CHAPTER es
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`Cooliung of Pharmaceutical ‘Dosage Forrnsi i
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`Stuart Choner, PhD
`‘Vice President, Resealth and Deveilopmenllnn
`Cololcon, Inc
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`West Point, ‘PA 19456 .
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`' The advances that occurred with equipment design, having .
`' begun by the development oftheWurster7.process and contin-
`uedbythe evolution of-side-vented pans, haveresulted
`the .
`gradual emergcnccof coating.processes_where drying efii- _-
`ciency can be maximized._- Thus, film coating began ‘as a ‘
`- process using ine1_‘ficient drying equipment, relying on_.hjghly
`volatile ‘coating formulations for success, and evolved into
`one in which the processiilg equipment is a major factor in
`ensuringthat rapid drying occurs.
`- Improved drying capabili- '_
`ties ha_ve'permitted increased use of ‘aqueous film-coating
`formulations.
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`. Advances in equipment design also have benefitcdthc sugar.
`coating process, where, because of Current Good Manufactur-
`. _'ing Practices (CGMP) and tomajntain product uniformity and
`performance,‘ the trend has been toward using fully automated _
`__processes. Nonetheless, film coating tends to dominate as
`- the-process of choice for tablet coating. I
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`I were held at the end of a suction tube, dipped andthenthe
`' Anyjntroduction to tablet coating '-must be-prefaced by an
`process. repeated for the other side of the pill. Not surpris-
`ilnportant question'~—'_"Why coat tablets?"——si_n‘ce inrnariy .
`ingly, these techniques often failed to produce a un_iformly,_ .
`- instances, the coating is being appliedto a" dosage form that
`, coated product.5
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`ln attempting to answer’
`Initially, the first sugar-coated pil_ls"seen in the US "were
`._this'-question, if oneexamines the market, it wilfbecome
`imported from France about 1842 ;-5 while Warner‘, a Philadel— '
`apparent that asignificant proportion of pharmaceutical solid
`dosage forms are coated._ The reasons for this range from
`_ phia pharmacist, became amongthe first indigenous manufac-
`turers in l856.5
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`- -the esthetic to a desire to control. the bioavaJ'labilil_y of the
`Rharmaceutical pan-coating processes aye based on those
`dmg, and include:
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`I used in the candy industry, where techniques werehighly . ..
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`‘Protecting the drugfrorn its surrounding environment_(pa1‘ticularly
`evolved, even" in the Middle Ages. Today, while most coating
`air, moisture and l.ight)'with a view to inlprovingstability.
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`pans are fabricated from stainless steel, early pans were made _
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`2. "Masking ofunpleasaru; taste and odor.
`from copper, because diying was effectedby means of an-
`' 3.
`Increasing the ease by means of which the product can be ingested in
`by the patient.
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`externally applied heat source. Current thinking, even with '
`conventional pans, is 1.1") diy the coated tablets -with a supply of
`' 4. Improving product identity, from the manufacturing plant, through
`heated air,‘ and remove the moisture and dust-laden airfrom
`iriterrnediaries and to the patient.
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`the vicinity of the pan by means of an a.iI~_extract'1on system.
`5. Facilitating handling, particularly in high-speed packaginglfilling
`line as", and autorna'ted'counters'in pharmacies, whereilie co ating nu'nirm'zes
`- Pan-coating processes underwent little further change until
`cross-contamination due to dusteliminaiion. '
`the late ._1940s and early 1950s; with the conventional pan‘
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`lmproving product appearance, parficularly where there are notice— - being the mainstay of all coating operations up to that time.
`able visible differences to tablet core ingredients from batch to "batch.
`However, in .the_ last 20 or 30 years-'there_have_been some
`'3.
`‘Reducing the risk ofinteraction between incompatible co mponents.
`significant advances made in coating-process technology,
`‘This would be achieved by using coated forms of one or more of the
`mainlygas a result of a steady evolution in pan design and. its
`'offe'nding ingredients (particula_rly active compounds).
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`associated ancillary equipment.
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`'8. _ Improvingproductmechanical integrity, since coated products gen-
`'lr_rterestingly.,
`in the early _yea_.rs of this development, an
`I erally are more resistant to mishandling [abrasion, attrition, etc).
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`‘ enti1'.ely'new__ form of technologyevolvcd,‘ that of fi.lm'coaI‘.ing.-
`9. Modifying drug release, as in enteric-coated, repeat-action and
`' Recognising the deficiencies of the sugar-coating process,
`sustained-releaseproducts.
`_advocates of film coating were achieving success by using
`‘Evolution of the Coating-Process}-Tablet coatingi.-'3
`coating systems involving highly volatile organic solvents.
`perhaps‘ one of the oldest pharrrfaceutical processes still in
`‘These circumvented the problems associated with the ineffi-
`-existence.
`' Although a great deal has been written about the
`ciency in the drying capabilities of. conventional equipment,
`materials and methods used, the coating process is still often _
`and enabled production-quotas to be met with significant
`‘recognised to be more of an art than a science, a factor which
`reductions in processin'g tirnesand materials used. The_dis-
`may be responsible for many of _the problems that can exist.
`advantage of this approach, however‘, always has been associ-,.
`Historically, the literature, cites_Rhazcs_(85{_}7932 AD) ".33 be-
`ated with the solvent systems used, which often employed"
`flammable and toxicmatcrials.
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`ing one of the earliest "tablet coaters," having used the r_nuci-
`lage of psyllium seeds to coat pills‘-that had an offending taste; -‘
`Subsequently, Avicenna’ was reported to have used gold and
`silver for p_ill "coating. Since then, there" have been many
`references to the different materialsluscd in “tablet coating?’
`White” mentioned the use of finely dividedtalc in what was at
`one time popularlyknown as “pearl coating,f' while Kremers
`- and Urdang3 described the introduction of the gelatin coating-
`of pills by Garotl in'1838.
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`An interestiI1g—reference“ reports the"-use of waxes to coat
`_ poison tablets. These waxes, being insoluble in all parts of
`the gastrointestinal tract, were intended to prevent accidental
`poisoning [the contents could be utilized by "breaking the
`' tablet prior to use). -
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`While earlier coated products were produced by individuals-
`- working in pharmacies, particularly when extemporaneous
`‘compounding was the order ofthe day, that responsibility now '
`3 has been assumed by the pharmaceuticalindustry. . The earli-
`est attempts to apply coatings to pills yielded variable’ results
`and usually required the handling of Single" pills. Such pills
`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 coated completely. Subsequently." the pills
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`-Fhatmaceutical Coating Processes’
`‘Basically, there are four major techniques for applying coat-
`- ‘tugs _to pharmaceutical solid dosage forms:
`[-.1) ‘sugar coat-
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`._.1sso .-
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`‘ A-m'erige__n Ex. 1056, p_. -1
`Amerigen Ex. 1056, p. 1
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`-..-..~_._._a.._._i.___-,_...,_-__,.,____________'
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`"comma-or PHAaMhcEuneacLoosAeE Foams
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`_ fing; (2) filnrcoating, (3) naicroencapsulation and ('4) compres-
`sioncoating.
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`- Although it could be argued that the use of mucilage. of
`' psyllitun seed," gelatin, etc, as already discussed, was anearly .
`- forrnof film coating, sugarcoattng is regarded as the ol’dest
`method for tablet coating, and involves the deposition from _'
`' :agueo'us solution of coatings based predoininantly on sucrose
`‘ias a raw material.
`_ The large quantities of coatingmatefial
`. Lthat are applied-and the inherent skill often required-of the___'
`‘operators combine to result in a long_and tedious process.
`Film coating, the deposition of a thin polymeric .filrn onto I
`the dos_age_forn1 from ‘solutions that were initially organlc- _'
`solvent-based, butwhich now rely rnoreand rnoreon water as ‘-
`' the prime solvent, has proven to-be,a'popular'_alternative to -
`sugar coating.
`— Microsncapsutation
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`a modified ' form of
`.coa_ting,'
`differing only in the size of the particles to becoated and the.
`methods bywhichthis is accomplished. .
`process is based
`on either mechanical methods such as pan ‘coating, ' air-
`_ suspension techniques, rnultioriflce centrifugaltechniques and
`modified spray-drying techniques, or physicochernical ones _
`‘involving coacervation-phase separation, where the material
`,to be coated is suspended in a solution of the polymer.
`. Phase _
`separation is facilitatedby the addition of a nonsolvent-, incorri-
`patihle polymer, inorganic salts or by altering the temperature
`‘of the system. '
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`Cmnpafssston coating .-incorp_o1_r_a'.tes the use of -modified
`tableting machines which -allow the‘ compaction of"a dry coat-
`ing-aroiind the tablet core produced on the same machine.
`The main advantage of this type of coating is that it'elin1inates'
`the_use of any solvent, whether aqueous or organic in nature.‘
`.However,_ this process_is mechanically complex and has not
`' proven popular as a method for coating tablets.
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`' Sager Quoting offfijrnigotressed Tablets‘
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`'_ While the term “sugar”. is somewhat ‘generic, and lends_
`‘itself to describing various rawmaterials, sugar coating relies
`mainly on the use of sucrose. . The main reason -for this is
`that, basedon the techniques involved, it is probably theonly
`material which has enabled smooth," high-quality coatings to
`be produced,'tha1'. are essentially
`and .tac_k-free at the end
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`Whfle the '_popula.ri_ty of sugar coating has been on the de-
`'- Cline, this process still retains some‘ popularity,‘ and many _
`' comp;-mics have irivested in the complete modernizationof .
`4- the process.
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`In spite of certain inherent difficulties associated with the
`sugar-coating process, products which have been eirpertly
`sugar coated still remain among themost elegant available.
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`-Since sugar coating is a multistep process, where esthetics
`of the final coated product is an important goal, it has been,_
`and still is in many companies, highly dependent on the_use of
`skilledrnanpower. For these reasons, the sugar—coating pro— I
`. cess is often protIacted.a.ud,tedious. Howeverkprocessing
`times havebeen reducedgradually in the last two decades by
`-the adoption of modern techniques and by the int1'oduc_tion‘o_f _
`' automation. ‘
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`The sugar-coating process can be subdivided into six main‘ _
`I steps:_ _(1) sealing, (2) sribcoating,' (3) srnoothing, (4) color
`coating, (5) polishing and (6) printing.
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`Seal1'ng—The sealing coat is applied directly to the tablet
`core for the purpose of separating the tablet ingredients-(p_ri-
`' marily the drug) and water (which is a major constituent of -
`" the coating formulation) in order to assure good_pr_oduc_t
`stability. Asecondary functionis to strengthen the tablet"
`. -core.
`Sealing coats _'usually consist of alcoholic solutions _
`,_ (approximately 10-30% solids) of resins such as shellac, zein,
`cellulose ‘acetate phthalate or polyvinyl acetate phthalate.
`_ Historically, shellac has proven to be -the most popular. mate-
`rial although it can cause impaired bioavailability due to SI
`,change"in resin properties on storage. A solution to this .
`problem has been to use a shellac—based formulation contain-
`-ing a measured quantity of polyvinylpyrrolidone (PVP).3 ,1
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`. The qu_aritities;o‘f'material‘ applied as _a' sealingicoat
`.'_deperid primarily on the t_abl_et arid',batch size.. However," .
`another.‘
`ortant‘-f" tor istablet porosity, since _-highly_pb._
`rous tablets wllltend
`soak _up the first application of solu-
`tion‘, thus preventing‘-it orn spreading uniformly across the ' _'
`surface’ of every tablet in the batch. Thus-, one or more‘
`"further applications of resin solution may
`necessary to
`ensure fliatthe tabletcores are sealed eEecl:iv'ely.'
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`' Since most sealing coats develop. a degree ‘of tack (sti_clri_-‘
`ness) at some time during the drying process, it is usrial.'t_,o
`apply a dusting powder to prevent tablets from
`gether or to the pain.‘ A common material used as "a dusting-
`powder is-asbestos-free talc. Oyerzealotis use of talc-_'may'-'
`"cause" problems, firstly, by irnparting a high degree of slip _I3_(_)
`'- the tablets, thus preventing them from rolling properly in the
`pan", and secondly. presenting a surface-at the beginning of the .
`-subcoating stage which is_very'di1licult to wet, resultingin
`inadequate subcoatbuildup, particularly on theedges.
`-If
`there is atendency for either of these problems to occur, one _
`" solution‘ is to replace part or all of the tale with _some otligr .-
`material such as terra alba, which will form a slightly rougher -,
`surface. Use oftalc now is being frowned upon because of its.
`potential carcinogenicity.
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`, If an enteric-coated product‘ is required, additional quanti-
`ties of the seal-coatsolution are_applied..
`In. this situation,
`however, it is preferable to use synthetic polymers such as_-
`" polyvinyl acetate phthalate or cellulose acetate phthalate, I_
`Subeoatirrg——-Subcoating is acritic_al_oper_ati_on in the sugar-I.
`coating process that can have_a marked effect on ultimate
`tablet quality. Sugar coatingis 'a process which often leads —
`to a 50 to 100% weight-increase, and.it is at the subcoating
`stage that most of the buildup occurs.
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`' Historically, subcoating has been achievedby the‘ applica- _'
`' -tion of 'a,gurn-based solution to the sealedtablet cores, and
`‘once thissolution has been i:listributed.uriifounly throughout:
`the "tablet mass, it is followed by a liberal dusting of powder, '_
`which serves to reduce tack "and facilitate tablet buildup.-
`.Tliis'procedure of application of gum. solution, -spreading,
`dusting and drying is continued until the requisite buildup has
`been achieved. Thus, the subcoating is a sandwich of alter» '_ . 2.‘
`.-nate layers of gum and powder. . Some exarnples of binder-_
`solutions are ‘shown in Table 1 and those of'du.sting_.powder'
`formulations in Table 2.
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`"While this approach has proved to be very efiective, particu-
`larly-where there is difficulty in covering-edges.
`If-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 onlywlll the ultimate .
`coating be brittle, but also dust will collect in the back-of the
`pan, afaétor which may contribute to excessive roughness.-',
`"An alternative appgoach which has proved popular; partlcu- 9
`larly when used in cordunction with an automated‘ dosing -"
`system, is the application ofa suspension sub-coat formulation.
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`Table-1'—Blnder‘Solution l‘ormukulons’1or_Subco‘a'tlr_rg I
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`- A,%w!w
`B.%wlw _
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`. "Gelatin
`- Gum acacia (powdered).
`Sucrose
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`Water .
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`3.7
`55.3 _
`—tEF-100.0 -'
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`45.0
`to.100.0
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`_.- Table 2——Dusllhg Pm_vder_Forn'uiIa_lIons lorsubcoallng _.
`A, ‘ls-w,r'w '
`B. %lv,r‘|-_v'_
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`Calcium ca.|_'bonate_
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`Titanium dioxide
`_ Talcfasbestos-free)
`Sucrose (powdered)
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`Gum acacia (powdered) .
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`40.0
`5.0
`25.0
`‘sac
`2.0
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`' .110
`61.0
`' sa.o ‘_
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`Amerigen Ex. 1056, p. 2
`Area-nEx.. 1056.09; 2 .
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`Table s—'ryplcar Suspension.Subcoalll_1g Formulation ' ' l
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`at wfw
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`25.0
`40.0
`20.0
`12.{l
`2.01.0
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`Distilled water
`Sucrose
`Calcium carbonate
`Talc (asbestos-free) -
`Gum acacia (powdered)
`Titanium dioxide ‘
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`l-n‘ such 'a formulation the powdered materials responsible for
`.-“coating buildup have been dispersed in‘ a gum-based solution.
`‘A typica.l« formulation is shown in Table 3. This approach
`'alloW3_tl1 solids loading to be matched more closely t_o.the
`bindirls
`pacity of the base solution, and often pennits the -
`less-experienced coater to achieve satisfactory results._ I
`Smoothing-_~Dependll1g on ‘how succe.ssfr_l]l1y‘the suhcoat
`was applied, it may be necessary to smooth out the tablet
`surface further prior to application of the
`coating.
`Smoothing usually c_a.n be accomplished by the application of
`a simple syrup solution (approximately 60 to 70% sugar sol-_
`l<.15)«
`the smoothing syrups (£Dl'Ii__2.ll'I a low_ percenfagelof _
`"titanium dioxide (1 to 5%) as an. opacifier. This can be
`particularly useful when the subsequent color-coating l‘orrnu- -
`lation-_I.l3e£ water—soluble dyes as colorants‘, since it makes the
`surface under_the color coating more retlefctive, resulting in a
`brighter,'cleaner final color.
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`Color ContIng—T_his stage often is the most critical in the
`successful completion of a sugar-coating process, and in-
`volvesthc multiple application of" syrup solutions (60 to 70%
`sugar solids) containing the requisite coloring matter. The
`‘types of coloring
`I_lsed'can.be divided into‘ two
`categories: dyes or. pigments. The distinction between the .
`two simply is one of solubility in the" coating fluid- Since ,
`water-soluble. dyes behave entirely dilferently than water-
`insoluble pigments, the application procedure used .in the
`color coating of tablets will depend on the type of colorant
`chosen.
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`'--Vfllen. by a skilled artisan, "water-soluble dyes produce"
`the most elegant of sugar-coated tablets, since it is possibleto
`obtain a cleaner, brighter final color. However, since water»
`soluble dyes are migratory colorants (that is to say, moisture
`that is removedfrom the coating on drying will cause rm'gra--
`tion of the colorant, resultingin a nonuniform appearance),
`great care"-must be exercised in their use, particularly when
`dark shades are required. This can be‘ achieved by applying
`_ small quantities of colored syrup that arejust sullicient to wet
`the surface of every tablet in the batch, and then allowing the
`tablets to dry slowly.
`‘It is essential that each application is
`allowed to dry thoroughly before‘ subsequent applications are
`made, otherwise moisture may become trappetlin the coating
`and may cause the tablets to “sweat" on standing.
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`The final color obtalned_ may result from up to 60_i.ndividual
`applications of colored syrup.. This factor, combined with"
`the need to dry each application slowly "and thoroughly, re-
`__ suits" in very long processing times (eg, assuming 50 applica- --
`tions are made which take between 15 and'30 minutes each,
`the coloring process can extend over a period of up to 25
`-hours).
`. Tablet color coating with pigments, as advocated by Tucker
`First of all,
`-9!» at,“ can present some significant advantages.
`since pigment colors are -water-insoluble, they present no
`' problems of migration since the colorarit remains where it is
`deposited.
`In addition, if_ the pigment. is opaque, or is com-
`_bined with an opacifier such as titanium dioxide, the desired
`. color can be,de'velope_d much more rapidly, thus resulting irla
`thinner‘ color coat.
`Since each color-symp application n_ow
`can be dried more rapidly, fewer applications are required and
`significant reductions can be made _in'hotl‘l processing times
`and costs.
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`I Although pigment‘-based color coatingslare by no means-'
`‘foolproof, they will permit more abuse than a dye color-
`- coating approach, and are more amenable for use by" less-
`skilled coaters. Pharrnaceutically acceptable pigments can,
`be" classified either as inorganic pigments (eg, titanium diox-'
`ide, iron oxides) or certified lakes.
`‘Certified lakes are pro- "
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`duced from water-soluble dyes by means of a process known
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`_as “lalcing," whereby the dye molecule becomes fixed to a
`suitable insoluble substrate" such asaluminum hydroxide.
`Certified lakesrparticularly 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
`shades to be achieved. However, the incorporation of pig-
`ments into the syrup solution is not as easy as with water-
`soluble dyes, since it is necessary to ensure that the pigment is
`wetted completely and dispersed uniformly. Thus, the use of
`pigment color concentrates, which are commercially avail-
`_ able, is usually beneficial.
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`Polishirlg—Sugar-coated tablets need to be polished in
`order to achieve a final gloss.‘ Polishingis achieved by apply- -
`, ing mixtures of waxes (beeswax, camauha wax, candelila wax
`or hard paraflin wax) to the tablets in a polishing pan. Such
`wax mixtures may be applied as powders or as dispersions in
`various organic solvents.
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`._PrinI:ing—lI_1 order to‘ identify sugar-coated tablets (in ad»
`won to shape,.size and color].ofte'n it is necessary to print
`the'm,'eitl'_ler before ‘or after polishing, using pharmaceutical .
`branding irlks, by means of the process of ofiset rotograuure.
`' Sugar-Coating Problems-—Various problems may be en-.
`countered during the sugar coating of tablets.
`It must be
`- remembered that any process in which tablets are kept tum-"'
`blirlg constantly can present difficulties if the tablets are not
`strong enough to withstand the applied stress. Tablets which
`.are too soft,‘ or have a tendency to laminate, may break up_and
`the fragments adhere to the surface of otherwim good tablets.
`Sugar-coating pans_ exhibit
`inherently poor mixing‘
`characteristics.
`If carelis not exercised
`the applica-
`tion of the various coining fluids, nonuniform distribution of
`-coating material can occur, resulting in an unacceptable range
`_ of sizes of finished tablets within the batch.
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`Overzealous use of dusting powders, particularly duringthe I
`subcoating st_ag'e,_ may result in a coating being formed in
`which the quantity of fillers exceeds the binding capacity of
`the polymer used in the formulation, creating so'ft'coatings or
`th0_se with increased tendency to crack.
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`irregularities in appearance‘ are not uncommon, and occur
`either as the result of .'color migration ' during drying .when
`water-soluble dyes are used, or of "washing back" when over:
`dosing of colored syrups causes the previously drted coating
`layers to be redissolved. Rough tablet surfaces will produce
`a "marbled" appearance durirlg polishing, since wax buildup _
`occurs in the small depre_ssions in the tablet surface.
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`Coa.ti1r'lg ofSolid Dosage Forms"
`Film coating involves the deposition of a thin, but uniforrll,
`film onto the surface of the substrate._ , Unlike sugar coating,
`the flexibility afi_'orded in film coating allows additional sub-'
`_stral'.es, other than just compressed tablets, to be considered
`(cg, powder; granules, nonpareils, capsules). Coatings essen-'
`tially are applied continuously to a moving bed of material,
`usually by means of a spray technique, although manual appli¢
`cation procedures have been used. -
`_
`'
`.
`Historically, film coating was introduced in the early 1950s
`_ in orderto combat the shortcomings of the-then predominant
`sugar-coating process. Film coating has proved successful
`as a result of the many advantages offered, incl_uding:
`Minimalweight increase (typically 2 to 3% of tablet core weight).
`_Sig_nificant reduction in processing times.
`'
`'
`-
`Increased process elhciency and output._
`_
`increased flexibility in formulations.
`lrnproved resistance to chippingof the coating.
`
`'
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`
`.="_:-‘495-99?
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`/
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`Amerigen Ex. 1056i',.p.'3 _
`Amerigen Ex. 1056, p. 3
`
`

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`‘I
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`_
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`I
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`-
`
`coating, the major process advan-
`In the early years of
`tages resulted from the greater volatility-of the organic sol-
`vents used. However, the use of such organic solventshas
`_ created many potential problems, including:
`1,‘ . Flammability hazards.
`2. Toxicity hazards.
`'
`.
`3__—- Concerns over envirolrtrnental pollution.
`- 4‘. I Cost [either relating to miniruizzing -iterns l—3,.or to the cost of the
`giolvents themselves].
`'
`-
`-' However, since the initial introduction of film coating,_signifi-"
`cant advances have been made in process technology -and
`equipment design. The emphasis has changed from needing
`highly volatile organic solvents (to achieve rapid drying), to
`attaining the same ultimate effect by designing equipment to
`have more efficient drying characteristics.
`.'
`.
`Thus, there-has been a transition from conventional pans to
`side-vented pans and fluid—bed equipment, and consequently
`from the problematic organic solvent-based process to an
`, aqueous -one.
`Filrn Coating Raw Mate1'ials——The major components in
`any film-coating formulation consist of ‘a pohrmer, plasticizer,
`colorant and solvent (or vehicle).
`‘
`-
`_
`_
`Ideal properties forthe polymer include solubility in a wide
`range of solvent systems to promote flexibility in formulation,
`an ability to produce coatings which have suitable mechanical _
`properties and the appropriate solubility in gastrointestinal
`fluids such that drug bioavailability is not compromised. -_
`-
`_ Cellulose ethers are the preferred polymers in film coating, '
`particularly hydroxypropyl methylcellulose.
`-Suitable substi-.
`tutes are hydroxypropyl cellulose, which may produce slightly -
`tackier coatings, and methylcellulose, although this has been
`reported to retard drug dissolution.” Alternatives to the
`cellulose ethers are certain acrylics, such as methacrylate and
`methyl methacrylate copolymers.
`'
`'
`Most polymers are employed assolutions ineither aqueous '
`or organic solvent-based systems.
`. Alternative systems em-
`ploy aqueous. dispersions of water~insoluble polymers (eg
`ethylcellulose). Such systems usually are combined‘ with
`aqueous solutions of water-soluble polymer in order to facili-
`tate rapid drug release.
`'
`'
`-
`'
`_
`Many of the commonly used polymers are available in a
`range of molecular-weight grades, a factor which also must be
`considered in the selection process. Mol_ecular weight may
`have an important influence on various properties of the coat-
`ing system and its ultimate performance, such as solution
`viscosity and mechanical strength and flexibility of the result-
`
`The incorporation of a plasticizer into the formulation im-
`proves the flexibility of the coating, reduces the risk.of the film
`cracking and possibly improves adhesion of the film to-the
`substrate. To ensure that these benefits are achieved, the
`plasticizer must show a high degree of compatibility with the
`' polymer, and be retained permanently in the film, if the prop-
`erties of the coating are to remain consistent on storage."
`Examples of typicalplasticizers include glycerin, propylene
`glycol, polyethylene glycols, triacetin, aeetylated morioglycer-'
`ide, citrate esters (eg, triethyl citrate) or‘ phthalate esters'(eg, _
`diethyl phthalate);
`'
`'
`'
`Colorants usually are used to improve the appearance of the
`product as well as to facilitate product identification.
`’Ad-
`diti'onally, certain physical properties of the coating (eg its
`performance as a moisture barrier) may be improved." As in
`-the case of sugar coating, colorants can be classified either as
`water—soluble-dyes or insoluble pigments.
`.
`_
`The use of water-soluble dyes is precluded with organic
`I‘ solvent-based film coating because of the lack of- solubility in
`the solvent system. Thus, the use of pigments, particularly
`aluminum lakes, provides the most useful means of coloring
`‘filrn~coating systems. Althoughit may seem obvious to use
`_water—soluble dyes in aqueous formulations, the use of pig-
`I merits is preferred, since:
`
`' 1. They are unlikely to interfere with'bioavailability"_ as do some
`water-soluble dyes.
`
`COATING or PHARMACEUTICAL DOSAGE FOFIMS
`
`‘.1653
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`' They help to reduce the permeability of the coating to moisture. '=’-‘
`2..
`3. They serve as bulking agents to increase the overall solids content in
`the coating dispersion.
`'
`I
`'
`4. They tend to be more light stable.
`
`The major solvents used ‘in film coating typically belong to
`one of these classes:
`alcohols, ketones, esters, ‘chlorinated
`- hydrocarbons and water.-
`Solvents serve to perfonn an impor-
`tant function in the film-coating process, since they aid in
`the application of the coating to the "surface of the substrate._
`Good interaction between solvent and polymeris necessary to
`ensure that optimal film properties are obtained when the
`coating dries.
`.This initial interaction between solvent and
`polymerwillyield maximum polymer-chain extension, produc- -
`ing films having the greatest cohesive str‘ength'and, thus, the
`best mechanical properties. An important ‘function of the _
`solvent systems also is to assure acontr.olled deposition of the
`°pob'mer onto the surface of the substrate so that a coherent
`- and adherent fil-rn coat is obtained. '
`_
`.
`'
`Although it is very difficult to give typical examples of
`filrn-coating formulatioris, since these will depend on the prop.
`erties of the materials used, such formulations usually are
`.based on 5 to 15%_(w/w) coating solids'_in the requisite
`vehicle (with the higher concentration range preferred for
`aqueous formulations), of which 60 to 79% is polymer, 6 to _
`7% is plasticizer and 20 to 30% isrpigment.
`
`_
`
`Jlilodified-lfletease Film Coatings
`
`
`
`_
`
`-Film coatings can be applied to pharmaceutical products in -_
`order to modify drug release- The USP describes two types
`' "of modified-release dosage forms, namely‘ those that are de-
`layed retease and those that are extended release. Delayed-
`release products often-are designedto prevent drug‘ release in
`the upper part of the gastrointestinal (GI) tract. Film coat.-
`ings used tofprepare this type of dosage form are commonly
`called enteric coatings.
`_
`_
`Extended-release products are de-, v
`_signed to extend drug release over a period of time, a result
`which can be achieved by the application of a sustr1imad- or
`.contr'olleoI4r_eLease film coating.
`_
`Enteric Coa.tings——Enteric coatings are those which re-._
`main intact‘-in the stomach, but will dissolve and release the‘
`contents ofthe dosage form once it reaches the small intestine.
`The purpose of an enteric coating is to delay the releaseof
`drugs which are inactivated by the stomach contents, (eg,
`pancreatin, erythromycin] or may cause nausea orbleeding by
`irritating the gastric mucosa (eg, aspirin‘, steroids).
`In addi-'
`tion, such coatings can be used to give a simple repeat-action
`elfect where additional drug that has been applied over the
`enteric coat is released in the stomach, while the remainder,
`- beingprotected by the coating, is released further down the
`gastrointestinal tract.
`-
`_
`The -action of enteric coatings results fro_m a difierence in
`composition of the respective gastric,-and intestinal environ-
`ments in regard to pH and enzymatic properties. Although
`there have been repeated ‘attempts to produce coatings which
`are subject to intestinal enzyme breakdown, this approach is
`not popular since _en'_zyrnatic decomposition of the film is
`rather slow." Thus, most currently‘ used enteric coatings are
`those which remain undissociated in-the low pH environment
`of the stomachobut readily ionize when the pH rises to about 4 -
`or 5.. The most effective enteric polymers are polyacids hav-
`ing a pK,, of 3 to'5. Coatings subject to enzymatic breakdown
`are being considered now as protective coatings suitable for
`the colonic delivery of polypeptide drugs.
`,
`-
`'
`.
`'
`Historically, the earliest enteric coatings used formalin-
`treated gelatin, "but this was unreliable since the polymeriza-
`'tion of gelatin-could not be .cori'trol|ed accurately, arid often
`,_ resulted in failure to release the drug, even in the lower intesti-
`nal tract. Another early candidate was shellac, but again the
`” main disadvantageresulted from -further polymerization that
`occurred on storage, often resulting in failure to release the .
`active contents. Pharmaceutical formulators now prefer to‘
`l use synthetic polymers to prepare more elfective enteric coat-
`ings.
`.
`1
`
`Amerigen Ex. 1056, p. 4
`. _Am'erigen E>__<.
`4 "
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`

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`1654 _ CHAPTER 93
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`In the first Fourlcxaniples, the final coated particles-can
`either be-filled into two-piece hard-gelatin capsulesor corn: _'
`_ pacted into tablets. Additionally, coated drugfion-exchange-
`resin complexes may be dispersed in viscous liquids to create _
`liquid suspensions.
`'
`.
`-
`,
`.
`.
`,A rather unique application of the film-coated, sustained-
`" release tablet is the elementary osmotic" pump.
`in thisde-.
`vice, a tablet core {formulated to contain osmotically active
`, ingredients}
`film coated with a semipermeable membrane,
`. which is subseqliently “pierced" with a laser to "create a deliv-
`ery orifice. On the ingestion" ofs'ucl.1 a device, the_ infusion of “
`water generates an osmotic pressure withiir the coated tablet
`that '_‘purrips” the drug in solution out through the orifice.
`.
`-With sustained-release products, o