`
`Coden: JPMSAE 66(1) 1-148 (1977)
`
`J~Z4"
`PHARMA.CY UDAILY
`~ Olf fftl~fJACY
`
`OURNALOF
`ACEUTICAL
`ENCES·
`
`A publication of the American Pharmaceutical Association
`
`
`
`Mylan Exhibit 1027, Page 1
`
`
`
`THE "DUMB COPS" IMAGE
`
`One day this past fall we were going through the daily Washington ritual
`of reviewing the current issue of the Federal Register-which is the
`principal means of keeping track of what is happening in the executive
`branch of government-when we spotted reference to a Presidential
`Proclamation which caught our eye. Specifically, the entry pertained to
`the designation of "Drug Abuse Prevention Week" and the thought struck
`us that this annual effort to promote means to control the problems of drug
`abuse was a bit later than usual this year.
`Upon turningto theProclamationinthat issue of the Federal Register,
`the explanation became immediately clear. Although the Proclamation
`was signed by President Ford on October 18 and printed rather promptly
`in the Federal Register dated October 20, nevertheless, the week being
`so designated was indicated as beginning October 17. Normally, such
`Proclamations appear at least two weeks or so before the pertinent date
`arid certainly not after the observance is to begin.
`Those familiar with the operation of executive agencies will recognize
`that.the tardiness here does not lie with the President, or the White House
`staff,-or the Federal Register but. rather, with the particular agency having
`prima-ry responsibility for the subject area. In this instance, we suspect
`that the fault lies with the Drug Enforcement Administration of the De(cid:173)
`partment of Justice.
`Whether or not DEA was responsible for this small flub, there is no
`question that the agency has been clearly at fault for a long string of other
`foul-ups and errors which. in toto, project the image of an inefficient,
`bungling agency.
`Whtm DEA was originally established some half-dozen years or so ago,
`a strong argument was made that responsibility for drug control involved
`scientific, medical, and other technical knowledge, which argues rather
`strongly that the agency should be placed within the U.S. Department of
`. Health, Education, and Welfare rather than the Department of Justice.
`Others. however, argued vocally that drug abuse control basically is a
`regulatory and enforcement activity and, as such, the agency more properly
`should be made part of the Department of Justice where other federal
`investigative and police activities are primarily centralized.
`In recent months, we have seen repeated instances where official notices,
`proposals, or finalized regulations issuing from DEA and published in the
`Federal Register have 'used terminology and nomenclature to describe
`the drugs involved which have been confusing, inconsistent. or otherwise
`inaccurate. In an effort to correct this problem, at our suggestion, the office
`of the United States Adopted Names (USAN) Council specifically com(cid:173)
`municated with the DEA and offered assistance in this regard. Not only
`did the DEA fail to take advantage of this offer but, in fact, actually re(cid:173)
`peated on at least two later dates the very error cited by the USAN Council
`office as an example of incorrect drug nomenclature being employed by
`the agency.
`There are many dedicated and well-qualified professionals who serve
`in the DEA. Undoubtedly, the bureaucratic bungling of the agency such
`as that described above and which projects a "dumb cop" image is highly
`embarrassing to those professional staff members. What is particularly
`unfortunate, however. is that this problem is so unnecessary. It could be
`readily corrected if those responsible for determining general agency policy
`and direction were just a bit more sensitive to the need to exercise rea(cid:173)
`sonable sophistication and care in the scientific and medically related
`aspects of their field of responsibility.
`
`r
`
`Journalof
`Pharmaceutical
`Sciences
`
`JANUARY 1977
`
`VOLUME 66 NUMBER 1
`
`MARY H. FERGUSON
`Editor
`
`L. LUAN CORRIGAN
`A.~sistant Editor
`
`SHELLY ELLIOTT
`Production Editor
`
`JANET D. SHOFF
`, Copy Editor
`
`EDWARD G. FELDMANN
`Contributing Editor
`
`SAMUEL W. GOLDSTEIN
`Contributing Editor
`
`LELAND J. ARNEY
`Director ofPublications
`
`EDITORIAL ADVISORY BOARD
`
`JOHN AUTIAN
`
`NORMAN R.
`FARNSWOR'l'H
`
`HARRY B. KOSTENBAUDER
`
`HRRBRR'l' A. LlEB;ERMAN
`
`WILLIAM O. FOYE
`
`DAVID E. MANN, JR.
`
`WlLLIAM ,I. JUSKQ
`
`GERALD J. PAPARlELLO
`
`The Journal of Pharmaceutical Sciences is published
`monthly by the American Pharmaceutical Association at
`2215 Constitution Ave., N.W., Washington, DC 20037.
`Second-class postage paid at Washington, D.C., and at ad(cid:173)
`ditional mailing office.
`All expressions of opinion and statements of supposed .
`fact appearing in articles or editorials carried in this journal
`are published on the authority of the writer over whose
`name they appear and are notto be regarded as necessarily
`expressing the policies or views of the American Pharma(cid:173)
`ceutical Association.
`Offices-Editorial, Advertising, and Subscription Of(cid:173)
`fices:2215 Constitution Ave., N.W., Washington, DC 20037.
`Printing Offices: 20th & Northampton Streets, Easton, PA
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`Annual Subscriptions-United States and foreign,
`industrial and government institutions $50, educational
`institutions $50, individuals for personal use only $30;
`single copies $5. All foreign subscriptions add $5 for postage.
`Subscription rates are subject to change without notice.
`. Members of the American Pharmaceutical Association may
`elect to receive the Journal of Pharmaceutical Sciences as
`a part of their annual $60 (foreign $65) APhA membership
`dues.
`Claims-Missing numbers will not be supplied if dues
`or subscriptions are in arrears for more than 60 days or if
`claims are received more tban 60 days after the date of the
`Issue, or if loss was due to failure to give notice of change of
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`foreigndelivery when its records indicate shipment has been
`made.
`Change of Address-Members and subscrihers should
`notify at once both the Post Office and the American
`Pharmaceutical Association, 2215 Constitution Ave., N.W.,
`Washington, DC 20037, of any change of address.
`© Copyright 1977,American Pharmaceutical Association,
`2.215 Constitution Ave., N.W., Washington, DC 20037; all
`rights reserved.
`
`I
`
`\.
`
`\
`
`L
`
`Mylan Exhibit 1027, Page 2
`
`
`
`
`-,
`
`JANUARY 1977
`VOLUME 66 NUMBER 1
`
`rI
`
`Journal of
`I Pharmaceutical
`Sciences
`
`REVIEW ARTICLE
`
`Pharmaceutical Salts
`
`STEPHEN M. BERGE *t, LYLE D. HIGHLEY *, and
`DONALD C. MONKHOUSE x
`
`Heyphrases 0 Pharmaceutical salts-general pharmacy, physico(cid:173)
`chemical properties, bioavailability, pharmaceutical properties, toxi(cid:173)
`cology, review 0 Salts, pharmaceutical-general pharmacy, physico(cid:173)
`chemical properties, bioavailability, pharmaceutical properties, toxi(cid:173)
`cology, review 0 Physicochemical properties-dissolution, solubility,
`stability, and organoleptic properties of pharmaceutical salts, review 0
`Bioavailability-formulation effects, absorption alteration and phar(cid:173)
`macokinetics of pharmaceutical salts, review 0 Toxicology-pharma(cid:173)
`ceutical salts, review
`
`CONTENTS
`
`Salt-forming agents are often chosen empirically. Ofthe
`many salts synthesized, the preferred form is selected by
`pharmaceutical chemists primarily on a practical basis:
`cost of raw materials, ease of crystallization, and percent
`yield. Other basic considerations include stability, hy(cid:173)
`groscopicity, and flowability of the resulting bulk drug.
`Unfortunately, there is no reliable way of predicting the
`influence of a particular salt species on the behavior of the
`parent compound. Furthermore, even after many salts of
`the same basic agent have been prepared, no efficient
`screening techniques exist to facilitate selection of the salt
`most likely to exhibit the desired .pharmacokinetic, solu(cid:173)
`bility, and formulation profiles.
`Some decision-making models have, however, been de(cid:173)
`veloped to help predict salt performance. For example,
`Walkling and Appino (1) described two techniques, "de(cid:173)
`cision analysis" and "potential problem analysis," and
`applied them to the selection of the most suitable deriva(cid:173)
`tive of an organic acid for development as a tablet. The
`derivatives considered were the free acid and the potassi(cid:173)
`um, sodium, and calcium salts. Both techniques are based
`on the chemical, physical, and biological properties of these
`specific derivatives and offer a promising avenue for de(cid:173)
`veloping optimal salt forms.
`Information on salts is widely dispersed throughout the
`pharmaceuticalliteratille, much of which addresses the
`use of salt formation to prolong the release of the active
`component, thereby eliminating various undesirable drug
`properties (2-6). This review surveys literature of the last
`25 years, emphasizing comparisons between the properties
`of different salt forms of the same compound. Included also
`is a discussion of potentially useful salt forms. Our purpose
`is twofold: to present an overview of the many different
`salts from which new drug candidates can be chosen and
`
`Vol. 66, No.1, January 1977 /1
`
`... , . . . . . . . . . . . . . . . .
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`_. . . . ..
`
`Potentially Useful Suits
`Physicochemical Studies
`Dissolution Rate
`Solubility _............................................
`Organoleptic Properties
`'.'
`_
`_. . . . .
`Stability
`Miscellaneous Properties
`Bioavailability
`Formulation Effects
`Absorption Alteration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`Pharmacokinetics
`_. . . . . . . . . . . . . . . . . . . . . . . .
`General Pharmacy
`Pharmacological Effect
`Dialysis
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`Miscellaneous
`Toxicological Considerations
`Toxicity of Salt Ion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`Toxicity of Salt Form
`Conclusions
`References
`
`.-........................
`
`2
`4
`5
`7
`8
`9
`10
`10
`11
`11
`13
`14
`14
`14
`14
`15
`15
`15
`16
`16
`
`The chemical, biological, physical, and economic char(cid:173)
`acteristics of medicinal agents can be manipulated and,
`hence, often optimized by conversion to a salt form.
`Choosing the appropriate salt, however, can be a very
`difficult task, since each salt imparts unique properties to
`the parent compound.
`
`Mylan Exhibit 1027, Page 3
`
`
`
`
`Table I-FDA-Approved Commercially Marketed Salts
`
`Anion
`
`Acetate
`Benzenesulfonate
`Benzoate
`Bicarbonate
`Bitartrate
`Bromide
`Calcium edetate
`Camsylate"
`Carbonate
`Chloride
`Citrate
`Dihydrochloride
`Edetate
`Edisylate"
`Estolate"
`Esylate"
`Fumarate
`Gluceptate/
`Gluconate
`Glutamate
`Glycollylarsanilates
`Hexylreeorcinate
`Hydrabamine"
`Hydrobromide
`Hydrochloride
`Hydroxynaphthoate
`
`Cation
`
`Organic:
`Benzathine"
`Chloroprocaine
`Choline
`Diethanolamine
`Ethylenediamine
`Meglumine '
`Procaine
`
`Percent"
`
`«Anion
`
`Percent"
`
`1.26
`0.25
`0.51
`0.13
`0.63
`4.68
`0.25
`0.25
`0.38
`4.17
`3.03
`0.51
`0.25
`0.38
`0.13
`6.13
`0.25
`0.18
`0.51
`0.25
`0.13
`0.13
`0.25
`1.90
`42.98
`0.25
`
`Iodide
`Iaethionate/
`Lactate
`Lactobionate
`Malate
`Maleate
`Mandelate
`Mesylate
`Methylbromide
`Methylnitrate
`Methylsulfate
`Mucate
`Napsylate
`Nitrate
`Pamoate (Embonate)
`Pantothenate
`Phosphate/diphosphate
`Polygalacturonate
`Salicylate
`Stearate
`Subacetate
`Succinate
`Sulfate
`Tannate
`Tartrate
`'I'eoclate/
`Triethiodide
`
`Percent"
`
`Cation
`
`0.66
`0.33
`0.33
`0.98
`0.66
`2.29
`0.66
`
`Metallic:
`Aluminum
`Calcium
`Lithium
`Magnesium
`Potassium
`Sodium
`Zinc
`
`2.02
`0.88
`0.76
`0.13
`0.13
`. 3.03
`0.38
`2.02
`0.76
`0.38
`0.88
`0.13
`0.25
`0.64
`1.01
`0.25
`3.16
`0.13
`0.88
`0.25
`0.38
`0.38
`7.46
`0.88
`3.54
`0.13
`0.13
`
`Percent"
`
`0.66
`10.49
`1.64
`1.31
`10.82
`61.97
`2.95
`
`" Percent is based on total number of anionic or cationic salts in use through 1974. b Camphorsu1fonate. c 1,2-Ethan~disu1fonate. d Lauryl sulfate.
`(' Ethanesulfonate. f Glucoheptonate. g p-Glycollamidophenylarsonate. h N,N'-Di(dehydroabietyl)ethylenediamine. '2-Hydroxyethanesulfonate.
`j 8-Chlorotheophyllinate. h N,N'-Dibenzylethylenediamine. I N-Methylglucamine.
`
`to assemble data that will provide, for the student and
`practitioner alike, a rational basis for selecting a suitable
`salt form.
`
`POTENTIALLY USEFUL SALTS
`Salt formation is an acid-base reaction involving either
`a proton-transfer or neutralization reaction and is there(cid:173)
`fore controlled by factors influencing such reactions.
`Theoretically, every compound that exhibits acid or base
`characteristics can participate in salt formation. Particu(cid:173)
`larly important is the relative strength of the acid Or
`base-the acidity and basicity constants of the chemical
`species involved. These factors determine whether or not
`formation occurs and are a measure of the stability of the
`resulting salt.
`The number of salt forms available to a chemist is large;
`surveys of patent literature show numerous new salts being
`synthesized annually. Various salts ofthe same compound
`.often behave quite differently because of the physical,
`chemical, and thermodynamic properties they impart to
`the parent compound. For example, a salt's hydrophobicity
`and high crystal lattice energy can affect dissolution rate
`and, hence, bioavailability. Ideally, it would be desirable
`if one could predict how a pharmaceutical agent's prop(cid:173)
`erties would be affected by salt formation.
`Tables I and II list all salts that 'were commercially
`marketed through 1974. The list was compiled from all
`agents listed in "Martindale The Extra Pharmacopoeia,"
`
`2 / Journal of Pharmaceutical Sciences'
`
`26th ed. (7). Table I categorizes all salt forms approved by
`the Food and Drug Administration (FDA), while Table II .
`lists those not approved by the FDA but in use in other l
`countries. (Only salts of organic compounds are considered i
`because most drugs are organic substances.) The relative,
`frequency with which each salt type has been used is cal(cid:173)
`culated as a percentage, based on the total number of an(cid:173)
`ionic or cationic salts in use through 1974. Because of
`simple availability and physiological reasons, the mono(cid:173)
`pro tic hydrochlorides have been by far the most frequent
`choice of the available anionic salt-forming radicals, out(cid:173)
`numbering the sulfates nearly six to one. For similar rea(cid:173)
`sons, sodium has been the most predominant cation.
`Knowledge that one salt form imparts greater water
`solubility, is less toxic, or slows dissolution rate would
`greatly benefit chemists and formulators. In some cases,
`such generalizations can be made. Miller and Heller (8)
`discussed some properties associated with specific classes '
`of salt forms. They stated that, in general, salt combina(cid:173)
`tions with monocarboxylic acids are insoluble in water and
`lend themselves to repository preparations, while those of
`dicarboxylic acids confer water solubility if one carboxylic
`group is left free. Pamoic acid, an aromatic dicarboxylic
`acid, is an exception since it is used as a means of obtaining ,
`prolonged action by forming slightly soluble salts with .
`certain basic drugs. Saias et al, (9) reviewed the use of this
`salt form in preparing sustained-release preparations.
`More recently, latentiation of dihydrostreptomycin (10)
`
`Mylan Exhibit 1027, Page 4
`
`
`
`
`Table Il-Non-FDA-Approved. Commercially Marketed.
`Salts
`
`Anion
`
`Percent"
`
`Adipate
`Alginate.
`Aminosallcylate
`Anhydromethylenecitrate
`Arecoliu·e
`Aspartate
`Bisulfate
`Butylbromide
`Camphorate
`Digluconate _
`Dihydrobroilllde
`Disuccinate
`Glycerophosphate
`Hemisulfate
`Hydrofluoride
`Hydroiodide
`MethylenebisCsalicylate)
`Napadisylate b
`Oxalate
`Pectinate
`Persulfate
`Phenylethylbarbiturate
`Picrate
`Propionate
`Thiocyanate
`'I'oaylate
`Undecanoate
`
`Cation
`
`Organic:
`Benethamine"
`Clemiaole"
`Diethylamine
`Piperazine
`'I'romethamine"
`Metallic:
`Barium
`Bismuth
`
`0.13
`0.13
`0.25
`0.13
`0.13
`0.25
`0.25
`0.13
`0.13
`0.13
`0.13
`0.13
`0.88
`0.13
`0.13
`0.25
`0.13
`0.13
`0.25
`0.13
`0.13
`0.13
`0.13
`0.13
`0.13
`0.13
`0.13
`
`Percent"
`
`0.33
`0.33
`0.33
`0.98
`0.33
`
`0.33
`0.98
`
`11 Percent is based on total number of anionic and cationic salts in use
`through 1974. b l.fi-Naphthalenedisulfonate. (" N-Benzylphenethylamine.
`d I-p-Chlorobenzyl-2-pyrrolidil1-1 f-ylmethylbenzimidazole. e Tris(hy(cid:173)
`droxymethyllaminomethane.
`
`using pamoic acid resulted in the formation of a delayed(cid:173)
`action preparation. Nurnerous studies using pamoate salts
`are dispersed throughout the literature (11-15).
`Alginic acid also has been used to 'prepare long-acting
`pharmaceuticals. Streptomycin alginate was prepared (16)
`and shown to be effective in sustained-release prepara(cid:173)
`tions. A striking example of a long-acting alginate salt is
`that of pilocarpine. When dispersed in sterile water and
`.dried to a solid gel, this compound was found useful in the
`preparation oflong-acting ophthalmic dosage forms (17).
`While liquidpreparations of the alginate and hydrochlo(cid:173)
`ride salts possess similar miotic activity, studies showed·
`that solid pilocarpine alginate flakes constricted pupil size
`more effectively and increased the duration of miosis sig-
`. nificantly when compared with the liquid preparations.
`Solid dose pilocarpine may be more uniformly available,
`because it diffuses more slowly through the gel matrix
`which holds the drug in reserve. In contrast, drops of the
`commonly employed solution dosage form release the dose
`immediately to the conjunctival fluid.
`Malek et al. (18) devised a unique way of prolonging
`action through salt formation; they showed that the dis(cid:173)
`tribution of several antibiotics could be markedly altered
`by merely preparing macromolecular salts. Since macro(cid:173)
`molecules and colloidal particles have an affinity for the
`lYmphatic system, streptomycin, neomycin, viomycin, and
`
`streptothrycin were combined with high molecular weight
`compounds such as polyacrylic acids, sulfonic or phos(cid:173)
`phorylated polysaccharides, and polyuronic derivatives.
`Parenteral administration of these compounds produced
`low blood levels of the antibiotic for long periods, while
`lymph levels were high. (In comparison, streptomycin
`sulfate gave high blood levels but low lymph levels.) This
`alteration in distribution caused the streptomycin to
`prolong its passage through the body, since lymphatic
`circulation- is quite slow.
`The appropriate choice of a salt form has been found to
`reduce toxicity. It can be rationalized that any compound
`associated with the normal metabolism of food and drink
`must be essentially nontoxic. The approach of choosing
`organic radicals that are readily excreted or metabolized
`opened up a new class of substances from which to select
`a salt form. For example, certain salts of the strong base
`choline have proven to be considerably less toxic than their
`parent compound. The preparation and 'properties of
`choline salts of a series of theophylline derivatives were
`reported (19), and it was shown that choline theophyllinate
`possessed a greater LD 50 than theophylline or its other
`salts (20). It was postulated that this agent would be less
`irritating to the GI tract than aminophylline, because "its
`basic constituent, choline, is an almost completely non(cid:173)
`toxic substance of actual importance "to the physiologic
`economy." This evidence led to the preparation of choline
`salicylate (21) as an attempt to reduce the GI disturbances
`associated with salicylate administration. Clinical st';'dies
`indicated that choline salicylate elicited a lower incidence
`of GI distress, was tolerated in higher doses, and was of
`greater benefit to the patient than was acetylsalicylic acid
`(aspirin).
`Amino acids and acid vitamins also have been used as
`salt-forming agents. Based on the evidence that coad(cid:173)
`ministration of amino acids with aminoglycoside antibi(cid:173)
`otics reduced their toxicity, a series of amino acid salts of
`dihydrostreptomycin was prepared (22). In all but one
`case, the acute toxicities of these salts were lower than the
`toxicity of the sulfate. The ascorbate and pantothenate
`also were synthesized and shown to be less toxic than the
`sulfate. Of the salts prepared, the ascorbate had the highest
`LD 50.
`The vitamins most commonly used for forming salts
`exhibiting reduced toxicity are ascorbic and pantothenic
`acids. Keller et al. (23) were the first to use pantothenic
`acid as a means of "detoxifying" the basic streptomyces
`antibiotics. Parenteral administration of the pantothen(cid:173)
`ates of streptomycin and dihydrostreptomycin had a sig(cid:173)
`nificantly reduced incidence of acute neurotoxicity in cats
`as compared with the sulfates. Subsequent studies (24-28)
`supported this finding and showed that the pantothenates
`of neomycin and viomycin also are less toxic. The ascorbate
`of oleandomycin was synthesized and its pharmacological
`properties were reported (29). Upon intramuscular injec(cid:173)
`tion in rats, it produced less irritation than the phos(cid:173)
`phate.
`p-Acetamidobenzoic acid, an innocuous metabolite of
`folic acid present in normal blood and urine, has been used
`in preparing salts. In particular, it yields stable salts with
`amines that otherwise tend to form hygroscopic products
`with conventional acid components (30).
`.
`Often the salt form is chosen by determining a salt
`
`Vol. 66, No.1, January 1977/3
`
`Mylan Exhibit 1027, Page 5
`
`
`
`
`component that will pharmacologically antagonize an
`unfavorable property or properties exhibited by the basic
`agent. Salts of N -cyclohexylsulfamic acid are an example
`of the practical application of this approach. N-Cyclo(cid:173)
`hexylsulfamic acid salts, better known as cyclamates, have
`a characteristic sweet, pleasing taste. Although presently
`under investigation by the FDA for potentially carcino(cid:173)
`genic properties, salts incorporating this compound can
`render unpleasant or bitter-tasting drugs acceptable. For
`example,
`the cyclamates of dextromethorphan and
`chlorpheniramine exhibit greatly improved bitterness
`thresholds compared to commonly occurring salts (31).
`Furthermore, their stability in aqueous solution was de(cid:173)
`scribed as good when maintained at a pH not greater than
`4.
`
`N -Cyclohexylsulfamic acid salts of thiamine hydro(cid:173)
`chloride and lincomycin also have been synthesized. Thi(cid:173)
`amine N -cyclohexylsulfamate hydrochloride was reported
`to have amore pleasant taste than other thiamine salts
`while having an equal or greater stability (32). Lincomycin
`cyclamate, shown to possess an enhanced thermal stability
`over its hydrochloride, was prepared (33) to test the hy(cid:173)
`pothesis that reduced lincomycin absorption in the pres(cid:173)
`ence of small quantities of cyclamates was due to a simple
`metathetic reaction. However, this assumption was found
`not to be true. An extensive study of the preparation and
`characterization of cyclamic acid salts of several widely
`used classes of drugs including antihistamines, antibiotics,
`antitussives, myospasmolytics, and local anesthetics was
`reported (34, 35).
`Various salts of penicillin and basic amine compounds
`have been formulated in an effort to produce a long-acting,
`nonallergenic form of penicillin. Since antihistamines
`appear to mitigate the symptomatology of penicillin re(cid:173)
`actions in some patients, coadministration of the two has
`been advocated. The preparation of the benzhydralamine
`salt of penicillin was an attempt to produce a repository
`form of penicillin with antiallergic properties (36). Blood
`levels achieved with this salt were comparable to those of
`penicillin G potassium; however, its antiallergic properties
`were not evaluated. In fact, the investigators noted that
`antihistamines can actually cause sensitization at times
`and stated that "despite their occasionally favorable in(cid:173)
`fluence on the symptoms of penicillin sensitivity, they
`contribute directly to the potential of drug sensitivity when
`co-administered with penicillin."
`Silver salts of sulfanilamide, penicillin, and other anti(cid:173)
`biotics have been prepared and represent cases where the
`species (ions) are complementary. When aqueous solutions
`of the salts were applied topically to burned tissue, they
`yielded the combined benefits ofthe oligodynamic action
`of silver and the advantages of the antibacterial agents
`(37),
`The use of 8-substituted xanthines, particularly the
`8-substituted theophyllines, as salt-forming agents was
`first reported in the preparation of a series of antihistamine
`salts (38-41). Synthesis ofthese xanthine salts was an at(cid:173)
`tempt to find a drug to counteract the drowsiness caused
`by the antihistamines with the stimulant properties of the
`xanthines. When an electronegative group is introduced
`into the xanthine molecule at the 8-position, the elec(cid:173)
`tron-drawing capacity of the substituent results in the
`creation of an acidic hydrogen at position 7. Thus, these
`
`4/ Journal of Pharmaceutical Sciences
`
`moderately strong acidic compounds can undergo salt
`formation with various organic bases.
`.
`The 8-halotheophyllines were the first group of xan- 1
`thines studied as potential salt-forming agents. Since the!
`report on the preparation of the 8-chlorotheophylline salt
`j
`of diphenhydramine (42), synthesis of the 8-halotheo-j
`phyllinates of a number of organic bases has been at(cid:173)
`tempted. The 8-chlorotheophyliine salts of quinine, 1
`ephded(rin)e, and strychnine were prepared and character-".!
`'I
`ize
`43 . These salts were less water soluble than the
`
`corresponding free alkaloidal bases. In a similar report, the I
`
`'.
`
`three synthetic narcotics,
`8-chlorotheophyllinates of
`meperidine, levorphanol, and metopon, were prepared
`(44 ) · ' l ' , !
`Pharmacological and clinical studies involving the 8(cid:173)
`bromotheophylline pyrilamine salt revealed the unusual 1
`I
`diuretic properties associated with the 8-halotheophylline
`portion of the compound (45, 46). This finding initiated,
`an investigation into the preparation of a soluble 8-bro,
`motheophylline salt of high diuretic activity. With readily
`available amines, over 30 salts' were synthesized and
`screened for diuretic activity (47), When tested against
`theophylline salts of the same amines, the 8-bromotheo(cid:173)
`phyllinates showed greater activity in every case.
`With the successful formation of 8-halotheophyllinates
`of organic bases, Morozowich and Bope (48) proposed that,
`if the halogen moiety was replaced with a more electro(cid:173)
`negative substituent such as a nitro group, a more acidic
`compound would be formed. Presumably, more stable salts
`would result and precipitation of the free xanthine deriv(cid:173)
`ative in the stomach would be less likely to occur. On this
`premise, they successfully prepared pharmacologically
`effective 8-nitrotheophyllinates of several pharmaceuti(cid:173)
`cally useful bases.
`Dueselet al. (19), in their study of choline theophylli(cid:173)
`nate, prepared the 8-chloro-, 8-bromo-, and 8-nitrotheo(cid:173)
`phylline salts of choline, Oral toxicity studies in mice
`showed that the LD50 of the 8-nitrotheophyllinate was
`much greater than that of either 8-halotheophylline. In
`fact, it remained nonlethal at doses as high as 5 g.
`Polygalacturonic acid, a derivative of pectin, has been
`used to prepare quinidine salts exhibiting reduced toxicity
`(49, 50). The compound possesses special demulcent
`properties and inhibits mucosal irritation. The rationale
`for use of this agent is to reduce the ionic shock to the GI
`mucosa resulting from the flood of irritating ions liberated
`by rapid dissociation of the conventional inorganic quin(cid:173)
`idine salts. Studies have shown that it is four times less
`toxic orally than the sulfate. This difference was attributed
`to the slower release of quinidine from the polygalactu(cid:173)
`ronate.
`Other compounds reported to be potentially useful as
`pharmaceutical salt forms are listed in Table III.
`
`PHYSICOCHEMICAL STUDIES
`
`Biological activity of a drug molecule is influenced by
`two factors: its chemical structure and effect at a specific
`site and its ability to reach-and then be removed from(cid:173)
`the site of action. Thus, a knowledge of the physicochem(cid:173)
`ical properties of a compound that influence its absorption,
`distribution, metabolism, and excretion is essential for a
`complete understanding of the onset and duration of ac-
`
`Mylan Exhibit 1027, Page 6
`
`
`
`
`Table III-Potentially Useful Salt Forms of Pharmaceutical Agents
`
`Salt-Forming Agent
`
`Compound Modified
`
`Modification
`
`Reference
`
`Acetylaminoacetic acid
`N_Acetyl_L_asparagine
`N-Acetylcystine
`Adamantoic acid
`Adipic acid
`N-Alkylsulfamates
`
`Anthraquinone-l,5-disulfonic acid
`Arabogalactan sulfate (arabino)
`Argi~ine
`
`Aspartate
`Betaine
`His(2-carboxychromon-5-yloxy)alkanes
`Carnitine
`4-Chloro-m-toluenesulfonic acid
`Decanoate
`Diacetyl sulfate
`Dibenzylethylenediamine
`Diethylamine
`Diguaiacyl phosphate
`Dioctyl sulfosuccinate
`Embonic (pamoic) acid
`
`Fructose 1,6-diphosphoric acid
`
`Glucose Lphosphoric acid, glucose
`6-phosphpric acid
`L-Glutamine
`Hydroxyriaphthoate
`2-(4-Imidazolyl) ethylamine
`Isobutanolamine
`Lauryl sulfate
`Lysine
`
`Methanesulfonic add
`ff-Methylglucamine
`
`N-Methylpiperazine
`Morpholine
`2-Naphthalenesulfonic acid
`Octanoate
`Probenecid
`Tannic acid
`Theobromine acetic acid
`3A,5-Trimethoxybenzoate
`
`'I'romethamine
`
`Doxycycline
`Erythromycin
`Doxycycline
`Alkylbiguanides
`Piperazine
`Ampicillin
`Lincomycin
`Cephalexin
`Various alkaloids
`Cephalosporins
`c-Sulfobenzylpenicillin
`Erythromycin
`. Tetracycline
`7- (Arninoalkyl)theophyllines
`Metformin
`Propoxyphene
`Heptaminol
`Thiamine
`Ampicillin
`Cephalosporins
`Tetracycline
`Vincamine
`Kanamycin
`2-Phenyl-3-methylmorpholine
`Tetracycline
`Erythromycin
`Tetracycline
`Erythromycin
`Erythromycin
`Bephenium
`Prostaglandin
`Theophylline
`Vincamine
`c-Sulfobenzylpenicillin
`Cephalosporine
`Pralidoxime (2-PAM)
`c-Sulfobenzylpenicillin
`Cephalosporins
`Phenylbutazone
`Cephalosporina.
`Propoxyphene
`Heptaminol
`Pivarnpicillin
`Various amines
`Propoxyphene
`Tetracycline
`Heptaminol
`Aspirin
`Dinoprost (prostaglandin F 2<y)
`
`Solubility
`Solubility, activity, stability
`Combined effect useful in pneumonia
`Prolonged action
`Stability, toxicity, organoleptic properties
`Absorption (oral)
`Solubility
`Stability, absorption
`Prolonged action
`Toxicity
`Stability, hygroscopicity, toxicity
`Solubility
`Gastric absorption
`Activity, prolonged prophylactic effect
`Toxicity
`Organoleptic properties
`Prolonged action
`Stability, hygroscopicity
`Prolonged action
`Reduced pain on injection
`Activity
`Organoleptic properties
`Toxicity
`Toxicity
`Solubility
`Solubility
`Solubility
`Solubility
`Solubility, activity, stability
`Toxicity
`Prolonged action
`Stability
`Organoleptic properties
`Toxicity, stability, hygroscopicity
`
`Solubility
`Toxicity, stability, hygroscopicity
`Reduced pain on injection
`Toxicity, faster onset of action
`Reduced pain on injection
`Organoleptic properties
`Prolonged action
`Organoleptic properties
`Prolonged action
`Activity
`Organoleptic properties
`Prolonged action
`Absorption (oral)
`Physical state
`
`51
`52
`53
`54
`55
`56
`57
`58
`59,60
`61
`62
`63
`64
`65
`66
`67
`68
`69
`70, 71
`72
`73
`74
`75
`76
`77
`
`77
`
`52
`78
`79
`80
`81
`62
`61
`82
`62
`72
`83
`72
`84
`68
`85
`86,87
`88
`89
`68
`90
`91
`
`tion, the relative toxicity, and the possible routes of ad(cid:173)
`ministration (2).
`In a review in 1960, Miller and Holland (92) stated that
`"different salts of the same drug rarely differ pharmaco(cid:173)
`logically;the differences are usually based on the physical
`properties." In a subsequent review (93), Wagner ex(cid:173)
`panded upon this statement, asserting that, although the
`nature of the biological responses elicited by a series of
`salts of the same parent compound may not differ appre(cid:173)
`ciably, the intensities of response may differ markedly.
`The salt form is known to influence a number of physi(cid:173)
`cochemical properties of the parent compound including
`dissolution rate, solubility, stability, and hygroscopicity.
`These properties, in turn, affect the availability and for(cid:173)
`mulation characteristics of the drug. Consequently, the
`pharmaceutical industry has systematically engaged in
`extensive preformulation studies of the physicochemical
`properties of each new drug entity to determine the most
`suitable form for drug formulation. Published information
`concerning such studies, however, is sparse. Preformula(cid:173)
`tion studies have been outlined, and the influence of the
`salt form on the volatility and hygroscopicity of an agent
`under investigation was discussed (94).
`
`In one such study, methylpyridinium-2-aldoxime
`(pralidoxime) salts were investigated (95). This study set
`out to prepare a salt with water solubility adequate to allow
`intramuscular injection of a low volume (2-3 ml) thera(cid:173)
`peutic dose. The original compound, the methiodide, had
`the disadvantages of limited aqueous solubility and high
`potential toxicity, since its high iodide content could result
`in iodism. On the bas