`

`

`

`
`
`Contents
`
`M p
`
`49
`50
`51
`52
`53
`54
`55
`
`Biotechnology and Drugs ........................976
`Aerosols .................................... 1000
`Quality Assurance and Control ................... 1018
`Stability of Pharmaceutical Products ............... 1025
`8ioavai|ability and Bioequivalency Testing ........... 1037
`Plastic Packaging Materials ...................... 1047
`Pharmaceutical Necessities ...................... 1058
`
`Part 6
`
`56
`57
`58
`59
`60
`61
`62
`63
`
`Part 7
`
`64
`65
`66
`67
`68
`59
`70
`71
`72
`
`73
`74
`75
`76
`77
`78
`79
`80
`81
`82
`83
`84
`85
`86
`87
`88
`89
`90
`91
`92
`93
`
`Pharmacokinetics and Pharmacodflmics
`
`Diseases: Manifestations and Pathophysiology ....... 1095
`Drug Absorption. Action, and Disposition ........... 1142
`Basic Pharmacokinetics and Pharmacodynamics ...... 1171
`Clinical Pharmacokinetics and Pharmacoclynamics ..... 1191
`Pnniciples of Immunology ....................... 1206
`Adverse Drug Reactions and Clinical Toxicology ...... 1221
`Pharmacogenomics ............................ 1230
`PharmacokineticsiPharmacodynamics in
`Drug Development ............................ 1249
`Pharmaceutical and Medicinal—Agents
`
`Diagnostic Drugs and Reagents ................... 1261
`Topical Drugs ................................ 1277
`Gastrointestinal and Liver Drugs .................. 1294
`Blood. Fluids. Electrolytes, and Hematological Drugs .
`. .1318
`Cardiovascular Drugs .......................... 1350
`Respiratory Drugs ............................. 1371
`Sympathomimetic Drugs ........................ 1379
`Cholinomimetic Drugs ......................... 1389
`Adreoergic Antagonists and Adrenergic
`Neuron Blocking Drugs ......................... 1399
`Antirnuscarinic and Antispasmodic Drugs ........... 1405
`Skeletal Muscle Relaxants ....................... 1411
`Diuretic Drugs ................................ 1422
`Uterine and Antimigraine Drugs .................. 1432
`Hormones and Hormone Antagonists .............. 1437
`General Anesthetics ........................... 1474
`Local Anesthetics ............................. 1479
`Antianxiety Agents and Hypnotic Drugs ............ 1486
`Antiepileptic Drugs ............................ 1501
`Psychopharmacologic Agents .................... 1509
`Analgesic, Antipyretic, and Anti-Inflammatory Drugs .
`, .1524
`Histamine and Antihistaminlc Drugs ............... 1543
`Central Nervous System Stimulants ................ 1551
`Antineoplastic Drugs ........................... 1556
`lmmunoactive Drugs ........................... 1588
`Parasiticides ................................. 1595
`
`immunizing Agents and Allergenic Extracts .......... 1600
`Anti—Infectives ................................ 1525
`Enzymes .................................... 1685
`Nutrients and Associated Substances .............. 1688
`Pesticides ................................... 1719
`
`Part 8
`
`Pharmagy Practice
`
`94
`95
`96
`97
`98
`99
`
`A Fundamentals of Pharmacy Practice
`Application of Ethical Principles to Practice Dilemmas . .1745
`Technology and Automation ..................... 1753
`The Patient: Behavioral Determinants .............. 1762
`Patient Communication ........................ 1770
`
`Patient Compliance ............................ 1782
`Drug Education ............................... 1796
`
`xxi
`
`Eton Ex. 1017
`3 of 15
`
`an 1 Orientation
`1
`Scope 01 Pharmacy ............................... 3
`2
`Evolution of Pharmacy ............................ 7
`3
`Ethics and Professionalism ......................... 20
`.1
`The Practice of Community Pharmacy ................ 30
`5
`Pharmacists in lndustry ........................... 35
`5
`PharmacistsrnGovernment,..........,..,.,.,.....40
`7
`Pharmacists and Public Health ...................... 51
`3
`Information Resources in Pharmacy and the
`Pharmaceutical Sciences .......................... 64
`Clinical Drug Literature ........................... 74
`Research ..................................... 87
`
`9
`10
`
`MWE5—_.__
`11
`Metrology and Pharmaceutical Calculations
`.
`.
`.
`.
`.
`,
`.
`.
`.
`. .99
`12
`Statistics ..................................... 127
`13
`Molecular Structure, Properties. and States of Matter
`.
`. .162
`14
`ComplexFormation
`......... .186
`15
`Thermodynamics .......
`...._..........
`..
`.. 201
`.
`.
`15
`Solutions and Phase Equilibria .
`.
`. .. .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.211
`.
`.
`17
`Ionic Solutions and Electrolytic Equilibria .
`.
`.
`.
`.
`. .231
`13
`Tonicitt, Osmoticity. Osmolality, and Osmolarity .
`.
`.
`. .250
`19
`Chemicti! Kinetics .... .
`.
`.
`.
`.
`.
`.
`.
`. .266
`.
`.
`20
`lnterfacial Phenomena .. .
`.
`.
`.
`. .. .. .
`...280
`21
`Colloidal Dispersions ................
`. .293
`22
`Coarse DISDErSiOl'IS ...................
`. .319
`23
`Rheology
`.....................
`.
`...... 335
`
`.
`
`.....
`
`.
`
`.
`
`Law.”—
`24
`inorganic Pharmaceutical Chemistry
`............... 361
`25
`Organic Pharmaceutical Chemistry ................. 386
`26
`Natural Products .......................... .
`.
`. .410
`27
`Drug Nomenclature—United States Adopted Names. .
`. .443
`28
`Structure-Activity Relationship and Drug Design ....... 468
`29
`Fundamentals of Medical Radionuclides ............. 479
`
`
`Part 4
`Pharmaceutical Testing, Analysis, and Control
`
`30
`31
`32
`33
`34
`35
`
`Analysrs of Medicinals ...........................495
`Biological Testing .............................. 553
`Clinical Analysis ............................... 565
`Chromatography .............................. 599
`Instrumental Methods of Analysis .................. 633
`Dissolution ................................... 672
`
`Part 5
`
`Pharmaceutical Manufacturing
`
`35
`37
`38
`39
`40
`41
`42
`43
`44
`45
`46
`47
`43
`
`Separation ................................... 691
`Powders ..................................... 702
`Property-Based Drug Design and Preformulation ....... 720
`Solutions Emulsions, Suspensions, and Extracts ....... 745
`Storiiization ................................... 776
`Parenteral Preparations .......................... 802
`Intravenous Admixtures ......................... 837
`Ophthalmic Preparations ......................... 850
`Medicated Topicals ............................. 871
`Oral Solid Dosage Forms ......................... 889
`Coating of Pharmaceutical Dosage Forms ............ 929
`Extended-Release and Targeted Drug Delivery Systems . .939
`The New Drug Approval Process and
`Clinical Trial Design ............................. 965
`
`Eton Ex. 1017
`3 of 15
`
`

`

`xxii
`
`CONTENTS
`
`100
`101
`102
`
`103
`104
`105
`106
`10?
`108
`109
`110
`
`111
`112
`113
`114
`115
`115
`
`Professional Communications .................... 1808
`The Prescription ______________________________ 1823
`Providing a Framework for Ensuring
`Medication Use Safety ......................... 1840
`Poison Control ............................... 1881
`Drug Interactions ............................. 1889
`Extemporaneous Prescription Compounding ......... 1903
`Nuclear Pharmacy Practice ...................... 1913
`Nutrition in Pharmacy Practice .................... 1925
`Pharmacoepidemiology ......................... 1958
`Surgical Supplies .............................. 1968
`Health Accessories ............................ 1979
`B Social. Behavioral. Economic, and
`Administrative Sciences
`Laws Governing Pharmacy ......................2015
`Re~engineering Pharmacy Practice .................2055
`Pharmacoeconomics ...........................2070
`Community Pharma
`cy Economics and Management .
`. .2082
`Product Recalls and Withdrawals ..................2098
`Marketing Pharmaceutical Care Senr'tces ............210?
`
`117
`
`118
`119
`
`120
`121
`122
`
`123
`124
`125
`126
`12?
`128
`129
`130
`131
`132
`133
`
`Documenting. Billing. and Reimbursement for
`pharmaceutical Care Services .................... 2114
`Pharmaceutical Risk Management ---------------- .2124
`Integrated Health Care Delivery Systems ............2130
`C Patient Care
`_
`Specialization in Pharmacy Practice ............... 2155
`Pharmacists and Disease State Managemem -------- 2163
`Development of a Pharmacy Care Plan 371d
`Patient Problem-Solving ........................ 2170
`Ambulatory Patient Care ........................ 217g
`Self-Care .................................... 2197
`Diagnostic Self-Care ........................... 2205
`Preventive Care ............................... 2223
`Hospital Pharmacy Practice ...................... 2247
`Emergency Medicine Pharmacy Practice ............ 2265
`Long-Term Care ..............................2272
`Aseptic Processing for Home Infusion Pharmaceuticals
`.2290
`The Pharmacisi's Role in Substance Use Disorders .....2303
`Complementary and Alternative Medical Health Care . .2318
`Chronic Wound Care .......................... 2342
`
`..-—.......__
`
`
`
`iEton Ex. 1017
`4 of 15
`
`Eton Ex. 1017
`4 of 15
`
`

`

`

`

`

`

`

`

`1050
`
`PART 5: PHARMACEUTICAL MANUFACTURING
`
`k ging are trans-
`Desirable features used for health care pac a
`b Tty seal-
`parency, thermal stability, ph?'si~al str:ngth, for:J di~pdsabil(cid:173)
`erties in a
`ability, biological barrier, radiation res1st~nce, a
`ity. Usually one cannot find all the _desired prop bined into
`single material, but two or more plastics can be com
`a composite packaging material.
`
`Failure Mode Analysis
`After development and subsequent distribution ?f plastic-pack(cid:173)
`aged items, functional problems may occur occas10nal~y. Re~olu(cid:173)
`tion of these problems requires analysis of the c~usative-fa1lure
`mode. This involves problem isolation, segregating the probl~m
`material to a particular batch, for example, to identify pote~tial
`causative factors. The failed parts are subjected to mechanical,
`microscopic, and chemical analysis for further determinati_on of
`how they differ from acceptable parts. The analytical techniques
`chosen are dictated by the observed mode of failure.
`Physical tests, such as mechanical, electrical, and optical de(cid:173)
`terminations, can be performed quickly, and control values ex(cid:173)
`ist in the form of manufacturers' specifications, which are read(cid:173)
`ily available. As the problem becomes more precisely focused,
`more specific and often elaborate testing is performed to isolate
`the cause further. For example, reduced stiffness of a part may
`be attributable to lowered molecular weight of the plastic. Mi(cid:173)
`croscopic analysis is rapid, and a skilled analyst often can iden(cid:173)
`tify the problem as a pinhole, improper seal, delamination of a
`composite material, or foreign material acting as a stress frac(cid:173)
`ture initiator.
`Chemical analysis of impurities that may cause bloom or
`prevent seal formation is often time consuming because of
`the tiny amounts present, the large variety of potential com(cid:173)
`pounds, and a lack of control information from the supplier. The
`expense and variety of chemical instrumentation available
`requires judicious selection of the approach to be used.
`
`CLASSIFICATION
`There are over 100 different polymer types available for use
`~hat ~an be classified further into two subcategories. These are
`ident_ified as thermo~lastics and thermosets (thermosetting
`plastics). Thermoplastics consist of those plastics that normally
`are rigid at operating temperatures but can be remelted and re(cid:173)
`processed. Thermosets consist of those plastics that, when sub(cid:173)
`Jected to heat, normally will become infusible or insoluble and
`as such cannot be remelted.
`'
`
`ADDITIVES AND MODIFIERS
`~hermoplastics can be modified greatly and have the·
`bes enhanced by the addition of specific additives As cihr pr~pelr(cid:173)
`·
`ma
`t
`·
`·
`emica s
`11
`Y a~ synergisbca Y, any two safe additives may have the
`potential to produce undesirable effects when comb" d F
`t~ese reasons, the FDA requires that these blends o me b" or
`~ com ma(cid:173)
`hons be evaluated totally prior to marketin
`.
`Chemical, pharmacologic~l and biolo . i g m pro uct form.
`d~cted ~o establish safety. Problems in~~ti;~;~~~tuld _be con(cid:173)
`migration to the surface of molded arts
`I ive~ mc~ude
`I ai:id lheachmg mto
`aqueous solutions. Additives used ro~f
`formulations are discussed below
`me Y m t ermoplastic
`Lubri~ants are used to assist p~ocessin of the
`.
`.
`t~e moldmg or extrusion operation, faci!Jatin fflas~1c dunng
`with metal surfaces. A commonly used I b . g ?W m contact
`~olyethylene is zinc stearate. The qua~ti~cant m the case of
`from formulation to formulation
`es employed va'ry
`Stabilizers are used to retard or rev
`polymer by heat and light during m~nu;n~ de_gradation of the
`!mprove its aging characteristics. Comm ac un~~ ~s well as to
`mcl~de ?rganometallic compounds fattyon ~dta ilhzer families
`game oxides.
`'
`ac1 sa ts, and inor-
`
`ts are a special type of stabilizer used t
`.
`.d
`_Ant_wxl ;n inhibiting formation of _free radicals. E o retard
`ox1dat1~~;ti{ amines, hindered. phenohc_s, thioesters, a~~lllples
`are aro C
`b" ati·ons of antioxidants with other add"t•
`Phos.
`h · t s om m
`.
`.
`1 1ve
`p I e . ·n undesirable chemical rea~t10ns. _Recent techs lllay
`resul~ I introduction of a desicca nt ~h_rectly mto plastic noJog,,
`permits
`t
`t ·on of moisture-sens1t1ve products Th Packag.
`·
`· g for pro ec 1
`.
`e Pr0c
`1
`~n
`training a desiccant m the po ymer stream£
`ess
`I
`!nv~ v:s e:ontainer wall. It is intended for medical di~r lllold.
`mgd i;e~tstrip kits, effervescent drugs,. and nutritionaFostic
`an 9 S me work also has been done with adding the a Pt_rO(J.
`ucts.
`o
`.
`k
`·
`n 1ozj
`10
`•
`.
`dant vitamin E t~ plastic pac agmg, perm1ttmg _food to tas .
`fresh for longer times. Oxyl::en scavengers c~n be mcorporatete
`directly into films, closure lmers, and ~on tamer walls and CUsd
`· d to the required oxygen-absorbmg capacity.11
`·
`tom1ze
`h "
`ft
`fl
`'b• .
`Plasticizers are used to ac ieve so ness, ex1 1hty, and
`d
`I .
`.
`Th
`met
`1
`ey a~e use comm?n y m plastic ma.
`flow during processmg.
`terials such as vinyls, cellulos1cs, and prop10nates. The m
`common are high boiling liquids, usually phthalates, ofwhfc~
`dioctyl phthalate is the most popular.
`.
`Antistatic agents are used to prevent the bmldup of stat·
`.
`f:
`i
`charges on the plastic sur a~e.
`.
`Slip agents are added pnmanly to pol_yolefins (polyethylene
`and polypropylene) to reduce the coefficient of friction of the
`material. These particular chemicals result in antitack and an.
`tiblock characteristics in the end product.
`Dyes and pigments are added to impart color.
`Surface treatments of film, by corona discharge or deposition
`of thin layers of other plastics, improve such properties as ink
`adherence, adherence to other films, heal sealability, or gas
`barrier.
`
`PROCESSING
`Besides the addition of additives, the manner in which a plas(cid:173)
`tic is formed into the desired configuration can affect the end
`properties. It is important that process parameters, such as
`temperature, pressure, and time, be controlled rigidly to ensure
`batch-to-batch uniformity for plastic objects. If process param·
`eters_are not controlled adequately, such deleterious effects on
`plas~Ic properties as thermal degradation, piece-part stresses,
`and mcox:rect physical dimensions may result. Process the_~al
`degradat10':1 of a plastic can affect the leaching charactenshcs
`of the plastic object, its permeation characteristics and its long·
`term ~tability during the shelf life of the pharma~eutical prod·
`~ct. Piece-part stresses may be relieved when the pharmaceu·
`tical p k
`·
`·
`d"t' •
`_ac ~ge Is subJected to certain environmental con I ion.,
`~esultmg m package failure during the shelflife of the produ_ct.
`mall stress fractures in the flange of thermoformed trays, 10:
`le roa)
`traduced durin th th
`.
`.
`g
`e
`ermoformmg process for examp •
`compromise sterility
`'
`.
`.
`Joyed for
`The more com
`· 1
`mon p astic-processmg methods emp
`.
`h
`P armaceutical
`k
`•
`pac agmg components follow.
`
`Injection Molding
`I tic 1,eiog
`Injection mold"
`·
`· .
`heated to a mg Is an mtermittent process, the P ~s
`O 8 ca1··
`ity (mold) a~~ted or viscous state and then fo:ced in:s in the
`. i?h pressure. The melted material coo artrf"
`cavit an
`mov!u Ad s~idifies. The mold is then opened and th; ~1Jlo5et·
`ting m~ter7\ e range _of_ th~rmoplastic and_ several t d: on l,01:
`injection' :;yJ- mtricate configurations can be obta
`tie caps
`a s c~n h_e InJection molded. Besides threa ined by
`
`0 mg of plastics.
`
`Extrusion
`eJ 10'
`. (f heat b s
`Extrusion is a c
`t"
`on muous process the plastic bein,, thfOtlg 1
`melted
`•
`t t
`'
`pl"'
`O
`r viscous
`ure
`die, resultin
`s a e a nd forced under press A slit-sh~
`.
`g m a configuration of desired s hape.
`
`Eton Ex. 1017
`8 of 15
`
`

`

`CHAPTER 54: PLASTIC PACKAGING MATERIALS
`
`1051
`
`Compression Molding
`Compression molding is used for thermosetting materials and
`is an intermittent process. The thermosetting material (powder
`or a tablet preform) is placed into a heated cavity (mold). The
`material melts and flows to fill the cavity. The mold is held un(cid:173)
`der pressure until the thermosetting material cures, after
`which the mold is opened and the part removed. As with injec(cid:173)
`tion molding, very intricate configurations can be obtained by
`compression molding of thermosetting materials.
`
`TYPES AND USES
`The following types of plastics are used commonly in health(cid:173)
`care practice; several of their properties and end uses are indi(cid:173)
`cated.
`
`Thermoplastics
`The ~ollowing are used commonly in injection molding, blow
`moldmg, extrusion, and fabricated sheeting.
`POLYETHYLENE-This polymer, PE, has the molecular
`structure (CH2)n and is the most pervasively used because it af(cid:173)
`fords essential properties for the least cost . The properties of
`poly~thylene vary according to molecular weight and type: low(cid:173)
`density (LDPE) or branched, and high-density (HDPE) or lin(cid:173)
`ear. The length and number of side-chain branches determine
`the degree of crystallinity and density. The linear type has a
`more regular molecular structure, hence is more crystalline
`and therefore is stronger, stiffer, more heat resistant, less per:
`meable to gases, and more resistant to oils than LDPE. Addi(cid:173)
`tionally, as crystallinity and density increase, opacity, tensile
`strength, surface hardness, and chemical resistance increase.
`Silicone oil and surfactants, however, can act as stress-crack
`agents, leading to crack formation in stressed areas, as the per(cid:173)
`meants spread apart the polymeric chains.
`Both LDPE ~nd HD:rE have relatively low water absorption,
`excellent electrical resistance, and high resistance to most sol(cid:173)
`vents and chemicals and are tasteless and odorless. PE is thus
`well suited to many applications in which only moderate-to-low
`he_at expos~re _will be encountered. Its use ranges from con(cid:173)
`tamers for hqmd or dry products to both laminated and unsup(cid:173)
`ported fi~ms for st:rile-device packaging and to molded parts
`for a _vanety of devi_ces and equipment. Unsupported polyethy(cid:173)
`le~e is used for shrmk wrapping, stretch wrapping, skin pack(cid:173)
`aging, and bags.
`With more tightly packed molecules HDPE has better mois(cid:173)
`ture-barrier properties with less elongation (better tensile
`s~rength) th~n LDPE. It is used widely, when rigidity and bar(cid:173)
`rier properties are preferr~d, for bottles of solid dosage form
`products. However, LDPE is used when flexibility is required
`for squeeze _bottles of sprays and drops, as well as drum liner~
`for bu_lk sohd drugs. Blown films of LDPE have very low haze
`and high ~loss, wh~reas HDPE films have higher haze, because
`ofcryst~l-mduced hght scattering, and are semiglossy. The less
`~rystalhne LDPE has a lower melting point with broader melt(cid:173)
`mg range tha_n doe~ HDPE and, therefore, is easier to heat seal.
`The low m~ltmg pomt, however, negates steam sterilization for
`LDPE, unhke HDPE.
`Polyethylene is used as a primary packing film, but its use
`as a s~alant, throug~ the application of heat and pressure, is
`more important. This application requires strong seals to be
`m~de at l?w te1!1perature that have good hot tack (ie, to main(cid:173)
`t:im seal mte~ty as the temperature cools). For this purpose,
`lmear low density polyethylene (LLDPE )is used. This resin has
`r~duced side ch~in branching and combines the clarity and den(cid:173)
`sity of LDPE with the toughness of HDPE. These characteris(cid:173)
`tic~ arise from the molecular structure, resulting from the re(cid:173)
`action ofHDPE with unsaturated comonomers such as butene
`hexene, o~ oc_te_ne. The incompatibility of these two types of
`polymers mhibits the sealant layer from forming a complete
`
`.
`.
`.
`die will result in a plastic sheet, and a circu
`tube of plastic. The extruded profile is
`1 l~r die will yield a
`generally by spraying with or immersio:oi: e
`to a solid st~te,
`chilled rolls for film material. A wide ran ~va}er, or by usu~g
`materials can be extruded. Typical extrul d O t~ermoplastic
`the pharmaceutical ipdustry are packagi e filpro iles used by
`tubing. Plastic packaging film also is form:~; ~f O
`and med~cal
`an extruded tube being blown into a large c r Yd w extrusion,
`after cooling.
`Y m er and then slit
`Besides simply imparting a new shape t th
`l
`0
`th
`,.
`t
`·
`e mo ten plas-
`·
`tic,
`e manu,ac urmg process can prefe
`t · ll
`.
`molecular chains in a given direction by retn tiah.Y orient the
`=
`.
`'
`. Th. . t
`s re c mg the plas
`-
`1 •
`tic.
`1s m urn auects physical properties s h
`·
`t
`t
`h •
`uc as c arity and
`gth
`th
`1mp~c s ~en . , as
`e c ams are oriented alon
`t
`bearing direction. Crystallites can be form d
`d g _he load(cid:173)
`yield increases in strength albeit at redu t ·e ~n 1orien~ed to
`•
`.
`'
`c ion me ongation at
`k B
`brea . arrier properties are improved £or pol
`B'
`I
`t d fil
`h
`ypropy ene
`1-
`· 11
`·
`axia y onen e 1 m as balanced properties ·f th
`·
`e same ex-
`·
`d •
`1
`t h .
`t f t
`ten o s re c mg 1s use m each direction Inc
`t fil
`·
`· th
`t.
`h '
`d'
`.
`·
`as 1 m, onen-
`ta ion m
`e m~c me irecbon is achieved by feeding the film
`through a series of rolls running at graduall
`·
`·
`.
`y mcreasmg
`d R 11
`h
`spee s. o s are eated sufficiently to bring the film to suit-
`able temperature below the melting point Tra
`·
`· b
`· d b
`·
`·
`nsverse orien-
`y use of a tenter frame wh· h h
`tation is o tame
`d'
`t
`as WO 1-
`,
`lC
`di
`b
`vergent en ess elts fitted with clips. These grip the fil
`that _as it travels _forwai:d, _it is ~rawn_ transversely
`~\~~
`reqmred draw ratio. Umaxial orientation is used for hi h-
`performance tape.
`g
`
`1a
`
`Composite Film Manufacture
`Multila?'er plastic str~ctures ~ermit incorporation of disparate
`properties_ no~ otherwise obtainable from one material. These
`mclude tailoring of gas barrier, heat sealability strength and
`adhesioi:i, to other material~ such as_ pap_er. Th~y are made by
`the basic methods of coating, lamination, and coextrusion.
`Coa~ings are applied to films as dispersions, as solutions in or(cid:173)
`game solvents, or as molten material. In metallization, coatings
`of aluminum are applied by vaporization of the molten metal
`under vacuum and condense on moving film. Lamination is the
`m?st_ versa~il_e process, permitting joining together of paper and
`foil, m addition to thermoplastics. Preformed dissimilar films
`are joined together with heat and adhesives, such as vinyl ac(cid:173)
`etate or polyurethanes. Coextrusion is less expensive than lam(cid:173)
`ination, where applicable, forming the composite structure
`without separately creating the component webs. From multi(cid:173)
`ple extruders, separate streams of different molten polymers
`~re simultaneously fed to a die that joins them while prevent(cid:173)
`mg their intermixing.
`
`Blow Molding
`The plastic is heated to a melted or viscous state and formed
`into a hollow cylinder (parison) either by extrusion or injection
`molding. If extruded, the parison is cut to the required length
`and transferred to the blowing cavity (mold). The bottom of the
`parison is pinched off by the mold, and air is blown into the
`parison, expanding the viscous plastic to the walls of the cavity,
`thus forming the desired container shape. The melted material
`cools in the cavity and solidifies. The mold is opened, and the
`container removed. Pharmaceutical bottles are blow molded
`from a wide range of thermoplastic materials, among which
`polyethylene and polypropylene predominate.
`
`Solvent Casting
`A liquid suspension of rubber is deposited on an endless belt,
`a_nd the solvent is vaporized. The belt carries the rubber mate(cid:173)
`~ai through a heat cabinet to cure it, whereupon the film is
`tripped off the belt, cooled, and wound onto reels.
`
`Eton Ex. 1017
`9 of 15
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`throughout its shelf life. A critical property of the seal is hot
`tac~, resistance of creep whi)~ warm, _because as the package
`is eJecte~ from ~he he_at-s~~l Jig, the still-warm bond line must
`It comprises two components: the
`support its entire weight.
`melt strength of the seal layer at the temperature of the seal
`and the interfacial adhesion of the sealant layer to the oppo(cid:173)
`site web.
`Choice o~film thickness affects both material costs and bar(cid:173)
`rier properties. Other conside_rations are machineability, pro(cid:173)
`duct10n rates, _depth of the blister, wall thickness and unifor(cid:173)
`mity of the_ blister, and sealing properties. Unplasticized, or
`rigid, ~".C 1s the most com~on material for forming film be(cid:173)
`caus~ 1t 1s the~moformed easily, has glass-like clarity, is inex(cid:173)
`pensive, has _h_1gh flexural _strength, good chemical resistance,
`low per~eab1hty to fats, 01ls, easy tintability, and has barrier
`properties that are adequate for many drugs. The typical film
`thickness of25_0 µm (10 mil) can be increased by applying a 25
`to 50 µm coatmg of PVDC (polyvinylidene chloride) that in(cid:173)
`creases the water vapor barrier properties 5- to 10-fold.
`For better protection, films are made from PVC and CTFE
`(chlorotrifluoroethylene, Aclar). Such films are 15-fold less per(cid:173)
`meable to moisture than is PVC of comparable thickness. Maxi(cid:173)
`mal protection from water vapor is provided by biaxially oriented
`polyamide/aluminum/PVC (nylon-Al-PVC) that gives barrier
`properties that are immeasurably low. Aluminum makes the
`material more recyclable. The cost is comparable to that of
`PVDC-coated PVC. Other mate1;als such as PP, PS, or PET have
`been tried for blister packs but have not achieved commercial
`success because of technical difficulties, poor barrier properties,
`or economic issues. The highest degree of protection is afforded
`by an all-foil package, which is cold-formable. The aluminum
`layer consists of several very thin layers rather than a single
`thick one to ensure that pinholes do not go all the way through
`the foil.24 Nondestructive blister inspection devices are used to
`check for leaks in a 30 s vacuum test cycle.
`For blister lidding, the selection of material structures de(cid:173)
`pends on product fragility and whether the blister must be child
`resistant (CR). Polyester/foil is selected for CR applications. For
`non-CR applications, lidding material is usually aluminum/pa(cid:173)
`per for fragile products or preprinted aluminum for sturdy
`products.25 A standard 25-µm thickness of aluminum is consid(cid:173)
`ered to be pinhole free and represents an optimum combination
`of cost and product protection. The hardness of the aluminum
`can be optimized either for facilitating a push-through opening
`or hindering it, if a child-proof feature is desired. Lidding ma(cid:173)
`terial also is perforated along the sealed seams to prevent it
`from being peeled from the formed film in one piece. The lidding
`material has a printing primer on one side and a heat-sealing
`lacquer on the other, which faces the product and forming film.
`A value-added feature is a peel-off-push-through foil, offered by
`a paper-polyester-aluminum laminate. The paper/PET lami(cid:173)
`nate first is peeled from the aluminum, and then the tablet is
`pushed through the aluminum.26
`Strip and sachet packaging are other unit-type packs used
`for tablets, capsules, powders, etc. Multidose packs for solid
`dosage forms can be made from PS, PVC, polyester, PP, or
`HDPE. The latter two are preferred for their better barrier
`properties toward moisture. All can be made child resistant and
`tamper evident/resistant using innovative closure systems re(cid:173)
`flecting the versatility of plastic materials. To discourage chil(cid:173)
`dren from biting a package, a non-toxic bittering agent can be
`added to the paper side of the blister. To combat counterfeiting,
`2D and 3D holographic security paper can be incorporated i~to
`blister laminate structures.27 A paperboard-based sleeve-blis(cid:173)
`ter card combines compliance assistance with child resistance,
`tamper evidence and elder friendliness. A die-cut hinge in the
`outer sleeve rele~ses a folded paperboard encased film/foil blis(cid:173)
`t~r slide card, which can be printed with dosage instructions to
`aid compliance.28
`COLLAPSIBLE TUBES AND FLEXIBLE POUCHES(cid:173)
`These are used to contain viscous and liquid-based topical prod(cid:173)
`ucts. They usually are constructed of metal or metal-lined, low-
`
`CHAPTER 54: PLASTIC PACKAGING MATERIALS
`
`1055
`
`density polyethylene, or a laminated material. Tubes are fabri(cid:173)
`cated by rolling and heat-sealing flat stock into a continuous
`tube, then trimming to length and attaching the head by injec(cid:173)
`tion molding. Metal tubes are airtight, light-proof, and imper(cid:173)
`meable and offer superior protection. Plastic tubes are
`lightweight, leakproof, and relatively nonbreakable. In . con(cid:173)
`trast to collapsible metal tubes that flatten as the product 1s re(cid:173)
`moved, plastic tubes have memo1?' that pe~mits them to retain
`their original shape after squeezmg. Lammate squeeze tubes
`offer the advantages of plastic with barrier properties close to
`those of metal. For some applications, an internal liner is used,
`shielding the product from the seam of the tube, which can
`cause crystallization.29
`INTRAVENOUS (IV) SOLUTIONS-Compared with
`glass bottles, plastic packaging offers nonbrea~ability ~1:d light
`weight, affording easier transport and handlmg. Add1tionally,
`flexible packaging permits collapsibility, which provides
`greater protection from aerial contamination. Also, squeezing
`the bag with a pressure cuff enables rapid administration of
`large fluid quantities in emergency situations. This puts a
`burst-strength requirement on both the material and the qual(cid:173)
`ity of the seals. A container designed to keep products sepa(cid:173)
`rated before mixing features a frangible seal between two or
`more pouch compartments that keeps multiple injectable solu(cid:173)
`tions apart until just before use. 30
`Because of its transparency, durability, autoclavability,
`and manufacturability at an economical cost, PVC has been a
`material of choice. The realities of shipping require pinhole re(cid:173)
`sistance. This is offered by flexible, high-yield strength mate(cid:173)
`rials like plasticized vinyl, rather than stiffer, more brittle
`materials like unmodified polyolefins. The polar nature of
`PVC permits rapid radiofrequency sealing of the bag, incorpo(cid:173)
`rating the port tubes for an IV administration set and medi(cid:173)
`cation sites. A polyolefin overwrap is used as a water-vapor
`barrier to prevent excessive moisture loss through the plasti(cid:173)
`cized PVC.
`Automatic packaging of IV solutions can be accomplished
`with an aseptic form (blow molding)-fill-seal system for rigid
`containers or a seal-fill-seal system for flexible containers. The
`latter requires preformed plastic film, which is reel-fed onto a
`forming manifold and side-sealed to form a tube, which is then
`filled. After incorporating fitments and closures, the final seal
`is made, and the completed container is cut from the web of
`material. The materials used are primarily polyethylene,
`polypropylene, and polyolefin, modified with rubber to in(cid:173)
`crease yield strength for flexible containers. Composite mate(cid:173)
`rials may be used, incorporating a heat-seal layer facing the so(cid:173)
`lution, an economical bulk layer for strength, and a polyester
`outside layer for scuff resistance and glossy appearance.31 Ad(cid:173)
`ditional considerations for IV container materials may be
`found in the chapters on parenteral preparations and intra(cid:173)
`venous admixtures.
`PHARMACEUTICAL COIL-Coil material is placed into
`bottles of solid oral dosage forms to prevent damage during
`shipping and handling. These materials include cotton, rayon,
`polyester, or an HDPE plastic spring. Purified rayon filler is a
`fibrous form of bleached, regenerated cellulose. Purified
`pol~ester _filler contains a number of addit