...HmhXEamrahP0nn
`
`1OOO6O11
`
`

`

`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, 1960, 1965, .1970, 1975,1980, 1985, 1990, by The Philadelphia College of
`Pharmacy and Science
`'
`
`All Rights Reserved
`
`Library of Congress Catalog Card No. 60-53334
`ISBN 0-912734-O4-3
`
`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 responsible 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 officiai United States Phormacopeio (USP) and/or the National
`Formulory (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, Eoston, Pennsylvania
`
`|nnoPharma Exhibit 11060602
`
`

`

`Table of Contents
`
`Part 1
`
`Orientation
`
`. . ..
`. . . . . . .
`. - - . . . . . . . . .
`1 Scope........... . .
`-
`-
`- -
`2
`EV°lU|‘l°I‘l °f Pl1°|‘m0¢Y - - - - - - -
`-
`- - - - - - - - - -
`.
`. . .
`3 Ethics
`.
`. .
`. . . . . . . . . .
`. . . . . . . . . .
`. . . . . . . . .
`4 The Practice of Community Pharmacy . . . . . . .
`. . .
`5 Opportunities for Pharmacists in the Pharmoceutl-
`.
`col industry . . . . . . . .
`.
`. . . .
`. . .
`.
`. .
`.
`.
`. . . . . .
`. .
`.
`6 Ph0f|'l"°¢l5i5 in G°Ve"|m9l‘“ - -
`-
`-
`-
`- - - - - - - - - -
`- - -
`7 Druglnformotion....--------»-----v---«----
`3 Research - - -
`- - - - -
`
`Part 2
`
`Pharmaceutics
`
`. . . .
`. . . . . . .
`. .
`9 Metrology and Calculation . . . . . .
`. .
`. .
`. . . . . . . . .
`10 Statistics . . . . . . . . . . . . . . . . . . . . .
`.
`.
`. .
`. . . . . . . . .
`11 Computer Science . . .
`. . . . . . . . . .
`12 Calculus . . . . . . . . . . . . .
`. . . . . . . . . . . . . . . . . .
`. .
`.
`13 Molecular Structu re. Properties and States of
`.
`. . .
`Matter
`. . . . . . . . . . . .
`.
`. . . . . . .
`.
`.
`.
`.
`.
`. . . . . .
`.
`. . .
`14 Complex Formation . . .
`. . . . . .
`.
`. . . . . . . . . .
`15 Thermodynamics...........................
`16 Solutions and Phase Equilibria .
`.
`. . . . . . . . . . .
`. . .
`17
`Ionic solutions and Electrolytic Equillbria . . . . .
`. . .
`16 Reaction Kinetics .
`. .
`.
`. . . . . . . .
`. .
`. . . . . . . . . .
`. . .
`19 Dispersesystc-ms.... . . .
`. . .
`20 Rheology . . . . . . . . . . . . . . . . . .
`
`. . . .
`
`. . . . .
`
`.
`
`. . . .
`
`.
`
`Part 5
`
`Pharmaceutical Chemistry
`
`. . . . .
`inorganic Pharmaceutical Chemistry . . .
`21
`. . . . .
`22 Organic Pharmaceutical Chemistry . . . .
`23 Natural Products
`. .
`.
`. . . . .
`. . . .
`. . . .
`. . . . . . . .
`24 Drug Non-renclature—United States Adapted
`Names . .
`. . . . . . . . . . . . . . . . . . .
`. . . .
`. . . . . . . . . .
`25 Structure-Activity Relationship and Drug
`Design
`
`. . .
`. . .
`.
`. .
`
`1
`Part 4
`
`.
`Testing and Analysis
`
`.
`. . . . . . . . .
`. . . . . . . . . .
`. . .
`.
`.
`. . . . . . . . .
`. .
`. .
`
`. .
`26 Analysis of Medicinois
`27 Biological Testing . . . . . .
`23 ClInlcalAnoly5is
`.
`.
`29 Chromatography . .
`. .
`30 instrumental Methods of Analysis
`31 Dissolution . . . . . . . . .
`.
`. . . . . . .
`. . .
`.
`
`. . . . . . . .
`. . . . . . . .
`
`. . .
`. . .
`
`3
`8
`20
`28
`
`33
`33
`49
`5°
`
`69
`104
`138
`145
`
`158
`162
`197
`207
`226
`247
`257
`310
`
`329
`356
`380
`
`412
`
`422
`
`435
`464
`495
`529
`555'
`589
`
`pm.‘ 5
`
`Radioisotope, in phflmuy and “amine
`
`.
`. .
`32 Fundamentals of Radioisotope: . . . . . . . . . . . .
`33 Medical Applications at Radioisatopes
`. . . . . . . . .
`
`605
`624
`
`'h°m°=°"“=-' “-1 "em-=' Aw
`M 6
`34 Diseases: Mamfesmflons and pmho_
`physiology................................
`35 Drug Absorption. Action and Disposition . , , .
`,
`,
`, ,
`as Basic Phormocoltinetics ........... . . . . . . .
`. . . .
`37 Clinic-alPhormocolrinetics... . .
`.
`. . . .
`. . . . . . .
`. ..
`38 Topical Drugs . . . . . . .
`. .
`. . . . . .
`.
`. . . . . . . .
`. . .
`. . .
`39 Gastrointestinal Drugs . . . . . . . . . .
`. . . . . . . . . . . . .
`40 Blood. Fluids. Electrolytes and Hematologic
`.
`.
`Drugs
`. . . . . . . . . . . . .
`.
`.
`. . . . .
`. .
`. .
`.
`. . . . . . . . .
`4‘! Cardiovascular Drugs
`. .
`. . . . . .
`.
`.
`.
`. .
`. . . . . . .
`. . .
`42 Respirator-yDrugs
`. . . .
`. ..
`43 Sympathomimetic Drugs . . . . . .
`. . . .
`. . .
`.
`. .
`
`. . . .
`
`.
`
`V
`
`655
`4597
`125
`746
`757
`774
`
`600
`631
`860
`B70
`
`xv
`
`889
`‘
`
`.
`
`.
`
`. . . . . . . . . .
`. . . . . . . .
`.
`44 Cholinomimetic Drugs . . . .
`45 Adrenergic and Aclrenergic Neuron Blocking
`, Dfugs ,,,,,,,,,,,_,.,,,,,,,,,,,.,,,_,,,_‘,,
`907
`46 Antimuscorinic and Antispasmodic Drugs
`. . . . . . .
`916
`47 1 5ke]e1g| Muscle Relaxants , , , , , , . . , . , , -,
`,
`, , , , ,
`929
`45 D[u|-efic Drugs
`, , , , _ . . _ _ .
`.
`. , . ,
`_ _ , , , , , , , , , , , _
`943
`49 Uterine and Antlmlgmlne Drugs
`. . . . . . . . . . . , , ,
`948
`50 Hormones . . . .
`. .
`. . . . . . . .
`. .-. . . . . . . . . . . . . . . . .
`1002
`51 Vitamins and Other Nutrients . . . . . . . . . . . . . . . . .
`1035
`52 Enzymes
`1039
`53 Genetolknesthetics.............. . .
`1048
`54 Local Anesthetics. . . . . .
`. . . .
`1057
`. . . . .
`. .
`. . . .
`55 sedatives and Hypnotics . . . . . . . . . .
`1072
`. . . . . ..
`. . . .
`56 Antlepileptics
`1082
`.
`. . . . . .
`. . . . . .
`. . .
`57 Psychopharmacologic Agents
`1097
`.
`. . . . . .
`. . . . . .
`55 Analgesics and Antipyreiics . . . . .
`1123
`59 Histamine and Antihistamines . . . . . . . . . .
`. . . . . .
`1132
`60 Central Nervous System Stimulants . . . . . .
`.
`. . . . .
`1136
`61 Anrineoplastic and lmmunosuppressive Drugs . . .
`1163
`62 Antimicrobial Drugs . . . . . . . .
`. . . . . . . . . .
`.
`.
`. . . . .
`1242
`63
`Porositicides . .
`. . .
`. . . . . . .
`. . . . .
`. . . . . . .
`. . . . . . .
`1249
`(:4 Pesticides . . .
`. . . . . . . . .
`. .
`.
`.
`. . . . . . . . . . . . . . . ..
`1272
`:55 Diagnostic Drugs
`. .
`. . . . . . . . . . . . .
`. . . . . .
`. . . . . .
`1286
`66 Pharmaceutical Necessities
`. . . . . .
`. . . .
`.
`.
`. . . . . .
`1330
`67 Adverse Drug Reactions .
`. . . . . . . . . . . .
`.
`.
`. . . . . .
`at}_Pi1armacogenetics............................1344
`69 Pharmacological Aspects of Drug Abuse .
`. . . . . . .
`1349
`70
`introduction of New Drugs
`.
`. . . . . . . . . . . . . . . . . .
`1365
`
`Biological Products
`
`Part 1
`_
`. . .
`. . .
`Principles oflmrnunoiogy . . . . . . .
`71
`72 immunizing Agents and Diagnostic Skin
`. . . .
`. . .
`Antigens . . . . . . . . . . . . . . . . . . .
`. . . . . . . .
`. . . .
`78 Allergenic Extracts . . . . . . . .
`. . . . . . . .
`. . . .
`. .
`74 Biotechnology and Drugs . .
`. . . . . . . . . . .
`.
`.
`. . . . .
`_
`
`.
`
`. . . . . .
`
`1379
`
`1369
`1405
`1416
`
`Ilart 6
`
`Pharmaceutical Preparations and Their
`Manufacture
`
`75 Preforrnulotlon . . . . . .'. . . . . . . . . . . . . . . . . . . . . . .
`76 Bioavailability and Bioequivalency Testing . . . . .
`TI Separation................................
`78 Sterilization . . . . . .
`. . . .
`. .
`79 Toniclty. Osmoticity, Osrnoiality and Osmolarity .
`80
`Plastic Packaging Materials
`.
`. . . . . . . . . . .
`.
`. . . . .
`51
`Stability of Pharmaceutical Products
`. . . . . .
`. . . . .
`
`. . . . . .
`. . .
`82 Quality Assurance and Control
`63 Solutions, Emulsions, Suspensions and
`. . .
`. . .
`Extractlves - - . -
`-
`-
`.
`.
`. - . -
`- - . . .
`.
`. . . . . . . .
`. . . . . .
`84 Parenteral Preparations . . . . . . . . . . . . . . .
`35
`intravenous Admixtures . . . . . . . . . . . . . . . . . . . . .
`
`. . . . . .
`
`1435
`1451
`1459
`1470
`1451
`1499
`1504
`
`1513
`
`1519
`1545
`1570
`
`1332
`fl2’;§i‘§l.:':lir'’;,‘:f§$i}Zl:2‘. : : : : 1 1 :3 1:: 1: : : : 3 : :2
`3?
`1615
`88 Powders . . . . . .
`. . . .
`. . . . . . . .
`.
`. . . . . . . . . . . . . . .
`1633
`B9 OraISol|dDosogeForn-is .
`. . . . .
`. . . . . . . . .
`. . . . ..
`166a
`90 Coating of Pharmaceutical Dosage Forms .
`. . . . . .
`1676
`91 Sustained-Release Drug Delivery Systems
`-
`- - - - -
`92 Ael'°5°'5----------------v---------------H 1594
`
`Pgff 9
`
`Fhgflnggeufigql P]-ggfige
`
`93 Ambulatory Patient Care . .
`94
`Institutional Patient Care .
`.
`95 Lang.TermCorei-'aciiities
`96 The Pharmacist and Public Health . .
`
`. . . . . . .
`.
`. . . . . .
`
`. . . . . .
`. . . .
`. .
`
`. . . . .
`. . . . .
`
`. . . .
`
`.
`
`.
`
`. . . . .
`
`1715
`1737
`1755
`1173
`
`|nnoPharma Exhibit 11060603
`
`

`

`. . . . . ..
`97 The Patient: Bahaviaralbeterminanrs . . .
`. . . . . .
`.
`93 Patient Communication . . . . . . .
`. . .. . . .
`. . . . . .
`.
`99 Drug Education . . .
`.
`. . .
`. . . .
`. . .
`. . .. . . .
`100 Patient Compliance
`. . .
`.
`. . . . . . . .
`. . . . . . . . . . . .
`101 The Prescription . . . .
`. . .
`. . . ._ . . .
`. . . .
`. . .
`. . . . .
`.
`.
`102 Drug interactions . .
`.
`. .
`.
`. . . . . . .
`. . . .
`. . .
`. . . . .
`.
`.
`103 Clinical Drug Literature .
`. . . . . . . . .
`. . . . . . . . . . .
`.
`104 Health Accessories
`.
`.
`. .
`. . . .
`. . . . .
`.
`.
`. . . . . . . . .
`.-
`
`1768
`1796
`1803
`1813
`1326
`1842
`1859
`1664
`
`.
`. . . . . . .
`.
`.
`. . . . . . . .
`.
`. .
`. . .
`106 Poison Control
`. . . . . . . .
`. .
`107 Laws Governing Pharmacy . . .
`103 Community Pharmacy Economics and
`. . . . .
`Management
`. .
`. .
`.
`.
`. . . . . . . . .
`.
`. . . .
`109 Dental Services . .
`.
`.
`-. . .'. . . . . . .
`., . . .
`. . . .
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`. ..
`. . .
`
`. . .
`. . .
`
`1905
`1914
`
`1940
`1957
`
`[ngex
`
`105 Surgical Supplies . .
`
`. . .
`
`.
`
`. . . . . . .
`
`. . . .
`
`. . . . . . . .
`
`. .
`
`1895'
`
`Alphabetic Index . . . . . . . . . . . .
`
`. . . .
`
`. .
`
`. . . . . . . .
`
`19157
`
`xvi
`
`|nnoPharma Exhibit 11060604
`
`

`

`1538
`
`CHAPTER 53
`
`pressure {eg, 3000 to 5000 psi} and than through the second
`stage at a greatly reduced pressure {eg, 1800 psi}. This
`breaks down any clusters formed in the first step.
`For szualbscale extemporeneous preparation of ernulu
`sions, the inexpensive bond homogenizer (available from
`Med Times) is particularly useful.
`it is probal>l3; the most
`efficient emulsifying apparatus available to the prescription
`pliarmaeist. The two phases, previously mixed in a bottle,
`are hand pumped through the apparatus. Recirculation of
`the emulsion through the apparatus will improve its quality.
`A honrogenizer does not incorporate air into the final
`product. stir may ruin an emulsion because the emulsifying
`agent is adsorbed preferentially at the airfvrater interface,
`followed by an irreversible precipitation termed denatm'izo~
`tion. This is particularly prone to occur with protein ernul«
`sifying agents.
`lriomogenisation may spoil an emulsion if the concentra-
`tion of the emulsifying agent in the formulation is less than
`that required to take care of the increase in surface area
`produced by the process.
`The temperature rise during homogenization is not Very
`large. However, temperature does play an important role in
`the ornulsifieation process. An increase in temperature will
`reduce the viscosity and, in certain instances, the iuterfaeial
`tension between the oil and the water. There are, however,
`many instances, particularly in the rnanufacturing of cos-
`metic creams and ointrnents, where the ingredients will fail
`to emulsify properly if they are processed at too high a
`eniperature. Emulsions of this type are processed first at
`an elevated temperature and than homogenised at e tern»
`zserature not exceeding 40”.
`Figure 83~il shows the flow through the homogenizing
`valve, the heart of the high-pressure APV Gaulin homoge«
`iser. The product enters the valve seat at high pressure,
`ores through the region between the valve and the seat at
`igb velocity with a rapid pressure drop and then is dis-
`charged as 3 homogenized product.
`It is postulated that
`circulation and turbulence are responsible mainly for the
`omogenisatiori that takes place. Different valve assem-
`lies, two stage valve assemblies and equipment with a wide
`range of capacities are available.
`The Macro Flow-Master Korn~l:£~n.ntor' employs a number
`of different actions, each of which takes the ingredients :1
`ittle further along in the process of subdividing droplets,
`until complete homogenization results.
`'I‘l1e machine is
`equipped with a pump which carries the liquid through the
`various stages of the process.
`In the first stage. the ingredi
`exits are forced between two specially designed rotors {gears}
`which shoot the liquid in opposite directions in a small
`ollaurbsr and, in this way, are mixed thoroughly. These
`rotors also set up a swirling action in the next chamber into
`
`
`
`Fig 33-6. Operation of the homogenizer value assembly {Courtesy
`APV Gauim}.
`
`which the liquid is forced and swirled hack and forth in
`eddies and orosscurrsnts. The second stage is a pulsing or
`vibrating action at rapid frequency. The product then
`leaves this chamber, goes through a small valve opening and
`is dashed against the wall of the homogenizing chamber.
`Pressure is applied, but it is not as great as that used in other
`types of homogenizers. Pressure is controlled accurately by
`adjusting devices on the front of the machine, and tempera-
`ture is controlled by passing eoolants through the stators.
`Ultrasonic Dc-vices-~—’I‘he preparation of emulsions by
`the use of ultrasonic vibrations also is possible. An oscilla-
`tor of high frequency (100 to 500 klla) is eonnectcd to two
`electrodes between which is placed a piezoelectric quarts
`plate. The quarts plate and electrodes are immersed in on
`oil bath and, when the oscillator is operating, high-frequency
`waves flow through the fluid. Emulsifioation is accom-
`plished by simply immersing a tube containing the emulsion
`ingredients into this oil bath. Considerable research has
`been done on ultrasonic emulsification, particularly with
`regard to the mechanism of emulsion formation by this
`me-thoszl. Limited data indicate that these devices will pro-
`duce stable emulsions only with liquids of low viscosity.
`The method is not practical, hoxvever, for large--scale produc-
`tion of ernulsions.
`Special techniques and equipment in certain instances,
`will produce superior emulsions, including rapid cooling,
`reduction in particle size or ultrasonic devices. A wide se-
`lection of equipment for processing both emulsions and sus-
`pensions has been described by Eisberg.” A number of
`improvements have been made to rualie the various process
`es more effective and energy-efficient.
`General methods are available for testing the instability of
`emulsions including bulk changes, centrifugal and ultracen-
`trifugal studies, dielectric nieasurernent, surface-area mea-
`surement and accelerated-motion studies.
`I.ow~shear rheo~
`logical studies measuring visooslasticity are suggested as the
`£)ptlII1alIlflSi1l1()(.l of stability testing.
`
`Suspensions
`The physical chemist defines the word “suspension” as a
`pm, and it is the preparations containing dispersed solids of
`two-phase system consisting of a finely divided solid dis-
`this magnitude or greater that are defined pharmaceutically
`as suspensions.
`persed in a solid. liquid or gas. The pharmacist accepts this
`Certain authors also include linlrnents, and the newer
`definition and can show that a variety of dosage forms fall
`sustained~rclease suspensions. in any discussion of this par»
`within the scope of the preceding statement. There is, how-
`ever, a reluctance to be sll—inclusive, and it is for this reason
`ticular subject. The former preparations now usually are
`that the main emphasis is placed on solids dispersed in
`considered as solutions although a number of older lini-
`ments were. in fact, suspensions. The sustaiued—rslease
`liquids.
`in addition, and because there is a need for more
`specific terminology, the pharmaceutical scientist differen-
`suspensions represent a very specialised class of preparation
`tiates between such preparations as suspensions, 1Tli}~:'.l;l1l‘8S,
`and, as such, are discussed in more detail in Chapter 91.
`magmas, gels and lotions.
`In a general sense, each of these
`Some injsoluhle drugs also are adzninister-ed in aerosol form;
`preparations represents a suspension, but the state of subdi-
`one example is dexernethasone phosphate suspended in a
`propellant mixture of iluoroclilorocarbons. More detail on
`vision of the insoluble solid varies from particles vehicle settle
`gradually on standing to particles Wlliifill are colloidal
`in
`aerosols is available in Chapter 92.
`nature. The lower limit of particle size is approximately 0.1
`Suspension formulation and control is based on the prin-
`
`|nnoPharma Exhibit 1106.0005
`
`

`

`S€}§..l}i1CJNS. EMULSFONS. 8USPENSiflNS AND EXT?’-‘u.AE}T!\.=’E3
`
`1539
`
`eiples outlined in Chapters 19 and 20. Formnlatioli imroltres
`more than suspending a solid in a liquid. A knowledge of
`the behavior of particles in liquids, of suspending agents and
`of flavors and colors is required to produce a satisfactory
`suspension.
`’
`~
`Briefly, the preparation of a stable suspension depends
`upon the appropriate dispersion of the drug in the suspend-
`ing medium. To ensure that the particles are trotted by the
`dispersion medium, a surfacsaetive agent should be used,
`especially if the dispersed phase is hydrophobic. The one
`pending ag set in the aqueous medium than can be added.
`Alternatively, the dry suspending agent can be mixed thor-
`oughly with the drug particles and then triturated with the
`diluent. Other approaches to suspension preparation Em
`clude the formation of a flocotilated suspension and also a
`flooculated preparation in a suspending vehicle. Details of
`these procedures are giseii in Chapter 19.
`The most efficient method of producing fine particles is by
`dry milling prior to susperzsion. Suspension equipment
`such as colloid mills or hoinogeiiisers normally are used in
`wet-milling finished suspensions to reduee particle agglom~
`erates. These machines (Fig 88-4} usually have a stator and
`a rotor whicli effects the dispersion action. Several methods
`of producing small urliform dry particles are 1”'i}i€1“£'}}1ILIlV€‘1‘li§a-
`tion fluid-energy grinding, spray-drying and controlled pre-
`cipitation with ultrasound as described by Nash?’
`The choice of an appropriate suspending agent depencls
`upon the use of the products {external or internal), facilities
`for preparation and the duration of storage.
`Preparations made extemporaneotssly for internal use
`riiay include, as suspending agents, acacia, metllylcellolose
`or other cellulose derivatives, sodium alginate or tragacanth.
`Extemporsoeons preparations of susgzvonsions for internal
`use showing good [low and suspending properties are provid
`ed by sodium carboxgsmethyloellulose 2.5%,
`tragacanth
`1.25% and gear gum 0.5%. Avioel R0591, s oepreoipitste of
`micro-crystalline cellulose and sodium carl1o:rymetli3rlcel1u-
`lose stabilized with hydroxypropyl rnethyloellulose, has
`been used as a suspencling vehicle for proprarrolol and or-
`phenadrine hydrochloride dispersions prepared from tab-
`lets.
`it also may serve as s general~pLtrpose suspending
`agent. Carlizopol ‘S84, 0.3% or greater, was s satisfaotory
`suspending agent for enlfametlissine 10%, maintaining a
`permanent suspension for more than 6 months.
`Agents suitable for external use include bentonite,
`methylcellulose or other cellulose derivatives, sodium algi«
`nets or trsgaoanth. Agents which may require high-speed
`equipment and which are suitable for internal or external
`use include aluroinum magnesium silicates and carbomer.“
`Preparations such as those merltioned above possess cer-
`tain advantages over other dosage forms. Some drugs ere
`insoluble in all acceptable media and, therefore, must be
`administered as a solid, nonsolotion dosage form itahlet,
`capsule, etc}, or as a suspension. Because of its liquid char-
`acter, the last preparation insures some t1i1iformii:y of dosage
`but does present some problems in maintaining a consistent
`dosage regimen. Disagreeahle tastes can be covered by us-
`ing a suspension of the drug or a derivative of the drug, an
`example of the latter being chloraztnplienicol palmitate.
`Suspensions plepared from ion-exehange resins containing
`an ionic drug can he used not only to minimise the taste of
`the drug but also to produce a prolongedection product,
`since the drug is exchanged slowly for other ions within the
`gastrointestinal tract.
`Suspensions also are ohemioally more stable than solu-
`tions. This particularly is important with certain antibiot-
`ics, end the pharmaoist often is called on to prepare such a
`suspension just prior to dispensing the medication.
`In midi»
`tion, a suspension is an ideal -dosage form for patients who
`have difficulty swallowing tablets or capsules, which is per»
`
`ticularl;-; important in adiriiriisterilig drugs to children. M:
`alternate nicthod to enhaxiee compliance ineltides 1",lavo2'ecl
`njrstatin ‘”popsio}es” which can be prepared liy freesiiig a
`suspension of the drug so that the taste is improved during
`the treaimeiit of oral caodidiaeis.
`
`Suspensions should possess certain basic properties. The
`dispersed phase should settle slowly arid lie redisperssd
`readily on slialring. They should not cake on settling and
`the Viscosity should be such that the preparation pours east
`ly. As with all dosage forms, there should be no question as
`to the chemical stability of the suspension. appropriate
`preserratises should be incorporated in order to rnioimiae
`rnioroliiologieal oontaminetion. The suspension must be
`acceptalz-lo to the patient on the basis of its taste, color and
`oosmetio qualities {elegance}, the latter two factors being of
`particular importance in preparations inietsded for e:-rternal
`use.
`
`Gets
`
`Pliarmacemiioal terminologjs; is, at best, confusing and no
`two authors will olassify gels, jellies, magmas, milks and
`mixtures in the same way. Title N1?‘ clesorilzed Gels as a
`special -::lass of pi1arrneoeu1;ieal preparations but eorisiaclerecl
`Jellies under the same heading. The latter preparations
`usually contain water-soluble active ir1gre<.lie1':ts and, there
`force, are considered in another part of this chapter. The
`USP definition for Gels is
`
`Gels are semisolid sggstems of either suspensioxis made up of small
`inorganic part.ioles or large organic: zmolecules interpetaeiraied by a li(;~
`uid.
`‘l9‘¢'i‘1ere {lie gel mass consists oi‘ :1 network of small discrete partirziesa.
`the gel is classified as a two~ohase .~’3}.‘:'stem icg, ;’~.lu:nizmm Hydroxide
`Gel}.
`in a two-phase systein, if the particle size of the <lis::se1'se<l phase is
`relatively large, the gel mass sometimes is roferrertl to as a magma (egg
`Beotonite llflagmal. Efiotii gels and imagines mag; lie tlilxotropie, forming»:
`semisolicls on Standing and i3e(‘.{:3‘niT";g Eirmici rm agitation.
`‘Hwy shmlld
`be shaken before use to ensure l1o:m;»gc11eit_~3 and sliould be labeled to
`that effect.
`Single-pliase gels Consist of orgemio maorozuolerulos distrilmted uni-
`formly tlorougliout E1 liquid in see}: a manner that no aopsrezsl. loomed»
`mics exist between the dispersed macromolecules and the liquid. Sinv
`gie-phase may he made {torn syritlietic tnaeroziioleeulus (cg, CaI‘i.?£?i}‘£t31‘,l
`or from normal gisxns (veg, Tragararrrtllzl. The latter preparations also are
`called lmacilag-as.
`rliilumgli these gels are mm111o11l}.= aqueous, alcohol
`and oils may he used as the coritiriuous phase. For example, mineral oil
`can be eornbinerl with e i}0i§.'etli§.'l3!1i': resin to form an oleaginoos oint-
`Ineni: base.
`
`The USP states that each 100 g of Aluminum Hydroxide
`Gel contains the equivalent of not less than 3.6 and not more
`than 4.4 g of aluminum oxide (331303), in the form of aIumi~
`non: hydroxide and hydratetil oxide, an-rl it Illa}? oontain
`varying quantities of basic aluminum oarbonate and bicar-
`bonate. The gel itself usually is prepared by the irtteraetioo
`of a soluble aluminum salt, such as a chloride or sulfate, with
`ammonia solution, sodium carbonate or liisarlionate. The
`reactions which occur during the preparation are
`
`scof“ + 33,0 —-»— 3:100,“ + sore“
`
`[A1(H3{}).,}3" + 301%“ —-» {a1(n._,0),,(oH},,1 + ergo
`
`2HCo,,f «r 0053"“ + 11,0 + so,
`
`The physical and ehernieel properties of the gel will be af~
`footed by the order of addition of reactants, pH of precipita-
`tion, temperature ofprecipitatioo, eoncentretisz-n of the reac-
`tants, the reactants used and the vCOI'.t(iil;i£)I1S of aging oi‘ the
`precipitated gel.
`Alomirium Hydroxide Gel is soluble in acidic {or very
`strongly basic) media. The mechanism in acidic media is
`
`Aluminum Hydoxidc Gel + SHQG we [Al{lig0l;;lQH)3]‘}
`[Al{Hg{3}3l0 + H304} W {:‘al(H2Ul_§(QH)3l+ + H30
`
`|nnoPharma Exhibit 1106.0006
`
`

`

`CHAPTER 84
`
`Parenteral Preparations
`
`Kenneth E Avls, D5:
`Emeritus Professor. Pharmaceutics
`College of Pharmacy
`University of Tennessee. Memphis
`The Health Science Center
`Memphis. TN 36163
`
`Dosage forms of drugs are designed to make it possible to
`introduce a drug into the body of a human or animal patient.
`Since the well-being, or even the life, of the patient may be
`affected, the dosage form must be designed and prepared in
`a manner intended to promote the safety of the patient.
`Concurrently, it is essential that the dosage form compli-
`ment or enhance the therapeutic effectiveness of the drug.
`Parenteral (Gk, pom enteron = beside the intestine) is the
`route of administration of drugs by injection under or
`through one or more layers of the skin or mucous mem-
`branes. Since this route circumvents these highly efficient
`protective barriers of the human body, exceptional purity of
`the dosage i‘orm_must be achieved. The processes used in
`preparing it must embody good manufacturing practices
`that will produce and maintain the required quality of the
`product. New developments in process technology and
`quality control should be adopted as soon as their value and
`reliability have been established as a means for further im-
`proving the quality of the product.
`
`T Hist;-iii ‘
`
`One of the most significant events in the beginnings of
`parenteral therapy was the first recorded injection of drugs
`into the veins of living animals, in about 1657, by the archi-
`tect Sir Christopher Wren. From such a very crude begin-
`ning, the technique for intravenous injection and knowledge
`of the implications thereof developed slowly during the next
`century and a half.
`In 1855 Dr Alexander Wood of Edin-
`burgh described what was probably the first subcutaneous
`injection of drugs for therapeutic purposes using a true by-
`podermic 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), Stanis-
`laua Limousin was developing a suitable container, the all-
`glass ampul.
`In the middle 19205 Dr Florence Seibert pro-
`vided proof that the disturbing chills and fever which often
`followed the intravenous injection of drugs was caused by
`patent 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 prepara-
`tion of parenteral dosage forms, the two that have probably
`contributed most are the development of I-IEPA-filtered
`laminar airflow and the development of membrane microfil-
`tration for solutions; The former made it possible ‘to
`achieve ultraclean environmental conditions for processing
`sterile products, and the latter made itpossible to remove
`from solutions by filtration both viable and nonviable parti-
`
`cles of microbial size and smaller. However, many other
`developments in recent years have produced an impressive
`advance in the technology associated with the safe and rob;
`able preparation of parenteral dosage forms. The following
`list identifies a few of the events which have contributed to
`that development.
`1926—Pa1-enterals were accepted for inclusion in the fifth
`edition of the National Farmulary.
`l933—The practical application of freeze-drying to clinical
`materials was accomplished by a team of scientists at
`the University of Pennsylvania.
`.1938--The Food, Drug and Cosmetic Act was passed by
`Congress, establishing the Food and Drug Adminis-
`tration (FDA).
`1944--The sterilant ethylene oxide was discovered.
`1946--The Parenteral Drug Association was organized.
`1961—'I‘he concept of laminar airflow was developed by WJ
`Whitfield.
`1962—The FDA was authorized by Congress to establish
`current good manufacturing practices (CGMP) regu-
`lations.
`-
`1965—Tota1 parenteral nutrition [TPNJ was developed by
`SJ Dudrick.
`1972-The Limulus Amebocyte Lysatc test for pyrogens in
`parenteral products was developed by JF Cooper.
`
`Administration
`
`Injections may be classified in five general categories:
`1. 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.
`,
`5. Emulsions.
`
`These injections may be administered by such routes as
`intravenous, subcutaneous, intradermal, intramuscular, in-
`traarticular and intrathecal. The nature of the product will
`determine the particular route of administration that may
`be employed. Conversely, the desired route of administra-
`tion will place requirements on the formulation. For exam-
`ple, 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 require strict attention to tonicity adjustment, oth-
`erwise irritation of the plentiful supply of nerve endings in
`this anatomical area would give-rise to pronounced pain.
`Injections intended for intraocular, intraspinal, intracister-
`nsl and intrathecal administration require the highest puri-
`ty standards because of the sensitivity of nerve tissue to
`irritant and toxic substances.
`When compared with other dosage forms, injections pos-
`sess select advantages.
`If immediate physiological action is
`
`1545
`
`|nnoPharma Exhibit 1106.060?
`
`

`

`1546
`
`CHAPTER 84
`
`needed from a drug, it usually can be provided by the intra-
`venous injection of an aqueous solution. Modification of
`the formulation 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 controlled more readily by
`parenteral administration since the irregularities of intesti-
`nal absorption are circumvented. Also, since the drug nor-
`mally is administered by a professionally trained person, it
`confidently may be expected that the dose was actually and
`accurately administered. Drugs can be administered paren-
`terally when they cannot be given orally because of the
`unconscious or uncooperative state of the patient, or because
`of inactivation or lack of absorption in the intestinal tract.
`Among the disadvantages of this dosage form are the re-
`quirement 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 lattersituation, unless a direct pharmacologi-
`cal antagonist is immediately available, correction of an er-
`ror 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 frequently will seek to reduce this
`by combining more than one drug in one injection. This is
`encountered most commonly when therapeutic agents are
`added to large-volume solutions of electrolytes or nutrients,
`commonly called “IV additives,” during intravenous admin-
`istration. Since these are aqueous solutions, there is a high
`potential for chemical and physical interactions. See Chap-
`ter 85. The pharmacist is the professional best qualified to
`cope with these incompatibilities. However, in the past,
`these have been handled largely at the patient’s bedside by
`the nurse and physician. Only recently has it been recog-
`nized that this professional area is the proper function of a.
`pharmacist and has been so stated by the Joint Commission
`on Accreditation of Hospitals.”-3
`As pharmacists have assumed increasing responsibility in
`this area, awareness has developed gradually 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.
`The development of a precipitate or a color change when
`preparations are combined is an immediate