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`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1013 - Page 1
`
`

`
`Table l-tr'DA-Approved Commercially Marketed Salts
`Percento
`
`Anion
`
`Percent"
`
`Table II-l
`Salts
`
`Acetate
`Benzenesulfonate
`Benzoate
`Bicarbonate
`Bitartrate
`Bromide
`Calcium edetate
`Camsylateb
`Carbonate
`Chloride
`Citrate
`Dihvdrochloride
`Edetate
`Edisvlate'
`Estoiated
`Esylate"
`Fumarate
`Gluceptate/
`Gluconate
`Glutamate
`Glycollylarsanilater
`Hexvlresorcinate
`Hydrabamineh
`Hydrobromide
`Hydrochloride
`Hydroxynaphthoate
`
`Cation
`
`1.26
`0.25
`0.51
`0.13
`0.63
`4.68
`0.25
`0.25
`0.38
`4.77
`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
`
`,Anion
`
`Iodide
`Isethionatet
`Lactate
`Lactobionate
`Malate
`Maleate
`Mandelate
`Mesvlate
`Metirylbromide
`Methylnitrate
`Methylsulfate
`Mucate
`Napsylate
`Nitrate
`Pamoate (Embonate)
`Pantothenate
`Phosphate/diphosphate
`Polygalacturonate
`Salicylate
`Stearate
`Subacetate
`Succinate
`Sulfate
`Tannate
`Tartrate
`Teoclatej
`Triethiodide
`
`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
`
`Adipate
`Alginate
`Aminosalicyle
`Anhydrometl
`Arecoline
`Aspartate
`Bisulfate
`Butylbromidt
`Camphorate
`Digluconate
`Dihydrobrom
`Disuccinate
`Glycerophosp
`Hemisulfate
`Hydrofluorid
`Hydroiodide
`Methylenebis
`Napadisylate
`Oxalate
`Pectinate
`Persulfate
`Phenylethylb
`Picrate
`Propionate
`Thiocyanate
`Tosylate
`Undecanoate
`
`Cation
`
`Organic:
`Benethami
`Clemizoled
`Diethylami
`Piperazine
`Tromethar
`Metallic:
`Barium
`Bismuth
`
`" Percent ii
`through 1974.
`d 1-p-Chloroi
`droxymethyll
`
`using pam(
`action pret
`are dispers
`Alginic z
`pharmaceu
`and shown
`tions. A str
`that of pik
`dried to a s
`preparatio
`While liqu
`ride salts 1
`that solid 1
`more effec
`nificantly
`Solid dose
`because it
`which holc
`commonly
`immediate
`M6lek e
`action thrr
`tribution c
`by merely
`molecules
`lymphatic
`
`Percent"
`
`Cation
`
`Percent"
`
`Metallic:
`Organic:
`0.66
`Aluminum
`0.66
`Benzathineh
`10.49
`Calcium
`0.33
`Chkrroprocaine
`1.64
`Lithium
`0.33
`Choline
`1.31
`Magnesium
`0.98
`Diethanolamine
`10.82
`Potassium
`0.66
`Ethvlenediamine
`61.97
`Sodium
`2.29
`Megluminel
`2.95
`Zinc
`0.66
`Procaine
`n percent is based on total number ofanionic or cationic salts in use through_1974. bCamphorsulfonate. " 1,2-Ethanedisulfo-nate. d.Lauryl.sulfate.
`";;-dt;"li;ia"pt'""r,t'.""rte. I' AiN' Di(dehydroabietyl)ethylenediamine.
`t 2-Hydroxvethanesulfonate.
`. ntiri"".rirJ""t"-] di;;;1;;;;;;;
`I N-Methylglucamine.
`, g-chlorotheophyltinal,e. h N,N'-Dibenzylethylenediamine.
`
`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 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 of the szrme 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 Pharrnaceuticol 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
`countries. (Only salts of organic compounds are considered
`because most drugs are organic substances.) The relative
`flequency with which each salt type has been used is cal-
`culated as a percentage, based on the total number of 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
`choice of the available anionic salt-forming radicals, out-
`numbering the sulfates nearly six to one. For similar rea-
`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-
`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 ol. (9) reviewed the use of this
`salt form in preparing sustained-release preparations.
`More recently, Iatentiation of dihydrostreptomycin (10)
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1013 - Page 2
`
`

`
`Table l-tr'DA-Approved Commercially Marketed Salts
`Percento
`
`Anion
`
`Percent"
`
`Table II-l
`Salts
`
`Acetate
`Benzenesulfonate
`Benzoate
`Bicarbonate
`Bitartrate
`Bromide
`Calcium edetate
`Camsylateb
`Carbonate
`Chloride
`Citrate
`Dihvdrochloride
`Edetate
`Edisvlate'
`Estoiated
`Esylate"
`Fumarate
`Gluceptate/
`Gluconate
`Glutamate
`Glycollylarsanilater
`Hexvlresorcinate
`Hydrabamineh
`Hydrobromide
`Hydrochloride
`Hydroxynaphthoate
`
`Cation
`
`1.26
`0.25
`0.51
`0.13
`0.63
`4.68
`0.25
`0.25
`0.38
`4.77
`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
`
`,Anion
`
`Iodide
`Isethionatet
`Lactate
`Lactobionate
`Malate
`Maleate
`Mandelate
`Mesvlate
`Metirylbromide
`Methylnitrate
`Methylsulfate
`Mucate
`Napsylate
`Nitrate
`Pamoate (Embonate)
`Pantothenate
`Phosphate/diphosphate
`Polygalacturonate
`Salicylate
`Stearate
`Subacetate
`Succinate
`Sulfate
`Tannate
`Tartrate
`Teoclatej
`Triethiodide
`
`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
`
`Adipate
`Alginate
`Aminosalicyle
`Anhydrometl
`Arecoline
`Aspartate
`Bisulfate
`Butylbromidt
`Camphorate
`Digluconate
`Dihydrobrom
`Disuccinate
`Glycerophosp
`Hemisulfate
`Hydrofluorid
`Hydroiodide
`Methylenebis
`Napadisylate
`Oxalate
`Pectinate
`Persulfate
`Phenylethylb
`Picrate
`Propionate
`Thiocyanate
`Tosylate
`Undecanoate
`
`Cation
`
`Organic:
`Benethami
`Clemizoled
`Diethylami
`Piperazine
`Tromethar
`Metallic:
`Barium
`Bismuth
`
`" Percent ii
`through 1974.
`d 1-p-Chloroi
`droxymethyll
`
`using pam(
`action pret
`are dispers
`Alginic z
`pharmaceu
`and shown
`tions. A str
`that of pik
`dried to a s
`preparatio
`While liqu
`ride salts 1
`that solid 1
`more effec
`nificantly
`Solid dose
`because it
`which holc
`commonly
`immediate
`M6lek e
`action thrr
`tribution c
`by merely
`molecules
`lymphatic
`
`Percent"
`
`Cation
`
`Percent"
`
`Metallic:
`Organic:
`0.66
`Aluminum
`0.66
`Benzathineh
`10.49
`Calcium
`0.33
`Chkrroprocaine
`1.64
`Lithium
`0.33
`Choline
`1.31
`Magnesium
`0.98
`Diethanolamine
`10.82
`Potassium
`0.66
`Ethvlenediamine
`61.97
`Sodium
`2.29
`Megluminel
`2.95
`Zinc
`0.66
`Procaine
`n percent is based on total number ofanionic or cationic salts in use through_1974. bCamphorsulfonate. " 1,2-Ethanedisulfo-nate. d.Lauryl.sulfate.
`";;-dt;"li;ia"pt'""r,t'.""rte. I' AiN' Di(dehydroabietyl)ethylenediamine.
`t 2-Hydroxvethanesulfonate.
`. ntiri"".rirJ""t"-] di;;;1;;;;;;;
`I N-Methylglucamine.
`, g-chlorotheophyltinal,e. h N,N'-Dibenzylethylenediamine.
`
`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 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 of the szrme 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 Pharrnaceuticol 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
`countries. (Only salts of organic compounds are considered
`because most drugs are organic substances.) The relative
`flequency with which each salt type has been used is cal-
`culated as a percentage, based on the total number of 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
`choice of the available anionic salt-forming radicals, out-
`numbering the sulfates nearly six to one. For similar rea-
`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-
`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 ol. (9) reviewed the use of this
`salt form in preparing sustained-release preparations.
`More recently, Iatentiation of dihydrostreptomycin (10)
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1013 - Page 3
`
`

`
`DIUAJJod
`
`poterlretr tr l(lelcreururo3 pero.rcldy-Vqg-uoN-Il olq"I
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`t / lL6I KtnnuoT'L oN'99 toA
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1013 - Page 4
`
`

`
`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 compoqnd can
`render unpleasant or bitter-tasting drugs acceptabie. For
`example, the cyclamates of dextromethorphan and
`chlorpheniramine exhibit greatly improved bitterness
`thresholds compared to commonly occurring salts (81.).
`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 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, myospasmol5rbics, 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-
`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 salts were applied topically to burned tissue, they
`yielded the combined benefits of the oligodlmamic 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-
`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 Z. Thus, these
`
`4 / Journal of Pharmaceutical Sciences
`
`Sal1
`
`Acetylaminoa
`N-Acetyl-L-a
`N-Acetylcyst
`Adamantoic a
`Adipic acid
`N-Alkylsulfar
`
`Anthraquinor
`Arabogalactar
`Arginine
`
`Aspartate
`Betaine
`Bis(2-carboxy
`Carni{ine
`4-Chloro-m-tr
`Decanoate
`Diacetyl sulfa
`Dibenzylethyl
`Diethylamine
`Diguaiacyl ph
`Dioctyl sulfosr
`Embonic (pan
`
`Fructose 1,6-d
`
`,
`
`can undergo ra11 Table III-
`moderately strong acidic compounds
`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-chlorotheophylline salt
`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 g-
`bromotheophylline pyrilamine salt revealed the unusual
`diuretic properties associated with theE-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 (4?). When tested against
`theophylline salts of the same amines, the 8-bromotheo-
`phyllinates showed greater activity in every case.
`With the successful formation of S-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 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.
`Duesel et al. (Lg), 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 LD56 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 demulceni
`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 foui timeJ 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.
`
`Glucose 1-pho
`6-phosphpri
`t,-Glutamine
`Hydroxynaph
`2-(4-lmidazoll
`Isobutanolami
`Lauryl sulfate
`Lvsine
`
`Methanesulfor
`N-Methylgluc
`
`N-Methylpipe
`Morpholine
`2-Naphthalenr
`Octanoate
`Probenecid
`Tannic acid
`Theobromine I
`3,4,5-Trimeth<
`
`Tromethamint
`
`tion, the rel
`ministration
`In a reviel
`"different se
`logically the
`properties."
`panded upor
`nature of th
`salts of the s
`ciably, the ir
`The salt f<
`cochemical tr
`dissolution r
`These prope
`mulation chr
`pharmaceuti
`extensive prr
`properties ol
`suitable form
`concerning s
`tion studies l
`salt form on
`under invest:
`
`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 rernoved from-
`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-
`
`Petitioner Alembic Pharmaceuticals Limited - Exhibit 1013 - Page 5
`
`

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