`
`
`
`JANUARY 1977
`
`Volume 66 Numberi
`
`JOURNAL OF
`aaNet ACEUTICAL
`FXeIENCES (8)
`
`
` A publication of the American Pharmaceutical Association
`
`Coden: JPMSAE 66(1) 1-148 (1977)
`
`sk24P
`PHARMACY LIBRARY
`SCHOCL OF PHARMACY
`
`
`
`Apotex Exhibit 1009.001
`
`Apotex Exhibit 1009.001
`
`

`

`Journal of
`Pharmaceutical
`Sciences
` VOLUME 66 NUMBER 1
`
`JANUARY 1977
`
`MARY H. FERGUSON
`Editor
`
`L. LUAN CORRIGAN
`Assisiant Hditor
`
`SHBLLY ELLIOTT
`~ Production Editar
`
`JANET B. SHOFF
`Copy Editor
`
`EDWARD G. FELDMANN
`Contributing Editer
`
`SAMUBI. W. GOLDSTEIN
`Contributing Editar
`
`LELAND J. ARNEY
`Director of Publications
`
`EDITORIAL ADVISORY BOARD
`
`JOHN AUTIAN
`
`HARRY B. KOSTENBAUDER
`
`NORMAN R.
`FARNSWORTH
`
`HERBERT A. LIEBERMAN
`
`WILLIAM 0. FOYE
`
`’ WILLIAM J. JUSKO
`
`DAVID E. MANN, JR.
`GERALD J. PAPAREELLO
`
`The fournal of Pharmaceutical Sciences is published
`monthly by the American Pharmaceutical Association at _
`2215 Constitution Ave., N.W., Washington, DC 20087.
`Second-class postage paid at Washington, D.C., and at. ad-
`ditional mailing office.
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`_ expressing the policies or views of the American Pharma-
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`Offices—Editorial, Advertising, and Subscription Of-
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`Subscription rates are subject. to change without notice.
`_ Membersof the American Pharmaceutical Association may
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`Claims—Missing numbers will not be supplied if dues
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`Change of Address—Members and subscribers should
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`© Copyright 1977, American Pharmaceutical Association,
`2215 Constitution Ave., N.W., Washington, DC 20037; all
`tights reserved.
`
`
`
`
`
`
`
`THE “DUMB COPS” IMAGE
`
`Oneday this pastfall 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 fo promote meansto control the problems of drug
`‘abuse was a bit later than usual this year.
`Upon turningto the Proclamationinthat 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
`and certainly not after the observanceis 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
`primary responsibility for the subject area. In this instatice, 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
`questionthat the agency has beenclearly at fault for a long string of other
`foul-ups and errors which, in toto, project the image of an inefficient,
`bungling agency.
`- When DEAwas originally established some half-dozen yearsor so ago,
`astrong 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. Departmentof
`‘Health, Education, and Welfare rather than the Departmentof Justice.
`Others, however, argued vocally that drug abuse control basically is a
`regulatory and enforcementactivity 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 whereofficial notices,
`proposals, or finalized regulations issuing from DEA and publishedin 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 andoffered assistance in this regard. Not only
`did the DEAfail to take advantageof 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
`
`

`

`
`
` 7
`Journal of
`Pharmaceutical
`Sciences
`
`JANUARY 1977
`VOLUME 66 NUMBER. 1
`
` © R
`
`EVIEW ARTICLE
`
`Pharmaceutical Salts
`
`i
`
`STEPHEN M. BERGE *+, LYLE D. BIGHLEY *, and
`DONALD C. MONKIIOUSE *
`
`
`
`_Keyphrases O Pharmaceutical salts—general pharmacy, physico-
`chemical properties, bioavailability, pharmaceutical properties, toxi-
`cology, review O Salts, pharmaceutical—general pharmacy, physico-
`chemical properties, bioavailability, pharmaceutical properties, toxi-
`cology, review O Physicochemical properties—dissolution, solubility,
`stability, and organoleptic properties of pharmaceutical salts, review O
`Bioavailability—formulation effects, absorption alteration and phar-
`macokinetics of pharmaceutical salts, review O Toxicology—pharma-
`ceuticalsalts, review
`
`CONTENTS
`
`2
`Potentially Useful Salts ....-......Decca cece eee eee eee
`4
`Physicochemical Studies 2.0.0... 00 0 cee cence tenet enenes
`Dissolution Rate... cece ee eects 5
`Solubility 2.00.00. cee eee eee e ens 7
`Orgaholeptic Properties ....... deen e eee eeeeae 8
`Stability . 0.00. cc cee eee eee ee
`9
`Miscellaneous Properties .......0. 00000 c cece eee eee ees
`10
`Bioavailability oo. 00.60 0c cece ce ccc cee ens ence nee eeeaeees
`10
`Formulation Effects .......0 0.000 c cece een eee nena
`Ii
`Absorption Alteration .....0..0. 000s ccc c tence wees anaes
`li
`Pharmacokinetics ....0...000.000cc cece e eset ee reeteeenees
`13
`General Pharmacy... ccc ccc cece lee cee ee eee ents
`14
`Pharmacological Effect
`...........0.2 00: s esses eeu seen 14
`Dialysis oo. 000. ccc cece eta e ere eects ere etna eee 14
`Miscellaneous
`........0000 00 cece eee cee teeta teen eee 14
`Toxicological Considerations ....2.c.cecceeecuceueuecetuees
`15
`Toxicity of Salton .. 2.0.20. c cece cece eee eter eeneeeeee
`15
`Toxicity of Salt Form ......04-2 020 e cece ee eee ete eee eens
`15
`. Conclusions seen ee tect e ete e eens Lec ccauueeeeusuetcauanes
`16
`References .. cc cc ccc cc cee usec ccue ee eeetseeseneeenes Levee
`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 he a very
`difficult task, since each salt imparts unique properties to
`the parent compound.
`
`Salt-forming agents are often chosen empirically. Of the
`manysalts 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 flowabitity 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 thesalt
`mostlikely to exhibit the desired pharmacokinetic, solu-
`bility, and formulation profiles.
`,
`Somedecision-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 biologicalproperties of these
`specific derivatives and offer a promising avenuefor 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 candidates-can be chosen and
`
`Vol. 66, No. 1, January 1977 / 1
`
`Apotex Exhibit 1009.003
`
`Apotex Exhibit 1009.003
`
`

`

`Table I-FDA-Approved Commercially Marketed Salts
`
`Percent
`
`*Anion
`
`Percent?
`
`Anion
`
`Acetate
`Benzenesulfonate
`Benzoate
`Bicarbonate
`Bitartrate
`Bromide
`Calcium edetate
`- Camsylate*
`Carbonate
`Chloride
`Citrate
`Dihydrochloride
`Edetate
`Edisylate®
`Estolate®
`Esylate®
`Fumarate
`Gluceptate!
`Gluconate
`Glutamate
`Glycollylarsanilate#
`Hexylresorcinate
`Hydrabamine*
`Hydrabromide
`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 |
`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
`
`
`Cation
`Percent™
`
`Organie:
`Benzathine*
`Chloroprecaine
`Choline
`.
`Diethanolamine
`Ethylenediamine
`Megiumine’
`Procaine
`
`:
`
`0.66
`0.338
`0.338
`0.98
`0.66
`3,99
`0.66
`
`:
`
`;
`Iodide
`Tsethionate!
`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 -
`Teociate/
`Triethiodide
`
`Cation
`
`Metallic:
`Aluminum
`Calcium
`Lithium
`Magnesium
`Potassium
`Sedium
`Zine
`
`2.02
`0.88
`0.76
`0.18
`0.13
`. 3.03
`0.38
`2,02
`0.76
`- 0.38
`0,88
`0.13
`0.26
`0.64
`1.01
`0.25
`3.16
`0,13
`0.88
`0.25
`0.38
`0.38
`7.46
`0.88
`3.64
`0.18
`0.13
`
`Pereent*
`
`0.66
`10.49
`1.64
`L31
`10.82
`61.97
`2.95
`
`© Percent is based on total number of anionic or cationic salts in use through 1974. * Camphorsulfonate. © 1,2-Ethanedisulfonate. ? Lauryl sulfate.
`* Kthanesulfonate. / Glucoheptonate. 2 p-Glycollamidophenylarsonate. * N,N’-Di(dehydroabietylethylenediamine. ‘ 2-Hydroxyethanesulfonate.
`/ &8-Chlorotheophyllinate. * V,N’-Dibenzylethylenediamine. ‘ N-Methylglucamine.
`
`3
`3
`
`
`
`
`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 andis there-
`fore controlled by factors influencing such reactions.
`Theoretically, every compoundthat exhibits acid or base
`characteristics can participate in salt formation. Particu-
`larly important is the relative strength of the acid or
`base—theacidity and basicity constants of the chemical
`species involved. These factors determine whetheror not
`formation occurs and are a measure of the stability of the
`resulting salt,
`The numberof salt forms available to a chemistis large;
`surveys of patentliterature show numerous new salts being
`synthesized annually. Varioussalts 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,”
`
`2 / Journal of Pharmaceutical Sciences’
`
`
`
`26th ed. (7). Table I categorizesall salt forms approved by 4
`
`the Food and Drug Administration (FDA), while Table II
`lists those not approved by the FDA but in use in other :
`countries, (Only salts of organic compounds are considered |
`because most drugs are organic substances.) The relative !
`
`frequency with which eachsalt type has been usedis cal- §
`culated as a percentage, based on the total numberof an-
`
`ionic or cationic salts in use through 1974. Because of !
`simple availability and physiological reasons, the mono- }
`
`protic hydrochlorides have been by far the most frequent 3
`choice of the available anionic salt-forming radicals, out- 4
`numbering the sulfates nearly six to one. For similar rea- 4
`sons, sodium has been the most predominantcation.
`i
`Knowledge that one salt form imparts greater water 3
`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) 3
`discussed some properties associated with specific classes 4
`of salt forms. They stated that, in general, salt combina- %
`tions with monocarboxylic acids are insoluble in water and 4
`lend themselves to repository preparations, while those of 3
`dicarboxylic acids confer water solubility if one carboxylic 4
`group is left free. Pamoic acid, an aromatic dicarboxylic §
`acid,is an exception sinceit is used as a meansof obtaining 4
`prolonged action by forming slightly soluble salts with 3
`certain basic drugs. Saias et al. (9) reviewed the use of this 4
`salt form in preparing sustained-release preparations. 3
`Morerecently, latentiation of dihydrostreptomycin (10) §
`
`Apotex Exhibit 109.004
`
`Apotex Exhibit 1009.004
`
`

`

`.
`
`0.13
`0.13
`0.25
`0.13
`0.13
`0.25
`0.25
`0.13
`0.13
`0.18
`0.13
`0.13
`0.88
`0.13
`0.13
`0.25
`0.13
`0.13
`0.25
`0.13
`0.13
`0.13
`0.18
`6.18
`0.18
`0.13
`0.13
`
`Percent*
`
`0.93
`0.33
`0.33
`0.98
`0.33
`
`0.83
`0.98
`
`‘
`
`Cation
`
`Organic:
`Benethamine®
`Clemizole#
`Diethylamine
`Piperazine
`‘Tromethamine®
`Metallic:
`Barium
`Bismuth
`
`
`:
`| Table 1I—Non-FDA-Approved Commercially Marketed
`streptothrycin were combined with high molecular weight
`compounds such as polyacrylic acids, sulfonic or phos-
`SaliseSOO
`
`phorylated polysaccharides, and polyuronie derivatives.
`Anion
`Percent
`
`Parenteral administration of these compounds produced
`
`Adipate
`low blocd levels of the antibiotic for long periods, while
`Alginate
`lymph levels were high. (In comparison, streptomycin
`Aminosalicylate
`
`sulfate gave high blood levels but low lymphlevels.) This
`Anhydromethylenecitrate
`
`Arecoline
`- alteration in distribution caused the streptomycin to
`Aspartate
`
`prolong its passage through the body, since lymphatic
`Bisulfate
`circulation. is quite slow.
`Butylbromide
`
`Camphorate
`The appropriate choice of a salt form has been found to
`Digluconate _
`
`reduce toxicity. It can be rationalized that any compound
`Dihydrobromide
`
`Disuccinate
`associated with the normal metabolism of food and drink
`
`Glyceraphosphate
`must be essentially nontoxic. The approach of choosing
`Hemisulfate
`
`organic radicals that, are readily excreted or metabolized
`Hydrofluoride
`Hydroiadide
`opened up a newclass of substances from whichto select
`
`Methylenebis(salicylate}
`asalt form. For example, certain salts of the strong base
`_Napadisylate®
`
`choline have proven to be considerably less toxic than their
`Oxalate
`
`Pectinate
`parent compound. The preparation and properties of
`Persulfate
`
`choline salts of a series of theophylline derivatives were
`Phenylethylbarbiturate
`
`Pierate
`reported (19), and it was shown that choline theophyllinate
`Propionate
`
`possessed a greater LDso than theophylline or its other
`Thiocyanate
`salts (20). It was postulated that this agent would be less
`Tosylate
`
`Undecanoate
`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 atternpt to reduce the GI disturbances
`associated with salicylate administration. Clinical studies
`indicated that cholinesalicylate 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 aminoacid salts of
`
`dihydrostreptomycin was prepared (22). In all but one
`using pamoic acid resulted in the formation of a delayed-
`case, the acute toxicities of these salts were lower than the
`action preparation. Numerousstudies using pamoatesalts
`toxicity of the sulfate. The ascorbate and pantothenate
`are dispersed throughout the literature (11-15).
`
`also were synthesized and shownto beless toxic than the
`Alginic acid also has been used to prepare long-acting
`sulfate. Of the salts prepared, the ascorbate had the highest
`pharmaceuticals. Streptomycin alginate was prepared (16)
`LDego.
`and shown to be effective in sustained-release prepara-
`
`The vitamins most commonly used for forming salts
`tions. A striking example of a long-acting alginate salt is
`
`exhibiting reduced toxicity are ascorbic and pantothenic
`_
`that of pilocarpine. When dispersed in sterile water and
`
`acids. Keller et al. (23) were the first to use pantothenic
`_ dried to a solid gel, this compound was found useful in the
`acid as a meansof “detoxifying” the basic streptomyces
`preparation of long-acting ophthalmic dosage forms (17).
`
`antibiotics. Parenteral administration of the pantothen-
`While liquid preparations of the alginate and hydrochlo-
`
`ates of streptomycin and dihydrostreptomycin hada sig-
`tide salts possess similar miotic activity, studies showed -
`nificantly reduced incidence of acute neurotoxicity in cats
`that solid pilocarpine alginate flakes constricted pupil size
`
`as compared with the sulfates. Subsequent studies (24-28)
`- more effectively and increased the duration of miosis sig-
`supported this finding and showed that the pantothenates
`"- nificantly when compared with the liquid preparations.
`
`of neomycin and viomycin also are less toxic. The ascorbate
`:, Solid dose pilocarpine may be more uniformly available,
`
`of oleandomycin was synthesized and its pharmacological
`i. because it diffuses more slowly through the gel matrix
`properties were reported (29). Upon intramuscularinjec-
`» which holds the drugin reserve. In contrast, drops of the
`
`-> commonly employed solution dosage form release the dose
`tion in rats, it produced less irritation than the phos-
`phate.
`--.
`Immediately to the conjunctival fluid.
`
`p-Acetamidobenzoic acid, an innocuous metabolite of
`Malek et al. (18) devised a unique way of prolonging
`folic acid present in normal bleod and urine, has been used
`. action through salt formation; they showed that the dis-
`
`in preparingsalts. In particular, it yields stable salts with
`F.. tribution of several antibiotics could be markedly altered
`by merely preparing macromolecularsalts. Since macro-
`amines that otherwise tend to form hygroscopic products
`with conventional acid components (30).
`FE. -Molecules and colloidal particles have an affinity for the
`~ lymphatic system, streptomycin, neomycin, viomycin, and
`Often the salt form is chosen by determining a salt
`
`Apotex Exhibit 1009.005
`
`“ Percent is based on total numherof anionic and cationic salts in use
`
`through 1974. ® 1,5-Naphthalenedisulfonate. * N-Benzylphenethylamine.
`
`# 1-p-Chlorobenzyl-2-pyrrolidin-1’-ylmethylbenzimidazole. ¢ 'Tris(hy-
`’ droxymethyl}aminomethane.
`
`Val. 66, No. 1, January 1977 / 3
`
`Apotex Exhibit 1009.005
`
`

`

`-
`
`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. Sincethe |
`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-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-
`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-
`negative substituent such as a nitro group, a moreacidic
`compound would be formed. Presumably, morestable salts
`would result and precipitation of the free xanthine deriv-
`ative in the stomach would heless likely to occur. On this
`premise, they successfully prepared pharmacologically
`effective 8-nitrotheophyllinates of several pharmaceuti-
`_cally useful bases.
`Duesele¢ af. (19), im 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 LDsq of the 8-nitrotheophylliate was
`much greater than that of either 8-halotheophylline. In
`fact, tt 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 mucosalirritation. The rationale
`for use of this agentis 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 TableIII.
`
`
`
`component that will pharmacologically antagonize an
`unfavorable property or properties exhibited by the basic
`agent. Saits 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 fer potentially carcino-
`genic properties, salts incorporating this compound can
`render unpleasantor 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 thiaminesalts
`while having an equal or greater stability (32). Lincomycin
`cyelamate, shown to possess an enhanced thermal stability
`over its hydrochloride, was prepared (33) to test the hy-
`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 (84, 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-
`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-administered 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 salis were applied topically to burnedtissue, 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 preparationofa series of antihistamine
`salts (38-41). Synthesis of these xanthinesalts 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
`
`
`
`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—
`the site of action. Thus, a knowledgeef 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
`
`

`

`Solubility
`Solubility, activity, stabilily
`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
`Organoleptie properties
`Prolonged action
`Stahility, 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, hygroseopicity
`
`52
`78
`79
`80
`g1-
`62
`G1
`82
`62
`72
`83
`72
`84
`68
`86
`86, 87
`88
`89
`68
`90
`91
`
`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
`
`Apotex Exhibit 1009.007
`
`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 aqueous solubility and high
`potential toxicity, since its high iodide content could result
`in iodism. On the basis of physiological compatibility,
`better water solubility, favorable stability, and relatively
`high percentage of oxime, the chloridesalt of pralidoxime
`was selected for therapeutic administration; it was claimed.
`that “the anion used to form the salt can confer physical
`properties of importance and significance for the formu-
`lation and administration of the compound” (95).
`Some physicochemical properties of a series of mineral
`acid salts of lidocaine also were determined (96). While the
`hydrochloride and hydrobromide were more hygroscopic,
`‘they were more soluble in a numberof solvents than the
`nitrate, perchlorate, phosphate, or sulfate salts.
`Dissolution Rate—Thedissolution rate of a pharma-
`ceutical agentis of major importanceto the formulator. In
`many cases, particularly with poorly soluble drugs, this
`characteristic best reflects the bioavailability of the com-
`
`Vol. 66, No. 1, January 1977 / §
`
`Table II1I—Potentially Useful Salt Forms of Pharmaceutical Agents
`
`
` Salt-Forming Agent Compound Modified Modification
`
`
`
`Reference
`
`51
`52
`53
`54
`55
`56
`57
`58
`59, 60
`61
`62
`63
`64
`G5
`66
`67
`68
`69
`70, 71
`72
`73
`74
`75
`76
`77
`
`77
`
`Acetylaminoacetic acid
`N-Acetyl-L-asparagine
`N-Acetyleystine
`Adamantoic acid
`Adipie acid
`N-Alkylsulfamates
`
`Anthraquinone-1,5-disulfonic acid
`Arabogalactan sulfate (arabino)
`Arginine
`,
`Aspartate
`Betaine
`Bis{2-carboxychromon-5-yloxyjalkanes
`Carnitine
`4-Chloro-m-toluenesulfonic acid
`Decanoate
`Diacetyl sulfate
`Dibenzylethylenediamine
`Diethylamine
`Diguaiacyl phosphate
`Diocty] sulfesuccinate
`Embonic (pamoic) acid
`
`Fructose 1,6-diphosphoric acid
`
`Glucose 1-phosphoric acid, glucose
`§-phosphoric acid
`L-Glutamine
`Hydroxynaphthoate
`2-(4-bnidazolyljethylamine
`Isobutanolamine
`Lauryl sulfate
`Lysine
`
`:
`
`Methanesulfonic acid
`N-Methylglucamine
`
`N-Methylpiperazine
`Morpholine
`2-Naphthalenesulfonic acid
`Octanoate
`Probenecid
`Tannic acid
`Theobromine acetic acid
`3,4,5-Trimethoxybenzoate
`
`Tromethamine
`
`Doxycycline
`Erythromycin
`Doxycycline
`Alkylbiguanides
`Piperazine
`Ampicillin
`Lincomycin
`Cephalexin
`Various alkaloids
`Cephalosporins
`a-Sulfobenzylpenicillin
`Erythromycin
`. Tetracycline
`7-(Aminoalkyl)theophyllines
`Metformin
`Propoxyphene
`Heptaminol
`Thiamine
`Ampicillin
`Cephalosporins
`Tetracycline
`Vincamine
`Kanamycin
`2-Phenyl-3-methylmorpholine
`‘Tetracycline
`Erythromycin
`‘Petracyciine
`Erythromycin
`Erythromycin
`Bephenium
`Prostaglandin
`Theophylline
`Vincamine
`e«-Sulfobenzylpenicillin
`Cephalosporins
`Pralidoxime (2-PAM)
`e-Sulfobenzylpenicillin
`Cephalosporins
`Phenylbutazone
`Cephalosporins.
`Propoxyphene
`Heptaminol
`Pivampicillin
`Various amines
`Propoxyphene
`Tetracycline
`Heptaminol
`Aspirin
`Dinoprost (prostaglandin F2,)
`
`_
`
`+
`
`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 drugrarely differ pharmaco-
`logically; the differences are usually based on the physical
`properties.” In a subsequent review (93),