2 0 TH EDITION
`
`Remington: The
`Science and
`Practice
`of Pharmacy
`
`ALFONSO R GENNARO
`Chairman of the Editorial Board
`and Editor
`
`ALVOGEN, Exh. 1050, p. 0001
`
`

`

`Editor: Daniel Limmer
`Managing Editor: Matthew J. Hauber
`Marketing Manager: Anne Smith
`
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`otherwise) for any injury resulting from any material contained herein. This
`publication contains information relating to general principles of medical care
`which should not be construed as specific instructions for individual patients.
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`current information, including contraindications, dosages and precautions.
`
`Printed in the United States of America
`
`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 the Joseph P Remington Estate
`
`Copyright 1948, 1951, by the Philadelphia College of Pharmacy and Science
`
`Copyright 1956, 1960, 1965, 1970, 1975, 1980, 1985, 1990, 1995, by the Phila(cid:173)
`delphia College of Pharmacy and Science
`
`Copyright 2000, by the University of the Sciences in Philadelphia
`
`All R ights Reserved
`Library of Congress Catalog Card Information is available
`ISBN 0-683-3064 72
`
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`material. If they have inadvertently overlooked any, they will be pleased to make
`the necessary arrangements at the first opportunity.
`
`The use of structural formulas from USAN and the USP Dictionary of Drug
`Names is by permission of The USP Convention. The Convention is not respon(cid:173)
`sible for any inaccuracy contained herein.
`Notice-This text is not intended to represent, nor shall it be interpreted to be, the
`equivalent of or a substitute for the official United States Pharmacopeia (USP)
`and/or the National Formulary (NF). In the event of any difference or discrep(cid:173)
`ancy between the current official USP or NF standards of strength, quality,
`purity, packaging a1id labeling for drugs and representations of them herein, the
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`
`00 01 02 03 04
`1 2345678 910
`
`ALVOGEN, Exh. 1050, p. 0002
`
`

`

`Table of Contents
`
`Part 1 Orientation
`
`1 Scope of Pharmacy . . . . . . . . . . . . . . . . . . . . . . . .
`2 Evolurion of Pharmacy . . . . . . . . • • . . . . . . . . . . . .
`J Erhics and Professionalism . . . . . . . . . . . . . . . . . . . .
`4 The Procrice of Communiry Pharmacy . . . . . . . . . . .
`5 Phormocim in lndusrry . . . . . . . . . . . . . . . . . . . . . .
`6 Phormocisrs in Governmenr . . . . . . . . . . . . . . . . . .
`7 PhormociSIS and Public Heolrh . . . . . . . . . . . . . . . . .
`8 lnformorion Resources in Pharmacy and rhe
`Pharmaceutical Sciences. . . . . . . . . . . . . . . . . . . . .
`9 Clinical Drug Uterorure . . . . . . . . . . . . . . . . . . . . . .
`10 Research. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`Part 2 Pharmoc• utlcs
`
`11 Pharmaceutical Calculations . . . . . . . . . . . . . . . . . .
`12 5rotistics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`1 J Nloleculor Srrucrure, Properties, and 5rores of NlotTer. . .
`14 Complex Formation. . . . . . . . . . . . . . . . . . . . . . . .
`15 Thermodynamics . . . . . . . . . . . . . . . . . . . . . . . . . .
`16 Solutions and Phase Equilibria . . . . . . . . . . . . . . . . .
`17 Ionic Solutions and Elecrrolyric Equilibria . . . . . . . . . .
`18 Toniciry, Osmoriciry, Osmololiry, and Osmoloriry....
`19 Chemical Kinetics . . . . . . . . . . . . . . . . . . . . . . . . .
`20 lnterfoclol Phenomena . . . . . . . . . . . . . . . . . . . . . .
`21 Colloidal Dispersions. . . . . . . • . . . . . . . . . • . . . . . .
`22 Coarse Dispersions . . . . . . . . • . . . . . . . . . • . . . . . .
`2J Rheology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`Part ~ Pharmac•utlcal Ch• mlstry
`
`24 Inorganic Phormaceurical Chemistry . . . . . . . . . . . .
`25 Organic Pharmoceuricol Chemistry . . . . . . . . . . . . .
`26 Narurol Producrs. . . . . . . . . . . . . . . . . . . . . . . . . . .
`27 Drug Nomenclarure-Unlred 5rares Adopted
`Names ... ..... .............. . .... . .....
`28 5rrucrure-Activiry l\elotionshlp and Drug Design . . . . .
`29 Fundomenrols of Rodionuclides . . . . . . . . . . . . . . .
`
`Part 4 Pharmaceutical T•stlng, Analysis and Control
`
`JO Analysis of Medicinals. . . . . . . . . . . . . . . . . . . . . . .
`J1 13iologicol Testing . . . . . . . . . . . . . . . . . . . . . . . . .
`J2 Clinical Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . .
`JJ Chromorogrophy . . . . . . . . . . . . . . . . . . . . . . . . . .
`J4 lnsrrumenrol Merhods of Analysis . . . . . . . . . . • . . . .
`JS Dissolution . . . . . . . . . . . . . . . .
`. . . . . . . . . . . . . .
`
`Part 5 Pharmaceutical Manufacturing
`
`J6 Sepororion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`J7 Powders .............•....•.............
`J8 Preformulorion ........................... .
`J9 Solutions, Emulsions, Suspensions, ond Exnocrs . . . . .
`40 5terilizarion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`41 Parenreral Preporotions . . . . . . . . . . . . . . . . . . . . .
`42 lnrrovenous Admixrures .................... .
`4J Ophrholm ic Prepararions . . . . . . . • . . . . . . . . . . . .
`44 Medicored Toplcols . . . . . . . . . . . . . . . . . . . . . . . .
`45 Oral Solid Dosoge Forms ........ .. ......... .
`46 (oaring of Phormoceuricol Dosoge Forms . . . . . • . .
`47 Conrrolled-Releose Drug-Delivery 5ysrems .....•..
`48 The lnrroduction of New Drugs . . . . . . . . . . . . . . . .
`
`J
`7
`19
`28
`JJ
`J8
`4 7
`
`60
`70
`81
`
`91
`1 24
`159
`18J
`198
`208
`227
`246
`26J
`27 5
`288
`J16
`JJS
`
`J59
`J85
`409
`
`441
`458
`469
`
`485
`540
`552
`58 7
`614
`654
`
`669
`681
`700
`721
`75J
`780
`807
`821
`8J6
`858
`894
`90J
`9JO
`
`49 13iotechnology and Drugs ................... .
`50 Aerosols . . . . . . . . . . . . . . . . . . . . . . . . • . . . . . . .
`51 Quoliry Assurance and Conrrol . . . . . . . . . . . . . .. .
`52 Srobiliry of Pharmaceutical Producrs .......... .. .
`SJ moovoilobillry and l3ioequ1volency Testing ....... .
`54 Plastic Packaging Moreriols .................. .
`55 Pharmaceutical Necessities . . . . . . . . . . . . . . . . .. .
`
`Part 6 Pharmacodynamlcs
`
`56 Diseases: Nlonifesrorlons and Porhophysiology
`57 Drug Absorprion, Acrion. and Disposirion ...... .. .
`58 13osic Phormocokinetics. . . . . . . . . . . . . . . . . . ... .
`59 Clinical Phormocokinerics . . . . . . . . . . . . . • . . ... .
`60 Principles of Immunology . . . • . . . . . . . . . . . . . . . .
`61 Adverse Drug l\eocrions ....•..............•.
`62 Phormocogenerics .......................•.
`6J Pharmacological Aspecrs of Subsronce Abuse ..... .
`
`Part 7 Pharmac• utlcal and Medlclnal Agents
`
`64 Diagnostic Drugs and Reagenrs ............... .
`65 Topical Drugs ............................ .
`66 Gasrrointestlnol and liver Drugs . . . . . . . . . . . . . . ..
`6 7 131ood, Fluids, Electrolytes, and Hemorologicol Drugs. . ..
`68 Cardiovascular Drugs ...................... .
`69 Respirotory Drugs. . . . . . . . . . . . . . . . . . . . . ....•
`70 Symporhomlmeric Drugs ................... .
`71 Cholinomimetic Drugs ..................... .
`72 Adrenergic and Adrenergic Neuron 131ocking Drugs . .
`7J Anrimuscorinic and Anrisposmodic Drugs ........ .
`7 4 Skeletal Muscle l\eloxonrs . . . . . . . . . . . . . . . . . . .•
`7 5 Diuretic Prugs . . . . . . . . . . . . . . . . . . . . . . . . . . ..
`76 Urerine and Antimigroine Drugs .............. .
`77 Hormones and Hormone Anrogonlsrs .......... .
`7 8 Generol Aneslhetics . . . . . . . . . . . . . . . . . . . . . . . .
`79 Local Anesrhetics ......................... .
`80 Sedative and Hypnotic Drugs . . . • . . . . . . . . . . . . .
`81 Antiepileptic Drugs . . . . . . . . . . . . . . . . • . . . . . . . .
`82 Psychopharmocologic Agenrs ................ .
`BJ Analgesic, Antipyretic, and Anri-lnflommotory
`Drugs ................................. .
`84 H1sromine and Antihisromlnic Drugs ............ .
`85 Cenrrol Nervous System Stimulonrs ............. .
`86 Anrineoplasric and lmmunoacrive Drugs . . . . .... .
`87 Anri-lnfecrives ............... . ........... .
`88 Porositicides ....... . ..................... .
`89 Immunizing Agenrs and Allergenic Exrrocrs ...... .
`
`944
`96J
`980
`986
`995
`1005
`1015
`
`105J
`1098
`1127
`1145
`1156
`1165
`1169
`1175
`
`1185
`1'200
`1219
`124J
`1274
`1297
`1J05
`1J14
`1J22
`1J28
`1JJJ
`1J44
`1J54
`1J58
`1J95
`1400
`1407
`1421
`1429
`
`1444
`1464
`1471
`1477
`1507
`1562
`1567
`
`Part 8 Pharmacy Practice
`
`Pan 8A Pharmacy Administration
`
`90 Lows Governing Pharmacy ... . ... .... ...... .
`91 Pharmocoeconomics ....... ... ... ... ...... .
`92 Marketing Pharmoceuticol Core Services ........ .
`9J Documenrlng and 13illing for Pharm aceutical Core
`Services ....................... . ....... .
`94 Communiry Pharmacy Economics and
`Management . ...... ..... . .. ... .. ... .. .•.
`95 Producr Recalls and Withdrawals ............. .
`
`1595
`1625
`16J4
`
`1640
`
`1650
`1666
`
`Part 8D Fundamentals of Pharmacy Practlc•
`
`96 Drug Education . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`1677
`
`xiv
`
`ALVOGEN, Exh. 1050, p. 0003
`
`

`

`97 The Prescriprion . . . . . . . . . . . . . . . . . . . . . . . . . ..
`98 Extemporaneous Prescriprion Compounding ..... .
`99 Poison Conrrol
`. . . . . . . . . . . . . . . . . . . . . . . . . . .
`100 Nurririon in Pharmacy Procrice ..... . . . ....... .
`101 Self-Core/Diognosric Producrs ................. .
`102 Drug lnrerocrions . . . . . . . . . . . . . . . . . . . . . . . . ..
`1 OJ Complemenrory and Alrernorive Medical Heolrh
`Core .................................. .
`104 Nuclear Pharmacy Practice ...•..............
`105 Enzymes
`. . ......... . .......... . . . ..... .
`106 Viromins and Orher Nurrienrs ...... . ......... .
`1 07 Pesricides . . . . . . . . . . . . . . . . . . . . . . . . . . .... .
`1 08 Surgical Supplies . . . . . . . . . . . . . . . . . . . . . . . . . .
`1 09 Heolrh Accessories . . . . . . . . . . . . . . . . . . . . . . . . .
`
`1687
`1706
`1716
`1725
`17J8
`1746
`
`1762
`1781
`1792
`1796
`1825
`1846
`1857
`
`Part 8C Patl•nt Car•
`
`110 Ambulorory Porienr Core ................... .
`111 lnstirurionol Porienr Core ................... .
`112 Long-Term Core Focilirles ................... .
`
`189J
`1911
`19J2
`
`11 J The Porienr: Oehoviorol Dererminonrs . . . . . ..... .
`114 Porienr Communicorion . . . . . . . . . . . . . . . ..... .
`. . . . . . . . . . . . . . . . . . . . . ..
`115 Porienr Compliance
`116 Phormocoepidemiology . . . . .
`. ............ .
`117 lnregrored Heolrh-Core Delivery Sysrems ........ .
`118 Home Heolrh Porienr Core
`. . . . . . . . .
`.
`. . . . . .
`11 9 Aseptic Technology for Home-Core
`Phormoceuricals . . . . . . . . . . . . . . . . . . ....... .
`
`1948
`1957
`1966
`1980
`1990
`2012
`
`2020
`
`App•ndlxes
`
`Dose Equivolenrs . . . . . . . . . . . . . . . . . . . . . . . . . .
`Periodic Chorr . . . . . . . . . . . . . . . . . . . . . . . . . .. .
`Logorirhms ............................. .
`
`20JJ
`20J4
`20J6
`
`Glossary and Index
`
`Glossory ..... . ......................... .
`Index ................................. .
`
`20J7
`20J9
`
`xv
`
`ALVOGEN, Exh. 1050, p. 0004
`
`

`

`462
`
`CHAPTER 28
`
`terminus of tyrosinyl-t-RNA
`30
`
`after puromycin is taken up, it blocks the subsequent protein
`synthesis.
`The isost eric replacement of ester groups does not a lways
`produce compounds with significant biological activity, as the
`modifica tion of acetylcholine ester (3) with an amide function
`resul ted in the amide analog (31)
`
`0
`I
`Cli3c NHtc19,N'tcH313
`
`c1-
`
`amide analog of acetylcholine
`31
`
`that does not show significant agonist or antagonist activity.
`One of the oldest nonclassic isosteric replacements that pro(cid:173)
`vided an important class of antibacterial agents was the re(cid:173)
`placement of carboxylic acid group of p-aminobenzoic acid
`CPABA, 32)
`
`H1N-o-COOH
`
`p-aminobenzolc acid
`32
`
`sulfanilamlde
`33
`
`with a sulfonamide group to give sulfanilamide (33).
`A final illustration of bioisosteric replacement in drug de(cid:173)
`sign is the replacement of the thiourea functiona l group of
`metiamide (34),
`
`X = S, metiamlde
`34
`X = NCN, cimetidlne
`35
`
`a hist amine H 2-blocker, with the cyanoguanidine group to pro(cid:173)
`duce the drug cimetidine (35). This bioisosteric replacement
`overcame the granulocytopenia toxicity that had been observed
`with metiamide, thus producing the popular antiulcer drug
`cimetidine.
`
`Stereochemistry
`
`An important consideration in drug- receptor interactions is
`the stereochemistry of the drug and the proper positioning of
`functional groups so that they will interact optimally with an
`enzyme or receptor . Four types of isomeric drugs will be con(cid:173)
`sidered: positional isomers, geometrical isomers, optical iso(cid:173)
`mers, and diastereomers.
`With positional, or constitutional, isomers the compounds
`have the same empirica l formula but the atoms of the molecule
`are rearranged in a different order. To illustrate positional
`isomers, one can consider the rela tionship of pentoba rbit al (36)
`
`H
`
`o~(~l~o
`Cli3CHz~NH
`tCH,lrCHCHrCHz
`II
`0
`amobarbital
`37
`
`pentobarbital
`36
`
`and amobarbital (37), both of which belong to the barbiturate
`family. These positional isomers differ only in the makeup of
`the 5-carbon side chain attached to the barbiturate ring sys(cid:173)
`tem. The former compound has a short duration of action while
`the latter has an intermediate duration of action.
`Another example of positional isomers is N -(tert-butvl 1-
`norepinephrine (38)
`·
`
`HO
`
`HO~CHzNHCICH313
`
`OH
`
`HO
`
`9-~CH2"HC(CH,J,
`
`HO
`
`N-tertiary-butyl norepinephrlne
`38
`
`terbutaline
`39
`
`and terbutaline (39). The resorcinol portion of 39 has served
`as a biologically effective replacement of the catechol group
`in 38. The resorcinol a nalog (39), in contrast to the catechol
`(38), is not a substrate for catechol-0-methyltransferase
`<COMT), a n im porta nt metabolic enzyme; therefore, it has a
`longer duration of action. Terbutaline is a usefu l selective
`132-adrene rgic stimu la nt for the treatment of bronchial
`asthma a nd related conditions, a nd it can be a dministered
`orally.
`Geometrical isomers are a nother important set of mole(cid:173)
`cules in which a possible differe nce in biological activi ty
`between isomers may exist. The trans, or E , isomer oftripro(cid:173)
`lidine (40)
`
`(trans or £-isomer)
`triprolldine
`40
`
`(els or Z-isomer)
`triprolidine
`41
`
`is over 1000 times as potent as the cis, or Z , isomer (41 ) as a
`H 1-histamine antagonist. Another example of a set of geomet(cid:173)
`rical isomers is the cis and trans-2-acetoxycyclopropyltrimethyl
`ammonium iodides (42 and 43),
`
`>6<
`
`CH3CO
`~
`
`N (~l3
`•1e
`
`(cis-1somer) (Z)
`cis·2-acetoxycyclopropyltrimethyl ammonium iodide
`42
`
`.ie
`~IC1i,J3
`CH3i°
`H
`
`0
`
`(trans-isomer) (£)
`rrans-2-acetoxycyclopropyltrimelhyl ammonium iodide
`43
`
`respectively. The trans isomer is much more potent as a mus(cid:173)
`carinic agonist than the cis isomer and also is a good substrate
`for the enzyme acetylcholinesterase.
`The term absolute configuration refers to the arrangement
`of atoms in space of a chiral compound. In a number of in(cid:173)
`sta nces there is a distinct difference in biological activity of the
`optical isomers (enantiomer s). For example, the RC - ) isomer of
`epinephrine (44)
`
`ALVOGEN, Exh. 1050, p. 0005
`
`

`

`'*" -~-----. '*" -~-----.
`.
`
`.. ~-----.
`
`·-
`
`II
`
`O!i
`
`NH
`I ··-.,
`CH3
`
`'•,
`B
`
`R (-)Isomer
`
`HO
`
`H
`
`NH
`2
`I '•.,
`CH3
`
`c
`
`B
`
`H
`
`H
`
`N~
`I 2 ·-.
`• c
`CH
`3
`
`B
`
`S (+)Isomer
`epinephrine
`epinephrine
`eplnlne
`45
`46
`44
`ii more potent on both a- and {:l-adrenergic receptors than the
`8( +) isomer ( 45). The binding of the isomer s of epinephrine and
`epinine (46) (the desoxy analog of epinephrine) is illustrated.
`'ftle three points of binding on the receptor are the catechol
`binding site {A), hydroxy binding site (8 ), and anionic binding
`lite <C).
`According to the Easson-Stedman theory,1' the relative or(cid:173)
`der of activity of the isomers on adrenergic receptors ar e
`B > S - deoxy. Only the R isomer can bind to all three sites,
`whereas both the S isomer and the deoxy isomer, which show
`limilar activity, can bind only to two of the sites. Refer to
`Chapter 13 for a discussion of isomerism.
`Although enantiomers have the same chemical and physical
`properties, except for the direction of rotation of polarized light,
`diastereomers have different physical properties. Diaste(cid:173)
`reomers are compounds with two or more chir al centers. While
`lR,28( - )-ephedrine ( 4 7)
`H~CH3NHCHJ
`0
`
`H
`
`OH
`
`1R,2S (- }-ephedrine
`1R,2R ( - )-olr-ephedrine
`47
`48
`baa direct activity on both a- a nd {:l-adrenergic receptors, the
`1R,2R ( - )-I/I-ephedrine ( 48) shows a-adrenergic blocking activ(cid:173)
`ity. Both diastereomers show indirect adrenergic activity.
`An important strategy often used in drug design is to take a
`conformationally flexible molecule and to convert it into a con(cid:173)
`fonnationally rigid molecule in order to find the optimum con(cid:173)
`fonnation for binding to a drug receptor. This approach may be
`used to introduce selectivity for receptors, eliminate undesired
`llide effects, and learn about the spatial relationships of func(cid:173)
`tional groups for receptors.
`Dopamine (49A)
`
`A
`
`,&:
`H*H
`
`H
`6•60•
`e
`
`0
`
`,&,"
`H$~
`
`NH2
`6 •1BO•
`c
`
`dopamine
`49
`~ exist in an infinite number of conformations about the
`•de-chain carbon-carbon bond. 'l\vo such conformations are
`
`STRUCTURE-ACTIVITY RELATIONSHIP AND DRUG DESIGN
`
`463
`
`illustrated (8 = 60° gauche and 8 = 180° trans conformation
`(49B and C)].
`Apomorphine (50)
`
`apomorphlne
`50
`
`o , agonlst
`51
`
`and 6,7-dihydroxy-2-aminotetralin (ADTN) (52)
`
`: :©ONH
`
`2
`
`6, 7-dihydroxy-2-aminotetralln (ADTN)
`52
`
`are two potent dopamine D1 and D2 agonists that exist in the
`trans conformation, whereas the selective D 1 agonist SKF
`38393 (51) does not exist in a similar conformation. Apomor(cid:173)
`phine, a conformationally rigid molecule, can bind to dopamine
`receptors.
`In other instances, a drug molecule may need conforma(cid:173)
`tional flexibility for proper binding to the receptor to produce
`biological activity in an induced-fit receptor model. Thus, con(cid:173)
`formational flexibility may in some instances be a prerequisite
`for drug agonist activity.
`
`Ionization
`
`Many of the substances used as drugs are weak acids or weak
`bases. Therefore, an important question is whether the charged
`or unch arged form of the drug binds to the receptor . Also of
`importance is the degree of ionization and the effect ionization
`may have upon a bsorption and distribution. In general, the
`ionization can be demonstrated as
`
`[Weak Acidsl
`
`AH
`( nonionized drug)
`
`[Weak Basesl
`
`BH•
`(ionized drug)
`
`;:::
`
`;::: A-+ W
`(ionized drug)
`B + W
`(nonionized drug)
`
`It is very difficult to know which molecular form of the drug is
`active if the charged and uncharged form of a drug is in equi(cid:173)
`librium in physiological solution; for example, with dopamine
`the pK,. of the amine is - 10. Thus, although most of the drug
`in solution is in the ionized form (49D), the un-ionized form of
`the drug molecule still may be the active form.
`The quaternary salt of dopamine (53)
`
`HO~ e JB ~NlCH3)3
`
`quaternary salt of dopamine
`53
`
`has been prepared and exhibits agonist activity on D2-
`receptors, indicating that the ionized form of the drug is a n
`active molecular species. However , it is almost impossible to
`determine if a primary, secondary, or tertiary amine is active
`as the un-ionized form of t he drug because these amines are
`always in equilibrium under physiological conditions.
`It has been shown that the permanently charged dimethyl(cid:173)
`sulfonium analog (54)
`
`ALVOGEN, Exh. 1050, p. 0006
`
`

`

`702
`
`CHAPTER 38
`
`p
`I, II, Ill
`
`+
`
`Table 38-1 . List of Symbols
`SYMBOL
`MEANING
`Amorphous solid state as left subscript designation
`a
`}'.
`Surface of solid state as right subscript designation
`Defective region of solid state as left subscript
`6
`designation
`Density
`Crystalline polymorphic forms of t he solid state as left
`subscript designation
`Positively charged, cationic species as superscript
`designation
`Negatively charged, anionic species as superscript
`designation
`Uncharged, free species as superscript designation
`Active ingredient in the solid state
`Dissolved form of the active ingredient
`Surface of active ingredient of charge i and solid state j
`Reactant of A in the solid state
`Dissolved form of reactant
`Saturation concentration
`Monohydrate as left subscript designation
`Anhydrous as left subscript designation
`n-Hydrate as left subscript designation
`Reduced water content as left subscript designation
`Increased water content as left subscript designation
`Mass
`Negatively charged anionic counterion
`Charge on the active ingredient as superscript
`designation
`Solid state form of t he active ingredient as left
`subscript designation
`Dissolution rate constant
`Recrystallization rate constant
`Permeability
`Positively charged cationic counterion
`Surface area
`
`O
`A
`a
`1 A~
`B
`b
`C5
`h
`Oh
`nh
`<h
`> h
`m
`An-
`
`j
`
`kd
`k,
`P
`Cn '
`s.
`
`SOLID-STATE CHARACTER
`
`In this chapter, 1A ; :i: is a notation that will be used to indicate
`solid-state changes. The A denotes the active drug entity. This
`may be a weak acid, a weak base, or a nonelectrolyte. When A
`dissolves, a denotes t he presence of this entity in solution; thus,
`dissolution of the solid A in water to form a will be shown
`schematically as
`
`where i as a plus sign ( +) represents the cationic form, or a
`minus sign ( - ) the anionic form, of A . The protonation or
`deprotonation of a weak basic or acidic group on A will simply
`be reflected in t he charge change that occurs. The scheme is
`nonstoichiometric because counter ions and charge-balance
`considerations have not been included.
`When a particular molecular organization or emphasis of
`the solid state is needed, it will be denoted with the left sub(cid:173)
`script}. A wide variety of different solid states, denoted by , A .
`are possible. For example, amorphous solids that have ran(cid:173)
`domly packed molecules a re denoted as 0 A in this chapter.
`Crystalline solids, on the other hand, have regular packing
`arrangements and are denoted in a number of ways. Two types
`of crystalline phases, polymorpbs and solvates, are possible for
`a given molecule depending on the crystallization conditions.
`Polymorphs are crystals that have the same molecule for(cid:173)
`mula but have different crystal structw·es. The Roman numer(cid:173)
`als I, II, III, ... are used to denote polymorphs; the most stable
`polymorph under ambient conditions is usua lly designated
`with Roman numeral I. This solid-state form of A will be
`denoted as 1A in this chapter.
`Solvates, on the other hand, a re crystals in which a solvent
`is incorporated into the crystal structure (polymorphs of sol(cid:173)
`vates could exist). The solvent may be highly bound in the
`crystal or it may be more loosely bound in ch annels within t he
`crystal. To simplify this discussion, only water of solvation will
`be considered. Hydrated solids are denoted by ,,hA, where 11 is
`a fraction or an integer. For example, ,,12 A denotes a hemihy(cid:173)
`drate while 3,, A denotes a trihydrate.
`In some situations, it will be useful to emphasize that a
`particular chemical reaction or physical change is occuning on
`the surface of a particle. For these purposes, the right subscript
`I will be used to emphasize the surface of the solid state. It
`should be noted that the right superscript i, used for charge
`designation, and the left subscript}, used for solid-state desig(cid:173)
`nation, are only general placeholders for more specific in(cid:173)
`stances that will be detailed below; on the other hand, the right
`subscript }; specifically denotes the surface of a solid particle
`and not a more general entity. For most situations, the full
`notation will not be used.
`In actual APis, crystal defective regions A~ are present.
`These were formed during large-scale synthesis and milling
`operations that reduced the API's particle size. In Figure 38-3,
`defective regions as well as crystalline and amorphous regions
`are shown diagrammatically.
`
`11,0
`A--+ a .
`
`(1)
`
`WATER: A MAJOR ENVIRONMENTAL VARIABLE
`
`The charge of A is denoted by the usual placement of a right
`superscript, i. The charge of A is assumed to be zero by default.
`For emphasis, a lack of charge may be shown explicitly as A0
`.
`For a weak acid, A0 represents the protonated form (in other
`notations this might be shown as HA). The ionized form of the
`weak acid, A - , represents A 0 minus the weak acid proton. For
`a weak base, A 0 denotes the uncharged base that can be pro(cid:173)
`tonated to A 0H +. Equations with A, shown with anows, a re not
`stoichiometric. Instead, they only show essential changes, so
`the focus can be placed on the relevant chemical, ionic, and
`solid-state alterations in the chemical entity. For example, in
`Equation 2, in which a chemical reaction changes the parent
`entity A into a different molecular solid B,
`
`A -+ B
`
`(2)
`
`there is no attempt to show the specific details of the functional
`groups that were changed to bring about the formation of B. In
`a similar manner, consider a reversible acid-base reaction
`
`A ----> A'
`~
`
`(3 )
`
`The presence or absence of moisture is one of the most impor(cid:173)
`tant environmental factors that can affect solid-state stability.
`The surface of an API particle can gain or lose water depending
`on the relative hwnidity (RH). Figure 38-3 shows how water
`vapor can form regions of dissolved drug on the surface of the
`API particle. The amorphous region would be expected to dis(cid:173)
`solve the fastest, and the crystalline region the slowest; that is,
`the rank order of dissolution would be A ,. > A6 > 1 A. Jn the
`Figure 38-3 diagram, this is indicated by the font size of the
`saturated dissolved form of A , a,, associated with each of these
`regions. This surface coating results in chemical and physical
`instability.
`Chemical I nstability: Water as a Molecular Mobilizer- In
`general, chemical reactivity is slow in solids because of the
`spacial separation of different reactive components. For exam(cid:173)
`ple, if a small amount of an impurity that can act as a catalyst
`is distributed heterogeneously in an API or a dosage form, the
`overa ll rate of reaction is limited because the reaction onlY
`occurs in microenvirorunental regions. However, in dosage
`forms, most APis are u sually in contact with moisture-bearing
`excipients and are stress-tested at elevated temperatures and
`humidity. The presence of an adsorbed layer of moisture in-
`
`ALVOGEN, Exh. 1050, p. 0007
`
`

`

`PREFORMULATION
`
`703
`
`~A 1 J
`
`Figure 38-3. Surface of a milled
`API and dissolution of surface re(cid:173)
`gions due to adsorbed moisture.
`
`(9)
`
`and a salt is transformed into a hemihydrate after passing
`through the amorphous form:
`
`H,O
`11,0
`uA • -->.A + _. hn A .
`
`( 10)
`
`Equations 7 to 10 emphasize solid-state changes. It is likely
`tha t most of these transformations may occur only after dis(cid:173)
`solving and forming a or a species forming a +.
`
`DECISION-POINTS IN THE DISCOVERY AND
`DEVELOPMENT OF AN API
`
`The term active pharmaceutical ingredient (API), also known
`as drug substance and bulk pharmaceutical chemical (BPC),
`highlights both a discovery and a development component. In
`this section, discovery Steps 1 to 4 will be introduced briefly.
`The focus will then shift to a detailed discussion of the devel(cid:173)
`opmental Steps 5 to 9. Using this background, the section
`Engineering in the Solid State will outline how early parallel
`integration of these activities can r educe the time from concept
`to market .
`The term expansion is used when choices are being en(cid:173)
`larged, and selection is used when choices are reduced by
`decision-making. Ultimately, the expansion and selection
`phases of discovery lead to a single choice, the best candidate
`for further development.
`1. Library expansion refers to additions to a company's chemical li(cid:173)
`brary. Established pharmaceutical companies have amassed hun(cid:173)
`dreds of thousands of compounds through previous discovery ef(cid:173)
`forts. These collections are cataloged carefully and are used
`systematically in mass screens.
`2. Series selection is a decision-making process in which the most
`active chemicals in the Library ar e identified using a high-through(cid:173)
`put biological assay. Typically, these assays are used to detect the
`ability of a small molecule to interact with a protein, in vitro. In the
`past, decisions regarding which leads will be pursued further were
`made based on activity, chemical diversity, patentability, and ana(cid:173)
`log synthetic potential. Today, developmental potential increas(cid:173)
`ingly is part of series selection d ecision-making.
`3. An.alog expansion is the increase in the number of compounds
`targeting a specific activity based on synthetic exploitation of the
`most promising leads.
`4. Analog selection is the decision-making process in which the best
`new chemical entity is chosen for further development. In the past ,
`in vitro activity alone was the dominat in g decision-maker; today, a
`blend of developmental issues a re surfacing earlier .
`
`Preformulation, as well as other areas of development such
`as metabolism, toxicology, and pharmacokinetics, will play an
`increasingly important role in Steps 1 to 4. Because a funda(cid:173)
`mental understanding of the solid sta te is essential for design(cid:173)
`ing appropriate physical property methodologies for Steps 1 to
`
`creases the catalytic reactivity of the impurity beca use water,
`acting as a molecular mobilizer, can transport different chem(cid:173)
`ical species la terally over the surface of the APL 1 Equa tion 4
`shows a chain of reactions from A to a degradant B,:
`
`(11,0)._ . c•talfllr 1•poru7
`I ll.OJ..-
`A - a
`
`(H,Ol._
`b ---+ B
`
`(4 )
`
`where b is the solubilized form of B . Moisture also induces
`solid-state changes in A. (Further discussion of moisture(cid:173)
`induced chemical instability will be treated in the section Hy(cid:173)
`drate Stability: Importance of the Critical Relative Humidity.)
`Microenvironmental pH: Moisture-Induced Sensitivity of
`Acids/Bases-Acid- base reactivity in the solid-state change
`will be enhanced by moisture. Equation 5 shows a moisture(cid:173)
`induced change of an anionic salt to its free acid on the surface
`of a drug particle:
`
`(H,Ol _
`A ! ---+ A~
`
`(5)
`
`Conversely, Equation 6 shows a moisture-induced surface con(cid:173)
`version of a cationic salt into its free base,
`
`(6)
`
`where A ... = HA +. Because the amount of solid drug is large
`compared to the amount of moisture, Equa tions 5 and 6 have
`been diagramed as irreversible reactions. Such solid-state
`changes can alter the physical properties of the APL For ex(cid:173)
`ample, if particles of the sodium salt of an insoluble acid form
`a surface coating of the free acid as in Equation 5, the dissolu(cid:173)
`tion r ate of the sw-face will be retarded. Testing methods are
`needed during the salt selection stage to anticipate this type of
`solid-state change (see under Salt S election ).
`Solvent-Mediated Transformations of Polymorphs: Water as
`a Transporter- If two polymorphic forms can exist at a given
`temperature, the metastable polymorph will be more soluble
`(see Salt S election , page 704). When this form is put in contact
`With water, the following solvent-mediated transformation c