recent technological advances in odd a review

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1461-5347/00/$ see front matter 2000 Elsevier Science Ltd. All rights reserved. PII: S1461-5347(00)00247-9

w The average development cost of a new

chemical entity (NCE) is approximately $150

350 million. It often costs substantially less to

develop new methods of administration for an

existing drug, which results in improved efficacyand bioavailability together with reduced dosing

frequency to minimize side effects. Therefore,

pharmaceutical companies are under constant

pressure to maximize the full potential of a drug

candidate at an early stage of its life cycle.This

objective can be accomplished by incorporating

the drug into various drug delivery systems.This

exercise can lead to extended patent life and con-

venient dosage forms that overcome previously

presented administration problems. For the last

two decades, there has been an enhanced de-

mand for more patient-compliant dosage forms.As a result, there are now approximately 350

drug delivery corporations and 1000 medical

device companies.The demand for their technol-

ogies was approximately $1420 billion in 1995

and, according to industry reports, this is

expected to grow to $60 billion1,2 annually.

Recent technological advances in

solid oral dosage forms

Oral administration is the most popular route

due to ease of ingestion, pain avoidance, versatil-

ity (to accommodate various types of drug can-

didates), and, most importantly, patient compli-

ance35. Also, solid oral delivery systems do not

require sterile conditions and are, therefore, less

expensive to manufacture.

Several novel technologies for oral deliveryhave recently become available to address the

physicochemical and pharmacokinetic character-

istics of drugs, while improving patient compli-

ance. Electrostatic drug deposition and coating6,

and computer-assisted three-dimensional print-

ing (3DP) tablet manufacture have also recently

become available7.

Oral fast-dispersing dosage forms

The novel technology of oral fast-dispersing

dosage forms is known as fast dissolve, rapid dis-

solve, rapid melt and quick disintegrating tablets.However, the function and concept of all these

dosage forms are similar. By definition, a solid

dosage form that dissolves or disintegrates

quickly in the oral cavity, resulting in solution or

suspension without the need for the adminis-

tration of water, is known as an oral fast-dispers-

ing dosage form.

Difficulty in swallowing (dysphagia) is com-

mon among all age groups, especially in elderly,

and is also seen in swallowing conventional

tablets and capsules8. An estimated 35% of the

general population,and an additional 3040% ofelderly institutionalized patients and 1822% of

all persons in long-term care facilities, suffer

from dysphagia.This disorder is associated with

many medical conditions, including stroke,

Parkinsons, AIDS, thyroidectomy, head and neck

radiation therapy, and other neurological disor-

ders, including cerebral palsy912. One study

showed that 26% of 1576 patients experienced

difficulty in swallowing tablets. The most com-

mon complaint was tablet size, followed by sur-

face, form and taste. The problem of swallowing

Recent technological advances in oral

drug delivery a reviewSrikonda Venkateswara Sastry, Janaki Ram Nyshadham and Joseph A. Fix

Srikonda Venkateswara

Sastry

Janaki Ram Nyshadham

and Joseph A. Fix

Pharmaceutical R&DYamanouchi Pharma

Technologies, Inc.

1050 Arastradero Road

Palo Alto

CA 94304

USA

tel: 1 650 849 8553

fax: 1 650 849 8616

e-mail: [email protected]

reviews research focus

138

PSTT Vol. 3, No. 4 April 2000

Despite disadvantages, oral drug delivery remains the preferred route of

drug delivery. Novel technologies with improved performance, patient

compliance, and enhanced quality have emerged in the recent past.

Oral fast-dispersing dosage forms, three-dimensional Printing (3DP)

and electrostatic coating are a few examples of a few existing technol-

ogies with the potential to accommodate various physico-chemical,

pharmacokinetic and pharmacodynamic characteristics of drugs. This

article provides a comprehensive review of these three technologies.


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tablets was more evident in geriatric and paediatric patients, as

well as travelling patients who may not have ready access to

water11

.Advantages of oral fast-dispersing dosage forms include:

administration to patients who cannot swallow, such as theelderly, stroke victims, healthcare facility and bedridden

patients; patients who should not swallow, such as those

affected by renal failure; and patients who refuse to swallow,

such as paediatric, geriatric and psychiatric patients13,14;

rapid drug therapy intervention13; more rapid drug absorption, as evident in one bioequiva-

lency study (Seligiline) through pre-gastric absorption from

the mouth, pharynx and oesophagus14,15;

convenience and patient compliance, such as disabledbedridden patients and for travelling and busy people whodo not have ready access to water14;

new business opportunities: product differentiation, line ex-tension and life-cycle management, exclusivity of product

promotion, and patent-life extension14,15.

Current oral fast-dispersing dosage form technologies

Although several technologies are available, few have reached

commercial marketed products. Box 1 shows the classification

of these technologies according to core manufacturing

processes. Several methods are employed in the preparation of

oral fast-dispersing tablets, such as modified tableting systems,floss, or Shearform formation by application of centrifugal

force and controlled temperature, and freeze drying.The inclu-

sion of saccharides seems to be the basis for most of these

technologies.The choice of material(s) depends on their rapid

dissolution in water, sweet taste, low viscosity to provide

smooth melt feeling, and compressibility1316. Even though

the various formulations share some commonalties in terms of

excipient selection, there is a distinct preparation method for

each technology.

Conventional tablet formulation methods with modifications

With some modifications, conventional tablet processingmethods and equipment can be used in the preparation of

these fast-disintegrating dosage forms.

The WOWTAB (Yamanouchi Pharma Technologies, Palo

Alto, CA, USA) tablet features sufficient hardness to maintain

the physical characteristics of the dosage form during produc-

tion and distribution, until it comes into contact with mois-

ture, such as saliva in the mouth17.

Tablets made by conventional compression methods usually

possess sufficient hardness to withstand the handling and

rigours of transportation. However, they lack fast disintegration

properties in the oral cavity as they are not intended for this

performance. Therefore, a fast disintegrating tablet with good

mechanical strength that could be manufactured with conven-

tional processing equipment was the objective of the formu-

lation development programme17.

It was noted that saccharides possess the qualities of fast dis-

solution in water or saliva and achieve the required tablet hard-

ness upon compaction. However, any individual saccharideeither possessed fast disintegration characteristics or good

hardness upon compaction,but not both. For example, manni-

tol, lactose, glucose, sucrose, and erythritol showed very quick

dissolution characters in the mouth and were identified as low

moldable sugars. In contrast, maltose, sorbitol, trehalose, and

maltitol showed adequate hardness upon compression and

were highly moldable, although their in vivo disintegration time

was very slow. As no single sugar possessed all the required

characteristics, a new composition was created by granulating a

low moldable sugar with a high moldable sugar.The tablets ob-

tained by compression of the new composition, after undergoing

139

PSTT Vol. 3, No. 4 April 2000 reviewsresearch focus

Box 1. Oral fast-dispersing tablet technologies

Technology Company

I. Conventional tablet processes with modifications

WOWTAB Yamanouchi Pharma

Technologies, 1050

Arastradero Road, Palo Alto,

CA, USA.

ORASOLV Cima Labs, Inc., 10000 Valley

Hill Road, Eden Prairies,

MN, USA

EFVDAS Elan Corp., Monksland

Athlone, County

Westmeath, Ireland.

FLASHTAB

Prographarm, Chaueauneuf-En-Thymeraia, France

II. Freeze drying method

ZYDIS R.P. Scherer, Frankland Road,

Swindon, UK

LYOC Farmalyoc, 5AV Charles

Marting, Maisons-Alfort,

France

QUICKSOLV Janssen Pharmaceutica, 1125

Trenton-Harbourton Road,

Titusville, NJ, USA

III. Floss formationFLASHDOSE Fuisz Technologies, 14555

Avion At Lakeside,

Chantilly, VA, USA


3/8

a humidification and drying process, exhibited both the fast

disintegration and adequate hardness required for oral fast dis-

integrating tablets. Simple physical mixing of a mannitol andmaltose combination did not result in a tablet with the required

qualities.

The process of granulation, in which low moldable sugar is

coated with high moldable sugar followed by a specific humidity

treatment, is required to achieve fast disintegration performance

characteristics. The resulting tablet had a hardness of at least

1.02.0 kg (tablet-size dependent) and presented a preferable

disintegration time of 140 seconds (typical values of15 s).

Various drug classes can be incorporated into the above combi-

nation to achieve a fast disintegrating tablet with proper perfor-

mance characteristics. A preferable ratio of 510% by weight of

high moldable sugar was found to be sufficient to achieve thedesired level of tablet hardness with rapid disintegration.

ORASOLV, a direct compression technology, utilizes effer-

vescence material and taste-masked active ingredients, and

requires only conventional manufacturing equipment18.The in-

clusion of effervescence causes the dosage form to quickly dis-

integrate following contact with water or saliva. By definition,

the effervescence material is a chemical reaction between an or-

ganic acid (citric acid, fumaric acid or maleic acid) and a base

(sodium bicarbonate, potassium bicarbonate or magnesium bi-

carbonate), thereby resulting in the generation of carbon diox-

ide.The concept of effervescence is a well-known formulation

art utilized in several dosage forms19

. However, the currenttechnology uses this concept in a modified fashion to achieve

fast-disintegrating dosage forms20.

The microparticles are prepared by a novel technique involv-

ing the dispersion of active ingredient into a suitable polymer

dispersion together with other excipients such as mannitol and

magnesium oxide. Typical polymers include ethyl cellulose,

methyl cellulose, acrylate and methacrylic acid resins.The active

material and mannitol are added to the polymeric dispersion

under stirring, followed by the addition of magnesium oxide.

Mannitol and magnesium oxide are added to aid active ingre-

dient release from the polymeric coating and are known as re-

lease promoters in the current technology.This mixture is driedfor one hour at 50C , delumped, and dried for another hour at

the same temperature.The material is then screened (8-mesh)

and dried for one hour at 60C.

The formed microparticles, effervescent agents and other

excipients, including flavourants, colourants and lubricants, are

blended and compressed into tablets at 1.02.0 kp hardness.

The tablets are fragile with in vivo disintegration times of less

than one minute20,21. Because the tablets are very soft, they are

packed into foilfoil blisters using a specially designed packag-

ing system. In an attempt to improve the friability of these

tablets, a novel method, known as particulate effervescent cou-

ple, is developed to prepare the effervescent mixture. In this

method the organic acid crystals are coated using a stoichio-

metrically less amount of base material as compared to theacid. The particle size of the organic acid crystals is carefully

chosen to be greater than the base material for uniform coating

of base material onto the acid crystals. The coating process is

initiated by the addition of a reaction initiator, in this case puri-

fied water.The reaction is allowed to proceed only to an extent

of completion of base coating on organic acid crystals.The re-

quired end-point for the reaction termination is determined by

measuring CO2 evolution.The resulting effervescent couple can

be used in tablet preparation by mixing with polymer-coated

active ingredient particulate material and other excipients such

as sweeteners, flavours and lubricants22.

Freeze drying process

ZYDIS (R.P. Scherer, Swindon, UK), using freeze drying

processes, is one of the first generations of fast disintegrating

dosage forms.There are approximately 12 marketed ZYDIS

products, including lorazepam, piroxicam, loperamide, lorati-

dine, enalapril and selegiline14,16. These formulations are

freeze-dried products of a combination of water-soluble ma-

trix material with drug, which is preformed in blister pockets

and freeze dried to remove the water by sublimation. The re-

sultant structures are very porous in nature and rapidly disinte-

grate or dissolve upon contact with saliva14,23.The process had

undergone several modifications to accommodate drugs withdifferent physicochemical characteristics, drug loading and

particle size, and matrix modifications to result in an accept-

able dosage form2430.

Drug loading for water insoluble drugs approaches 400 mg.

The ideal drug characteristics are relative water insolubility

with fine particle size and good aqueous stability in the sus-

pension. As the dose is increased, it becomes more difficult to

achieve the optimum formulation14,16.The upper limit for drug

loading is much lower (approximately 60 mg) for water sol-

uble drugs. The primary problems associated with water sol-

uble drugs are the formation of eutectic mixtures, resulting in

freezing-point depression and the formation of a glassy solidon freezing which might collapse on drying because of loss of

the supporting structure during the sublimation process14,16,27.

The addition of crystal-forming agents such as mannitol,

which induce crystallinity and hence impart rigidity into the

amorphous material, can be employed to prevent the collapse

of the structure.The soluble drugs can be complexed with ion

exchange resins to prevent the collapse of the structure, which

is also useful in masking the bitter taste of medicaments16,39.

The sedimentation of larger drug particles may lead to the loss

of the product. The appropriate particle size is less than 50

microns, although larger particle size drug material can be

140

PSTT Vol. 3, No. 4 April 2000reviews research focus


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formulated by the use of suitable suspending agents, such as

gelatin, and flocculating agents such as xanthan gum16,30. Sol-

uble drugs can also be incorporated into the formulation bytheir organic solvent-solution deposition onto preformed ma-

trix, and subsequent removal of solvent by evaporation16,25.

The matrix characteristics of the formulation are equally im-

portant in the product development.Typically, the matrix con-

sists of polymers such as gelatin, dextran or alginates as glassy

amorphous compounds providing structural strength; saccha-

rides such as mannitol or sorbitol to provide crystallinity, hard-

ness and elegance; and water as a manufacturing process media

to induce the porous structure upon sublimation during the

freeze-drying step. The formulation can also contain taste-

masking agents such as sweeteners, flavourants, pH-adjusting

substances such as citric acid, and preservatives such asparabens to ensure aqueous drug suspension stability prior to

the freeze-drying step. Finally, the freeze dried formulations are

manufactured and packaged in PVC or PVDC plastic packs, or

may be packed into Aclar laminates or aluminum foilfoil

preparations to protect the product from external moisture14,16.

Floss formation techniques

The FLASHDOSE (Fuisz Technologies, Chantilly, VA, USA)

dosage form utilizes the Shearform technology in association

with Ceform TI technology as needed, to eliminate the bitter

taste of the medicament. The Shearform technology is em-

ployed in the preparation of a matrix known as floss, which ismade from a combination of excipients, either alone or in

combination with drugs.The floss is a fibrous material similar

to cotton-candy fibers, commonly made of saccharides such as

sucrose, dextrose, lactose and fructose31. For the preparation of

sucrose fibers, temperatures ranging from 180266F are em-

ployed.However, the use of other polysaccharides such as poly-

maltodextrins and polydextrose can be transformed into fibers

at 3040% lower temperatures than those used for sucrose fiber

production.This modification permits the safe incorporation of

thermolabile drugs into the formulation32.The manufacturing

process can be divided into the four steps detailed below.

Floss blend. Initially, approximately 80% sucrose in combinationwith mannitol or dextrose and approximately 1% surfactant is

blended to form the floss mix.The surfactant acts as a crystalliza-

tion enhancer in maintaining the structure and integrity of the

floss fiber.The enhancer also helps in the conversion of amor-

phous sugar into crystalline sugar, from an outer portion of

amorphous Shearform sugar mass, and subsequently converting

the remaining portion of the mass to complete crystalline struc-

ture.This process helps to retain the dispersed active ingredient in

the matrix, thereby minimizing migration out of the mixture33.

Floss processing. The matrix is produced by subjecting the carrier

material to flash heat and flash flow processing in a heat pro-

cessing machine.The floss formation machine is similar to a

cotton-candy fabricating type, consisting of a spinning head

and heating elements. In the flash heat process, the carrier ma-terial is heated sufficiently to create an internal flow condition,

followed by its exit through the spinning head that flings the

floss by centrifugal forces generated by rotation.The spinning

head rotates at approximately 20003600 rpm, providing suf-

ficient centrifugal forces. Heating blocks are positioned around

the circumference as a series of narrow slots located between

the individual heating blocks. A series of grooves, located on

the inner circumference of the crown and configured on the

outside of the rim of the heaters, narrow the width of the aper-

ture while increasing the path length of the exiting material,

resulting in the production of fibers.The material is essentially

heated upon contact with heaters, flows through the aperturesunder centrifugal forces, and draws into long, thin floss fibers.

The produced fibers are usually amorphous in nature3436.

Floss chopping and conditioning. The fibers are conditioned to a

smaller particle size by chopping and rotation action in a high

shear mixer-granulator. The conditioning is performed by

partial crystallization through an ethanol treatment (1%)

sprayed on to the floss that is subsequently evaporated, result-

ing in floss with improved flow and cohesive properties31.

Tablet blend and compression. The chopped and conditioned floss

fibers are blended with active ingredient along with other

standard tableting excipients, such as lubricants, flavours and

sweeteners. The resulting mixture is compressed into tablets.The active can also be added to the floss blend before subject-

ing it to the flash heat process (personal communication: Prior,

D.V. (1999) Fuiszs Flash Dose Tablet Technology, 19).

In one modification to this process, a curing step is added to

improve the mechanical strength of the barely molded FLASH-

DOSE dosage form in plastic blister package depressions. The

curing involves the exposure of the dosage forms to elevated

temperature and humidity conditions, such as 40C and 85%

RH for 15 minutes.The curing step is expected to cause crys-

tallization of the floss material that leads to binding and bridg-

ing to improve the structural strength37.This new class of quick

disintegrating oral delivery systems incorporating active ingre-dients with varying physicochemical characteristics adds a

value in terms of improved patient compliance as a result of

their unique properties.

Three-dimensional printing technology in the preparation

of oral delivery systems

This novel technology was developed to address several prob-

lems associated with drug release mechanisms and release rates.

Drug release rates tend to decrease from a matrix system as a

function of time based on the nature and method of prepar-

ation of the dosage form38,39.Various methods are employed to

141



5/8

address these problems through geometric configurations, in-

cluding the cylindrical rod method and cylindrical donut sys-

tems40,41

. The 3DP method provides several strategies, besideshaving the advantages mentioned above, including the zero

order drug delivery, patterned diffusion gradient drug release

by microstructure diffusion barrier technique, cyclic drug

release, and other types of drug release profiles7.The technique

is often referred to as solid free-form fabrication or computer

automated manufacturing or layered manufacturing.

The 3DP method utilizes ink-jet printing technology to create

a solid object by printing a binder into selected areas of sequen-

tially deposited layers of powder.As shown in Fig. 1, each part is

built upon a platform located on a piston-supported pin. The

powder bed, initially spread over the platform by a powder roller,

is selectively printed with the ink-jet printing head by a binder tofuse the powders together in the desired areas.The piston de-

scends to accommodate additional printing layers.The process is

repeated until the design is complete42.The instructions for each

layer are derived from Computer Aided Design (CAD) represen-

tation of the component.The 3DP instrument consists of a pow-

der dispersion head driven reciprocally along the length of the

powder bed. An ink-jet print head prints the binder into the

powder bed by selectively producing jets of a liquid binder

material to bind the powdered material at specified regions.

This process is repeated to build up the device layer by

layer7,42,43.Activities that dictate the construction and completion

of the dosage form using 3DP technique are detailed below.

Material selection

The processing method dictates the type and form of matrix-

forming polymer material for the specific design of the

system. The polymer may be in the solution form for

Steriolithography (SLA) or fine particles for any remaining

methods including the 3DP technique. In addition, the SLA

polymer should be photopolarizable, and in the later methods

the polymer is preferably in the form of particles and is solidi-fied by the application of heat, solvent, or binder. Commonly

used polymers are ethylene vinyl acetate, poly(anhydrides),

polyorthoesters, polymers of lactic acid and glycolic acid and

proteins such as albumin or collagen, and others including

polysaccharides such as lactose42,43.

Binder selection

Binder function may depend on the end-performance of the

binder itself, such as a solvent for the polymer and/or active

agent or an adhesive to the polymer particles.The binder func-

tion may also depend on the type of release mechanism in-

volved. In the erosion-type devices, the solvent is used eitherto dissolve the matrix or may contain a second polymer de-

posited along with the drug. In other applications, the binder

is required to harden rapidly upon deposition, and therefore

the next layer is not subjected to particle rearrangement from

capillary forces44,45.

Patterns for active agent printing

The active agent can be embedded into the device as either a dis-

persion along the polymeric matrix or as discrete units in the

matrix structure. In the former method, it is mixed with binder

polymer and deposited on the matrix, and in the latter type it is

dispersed in a non-solvent to the matrix polymer and deposited.Therefore, through the correct selection of the polymer material

and binder system, the drug release mechanisms can be tailored

to suit a variety of requirements.The resulting systems can be

acid-erosion type, enteric-erosion type, pulsed controlled

release, pulsed immediate or controlled release and so on43.

Novel delivery systems designed by 3DP technology can help

to resolve several problems associated with drug release mecha-

nisms and release rates.

Electrostatic deposition technology for pharmaceutical

powder coating

In terms of solid dosage form manufacturing, although therehave been many developments in raw materials and processes,

the fundamental principles have essentially remained un-

changed46. New technologies involving dry manufacturing

processes for the powder coating of active pharmaceutical

ingredients onto various surfaces by direct electrostatic depo-

sition have emerged.This revolutionary approach eliminates

traditional manufacturing procedures of blending powders,

granulation, drying, lubrication, compression and coating in

pharmaceutical product development and manufacturing

processes47.The process is less operator-dependent, is continu-

ous and is considerably faster48.

142


Figure 1. Schematic representation for three-dimensional printing

(3DP) technology in tablet preparation. Adopted from the presentation,

Pulsatory Multi-release Oral Drug Delivery Devices Fabricated by 3D

Printing, by Katstra, W., Controlled Release Society, 22 June 1999,

Boston, MA, USA.

Pharmaceutical Science & Technology Today

Z

Stage 1

X-Y motion

Stage 2 Stage 3 Finalproduct

PowderSpreadingbar

Printhead Binderdroplets


6/8

Key technologies

Accudep technology is developed by Delsys (Princeton, NJ,

USA). The principles of electrostatic deposition stem frombasic physics: opposite charges attract. Material deposition

occurs when a pattern of charges is established on the substrate

where the deposition is desired, and a supply of material to be

deposited is delivered in the form of small, charged particles.

The pattern of charges on the substrate will establish an elec-

trical field, E, that interacts with charges on the material to be

deposited according to Coulombs Law: this states that a force,

F, will act on these particles proportional to the electric field

and charge Q on the particle: F q E.The charged particles

will be moved by this force, transported to the substrate, and

deposited in a pattern determined by the charge on the sur-

face.The key components in the technology may be summa-rized as four main areas.

Active pharmaceutical ingredient.The technology allows the production

of material with controlled size, morphology, uniform flow and

charging properties. Intrinsic surface properties of active ingre-

dients can be modified to enhance charging and handling.

Substrate. The substrate, an insulating film, is defined as the base

upon which the drug is deposited. The substrate mechanical

properties, such as thickness, modulus and strength, and the

electrical property of bulk resistivity are critical49.

Electrostatic chuck. A chuck is a clamp or a device that holds an ob-

ject. The role of an electrostatic chuck is to hold the substrate

and provide the charged pattern onto the substrate in this tech-nology. The electrostatic chuck can be equipped with an elec-

trode for sensing the number of particles attracted to the chuck,

thereby ensuring an accurate amount of particles50.

Field deposition process. The charging is achieved by using a three-

layer structure that has a conducting backplane electrode, an

insulating layer and a patterned conducting top electrode.This

controlled field deposition process enables the material to be

directly deposited onto a single layer substrate47.

The accurate deposition of dry powder materials onto a va-

riety of substrates involves a combination of several proprietary

techniques47.These include powder preparation; accurate defi-

nition of charged patterns on substrate surfaces; charging drypowder materials; adhesion-control of electrostatic deposits;

and process control.

Electrostatic powder coating system

Another technology relating to the design and operation of dry

powder electrostatic tablet coaters and the development of

coating materials has emerged from Phoqus Pharmaceutical

Technologies (Goudhurt, UK)6. The electrophotographic

process contains six steps (Fig. 2). In the first step, a corona

discharge caused by air breakdown charges the surface of a

photoreceptor acting as an insulator. Light, reflected from the

image or produced by a laser, then discharges the normally in-

sulating photoreceptor, producing a latent image. In the third

step, electrostatically charged and pigmented polymer particles

called toner and approximately 10 microns in diameter are

brought into the vicinity of the latent image. By virtue of the

electrical field created by the charges on the photoreceptor, the

toner adheres to the latent image, transforming it into a real

image. Next, the developed toner on the photoreceptor is

transferred to paper by corona charging the back of the paperwith a charge that is the opposite to that of the toner particles.

In the fifth step, the image is permanently fixed to the paper by

melting the toner into the paper surface. Finally, the photo-

receptor is discharged and cleaned of any excess toner using

coronas, brushes and scrappers and/or blades6.

Electrostatic powder coating process

A prototype of the electrostatic powder coating process was

constructed (Fig. 2). Charge is applied to a rotating cylinder

with a bed of powder, and electrocharged powder adheres to

this cylinder.The powder delivery system (PDS) comes into

close proximity to the tablets that are vacuum-held in depres-sions around another cylinder, and is given an opposite charge

to the powder by means of a high-tension electrode.The pow-

der transfers from the PDS cylinder to the exposed tablet sur-

face. Fusion of the powder to form a film is achieved by brief

exposure to a source of long-wave infrared radiation.This elec-

trostatic coating machine and process is solvent-free.

Therefore, the process steps related to liquid film coating can

be eliminated, resulting in considerable energy savings. Several

materials were identified with satisfactory properties for use in

the process. Some of the acrylic polymers have high resistivity,

reasonably low melting points and glass transition temperatures,

143


Figure 2. Schematic of electrophotographic process used in

electrostatic coating. Adopted from the presentation, Pharmaceutical

Dry Powder Electrostatic Coating, by Whittman, M. et al., The European

Pharmaceutical Technology Conference, April, 1999, Utrecht,The Netherlands.

Pharmaceutical Science & Technology Today

5. Fuse

6. Clean

6a. Dissipate charge(Light)

1. Charge the drum (Corona)

2. Expose the image

3. Develop the image

4. Transfer image

Heat

HeatPhotoreceptor

drumTribocharged

forier


7/8

and good melt flow.The resistivity of the coating formulation,

dependent on the formulation composition, is important as it

determines the ability of the formulation to retain charge6

.

Advantages

The application of the technology to active pharmaceutical in-

gredients can shorten the development cycles by simplifying

new drug formulation and manufacturing scale-up, increasing

quality and speed while also reducing costs, and developing a

new generation of innovative solid oral dosage forms and dry

powder inhalers.Because every dose is measured,improved con-

tent uniformity can be obtained.An enhanced stability profile

can be expected as a result of the presence of fewer excipients,

thereby minimizing incompatibility and analytical issues.The

ability of the technology to adjust dose levels provides a multi-dose capability for rapid clinical and toxicological evaluation of

the product.The self-contained and controlled work area enables

improved environmental controls and containment of hazardous

materials.The technique provides capability to perform 100%

on-line inspection, leading to enhanced quality control47.

Conclusions

The three technologies described demonstrate how recent ad-

vances in formulation development and processing technol-

ogies are evolving to meet efforts to achieve more sophisti-

cated drug delivery systems. As evidenced by these

technologies, this evolution may involve modifying formu-lation composition and processing to achieve new perfor-

mance end-points (fast-melt technologies) or the merger of

new technological advances (three-dimensional printing and

electrostatic powder deposition) with traditional pharmaceuti-

cal processing techniques for the production of novel dosage

forms. It is reasonable to expect that future trends in drug de-

livery system innovation will continue to bring together dif-

ferent technological disciplines to create novel technologies.

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3 Sastry, S.V. et al. (1997) Atenolol gastrointestinal therapeutic system. I.

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145


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