`

`

`

`
`
`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. 1014
`3 of 11
`
`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. 1014
`3 of 11
`
`

`

`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. 1014
`4 of 11
`
`Eton Ex. 1014
`4 of 11
`
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`CHAPTER 41: PARENTERAL PREPARATIONS
`
`813
`
`nuents (lipopolysaccharides, LPS) of the cell wall of gram(cid:173)
`~:gative ba~teria (eg, P~e_udomona~ sp, Salmonella sp, Es(cid:173)
`cherichia colzJ. Gram-positive bacten~ and fungi also produce
`yrogens but oflower potency and of different chemical nature.
`~ram-positive bacteria produc~ peptidoglycans wherease fungi
`roduct ~-glucans, both of which can cause non-endotoxin py(cid:173)
`~ogenic res~on~es. Endotoxins a7e lipopolysaccharides that typ(cid:173)
`ically exist m h1g~ molecul_ar weight aggregate forms. However,
`the monomer umt of LPS 1s less than 10,000 daltons, enabling
`endotoxin easily to pass through sterilizing 0.2 micron filters.
`Studies have shown that the lipid portion of the molecule is re(cid:173)
`sponsible for the biological activity. Since endotoxins are the
`most potent pyrogens and gram-negative bacteria are ubiqui(cid:173)
`tous in the environment, especially water, this discussion fo(cid:173)
`cuses on endotoxins and the risk of their presence as contami(cid:173)
`nants in sterile products.
`Pyrogens, when present in parenteral drug products and
`injected into patients, can cause fever, chills, pain in the back
`and legs, and malaise. Although pyrogenic reactions are rarely
`fatal, they can cause serious discomfort and, in the seriously
`ill patient, shock-like symptoms that can be fatal. The inten(cid:173)
`sity of the pyrogenic response and its degree of hazard will be
`affected by the medical condition of the patient, the potency of
`the pyrogen, the amount of the pyrogen, and the route of ad(cid:173)
`ministration (intrathecal is most hazardous followed by intra(cid:173)
`venous, intramuscular, and subcutaneous). When bacterial
`(exogenous) pyrogens are introduced into the body, LPS tar(cid:173)
`gets
`circulating mononuclear
`cells
`(monocytes
`and
`macrophages) that, in turn, produce pro-inflammatory cy(cid:173)
`tokines such as interleukin-2, interleukin-6, and tissue necro(cid:173)
`sis factor. Besides LPS, gram-negative bacteria also release
`many peptides (eg, exotoxin A, peptidoglycan, and muramuyl
`peptides) that can mimic the activity of LPS and induce cy(cid:173)
`tokine release. The Limulus Amebocyte Lysate (LAL) test, dis(cid:173)
`cussed later, can only detect the presence of LPS. It has been
`suggested that a new test, called Monocyte Activation Test,
`replace LAL as the official pyrogen test because of its greater
`sensitivity to all agents that induce the release of cytokines
`that cause fever and a potential cascade of other adverse
`physiological effects. 19
`CONTROL OF PYROGENS-In general, it is impractical,
`if not impossible, to remove pyrogens once present without ad(cid:173)
`versely affecting the drug product. Therefore, the emphasis
`should be on preventing the introduction or development ofpy(cid:173)
`rogens in all aspects of the compounding and processing of the
`product.
`Pyrogens may enter a preparation through any means that
`will introduce living or dead microorganisms. However, current
`technology generally permits the control of such contamination,
`and the presence of pyrogens in a finished product indicates
`processing under inadequately controlled conditions. It also
`should be noted that time for microbial growth to occur in(cid:173)
`creases the risk for elevated levels ofpyrogens. Therefore, com(cid:173)
`pounding and manufacturing processes should be carried out as
`expeditiously as possible, preferably planning completion of the
`~rocess, including sterilization, within the maximum allowed
`bme according to process validation studies. Aseptic processing
`guidelines require establishment of time limitations through(cid:173)
`out processing for the primary purpose of preventing the in(cid:173)
`crease of endotoxin (and microbial) contamination that subse(cid:173)
`quently cannot be destroyed or removed.
`t Pyrogens can be destroyed by heating at high tempera(cid:173)
`u~es. A typical procedure for depyrogenation of glassware
`;~00 equipment is maintaining a dry heat temperature of
`4 h C _for ~5 mi1:. Exposure for 650°C for 1 min or 180°C for
`{ h~ew1se will destroy pyrogens. The usual autoclaving
`~~fu~_wdl n~t do so. Heating with strong alkali or oxidizing
`th
`ions will destroy pyrogens. It has been claimed that
`py°rough washing with detergent will render glassware
`frerogen-free if subsequently rinsed thoroughly with pyrogen(cid:173)
`des~r wa~er. Rubber stoppers cannot withstand pyrogen-
`uctive temperatures, so reliance must be placed on an
`
`effective sequence of washing, thorough rinsing with WFI,
`prompt sterilization, and protective st?rage t~ ensure ade(cid:173)
`quate pyrogen control. Similarly, plastic cont~me:s and ?e(cid:173)
`vices must be protected from pyrogenic contammat10n dur~ng
`manufacture and storage, since known ways of destroymg
`pyrogens affect the plastic adversely._ ~t has been reported
`that anion-exchange resins and positively charged mem(cid:173)
`brane filters will remove pyrogens from water. Also, al(cid:173)
`though reverse osmosis membranes will eliminate them, t~e
`most reliable method for their elimination from water is
`distillation.
`A method that has been used for the removal of pyrogens
`from solutions is adsorption on adsorptive agents. Ho~ever,
`since the adsorption phenomenon also may c~use se~ective re(cid:173)
`moval of chemical substances from the solut10n, this m~thod
`has limited application. Other in-proc_ess metho~s for their de-
`struction or elimination include selective extract!on proc_edur~s
`and careful heating with dilute alkali, dilute acid, or mild ~x1-
`dizing agents. In each instance, the method must be studied
`thoroughly to be sure it will not have an adverse effe~t on the
`constituents of the product. Although ultrafiltra~10n no~
`makes possible pyrogen separation on a molecular-weight basis
`and the process of tangential flow is making; la:g~-scale pro(cid:173)
`cessing more practical, use of this technology 1s limited, except
`in biotechnological processing.
`SOURCES OF PYROGENS-Through understanding the
`means by which pyrogens may contaminate parenteral prod(cid:173)
`ucts their control becomes more achievable. Therefore, it is im(cid:173)
`port;nt to know that water is probably the greatest potential
`source of pyrogenic contamination, since water is essential for
`the growth of microorganisms and frequently contaminated
`with gram-negative organisms. When microorganisms metabo(cid:173)
`lize, pyrogens will be produced. Therefore, raw water can be ex(cid:173)
`pected to be pyrogenic and only when it is appropriately treated
`to render it free from pyrogens, such as WFI, should it be used
`for compounding the product or rinsing product contact sur(cid:173)
`faces such as tubing, mixing vessels, and rubber closures. Even
`when such rinsed equipment and supplies are left wet and im(cid:173)
`properly exposed to the environment, there is a high risk that
`they will become pyrogenic. Although proper distillation will
`provide pyrogen-free water, storage conditions must be such
`that microorganisms are not introduced and subsequent
`growth is prevented.
`Other potential sources of contamination are containers
`and equipment. Pyrogenic materials adhere strongly to glass
`and other surfaces, especially rubber closures. Residues of so(cid:173)
`lutions in used equipment often become bacterial cultures,
`with subsequent pyrogenic contamination. Since drying does
`not destroy pyrogens, they may remain in equipment for long
`periods. Adequate washing will reduce contamination and
`subsequent dry-heat treatment can render contaminated
`equipment suitable for use. However, all such processes must
`be. val~dated to. ensur~ th~ir effectiveness. Aseptic processing
`gmdelmes :r:eqmre validation of the depyrogenation process by
`demonstratmg at least 3-log reduction in an applied endotoxin
`challenge.
`Solutes ~ay be a source of pyrogens. For example, the
`ma1:ufacturmg of bulk chemicals may involve the use of pyro(cid:173)
`ge~1c water for process steps such as crystallization, precipi(cid:173)
`tation, or washmg. Bulk drug substances derived from cell
`cult_ure fermentation will almost certainly be heavily pyro(cid:173)
`gemc. Therefore, all lots of solutes used to prepare parenteral
`p:r:oducts should be tested to ensure that they will not con(cid:173)
`tnbute unacceptable quantities of endotoxin to the finished
`product. It is standard practice today to establish valid endo(cid:173)
`toxin limits on active pharmaceutical ingredients and most so(cid:173)
`lute additives.
`The manufacturing process must be carried out with great
`care and as rapidly as possible, to minimize the risk of micro(cid:173)
`bial contamination. Preferably, no more product should be pre(cid:173)
`pare~ than can be processed completely within one working
`day, mcluding sterilization.
`
`(cid:141)
`
`Eton Ex. 1014
`11 of 11
`
`