ALKERMES EXH. 2005
`ALKERMES EXH. 2005
`Luye v. Alkermes
`Luye v. Alkermes
`IPRZO16-1095 & |PR2016-1096
`IPR2016-1095 & IPR2016-1096
`
`

`
`17m
`
`EDITION
`
`Remington's
`
`
`
`ALFONSO R GENNARO
`
`Editor, and Chairman
`of the Editorial Board
`
`

`
`. Pharmaceutical A
`
`Sciences
`
` 19a5
`
`EMACK PUBLISHING COPMANY
`‘Egston, Pennsylvania 18042
`
`

`
`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
`
`Copyright 1926, 1936, by Joseph P Remington Estate
`Copyright 1948, 1951, by‘ The Philadelphia College of. Pharmacy and Science
`Copyright © 1956, 196.o,.,’1965»,‘ 1970, 1975, 1930, 1985, by The Philadelphia College of,Pha;m§¢y and
`Science
`,
`..
`'
`'
`'
`~.
`I
`‘
`
`All Rights Reserved
`
`Library of Congress Catalog Card No 60-53334
`ISBN O-912734-03-5
`
`The use of portions of the text of USP XX, NF XV, and USAN and the USP Dictionary of Drug
`Names is by permission of the USP Convention. The Convention is not responsible for any
`inaccuracy of quotation or for any false or misleading implication that may arise from
`separation of excerpts from the original context or by obsolescence resulting from
`publication of a supplement.
`
`NOTICE—This text is not intended to represent, nor shall it be interpreted to be, the equivalent
`of or a substitute for the official United States Pharmacopeia (USP) and/or the National
`Formulary (NF).
`In the event of any difference or discrepancy 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.
`
`Printed in the United States of America by the Mach Printing Company, Easton, Pennsylvania
`
`

`
`Table of Contents
`
`Part 1
`
`Orientation
`
`.
`.
`Scope
`1
`2 Evolution of Pharmacy
`3 Ethics
`.
`.
`.
`4 Pharmacists in Practice
`
`V5 Pharmacists in Industry
`6 Pharmacists in Government
`
`7 Drug Information .
`8 Research
`
`Part 2
`
`Pharmaceutics
`
`9 Metrology and Calculation .
`10 Statistics
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`11 Computer Science
`.
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`12 Calculus
`13 Molecular Structure, Properties, and States of
`Matter
`.
`.
`"
`14 Complexation _
`,
`.
`.
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`15 . Thermodynamics .
`,16 Solutions and Phase Equilibria
`17
`Ionic Solutions and Electrolytic Equilibria
`18 Reaction Kinetics .
`19
`lnterfaciol Phenomena
`.
`.
`.
`.
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`20 Colloidal Dispersions
`21
`Particle Phenomena and Coarse Dispersions
`22 Rheology .
`'
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`.
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`Pharmaceutical Chemistry
`
`3
`8
`19
`27
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`34
`42
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`49
`59
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`69
`104
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`140
`148
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`161
`156
`.198
`207
`230
`249
`258
`271
`301
`330
`
`’ 44
`45
`46
`47
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`48
`49
`50
`51
`52
`53
`. 54
`55
`56
`57
`58
`59
`60
`61
`62
`63
`64
`65
`66
`67
`68
`69
`70
`7 1
`72
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`.
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`Respiratory Drugs
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`Sympathomimetic Drugs .
`Cholinomimetic (Parasympathomimetic) Drugs
`Adrenergic and Adrenergic Neuron Blocking Drugs
`
`Antimuscarinic and Antispasmodic Drugs
`Skeletal Muscle Relaxants
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`Diuretic Drugs
`Uterine and Antimigraine Drugs
`Hormones .
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`Vitamins and Other Nutrients .
`Enzymes
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`General Anesthetics
`Local Anesthetics .
`
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`Sedatives and Hypnotics .
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`Antiepileptics
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`Psychopharmacologic Agents
`Analgesics and Antipyretics
`Histamine and Antihistamines
`.
`Central Nervous System Stimulants
`Antineoplastic and Immunosuppressive Drugs .
`Antimicrobial Drugs .
`.
`Parasiticides .
`.
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`Pesticides .
`.
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`Diagnostic Drugs
`Pharmaceutical Necessities
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`Adverse Effects of Drugs .
`.
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`Pharmacogenetics
`Pharmacological Aspects of Drug Abuse
`Introduction of New Drugs
`
`.
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`866
`876
`894
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`911
`921
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`933
`946
`951
`
`1002
`1035
`1039
`1048
`
`1059
`1075
`1084
`1099
`1124
`1133
`1139
`1158
`1234
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`1241
`1264
`1278
`1321
`1336
`1341
`1357
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`Part 3
`
`Inorganic Pharmaceutical Chemistry .
`23
`24 Organic Pharmaceutical Chemistry
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`25 Natural Products
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`26 Drug Nomenclature—United States Adopted
`Names
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`27 Structure-Activity Relationship and Drug Design
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`349
`374
`397
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`428
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`435
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`73
`74
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`75
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`Part 1
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`Biological Products
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`.
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`_.
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`Principles of Immunology
`lmmunizing Agents and Diagnostic Skin Anti-
`gens........
`Allergenic Extracts .
`.
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`1371
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`1380
`1396
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`Part 4
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`Radioisotopes in Pharmacy and Medicine
`
`28 Fundamentals of Radioisotopes .
`29 Medical Applications of Radioisotopes
`
`Part 5
`
`Testing and Analysis
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`30 Analysis of Medicinals
`31 Biological Testing .
`.
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`32 Clinical Analysis
`.
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`33 Chromatography .
`34
`Instrumental Methods of Analysis
`35 Dissolution
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`Part 6
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`Pharmaceutical and Medicinal Agents
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`36 Diseases: Manifestations and Pathophysiology
`
`’\ 37 Drug Absorption, Action, and Disposition
`38 Basic Pharmacokinetics
`.
`.‘
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`39 Principles of Clinical Pharmacokinetics
`40 Topical Drugs
`.
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`41 Gastrointestinal Drugs .
`.
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`42 Blood, Fluids, Electrolytes, and Hematologic
`Drugs
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`43 Cardiovascular Drugs
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`453
`471
`
`503
`550
`559
`593
`619
`653
`
`713
`741
`762
`773
`792
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`816
`843
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`Part 6
`
`Pharmaceutical Preparations and Their
`Manufacture
`
`\76
`77
`75
`79
`so
`81
`82
`so
`84
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`85
`86
`87
`88
`89
`T732’
`3 92
`L793
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`Preformulation .
`Bioavailability and Bioequivalency Testing .
`Separation
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`Sterilization .
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`Tonicity, Osmoticity, Osmolality, and Osmolarity .
`Plastic Packaging Materials
`Stability of Pharmaceutical Products
`.
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`.
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`Quality Assurance and Control
`.
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`Solutions, Emulsions, Suspensions, and Extrac-
`tives..
`
`Parenteral Preparations .
`Intravenous Admixtures
`
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`.'
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`Ophthalmic Preparations
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`Medicated Applications
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`Powders
`.
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`Oral Solid Dosage Forms .
`Coating of Pharmaceutical Dosage Forms .
`Sustained Release Drug Delivery Systems
`Aerosols
`
`.
`.
`
`Part 9
`
`Pharmaceutical Practice
`
`94
`95
`96
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`Ambulatory Patient Care
`Institutional Patient Care
`Long-Term Care Facilities
`
`XV
`
`1409
`1424
`1432
`1443
`1455
`1473
`1478
`1487
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`1492
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`1518
`1542
`
`1553
`1567
`1585
`1603
`1633
`1644
`1662
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`1681
`1702
`1723
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`

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`1737;
`1749
`1757
`1764
`1778
`1796
`1817
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`1824
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`105 __.Sorgica|vSupplies
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`106
`Poison Control
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`107 LawsGoverning Pharmacy
`108 Pharmaceutical Economics and Management
`109 Dental Services
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`_.,
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`1869
`1879
`1890
`1917
`1935
`
`Alphabeticlndex
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`1946
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`'9'-‘ex
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`97 The Pharmacistand Public Health .
`.
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`98 The Patient: Behavioral Determinants.
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`99 PatientCommunication .
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`. g.
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`100 PatientvCompliance .
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`._
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`_;
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`101 The Prescription
`.
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`;~ .
`.
`. -. .
`..
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`102 Drug Interactions .
`.
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`».
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`.‘ ._
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`..
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`103 Utilization and Evaluation of Clinical Drug
`Literature .
`.
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`,.
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`.-
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`..
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`104 Health Accessories
`
`ii
`ii
`lg
`I;
`ls
`E}
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`,
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`
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`,A...........‘
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`.....;
`.
`l’?'\
`
`.. I
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`

`
`
`
`Parenteral Preparations ..
`
`CHAPTER 85
`
`m
`Kenneth E Avls, Dscj
`.
`Goodman Ptofessor and Chairman. Depart_ment olnllharmaceutlcs
`College of Pharmacy. University of Tennessee Center for the Health Sciences ,
`Memphls. TN 36163
`’
`
`The term parenteral (Gk, para, enteron .= beside the in-
`testine) refers to the route of administration of drugs by in-
`jection underor through one or more layers of skin or mucous
`membrane. ‘Since this route circumvents the highly efficient
`protective barriers of the human body, the skin and mucous
`membranes, exceptional purity of the dosage form must be
`achieved. ~ The processes utilized in preparing thedosage form
`must embody good manufacturing practices that will produce
`and maintain the required quality of ‘the product. '
`' New de-
`velopments in process technology and quality control should
`be adopted as soon as their value and reliability have been
`established as a means for furtherimproving the quality of the
`product.
`i
`..
`'
`’
`..
`
`History‘
`
`One of the most significant events in thebeginnings of
`parenteral therapy was the first recorded injection of drugs
`into the veins of living animals, in about the year 1657, by the
`architect Sir Christopher _Wren. From m such a very crude
`beginning,
`the technique. ‘for. __.intr'aven"ous
`injection and
`knowledge of the implications -thereof developed slowlyduring
`the next century and a half.
`In 1855 Dr Alexander Wood of
`Edinburgh described what was probably the first subcuta-
`neous injection of drugs for therapeutic purposes using a true
`hypodermic syringe.
`The latter half of the 19th century brought increasing
`concern for safety in the administration of parenteral solu-
`tions, largely because of the work of Robert Koch and Louis
`Pasteur. While Charles Chamberland was developing both
`hot-air and steam sterilization techniques and the first bac-
`teria-retaining filter (made of unglazed porcelain), Stanislaus
`Limousin was developing a suitable container, the all—glass
`ampul.
`In the middle 1920s Dr. Florence Seibert provided
`proof that the disturbing chills and fever which often followed
`the intravenous injection of drugs was caused by potent
`products of microbial growth, pyrogens, which could be
`eliminated from water by distillation and from glassware by
`heating at elevated temperatures.
`.
`-
`' Of the recent developments that have contributed to the
`high quality standards currently achievable in the preparation
`of parenteral dosage forms, the two that have probably con-
`tributed most are the development of HEPA—filtered laminar
`air flow and the development of membrane microfiltration for
`solutions. The former has made it possible to achieve ultra-
`clean environmental conditions for the processing of sterile
`products, and the latter has made it possible to remove from
`solutions by filtration both viable and nonviable particles of
`microbial size and smaller. However, many other develop-
`ments in recent years have produced an impressive advance
`in the technology associated with the safe and reliable prep-
`aration of parenteral dosage forms. The following list iden-
`tifies a few of the events which have contributed to that de-
`velopment.
`1926——Parenterals were accepted for inclusion in the fifth
`edition of the National Formulary.
`
`1933——The practical application of freeze-drying" to clinical
`’
`materials was accomplished by a tea_m_of,scientists at
`-“the University of Pennsylvania._ ,
`.
`M
`1938——T.he Food, Drug and Cosmetic ‘Act waspassed, by
`Congress, establishing the Food_:and Drug Adminis-
`tration (FDA).
`I 1'944.—Thelsterilant ethylene" oxide was discovered,
`I If
`1946—The Parenteral Drug Association was organized.
`196_1—,The concept of laminarairflow was developed by WJ
`, Whitfield,
`._
`.,
`..:
`‘
`1962-.-The FDA -was authorized by Congress to establish
`current good manufacturing practices.(CGMP) regu-
`lations..
`,
`.
`.
`A_
`_ V.
`.
`1965——Total parenteral nutrition (TPN) was developed by
`._
`»
`SJDudrick..
`..
`..
`.
`=-
`1972—The Limulus Amebocyte,Lysa_te test for pyrogens in
`parenteral products was developed by JFCooper-.
`_
`.
`
`Administration _
`(1)
`Injections may be classified five general categories:
`solutions ready for injection, (2) dry, soluble products ready
`to be combined with a solvent just prior to use, (3) suspensions
`ready for injection, (4) dry, insoluble products ready to be
`- combined with a vehicle just prior to use, and (5) emulsions.
`These injections may be administered by such routes as in-
`travenous, subcutaneous, intradermal, intramuscular, intra-
`spinal, intracisternal, and intrathecal. The nature of the
`product will determine the particular route of administration
`that may be employed. Conversely, the desired route of ad-
`ministration will place requirements on the formulation. For
`example, suspensions would not be administered directly into
`the blood stream because of the danger of insoluble particles
`blocking capillaries. Solutions to be administered-subcuta-
`neously would require strict attention to tonicity adjustment,
`otherwise irritation of the plentiful supply of nerve endings
`in this anatomical area would give rise to pronounced pain.
`Injections intended for intraocular, intraspinal, intracisternal,
`and intrathecal administration require the highest purity
`standards because of the sensitivity of nerve tissue to irritant
`and toxic substances.
`I
`When compared with other dosage forms, injections possess
`select advantages.
`If immediate physiological action is
`needed from a drug, it usually can be provided by intravenous
`injection of an aqueous solution. Modification of the for-
`mulation or another route of injection can be used to slow the
`onset and prolong the action of the drug. The therapeutic
`response of a drug is more readily controlled by parenteral
`administration since the irregularities of intestinal absorption
`are circumvented. Also, since the drug normally is adminis-
`tered by a professionally trained person, it may be confidently
`expected that the dose was actually and accurately adminis-
`tered. Drugs can be administered parenterally when they
`cannot be given orally because of the unconscious or unco-
`operative state of the patient, or because of inactivation or lack
`of absorption in the intestinal tract. Among the disadvan-
`
`1518
`
`

`
`tages of this dosage formare the requirement of asepsis at
`administration, the risk of tissue toxicity from local irritation,
`the real or psychological pain factor, and the difficulty in
`correcting an error, should one be made.
`In the latter situa-
`tion, unless a direct pharmacological antagonist is immedi-
`ately available, correction of an error may be impossible. One
`other disadvantage is that daily or frequent administration
`, poses difficulties, either for the patient to visit a professionally
`trained person or to learn to inject oneself.
`
`Parenteral Combinations
`
`Since there is a degree of discomfort for the patient with
`each injection, a physician will frequently seek to reduce this
`discomfort by combining more. than one drug in one injection.
`This is most commonly encountered when therapeutic agents’
`are added to large-volume solutions of electrolytes or nutri-
`ents, commonly called “IV additives,” during intravenous
`administration. Since these preparations would be aqueous
`solutions, there is a high potential for chemical and physical
`interactions to occur. See Chapter 101. The pharmacist is
`the professional best qualified to cope with these incompati-
`bilities. However, in the past, these have been handled largely
`_at the patient’s bedside by the nurse and physician. Only
`recently has it been recognized that this professional area is
`the proper function of a pharmacist and has been so stated by
`the Joint Commission on Accreditation of Hospitals?
`'
`As pharmacists have assumed increasing responsibility in
`this area, awareness has gradually developed of the wide-
`spread occurrence of visible, as well as invisible, physical,
`chemical, and therapeutic incompatibilities when certain
`drugs are combined or added to intravenous fluids.
`Development of a precipitate or a color change when
`preparations are combined is an immediate warning that an
`alteration has occurred. Such a combination should not be
`administered to the patient because the solid particles may
`occlude the blood vessels, the therapeutic agent may not be
`available for absorption, or the drug may have been degraded
`into toxic substances. Moreover, in other instances changes
`not visually apparent may have occurred which could be
`equally or more dangerous to the welfare of the patient.
`’-The almost innumerable potential combinations present
`a complex situation even for the pharmacist.
`In an attempt
`to organize theinformation available and to aid the pharma-
`cist in making rapid decisions concerning potential problems,
`a number of charts have been compiled based on the visible
`changes that may be observed when two or more preparations
`are combined. The value of such charts islimited by such
`factors as frequent changes in commercial products, variations
`in order of mixing or the proportions in the mixture, differ-
`ences in concentration of each ingredient, or variations in the
`period of time that the combination is held before use.
`As studies have been undertaken and more information has
`been-gained, it has been shown that knowledge‘ of variable
`factors such as pH and the ionic character ofthe active con-
`stituents. aids substantially in understanding and predicting
`potential incompatibilities. -Kinetic studies of reaction rates
`may be- utilized to describe or predict the extent of degrada-
`tion. Ultimately, a thorough study should be undertaken of
`each therapeutic agent in combination with other drugs and
`‘intravenous fluids, not only of generic" but of commercial
`preparations, from thephysical, chemical, and therapeutic
`aspects. Such studies are being undertaken and some have
`been reported.
`_
`_
`Ideally, no parenteral combination should be administered
`unless it has been thoroughly studied to. determine the effect
`of the combination on the therapeutic value and the safety of
`each such combination. However, such an ideal situation does
`not and may never exist. Therefore, it is the responsibility
`of the pharmacist to‘ be as familiar as possible with the phys-
`
`PARENTERAL PREPARATIONS
`
`1519
`
`ical,_chemical, and therapeutic aspects of parenteral combi-
`nations and to exercise the best possible judgment as to
`whether or not the specific combination extemporaneously
`prescribed is suitable for use in a patient. A service to phar-
`macists has been provided through reviews of this subject
`area.3
`
`General Requirements
`
`An inherent requirement for parenteral preparations is that
`they be of the verybest quality and provide the maximum‘
`safety for the patient. Therefore, the pharmacist, being re-
`sponsible for their preparation, must utilize skills and re-
`sourcefulness at the highest-level of efficiency to achieve this
`end. Among the areas requiring dedicated attention are the
`following:
`'
`
`1. Possession and application of high moral. and professional ethics.
`Even the thought of using inferior techniques or ingredients in a manu-
`facturing process must not be countenanced by the pharmacist. The
`proper attitude of the person responsible for the preparation of the product
`is its most vital ingredient.
`_
`,
`»
`,
`.
`2. The pharmaceutical training received must be utilized to the fullest
`vane .
`measarre. The challenges to this knowledge bank will be many and
`3. Specialized techniques will be required for the manufacture ofsterile '.
`preparations, employing them with alertness and sound judgment. These
`techniques must be , subjected to continuous critical review for faults,
`omissions, and improvements.
`‘
`'
`,
`’
`4.
`Ingredients of the highest quality obtainable must be utilized. At
`times ingredients may require special purification beyond that of the
`commercial supply. This will normally require that cost factors be given
`second place in_importance.
`5. The stabilityand effectiveness of the product must be established
`with substantiating data, either from original or published sources. This
`must take into account process variations and differences-in ingredient
`specifications from plant to plant.
`‘
`.
`.
`.
`6. A well-defined and controlled program must be established to assure
`the quality of the product and the repetition of valid production proce-
`dures. This involves evaluation of all ingredients, vigilant controls of"all
`steps in the production procedures, and careful evaluation of the finished
`product.
`.
`
`Injections or other sterile products are rarely prepared in
`the communitypharmacy because of the ‘lack of adequate
`facilities necessary to prepare a reliable and safe product.
`In some hospital pharmacies injections or irrigating fluids
`are manufactured, but in an increasing number aseptic pro-
`cessing is utilized primarily‘ in the addition of various drugs
`to intravenous solutions for the individual patient. The vast
`majority of injectable products used" clinically are prepared
`by thepharmaceutical industry.
`
`General Process
`
`The preparation of a parenteral product may be considered
`to encompass four general areas as follows:
`(1) procurement
`and selection of the components, (2) production facilities and
`procedures, (3) control of quality, and (4) packaging and la-
`beling. The components of the product to be procured in-
`cludevehicles, solutes, containers, and closures. ‘ The steps
`constituting production include the maintenance of facilities
`and equipment, preparing and controlling the "environment,
`cleaning the containers and equipment, preparing the product,
`filtering the solution, filling ‘containers with the, product,
`sealing the containers, and sterilizing the product. Control
`of quality includes th,e.evalua_tion of the components,_vali—
`dation of equipment and processes, deter.Inination_that the
`production has been executed within prescribed_requirements,_
`and performance of necessary evaluative tests on the finished
`product. The final area of packaging and labeling includes
`all steps necessary to identify the finished product and enclose
`it in -such manner that it is safely and properly prepared for
`sale and delivery to the user.
`In the following sections, these
`four areas "and appropriate subtopics will be discussed in de-
`tail.
`
`

`
`1520
`
`CHAPTER 85
`
`Components .and Containers
`
`Establishing specifications to insure the quality of each of
`the components of an injection is of vital. importance, These
`specifications will be coordinated with the requirements of
`the specific formulation and will not necessarily be identical
`for a particular component if used, in, several different for-
`mulations.
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`-
`The most stringent requirements normally will be en-
`countered with aqueous solutions, particularly if the -product
`is to be sterilized at an elevated temperature where reaction
`rates, will be greatly accelerated. Modification of -aqueous
`‘ vehicles to include a glycol, or replacement -with a nonaqueous.
`vehicle, will usually reduce’ reaction rates. _ _Dry preparations
`pose relatively few reaction problems but may require defin-
`itive physical specifications for ingredients that must have
`certain solution. or dispersion characteristics when a vehicle
`is added.
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`Containers and closures are herein considered components
`of the-product because they are in prolonged, intimate contact-
`with the product and may release substances or remove in-
`gredients from the product. While not usually considered a
`part of a container, administration devices are a part of a
`container system and their_effect upon the product must be
`assessed even though the contact period is ‘usually’ brief.
`
`Vehicles '
`
`, Since most liquid injections are quite dilute‘, the component
`present in the highestproportion is the vehicle. A vehicle
`normally has no therapeutic activity and is nontoxic. How-
`ever, it is of great importance in the formulation-since it pre-
`sents to body tissues the form of the active constituent for
`absorption. Absorption normally occurs most rapidly and
`completely when a drug ispresented as an aqueous solution.
`Modification of the vehicle with water—miscible liquids or
`substitution with water-immiscible liquids normally decreases
`the rate of absorption; Absorption froma suspension may
`be affected by such factors as the viscosityiof the vehicle, its
`capacity for wetting thesolid particles, the solubility equi-
`librium produced by the vehicle, and the distribution coeffi-
`cient between the vehicle and aqueous body systems.
`,
`The vehicle of greatest’ importance for parenteral products
`is water. Water of suitable qualityfor parenteral adminis-
`tration must be prepared either by distillation or by reverse
`osmosis. Only by these means is it possible to separate ade-
`quately various liquid, gas and solid contaminating substances
`from water.
`I
`
`Preparation of Water
`
`In general, a conventional still consists of a boiler (evapo-
`rator) containing raw water (distilland), ‘a source of heat to
`vaporize the water in the evaporator, a headspace above the
`level of distilland with condensing 'su_rfa__c‘es for refluxing the
`vapor and thereby returning nonvolatile. impurities tothe
`distilland, a means for eliminating volatile impurities before
`the hot water vapor is condensed, and a-,co_ndenser for re-
`moving the heat of vaporization, "thereby converting the water
`vaP.0r to a liquid distillate.
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`A It "should be apparent_ that the specific construction features
`of a still and the process specifications will markedly affect
`the quality ofdistillate obtained from a still.
`jTh'ose required
`for producing high-purity water, such as Water for Injection
`USP, must be considerably more stringent than those required
`for_ Purified Water USP. _,Among the factors that must be
`lconsiderediare:
`'
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`,1.
`- The quality of the raw water will affect the quality of the distillate.
`It maybe necessary that the raw water he first softened, deionized, or
`
`‘
`
`treated by reverse osmosis to obtain a final distillate of adequate
`quality.
`_
`.
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`2. The size of the evaporator will affect the efficiency. The evaporator
`should be large enough to provide a low vapor velocity, thus reducing en-
`trainment of distilland either as a film on vapor bubbles or as separate
`droplets.
`‘3. The baffles (condensing surfaces) determine the effectiveness of
`refluxing. They should be designed to efficiently remove entrainment
`at optimal vapor velocity, collecting and returning the heavier droplets
`contaminated with distilland.
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`,
`4. Redissolving of volatile impurities in the distillate reduces purity.
`Therefore, volatile.impurities should be separated efficiently from the hot
`water ‘vapor and eliminated by aspirating to the drain or venting to the
`atmosphere.
`‘
`_5. Contamination of the vapor and distillate from the metal parts of
`the still can occur. Present standards for high-purity stills are that all
`parts contacted by the vapor or distillate should be constructed of metal
`coated with pure tin, of 304 or 316 stainless steel, or of chemically resistant
`glass.
`'
`
`Design features of a still also influence its efficiency of op-_
`eration, relative freedom from maintenance problems, or the
`extent of automatic operation.‘ Stills may be constructed of
`varying size, rated according to the volume of distillate that
`can be produced per hour of operation under optimum con-
`ditions. Only stills designed to produce high-purity water
`may be considered for use in the production of Water for In-
`jection (WFI).
`.
`.
`Conventional commercial stills designed for the production
`of high-purity water, such as shown in Fig 85-1, are available
`from several suppliers.*
`Compression Distillation—The vapor compression still,
`primarily designed for the production of large volumes of high
`purity distillatewith‘ low consumption of energy and water,
`
`* Am Sterilizer, Barnstead, Consolidated, Corning, Finn-Aqua.
`
`Fig. 85-1. High-purity still and. sealed water storage system. A:
`Evaporator; B: high-purity baffle unit; 0: condenser; D:
`storage tank
`with ultraviolet lamp; E: control panel (courtesy, Ciba-Geigy).
`
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`EXHAUST SYSTEMS
`
`Fig. 85-2. Vapor compression still.
`
`is illustrated diagrammatically in Fig 85-2. To start, the feed
`water is heated in the evaporator to boiling. The vapor pro-
`duced in the tubes is separated from entrained distilland in
`the separator and conveyed to a compressor which compresses
`the vapor and raises its temperature to approximately 224°F.
`It then flows to the steam chest where it condenses on the
`outer surfaces of the tubes containing distilland; thereby the
`vapor is condensed and drawn offas distillate while giving up
`its heat to bring the distilland in the tubes to the‘boiling
`point.
`_
`_ Vapor compression stills are availablein capacities from 50
`to 2800 gal/hour (Aqua-Chem, Barnstead, Meco).
`' Multiple-Effect Stills—The multiple-effect still also is
`designed to conserve energy and water usage.
`In principle,
`this still is simply a series of single effect stills running at
`differing pressures. A series of up to seven effects may be
`used, with the first effect operated at the highest .pressure and
`the last effect at atmospheric pressure. Steam from an ex-
`ternal source is used in the first effect to generate steam from
`raw water. The generated steam is under pressure and is used
`as the power source to drive the second effect. The steam
`used to drive the second effect condenses as it gives up its heat
`of vaporization and forms distillate. This process continues
`until the last effect when the steam is at atmospheric pressure
`and must be condensed in a heat exchanger. _
`The capacity of a multiple—effect still can be increased by
`adding effects. The quality of distillate also will be affected
`by the inlet steam pressure, thus" a 600 gallon per hour unit
`designed to operate at 115 psig steam pressure could be run
`at approximately 55 psig and would deliver about 400 gallons
`per hour. These stills have no moving parts and operate
`quietly. They are available in capacities from about 50 to
`7,000 gallons per hour (AMSCO, Barnstead, Finn-Aqua).
`Reverse 0smosis—Reverse osmosis has recently been
`added by the USP as a method suitable for preparation of
`Water for Injection. As thenarne suggests, the natural pro-
`cess of selective permeation of molecules through a semiper-
`meablemembrane separating two aqueous solutions of dif-
`ferent concentrations is reversed. Pressure, usually between
`200 and 400 psig, is applied to overcome osmotic pressure and
`force pure water to permeate through the membrane.
`Membranes, usually composed of cellulose esters or polyam—
`ides, are selected to provide an efficient rejection of contam-
`inant molecules in raw water. The molecules most difficult
`to remove are small inorganic molecules such as sodium
`chloride. Passage through two membranes in series is
`sometimes utilized to increase the efficiency of removal of
`these small molecules and to decrease the risk of structural
`failure of a membrane to remove other contaminants, siich as
`bacteria and pyrogens (for additionalinformation concerning
`
`PARENTERAL PREPARATIONS
`
`1521
`
`reverse osmosis see under this title in Chapter 78, and Fig.
`78-21, in that chapter; also the discussion under Water in
`Chapter 84).
`‘
`Currently, extensive validation is being undertaken to de-
`termine whether, in fact, this method is capable of consistently
`producing high-purity water of a quality equal or superior to
`that producible by distillation..
`
`Water for Injection USP
`
`This is a high-purity water intended to be used as a vehicle
`for injectable preparations. Sterile Water for Injection USP
`is described in a separate monograph and differs in that it is
`intended as a packaged and sterilized product.
`>
`Storage—If WFI cannot'be used immediately after it is‘
`produced, the USP permits storage at room temperature for
`a period not exceeding 24 hours or for longer periods at a
`temperature too high or too low for microbial growth to occur.
`Therefore, WFI usually is collected directly from the reverse
`osmosis unit or a still in a closed system designed to prevent
`recontamination of the water and to hold it at a constant
`temperature of 60—80°C. The system may range from a rel-
`atively small single storage tank with a draw-off spout (Figure
`85-1) to a very large system holding several thousand gallons
`of water. The stainless steel tank in such a system is usually
`connected to a welded stainless steel distribution loop
`supplying the various use sites with a continuously circulating
`water supply. The tank would be provided with a hydro-
`phobic membrane vent filter capable of excluding bacteria and
`nonviable particulate matter. Such a vent filter is necessary
`to permit changes in pressure during filling and emptying of
`the tank. The material of construction for the tank and
`connecting lines is usually electropolished 316L stainless steel
`with heliarc welded pipe. The tanks also may be lined with
`glass or a coating of puretin. Such systems are very carefully
`designed and constructed and often constitute the most costly .
`installation within the plant.
`When the water cannot be used at 80°C, heat exchangers
`must be installed to reduce the temperature at the point of
`use. Bacterial retentive filters should not be installed in such
`systems because of the risk of bacterial build-up on the filters
`and the consequential release of pyrogenic substances.
`Purity—The USP monographs provide standards of purity
`for