`
`JANUARY 1977
`
`Volume 66 Number 1
`
`PHARP‘lAcY Lima?
`W a? mmmv
`
`A publication bf the American Pharmaceutical Association
`
`Coden: JPMSAE 66(1) 1-148 (1977)
`
`gnaw?
`
`ApoteX Exhibit 1009.001
`
`
`
`Apotex Exhibit 1009.001
`
`

`

`Journal of
`Pharmaceutical
`Sciences
`
`JANUARY 1977'
`
` VOLUME 66 NUMBER 1
`
`MARY H. FERGUSON
`Editor
`
`L. LUAN CORRIGAN
`Assistant Editor
`
`SHELLY ELLIOTT
`' Production Editor
`
`,JANET D. SHOFI"
`Copy Editor
`
`EDWARD G. FELDMANN
`Contributing Editor
`
`SAMUEIr W. GOLDSTEIN
`ContributingEditor
`
`LELAND J. ARNEY
`Director ofPuincotions
`
`EDITORIAL ADVISORY BOARD
`
`JOHN AUTIAN
`
`HARRY B. KOSTENBAUDER
`
`NORMAN R.
`FARNSWORTH
`
`HERBERT A. LIEBERMAN
`
`WILLIAM G. FOYE
`
`' WILLIAM J. JUSKO
`
`DAVID E. MANN, JR.
`GERALD J. PAPARIELLO
`
`The Journal of Pharmaceutical Sciences is published
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`© Copyright 1977, American Pharmace utical Association,
`2215 Constitution Ave, N.W., Washington, DC 20037; all
`rights reserved.
`
`
`
`
`
`
`
`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 turning to the Proclamation in that issue of the Federal Regis ter,
`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
`and certainly not after the observance is to begin.
`Those familiar with the operation of executive agencies will recognize
`thatthe tardiness here does not lie with the President, or the White House
`staff,-or the Federal Register but, rather, with the particular agency having
`primary responsibility for the subject area. In this instance, we suspect
`that the fault lies with the Drug Enforcement Administration of the De-
`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.
`- When 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~
`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-
`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-
`sonable sophistication and care in the scientific and medically related
`aspects of their field of responsibility.
`
`
`
`ApoteX Exhibit 1009.002
`
`Apotex Exhibit 1009.002
`
`

`

`
`
`
`
`Journal of
`Pharmaceutical
`Sciences
`
`JANUARY 1977
`VOLUME as NUMBER 1
`
` ® R
`
`E VIE W ARTICLE
`
` i
`
`Pharmaceutical Salts
`
`STEPHEN M. BERGE *i, LYLE D. BIGHLEY *, and
`DONALD C. MONKHOUSEx
`
`
`
`,KeyphrasesEIPharmaceutical saltsigeneral pharmacy, physico-
`chemical properties, bioavailability, pharmaceutical properties, toxi—
`cology, review El Salts, pharmaceuticaligeneral pharmacy, physica-
`chemical properties, bioavailability, pharmaceutical properties, toxi-
`cology, review I: Physicochemical properties—dissolution, solubility,
`stability, and organoleptic properties of pharmaceutical salts, review El
`Bioavailability—formulation effects, absorption alteration and phar-
`macokinetics of pharmaceutical salts, review El Toxicologyipharma-
`ceutical’ salts, review
`
`CONTENTS
`
`Potentially Useful Salts ...........' .......................
`Physicochemical Studies ..................................
`Dissolution Rate .
`.
`.
`.
`.
`.
`.
`.
`._ ............................
`Solubility .............................................
`Orgaholeptic Properties ....... . ....................._ .....
`Stability ..............................................
`Miscellaneous Properties ................................
`Biocoailability ..........................................
`' Formulation Effects ....................................
`Absorption Alteration ...................................
`Pharmacokinetics ......................................
`General Pharmacy .......................................
`Pharmacological Effect .................................
`Dialysis ...............................................
`Miscellaneous .........................................
`Toxicological Considerations ..............................
`Toxicity of Salt Ion .....................................
`Toxicity of Salt Form ...................................
`. Conclusions ....... ' ............... ........................
`References ......................................... i.....
`
`_
`
`2
`4
`5
`7
`8
`9
`10
`10
`11
`11
`13
`14
`l4
`14
`14
`15
`15
`15
`16
`16
`
`The chemical, biological, physical, and economic char—
`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.
`
`Salt—forming agents are often chosen empirically. Of the
`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—
`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-
`bility, and formulation profiles.
`7
`Some decision-making models have, however, been de-
`veloped to help predict salt performance. For example,
`Walkling and Appino (1) described two techniques, “de-
`cision analysis” and “potential problem analysis,” and
`applied them to the selection of the most suitable deriva-
`tive of an organic acid for development as a tablet. The
`derivatives considered were the free acid and the potassi-
`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-
`veloping optimal salt forms.
`Information on salts iswidely dispersed throughout the
`pharmaceutical literature, 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 candidatescan be chosen and
`
`Val. 66, No. 1, January 1977/ 1
`
`Apotex Exhibit 1009.003
`
`Apotex Exhibit 1009.003
`
`

`

`Table I—FDA-Approved Commercially Marketed Salts
`
`Percent‘J
`
`*Anion
`
`Percent"
`
`Anion
`
`Acetate
`Benzenesulfonate
`Benzoatc
`Bicarbonate
`Bitartrate
`Bromide
`Calcium edetate
`- Camsylateb
`Carbonate
`Chloride
`Citrate
`Dihydrocihloride
`Edetate
`Edisylater
`Estolated
`Esylate"
`Fumarate
`Gluceptatelr
`Gluconate
`Glutamate
`Glycollylarsanilateg
`l-lexylresorcinate
`l-lydrabamineh
`Hydrobrornide
`Hydrochloride
`Hydroxynaphthoate
`
`1.26
`0.25
`0.51
`0.13
`0.63
`4.68
`0.25
`0.25
`0.38
`4.17
`3.03
`0.51 7
`0.25
`0.38
`0.13
`0.13
`0.25
`0.18.
`0.51
`0.25
`0.13
`0.13
`0.25
`1.90
`42.98
`0.25
`
`.
`Iodide
`Isethionate'
`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 _
`TeoclateJ
`Triethiodide
`
`Cation
`
`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
`0.38
`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
`
`
`
`
`Cation
`Percent“ '
`
`Organic.
`Benzathinek
`Chloroprocaine
`Choline
`Diethanolamine
`Ethylenediamine
`Meglumine"
`Procaine
`
`0.66
`0.33
`0.33
`0.98
`0.66
`2.29
`0.66
`
`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-
`fore controlled by factors influencing such reactions.
`Theoretically, every compound that exhibits acid or base
`characteristics can participate in salt formation. Particu-
`larly important is the relative strength of the acid 0r
`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 of the 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-
`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,” 7
`
`2 / Journal of Pharmaceutical Sciences‘
`
`
`
`" Percent1s based on total number of anionic or cationic saltsin use through 1974. 5 Camphorsulfonate. C 1,2-Ethanedisulfonate. d Lauryl sulfate
`" Ethanesulfonate. f Glucoheptonate. 5 p-Glycollamidophenylarsonate. “N,N’-Di(dehydroabietyl)ethylenediamine. * 2Hydroxyetbanesulfonate.
`J 8—Chlorotheophyllinate. h N,N’—Dibenzylethylenediamine. IEN— Methylglucamine.
`
`26th ed. (7). Table I categorizes all salt forms approved by
`the Food and Drug Administration (FDA), while Table II 5
`lists those not approved by the FDA butIn use in other
`countries. (Only salts of organic compounds are considered
`because most drugs are organic substances.) The relative -
`frequency with which each salt type has been used is cal- -_
`culated as a percentage, based on the total number of an— I
`ionic or cationic salts in use through 1974. Because of 1
`simple availability and physiological reasons, the mono—
`protic hydrochlorides have been by far the most frequent :5
`choice of the available anionic salt—forming radicals, out-
`numbering the sulfates nearly six to one. For similar rea- I‘
`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- E;
`tions with monocarboxylic acids are insoluble in water and :
`lend themselves to repository preparations, while those of :1;
`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 j
`prolonged action by forming slightly soluble salts with '
`certain basic drugs. Saias at at. (9) reviewed the use of this 7.
`salt form in preparing sustained-release preparations. '
`More recently, latentiation of dihydrostreptomycin (10) _.
`
`Apotex Exhibit 1009.004 .
`
`Apotex Exhibit 1009.004
`
`

`

`B
`
`I Table II—Non-FDA—Approved Commercially Marketed
`Saltsf——————-——
`
`Anion Percent‘zW
`
`Adipate
`Alginate
`_
`Aminosalicylate
`Anhydromethylenecrtrate
`Arecolirie
`Aspartate
`Bisulfate
`Butylbromide
`Camphflrate
`Digluconate _
`Dihydrobromide
`Disuccinate
`Glycerophosphate
`Hemisulfate
`Hydrofluoride
`Hydroiodide
`Methylenebis(salicylate)
`_ Napadisylate”
`,
`Oxalate
`Pectinate
`Persulfate
`Phenylethylbarbiturate
`Picrate
`Propionate
`Thiocyanate
`Tosylate
`Undecanoate
`
`‘
`
`.
`
`0.13
`0.13
`0.25
`0.13
`0.13
`0.25
`0.25
`0,13
`0.13
`0.13
`0.13
`0.13
`0,33
`0_13
`0_13
`(125
`0.13
`0.13
`0.25
`0.13
`0,13
`0.13
`0,13
`(113
`013
`013
`0,13
`
`Cation
`Percent"
`
`
`Organic:
`Benetbamine"
`Clemizoleti
`Diethylamine
`Piperazine
`'I‘romethamine"
`Metallic:
`Barium
`Bismuth
`
`0.33
`033
`033
`0.98
`0.33
`
`0.33
`0.98
`
`“ Percent is based on total number of anionic and cationic salts in use
`through 1974. " 1,57Naphthalenedisulfonate. '3 N-Benzylphenetbylamine.
`‘1 1-p~ChlorobenzyleZepyrrolidinel’eylmethylbenzimidazole. 9 Tris(hyv
`‘ droxymethyl)aminomethane.
`
`using pamoic acid resulted in the formation of a delayed-
`action preparation. Numerous 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-
`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 of long—acting ophthalmic dosage forms (17).
`While liquidpreparations of the alginate and hydrochlo-
`
`_
`
`'
`
` ride salts possess similar miotic activity, studies showed '
`
`2'
`
`"
`
`that solid pilocarpine alginate flakes constricted pupil size
`7' 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
`i; action through salt formation; they showed that the dis-
`: tribution of several antibiotics could be markedly altered
`by merely preparing macromolecular salts. Since macro-
`'1". molecules and colloidal particles have an affinity for the
`3' 13mlphatic system, streptomycin, neomycin, viomycin, and
`
`streptothrycin were combined with high molecular weight
`compounds such as polyacrylic acids, sulfonic or phos-
`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 LD50 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—
`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 studies
`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-
`ministration of amino acids with aminoglycoside antibi-
`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 pantothen‘a‘te
`also were synthesized and shown to be less toxic than the
`sulfate. Of the salts prepared, the ascorbate had the highest
`LD50.
`The vitamins most commonly used for forming salts
`exhibiting reduced toxicity are ascorbic and pantothenic
`acids. Keller et all. (23) were the first to use pantothenic
`acid as a means of “detoxifying” the basic streptomyces
`antibiotics. Parenteral administration of the pantothen-
`ates of streptomycin and dihydrostreptomycin had a sig—
`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-
`tion in rats, it produced less irritation than the phos-
`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
`
`Apotex Exhibit 1009.005
`
`Apotex Exhibit 1009.005
`
`

`

`1‘
`
`I
`
`3
`
`'
`
`_j-
`
`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-
`- hexylsulfamic acid salts, better known as cyclamates, have
`a characteristic sweet, pleasing taste. Although presently
`under investigation by the FDA for potentially carcino-
`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-
`scribed as good when maintained at a pH not greater than
`4.
`
`'
`
`N-Cyclohexylsulfamic acid salts of thiamine hydro-
`chloride and lincomycin also have been synthesized. Thi-
`amine N—cyclohexylsulfamate hydrochloride was reported
`to have a' more 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 by
`pothesis that reduced lincomycin absorption in the pres-
`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 syrnptomatology of penicillin re-
`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-
`fluence on the symptoms of penicillin sensitivity, they
`contribute directly to the potential of drug sensitivity when
`co-adrninistered with penicillin.”
`Silver salts of sulfanilamide, penicillin, and other anti-
`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 of the 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 (38741). Synthesis of these xanthine salts was an at-
`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-
`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-
`thines studied as potential salt-forming agents. Since the
`report on the preparation of the 8-chlorotheophyllinesalt .
`of diphenhydramine (42), synthesis of the 8-halotheo-
`phyllinates of a number of organic bases has been at-
`tempted. The 8—chlorotheophylline salts of quinine,
`ephedrine, and strychnine were prepared and character-
`ized (43). 'These salts were less water soluble than the
`corresponding free alkaloidal bases. In a similar report, the
`8-chlorotheophyllinates of three synthetic narcotics,
`meperidine, levorphanol, and metopon, were prepared
`(44).
`,
`Pharmacological and clinical studies involving the 8-
`bromotheophylline pyrilamine salt revealed the unusual
`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'bI‘Or
`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-
`phyllinates showed greater activity in every case.
`With the successful formation of 8—halotheophyllinates
`of organic bases, Morozowich and Rope {48) proposed that,
`if the halogen moiety was replaced with a more electro-
`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-
`ative in the stomach would be less likely to occur. On this
`premise, they successfully prepared pharmacologically
`effective 8-nitrotheophyllinates of several pharmaceuti-
`_cally useful bases.
`Dueselet al. (19), in their study of choline theophylli-
`nate, prepared the 8—chloro-, 8-bromo-, and 8—nitrotheo—
`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-
`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»
`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 reachiand then be removed fromfi
`the Site of action. Thus, a knowledge of the physicochem-
`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-
`
`Apotex Exhibit 1009.006
`
`
`
`Apotex Exhibit 1009.006
`
`

`

`Table III—Potentially Useful Salt Forms of Pharmaceutical Agents
`
`
` Salt—Forming Agent Compound Modified Modification
`
`
`
`Reference
`
`Acetylaminoacetic acid
`NsAcetyl-L-asparagine
`NAAcetylcystine
`Adamantoic acid
`Adipic acid
`N-Alkylsulfamatcs
`
`Anthraquinonev1,57disulfonic acid
`Arabogalactan sulfate (arabino)
`Arginine
`'
`Aspartate
`Betaine
`Bis(2-carhoxychromon—5—yloxylalkanes
`Carnitine
`4AChlorormstoluenesulfonic acid
`Decanoate
`Diacetyl sulfate
`Dibenzylethylenediamine
`Diethylarnine
`Diguaiacyl phosphate
`Dioctyl sulfosuccinate
`Embonic (pamoic) acid
`
`Fructose 1,6-diphosphorie acid
`
`Glucose lrphosphoric acid, glucose
`6—phosphoric acid
`LeGlutamine
`Hydroxynaphthoate
`2—(4-huidazolyl)ethylamine
`lsobutanolamine
`Lauryl Sulfate
`Lysine
`
`'
`
`Methanesulfonic aci'cl
`NrMethylglucam'me
`
`N-Methylpiperazine
`Morpholjnc
`27Naphthalenesulfonic acid
`Octanoate
`Probenecid
`Tannic acid
`Theobromine acetic acid
`3,4,57’1‘rin1ethoxybenzoate
`
`Tromethamine
`
`Doxycycline
`Erythroruycin
`Doxycycline
`Alkylhiguanides
`Piperazine
`Ampicillin
`Lincomycin
`Cephalexin
`Various alkaloids
`Cephalosporins
`u-Sulfobenzylpenioillin
`Erythromycin
`_ Tetracycline
`7—(Aminoalkyl)theophyllines
`Metformin
`Propoxyphene
`Heptaminol
`Thiamine
`Ampicillin
`Cephalosporins
`Tetracycline
`Vincamine
`Kanamycin
`2-Phenyl—3—1nethylmorpholine
`Tetracycline
`Erythromycin
`Tetracycline
`Erythrornycin
`Erythrornycin
`Bephenium
`Prostagland in
`Theophylline
`Vincamine
`cr-Sulfobenzylpenicillin
`Cephalosporins
`Pralidoxime (2-PAM)
`a—Sulfobenzylpenicillin
`Cephalosporins
`Phenylhutazone
`Cephalosporins.
`Propoxyphene
`Heptaminol
`Pivampicillin
`Various amines
`Propoxyphene
`Tetracycline
`Heptaminol
`Aspirin
`Dinoprost (prostaglandin F2")
`
`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
`
`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
`
`Solubility
`Toxicity, stability, hygroscopicity
`Reduced pain on injection
`Toxicity, faster onset of action
`Reduced pain on injection
`Organoieptic properties
`Prolonged action
`Organoleptic properties
`Prolonged action
`Activity
`Organoleptic properties
`Prolonged action
`Absorption (oral)
`Physical state
`
`:
`
`tion, the relative toxicity, and the possible routes of ad-
`ministration (2).
`In a review in 1960, Miller and Holland (92) stated that
`“different salts of the same drug rarely differ pharmaco-
`logically; the differences are usually based on the physical
`properties.” In a subsequent review (93), Wagner ex—
`' 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-
`ciably, the intensities of response may differ markedly.
`The salt form is known to influence a number of physi-
`cochemical properties of the parent compound including
`7.
`f__ dissolution rate, solubility, stability, and hygroscopicity.
`These properties, in turn, affect the availability and for-
`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—
`
`.
`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—
`peutic dose. The original compound, the methiodide, had
`the disadvantages of limited aq