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`Page 1 of 40
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`KVK-TECH EXHIBIT 1027
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`Page 1 of 40
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`KVK-TECH EXHIBIT 1027
`
`

`

`Editor: Daniel Limmer
`Managing Editor: Matthew J. Hauber
`Marketing Manager: Anne Smith
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`Lippincott Williams & Wilkins
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`!'-~ publication contains information relating to general principles of medical care
`,:.._:; which should not be construed as specific instructions for individual patients.
`Manufacturers' product information and package inserts should be reviewed for
`· -:.
`current information, including contraindications, dosages and precautions.
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`.,___- Printed in the United States of America
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`Entered according to Act of Congress, in the year 1885 by Joseph P Remington,
`in the Office of the Librarian of Congress, at Washington DC
`
`Copyright 1889, 1894, 1905, 1907, 1917, by Joseph P Remington
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`Copyright 1926, 1936, by the Joseph P Remington Estate
`
`Copyright 1948, 1951, by the Philadelphia College of Pharmacy and Science
`
`Copyright 1956, 1960, 1965, 1970, 1975, 1980, 1985, 1990, 1995, by the Phila(cid:173)
`delphia College of Pharmacy and Science
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`~ght 2000, bJ\the University of the Sciences in Philadelphia
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`All!Ug1us~
`Library of Congress Catalog Card Information is available
`ISBN 0-683-3064 72
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`The publishers have made every effort to trace the copyright holders for borrowed
`material. If they have inadvertently overlooked any, they will be pleased to make
`the necessary arrangements at the first opportunity.
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`The use of structural formulas from USAN and the USP Dictionary of Drug
`Names is by permission of The USP Convention. The Convention is not respon(cid:173)
`sible for any inaccuracy contained herein.
`Notice-This text is not intended to represent, nor shall it be interpreted to be, the
`equivalent of or a substitute for the official United States Pharmacopeia (USP)
`and/or the National Formulary (NF). In the event of any difference or discrep(cid:173)
`ancy between the current official USP or NF standards of strength, quality,
`purity, packaging and labeling for drugs and representations of them herein, the
`context and effect of the official compendia shall prevail.
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`Page 2 of 40
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`'(cid:173)
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`Tobie of Contents
`
`Port 1 Orientation
`
`1 Scope of Pharmacy . . . . . . . . . . . . . . . . . . . . . . . .
`2 Evolution of Pharmacy . . . . . . . . . . . . . . . . . . . . . .
`3 Ethics and Professionalism. . . . . . . . . . . . . . . . . . . .
`4 The Practice of Community Pharmacy . . . . . . . . . . .
`5 Pharmacists in Industry . . . . . . . . . . . . . . . . . . . . . .
`6 Pharmacists in Government . . . . . . . . . . . . . . . . . .
`7 Pharmacists and Public Health. . . . . . . . . . . . . . . . .
`8 Information P,esources in Pharmacy and the
`Pharmaceutical Sciences. . . . . . . . . . . . . . . . . . . . .
`9 Clinical Drug Literature . . . . . . . . . . . . . . . . . . . . . .
`1 0 P.esearch. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`Port 2 Pharmaceutics
`
`11 Pharmaceutical Calculations . . . . . . . . . . . . . . . . . .
`12 Statistics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`13 Molecular Structure, Properties, and States of Motter. . .
`14 Complex Formation. . . . . . . . . . . . . . . . . . . . . . . .
`15 Thermodynamics . . . . . . . . . . . . . . . . . . . . . . . . . .
`16 Solutions and Phose Equilibria . . . . . . . . . . . . . . . . .
`17 Ionic Solutions and Electrolytic Equilibria. . . . . . . . . .
`18 Tonicity, Osmoticity, Osmolality, and Osmolarity. . . .
`19 Chemical Kinetics . . . . . . . . . . . . . . . . . . . . . . . . .
`20 Interfacial Phenomena. . . . . . . . . . . . . . . . . . . . . .
`21 Colloidal Dispersions. . . . . . . . . . . . . . . . . . . . . . . .
`22 Coarse Dispersions . . . . . . . . . . . . . . . . . . . . . . . . .
`23 P.heology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`Port ::l Phormoceuticol Chemistry
`
`24 Inorganic Pharmaceutical Chemistry . . . . . . . . . . . .
`25 Organic Pharmaceutical Chemistry . . . . . . . . . . . . .
`26 Natural Products. . . . . . . . . . . . . . . . . . . . . . . . . . .
`27 Drug Nomenclature-United States Adopted
`Names.................................
`28 Structure-Activity P.elotionship and Drug Design. . . . .
`29 Fundamentals of P,odionuclides . . . . . . . . . . . . . . .
`
`Port 4 Phormoceuticol Testing, Analysis ond Control
`
`30 Analysis of Medicinals. . . . . . . . . . . . . . . . . . . . . . .
`31 13iological Testing
`. . . . . . . . . . . . . . . . . . . . . . . . .
`32 Clinical Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . .
`33 Chromatography. . . . . . . . . . . . . . . . . . . . . . . . . .
`34 Instrumental Methods of Analysis. . . . . . . . . . . . . . .
`35 Dissolution. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`Port 5 Phormoceuticol Manufacturing
`
`36 Separation ............................. .
`37 Powders ............................... .
`38 Preformulation ........................... .
`39 Solutions, Emulsions, Suspensions, and Extracts .... .
`40 Sterilization ............................. .
`41 Parenteral Preparations .................... .
`42 Intravenous Admixtures .................... .
`43 Ophthalmic Preparations ................... .
`44 Medicated Topicols ....................... .
`45 Oral Solid Dosage Forms ................... .
`46 Coating of Pharmaceutical Dosage Forms ....... .
`47 Controlled-P.eleose Drug-Delivery Systems ....... .
`48 The Introduction of New Drugs ............... .
`
`3
`7
`19
`28
`33
`38
`4 7
`
`60
`70
`81
`
`91
`124
`1 59
`183
`198
`208
`227
`246
`263
`27 5
`288
`316
`335
`
`359
`385
`409
`
`441
`458
`469
`
`485
`540
`552
`587
`614
`654
`
`669
`681
`700
`721
`753
`780
`807
`821
`836
`858
`894
`903
`930
`
`49 13iotechnology and Drugs ................... .
`50 Aerosols ............................... .
`51 Quality Assurance and Control ............... .
`52 Stability of Pharmaceutical Products ............ .
`53 13ioovoilobility and 13ioequivolency Testing ....... .
`54 Plastic Pocl~oging Materials .................. .
`55 Pharmaceutical Necessities .................. .
`
`Port 6 Pharmacodynamics
`
`56 Diseases: Manifestations and Pathophysiology
`57 Drug Absorption, Action, and Disposition ........ .
`58 13osic Phormocol~inetics ..................... .
`59 Clinical Phormocol~inetics ................... .
`60 Principles of Immunology ............... .
`61 Adverse Drug P,eoctions . . . . . . . . . . . . . . . . .
`62 Pharmacogenetics .................... .
`63 Pharmacological Aspects of Substance Abuse ..
`
`Port 7 Pharmaceutical and Medicinal Agents
`
`64 Diagnostic Drugs and P.eogents ............... .
`65 Topical Drugs ............................ .
`66 Gastrointestinal and Liver Drugs ............... .
`67 13lood, Fluids, Electrolytes, and Hematological Drugs ... .
`68 Cardiovascular Drugs ...................... .
`69 P,espirotory Drugs ......................... .
`70 Sympathomimetic Drugs ................... .
`71 Cholinomimetic Drugs ..................... .
`72 Adrenergic and Adrenergic Neuron 131ocl~ing Drugs ..
`73 Antimuscorinic and Antispasmodic Drugs ........ .
`7 4 Sl~eletol Muscle P.eloxonts ................... .
`7 5 Diuretic Drugs ........................... .
`7 6 Uterine and Antimigroine Drugs .............. .
`77 Hormones and Hormone Antagonists .......... .
`7 8 General Anesthetics ....................... .
`79 Local Anesthetics ......................... .
`80 Sedative and Hypnotic Drugs . . . . . . . . . . . . . . . . .
`81 Antiepileptic Drugs ........................ .
`82 Psychopharmacologic Agents ................ .
`83 Analgesic, Antipyretic, and Anti-Inflammatory
`Drugs ................................. .
`84 Histamine and Antihistominic Drugs ............ .
`85 Central Nervous System Stimulants ............. .
`86 Antineoplastic and lmmunooctive Drugs ........ .
`87 Anti-lnfectives ........................... .
`88 Parositicides ............................. .
`89 Immunizing Agents and Allergenic Extracts ...... .
`
`Port 6 Pharmacy Practice
`
`Port &A Pharmacy Administration
`
`944
`963
`980
`986
`995
`1005
`1015
`
`1053
`1098
`1127
`1145
`1156
`1165
`1169
`1175
`
`1185
`1200
`1219
`1243
`1274
`1297
`1305
`1314
`1322
`1328
`1333
`1344
`1354
`1358
`1395
`1400
`1407
`1421
`1429
`
`1444
`1464
`1471
`1477
`1507
`1562
`1567
`
`90 Lows Governing Pharmacy ................. .
`91 Pharmocoeconomics ...................... .
`92 Morheting Pharmaceutical Core Services ........ .
`93 Documenting and 13illing for Pharmaceutical Core
`Services ............................... .
`94 Community Pharmacy Economics and
`Management ........................... .
`95 Product P.ecolls and Withdrawals ............. .
`
`1595
`1625
`1634
`
`1640
`
`1650
`1666
`
`Port 60 Fundamentals of Pharmacy Practice
`
`96 Drug Education .......................... .
`
`1677
`
`xiv
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`Page 3 of 40
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`

`

`97 The Prescription .......................... .
`98 Extemporaneous Prescription Compounding ..... .
`99 Poison Control .......................... .
`1 00 Nutrition in Pharmacy Practice ............... .
`101 Self-Core/Diagnostic Products ................. .
`1 02 Drug Interactions ......................... .
`1 OJ Complementary and Alternative Medical Health
`Core .................................. .
`1 04 Nuclear Pharmacy Practice ................. .
`1 05 Enzymes .............................. .
`1 06 Vitamins and Other Nutrients ................ .
`1 07 Pesticides .............................. .
`108 Surgical Supplies ......................... .
`1 09 Health Accessories ........................ .
`
`Port 8C Patient Core
`
`110 Ambulatory Patient Core ................... .
`111 Institutional Patient Core ................... .
`112 Long-Term Core Facilities ................... .
`
`1687
`1706
`1716
`1725
`17J8
`1746
`
`1762
`1781
`1792
`1796
`1825
`1846
`1857
`
`189J
`1911
`19J2
`
`11 J The Patient: l3ehoviorol Determinants
`114 Patient Communication .................... .
`115 Patient Compliance ...................... .
`116 Phormocoepidemiology ................... .
`117 Integrated Health-Core Delivery Systems ........ .
`118 Home Health Patient Core ................. .
`119 Aseptic Technology for Home-Core
`Pharmaceuticals ......................... .
`
`Appendixes
`
`Dose Equivalents ......................... .
`Periodic Chart ........................... .
`Logarithms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`1948
`1957
`1966
`1980
`1990
`2012
`
`2020
`
`20JJ
`20J4
`20J6
`
`Glossary and Index
`
`Glossary ............................... .
`Index ................................. ·
`
`20J7
`20J9
`
`XV
`
`Page 4 of 40
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`

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`--
`
`Coating of Pharmaceutical Dosage Forms
`
`CHAPTER 46
`
`Stuart C Porter, PhD
`President
`PPT
`Hatfield, PA 19440
`
`I
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`8.
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`4.
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`6.
`
`Any introduction to tablet coating must be prefaced by an
`important question-Why coat tablets?-since in many in(cid:173)
`stances, the coating is being applied to a dosage form that
`already is functionally complete. In attempting to answer this
`question, if one examines the market, it will become apparent
`that a significant proportion of pharmaceutical solid dosage
`forms are coated. The reasons for this range from the esthetic
`to a desire to control the bioavailability of the drug, and include
`1. Protecting the drug from its surrounding environment (particularly
`air, moisture, and light) with a view to improving stability.
`2. Masking of unpleasant taste and odor.
`3.
`Increasing the ease by which the product can be ingested by the
`patient.
`Improving product identity, from the manufacturing plant, through
`intermediaries, and to the patient.
`5. Facilitating handling, particularly in high-speed packaging/filling
`lines, and automated counters in pharmacies, where the coating
`minimizes cross-contamination due to dust elimination.
`Improving product appearance, particularly where there are notice(cid:173)
`able visible differences in tablet core ingredients from batch to
`batch.
`7. Reducing the risk of interaction between incompatible components.
`This would be achieved by using coated forms of one or more of the
`offending ingredients (particularly active compounds).
`Improving product mechanical integrity, since coated products gen(cid:173)
`erally are more resistant to mishandling (abrasion, attrition, etc).
`9. Modifying drug release, as in enteric-coated, repeat-action and
`sustained-release products.
`EVOLUTION OF THE COATING PROCESS-Tablet
`coating is perhaps one of the oldest pharmaceutical processes
`still in existence. Historically, the literature cites Rhazes (850-
`932 AD) as being one of the earliest tablet coaters, having used
`the mucilage of psyllium seeds to coat pills that had an offend(cid:173)
`ing taste. Subsequently, Avicenna 1 was reported to have used
`gold and silver for pill coating. Since then, there have been
`many references to the different materials used in tablet coat(cid:173)
`ing. White2 mentioned the use of finely divided talc in what was
`at one time popularly known as pearl coating, while Kremers
`and Urdan~ described the introduction of the gelatin coating
`of pills by Garot in 1838.
`An interesting reference 4 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 poi(cid:173)
`soning (the contents could be utilized by breaking the tablet
`prior to use).
`While earlier coated products were produced by individuals
`working in pharmacies, particularly when extemporaneous
`compounding was the order of the day, that responsibility now
`has been assumed by the pharmaceutical industry. The earliest
`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 that
`would have to be repeated more than once to ensure that the
`
`894
`
`pill was coated completely. Subsequently, the pills were held at
`the end of a suction tube, dipped, and then the process repeated
`for the other side ofthe pill. Not surprisingly, these techniques
`often failed to produce a uniformly coated product. 5
`Initially, the first sugar-coated pills seen in the US were
`imported from France about 18425
`; while Warner, a Philadel(cid:173)
`phia pharmacist, became among the first indigenous manufac(cid:173)
`turers in 1856.6
`Pharmaceutical pan-coating processes are based on 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, while early pans were made
`from copper, because drying was effected by means of an ex(cid:173)
`ternally applied heat source. Current thinking, even with con(cid:173)
`ventional pans, is to dry the coated tablets with a supply of
`heated air and remove the moisture and dust-laden air from
`the vicinity of the pan by means of an air-extraction system.
`Pan-coating processes underwent little further change until
`the late 1940s and early 1950s, with the conventional pan being
`the mainstay of all coating operations up to that time. How(cid:173)
`ever, in the last 30 or 40 years there have been some significant
`advances made in coating-process technology, mainly as are(cid:173)
`sult of a steady evolution in pan design and its associated
`ancillary equipment.
`Interestingly, in the early years of this development, an
`entirely new form of technology evolved, that of film coating.
`Recognizing the deficiencies of the sugar-coating process, ad(cid:173)
`vocates of film coating were achieving success by using coating
`systems involving highly volatile organic solvents.
`These solvents circumvented the problems associated with
`the inefficiency in the drying capabilities of conventional equip(cid:173)
`ment and enabled production quotas to be met with significant
`reductions in processing times and materials used. The disad- ·
`vantage ofthis approach, however, always has been associated
`with the fact that the solvents used were often flammable and
`toxic.
`The advances that occurred with equipment design, having
`begun by the development of the Wurster7 process and contin(cid:173)
`ued by the evolution of side-vented pans, have resulted in the
`gradual emergence of coating processes in which drying effi(cid:173)
`ciency can be maximized. Thus, film coating began as a process
`using inefficient drying equipment, relying on highly volatile
`coating formulations for success, and evolved into one in which
`the processing equipment is a major factor in ensuring that
`rapid drying occurs. Improved drying capabilities have permit(cid:173)
`ted common use of aqueous film-coating formulations.
`Advances in equipment design also have benefited the
`sugar-coating process, where, because of current Good Manu(cid:173)
`facturing Practices (cGMP) and to maintain product uniformity
`and performance, the trend has been toward using fully auto(cid:173)
`mated processes. Nonetheless, film coating tends to dominate
`as the process of choice for tablet coating.
`
`Page 5 of 40
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`

`

`PHARMACEUTICAL COATING PROCESSES
`
`Basically, there are four major techniques for applying coatings
`to pharmaceutical solid dosage forms: (1) sugar coating, (2) film
`coating, (3) microencapsulation and (4) compression coating.
`Although it could be argued that the use of mucilage of
`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 as
`a raw material. The large quantities of coating material that
`are applied and the inherent skill often required of the opera(cid:173)
`tors combine to result in a long and tedious process. The intro(cid:173)
`duction of improved formulations and processing techniques
`has resulted, however, in a significant reduction in processing
`times (from several days to less than 1 day).
`Film coating, the deposition of a thin polymeric film onto the
`dosage form from solutions that were initially organic-solvent(cid:173)
`based but which now rely more and more on water as the prime
`solvent has proven to be a popular alternative to sugar coating.
`Microencapsulation is a modified form of film coating, dif(cid:173)
`fering only in the size of the particles to be coated and the
`methods by which this is accomplished. This process is based
`on either mechanical methods such as pan coating, air-suspension
`techniques, multiorifice centrifugal techniques, and modified
`spray-drying techniques, or physicochemical ones involving
`coacervation-phase separation, in which the material to be
`coated is suspended in a solution of the polymer. Phase sepa(cid:173)
`ration is facilitated by the addition of a nonsolvent, incompat(cid:173)
`ible polymer or inorganic salts or by altering the temperature of
`the system.
`Compression coating involves the use of modified tableting
`machines that allow the compaction of a dry coating around the
`tablet core produced on the same machine. The main advan(cid:173)
`tage ofthis type of coating process is that it eliminates the use
`of any solvent, whether aqueous or organic in nature. However,
`this process is mechanically complex and has not proven pop(cid:173)
`ular as a method for coating tablets. Compression technology
`has, in recent times, been readopted as a means of applying
`special coatings for novel drug-delivery applications.
`
`Sugar Coating of Compressed Tablets
`
`While the term sugar is somewhat generic and lends itself to
`describing various raw materials, sugar coating relies mainly
`on the use of sucrose. The main reason for this is that sucrose
`is one of the few materials that enables smooth, high-quality
`coatings to be produced that are essentially dry and tack-free at
`the end of the process.
`While the popularity of sugar coating has certainly declined,
`this process is still used by many companies that have invested
`in the complete modernization of the process.
`In spite of certain inherent difficulties associated with the
`sugar-coating process, products that have been expertly sugar
`coated still remain among the most elegant available.
`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
`skilled manpower. For these reasons, the sugar-coatir:g pr~cess
`is often protracted and tedious. However, processmg times
`have been reduced gradually in the last few decades by the
`adoption of modern techniques and by the introduction of
`automation.
`The sugar-coating process can be subdivided into six main
`steps: (1) sealing, (2) subcoating, (3) smoothing, (4) color coat(cid:173)
`ing, (5) polishing, and (6) printing.
`SEALING-The sealing coat is applied directly to the tablet
`core for the purpose of separating the tablet ingredients (pri(cid:173)
`marily the drug) and water (which is a major constituent of the
`
`COATING OF PHARMACEUTICAL DOSAGE FORMS
`
`895
`
`coating formulation) in order to ensure good product stability.
`A secondary function is to strengthen the tablet core. Sealing
`coats usually consist of alcoholic solutions (approximately 10 to
`30% solids) of resins such as shellac, zein, cellulose acetate
`phthalate, or polyvinyl acetate phthalate.
`Historically, shellac has proven to be the most popular ma(cid:173)
`terial, although it can cause impaired bioavailability due to a
`change in resin properties on storage. A solution to this prob(cid:173)
`lem has been to use a shellac-based formulation containing a
`measured quantity of polyvinylpyrrolidone (PVP). 8
`The quantities of material applied as a sealing coat will
`depend primarily on the tablet and batch size. However, an(cid:173)
`other important factor is tablet porosity, since highly porous
`tablets will tend to soak up the first application of solution,
`thus preventing it from spreading uniformly across the surface
`of every tablet in the batch. Thus, one or more further appli(cid:173)
`cations of resin solution may be necessary to ensure that the
`tablet cores are sealed effectively.
`Since most sealing coats develop a degree of tack (stickiness)
`at some time during the drying process, it is usual to apply a
`dusting powder to prevent tablets from sticking together or to
`the pan. A common material used as a dusting powder is
`asbestos-free talc. Overzealous use of talc 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,
`presenting a surface at the beginning of the subcoating stage
`that is very difficult to wet, resulting in inadequate subcoat
`buildup, particularly on the edges. If there is a tendency for
`either of these problems to occur, one solution is to replace part
`or all of the talc with some other material such as terra alba,
`which will form a slightly rougher surface. Use of talc now is
`being frowned upon because of its potential carcinogenicity.
`If an enteric-coated product is required, additional quanti(cid:173)
`ties of the seal-coat solution are applied. In this situation,
`however, it is preferable to use synthetic polymers such as
`polyvinyl acetate phthalate or cellulose acetate phthalate.
`SUBCOATING-Subcoating is a critical operation in the
`sugar-coating process that can have a marked effect on ulti(cid:173)
`mate tablet quality. Sugar coating is a process that often leads
`to a 50 to 100% weight increase, and it is at the subcoating
`stage that most of the buildup occurs.
`Historically, subcoating has been achieved by the applica(cid:173)
`tion of a gum-based solution to the sealed tablet cores, and once
`this solution has been distributed uniformly throughout the
`tablet mass, it is followed by a liberal dusting of powder, which
`serves to reduce tack and facilitate tablet buildup. This proce(cid:173)
`dure 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 alternate lay(cid:173)
`ers of gum and powder. Some examples of binder solutions are
`shown in Table 46-1 and those of dusting powder formulations
`in Table 46-2.
`While this approach has proved to be very effective, partic(cid:173)
`ularly 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 only will the ultimate coating be
`brittle, but also dust will collect in the back of the pan, a factor
`that may contribute to excessive roughness. An alternative
`approach that has proved popular, particularly when used in
`conjunction with an automated dosing system, is the applica(cid:173)
`tion of a suspension subcoat formulation. In such a formulation
`
`Table 46-1. Binder Solution Formulations
`for Subcoating
`
`Gelatin
`Gum acacia (powdered)
`Sucrose
`Water
`
`A,%w/w
`3.3
`8.7
`55.3
`to 100.0
`
`B,%w/w
`6.0
`8.0
`45.0
`to 100.0
`
`Page 6 of 40
`
`

`

`896
`
`CHAPTER 46
`
`Table 46-2. Dusting Powder Formulations
`for Subcoating
`
`Calcium carbonate
`Titanium dioxide
`Talc (asbestos-free)
`Sucrose (powdered)
`Gum acacia (powdered)
`
`A,% w/w
`40.0
`5.0
`25.0
`28.0
`2.0
`
`B,%w/w
`
`1.0
`61.0
`38.0
`
`the powdered materials responsible for coating buildup have
`been dispersed in a gum-based solution. A typical formulation
`is shown in Table 46-3. This approach allows the solids loading
`to be matched more closely to the binding capacity of the base
`solution and often permits the less-experienced coater to
`achieve satisfactory results.
`SMOOTHING-Depending on how successfully the sub(cid:173)
`coat was applied, it may be necessary to smooth out the tablet
`surface further prior to application of the color coating.
`Smoothing usually can be accomplished by the application of a
`simple syrup solution (approximately 60 to 70% sugar solids).
`Often, the smoothing syrups contain a low percentage of
`titanium dioxide (1 to 5%) as an opacifier. This can be partic(cid:173)
`ularly useful when the subsequent color-coating formulation
`uses water-soluble dyes as colorants, since it makes the surface
`under the color coating more reflective, resulting in a brighter,
`cleaner final color.
`COLOR COATING-This stage often is the most critical in
`the successful completion of a sugar-coating process and in(cid:173)
`volves the multiple application of syrup solutions (60 to 70%
`sugar solids) containing the requisite coloring matter. The
`types of coloring materials used can be divided into two cate(cid:173)
`gories: dyes or pigments. The distinction between the two sim(cid:173)
`ply is one of solubility in the coating fluid. Since water-soluble
`dyes behave entirely differently from water-insoluble pig(cid:173)
`ments, the application procedure used in the color coating of
`tablets will depend on the type of colorant chosen.
`When used by a skilled artisan, water-soluble dyes produce
`the most elegant of sugar-coated tablets, since it is possible to
`obtain a cleaner, brighter final color. However, since water(cid:173)
`soluble dyes are migratory colorants (that is to say, moisture
`that is removed from the coating on drying will cause migration
`of the colorant, resulting in 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 are just sufficient to wet the
`surface of every tablet in the batch, and then allowing the
`tablets to dry slowly. It is essential that each application be
`allowed to dry thoroughly before subsequent applications are
`made, otherwise moisture may become trapped in the coating
`and may cause the tablets to sweat on standing.
`The final color obtained may result from up to 60 individual
`applications of colored syrup. This factor, combined with the
`need to dry each application slowly and thoroughly, results in
`very long processing times (eg, assuming 50 applications are
`made, which take between 15 and 30 min each, the coloring
`process can extend over a period of up to 25 hr). The recent
`introduction of specialized, dye-based formulations has obvi(cid:173)
`ated many of the problems described here.
`Tablet color coating with pigments, as advocated by Tucker
`et al, 9 offers some significant advantages. First of all, since
`pigment colors are water-insoluble, they present no problems of
`migration since the colorant remains where it is deposited. In
`addition, if the pigment is opaque or is combined with an
`opacifier such as titanium dioxide, the desired color can be
`developed much more rapidly, thus resulting in a thinner color
`coat. Since each color-syrup application now can be dried more
`rapidly, fewer applications are required, and significant reduc(cid:173)
`tions can be made in both processing times and costs.
`Although pigment-based color coatings are by no means
`foolproof, they will permit more abuse than a dye color-coating
`
`approach and are more amenable for use by less-skilled coat(cid:173)
`ers. Pharmaceutically acceptable pigments can be classified
`either as inorganic pigments (eg, titanium dioxide, iron oxides)
`or certified lakes. Certified lakes are produced from water(cid:173)
`soluble dyes by means of a process known as laking, whereby
`the dye molecule becomes fixed to a suitable insoluble 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
`shades to be achieved. However, the incorporation of pigments
`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 available, is usually
`beneficial.
`POLISHING-Sugar-coated tablets need to be polished to
`achieve a final elegance. Polishing is achieved by applying
`mixtures of waxes (beeswax, carnauba wax, candelila wax, or
`hard paraffin wax) to the tablets in a polishing pan. Such wax
`mixtures may be applied as powders or as dispersions in vari(cid:173)
`ous organic solvents.
`PRINTING-To identify sugar-coated tablets (in addition
`to shape, size, and color) often it is necessary to print them,
`either before or after polishing, using pharmaceutical branding
`inks, by means of the process of offset rotogravure.
`SUGAR-COATING PROBLEMS-Various problems may
`be encountered during the sugar coating of tablets. It must be
`remembered that any process in which tablets are kept tum(cid:173)
`bling constantly can cause problems if the tablets are not
`strong enough to withstand the applied stress. Tablets that are
`too soft or have a tendency to laminate may break up and the
`fragments adhere to the surface of otherwise good tablets.
`Sugar-coating pans exhibit inherently poor mixing charac(cid:173)
`teristics. If care is not exercised during the application of the
`various coating fluids, nonuniform distribution of coating ma(cid:173)
`terial 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, may result in a coating being formed in which
`the quantity of fillers exceeds the binding capacity of the poly(cid:173)
`mer used in the formulation, creating soft coatings or those
`with increased tendency to crack.
`Irregularities in appearance are not uncommon and occur
`eith