent during formulation and solubility

or dissolution of drug in saliva after putting the film in oral cavity. So, the solubility behaviour of drug remains one of the most

challenging aspects in formulation of oral film.

Techniques for solubility enhancement in oral film

Hydrotrophy [8]

Hydrotrophic effect means the increase in saturation solubility of a substance in water by the addition of either organic salts or non-

electrolytes which must be physiologically compatible for pharmaceutical application. These hydrotrophic substances are able to

increase the number of hydrogen bridges in the water clusters. This makes the water more hydrophobic and thus it is a better solvent

for non-polar drug.

Hydrotrophic agents like sodium acetate, sodium alginate, sodium benzoate, urea etc. are ionic organic salts with large anions or

cations that are themselves very soluble in water result in “salting in” of non-electrolytes called “hydrotrophic salts” a phenomenon

known as “Hydrotrophism”.

Actual mechanism of hydrotrophy is by improvement of solubility which is closely related to complexation including a weak

interaction between the hydrotrophic agents like sodium benzoate, sodium acetate, sodium alginate, urea and the poorly soluble drugs.

Solubility enhancement in oral film can be done by this technique. During film preparation, organic salts or non- electrolytes

mentioned above are added in aqueous solution containing drug and after complete drug solubilisation; solution is transferred to

polymer solution containing other excipients and further film is prepared by one of the techniques.

Advantages of Hydrotrophic solubilization technique:

1. Hydrotrophy is suggested to be superior to other solubilisation method, such as miscibility, micellar solubilisation, co- solvency

and salting in, because the solvent used in this technique is independent of pH, has high selectivity and does not require

emulsification.

2. It only requires mixing the drug with the hydrotrope in water.

3. It does not require chemical modification of hydrophobic drugs or organic solvents.

4. The hydrotropes are known to self-assemble in solution.

Use of precipitation inhibitors [8]

Drug precipitation is an increase in free drug concentration above equilibrium solubility which results in super- saturation.

Precipitation inhibitors prevent drug from super- saturation and keep drug in solubilised form. This can be prevented by use of inert

polymers such HPMC, PVP, PVA, PEG etc.

In case of film formulation, drug precipitation results in decrease in drug content of film. So, precipitation inhibitor can be used in the

formulation which will prevent drug precipitation by keeping it in a solubilised form as well as will keep drug content intact.

Inhibitors such as PVP, HPMC, and PVA show dual mechanism in formulation i.e. film forming property and precipitation inhibition.

However, PEG also acts as a plasticizer and precipitation inhibitor.

Co-solvency

Co-solvency is the best and easy method in oral film formulation. It is defined as the addition of a water –miscible or partially

miscible organic solvent (i.e. co-solvent to water) to increase solubility of a nonpolar drug. Co-solvents are mixtures of water and one

or more water miscible solvents used to create a solution with enhanced solubility for poorly soluble compounds [7].

Weak electrolytes and non-polar molecules have poor water solubility and it can be enhanced by changing polarity of solvent which

further change the solubility of drugs. Co- solvent system works by reducing the interfacial tension between the aqueous solution and

hydrophobic solute. It is also commonly called as solvent blending.

Most co- solvents have hydrogen bond donor and/ or acceptor groups as well as small hydrocarbon regions. Their hydrophilic

hydrogen bonding groups ensure water miscibility, while their hydrophobic hydrocarbon regions interfere with water’s hydrogen

bonding network, reducing the overall intermolecular attraction of water. By disrupting water’s self- association, co- solvents reduce

ability of water to squeeze out nonpolar, hydrophobic compounds, thus increasing solubility.

Examples of co-solvents used in this technique are polyethylene glycol, propylene glycol, ethanol or glycerol [8].

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Advantages of co-solvency [8]

1. This is a simple and rapid process to solubilise drug in aqueous solution while formulating oral film.

2. High degree of increase in solubility appears as compared to other solubilisation techniques.

3. Toxicity problems do not appear.

4. Over complexing agents, it does not require identification of a suitable substance that will form the complex.

Micellar solubilisation

Surfactants are compounds that have molecular structures with two distinct regions: A polar (hydrophilic) head group and a nonpolar

(hydrophobic tail). Surfactants can lower surface tension and improve the solubility of lipophilic drug in formulation [7, 8].

Table 4: Types of surfactants

Sr. No. Types Speciality Examples

1 Anionic Hydrophilic group carries a negative

charge.

Potassium Laurate, SLS

2 Cationic Hydrophilic group carries a positive

charge.

Benzalkonium Chloride,

Cetrimide

3 Ampholytic or zwitterionic Molecule carries both negative and

positive charge.

N-dodecyl-N, N-

dimethylbetaine

When the concentration of surfactants exceeds their critical micelle concentration (CMC, which is in the range of 0.05-0.10% for most

surfactants), micelle formation occurs, entrapping the drugs within the micelles [8]. In film formulation, surfactant particles will form

a micelle around insoluble drug particle in aqueous solution and enhance its solubility. Surfactants also act as permeation enhancers in

oral film which can enhance permeability of dosage form. Surfactants used in oral film formulation are Sodium lauryl sulfate, tween

80, Sodium dodecyl sulfate, poloxamer 407 etc [5, 9].

Solid dispersion

The solid dispersion approach to reduce particle size and therefore increase the dissolution rate and absorption of drugs was first

recognised in 1961. The term refers to dispersion of one or more active ingredients in an inert carrier in a solid state, frequently

prepared by the melting (fusion) method, solvent method or fusion – solvent method. Most commonly used hydrophilic carriers for

solid dispersion are poloxamer 407, polyvinylpyrrolidone, polyethylene glycols, etc [7].

Irbesartan solid dispersion was prepared by using polyvinylpyrrolidone as a hydrophilic carrier and mannitol as a solvent for

evaporation [11].

Methods of preparation of solid dispersion [12] are explained below.

Melting method (Fusion method)

The melting or fusion method was first proposed by Sekiguchi and Obi to prepare fast-release solid dispersion dosage forms. The

physical mixture of a drug and a water-soluble carrier was heated directly until it melted. The melted mixture was then cooled and

solidified rapidly in an ice bath under vigorous stirring. The final solid mass was crushed, pulverized, and sieved. Such a technique

was subsequently employed with some modification by Goldberg et al and Chiou and Riegelman. To facilitate faster solidification, the

homogeneous melt was poured in the form of a thin layer onto a ferrite plate or a stainless steel plate and cooled by flowing air or

water on the opposite side of the plate.

Hot melt extrusion

Melt extrusion is essentially the same as the fusion method except that intense mixing of the components is induced by the extruder.

In hot melt extrusion method, first the drug is mixed with carriers in solid form. Then, the extruder having heaters melts the mixture.

Finally, the melt is shaped in to films by the cavities of dies. There are certain benefits of hot melt extrusion, viz. fewer operation

units, better content uniformity, an anhydrous process [4].

Solvent method

Another commonly used method of preparing a solid dispersion is the dissolution of drug and carrier in a common organic solvent,

followed by the removal of solvent by evaporation. In this method, volatile solvents are used to evolve completely and quickly from

dispersion. Examples of solvents are polyethylene glycols, ethanol, mannitol, acetone etc.

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Kneading method

In the kneading method, the drug and polymer are triturated using a small volume of solvent (the minimum amount of organic solvent

possible) to obtain a thick paste, which is needed for a determined time and then dried in an oven if temperature does not affect the

system’s characteristics.

Gupta M.M.et.al. (2011) reported that Meclizine hydrochloride, a poorly water soluble drug, can be successfully formulated into fast

dissolving films with solubilizers such as β- cyclodextrine by kneading method in molar ratio 1:1. Meclizine hydrochloride film shows

83.52% drug release in 30 minutes, but complexation has improved solubility and drug release to 99% in 30 minutes [27].

This method was also used for solubility enhancement of Valsartan by Raza R.et.al. (2012) for development of oral film in which

drug and polymers such as hupu gum and guar gum were used. Dissolution of valsartan film was found to be 83.15% in 60 minutes;

dissolution of film made by solid dispersion was improved to 89.04% in 60 minutes [30].

Cogrinding method

In the cogrinding method, the drug is triturated with a minimum quantity of the solvent in a glass mortar until it is dissolved. The

carrier is then added, and the suspension is triturated rapidly at room temperature until the solvent is evaporated.

Advantages of Cogrinding [8]

1. Rapid dissolution rates which will further result into an increase in the rate and extent of the absorption of the drug.

2. Transformation of liquid form of drug to solid form.

3. Protection of certain drugs by PEGs against decomposition by saliva to allow buccal absorption.

Complexation

Complexation is the association between two or more molecules to form a non- bonded entity with a well defined stichiometry. It

relies on relatively weak forces such as hydrogen bonding, London forces and hydrophobic interactions [8, 13].

Table 5: List of complexing agents [7]

Sr. no. Types Examples

1 Inorganic IB-

2 Coordination Hexamine cobalt (III) chloride

3 Chelates EDTA, EGTA

4 Metal- olefin Ferrocene

5 Inclusion Cyclodextrins, choleric acid

6 Molecular complexes Polymers

Generally inclusion complexation is used in oral film formulation for solubility enhancement. Inclusion complexation shows dual

action in oral film formulation i.e. solubility enhancer as well as taste masking agent [22]. Inclusion complexes are formed by the

insertion of the nonpolar molecule or the nonpolar region of molecule (known as guest) into the cavity of another molecule (known as

host). The most commonly used host molecules in oral film are cyclodextrins. From the four types of cyclodextrins i.e. α, β, γ, δ;

hydroxypropyl β cyclodextrin is generally used.

Table 6: Types of cyclodextrins [7]

α β γ Δ

Molecular formula C36H60O30 C42H70O35 C48H80O40 -

Optical rotation +150.5 +160.0 +177.4 -

Dextrose molecules 6 7 8 9

Molecular weight 972 1135 1297 1459

Cavity diameter(A°) 4.7-5.3 6-6.5 7.5-8.3 10.3-11.2

Solubility (g/100ml) 14.5 18.5 23.2 -

Cyclodextrins are cyclic oligosaccharides containing 1, 4-linked glycopyranose units with a hydrophilic hydroxyl group on their outer

surface and a hydrophobic cavity in the center. [14].

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Generally, if lipophilic drug is used for the formulation of oral film, it adheres to the central part of cyclodextrin and due to outer

hydrophilic nature, the whole inclusion complex get solubilised in the aqueous solution during oral film formulation. Cyclodextrins

also act as a permeability enhancer. So, this complex also enhances oral permeability of drug through biological membrane [14].

Desai P.et.al. (2012) have concluded that formulation of Domperidone oral film with β-cyclodextrin exhibited better solubility and

dissolution properties than pure drug alone. Statistically significant differences were found in terms of dissolution in all domperidone

– β- cyclodextrine inclusion. Complexation has improved drug release to 95.90% in 30 minutes [28].

Another author Dinge A.et.al. (2008) have enhanced solubility of Triclosan in oral film by use of poloxamer 407 and Hydroxypropyl

β- cyclodextrin. Films containing triclosan- poloxamer 407 showed better in vitro dissolution profile and in vitro antimicrobial activity

as compared to films containing triclosan - Hydroxypropyl β- cyclodextrin complex [29].

2. Taste masking of bitter and obnoxious drug

Taste is an important parameter in case of fast dissolving oral film. Oral film has to remain in contact with oral mucosa until it

completely dissolves in saliva in oral cavity. For this, taste of bitter drugs should be masked. So, taste masking becomes a prerequisite

for bitter drugs used in fast dissolving oral film to improve the patient compliance especially in the paediatric and geriatric population

[15, 17].

Taste is the ability to respond to dissolved molecules and ions‐ “gatekeeper to the body”. Human uses taste receptor cells that are

clustered into onion‐shaped organs called taste buds for detection of taste. A taste bud contains a pore which opens out to surface of

the tongue and passing molecules and ions into the mouth to reach to the receptor cells inside [16, 19].

Human have around 10,000 taste buds which appear in foetus at about three months. A single taste bud bears 50‐100 taste cells and

each taste cells have receptors on its apical surface. These are trans-membrane proteins which bind to the molecules and ions that give

rise to the four primary taste sensations namely ‐ salty, sour, sweet and bitter. Recently, a fifth basic taste umami has been discovered.

The umami is the taste of certain amino acids (eg. monosodium glutamate) [20, 21].

Ideal taste masking process and formulation [17]

1. It involves least number of equipments and processing steps.

2. This requires minimum number of excipients for an optimum formulation.

3. There is no adverse effect on drug bioavailability.

4. It requires excipients that are economical and easily available.

5. Manufacturing cost is least.

6. It can be carried out at room temperature.

7. It requires excipients that have high margin of safety.

8. This is a rapid and easy to prepare.

Factors that are taken into consideration during the taste-masking formulation process include

1. Bitterness of the API.

2. Required dose load.

3. Drug particulate shape and size distribution.

4. Drug solubility and ionic characteristics.

5. Required disintegration and dissolution rate of the finished product.

6. Desired bioavailability.

7. Desired release profile.

8. Required dosage form.

Taste masking techniques

Taste masking with sweeteners and flavours

This is very simple and mostly used technique for oral film formulation. Very minimum amount of sweetener and flavour are required

for formulation to mask the bitter taste of drug.

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Sweeteners [17]

Generally, sweeteners are used in the concentration of 3 to 6% w/w either alone or in combination. Sweeteners play an important role

in food products & pharmaceutical dosage forms which are disintegrated or dissolved in oral cavity. The sweetness of taste in

formulation is more preferred by paediatric population. So, natural & artificial sweeteners are used to improve palatability of

formulations. Traditional source of sweetener is sucrose (derived from cane or beet in liquid or dry state), dextrose, fructose, maltose

and glucose. The sweetness of fructose rapidly spread in the mouth as compared to sucrose and dextrose.In addition to this, it is

sweeter than sorbitol and mannitol and thus used widely as a sweetener. Because of the good mouth feel and cooling sensation,

polyhydric alcohols i.e. sorbitol, mannitol, isomalt and maltitol are generally used in combination with natural sweeteners. Polyhydric

alcohols are less carcinogenic and do not have bitter after taste which is important property to be considered in formulating oral film

formulations [1, 5].

However, natural sweeteners are restricted in people who are on diet or in diabetic patients. Because of which, artificial sweeteners

have taken a place of natural sweeteners.

Table 7: Examples of first and second generation artificial sweeteners

First Generation Second Generation

Aspartame

Saccharin sodium

Cyclamate

Acesulfame-K

Alitame

Neotame

Sucralose

Acesulfame-K and sucralose have more than 200 and 600 time sweetness. Neotame and alitame have more than 2000 and 8000 time

sweetening power as compared to sucrose. Rebiana which is a herbal sweetener, derived from plant Stevia rebaudiana (South

American plant) has more than 200 - 300 time sweetness. The disadvantage of artificial sweetener is the after taste effect. This can be

reduced by mixing natural and artificial sweeteners [4]. Examples of types of sweeteners are given below.

Types of sweeteners

Natural sweetener

Fructose, Sucrose, glucose, Liquorice, Honey, Glycerol, Sorbitol, mannitol

Artificial sweetener

Saccharin sodium, Aspartame

Nutritive: Fructose, Sucrose and Glucose

Polyols: Sorbitol, Mannitol, Xylitol, Maltitol, Erythritol,.

Non-Nutritive: Sucralose, Aspartame, Neotame and Saccharine.

Novel sweeteners: Tagatose, Trehalose.

Table 8: Relative sweeteness of commonly used sweeteners

Sweetening agents Relative sweetness*

Comment

Aspartame 200 Not very stable in solution

Acesulfame 137-200 Bitter after taste if used in

higher concentration

Potassium Cyclamate 40 Banned

Glycerrhizin 50 Moderately expensive

Lactose 0.16 Large amount required

Manitol 0.60 Negative heat of solution

Saccharin 450 Unpleasent after taste

Sucrose 1 Most commonly used

Sucralose 600 Synergestic sweetening effect

*Sucrose is taken as a standard of 1 for comparison.

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Panchal M.S.et.al. has reported taste masking of Ropinirole hydrochloride by sucralose and aspartame (artificial sweeteners) for

formulation of mouth dissolving films [32].

Flavours [16]

Flavouring agents can be selected from the oleo resins, synthetic flavour oils, extract derived from various parts of the plants like

fruits, leaves and flowers. Flavours can be used alone or in the combination. Any flavour can be added such as essential oils or water

soluble extracts of menthol, intense mints such as sweet mint, peppermint, spearmint, cinnamon, wintergreen, clove, sour fruit flavour

such as orange, lemon or sweet confectionary flavours such as chocolate, vanillin or fruit essence like cherry, apple, pineapple,

raspberry. The amount of flavour needed to mask the taste depends on the flavour type and its strength. Flavours are generally not

accepted by patients who get accustomed by natural sweeteners. Flavours along with sweeteners show synergism in improvement in

taste masking of formulation. Examples of flavours are mentioned below.

Natural Flavours

Juices - Raspberry

Extracts - Liquorices

Tinctures -Ginger

Spirits - Lemon & Orange

Syrups – Blackcurrant

Aromatic Oils – Peppermint & Lemon

Aromatic waters - Anise & Cinnamon

Synthetic Flavors

Powders, Alcoholic solutions, Aqueous solutions

Table 9: Flavour selection for taste masking

Basic taste Masking agents

Salt Peach, Butterscotch, maple, wintergreen mint, apricot,

vanilla,

Bitter chocolate, Wild cherry, anise, walnut, mint,

Sweet Fruit and cherry, Vanilla.

Sour Liquorice, Raspberry, Citrus flavour, root beer.

Taste masking by formulation of inclusion complexesInclusion complexation plays a dual nature in case of oral film formulation. It

shows both actions of solubility enhancer and taste masking agent. Complexing agents (Cyclodextrins) have inner lipophilic nature

and outer hydrophilic nature. The lipophilic drug adheres to the central part of complexing agent keeping outer hydrophilic part in

contact with saliva. So, bitter taste of drug remains unavailable to oral cavity and patient shows acceptability for that drug.

Cyclodextrins also act as a permeability enhancer. So, this complex also enhances oral permeability of drug through biological

membrane [14].

Dinge A.et.al. (2008) have reported that Eugenol containing films of Triclosan – poloxamer 407 has improved acceptability with

respect to taste masking by human volunteers [29].

The results shown by Preis M.et.al. (2012) by the use of X-ray diffraction and polarized light microscopy have observed no

recrystallization of Dimenhydrinate in the formulation when cyclodextrin or maltodextrin were used as solubilising and complexing

agent for development of a taste masked orodispersible film containing Dimenhydrinate [22].

This technique was also used by Bhyan B.et.al. (2012) for taste masking of Rizatriptan benzoate by maltodextrin which was used as a

film forming polymer as well as taste masking agent in the formulation of oral film of Rizatriptan benzoate [31].

Taste masking by bitterness inhibitors [16]

The development of a specific universal inhibitor for bitter taste has been widely required in the fields of taste physiology and

pharmaceutical sciences, but no such inhibitors has been available. Use of these bitterness inhibitors is very easy and it does not

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require any another method to use in oral film formulation. Sodium acts at peripheral taste level rather than a cognitive effect. So,

sodium salts are used as bitterness inhibitors.

In oral film formulation, bitterness inhibitor is added in aqueous drug solution and is soluble due to salt form. Then, polymer and drug

solutions are added with each other after stirring until all components of solutions are solubilised. After that, film is casted and dried.

Sodium salts such as sodium chloride, sodium acetate, sodium gluconate have been shown to be potent inhibitors of some bitter

compounds.

Taste masking by using effervescent agents [14]

Effervescent agents have been shown to be useful and advantageous for oral administration of drugs and have been incorporated for

use as taste masking agents for dosage forms that are not dissolved in water before administration. A taste masking generator of

carbon dioxide and a taste bud desensitizing composition (e.g. Oral anaesthetic such as benzocaine) are required in this technique. The

formulation contains the drug in combination with effervescent agent to promote their absorption in the oral cavity and to mask their

bitter taste.

2. Reduction in drying time of film [23]

Drying time plays an important role in oral film formulation and also in case of rate of production of oral film in industries. Generally,

hot air oven is not used for drying of oral film of thermo labile drugs. So, oral film is dried at room temperature. But, it takes more

time to dry (about one day).

Panchal M. S.et.al. (2012) has reported that time taken by formulation for drying was found to be 24 hours at room temperature for

the formulation of mouth dissolving film of Ropinirole hydrochloride prepared by using Pullulan polymers [32].

35°C temperature for 12 hours was used by Jadhav S. D.et.al. (2012) for drying fast dissolving oral film of Levocetirize

Dihydrochloride [33].

Time taken by formulation for drying was found to be 24 hours at 50°C for the formulation of fast dissolving oral film of Salbutamol

Sulphate investigated by Prasanthi N. L.et.al. (2011)[34].

Another temperature conditions were used by Prasanna D.et.al. (2012) which reported that time taken by formulation for drying was

found to be 24 hours at 60°C for the formulation of fast dissolving oral film of Zolmitriptan [35]. Similar temperature conditions were

used by Shelke P. V.et.al.(2012) for formulation of rapidly disintegrating film of Amlodipine besylate [37].

Cilurzo F.et.al. (2008) used temperature conditions along with stirring and reported that time taken by formulation for drying was

found to be 3 min at 100°C for the formulation of fast dissolving oral film made of Maltodextrins with a horizontal air circulation of

1200 rpm [36].

Murata Y.et.al. (2012) observed that time taken by formulation for drying was found to be 24 hr at 37°C for development of film

dosage form containing Allopurinol [38].

Reduction in drying time can be achieved by following ways

1. By increase in temperature without developing cracks to film.

2. Selection of ingredients in film specially type and concentration of polymer and plasticizer i.e. addition of those polymers and

plasticizers which form less viscous solution sothat drying time will be minimum and prevention of use of those polymers and

plasticizers which form highly viscous solution so that drying time will be increased.

3. Drying time can be minimized by use of suitable dryers.

4. Increase in area of film will expose large surface to drying environment and further will reduce drying time.

Following factors are responsible for increase in drying time:

Depth of formulation solution in container [23]

This is a main factor responsible for drying time. Depth of solution in container that could be dried at room temperature to obtain film

within a reasonable time is found to be 3.5 mm. Depth of solution greater than 3.5 mm took much longer periods of time to dry and

produced poor quality films. Depth of solutions less than 3.5 mm does not spread evenly in petri dish which also increases drying

time. Therefore, the volume of formulation solution needed for each container (petri dish) is calculated below.

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Volume of formulation solution needed= area of container × depth of formulation solution

Type of polymers used in formulation [23]

In the 3D structure of polymer solution, solvent and polymer are in solubilised state forming solvent cavities in polymer structure due

to viscous nature of polymer. During drying of film, solvent entrapment takes place from these cavities resulting in drying of film.

Polymers such as methylcellulose, sodium methylcellulose, moderate to high grades (E15, E50) of hydroxyl propyl methyl cellulose,

hydroxyl propyl cellulose, polyethylene oxide, polyvinyl alcohol, polyvinyl pyrrolidone and sodium alginate produce film which is

not easily pourable, sticky, hard, brittle and having high dissolution and disintegration time and results in increase in drying time. Low

grades (E3, E5) of HPMC are the best polymers to get film in a reasonable time.

Natural polymers such as carrargeenan, guar gum form a highly viscous solution in water resulting in difficulty in formulation and

increase in drying time of film. However, semi- synthetic and synthetic polymers such as HPMC grades form less viscous solution in

water which is easily pourable in container and resulting in decrease in drying time.

Viscosity of formulation solution

In general, as viscosity of solution increases, drying time increases. In case of HPMC, as grades of HPMC i.e. E3, E5, E6, E15, E50

increases, viscosity of solution increases and thus, drying time increases. The average viscosities of 2% aqueous solution of HPMC E3

LV (MW ~ 15,600) and HPMC E5 LV (MW ~ 25,300) are 3 and 5 cps, respectively.

In case of viscous solutions, stickiness is another problem which forms an obstacle during drying. Films produced from highly viscous

polymers i.e. natural polymers, high grade HPMC stick to container. So, it creates difficulty in drying of film due to less surface

exposure to drying temperature and also, difficulty in withdrawing of film from container.

Concentration of plasticizer

In general, concentration of plasticizer used in film formulation is upto 20%. Concentration higher than 30% shows problems in

drying the films. Then, formed films are sticky, difficult to handle and remove from container. Concentration less than 10% is not

enough to plasticize film. Concentration of plasticizer in a film should be such that it should help to provide flexibility to film without

stickiness and considerable increase in solvent retension.

Area of film exposed for drying

As area of film is increased, large surface and solvent cavities are exposed to drying temperature resulting in quick entrapment of

solvent from film and decrease in drying time of film.

3. High dose incorporation in film [23]

Dose of drug in oral film formulation can be increased by increasing area of container. Only area should be increased keeping

thickness of formulation solution constant so that volume of solution needed for formulation is also increased which help in

incorporation of high dose and reduction in drying time also. Volume of formulation solution needed is calculated by following

formula [23]. If petri dish is considered as a container, then volume of formulation solution is given below.

Volume of formulation solution = area of petri dish × depth of formulation solution in dish

= x 0.35 cm

Volume of formulation solution = 0.35 cm3

From literature survey, the highest dose to be incorporated in fast dissolving oral film is found to be 62.5 mg for the formulation of

Simethicone oral film. Dose of drug incorporated in oral film was found to be in the range of 2 – 62.5 mg [39, 40]. High dose of drug

can be incorporated in oral film by increase in the area of film, increase in solubility of drug in formulation.

4. Co-administration of drugs

Use of more than one drug i.e. co- administration of drugs is a very difficult task in oral film formulation. Because, it may affect

disintegration time as well as dissolution rate of formulation.

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Combination of more than one drug can be possible by two ways

Multilayered oral film

In this type of oral film, films of different drugs are placed one above the other. The dosage forms obtained have similar look, feel and

size as a regular tablet. Each layer in the layered dosage form is in place to perform a function: drug carrier layer, solubilising layer,

taste masking layer, etc. The figure 4 below illustrates the concept.

Figure: 2 Multi-layered oral film

In the formulation of this type of oral film, individual films of drugs and excipients are prepared. All these individual films are kept on

one above the other to form multi- layer matrix. In multi- layer matrix, excipient film is kept between two drugs in order to avoid the

occurrence of any chemical reaction. Then, multi- layer matrix is cut in tablet shape.

Co-adjacent oral film

In this type of film, half area of film is occupied by one drug candidate and another half by another drug. This can be possible by

increasing area of oral strip.

5. Stability of film against humidity and temperature

Fast dissolving oral film consists of about 45% of polymer which is hydrophilic in nature [5]. In the humid atmosphere, film will

absorb water and get liquefied due to dissolution of film in water. So, the stability of film against humidity is very difficult and

challenging task.

Amorphous drugs often have higher dissolution rates than their crystalline forms, but lower physical stability during storage. Addition

of crystallisation inhibitors such as hydrophilic polymers to the amorphous drug to form a film formulation is the best method to

prevent drug crystallisation. In the film formulation, polymers can decrease the molecular mobility of the drug, therefore reducing

driving force of crystallisation and improving the physical stability of the amorphous drugs. If the API is freely soluble in the polymer,

then the system should have excellent physical stability. If the API is not freely soluble in the polymer and is present at a

supersaturated concentration, then stability is an issue [24, 25].

Though oral film formulation is the best method to prevent drug crystallisation, it shows crystallisation of drug at higher humidity and

temperature conditions.

Gaisford S.et.al. (2009) has reported crystallisation at higher temperature of Indomethacin – Polyvinylpyrrolidone (PVP) fast

dissolving oral films with isothermal calorimetry method and concluded that an increase in temperature resulted in increase in

crystallisation rate [25].

However, Soutari N.et.al. (2012) has quantified crystallisation rates of Indomethacin oral films at higher humidity by using Dynamic

mechanical analysis (DMA) and concluded that rates of crystallisation were seen to increase with increase in humidity i.e. 50% RH,

60% RH, 75% RH & so on [26].

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Phase separation of drug from amorphous to crystalline due to moisture is known as moisture induced phase separation. Highly

hygroscopic polymers form hydrogen bonds with water molecules. So, if the drug- polymer bond is weaker than the polymer- water

interaction, then it may be disrupted and replaced by polymer- water interaction under high humidity which enhances phase separation

and drug recrystallises [24].

Sheng Q.et.al. (2013) have observed stabilisation of amorphous drug under high humidity using oral film. He has reported phase

transition of four model drug films by using FT- IR spectra and SEM photograph and concluded that degree of crystallisation of model

drug films stored in dry conditions were lower than those films stored in humid conditions [24].

Following factors can influence physical stability of film:

1. Tg (glass transition temperature) of drug and polymer

2. Miscibility between polymer and drug

3. Viscosity of polymer

4. Drug- polymer interaction

6. Need special packaging [41]

In the pharmaceutical industry, it is vital that the package selected adequately preserve the integrity of the product. A variety of

packaging options are available for fast dissolving films. An aluminium pouch is the most commonly used packaging material. APR-

Labtec developed the Rapid card, patented packaging system designed for the Rapid films. The rapid card has same size as a credit

card and holds three rapid films on each side. Every dose can be taken out individually.

Figure 3: Rapid card

The material selected must have the following characteristics

1. They must protect the preparation from environmental conditions.

2. They must be FDA approved.

3. They must meet applicable tamper-resistant requirement

4. They must be non-toxic.

5. They must not be reactive with the product.

6. They must not impart tastes or odours to the product.

Following are some types of packaging systems of oral films

Foil, paper or plastic pouches

The flexible pouch is a packaging material capable of providing not only a package that is temper- resistance, but also a package with

a high degree of environmental protection. A flexible pouch is usually formed during the product filling operation by either vertical or

horizontal forming, filling, or sealing equipment. The pouches can be single pouches or aluminium pouches.

Single pouch and Aluminium pouch

Film pouch is a peel able pouch for “quick dissolve” soluble films with high barrier properties. The pouch is transparent for product

quick watch. Using a 2-structure combination allows for one side to be clear and the other to use a cost-effective foil lamination. The

foil lamination has essentially no transmission of gas and moisture. The package provides a flexible thin film alternative for

nutraceutical and pharmaceutical applications. The single dose pouch provides both product and dosage protection. Aluminium pouch

is the most commonly used pouch.

Blister card with multiple units

The blister container consists of two components: the blister, which has a cavity that holds the product and the lid stock, which is the

material that seals the blister. The blister package is formed by heat –softening a sheet of thermoplastic resin and vacuum-drawing the

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softened sheet of plastic into a contoured mould. After cooling, the sheet is released from the mould and proceeds to the filling station

of the packaging machine. The semi–rigid blister previously formed is filled with the product and lid with the heat sealable backing

material. The film selection should be based upon the degree of protection required. Generally, the lid stock is made of aluminium

foil. The material used to form the cavity is typically a plastic, which can be designed to protect the dosage form from moisture.

Barrier Films

Many drug preparations are extremely sensitive to moisture and therefore, require high barrier films. Several materials use to provide

moisture protection such as Polychlorotrifluoroethylene (PCTFE) film, Polypropylene. Polypropylene does not stress crack under any

conditions. It is an excellent gas and vapour barrier. Lack of clarity is still a drawback.

7. Dose uniformity

Film which is to be made in a container has to cut into desired area containing required dose of drug. So, to get a uniform dose in all

films which cut into desired area is a challenging task.

Dose uniformity depends upon following factors:

Drug and excipients should be soluble in aqueous solution. Because, insoluble drug and excipients may form a suspension which was

not be uniformly distributed. The insoluble matter may degrade drug forming degradation products which can convert amorphous drug

into crystalline and may affect dissolution of film formulation.

Solution to be poured into container should not be highly viscous. The viscosity of film formulation depends on polymer used.

Generally, natural polymers like guar gum, carrargeenan form a highly viscous solution which forms a difficulty in pouring into a

container due to their high molecular weight. This highly viscous solution may not be distributed uniformly and may gather at one part

of container.

Surface of the bottom of the container should be flat. Rough surface may affect uniformity of drug content in film and maximum

amount of drug may collect at one half of film while, other half may get remaining drug content.

Drying temperature should be below melting point of drug and excipients. High temperature may degrade drug and excipients during

drying.

Content uniformity is measured by assay method of drug determined by specification in different pharmacopoeia. It is determined by

estimating the API content in individual film. Limit of content uniformity should be 85- 115% [3, 5].

Following remedies can maintain content uniformity in film

Content uniformity of film can be maintained by using water soluble drug and excipients or making drug soluble in aqueous medium

by various solubilising techniques. In addition to this, one more technique to maintain the same is by use of semi- synthetic polymers

like HPMC and HPC in film formulation or making combination of both natural and semi- synthetic polymers in formulation to get

less viscous solution.

CONCLUSION

This review has focused to overcome the challenges like insolubility of drug, taste masking of bitter drug, drying time reduction, high

dose incorporation, and stability, packaging and dose uniformity of film which were generally appeared in formulation and

development of fast dissolving oral film. Insolubility of drug is a main challenge. Because, it affects dissolution and subsequent

bioavailability of drug, stability and dose uniformity of film. Patients such as paediatrics and geriatrics do not accept bitter and

obnoxious drugs. So, taste masking of drug is also a challenge for oral film. Viscosity of casting solution plays an important role in

overcoming challenges like drying time reduction, high dose incorporation and dose uniformity of drug. One of the possible solutions

to improve drug solubility is use of β - cyclodextrin. In addition to improvement in solubility, it improves subsequent dissolution rates

and taste masking of drug. Thus single solution to challenge can address multiple challenges. This review in future may guide

researchers to overcome the challenges in preparation of fast dissolving oral film.

This review recommends future research in area of casting of insoluble, bitter and obnoxious drug into fast dissolving film. The

research can be explored in the area of reduction in drying time, maintenance of dose uniformity, co-administration of drugs and

stability of film against humidity and temperature.

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ABBREVIATIONS

API: Active Pharmaceutical Drug, BCS: Biopharmaceutical Classification System, D: Dopamine, OTC: Over The Counter, PVA:

Poly Vinyl Alcohol, PVP: Polyvinyl Pyrrolidone, PEG: Poly Ethylene Glycol, SLS: Sodium Lauryl Sulphate, hrs: Hours.

REFERENCES

1. Nehal Siddiqui M. D., A short review on “ A Novel Approach in Oral Fast Dissolving Drug Delivery System and Their

Patents”, Advances in Biological Research 2011; 5:6: 291-303.

2. Arya A., Chandra A., Sharma V., Pathak K., Fast Dissolving Oral Films: An Innovative Drug Delivery System and Dosage

Form, International Journal of ChemTech Research 2010; 2:1: 576- 83.

3. Dhere P., Patwekar S., Review on preparation and evaluation of oral disintegrating films, International Journal of Pharmacy

& Technology 2011; 3:4: 1572- 85.

4. Kaur R., Bala R., Malik D., A Novel Approach In Oral Fast Dissolving Drug Delivery System- A Review, American Journal

of PharmaTech Research 2012; 2:1: 88 – 104.

5. Dixit R., Puthli., Oral strip technology: Overview and future potential, Journal of Controlled Release 2009; 139: 94- 107.

6. Thakur R., Narwal S., Orally Disintegrating Preparations: Recent Advancement In Formulation And Technology, Journal of

Drug Delivery & Therapeutics 2012; 2:3: 87- 96.

7. Limbachiya M., Solubility Enhancement Techniques For Poorly Soluble Drugs: A Review, International Journal of

Pharmaceutical Research and Development 2012; 4:4: 71- 86.

8. Mukherjee S., Patel P., Patel A., Patel H., Patel P., A Review On Solubility Enhancement Techniques, International Journal

Of Pharmaceutical Research And Bio- Science 2012; 1:1.

9. Khan R., Study Of Dissolution Enhancement Property Of Poloxamer 407 Using BCS Class II Drugs, International Journal of

Pharmaceutical Research and Development 2012; 3:12: 25- 32.

10. Kumar S., Gupta S., Sharma P., Dissolution rate enhancement of aceclofenac by solid dispersion technique, Asian Journal of

Pharmacy and Life Science 2011; 1:4: 396- 400.

11. Chawla G., Bansal A., Improved dissolution of a poorly water soluble drug in solid dispersion with polymeric and non-

polymeric hydrophilic additives, Acta Pharm 2008; 58: 257- 74.

12. Joshi M., Tiwari G., Tiwari R., Pandey S., Pandey P., Rai A., Solid dispersion: A technology for the improvement of oral

bioavailability of poorly water soluble drugs, Current Pharma Research 2012; 2:4: 668-77.

13. Birhade S., Bankar V., Gaikwad P., Pawar S., Preparation and evaluation of Cyclodextrin based binary systems for taste

masking, International Journal of Pharmaceutical Sciences and Drug Research 2010; 2:3: 199- 203.

14. Patil S., Bankar V., gaikwad P., Pawar S., Taste masking by inclusion complexation : A review, International Journal of

Pharmaceutical Research and Development 2011; 3:7: 35 – 47.

15. Wadhwa J., Puri S., Taste masking : A novel approach for bitter and obnoxious drugs, International Journal of

Biopharmaceutical & Toxicological Research 2011; 1:1: 47- 60.

16. Sharma S., Lewis S., Taste masking technologies: a review, International Journal of Pharmacy & Pharmaceutical Sciences

2010; 2:2: 6- 13.

17. Tripathi A., Pawar D., Patel U., Taste masking : a novel approach for bitter & obnoxious drugs, Journal of Pharmaceutical

Science & Bioscientific research 2011; 1:3: 136-42.

18. Vummaneni V., Nagpal D., Taste masking technologies: an overview and recent updates, International Journal of Research in

Pharmaceutical and Biomedical Sciences 2012; 3:2: 510- 24.

19. Sikanadar M., Malviya R., Sharma P., Taste masking: an important pharmaceutical technology for the improvement of

organoleptic property of pharmaceutical active agents, European Journal of Biological Sciences 2011; 3:3: 67- 71.

20. Mirajkar R., Devkar M., Kokare D., Taste masking methods and agents in pharmaceutical formulation, International

Research Journal of Pharmacy 2012; 3:8: 67- 70.

21. Roger E., Masking bitter taste of pharmaceutical actives, Taste masking actives.

22. Preis M., Pein M., Breitkrreutz J., Development of a taste – masked orodispersible film containing Dimenhydrinate,

Pharmaceutics 2012; 4: 551- 62.

23. Chauhan S., Lin S., Madan P., Preparation and evaluation of nicotine hydrogen tartrate fast dissolving films for smoking

cessation, Asian Journal of Pharmaceutical sciences 2012; 7:3: 181-92.

24. Yuen C., Yang Z., McAuley W., Stabilisation of amorphous drugs under high humidity using pharmaceutical films,

European Journal of Pharmaceutics and Biopharmaceutics 2013.

25. Gaisford S., Verma A., Saunders M., Royall P., Monitoring crystallisation of drugs from fast dissolving oral films with

isothermal calorimetry, International Journal of Pharmaceutics 2009; 380: 105-11.

www.iajpr.com

Pag

e64

07


26. Soutari N., Buanz A., Mine O., Tuleu C., Gaisford S., Quantifying crystallisation rates of amorphous pharmaceutical with

dynamic mechanical analysis (DMA), International Journal of Pharmaceutics 2012; 423: 335- 40.

27. Gupta M., Patel M., Kedawat M., Enhancement of dissolution rate of rapidly dissolving oral film of meclizine hydrochloride

by complexation of meclizine hydrochloride with β – cyclodextrin, Journal Of Applied Pharmaceutical Science 2011; 1:9:

150- 3.

28. Desai P., Basu B., Design and evaluation of fast dissolving film of domperidone, International Research Journal of Pharmacy

2012; 3:9: 134- 45.

29. Dinge A., Nagarsenkar M., Formulation and evaluation of fast dissolving films for delivery of Triclosan to the oral cavity,

AAPS PharmSciTech 2008; 9:2: 349- 56.

30. Kaza R., Kumar R., Design and characterization of fast dissolving films of valsartan, International Journal of Innovative

Pharmaceutical Research 2012; 3:2: 212-9.

31. Bhyan B., Jangra S., Formulation and evaluation of fast dissolving sublingual films of Rizatriptan benzoate, International

Journal of Drug Development & Research 2012; 4:1: 133- 43.

32. Panchal M., Patel H., Bagada A., Vadalia K., formulation and evaluation of mouth dissolving film of Ropinirole

hydrochloride by using pullulan polymers, IJPRAS 2012; 1:3: 60-72.

33. Jadhav S., Kalambe R., Jadhav C., Tekade B., Patil V., Formulation and evaluation of fast dissolving oral film of

Levocetrizine dihydrochloride, International Journal Of Pharmacy and Pharmaceutical sciences 2012; 4:1: 337- 42.

34. Prasanthi N., Krishna C., Gupta E., Rao R., Design and development of sublingual fast dissolving films for an anti-asthmatic

drug, Scholars Research Library 2011; 3:1: 382- 95.

35. Desu P., Sahu M., Formulation and evaluation of fast dissolving film of Zolmitriptan, International Research Journal of

Pharmacy 2012; 3:5: 373- 6.

36. Cilurzo F., Cupone I., Minghetti P., Selmin F., Montanari L., Fast dissolving films made of maltodextrins, European Journal

of Pharmaceutics and Biopharmaceutics 2008; 70: 895-900.

37. Shelke P., Dumbare A., Gadhave M., Jadhav S., Sonawane A., Gaikwad D., Formulation and evaluation of rapidly

disintegrating film of amlodipine besylate, Journal of drug delivery & Therapeutics 2012; 2:2: 72- 5.

38. Murata Y., Kofuji K., Nishida N., Kamaguchi R., Development of filmdosage form containing allopurinol for prevention and

treatment of oral mucositis, International Scholarly Research Network 2012; 1-5.

39. Alpesh R. P., Dharmendra S. P., Jignyasha A. R., Fast Dissolving Films (FDFs) As A Newer Venture In Fast Dissolving

Dosage Forms, International Journal of Drug Development & Research 2009; 2:2: 232- 46.

40. Dipika P., Dr. Upendra P., Bhavin B., Aditi T., Dhiren D., Ghanshyam P., Orally Fast Dissolving Films As Dominant Dosage

Form For Quick Release, International Journal Of Pharmaceutical Research And Bio-Science 2012; 1:3: 27- 41.

41. Pandya K., Patel K., Patel M., Patel N., Fast dissolving films: a novel approach to oral drug delivery, Asian Journal of

Pharmaceutical Science & Technology 2013; 3:1: 25-31.

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