I
`
`Page 1
`
`Dr
`
`Reddy'
`
`S
`
`EXh. 1061
`
`Page 1 Dr. Reddy's Exh. 1061
`
`

`

`in the year 1885 by Joseph P Remington,
`Entered according to Act of Congress,
`in the Office of the Librarian of Congress, at Washington, DC
`
`Copyright 1889, 1894, 1905, 1907, 1917,by Joseph P Remington
`Copyright 1926, 1936, by Joseph P Remington Estate
`Copyright 1948, 1951, by The Philadelphia College of Pharmacy and Science
`
`Copyright
`Science
`
`1956, 1960, 1965, 1970, 1975, 1980, 1985, by The Philadelphia College of Pharmacy and
`
`All Rights Reserved
`
`Library of Congress Catalog Card No 60-53334
`
`ISBN 0-912734-03-5
`
`The use of portions of the text of USP XX, NF XV, and USAN and the USP Dictionary of Drug
`Names is by permission of the USP Convention.
`The Conventionis
`not responsible for any
`inaccuracy of quotation or for any false or misleading implication that may arise from
`separation of excerpts from the original context or by obsolescence resulting from
`publication of a supplement,
`
`NoTIcE—This text is not intended to represent, nor shall it be interpreted to be, the equivalent
`for the official United States Pharmacopeia
`of or a substitute
`(USP) and/or
`the National
`(NF).
`In the event of any difference or discrepancy between the current official
`Formulary
`USP or NF standards of strength, quality, purity, packaging and labeling for drugs and
`the context and effect of the official compendia shall
`representations
`of them herein,
`prevail.
`
`Printed in the United States of America by the Mack Printing Company, Easton, Pennsylvania
`
`Page 2 Dr. Reddy's Exh. 1061
`
`

`

`CHAPTER 9h
`
`Coating of Pharmaceutical Dosage Forms
`
`Stuart C Porter, PhD
`Vice President, Research and Development
`Colorcon,
`Inc
`West Point, PA 19466
`
`particularly
`in tablet core
`
`Introduction
`Any introduction to tablet coating must be prefaced by an
`question —"Why coat tablets?" —since in many
`important
`instances,
`the coating is being applied to a dosage form that
`In attempting to answer
`is already functionally complete.
`this
`if one examines the market,
`it will be immediately
`question,
`obvious that a significant proportion of pharmaceutical
`solid
`dosage forms are coated. The reasons for this range from the
`aesthetic to a desire to control the bioavailability of the drug,
`and include the following:
`1. Protection of the drug from its surrounding
`environ-
`ment
`air, moisture,
`and light) with a view to
`(particularly
`stability.
`improving
`2. Masking of unpleasant
`taste and odor.
`3.
`Increasing the ease by means of which the product can
`be ingested by the patient.
`4. Improving
`from the manufacturing
`product
`identity,
`and to the patient.
`through intermediaries
`plant,
`5. Facilitating
`particularly
`handling,
`in high
`speed
`lines, and automated
`counters
`in phar-
`packaging/filling
`macies, where the coating minimizes
`cross-contamination
`due
`to dust elimination.
`6.
`in product
`Improvement
`appearance,
`where there are noticeable visible differences
`from batch to batch.
`ingredients
`7. Reducing the risk of interaction between incompatible
`This would be achieved by using coated forms
`components.
`of one or more of the offending ingredients
`(particularly active
`compounds).
`8.
`in product mechanical
`Improvement
`coated products are generally more resistant
`(abrasion, attrition, etc).
`9. Modification of drug release, as in enteric-coated,
`peat-action, and sustained-release
`products,
`Evolution of the Coating Process —Tablet coating is
`perhaps one of the oldest pharmaceutical
`processes still
`in
`existence, and although a great deal has been written about
`the materials
`and methods used, as a process it is still often
`recognized to be more of an art than a science, a factor which
`that can
`for many of the problems
`is obviously responsible
`cites Rhazes (850—932 AD)
`exist. Historically,
`the literature
`as being one of the earliest "tablet coaters," having used the
`mucilage of psyllium seeds to coat pills that had an offending
`taste. Subsequently, Avicenna was reported to have used
`gold and silver for pill coating. Since then,
`there have been
`to the different materials used in "tablet
`many references
`coating." White2 mentioned the use of finely divided talc in
`known as "pearl coating,"
`what was at one time popularly
`while Kremers,and Urdang3 describe the introduction of the
`gelatin coating of pills by Garot in 1838.
`reference4 reports the use of waxes to coat
`An interesting
`poison tablets. These waxes, being insoluble
`in all parts of
`the gastrointestinal
`tract, were intended to prevent accidental
`(the contents
`poisoning
`could be utilized by breaking the
`tablet prior to use).
`
`since
`integrity,
`to mishandling
`
`re-
`
`that must be stressed is that much of the earlier
`A point
`coated products were produced by individuals working
`in
`pharmacies, particularly when extemporaneous
`compounding
`was the order of the day, and although responsibility
`for tablet
`coating has now been assumed by the pharmaceutical
`indus-
`still practiced their art until quite re-
`try, skilled individuals
`cently.
`The earliest attempts
`to apply coatings to pills obviously
`resulted in variable products, and required the handling of
`single pills. These would have been mounted on a needle or
`held with a pair of forceps and literally dipped into the coating
`fluid, a procedure which would have to be repeated more than
`once to ensure that the pill was completely coated. Subse-
`the pills were held at the end of a suction tube, dipped
`quently,
`and then the process repeated for the other side of the pill.
`failed to yield a unifgrmly
`these techniques
`Not surprisingly,
`coated product.s
`the first sugar coated'pills
`Initially,
`seen in
`the US were imported from France circa 18425; while Warner,
`a Philadelphia
`pharmacist, became among the first indigenous
`in 1856,
`manufacturers
`for the coating of a large number of tablets are
`Methods
`essentially derived from those used in the candy industry,
`where techniques were highly evolved, even in the Middle
`Ages. Today, most coating pans are fabricated from stainless
`steel, although early pans were made from copper owing to the
`fact that drying was effected by means of an externally applied
`heat source. Current
`even with conventional pans,
`thinking,
`is to dry the coated tablets with a supply of'heated air, and to
`extract the moisture and dust
`laden air from the vicinity of
`the pan.
`Further evolution in the coating process tended to remain
`the late 1940's and early 1950's, with the
`static until
`somewhat
`conventional pan being the mainstay of all coating operations
`up to that time. However,
`in the last twenty or thirty years
`there have been some significant
`advances made in coating
`advances often pre-empted by a steady evolution
`technology,
`in pan design and its associated ancillary equipment.
`in the early years of this development,
`Interestingly,
`an
`that of film coating.
`entirely new form of technology evolved,
`the deficiencies of the sugar coating process,
`Recognizing
`advocates of film coating were achieving success by utilizing
`coating systems
`highly volatile organic solvents.
`involving
`These circumvented
`the problems associated with the inef-
`ficiency in the drying capabilities of conventional
`equipment,
`to be met with significant
`and enabled production
`quotas
`in processing times and materials used. The dis-
`reductions
`advantage of this approach, however, has always been asso-
`ciated with the solvent system, which often used flammable
`and toxic materials.
`The advances that occurred with equipment design, having
`of the Wurster7 process and con-
`begun by the development
`tinued by the evolution of side-vented pans, have resulted in
`the gradual emergence of coating processes where drying ef-
`ficiency tends to be maximized.
`Thus, film coating began as
`a process utilizing inefficient drying equipment,
`relying on
`for success
`volatile
`coating formulations
`and has
`highly
`
`1633
`
`Page 3 Dr. Reddy's Exh. 1061
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`

`

`1634
`
`CHAPTER 91
`
`evolved into one in which the processing equipment
`is a major
`factor. The latter has been largely responsible
`for the return
`to an aqueous process.
`the advances
`design have also
`in equipment
`Obviously,
`benefited the sugar coating process, where, because of Good
`(GMP) and the need to maintain
`Procedures
`Manufacturing
`the trend has been
`product uniformity
`and performance,
`toward fully automated processes. Nonetheless
`film coating
`tends to maintain a somewhat dominant position in the area
`of tablet coating.
`
`Pharmaceutical Coating Processes
`
`there are four major
`Basically,
`for applying
`techniques
`to pharmaceutical
`(1) Sugar
`solid dosage forms:
`coatings
`(2) Film Coating,
`(3) Microencapsulation
`and (4)
`Coating,
`Compression Coating.
`the use of mucilage of
`it could be argued that
`Although
`psyllium seed, gelatin, etc, as already discussed was an early
`form of film coating, sugar coating is regarded as the oldest
`method for tablet coating, and involves the deposition from
`aqueous solution of coatings based predominantly
`on sucrose
`The large quantities of coating material
`as a raw material.
`skill often required of the
`that are applied and the inherent
`in a long and tedious process.
`operators combine to result
`the deposition of resins as a thin membrane
`Film coating,
`that were initially or-
`onto the dosage form from solutions
`ganic-solvent based, but which are beginning to rely more and
`more on water ds the prime solvent, have proven to be a pop-
`to sugar coating.
`ular alternative
`is a modified form of film coating,
`Microencapsulation
`differing from the latter only in the size of the particles
`(or
`to be coated and the methods by which this
`liquid droplets)
`It is based on either mechanical methods
`is accomplished.
`such as pan coating, air suspension techniques, multi-orifice
`techniques, and modified spray drying techniques,
`centrifugal
`sepa-
`ones involving coacervation-phase
`or physicochemical
`to be coated is suspended in a so-
`ration, where the material
`lution of the polymer.
`Phase separation is facilitated by the
`ad@tion of a nonsolvent,
`incompatible
`inorganic
`polymer,
`salts, or by altering the temperature
`of the system.
`the use of modified ta-
`coating incorporates
`Compression
`bletting machines which allow the compaction of a dry coating
`around the tablet core produced on the same machine. The
`main advantage of this type of coating is that it eliminates
`the
`aqueous or organic in nature,
`use of any solvent, whether
`it involves a mechanically
`the fact that
`complex
`However,
`operation has obviously been a prime factor in limiting its
`technique.
`adoption as a popular
`The latter two approaches
`fall outside the scope of this
`chapter, which will be confined to processes in which liquid
`systems are applied to the surface of a solid dosage form, no
`matter how diverse that substrate might be. See Chapter
`90.
`
`Sugar Coating of Compressed Tablets
`is a process which relies
`Sugar coating, as the name implies,
`on the use of two main raw materials, namely sucrose and
`Sugar is a somewhat generic term that lends itself to
`water.
`For the purposes of sugar coating,
`a whole class of materials.
`the only material which has stood the test of time is sucrose.
`is that based on the techniques
`The main reason for this,
`it is probably the only material which has enabled
`evolved,
`smooth, high quality coatings to be produced, which are es-
`sentially dry and tack free at the end of the process.
`for the coating of solid dosage
`other methods
`Although
`forms have been and are being evolved, a significant propor-
`tion of all coated products are still sugar-coated,
`and some
`companies are spending vast amounts of capital
`to thoroughly
`
`In spite of certain inherent difficulties
`update the process.
`associated with the sugar coating process, products which have
`been expertly sugar coated still remain among the most ele-
`gant available.
`Since sugar coating is a multi-step process, where success
`is still measured in terms of the elegance of the final product,
`it has been, and still is in many companies, highly dependent
`on the use of skilled manpower.
`These factors, combined with
`a certain amount of folklore, are responsible
`for the process
`being long and tedious. However, processing times have
`two decades by the
`in the last
`been improved
`gradually
`adoption of modern techniques
`of
`and by the introduction
`automation.
`The sugar coating process can be subdivided
`into the fol-
`(1) Sealing, (2) Subcoating,
`(3) Smoothing,
`lowing stages:
`(4)
`(5) Polishing, and (6) Printing.
`Coloring,
`Sealing —The sealing coat is applied directly to the tablet
`core for the prime purpose of separating the tablet core (and
`from the aqueous solu-
`contained therein)
`active ingredients
`tions used in the remainder of the coating process. A secon-
`dary function is to strengthen the tablet core. Sealing coats
`(approximately 10-30%
`usually consist of alcoholic solutions
`solids) of resins
`acetate
`cellulose
`such as shellac,
`zein,
`acetate phthalate.
`or polyvinyl
`Historically,
`phthalate,
`shellac has proven to be the most popular material although
`its use can lead to problems of impaired bioavailability
`owing
`to a change in resin properties on storage. A solution to this
`problem has been to use a shellac-based
`con-
`formulation
`of polyvinylpyrrolidone
`a measured
`quantity
`taining
`(PVP).s
`applied as a sealing coat will
`The quantities of material
`obviously depend on the tablet size and pan charge. However,
`factor is the tablet porosity, since highly
`another
`important
`tend to soak up the first application of
`porous tablets will
`it
`from spreading
`thus
`solution,
`uniformly
`preventing
`the whole tablet mass. Thus, one or more further
`throughout
`applications of resin solution may be necessary to ensure the
`cores are sealed.
`Since most sealing coats develop a degree of tack at some
`time during the drying stages, their use is usually accompanied
`by one or more applications of a dusting powder
`to prevent
`tablets from sticking together or to the pan. A common ma-
`terial used as a dusting powder
`is asbestos-free talc, Over-
`zealous use of this material may cause problems,
`firstly, by
`imparting a high degree of slip to the tablets thus preventing
`them from rolling properly in the pan, and secondly, pre-
`senting a surface at the beginning of the subcoating stage
`to wet, resulting in inadequate
`subcoat
`which is very difficult
`If there is a tendency for
`on the edges.
`build-up, particularly
`to occur, one solution is to replace
`either of these problems
`such as terra
`part or all of the talc with some other material
`alba, which will form a slightly rougher surface.
`If an enteric coated product
`it is usually achieved
`is desired,
`at the seal coat stage by extending the number of applications
`such as
`made, preferably using an en'teric coating polymer
`or cellulose acetate phthalate.
`polyvinyl acetate phthalate
`Subcoating —Subcoating is a critical operation in the sugar
`coating process that can have a marked effect on ultimate
`Sugar coating is a process which leads to a
`tablet quality.
`increase, and it is at the subcoating stage that
`50—100% weight
`most of the build-up occurs, mainly to develop the basis of an
`tablet profile.
`elegant
`subcoating has been achieved by the applica-
`Historically,
`tion of a gum-based solution to the sealed tablet cores, and
`the tablet
`once this has been uniformly distributed throughout
`mass, to follow by a liberal dusting of powder which serves to
`reduce tack and facilitate tablet buildup. This procedure of
`application of gum solution,
`spreading, dusting, and drying
`the requisite build-up has been achieved.
`is continued until
`the subcoating is a sandwich of alter-
`Thus,
`in this situation,
`
`Page 4 Dr. Reddy's Exh. 1061
`
`

`

`Table I—Binder Solution Formulations
`
`for Subcoating
`
`Gelatin
`Gum acacia (powdered)
`Sucrose
`Water
`
`A,%w/w
`
`B,%w/w
`
`3.3
`8.7
`55.3
`to 100.0
`
`6.0
`8.0
`45.0
`to 100.0
`
`Table II—Dusting Powder Formulations
`
`for Subcoating
`
`Calcium carbonate
`Titanium dioxide
`Talc (asbestos-free)
`Sucrose (powdered)
`Gum acacia (powdered)
`
`A,% w/w
`
`B, % w/w
`
`40.0
`5.0
`25.0
`28.0
`2.0
`
`1.0
`61.0
`38.0
`
`Table III—Typical Suspension Subcoating Formulation
`
`Distilled water
`Sucrose
`Calcium carbonate
`Talc (asbestos-free)
`Gum acacia (powdered)
`Titanium dioxide
`
`% w/w
`
`25.0
`40.0
`20.0
`12.0
`2.0
`1.0
`
`Some examples of binder
`nate layers of gum and powder.
`solutions are shown in Table I, and those of dusting powder
`in Table II.
`formulations
`This approach has proved to be very effective, particularly
`if
`where there is difficulty in covering edges, etc. However,
`care is not taken, a "lumpy" subcoat will be the result. Also,
`if the amount of dusting powder applied is not matched to the
`binding capacity of the gum solution, not only will the ultimate
`coating be very weak, but also, dust will collect in the back of
`to ultimate
`the pan, a factor which may contribute
`rough-
`ness.
`approach which has proved popular, par-
`An alternative
`ticularly when used in conjunction with an automated dosing
`is the application of a suspension subcoat formulation,
`system,
`for coating
`in which the powdered materials
`responsible
`build-up have been incorporated into a gum-based solution.
`is shown in Table III.
`An example of such a formulation
`loading to be
`the solids
`this approach
`allows
`Obviously,
`matched more closely to the binding capacity of the base so-
`lution, and often permits the less experienced coater to pro-
`duce satisfactory subcoats with the minimum of problems,
`Smoothing —Depending on how successfully the subcoat
`there may be a necessity for further
`smoothing
`was applied,
`if the latter
`to be achieved prior to color coating, particularly
`by means of a dye coating process,
`is to be accomplished
`by the application
`Smoothing can usually be accomplished
`60-70% sugar
`of a simple
`syrup solution
`(approximately
`solids).
`syrups contain a low percentage of
`Often the smoothing
`titanium dioxide (1—5%) as an opacifier. This can be partic-
`ularly useful when following with a dye color coating process
`the color coating more reflec-
`since it makes the layer under
`tive, resulting in a brighter, cleaner ultimate color,
`Color Coating —In many ways, color coating is the most
`step in the successful completion of a sugar coating
`important
`application of
`process. This is achieved by the multi-step
`(60-70% sugar solids) containing the
`simple syrup solutions
`coloring matter. The types of coloring materials
`requisite
`used can be divided into two categories:
`dyes and pigments.
`The distinction between the two is simply one of solubility in
`the coating fluid. Since water-soluble
`dyes behave entirely
`
`COATING OF PHARMACEUTICAI DOSAGE FORMS
`
`1635
`
`the application
`than water-insoluble
`differently
`pigments,
`procedure used in the color coating of tablets will depend on
`the type of colorant chosen.
`dyes pro-
`When utilized by a skilled artisan, water-soluble
`duce the most elegant of sugar-coated tablets, mainly because
`since
`they yield a much cleaner, brighter color. However,
`dyes are migratory colorants (that is to say, as
`water-soluble
`this will tend to cause
`the moisture is drawn out of the tablets,
`migration of the color, leading to a nonuniform distribution
`of color), great care must be exercised in their use, particularly
`This involves the application
`when dark shades are required.
`of volumes of coating solution (containing low concentrations
`of colorant), which are capable ofjust wetting the entire tablet
`mass, and then allowing the tablets to dry very slowly to pre-
`It is essential
`that each application is
`vent color migration.
`applications are
`allowed to dry thoroughly before subsequent
`made, otherwise moisture may become trapped in the coating
`and may cause the tablets to "sweat" on standing.
`in order to achieve the requisite color uniformity
`Finally,
`it may be necessary to make 60 repeat appli-
`and intensity,
`cations of color solution. This factor, combined with the need
`results in very
`to dry each application slowly and thoroughly,
`are made
`long processing times (eg, assuming 50 applications
`the coloring
`which take between 15 and 30 minutes
`each,
`process can extend over a period of up to 25 hours).
`Tablet color coating with pigments, as advocated by Tucker
`First of all,
`et al,s can present some significant advantages.
`they present no
`colors are water
`insoluble,
`since pigment
`problems of migration since the colorant remains where it is
`if the pigment
`In addition,
`is completely opaque,
`deposited.
`or the system is formulated with an opacifier such as titanium
`the desired color can be developed much more rap-
`thus resulting in a thinner color coat. Since each ap-
`idly,
`savings can
`significant
`plication can be dried more rapidly,
`be made in processing times,
`color coatings are by no means
`Although pigment-based
`they will permit more abuse than a dye color coating
`foolproof,
`for use by less skilled
`and are more amenable
`approach,
`acceptable pigments can be clas-
`coaters. Pharmaceutically
`iron
`(eg, titanium dioxide,
`sified either as inorganic pigments
`oxides) or certified lakes. Certified lakes are produced from
`dyes by means of a process known as "laking"
`water-soluble
`whereby the dye molecule becomes fixed to a suitable insol-
`uble substrate such as aluminum hydroxide.
`Certified lakes, particularly when used in conjunction with
`an opacifier such as titanium dioxide, provide an excellent
`means of coloring sugar coatings and permit a wide range of
`of pig-
`the incorporation
`shades to be achieved. However,
`into the syrup solution is not as easy as with water-
`ments
`it is necessary to ensure
`soluble dyes, since with the former,
`is completely wetted and dis-
`that all the insoluble matter
`persed. Thus the use of prepared pigment color concentrates,
`is usually beneficial.
`which are commercially available,
`Polishing —In order to impart
`the requisite gloss to the
`the tablets, when dry, are submitted to a pol-
`final product,
`(beeswax, carnauba wax,
`ishing process where wax mixtures
`candelilla wax, hard paraffin wax, etc) are applied either as
`finely divided powder mixtures or as suspensions or solutions
`in wax or canvas-lined
`to the tablets
`solvents
`in various
`Printing —In order to identify sugar-coated tablets apart
`pans,
`them
`from shape, size, and color, it is often necessary to submit
`to the pol-
`to a printing stage, either prior to or subsequent
`branding inks by means
`ishing stage, using pharmaceutical
`of the process of offset rotogravure,
`Sugar Coating Problems —Various problems may be
`It must be
`encountered during the sugar coating of tablets,
`that any process in which tablets are kept con-
`remembered
`if the tablets are not
`stantly tumbling can present difficulties
`the stress encountered.
`Tablets
`strong enough to withstand
`
`'ioxide,
`
`Page 5 Dr. Reddy's Exh. 1061
`
`

`

`1636
`
`CHAPTER 91
`
`which are too soft, or have a tendency to laminate, may break
`adhere to the surface of otherwise good
`up and the fragments
`inherently poor mixing
`Sugar coating pans exhibit
`tablets.
`If care is not exercised during the application
`characteristics.
`of
`coating fluids, nonuniform distribution
`of the various
`coating material can occur, resulting in an unacceptable
`range
`of sizes of finished tablets within the batch. Overzealous use
`of dusting powders, particularly
`during the subcoating stage,
`in a coating being formed in which the solid par-
`may result
`in the for-
`ticulate matter exceeds the capacity of the binder
`creating soft coatings or those with increased ten-
`mulation,
`dency to crack.
`is a common problem, particularly
`Color nonuniformity
`Since the latter have a
`dyes are used.
`when water-soluble
`lack of control over the drying
`tendency to migrate easily,
`in nonuniform distribu-
`phases during the process can result
`tion of the coloring material. Rough tablets are obtained ei-
`ther as the result of too rapid drying or lack of uniform dis-
`This is
`of coating fluid after each application.
`tribution
`during the color coating stage, when
`particularly troublesome
`as "marbling" after subse-
`the problem may be highlighted
`quent polishing.
`
`Film Coating of Solid Dosage Forms
`Film coating involves the deposition of a thin, but uniform,
`onto the surface of the substrate.
`Unlike sugar
`membrane
`the flexibility afforded in film coating allows addi-
`coating,
`to be
`tional substrates, other than just compressed tablets,
`capsules).
`nonpareils,
`considered
`granules,
`(eg, powder,
`to a moving bed
`Coatings are essentially applied continuously
`of material, usually by means of a spray technique,
`although
`manual application procedures have been used.
`film coating was introduced in the early 1950's
`Historically,
`the shortcomings of the then predominant
`in order to combat
`sugar coating process. That it has proven successful must be
`attributed to its major advantages which include:
`increase (typically 2—3% of tablet core
`
`(1) Minimal weight
`weight)
`reduction in processing times
`(2). Significant
`Increased process efficiency and output
`(3)
`Increased flexibility in formulations
`(4)
`Improved resistance to chipping of the coating.
`(5)
`
`The major process advantages were derived from the greater
`in spite of
`volatility of the organic solvents used. However,
`that certain
`its success, there has always been an awareness
`to be a limiting
`could prove
`ultimately
`disadvantages
`factor.
`are mainly attributed to the organic
`These disadvantages
`solvents used in the process and include:
`
`(1) Flammability
`hazards
`(2) Toxicity hazards
`(3) Concerns over environmental
`pollution
`items 1—3, or to the
`(4) Cost (either relating to minimizing
`cost of the solvents
`themselves).
`
`in the interim since its introduction,
`significant
`However,
`advances have been made in process technology and equip-
`ment design. The emphasis has changed from requiring the
`presence of highly volatile organic solvents so that the product
`effect by de-
`to achieving the same ultimate
`dries rapidly,
`to have more efficient drying character-
`signing equipment
`istics.
`there has been a transition from conventional
`pans
`Thus,
`and conse-
`to side-vented
`pans and fluid-bed
`equipment,
`process
`quently from the problematic organic solvent-based
`to aqueous systems.
`Film Coating Raw Materials —The major components
`
`consist of polymer, plasticizer,
`in any film coating formulation
`(or vehicle).
`colorant, and solvent
`is solubility in a wide
`for the polymer
`A major requirement
`range of solvent systems
`to promote f1exibility in formulation.
`it must possess an ability to produce coatings
`In addition,
`Because of the
`which have suitable mechanical properties.
`of the coating, such as being exposed to
`various requirements
`should meet certain per-
`the polymer
`gastrointestinal
`fluids,
`formance characteristics.
`Cellulose ethers constitute the majority of polymer
`types
`hydroxypropyl methylcel-
`used for film coating; particularly
`cellulose,
`substitutes
`are hydroxypropyl
`Suitable
`lulose.
`which may produce slightly tackier coatings, and methylcel-
`lulose, although this has been reported to retard drug disso-
`o Alternatives
`ethers are certain
`to the cellulose
`lution.
`acrylics, which are copolymers of methacrylic
`acid and methyl
`methacrylate.
`Most polymers are employed as solutions in either aqueous
`An alternative
`system
`or organic solvent based systems.
`such as ethylcellulose
`utilizes certain water-insoluble
`polymers
`An ad-
`some of the acrylics as aqueous dispersions.
`and/or
`factor to be considered in the selection of polymers
`ditional
`concerns the various molecular weight grades available for
`influ-
`each type. Molecular weight may have an important
`ence on various properties of the coating system and its ulti-
`such as solution viscosity and mechanical
`mate performance,
`strength and flexibility of the resultant
`film.
`The incorporation of a plasticizer
`into the formulation lends
`stress.
`thus better able to withstand
`flexibility to the film,
`This reduces the risk of the film cracking and possibly im-
`proves adhesion of the film to the substrate. To ensure that
`the plasticizer must show a high
`these benefits are achieved,
`and a degree of
`degree of compatibility with the polymer,
`if the properties of the coating are to be stable
`permanence
`on storage. Examples of typical plasticizers
`include glycerin,
`triacetin, acetylated
`glycol, polyethylene
`glycols,
`propylene
`citrate)
`and
`esters
`citrate
`triethyl
`(eg,
`monoglyceride,
`esters (eg, diethyl phthalate).
`phthalate
`Colorants are usually used to enhance the aesthetic appeal
`identification.
`of the product as well as to increase product
`they can enhance
`certain circumstances,
`under
`However,
`certain necessary physical properties of the applied film coats.
`As in the case of sugar coating, colorants can either be classi-
`dyes or insoluble pigments.
`fied as water-soluble
`dyes is precluded with organic
`The use of water-soluble
`solvent based film coating because of lack of solubility in the
`solvent system. Thus, the use of pigments, particularly the
`aluminum lakes, provides the most useful means of coloring
`film coating
`in aqueous
`film coating systems.
`Obviously,
`dyes as colorants,
`for using water-soluble
`there is potential
`still offer some significant advan-
`although in fact, pigments
`tages for the following reasons:
`
`of the
`
`dyes to interfere
`
`(1) The tendency of some water-soluble
`with bioavailabilityii
`of reduction
`(2) The possibility
`in permeability
`are usediz
`coating to moisture when pigments
`to increase overall
`serve as a bulking agent
`(3) Pigments
`solids content
`in coating system.
`The major solvents used in film coating typically belong to
`alcohols, ketones, esters, chlo-
`one of the following classes:
`Solvents serve to perform
`and water.
`rinated hydrocarbons,
`function in the film coating process, since they
`an important
`to the
`facilitate the delivery of the film forming materials
`surface of the substrate. Good interaction between solvent
`film proper-
`is necessary to ensure that optimal
`and polymer
`interac-
`ties are derived when the coating dries. This initial
`tion between solvent and polymer will yield maximum poly-
`mer chain extension, producing films having the greatest co-
`
`Page 6 Dr. Reddy's Exh. 1061
`
`

`

`COATING OF PHARMACEUTICAI DOSAGE FORMS
`
`1637
`
`This has similar stability to PVAP
`phthalate.
`methylcellulose
`in the same pH range. A final example of
`and dissociates
`are those based on methacrylic
`currently
`used polymers
`acid—methacrylic
`acid ester copolymers with acidic ionizable
`groups. They have been reported to suffer from the disad-
`vantage of having delayed breakdown even at relatively high
`pH 13
`Sustained Release Coatings —The concept of sustained
`release formulations was developed in order to eliminate the
`need for multiple dosage regimens, particularly for those drugs
`requiring reasonably constant blood levels over a long period
`it has also been adopted for those drugs
`of time.
`In addition,
`in high doses, but where too
`which need to be administered
`side effects (eg,
`rapid a release is likely to cause undesirable
`the ulceration that occurs when potassium chloride is rapidly
`tract).
`released in the gastrointestinal
`used to obtain the desired drug
`Formulation methods
`in-
`forms
`action dosage
`rate from sustained
`availability
`clude:
`Increasing the particle size of the drug
`1.
`2. Embedding the drug in a matrix
`3. Coating the drug or dosage form containing the drug
`such as
`4. Forming complexes of the drug with materials
`resins.
`ion-exchange
`
`Only those methods which involve some form of coating fall
`within the scope of this chapter.
`Materials which have been found suitable for producing
`4*
`sustained release coatings include:
`1. Mixtures of waxes (beeswax, carnauba wax, etc) with
`stearic acid, palmitic acid, glyceryl
`glyceryl monostearate,
`and cetyl alcohol. These provide coatings
`monopalmitate,
`in the gastroin-
`which are slowly dissolved or decomposed
`tract.
`testinal
`2. Shellac and zein, polymers which remain intact until
`contents becomes less acidic.
`the pH of gastrointestinal
`around the
`3. Ethylcellulose, which provides a membrane
`the gastrointestinal
`intact
`throughout
`particle and remains
`it does permit water to permeate the film,
`tract. However,
`dissolve the drug, and diffuse out again.
`4. Acrylic resins, which behave similarly 7o ethylcellulose
`as a diffusion controlled drug release coating material.
`the common method of producing a sustained
`Traditionally,
`ap-
`one of the following
`involved
`product
`has
`release
`proaches.
`containing the drug which could be sphero-
`A granulation
`is prepared. Dried granules
`if desired,
`nized prior to drying,
`are coated and then either filled into c