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258 Recent Patents on Drug Delivery & Formulation 2008, 2, 258-274

1872-2113/08 $100.00+.00 © 2008 Bentham Science Publishers Ltd.

Orally Disintegrating Systems: Innovations in Formulation and Technology

Honey Goel1, Parshuram Rai

2, Vikas Rana

1,* and Ashok K. Tiwary

1,*

1Pharmaceutics Division, Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala,

India-147002. 2Pharmaceutics Division, Shivalik College of Pharmacy, Naya Nangal, Punjab, India -140126

Received: May 21, 2008; Accepted: August 5, 2008; Revised: August 18, 2008

Abstract: Orally disintegrating systems have carved a niche amongst the oral drug delivery systems due to the highest

component of compliance they enjoy in patients especially the geriatrics and pediatrics. In addition, patients suffering

from dysphagia, motion sickness, repeated emesis and mental disorders prefer these medications because they cannot

swallow large quantity of water. Further, drugs exhibiting satisfactory absorption from the oral mucosa or intended for

immediate pharmacological action can be advantageously formulated in these dosage forms. However, the requirements

of formulating these dosage forms with mechanical strength sufficient to with stand the rigors of handling and capable of

disintegrating within a few seconds on contact with saliva are inextricable. Therefore, research in developing orally

disintegrating systems has been aimed at investigating different excipients as well as techniques to meet these challenges.

A variety of dosage forms like tablets, films, wafers, chewing gums, microparticles, nanoparticles etc. have been

developed for enhancing the performance attributes in the orally disintegrating systems. Advancements in the technology

arena for manufacturing these systems include the use of freeze drying, cotton candy, melt extrusion, sublimation, direct

compression besides the classical wet granulation processes. Taste masking of active ingredients becomes essential in

these systems because the drug is entirely released in the mouth. Fluid bed coating, agglomeration, pelletization and

infusion methods have proven useful for this purpose. It is important to note that although, freeze dried and effervescent

disintegrating systems rapidly disintegrate in contact with fluids, they do not generally exhibit the required mechanical

strength. Similarly, the candy process cannot be used for thermolabile drugs. In the light of the paradoxical nature of the

attributes desired in orally disintegrating systems (high mechanical strength and rapid disintegration), it becomes essential

to study the innovations in this field and understand the intricacies of the different processes used for manufacturing these

systems. This article attempts at discussing the patents relating to orally disintegrating systems with respect to the use of

different formulation ingredients and technologies.

Keywords: Orally disintegrating tablets, mouth dissolving tablets, fast disintegrating tablets, chewing gums, fast dissolving films, superdisintegrants.

INTRODUCTION

A vast variety of pharmaceutical research is directed at developing new dosage forms. Most of these efforts have focused on either formulating novel drug delivery systems or increasing the patient compliance. Among the dosage forms developed for facilitating ease of medication, the orally disintegrating systems have been the favorite of product development scientists. Table 1 [1-17] enlists the various drugs and ingredients formulated in to orally disintegrating tablets (ODT).

The concept of orally disintegrating dosage forms has emerged from the desire to provide patients with more conventional means of taking their medication. Interestingly, the demand for ODT has enormously increased during the last decade, particularly for geriatric and pediatric patients who experience difficulty in swallowing conventional tablets and capsules. Hence, they do not comply with prescription, which results in high incidence of ineffective therapy [18].

In disease conditions such as motion sickness, sudden episodes of attacks of coughing and repeated emesis *Address correspondence to these authors at The Department of Pharma-ceutical Sciences and Drug Research, Punjabi University, Patiala, India; Tel:

+91-09417457385; E-mail:[email protected]; [email protected].

swallowing conventional tablets be comes difficult. Orally disintegrating dosage forms can serve as an effective alternative mode of drug delivery in such situations. When put in the mouth, these dosage forms disintegrate instantly to release the drug, which dissolves or disperses in the saliva. Thereafter, the drug may get absorbed from the pharynx and oesophagus or from other sections of g.i.t as the saliva travels down. In such cases, bioavailability is significantly greater than that observed from conventional tablet dosage form [19-22]. Hence, orally disintegrating systems may be anticipated to result in achievement of the required peak plasma concentration rapidly for drugs stable in the gastric pH. The orally disintegrating dosage forms could be suitable for neuroleptics, cardiovascular agents, analgesics, anti-allergics and drugs for erectile dysfunction. The US FDA approved products of this category are summarized in Table 2 [23]. In the light of the above, the present article aims at critically analyzing various formulation and technological developments with respect to orally disintegrating systems.

ORALLY DISINTEGRATING TABLETS (ODTs)

The performance of ODTs depends on the technology used in their manufacture. The orally disintegrating property of these tablets is attributable to the quick ingress of water into the tablet matrix, which creates porous structure and results in rapid disintegration. Hence, the basic approaches to

Orally Disintegrating Systems: Advancements Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3 259

Table1. Ingredients and Technologies Used for Formulating Orally Disintegrating Systems

Orally

Disintegrating

System

Drug Disintegrating Agents Other formulation

Ingredients

Technology Disintegration

Time

Reference

No.

FDT Capecitabine Crospovidone

(intragranular and

extragranular)

Hypromellose (binder),

mannitol, microcrystalline

cellulose, Pharmaburst C

Wet granulation

and compression

50 sec (for

125mg tablet)

[1]

FDT Acetaminophen and

/ or Sodium

ibuprofen, Ibuprofen

lysine, Naproxen

Sodium,

Flurbiprofen

Sodium, Diclofenac

Potassium

Xylitol, croscarmellose

sodium, acetaminophen

and NSAID for

preparing melt mass

granules

Microcrystalline cellulose,

colloidal silicon dioxide,

magnesium stearate, stearic

acid

Melt extrusion

method and

compression

Less than 60

sec

[2]

FDT Amlodipine Besilate Avicel PH 101 or 301,

mannitol

Eudragit EPO Direct

compression

followed by

sublimation

0.25-.63 min [3]

FDT Modafinil Croscarmellose sodium,

MCC

Lactose, pregelatinized

starch

Wet granulation --- [4]

FDT Resperidone Mannitol, aspartame,

PEG 400, PEG 4000.

MCC (Ph 200), Gelucire

44/14

Spray drying and

compression

Less than 30

sec

[5]

FDT Clarithromycin or

Cefixime

Carrageenan NF,

tricalcium phosphate,

Pellets of drug composed

of Avicel PH 105,

Low-substituted

hydroxypropylcellulose,

Sucrose stearate

Extrusion-

spheronization

Less than 60

sec

[6]

FDT Famotidine Mannitol, PVP K30,

dextran, sucralose

Sugar spheres, lactose Freeze drying 2-6 sec [7]

FDT Epinephrine

bitartrate

Microcrystalline

cellulose (PH-301),

Crospovidone, mannitol

Low-substituted

hydroxypropyl cellulose

(LH11), magnesium

stearate

Direct

Compression

<10 sec [8]

FDT Diclofenac

Acetylsalicylic Acid

Mannitol (20.0 kg),

sodium

carboxymethylcellulose

Citric acid in ethanol,

ethylcellulose, aspartame

Molding,

decompression

----- [9]

FDT

Solid dispersion

ADH Croscarmelllose sodium Sodium bicarbonate,

lactose

Granulation ------ [10]

FDT Ibuprofen

Indomethacin

Naproxen

Diclofenac

Crospovidone, SSG,

mannitol, MCC, xanthan

gum

Silica, magnesium stearate,

sodium saccharine, talc

Direct

Compression

8-15 sec [11]

FDT Ondansetron Sodium starch glycolate

Polacrillin potassium

microcrystalline

cellulose

Colloidal silicon dioxide,

aspartame, purified talc

Direct

Compression

10-15sec [12]

FDT Fexofenadine Mannitol,

crospovidone

Precipitated silica,

magnesium stearate

sucralose

Direct

Compression

15-20 sec [13]

260 Recent Patents on Drug Delivery & Formulation, 2008, Vol. 2, No. 3 Tiwary et al.

(Table 1) Contd….

Orally

Disintegrating

System

Drug Disintegrating Agents Other Formulation

Ingredients

Technology Disintegration

Time

Reference

No.

FDT Ascorbic acid,

Cimetidine

Erythritol, D-mannitol,

microcrystalline

cellulose

Corn starch, pregelatinized

starch

Molding, direct

Compression

31-37 sec [14]

FDT Topiramate Mannitol, croscarmellose

sodium

Hydroxypropyl- -

cyclodextrin, PEG 3350

mannose, silicon dioxide

lactose

Wet Granulation --

[15]

FDT Sildenafil granules Crosslinked povidone Lemon flavour, aspartam,

mannitol

Freeze drying < 30 sec [16]

FDT Olanzapine

Donepezil

MCC, mannitol Sodium stearyl fumerate,

polacrilin potassium, SlS,

aspartam, stawberry flavour

Direct

compression

< 30 sec [17]

Table 2. List of US FDA Approved Products Available in the Market [23]

Patented

Technology Products

® Name of

the Company Composition

Claritin

Reditab

R. P. Scherer / Schering Plough,

Kenilworth, USA.

Micronized loratidine (10mg),

citric acid, mannitol, gelatin, mint flavor

Feldene Melt Pfizer Inc, NY, USA. Piroxicam (10 or 20 mg), mannitol, gelatin, aspartame, citric anhydrous

Maxalt-MLT R.P.Scherer / Merck & Co., NY, USA. Rizatriptan (5 or 10 mg), mannitol, gelatin, aspartame, peppermint

flavor

Pepcid RPD Merck & CO., NY, USA. Famotidine (20 or 40 mg), mannitol, gelatin,aspartame

Zyprexa Zydis R.P.Scherer/Eli Lilly, Indianapolis,

USA.

Olanzapine (5, 10, 15 or 20 mg), mannitol, gelatin, aspartame, methyl

paraben sodium, propyl paraben sodium

Zydis

Zofran ODT R.P.Scherer/Glaxo Wellcome,

Middlesex, UK.

Ondansetron (4 or 8 mg), mannitol, gelatin, aspartame, methyl paraben

sodium, propyl paraben sodium, strawberry flavor

Remeron Soltab CIMA / Organon,

Glaxo Wellcome, Middlesex, UK.

Mirtazepine (15,30 or 45 mg), mannitol, aspartame, citricacid

crosspovidone, Avicel, NaHCO3, HPMC, magnesium stearate

povidone, PMA, starch, sucrose, orange flavor Orasolv

Tempra First Tabs CIMA / Mead Johnson, Bristol Myers

Squibb, NY, USA.

Acetaminophen (80 or 160 mg),

mannitol (currently available in Canada)

Nulev CIMA/Schwarz Pharma. Hyoscyamine sulphate (0.125mg), aspartame, colloidal silicon dioxide

crospovidone, mint flavor, magnesium stearate, mannitol, Avicel

Durasolv

Zoming ZMT CIMA / AstraZeneca, Wilmington,

USA.

Zolmitriptan (2.5mg), mannitol, aspartame, citric acid anhydrous

crospovidone, Avicel, sodium bicarbonate, magnesium stearate

colloidal silicon dioxide, orange flavor

develop ODTs include maximizing the porous structure of the tablet matrix, incorporating the appropriate disintegrating agent and using highly water-soluble excipients in the formulation [24]. Figure (1) depicts the various techniques used for making ODTs utilizing heat based processes.

I. Technologies Employing Heating Process

Cotton Candy Process or its Modifications

The cotton candy process is also known as the “candy floss” process and forms the basis of Flash Dose technology. The process comprises of formulation of matrix from


saccharides or polysaccharides which is processed into amorphous floss by simultaneous action of flash melting and centrifugal force [25]. There are various preblend mixtures used in the manufacture of ‘floss’, few of which are summarized in Table 3 [26,27]. The matrix is then cured or partially recrystallised to provide a compound with active ingredients and other excipients and subsequently com-

pressed to form an ODT. However, the high processing temperature limits the use of this technology to thermostable compounds only [28].

Flash flow processing can be accomplished in several ways. Flash-heat and flash-shear are two processes which are quite popular. In the flash-heat process, the feedstock material is heated sufficiently to create an internal flow

Fig. (1). Schematic representation of the processes involved in the preparation of ODTs by employing heat based technology.


condition that forces part of the feedstock to move at sub-particle level with respect to the rest of the mass and exit from the openings provided in the perimeter of a spinning head. The centrifugal force created in the spinning head flings the flowing feedstock material outwardly from the head so that it reforms with a changed structure. The force necessary to separate and discharge the flowable feedstock is the centrifugal force that is produced by the spinning head. One preferred apparatus for implementing a flash heat process is a "cotton candy" fabricating type of machine.

In the flash-shear process, a shear form of matrix is formed by raising the temperature in the feedstock material. The feedstock material contains a non-solubilized carrier (e.g sucrose, dextrose). The flowability of shear form matrix was increased by firstly crystallizing the matrix either before or after the addition of crystallizing promoters (e.g. polyvinyl pyrrolidone, ethanol or surfactants like tweens and spans). The flowable comestible units were compressed (6-8 strong cobb units) to form low density, highly disintegratable tablets. The ingredients in an ODT formulations included were magnesium hydroxide and aluminium hydroxide for drugs like aspirin, acetaminophen, cimetidine, ranitidine etc. [29]. In a patented process, a mixture of active ingredient and amorphous sugar was subjected to a flash flow process where the sugar crystallized in the form of a type of candy floss. The candy floss containing voluminous composition was shaped into tablets with small forces (80 psi) and then subjected to moist atmosphere for curing [30]. A flash melt pharmaceutical dosage form comprising a medicament and a combination of dispersing agent, a distributing agent and a binder was patented by Kothari et al. (2006). The four excipients, medicament and suitable conventional ingre-dients were dry granulated [31]. Another, flash melt dosage form of aripiprazole, chlorpheniramine maleate, psuedoe-phedrine, diphenhydramine HCl, phenylpropanolamine, cimetidine, loperamide, meclizine, entecavir, cefprozil, pravastatin, captopril, fosinopril, irbesartan, omapatrilat, gatifloxacin or desquinolone was prepared by using a combi-nation of a superdisintegrant, dispersing agent, distributing agent and binder by dry granulation process [32].

Wet Granulation Method

Julia et al. (2006, 2007) prepared fast water dispersible tablets containing domperidone. A combination of D-mannitol and maize starch gum was used as the binder. The mixture of domperidone and microcrystaline cellulose (10-30%) was mixed with binder solution and granulated in a high shear mixer. The dried granules were mixed with

magnesium stearate, flavours (Strawbarry, mango etc.) and compressed to form tablets. The tablets were found to exhibit low friability (less than 1%) and hardness value of 3 to 6 Kp. The tablets disintegrated within 1 min. Hence, the formu-lated tablets exhibited both enhanced structural integrity and decreased disintegration time [33, 34]. The capecitabine tablet (approved for colon and breast cancer) prepared by using traditional disintegrants such as lactose and croscarmellose sodium is not easily swalloable due to its high dose and requires approximately 7-12 minutes for disintegration in water depending on the size of the tablet. This is because the tablet disintegrates by surface erosion and is not amenable to rapid dispersion or disintegration in water prior to oral administration to swallowing-compromised patients. Bachynsky et al. (2008) developed rapidly disintegrating film coated capecitabine tablets using wet ganulation method by employing hypromellose as binder and lactose as diluent. These tablets were found to possess hardness of 8-13 Strong Cobb units and disintegrated in water in less than 1min. This duration was 8-13 fold shorter than that required by traditional tablets. The other commonly employed disintegrants for this purpose include cros-povidone (particle size< 15-400 ), Croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypro-pylcellulose, Pharmaburst C™, a mannitol/sorbitol combi-nation or any combination of these, together with other pharmaceutically acceptable excipients [1]. A process for producing tablets using wet granulation was developed in which initially active ingredients; water soluble binder and water-soluble bulking agent were tabletted under very low pressure. The resulting tablets were then moistened and subsequently dried [35, 36].

Melt extrusion Method

Preparation of ODTs of NSAID and paracetamol by melt extrusion method was patented by Sherry et al. (2008). The method involved dry blending of sugar alcohol and drugs with other excipients that may be present in the granular component. This powder mixture was heated at a tempe-rature of 100 to 165°C in an extruder in order to completely melt the sugar alcohol. This resultant mass consisting of fully or partially molten sugar alcohol (xylitol, sorbitol, mannitol, etc.) and non-molten (NSAID (ibuprofen, naproxen, diclofenac) or paracetamol) and other optional excipients was poured on cooled stainless steel trays or a cooled moving belt (10°C) and allowed to cool. The molten mixture typically solidified within 60 sec. The solid mass thus formed was milled by passing through a cone mill fitted

Table 3. Various Preblend Compositions Used in Floss Processes

Floss preblend compositions Drugs Reference No.

Sucrose (78.25%), sorbitol (11.0%), xylitol (10.0%) and tween 80

(0.75%)

Ibuprofen, cimitedine, vitamin C, calcium carbonate/vitamin D

or acetaminophen

[26]

Sucrose (84.5%), mannitol (5.0%), sorbitol (5.0%), xylitol (5.0%),

polysorbate 80 (0.5%)

Ibuprofen, cimitedine, vitamin C, calcium carbonate/vitamin D

or acetaminophen

[26]

Sucrose (84.75%), sorbitol (12.00%), - lactose (3.00%), tween 80

(0.25%)

Ibuprufen, aspirin, acetaminophen [27]


with a screen with a round hole of 1 mm diameter. The resulting granules were blended with extra-granular components namely, colloidal silicon dioxide, magnesium stearate, stearic acid, lactose, dicalcium phosphate and microcrystalline cellulose in a blender. The blended material was fed to a rotary tabletting machine and compressed into tablets under compaction force ranging from 4 kN to 14 kN. It was reported that tablets obtained from fully melted xylitol were more robust than tablets produced by conventional dry blending process [2]. It is important to note that the sugar alcohol can be melted under pressurised conditions at a temperature below its normal melting point. Further, if melting was carried out by heating in a vessel to a temperature above the melting point of the sugar alcohol or by extrusion in a heated extruder, the maximum temperature was normally determined by the thermal stability of the molten sugar alcohol and the incorporated ingredients. Generally, the higher the temperature, the more quickly the sugar alcohol will melt although, this needs to be balanced by the energy input required for heating the sugar alcohol Table 4. For highest efficiency, it is advisable to heat the sugar alcohol to 10-30°C above its melting point to keep energy costs to a minimum. Kuno et al. (2005) prepared ODTs containing high melting (erythritol, m.p 122°C) and low melting (xylitol, m.p 93-95°C) sugar alcohols. They were heated to 93°C for 15 min. The hardness and oral disintegation time of the heated tablets increased with an increase of the xylitol content. Further, after heating, the median pore size of the tablets was found to increase and the tablet hardness too increased. Moreover, the increase in tablet hardness with heating and storage did not depend on the crystal state of the lower melting sugar alcohol. This suggested that a phase transition of sugar alcohols during the manufacturing process as well as presence of the combination of the low and high melting sugar alcohols contributed to the decrease in the disintegration time and increase in the hardness of the ODTs [37]. In another patent, escitalopram base was prepared from escitalopram salts of hydrobromic or oxalic acid. The crystalline escitalopram base and mannitol (Pearlitol SD) were melt agglomerated in a high shear mixer rotating at a speed of 500 rpm and kept at a temperature of 50°C. The resulting mixture was mixed with mannitol (extragranular), microcrystalline cellulose and magnesium stearate. This mixture was compressed directly in to tablets at a hardness of 22N. The resulting tablets exhibited DT of less than 120 sec [38].

Wow Tab technology was patented by Yamanouchi Pharmaceutical Co. Rapidly disintegrating tablets were prepared by using a combination of saccharides possessing low and high moldability. The active ingredient was mixed with a saccharides possessing low moldability and granu-lated with a saccharides possessing high moldability followed by compression into tablets [39-41]. Saccharides can be divided into high and low compressibility categories. For preparing ODT with improved compressibility, a low compressible saccharide (modified by coating and granu-lation) was mixed with a highly compressible saccharide. The high compressibile saccharide used in the form of a binder solution was present in an amorphous state after granulation process. The change from amorphous to

Table 4. Melt Extrusion Temperature Conditions of Sugar

Alcohols [37]

Sugar alcohols Melting Point (° C) Melt extrusion range

(° C)

D-sorbitol 98 to 100 108 -132

Xylitol 95 to 97 102 -127

Adonitol 102 to 104 112 - 134

Arabitol 101 to 104 111 -134

Mannitol 167 to 170 177 - 200

meso-Erythritol 120 to 123 130-153

crystalline state intentionally by a conditioning process involved preparation of granules by spraying maltose solution followed by compression. This resulted in tablets possessing high hardness by strengthening adhesion between particles. The conditioning process made it possible to achieve sufficient hardness while maintaining a low disintegration time [42].

Sublimation Process

The key to rapid disintegration of ODT is the preparation of a porous structure in the tablet matrix. To generate such a porous matrix, volatile ingredients are incorporated in the formulation that is later subjected to a process of subli-mation. Highly volatile ingredients like ammonium bicarbonate, ammonium carbonate, benzoic acid, menthol, camphor, naphthalene, urea, urethane or phthalic anhydride could be compressed along with other excipients into a tablet [43]. The volatile material is then removed by sublimation leaving behind a highly porous matrix. Tablets manufactured by this technique are reported to usually disintegrate in 10-20 sec. Even solvents like cyclohexane, benzene could be used as pore forming agents [44]. Koizumi et al. (1997) applied the sublimation technique to prepare highly porous compressed tablets that were rapidly soluble in saliva. Mannitol and camphor were used, respectively, as tablets matrix and subliming material. Camphor was vaporized by subliming in vacuum at 80°C for 30 min to develop pores in the tablets [45]. Gohel et al. (2004) used camphor along with Crospovidone to prepare fast disintegrating tablets of nimesulide [46].

In a patent, the technique comprised of first mixing an active ingredient, an acrylic copolymer and at least a pharmaceutically acceptable additive to obtain a mixture. This mixture was then compressed to obtain a compact. The compacted tablets were isothermally heated at a temperature of 50°C to 100°C for a given period of time [3]. For example, 115.36 g of crystalline cellulose (Avicel PH301), 173.04 g of mannitol and 11.6 g of aminoalkyl methacrylate copolymer (EUDRAGIT- EPO) were mixed at 800 rpm for 3 minutes. Portions of the obtained mixture were tableted (2.0 kN, 2.5 kN or 2.9 kN) with target weight of 180 mg. After keeping at 80°C for 10 hours, the obtained compacts were allowed to stand and cool to room temperature to obtain rapidly disintegrating tablets.


II. Technologies not Employing Heating Process

Freeze Drying

Freeze drying (lyophilisation) is a process in which solvent is removed from a frozen drug solution or suspension containing structure forming excipients Fig. (2). The resu-lting tablets are usually very light and have a highly porous structure that allows rapid dissolution. The unit dissolves almost instantly when placed on tongue to release the incorporated drug. The entire freeze-drying process is done at non-elevated temperature, therefore eliminating adverse thermal effects that may affect the drug stability during processing.

Yarwood (1990) patented the process for preparing freeze dried tablet in which the drug was physically entrap-ped or dissolved in the matrix of a fast-dissolving carrier material. When placed in the mouth, the frozen structure disintegrated instantaneously. The process involved removal of water by sublimation upon freeze drying from the liquid mixture of drug, matrix former, and other excipients filled into preformed blister pockets [47]. The matrix structure formed was highly porous and rapidly disintegrated upon contact with saliva [48]. The ODTs may contain many materials designed to achieve a number of objectives. Poly-mers such as gelatin, dextran or alginates are incorporated for imparting strength and resistance during handling. These

Fig. (2). Schematic representation of the process involved in the different methods for preparation of ODTs without using heating process


agents form an amorphous structure, which imparts strength. Crystallinity, elegance and hardness are imparted by saccharides such as mannitol or sorbitol. Water used in the manufacturing process ensures the production of porous units to achieve disintegration. Various gums are added for preventing sedimentation of dispersed drug particles during the manufacturing process. Collapse protectants such as glycine prevent the shrinkage of ODTs during long term storage. Finally, packing in blister packs protects the formulation from moisture during storage [24]. The formulation ingredients added in ODTs prepared by freeze drying method are summarized in Table 5.

Durasolv is the patented technology of CIMA Labs. It is an applied technology for products requiring low amounts of active ingredients. Tablets prepared by this process, utilized a combination of non compressible fillers, a taste masking excipient and active ingredient. The dry blend of these ingredients was compressed into tablets using a conventional rotary tablet press [49]. Tablets were reported to possess higher mechanical strength and were sufficiently robust to be packaged in blister packs or bottles.

A freeze dried dosage form was prepared by bonding or complexing a water-soluble active ingredient (phenyle-phrine, chlorpheniramine maleate, triprolidone or pseudo-ephedrine) with an ion exchange resin, Amberlite IPR-276 or IPR-69 (a copolymer of styrene and divinyl benzene) to form a substantially water insoluble complex. This complex was stirred for 24 hrs with an appropriate carrier and then freeze dried (-40°C to -150°C). The ratio of drug: resin was 1:5. The degree of complexation of the active ingredient (alkaline in nature) can be increased by adjusting pH of resin to 8. The formulation was found to disintegrate in 4-5 sec. [50]. In another method, freeze dried dosage form was made by adding xanthan gum to a suspension of gelatin and active agent [51]. A process patented by Scherer Corporation involved freeze-drying of a dispersion containing a hydrophilic active ingredient and surfactant in a non-aqueous phase, and a carrier material in an aqueous phase [52]. Although, this technique produced a product that rapidly disintegrated in water or in the oral cavity, the drawback of

poor physical integrity of the physical structure severely limited further manufacturing operations (such as forming blister packs). Another significant drawback associated with the freeze drying technique in manufacturing these dosage forms is the high production cost, because of the lengthy duration of each freeze drying cycle. Moreover, the thermal shocks might physically modify the physicochemical properties of the outer membrane of microencapsulated particles.

Effervescent Disintegration System

Another process developed by CIMA Labs is the Orasolv Technology [53]. In this process, an effervescent disin-tegrating agent is employed. The effervescent excipient (known as effervescent couple) is prepared by coating the organic acid crystals with a stoichiometrically lesser amount of material that is alkaline in nature. The particle size of the organic acid crystals is carefully chosen to be larger than the alkaline excipient to ensure uniform coating of the alkaline excipient on the acid crystals. The coating process is initiated by the addition of a reaction initiator (water). The reaction is allowed to proceed only to the extent of completing the coating of alkaline material on organic acid crystals. The required end point for reaction termination is determined by measuring carbon dioxide evolution. Then, the excipient is mixed with the active ingredient or its micro particles alongwith other standard tableting excipients and finally compressed into tablets. Saliva activates the effervescent agent, causing the tablet to disintegrate [54, 55].

An effervescent formula was designed for acetylsalicylic acid. The key excipients included CO2 donor (eg. alkali metal and alkaline earth metal carbonates and bicarbonates like sodium bicarbonate) and an acidic component for liberating CO2 from donor. The other ingredients in the formulation were monosaccharides (glucose, maltodextrin etc.), binders (glycine, polyvinylalcohol) and wetting agents (dioctyl sodium sulphosuccinate). The prepared ODTs immediately sank to the bottom and were observed to get moistened throughout. Disintegration was spontaneous (2-5 sec) with evolution of CO2 [56].

Table 5. Excipients Used in the Manufacture of FDT Using Freeze Drying Technique [47]

Excipients Main Purpose Examples

Polymer Strength and rigidity Gelatin, alginate, dextrin, hydrolyzed dextran,

poly(vinyl alcohol), polyvinyl pyrrolidone

Polysaccharides Crystallinity, hardness and palatability Mannitol and sorbitol

Collapse protectants Prevention of shrinking Glycerin

Flocculating Agents Uniform dispersion Xanthan and acacia gum

Preservatives Prevention of microbial growth Parabens

Permeation enhancer Transmucosal permeability enhancer Sodium lauryl sulphate

pH adjusters Chemical stability Citric acid and sodium hydroxide

Flavours and sweeteners Patient compliance Aspartame, orange flavor

Water Porous unit formation ------


Direct Compression Method

Direct compression is viewed as the technique of choice for the manufacture of tablets containing thermolabile and moisture-sensitive drugs. Although, it affords many advan-tages, it is still not as popular as wet granulation method. Successful tablet production depends on achievement of the right balance between brittle fracture and plastic behavior within the compression mixture, which, in turn, is dependent upon the compressional characteristics of the drug substance and the excipients. Theoretically, substances such as microcrystalline cellulose undergo plastic deformation while dicalcium diphosphate undergoes brittle fracture during direct compression. However, in practice, most excipients and drugs get compacted by a combination of these mechanisms. The excipients could be ranked in descending order in terms of their brittleness: microcrystalline cellulose > spray-dried lactose > -lactose > -lactose > -lactose monohydrate > dicalcium phosphate dihydrate. The main advantage of wet granulation is that the poor compressional and flow properties exhibited by many drug substances can be masked as a result of their incorporation into a granule, allowing batch-to-batch differences to be ‘submerged in a sea of starch paste or povidone’. However, with the judicious choice of excipients combined with an appropriate drug substance, the reward for establishing a direct compression process can be substantial. A summary of the advantages and disadvantages of direct compression have been outlined in Table 6. A more detailed discussion on the influence of different types and properties of directly compressible excipients on release of drugs from solid dosage forms has been compiled by Tiwary et al. (2008) recently [57].

Microcrystalline cellulose (MCC) is a good excipient for direct compression processing. Microcrystalline cellulose has inherently high compactibility due to its plastic deformation and limited elastic recovery. It usually provides good dispersion and uniform mixing with drugs. However, the material flow properties are relatively poor for most grades of microcrystalline cellulose. Intermittent and non-uniform flow can occur as the formulation moves from the hopper to the die on a tablet press. This non-uniform flow can lead to drug content variation in the finished tableted dosage form. Staniforth et al. (2002) patented a formulation for improving the direct compression property of micro-crystalline cellulose. MCC and compressibility augmenting agent, were mixed with sustained release carrier (ethyl-cellulose, acrylic and methacrylic polymers, polysaccharides,

hydroxy ethyl amylose etc.). The active ingredients were added to water and vigorously stirred. The resulting aqueous slurry containing intimately combined materials was spray dried to provide an agglomerated material which was directly compressed to form ODTs. The resulted self-binding tablets disintegrated rapidly when placed in water. The coprocessed composition was found to be useful for both water soluble and water insoluble drugs (antihistaminics, analgesics, NSAIDs, antiemetics, antitussives, etc.) [58]. An excipient comprising microcrystalline cellulose having a degree of polymerization of 190 to 210 and an acetic acid holding capacity of 280% or more was prapared. The excipient exhibited high compactibility and high rate of disintegration. It was obtained by heat treatment an aqueous dispersion (40 %w/w) of purified cellulose particles at 100 ºC followed by drying [59]. Tablets were prepared by directly compressing a solid mixture containing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (5 to 140 mg), anhydrous lactose (20-80 %w/w), granulated microparticles cellulose (0.001-50%w/w), sodium CMC (2mg/tablet), magnessium stearate (1mg/tablet), mannitol (10-50%) and calcium hydrogen phosphate (5-50%w/w). The tablet disintegrated with in 90 sec when 80% mannitol was added. However, the disintegration time reduced to 15 sec when concentration of MCC was increased from 0-80 %w/w. Further, the assay of the active ingredient indicated its stability in the presence of excipients [60].

ODTs with improved compressibility were prepared by employing a colloidal solution of augumenting agent like stearic acid in polyvinyl pyrrolidone (PVP). The solution was prepared by adding hot (90 ºC) aqueous solution of PVP K30 to 2% w/w molten stearic acid under stirring conditions. The colloidal solution was cooled to 70ºC and then appropriate quantity of co-processed starch or cellulose (like sodium starch glycolate) was added to produce a suspension. The suspension was stirred for 10 min and then kept for drying in an oven. The resulting mass was compressed into tablets. These tablets disintegrated in less than 1min [61, 62]. Another method of modifying the characteristics of microcrystalline cellulose involved subjecting cellulose to the hydrolytic action by treatment with hydrochloric acid at boiling temperature. The amorphous cellulosic material was removed and aggregated crystalline cellulose was formed. The aggregates were collected by filtration, washed with water and aqueous ammonia. They were then disintegrated into small fragments after blending [63]. MCC is water-

Table 6. Ideal Requirements, Advantages and Limitations of Direct Compression

S. No Ideal requirements Advantages Limitations

1. Flowability Cost effective production Segregation

2. Compressibility Better stability of API Variation in functionality

3. Dilution Potential Faster dissolution Low dilution potential

4. Reworkability Less wear and tear of punches Reworkability

5. Stability Simple validation Poor compressibility of API

6. Controlled Particle Size Low microbial contamination Lubricant sensitivity


insoluble, but it has the ability to draw fluid into the tablet lattice by capillary action. The tablet then swells on contact with water and hence, microcrystalline cellulose acts as disintegrating agent. The material has better self lubricating capability as compared to other excipients. However, exposure of MCC to moisture in wet granulation process severely reduces its compressibility. Hence, larger amount of this material is needed to obtain an acceptable compressed final product. Therefore, it is acceptable to be used in tablets prepared by direct com-pression method.

Silicified MCC was prepared and is available as PROSOLVSMCC

™. Silicification of MCC results in an

intimate association between colloidal silica and MCC particles. This product is available in a median particle size (by sieve analysis) in the range of 50 m to 90 m. It has good compressibility and disintegration properties. Thus, it is suitable for in both wet granulation as well as direct compression method [64-68].

Paroxetine immediately disintegrating tablets were prepared by using a dry blend of paroxetine, a water soluble dispersing agent (polyvinyl pyrrolidone), calcium carbonate, sodium starch glycolate and a taste masking agent (potassium salt of polyacrylic acid ion exchange copoly-mers) [69]. Meloxicam directly compressed fast disinteg-rating tablets were prepared by using starch (20-50 % w/w) and cellulose [70]. A directly compressible tablet of para-cetamol, ibuprofen or vitamin C was prepared using STAR-LAC

®, aspartame and magnesium stearate. The tablets

prepared at a hardness of 45N, were found to disintegrate in less than 30 sec in mouth [71]. Hence STARLAC

® was

found to have super disintegration properties, although it consisted of just starch and lactose [72]. Crosslinked amylose tablets exhibit low degree of cross-linking and swell in aqueous media. Powder of crosslinked amylose having a specific crosslinking degree for use as a binder/disintegrant in tablets was prepared by direct compression [73]. Powders of crosslinked amylose with a high crosslinking degree are said to allow tablets to disintegrate quickly (in less than a minute) owing to their high capacity to absorb water with excessive swelling. A non swelling crosslinked cellulose having a crosslinking degree ranging from 2 to 50 and prepared by crosslinking cellulose (fibrous cellulose or microcrystalline cellulose) with a cross-linking agent (epichlorhydrin, sodium trimetaphosphate, adipic-acetic anhydride, phosphorous oxychloride, formaldehyde and di-epoxides) was prepared. The relative amount of crosslinking agent per 100g of cellulose was 2-50 g [74]. A water dispersible tablet of lamotrigine was prepared by using 0.25-40 %w/w of pharmaceutically acceptable swellable clay in the granules. The use of swellable clay was found to retard the disintegration time of the tablet [75, 76].

Azithromycin is not considered to be amenable to the production of directly compressible tablets. The directly compressible tablet comprised of 1-80%w/w of azithro-mycin monohydrate hemi-isopropanol solvate or azithro-mycin monohydrate hemi-n-propanol solvate. The tablets produced by this method were found to possess acceptable hardness and friability. The Carr's compressibility index of the dry blend was found to be less than 34% [77].

Luber et al. (2008) patented a swallowable immediate release tablet consisting of at least 60% w/w of acetaminophen, 1-10 % w/w of a powdered wax (5 to 100 microns) having a melting point greater than 90°C, and less than about 25 % w/w of a disintegrant. The powdered wax included linear hydrocarbon (polyalkalene waxes) or other waxes (shellac wax, microcrystalline wax, carnauba wax, spermaceti wax, bees wax etc.). Sweeteners (aspartame, acesulfame potassium, sucralose) and disintegrants (micro-crystalline cellulose, starch, sodium starch glycolate, cross polypyrrolidone) were added on the disintegrant mixture. The powdered waxes melted at body temperature and disintegrants added to tablet swelled on coming in contact with saliva. This resulted in quick disintegration of tablets. Various drugs like analgesics, antipyretics (acetaminophen, ibuprofen), antihistaminics, diuretics etc. could be advantageously formulated into this type of tablets. The results indicated that the active constituents released from swellable immediate release tablets were in the range of 98-100% within 30 min in 5.8 pH buffers [78].

Robinson et al. (2006) developed a compressed, che-wable tablet containing active ingredient, water-disin-tegratable, compressible carbohydrate and binder. These components were dry blended and compressed into a convex-shaped tablet having a hardness of about 2 to about 11 kp/cm

2 . The tablets exhibited a friability of less than 1%.

Objectionable taste of active ingredients could be masked by coating with a taste masking composition. Compressing at reduced force reduces the fracture of the coating used for masking the unpleasant taste of the active ingredient. These convex-shaped, chewable tablets were softer than conventional chewable tablets, which resulted in improved product taste, mouthfeel, and ease of chewing. The convex tablet geometry significantly reduced the tablet friability at a given compression force. This reduction in tablet friability allowed the use of lower compression forces and lower tablet hardness, while maintaining the ability to process the tablets with conventional bulk handling equipment and package them in conventional bottles [79].

Crosslinked celluloses or modified celluloses are highly useful for orally disintegrating system. They offer quick disintegration due to which they are called ‘superdisin-tegrants’. The properties of few commonly used super-disintegrants are enlisted in Table 7 [80, 81]. These super-disintegrants are often mixed with conventional disintegrants for achieving the desired effect. Few important commercial brands and their use are summarized in Table 8. Ac-Di-Sol

®

is an internally crosslinked form of sodium carboxy-methylcellulose. It differs from soluble sodium carboxy-methylcellulose because its cross-linking ensures that the product becomes essentially water insoluble. Internall, crosslinking is induced by lowering the pH of sodium carboxymethyl cellulose solution and then heating it without chemical additives. The Ac-Di-Sol

® is virtually insoluble,

yet highly hydrophillic and therefore, swellable. It is effective for both direct compressed (1-3 %w/w) as well as wet granulated (6-8 %w/w) formulations [82].

Tian et al. (2005) developed a method for preparing ODTs using superdisintegrants (crospovidone, croscar-mellose sodium, sodium starch glycolate) and mannitol. An


Table 7. Properties of Modified Starches/Celluloses Used in ODTs [80-81]

S. No. Superdisintegrant Properties

1. Croscarmellose sodium High swelling capacity, effective at low concentration (0.5-2.0%), can be used up to 5%

2. Crospovidone Completely insoluble in water. Rapidly disperses and swells in water, but does not gel even after

prolonged exposure. Greatest rate of swelling compared to other disintegrants. Greater surface area to

volume ratio than other disintegrants. Effective concentration (1-3%). Available in micronized grades if

needed for improving state of dispersion in the powder blend

3. Sodium starch glycolate Absorbs water rapidly, resulting in swelling up to 6%. High concentration causes gelling and loss of

disintegration

Table 8. Application of Various Commercially Used Combinations of Modified Cellulose/Starch Used in ODTs [80-81]

Superdisintegrants and Disintegrants Applications

Brand Name Common Name Classification Functional

Category Properties

EMC at 25ºC/

90%RH Typical Uses

CL-Kollidon Crospovidone Polyvinyl-pyrrolidone Tablet super

disintegrant

Swelling (18% in

10s), (45% in 20s) 62%

Disintegrant

(Dry and Wet

granulation)

Ac-DiSol Croscarmellose

Sodium

Cellulose, carboxymethyl

ether, sodium salt crosslinked

Tablet and

capsule

disintegrant

Wicking and

swelling

(12% in 10s),

(23% in 20s)

88% Disintegrant for

capsules, tablets and

granules

Explotab

Primojel

Sodium starch

glycolate

Sodium carboxymethyl

starch

Tablet and

capsule super

disintegrant

Swelling capacity

(300 times)

-- Disintegrant

(Dry and Wet

granulation)

Explotab

V17

Sodium starch

glycolate

(Cross linked substituted

carboxymethyl ether) sodium

carboxymethyl starch

Super

disintegrant

More swelling

than Explotab

--- Disintegration and

dissolution aid. Not

for use in wet

granulation

Explotab

CLV

Sodium starch

glycolate

(Cross linked low substituted

carboxymethyl ether)Sodium

carboxymethyl starch

Super

disintegrant

Swelling --- Use in wet

granulation and high

shear equipment

L-HPC Hydroxypropyl

cellulose(low

substituted)

Cellulose, 2-hydroxypropyl

ether

Tablet and

capsule super

disintegrant

Swelling

(13% in 10s),

(50% in 20s)

37% Disintegrant and

Binder in wet

granulation

Amberlite

IRP 88

Polacrillin

Potassium

Cation exchange resin Diluent and

disintegrant

Swelling Disintegrant

Starch 1500 Starch,

pregelatinized

Pregelatinized

starch

Diluent , binder

and disintegrant

Hygroscopic 22% Binder/diluent and

disintegrant

Avicel Microcrystalline

cellulose

Cellulose Tablet and

capsule diluent,

Tablet

disintegrant

Hygroscopic,

swelling-(12% in

10s), (18% in 20s)

18% Binder/diluent,

lubricant and

disintegrant

equal part of superdisintegrant was mixed with mannitol to form agglomerates by adding water. The agglomerates were dried in a forced air oven at 55ºC and screened though a 500

micron sieve. Powdered mannitol was separately agglo-merated with purified water in a granulator and dried in a fluid bed drier at 60ºC. Superdisintegrant agglomerates (13


%w/w) were mixed with mannitol agglomerates (86%) and compressed. The resultant ODTs possessed hardness of 1.5 Kp and disintegrated within 10.5 sec [83]. A method for improving the compressibility of a superdisintegrant by causing a partial or complete internal co-transformation of superdisintegrant particles or by temporarily opening up the particles and adding an augmenting agent (surface active agents e.g. sodium lauryl sulphate, docusate sodium or oligomers and polymers eg. cyclodextrin or maltodextrins) was proposed. This incor-porated ingredients enhanced the properties of the super-disintegrant relative to the unmodified particles of the superdisintegrants [84].

ORALLY DISINTEGRATING FILMS

Films containing a pharmaceutically active ingredient were prepared by Fuchs et al. (1979). These films may be formed into a sheet, dried and then cut into individual doses. The Fuchs disclosure claims the fabrication of a uniform film, which included a combination of water soluble polymers, surfactants, flavors, sweeteners, plasticisers and drugs. These flexible films were claimed to be useful for oral, topical or enteral use. Examples of specific uses disclosed by Fuchs include application of the films to mucosal membrane areas of the body, including the mouth, rectum, vagina, and nasal and ear areas. Examination of films made in accordance with the process disclosed by Fuchs, however, reveals that such films suffered, from the aggregation or conglomeration of particles, (self-aggre-gation), making them inherently non-uniform. This could be attributed to Fuchs' process parameters, which although not disclosed, likely included the use of relatively long drying times, thereby facilitating intermolecular attractive forces, convection forces, air flow etc. [85]. Schmidt (2004) specifically pointed out that the methods disclosed by Fuchs did not provide a uniform film. Schmidt abandoned the idea that a mono-layer film, as described by Fuchs, may provide an accurate dosage form and instead attempted to solve this problem by forming a multi-layered film. Moreover, his process is a multi-step process that adds expense and complexity and is not practical for commercial use [86].

In an attempt to overcome the non-uniformity, Horstmann et al. (1997) and Zerbe et al. (1999) incorporated additional ingredients, i.e. gel formers and polyhydric alcohols respectively, to increase the viscosity of the film prior to drying in an effort to reduce aggregation of the components in the film [87, 88]. However, these methods displayed the disadvantage of requiring additional com-ponents, which translated to additional cost and manu-facturing steps. Furthermore, both methods employed the conventional time-consuming drying methods like a high-temperature air-bath (drying oven), drying tunnel, vacuum drier, or other such drying equipment. The long length of drying time aids in promoting the aggregation of the active ingredients and other adjuvants, not withstanding the use of viscosity modifiers. Such processes also run the risk of exposing the active ingredients (a drug, or vitamin C, or other components) to prolonged exposure to moisture and elevated temperatures, which may render them ineffective or even harmful.

Conventional drying methods generally include the use of forced hot air using a drying oven and drying tunnel. The

difficulty in achieving a uniform film is directly related to the rheological properties and the process of water evaporation in the film-forming composition. When the surface of an aqueous polymer solution comes in contact with a high temperature air current, such as a film-forming composition passing through a hot air oven, the surface water is immediately evaporated forming a polymer film or skin on the surface. This seals the remainder of the aqueous film-forming composition beneath the surface, forming a barrier through which the remaining water has to force itself during further evaporation to form a dried film. As the temperature outside the film continues to increase, water vapor pressure builds up under the surface of the film, stretching the surface of the film, and ultimately ripping the film surface open allowing the water vapor to escape. As soon as the water vapor has escaped, the polymer film surface reforms, and this process is repeated, until the film is completely dried. The result of the repeated destruction and reformation of the film surface is observed as a “ripple effect” which produces an uneven and therefore, non-uniform film. Frequently, depending on the polymer, a surface will seal so tightly that the remaining water is difficult to remove, leading to very long drying times, higher temperatures, and higher energy costs. In spite of these problems, attempts are being made for formulating orally dissolving films due to the advantages associated with their use.

Orally soluble films containing antimicrobial agents, NSAIDs, antitussives, antihistaminics etc. were formulated by using film forming agents (Pullulan, HPMC, HEC, Polyvinylpyrrolidone etc.), binders [starch (up to 10 %w/w)], thickeners (carboxymethylcellulose, xanthan gum, traga-canth, guar gum etc.), plastizers (sorbitol, glycerin, PEG, PG), surfactants (span 80, polyoxyethylene ether), stablizers, cooling agents, emulsifiers, flavoring agent and encapsulated taste masked drugs [89]. The results suggested that Pullulan was a good choice for this purpose because it possessed excellent adhesive property. The orally soluble films when prepared with Pullulan or gelatin resulted in thick delivery units that lasted for 5-10 minutes depending on the amount of saliva and vigor of rubbing the tongue. Similar result was obtained when orally soluble film containing electrolytes was formulated [90, 91].

Ozaki et al.(1996) patented a product containing high Pullulan content for preparing edible films. In addition to Pullulan, the other ingredients included in the films were polysaccharides polyhydric alcohols and flavor-imparting agents [92].

Masao (2004) patented water resistant and heat resistant edible films by employing glucomannan (1: 2 mixture of glucose and mannose with acetyl and phosphate groups forming pendant ester linkage), natural polysaccharide (Pullulan, carragenen, cellulose, xanthan gum) and poly-hydric alcohol (glycerine). A glucomannan either inde-pendently or in combination with other natural poly-saccharide (Pullulan) having multiple hydroxyl groups and polyhydric alcohols together were mixed in either absence or presence of alkali. The reaction between glucomannan and natural polysaccharides resulted in formation of water


resistant films [93]. These films did not contain essential oils unlike those prepared by Ozaki et al. [92].

Hijiya et al. (1985) patented the use of Pullulan in coating and as packing material for food and phar-maceuticals apart from its use in edible films [94]. Also, a gradually disintegrable molded article in the shape of film containing Pullulan was invented. This article contained a particular heteromannan like locust bean gum [95]. Leung et al. (2006) patented water soluble films containing Pullulan and antimicrobially effective amount of essential oils like thymols, methylsalicylate, eucalyptol and menthol. The edible films were found to be effective against germs responsible for gingivitis and bad breath [96].

Fuisz et al. (2008) prepared non-self-aggregating orally disintegrating films. The films included at least one soluble polymer (e.g., cellulosic material, polyethylene oxide, a polysaccharide, gum, protein, starch, glucan, and their combinations). Carboxymethyl cellulose, hydroxy methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose hydroxypropylmethyl cellulose or polyethylene oxide was proposed to be suitable for use in these films. In addition, water soluble gums like gum arabic, xanthan gum, traga-canth, acacia, carageenan, guar gum, locust bean gum, pectin or alginates may be used. Water soluble polysaccharides such as polydextrose, dextrin, and dextran could also be used. In addition, unlike conventional films, these films were free from anti-foaming or defoaming agents. The inclusion of foam reducing flavoring agent (e.g., menthol, cherry menthol, cinnamint, spearmint, peppermint, orange flavor, natural raspberry or their combinations) provided a non-self-aggregating uniform film. The films were dried by drying the

bottom surface of the film first or otherwise preventing the formation of polymer film (skin) on the top surface of the film prior to drying the depth of the film. This was achieved by applying heat to the bottom surface of the film with substantially no top air flow, or alternatively by introducing them into controlled microwave environment to evaporate the water or other polar solvents within the film, again with substantially no top air flow [97].

Myers et al. (2008) patented fast-dissolving films con-taining at least one drug and a water soluble polymer com-position (polyethylene oxide in combination with carboxy-methylcellulose, polyvinylpyrrolidone or starch). The films were administered alongwith fluid in the oral cavity. The films dissolved and formed a solution or dispersion for ingestion by the subject. The results indicated that, ingestion of the solution or dispersion provided increased blood levels of drugs as compared to the film taken without the fluid [98].

TASTE MASKING TECHNOLOGIES

Pharmaceutically active ingredients may leave an unpleasant taste after administration. A new generation of rapidly dissolving and safely swallowable tablets films etc. that are being developed should have sweet and pleasant taste. Various investigators have patented orally dis-integrating/dissolving system containing taste masked drugs [99-102]. Some of the methods used to mask the taste of the drugs are summarized in Table 9 .

Cumming et al. (2000) patented a taste-masked micro-matrix powder in which the ratio of a cationic copolymer (synthesized form di-methylaminoethyl methacrylate and neutral methacrylic acid esters) compared to a drug having

Table 9. Technologies Used for Masking the Taste of Active Ingredients [99-102]

S. No. Technology Excipients Active Ingredient Method

1. Fluidized bed coating Methyl cellulose (MC),

Acesulfame(AS), HPMC

Northindrone, tamoxifen,

caffeine, acetaminophen,

rilmazafone HCl

-MC and AS solution charged to fluidized bed drier

containing sieved northindrone.

- Internal temperature maintained at 115˚F

- Coating completed in 3 min.

2. Agglomeration

process

Sweetener :- Sodium

saccharin; acesulfeme

Dry blend;-

HPMC

Silica dioxide

Polythiazide

Polythiazide -Sweetener solution sprayed on dry blend to form

agglomerated granules

- Wet mixture was dried in a convection oven at

103˚F for 17 hrs.

- Dried product size reduced, sieved (#100)

3. Pelletization process Dry Blend:-

Aspartame,

HPC and

Gum arabic

Loratidine - Crushed ice was mixed with dry blend mixture to

form spherical particles.

- Wet spherical particles were dried in a tray drier at

55˚C

4. Infusion method Dry blend:-

Sucralose,

Fluoxetine and

Polyvinyl pyrrolidone

Fluoxetine -Propylene glycol: water (40:60) was used to mix dry

blend, HPMC was added. Mixing was continued at

high speed for 3 min. The particles obtained were

screened (#100)


poor organoleptic properties was 6:1 [103]. Taste masking can also be done by using Eudragit L-100 by employing drug: ratio of 10:1 [104]. However, taste masked micro-matrix powder prepared from cationic polymer is reported to be superior to that produced by using methacrylates. Further, this micro-matrix powder could be used in oral dosage forms (like sprinkles, suspensions, chewable tablets, fast melting tablets and effervescent tablets, immediate release or sustained release dosage forms). The results indicated that the cationic copolymers could be useful in not only masking the bitter taste of drugs but also in retarding the release of drugs.

Becicka et al. (2007) patented a method for masking the taste of bitter pharmacological active ingredients. Dibutyl sebacate, water, ethylcellulose and polyethylene glycol were mixed and then loperamide HCl and cationic resin (Amberlite

®) were added to form a homogenous mixture.

The granules of this mixture were prepared using rotary evaporator under vacuum at a temperature of 65˚C. The dried granules were sieved and could be used for the preparation of orally disintegrating dosage forms [105]. A polacrilin resin (porous copolymer of methacrylic acid crosslinked with divinyl benzene, AMBERLITE) was used to mask bitter taste of drugs like citrizine dihydrochloride, levocitrizine, etc. A wet granular mass of drug with cationic resin was prepared. The dried granules were mixed with mannitol, crospovidone, microcrystaline cellulose, magne-sium stearate, etc. to form directly compressed chewable tablets [106, 107]. Similarly, taste masking agents like aminoalkyl methacrylate copolymer E, polyvinylacetal diethylamino acetate, an ethylacrylate / methacrylate coploy-mer and ethylcellulose were used for pharmacological active agents like mifiglinide calcium hydrate [108]. Orodis-persible, gastroprotective and taste masked formulations containing gastrolesive active principles like ibuprofen, diclofenac, aspirin etc. in association with hydrogenated phosphatidylcholine were prepared along with Kollidon K30, aspartame and colloidal silica. These tablets disin-tegrated in less than 30 sec and did not show any gastric irritation even in presence of gastrolesive agents [109]. In another patent taste masking was achieved by using starch. The active ingredient was formulated with starch to form micro particles [110]. Various types of orally disintegrating formulation containing drugs in the taste masked form are discussed below.

1. Chewing Gums

Chewable tablets containing coated particles of active drugs are well-known dosage form. They are intended to disintegrate in the mouth during chewing. Advantages over dosage forms meant for swallowing include improved bioavailability through the immediate disintegration, patient convenience (elimination of the need for water) and patience acceptance (pleasant taste).

Nevertheless, a common problem of chewable tablets is that chewing can cause a breakdown of the membrane that coats the active particles. Furthermore, the extent of mastication, which is associated with the length of time for which a drug remains in the mouth, plays a critical role in determining the amount of taste masking. As a result, the drug's unpleasant taste and throat grittiness are often

perceived by the patient. Various medicated chewing gums are enlisted in Table 10 [111-114].

Sozzi et al. (2008) patented a method of producing a chewing gum powder for use in preparing compressed chewing gum. It was prepared by mixing a soft gum base (penetration index >15 ddm) followed by drying (35°C-75° C). The mixture was cooled from 0 to -40°C and then ground to form particles of 10 mesh size. The powder was mixed with additional ingredients and compressed to form chewing gums having chewability and softness charac-teristics comparable to or better than extruded chewing gums [115].

Nissen (2008) patented chewing gum tablets comprising at least two cohered chewing gum modules. The tableted chewing gum was formed by compression of chewing gum granules. The gum base granules contained an elastomer system (10% w/w of the tablet weight. The compressed chewing gum tablet was found to have extremely impressing abilities of incorporating well-defined amounts of chewing gum ingredients combined with acceptable rheological properties of the compete tablet [116]. A palatable, edible soft chewable medication vehicle was patented by Paulsen et al. (2008). The process for manufacturing did not involve heat or addition of water during mixing. The process resulted in stable concentration of active ingredient. The product had consistent weight and texture [112].

2. Multiparticulates or Microparticulates

Among the variety of coating technologies, micro encapsulation is widely recognized as a versatile technique for the coating of particles of active drugs to enhance their therapeutic value. Advantageously, any multiparticulate ODT should posses a physical integrity approaching that of a conventional tablet without limiting the disintegration performance of the tablet.

Dobetti et al. (2003) patented an ODT for a drug in multiparticulate form by using water soluble inorganic excipients and disintegrants. The disintegration time was found to be less than 30 sec. A rapidly disintegrating multiparticulate tablet capable of disintegrating in the mouth in less than 40 sec was described [117]. The tablet consisted of an excipient and an active ingredient in the form of microcrystals coated with a coating agent. The excipient comprised of disintegrating agent (3-55%w/w) and soluble diluent (40-90%w/w) consisting of polyols having less than 13 carbon atoms. The polyols in directly compressible form were composed of particles whose diameter was 100-500 m. In the powdered form, the particle size of polyols was less than 100 m. The polyols may be mannitol, xylitol, sorbitol or malitol. Further, superior tablet properties and disintegration time less than 75 sec could be achieved by choosing appropriate amount of insoluble inorganic salts used as filler/diluent (eg.- di or tribasic calcium phosphide), organic fillers eg microcrystalline cellulose), soluble com-ponents (lactose) and superdisintegrants (crosslinked polyvinylpyrrolidone) [118].

Microcapsules of active ingredients (50-300 m) were prepared and then formulated in to orally disintegrating tablets. In addition to necessary ingredients, the dosage form contained viscosity enhancer, which was sufficient to provide a swellable, organoleptically acceptable mass. The


viscosity enhancer included methylcellulose, HPMC, HEC or carbopol [119].

Ziegler et al. (2008) developed a multiparticulate dosage form containing a sparingly water soluble antibiotic and a combination of carrageenan and tricalcium phosphate and sucrose ester. Also, an administration system having this dosage form arranged in a drinking straw with at least one barrier device for single administration, optionally together with a conveying liquid was described. The product was prepared by mixing the starting materials in a high speed mixer and then wet granulating and extruding the moist granules through an extruder with a 0.5 0.5 mm extrusion die at extrudate temperatures of below 35°C. The extrudates were spheronised in a suitable spheroniser and the resultant pellets were dried in a fluidised bed down to a residual moisture content of below 10%. The dried pellets were classified by the screening method and the 250 to 710 μm fraction of all the screening operations was combined. The rapid release of sparingly wettable antibiotics was reported when the carragenan to tricalcium phosphate ratio in the pellets was 1:2 [6].

3. Microspheres or Comestible Units

The comestible units of ibuprofen or acetaminophen were prepared by spinning method followed by coating of microspheres with taste masked polymeric solution. An ibuprofen or acetaminophen powder feedstock was fed to the 5-inch spinning head. The head was rotated at about 3600 rpm while the heating elements were raised to a temperature which produced liquiflash conditions. The feedstock also

contained 10% Compritol 888 ATO and 2% Gelucire 50/13 Compritol 888 ATO is glycerol behenate NF, a lipophilic additive from Gattefosse S.A. The spinning head forced the material through the screen and the product was permitted to fall free from a distance of 6 to 8 feet below the head. The product consisted of spheres having a highly consistent particle size, with diameter ranging from about 50 to 200 microns. At a composition level of 88% w/v ibuprofen, the time for dissolution for most of the ibuprofen was about 15 minutes. Virtually total dissolution occurred at around 20 to 25 minutes. These results show high predictability of drug delivery using these microspheres. The microspheres can be coated with taste masking coatings containing ethyl acrylate, methyl methacrylate polymers or hydroxypropyl methyl-cellulose polymers [26].

4. Microcapsules

Among the variety of coating technologies, micro encapsulation is widely recognized as a versatile technique for the coating of particles of active drugs to enhance their therapeutic value. Microencapsulation is achieved by two distinct processes, namely coacervation/phase separation and air suspension coating. These processes envelop small particles of the drug substance into minute, discrete, solid packages which to the naked eye appear as a fine powder. Although, in the marketplace there are many different solid dosage forms for peroral administration containing microencapsulated drugs, such as tablets, capsules, sachets, etc., presently there is a strong demand for multiparticulate palatable dosage forms characterized by a rapid disin-tegration time [120].

Table 10. Formulation and Technologies Patented for the Manufacture of Chewing Gums, Films and Multiparticulate Systems

Orally

Disintegrating

System

Drug Disintegrating Agents Other Formulation

Ingredients Technology

Disintegration

Time

Reference

No.

Orally

disintegrating

films

Dextromethorphan

HBr

Film forming solution-

Polyethylene oxide,

hydroxypropyl

methylcellulose, polydextrose,

Sucralose, mono-ammonium

glycyrrhizinate

Sodium bicarbonate

magnesium stearate

hydrophilic titanium

dioxide

Film casting

method

Less than 60

sec [97]

Wafers Buprenorphine

hydroxypropyl

methylcellulose,

Carboxymethyl cellulose

gelatin, pullulan

Polyox, polyvinyl

alchohol, polyvinyl

pyrrolidone

Film casting

method <30 sec [111]

Chewable

dosage forms Ivermectin

Starch 1500, polyethylene

glycol 3350, Croscarmellose

sodium

Glycerin, vegetable Oil

(soybean), magnesium

stearate, yeast flavoring

sodium lauryl sulfate

FD&C carmine dye

Molding

method ----- [112]

Chewing

dosage forms

Magnolia Bark

extract (5%)

Mannitol, sorbitol

lecithin

Glycerin, lycasin

NaHCO3 Encapsulation

Masticating

time-3-5min [113]

Multiparticulate

systems

Guaifenesine,

prednisolone

phosphate sodium

Microcrystaline cellulose,

Povidone K25, sodium

carboxymethyl cellulose

Eudragit EPO, sodium

hydrogen carbonate

stearic acid

Pellet formation

followed by

coating

---- [114]


5. Nanocrystals

NanoCrystal technology [121] is aimed at improving compound activity and final product characteristics. Decreasing particle size increases the surface area, which leads to an increase in dissolution rate. This can be accomplished predictably and efficiently using NanoCrystal technology. Nano Crystal particles are small particles of drug substance, typically less than 1000 nanometers (nm) in diameter, which are produced by milling the drug substance using proprietary wet milling technique. NanoCrystal colloidal dispersions of drug substance are combined with water-soluble GRAS ingredients. They are then filled into blisters, and lyophilized. The resultant wafers are remarkably robust, yet dissolve in very small quantities of water within seconds. This approach is especially attractive while working with highly potent or hazardous materials because it avoids manufacturing operations (e.g. granulation, blending, and tableting) that generate large quantities of aerosolized powder and present a higher risk of exposure. The freeze-drying approach also enables small quantities of drug to be converted into ODT dosage forms because manufacturing losses are negligible.

CURRENT & FUTURE DEVELOPMENTS

The innovations in the arena of formulating ODTs are aimed at both increasing the performance of the dosage form by decreasing the disintegration time and increasing the patient compliance by masking the objectionable taste of the active ingredients. These achievements require constant up gradation of formulation variables as well as technologies involved in the production of dosage forms. This article attempted to unveil the strategies that have been used by inventors for improving the performance and acceptability of ODTs. The use of superdisintegrants for achieving these aims is not new. However, with the improvement design of new techniques, it has become possible to develop ODTs with reduced content of superdisintegrants and with better mouth feel. Further, incorporation of active ingredients in dosage forms such as fast dissolving films, chewing gums and micro particles are expected to provide a highly acceptable means of delivery drugs to especially, pediatric and geriatric patients. The use of techniques like freeze drying, direct compression and effervescense are highly suitable for formulating stable and acceptable dosage forms of vitamins, enzymes and thermolabile drugs. The development of Durasolv and Orasolv technologies are worth mentioning in this regard. Similarly, considerable research towards producing modified microcrystalline cellulose or starch in order to engineer them suitable for direct compression has significantly reduced the product development time for optimizing ODT formulation. The application of nanotechnology to formulation is expected to further enhance the acceptance and performance of these dosage forms. However, not much work seems to have been done in this particular specialized area. Nevertheless, judicious use of excipients and technology can be expected to make the task of formulating an acceptable and effective ODT easier than before.

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