Appendix
`
`Contents
`
`by P. Heinrich Stahl
`
`1. Usage Frequency of Acids and Bases for Forming Drug Salts
`
`2. Tables of Salt-Forming Acids and Bases
`List of Salt Formers
`
`GRAS and ADI
`
`3. Diagrams
`
`3.1. Nomographs for Predicting pH Values of Aqueous Solutions of Salts
`
`3.2. Aqueous Solutions of Lactic Acid
`' REFERENCES
`
`1. Usage Frequency of Acids and Bases for Forming Drug Salts
`
`In the updated survey [1] of their earlier review [2] on salts of drug sub-
`stances, Berge, Bighley, and Monkhouse listed the currently used salt forms
`of drugs based on the monographs in The Martindale Extra Pharmacopoeia
`
`1993. They found 113 different anions (of which 13 are inorganic) and only
`38 different cations (ll of them inorganic).
`
`A survey in the 1995 issue of Index Nominum led to the following results:
`
`
`Number of drug salts
`with counter—ion
`
`acidic
`
`Total
`
`1820
`
`1346
`
`basic
`
`474
`
`Percentage
`
`73.96%
`
`26.04%
`
`Involved number of different
`
`acids (anions)
`
`cations (bases)
`
`l4
` Total
`
`organic
`
`inorganic
`
`101
`
`7
`
`1 08
`
`23
`
`3 7
`
`The surveys make apparent that acids by far outnumber the bases in their
`function as pharmaceutical salt formers. An important reason for the scarcity
`of available bases may be the fact that several nitrogenous bases themselves
`
`Apotex Exhibit 1022.001
`
`Apotex Exhibit 1022.001
`
`

`

`330
`
`PHARMACEUTICAL SALTS:
`
`exert biological and pharmacodynamic activities, and indeed the majority of
`drug substances are bases. Also most inorganic cations, within certain limits of
`
`concentration and intake, fulfill essential biological functions, and, for this
`
`reason, they can serve as relatively ‘inert’ counter-ions only in exceptional
`cases.
`
`A more realistic picture of the present frequency of use is obtained, when
`current national desk—top references of drugs on national markets are con-
`sulted. As an example the German ‘Rote Liste 1999’ renders the following fig—
`ures:
`
`
`
`Number of drug salts
`with counter—ion
`
`acidic
`
`Total
`
`Percentage
`
`820
`
`612
`
`74.63%
`
`Involved number of different
`
`acids (anions)
`
`
`
`organic
`
`inorganic
`
`46
`
`9
`
`55
`
`[ Total
`
`Interestingly, although the number of drug salts is less than half of the
`number listed in a cumulative drug inventory, the ratio of basic to acidic drug
`substances is identical. The frequency of the most relevant acids and bases is
`
`shown graphically in Figs. 1 and 2.
`
`
`
`Hydrochloride
`
`shaded, organic acid
`
`Sulfate
`
`Hydrobromide
`Tartrate
`
`Mesyiate
`Maleate
`Citrate
`
`Phosphate
`Acetate
`Pamoate/Embonate
`
`Hydroiodide
`Nitrate
`Lactate
`
`Methylsuliate
`Fumarale
`
`black, mineral acid
`
`0
`
`10
`
`2o
`
`30
`
`4o
`
`50
`
`60
`
`Frequency of Salt-Forming Acids [%]
`
`Fig. 1. Distribution of salts with the 15 most frequently occurring acids (anions)
`
`Apotex Exhibit 1022.002
`
`Apotex Exhibit 1022.002
`
`

`

`
`
`PROPERTIES, SELECTION, AND USE 331
`
`Calcium
`Potassium
`
`Magnesium
`Meglumine
`Ammonium
`Aluminum
`Zinc
`
`Piperazine
`Tromethamine
`Lithium
`Choline
`
`i---_____________-_________._______i
`
`Diethylamine
`4-Phenylcyclohexylamine
`Benzathine
`
`_
`
`"A --____M,_-_.-s__,.-Muwhmq
`.
`I
`black, mineral bases
`i
`shaded, organic bases l
`
`o
`
`10
`
`20
`
`so
`
`40
`
`50
`
`60
`
`Frequency of Salt-Forming Bases [°/o]
`
`Fig. 2. Distribution of salts with the 15 most frequently occurring bases (cations)
`
`2. Tables of Salt-Forming Acids and Bases
`
`List of Salt Formers
`
`The comprehensive reviews on pharmaceutical salts by Berge, Big/Iley,
`and Monk/muse [1] [2] are frequently referred to when the formation of salts
`of an new chemical entity is considered. While these authors presented the
`results of a survey on the approval status of drug salts 25 years ago, the
`present-day situation is different. Accumulated knowledge and experience
`
`has led to a reduction of the number of acids and bases regarded as innocu-
`
`ous. Moreover, national health authorities reacted in different ways to certain
`
`findings in this area. Therefore, it was deemed timely to put up a revised list
`of useful salt-forming acids and bases.
`In the following tables, an attempt has been made to group the salt-form-
`ing acids and bases into classes offirst, second, and third choice. The follow—
`ing criteria for assignment to the respective classes were applied.
`
`1. First Class salt-formers are those of unrestricted use for that purpose be-
`
`cause they form physiologically ubiquitous ions, or because they occur as
`intermediate metabolites in biochemical pathways. The first group is typ-
`ically and quite impressively represented by the past and present use fre—
`
`quency of hydrochlorides/chlorides and sodium salts. The second group
`
`comprises many acids present in food of vegetable origin, or those gen-
`
`erated in the body’s metabolic cycles.
`
`Apotex Exhibit 1022.003
`
`Apotex Exhibit 1022.003
`
`

`

`
`
`332 PHARMACEUTICAL SALTS:
`
`2. Second Class salt-formers are considered those that are not natUrally oc—
`curring, but, so far, during their profuse application have shown low tox-
`
`icity and good tolerability.
`
`3. Third Class salt-formers might be interesting under particular circum-
`
`stances in order to achieve special effects such as ion-pair formation. or
`
`for solving particular problems. Some of them are assigned to this class
`
`because they have their own pharmacological activity. Also some of the
`
`acids and bases were used much less frequently in the past. No prohibi-
`
`tive adverse findings are currently known to the author except those in—
`
`dicated in the monographs (cf. Chapt. 12).
`
`The reader is also referred to Chapt. 5, Sect. 3.3.3, for further comments
`on the classification, also to the remarks on individual acids and bases in the
`
`monographs of Chapt. 12.
`
`It is recommended to search for the latest safety records in the RTECS in-
`
`ventory and in literature at the time when a Class3 acid or base would be
`considered for salt formation with an NCE.
`
`GRAS and ADI
`
`While there is a chance to change unfavorable drug properties to the bet-
`
`ter by selecting less commonly used salt formers, there may be limitations
`with respect to the acceptability. Some substances may be considered-unob-
`jectionable because they are used profusely in food processing. This is indi—
`cated by an ADI (=Acceptable Daily Intake) assigned to them (WHO); in the-
`USA, the FDA grants the GRAS (= ‘Generally Regarded As Safe’) status to
`
`food additives and processing aids [3][4].
`The ADI for man, expressed on a body weight basis, is the amount of a .
`food additive that can be taken daily in the diet. even over a lifetime, with-
`out risk.
`
`An ADI is assigned by the Joint FAO/WHO Expert Committee on Food
`Additives only to those substances for which the available data include either
`the results of adequate short-term and long-term toxicological investigations,
`or satisfactory information on the biochemistry and metabolic fate of the
`
`compound, or both.
`
`An ADI without an explicit indication of the upper limit of intake (‘ADI
`not specified’) may be assigned to substances of very low toxicity, especial-
`ly those that are food constituents or that may be considered as foods or nor—
`mal metabolites in man.
`,
`While the ADI is limiting for the use of additives in food, it has no legal
`
`significance for the use in drug preparations. Nevertheless, this value serves
`
`as a reference mark for pharmaceutical applications.
`
`Apotex Exhibit 1022.004
`
`Apotex Exhibit 1022.004
`
`

`

`PROPERTIES, SELECTION, AND USE
`
`333
`
`Abbreviations in Tables I —8: A: indicates an acidic pKa; B: indicates a
`basic pKa; Mr: relative molar mass; ADI: accepted daily intake (WHO); n.s.:
`
`ADI notsspecified; GRAS: +: ‘generally regarded as safe’, #2 some of the salts
`
`are GRAS. Values given in italics were estimated with PALLAS pKalC 3.2
`
`(CompuDrug Chemistry Inc).
`
`Apotex Exhibit 1022.005
`
`Apotex Exhibit 1022.005
`
`

`

`334
`
`PHARMACEUTICAL SALTS:
`
`Class Acid
`
`Table 1. Acids: Alphabetical Order
`
`(+1-Camphor—10-su1fonic acid
`
`232.29
`
`Capric acid (decanoic acid)
`
`Capmic acid (hexanoic acid)
`
`Caprylic acid (octanoic acid)
`Carbonic acid
`
`Cinnamic acid
`
`Citric acid
`
`Cyclamic acid
`
`Decanoic acid (sec capric acid)
`
`Dodccylsulfuric acid
`Ethane-1,2-disu1fonic acid
`
`Ethanesult‘onic acid
`
`172.27
`
`I 16.16
`
`[44.22
`44.01
`
`148.16
`
`192.13
`
`179.24
`
`266.40
`190.20
`
`1 10.13
`
`Ethancsulfonic acid. 2—hydroxy— 126.13
`Formic acid
`46.02
`
`Fumaric acid
`
`Galactaric acid
`
`Gcnlisic acid
`
`DaGlucoheptonic acid
`D—Gluconic acid
`
`D~Glucur0nic acid
`
`Glutamic acid
`
`Gluiaric acid
`
`Gluturic acid. 2—ox0—
`
`Giyccrophosphoric acid
`
`Glycolic acid
`
`1 16.08
`
`210.14
`
`154.12
`
`226.18
`196.16
`
`194.14
`
`147.13
`
`132.12
`
`146.10
`
`172.08
`
`76.05
`
`l 3 1 2 1 l 2 2 3 2 3 1 3 2 l 3 I 2
`
`'JJNNNN
`[JI-iH
`
`I—I-IN—I—nI—H
`
`Acetic acid
`
`Acetic acid, 2,2-dichloro-
`
`Adi pic acid
`
`Alginic acid
`L-Aswrbic acid
`
`[:Aspartic acid
`Benzencsulfonic acid
`
`Benzoic acid
`
`Benzoic acid. 4—aceiamido-
`
`(+)-Camphoric acid
`
`240 000
`176.13
`
`133.11
`158.18
`
`122.12
`
`179.18
`
`200.24
`
`
`
`>>>>>>>>>>>>>>>>>>
`>>>>>>>>>>>>>>>>
`
`Hexanoic acid (see mpmic acid)
`
`Hippuric acid
`
`179.17
`
`Apotex Exhibit 1022.006
`
`Apotex Exhibit 1022.006
`
`

`

`PROPERTIES, SELECTION, AND USE
`
`335
`
`Table 1 (com)
`
`
`
`NMN~——Nu—N—Ibd
`
`wuu—u—u—u—nw-MMNN-N—NNN
`
`
`
`Hydrobromic acid
`Hydrochloric acid
`
`Isobulyric acid
`Dl.-Lactic acid
`
`Lactobionic acid
`
`Lauric acid
`
`Malcic acid
`
`(—)-l.-Malic acid
`
`Malonic acid
`
`DL—Mandelic acid
`
`Methanesulfonic acid
`
`80.92
`36.46
`
`88.11
`90.08
`
`358.30
`
`200.32
`
`116.08
`
`134.09
`
`104.06
`
`152.15
`
`96.10
`
`Mucic acid (see galacmric acid}
`
`Naphthalene—1.5-disulfonic acid 332.26
`
`Naphthalene-Z-sulfunic acid
`
`2-Naphthoic acid. l-hydroxy-
`Nicolinic acid
`
`Nitric Acid
`
`Octanoic acid (see mprylic acid)
`Olcic acid
`
`()rotic acid
`
`Oxalic acid
`
`Palmitic acid
`
`Pamoic acid (embonic acid)
`
`Phosphoric acid
`
`Propionic acid
`
`(—)-L—Pyroglulamic acid
`
`Salicylic acid
`
`Salicylic acid. 4-amino—
`
`Sebacic acid
`
`Slearic acid
`
`Succinic acid
`
`Sulfuric acid
`
`(+1—L-Tartaric acid
`
`Thiocyanic acid
`
`p-Toluenesulfonic acid
`
`Undecylcnic acid
`(undec—lO—cnoic acid)
`
`208.24
`
`188.17
`123.11
`
`63.02
`
`282.45
`
`156.10
`
`90.04
`
`256.42
`
`388.38
`
`98.00
`
`74.08
`
`129.11
`
`138.12
`
`153.14
`
`202.25
`
`284.49
`
`118.09
`
`98.08
`
`150.09
`
`59.09
`
`172.21
`
`184.27
`
`
`
`>>>>>>>>>>>>>>>>>>
`
`
`
`>>>>>>>>>>>
`
`>>>>>
`
`
`
`Apotex Exhibit 1022.007
`
`Apotex Exhibit 1022.007
`
`

`

`336
`
`PHARMACEUTICAL SALTS:
`
`Table 2. Acids: Sorted by Increasing pK“ Value
`
`Class Acid
`
`up 10
`
`Status
`
`>>>>>>>>>>>>>>>>>>>>>>>>>>>
`
`
`>>>>
`
`>
`
`
`
`Decanoic acid (sec cupric acid)
`
`Hexanoic acid (see c-aproic acid)
`
`Mucic acid (see galacmric acid)
`
`Octanoic acid (see caprylic acid)
`
`Hydrobromic acid
`
`Hydrochloric acid
`
`Naphthalene—l.5~disulfonic acid
`Sulfuric acid
`
`Ethane-l .2-disulf0nic acid
`
`Cyclamic acid
`
`p—Toluenesulfonic acid
`
`Thiucyanic acid
`Nitric Acid
`
`Methanesulfonic acid
`
`Dodecylsulfuric acid
`
`Naphthalene—Z—sulfonic acid
`Benzenesulfonic acid
`
`Oxalic acid
`
`Acetic acid. 2.2-dichlom-
`
`Glycerophosphoric acid
`
`Ethanesulfonic acid. 2-hydroxy-
`
`L—Aspanic acid
`Malcic acid
`
`Phosphoric acid
`Elhancsulfcnic acid
`
`(+)-Camphor-10-sulf0nic acid
`Gluiamic acid
`
`Alginic acid
`
`Pamoic acid (embonic acid)
`
`Glularic acid. 2—0x0—
`
`2-Naphlhoic acid. l-hydroxy-
`Malonic acid
`
`Genlisic acid
`
`Salicylic acid
`
`(+)—L-Tartaric acid
`
`80.92
`
`36.46
`
`332.26
`
`98.08
`
`190.20
`
`179.24
`
`172.21
`
`59.09
`
`63.02
`
`96.10
`
`266.40
`
`208.24
`
`158.18
`
`90.04
`
`128.95
`
`172.08
`
`126.13
`
`133.1 1
`
`1 16.08
`
`98.00
`
`1 10.13
`
`232.29
`
`147.13
`
`240 000 2 2.4
`388.38
`
`146.10
`
`188.1?1
`
`104.06
`
`154.12
`
`138.12
`
`150.09
`
`3 1 2 l 2 2 2 l 3 2 2 2 2 2 3 l 2 1 1 l 2 3 l 2 2
`
`. 2 2 2 2 3 l l
`
`
`
`Fu maric acid
`
`116.08
`
`Apotex Exhibit 1022.008
`
`Apotex Exhibit 1022.008
`
`

`

`PROPERTIES. SELECTION, AND USE
`
`337
`
`
`
`Table 2 (cont)
`
`Mi
`
`pKan
`
`
`
`GRAS
`Status
`
`Ga1aclaric acid
`
`Citric acid
`
`I)»Glucur0nic acid
`
`Lactobionic acid
`
`Salicylic acid, 4-aminn—
`
`Gl'ycolic acid
`
`D-Glucoheplonic acid
`
`(—1-[.-Pyr0g1ulamic acid
`D1.-Mandclic acid
`
`(—1-L-Malic acid
`
`Hippuric acid
`Formic acid
`
`D-Gluconic acid
`
`DL-Laclic acid
`
`Oleic acid
`
`L-Ascorbic acid
`
`Bcnmic acid
`
`Succinic acid
`
`210.14
`192.13
`
`3.08
`3.128
`
`194.14
`
`3.18
`
`358.30
`
`153.14
`
`76.05
`
`226.18
`
`129.11
`
`3.2
`
`3.25
`
`3.28
`
`3.3
`
`3.32
`
`152.15
`
`3.372
`
`A 3.63
`A 4.761
`
`A
`A 6.396
`
`A
`
`n.5,
`
`+
`
`A
`
`A
`
`A [0
`
`A 3.5
`
`B
`
`A
`
`A
`
`A
`
`A
`
`134.09
`
`3.459
`
`A 5.097
`
`A
`
`179.17
`
`46.02
`
`196.16
`
`90.08
`
`3.55
`
`3.75
`
`3.76
`
`3.86
`
`282.45
`
`(a. 4
`
`[76.13
`
`122.12
`
`4.17
`
`4.19
`
`A
`
`A
`
`A
`
`A
`
`A
`
`A 11.57
`
`A
`
`A
`
`+
`
`#
`
`+
`
`+
`
`+
`
`n.s.
`
`50
`
`n.s.
`
`
`
`
`mI————NNNm—N——u_mflN~N—_u—uuN—_MNH_—
`
`N
`
`
`
`Benzoic acid. 4—acetamido—
`
`179.18
`
`4.3
`
`A
`
`118.09
`
`4.207
`
`A 5.635
`
`Glutaric acid
`Cinnamic acid
`
`. Adipic acid
`Scbacic acid
`
`(+)—Camphoric acid
`Acetic acid
`
`Caproic acid (hexanoic acid)
`Nicotinic acid
`
`lsobutyric acid
`
`Propionic acid'
`
`Capric acid (dccanoic acid)
`Lauric acid
`
`Palmitic acid
`
`Slcaric acid
`
`Undccylcnic acid
`(undcc-lO—enoic acid)
`
`13212
`
`4.34
`
`A 5.27
`
`148.16
`
`4.404
`
`A
`
`146.14
`
`202.25
`
`4.44
`
`4.59
`
`A 5.44
`
`A 5.59
`
`200.24
`
`4.716
`
`A 5.83
`
`60.05
`
`4.756
`
`A
`
`116.16
`123.11
`
`88.11
`
`74.08
`
`172.27
`200.32
`
`256.42
`
`284.49
`
`184.27
`
`4.8
`4.85
`
`4.86
`
`4.87
`
`4.9
`4.9
`
`4.9
`
`4.9
`
`4.9
`
`A
`A 2.07
`
`A
`
`A
`
`A
`A
`
`A
`
`A
`
`A
`
`
`
`
`
`+
`
`4-
`
`+
`
`+
`
`+
`
`+
`
`5
`
`rm.
`
`n.s.
`
`n.s
`11.5.
`
`n.s.
`
`n.s.
`
`n.s.
`
`A
`
`A
`
`A
`
`A
`
`A
`
`B
`
`Caprylic acid (octanoic acid]
`Orotic acid
`
`144.22
`156.10
`
`4.91
`5.85
`
`A
`A 8.95
`
`A
`
`Carhdnic acid
`
`44.01
`6.46
`A 10.3
`A
`Lil's.
`+
`
`Apotex Exhibit 1022.009
`
`Apotex Exhibit 1022.009
`
`

`

`338
`
`PHARMACEUTICAL SALTS:
`
`Table 3. Acids: Sorted by Increasing Molecular Weight
`
`
`
`Decanoic acid 1 sec capric avid)
`Hexanoic acid (sec ('apmic acid)
`
`Mucic acid (sec gaiaclaric arid}
`
`Octanuic acid (566 capryiir arid)
`
`Hydrochloric acid
`Carbonic acid
`
`Formic acid
`
`Thiocyanic acid
`Acetic acid
`
`Nitric Acid
`
`Propionic acid
`
`Glycnlic acid
`
`Hydrobromic acid
`
`Isobutyric acid
`Oxalic acid
`
`DL—Lactic acid
`
`Meihanesulfonic acid
`
`Phosphoric acid
`Suii‘uric acid
`
`Malonic acid
`
`Elhancsuifonic acid
`
` 6.46
`
`3.75
`
`—I.33
`
`4.756
`
`—1.32
`
`4.87
`
`3.28
`
`4.86
`
`1.271
`
`3.86
`
`—l.2
`
`1.96
`
`36.46
`
`44.01
`
`46.02
`
`59.09
`
`60.05
`
`63.02
`
`74.08
`
`76.05
`
`80.92
`
`88.1 l
`
`90.04
`
`90.08
`
`96. IO
`
`98.00
`
`98.08
`
`104.06
`
`2.826
`
`1 10.|3
`
`2.05
`
`10.3
`
`4.266
`
`7.12
`
`1.92
`
`5.696
`
`n.s.
`
`n.s.
`
`n.s.
`
`[1.5.
`
`n.s.
`
`6
`
`12.32
`
`A
`
`
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+ + +
`
`,
`
`+
`
`+
`
`ms.
`
`n.s.
`
`n3.
`
`9.60
`
`B
`
`>>>>
`
`6.23
`
`5.635
`
`2.07
`
`5.27
`
`3.65
`
`5.097
`
`13.82
`
`>>
`
`
`
`5 +
`
`.
`
`Apotex Exhibit 1022.010
`
`A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A
`
`
`
`1 16.08
`
`| 16.08
`
`1 16.16
`
`3.03
`
`1.92
`
`4.8
`
`1 18.09
`
`4.207
`
`122.12
`
`123.1 I
`
`126.13
`
`128.95
`
`129.1 1
`
`132.12
`
`133.1 1
`
`134.09
`
`138.12
`
`144.22
`
`4. 19
`
`4.85
`
`[.66
`
`1.35
`
`3.32
`
`4.34
`
`1.88
`
`3.459
`
`2.97
`
`4.91
`
`146.10
`
`2. 7
`
`146.14
`
`4.44
`
`Fumaric acid
`
`Malcic acid
`
`Caproic acid (hexanoic acid)
`Succinic acid
`
`Benzoic acid
`
`Nicminic acid
`
`Ethanesulfonic acid. 2-hydroxy-
`Acetic acid. 2.2—dichloro-
`
`(—J-L-Pyrogiutamic acid
`Glularic acid
`
`L-Aspartic acid
`
`(—i—L—Malic acid
`
`Salicylic acid
`
`Caprylic acid (octanoic acid)
`Glutaric acid. 2-0x0—
`
`Adipic acid
`
`l I 3 l l 3 2 l 3 2 2 l 2 l I 2 2 l 1 3 I 2 2 2 3 2 l l l 3 2 2 l
`
`Apotex Exhibit 1022.010
`
`

`

`339
`PROPERTIES, SELECTION, AND USE
`
`Table 3 (cont)
`
`I-I- pKuz
`
`147.13
`
`4.25
`
`Glutamic acid
`Cinnamic acid
`
`(+)-L-Tartaric acid
`
`DL-Mandelic acid
`
`Salicylic acid. 4-amin0-
`Gcnlisic acid
`
`Orotic acid
`
`Benzenesulfonic acid
`
`Glycerophosphoric acid
`
`p-Toluenesuifonic acid
`
`Ciipric acid (decanoic acid)
`L-Ascorbic acid
`
`Hippuric acid
`
`Benzoic acid, 4-acetamid0—
`
`Cyclamic acid
`
`I
`
`Undecylenic acid
`(undec-l 0-enoic acid)
`
`
`
`148.16
`
`4.404
`
`150.09
`
`3.02
`
`4.36
`
`1'0
`
`8. 95
`
`6.19
`
`11.57
`
`152.15
`
`3.372
`
`153.14
`
`154.12
`
`156.10
`
`158.18
`
`172.08
`
`3.25
`
`2.93
`
`5.85
`
`0.7
`
`1.47
`
`172.21
`
`—1.34
`
`172.27
`
`176.13
`
`179.17
`
`179.18
`
`179.24
`
`184.27
`
`4.9
`
`4.17
`
`3.55
`
`4.3
`
`~ —2.01'
`
`4.9
`
`2-Naphthoic acid. l—hydroxy-
`
`188.17
`
`2. 7
`
`13.5
`
`190.20
`
`—2.1
`
`>
`
`WNblh—r—i—NI-INNNEAUHU-I
`NNNNr-tNNh‘uHHNHh-‘NHHMNN
`
`Ethane- 1.2-disu1fonic acid
`
`Citric acid
`
`D-Glucuronic acid
`
`D-Gluchic acid '
`
`(+)—Camph0ric acid
`Lauric acid
`
`Scbacic acid
`
`Naphthalene—2—su1fnnic acid
`Galactaric acid
`
`D-Glucohcptonic acid
`
`(+)—Camph0r-10-su1f0ni‘c acid
`Palmitic acid
`
`liodecylsulfuric acid
`Oleic acid
`
`Stearic acid
`
`Naphthalene—1.5-disulfonic acid
`Laclobionic acid
`
`Pamoic acid (embonic acid)
`
`192.13
`
`194.14
`
`196.16
`
`200.24
`
`200.32
`
`202.25
`
`208.24
`
`210.14
`
`226.18
`
`232.29
`
`256.42
`
`266.40
`
`282.45
`
`284.49
`
`332.26
`
`358.30
`
`388.38
`
`Alginic acid
`
`240 000
`
`3.128
`
`3.18
`
`3.76
`
`4.716
`
`4.9
`
`4.59
`
`0.17
`
`3.08
`
`3.3
`
`2.17
`
`4.9
`
`—0.()9
`
`ca. 4
`
`4.9
`
`—3.37
`
`3.2
`
`2.51
`
`> 2.4
`
`
`
`>>>>>>>>>>>>>>>>
`>>>>>>>>>>>>>>>>>>>>
`
`
`
`71.5
`
`4.761
`
`5.59
`
`3.63
`
`A
`
` 6.396
`
`Apotex Exhibit 1022.011
`
`Apotex Exhibit 1022.011
`
`

`

`340
`
`PHARMACEUTICAL SALTS:
`
`Table 4. Acids: Sorted by Class
`
`
`
`Status
`
`Decanoic acid (see capric acid)
`
`Hexanoic acid (sec capror'c arid)
`
`Mucic acid (see galacraric acid)
`
`
`Octanoic acid (see c'apljvlic acid)
`
`Class 1
`
`Acetic acid
`
`Adipic acid
`L—Ascorbic acid
`
`L-Aspariic acid
`
`Capric acid (decanoic acid)
`Carbonic acid
`
`Citric acid
`
`Fumaric acid
`
`Gaiactaric acid
`
`D-Glucoheptonic acid
`D-Gluconic acid
`
`D—Glucuronic acid
`
`Glutamic acid
`
`Glularic acid
`
`Glycerophosphon'c acid
`
`60.05
`
`146.14
`176.13
`
`133.] l
`
`[72.27
`44.01
`
`192.13
`
`116.08
`
`210.14
`
`226. l 8
`196.16
`
`194.14
`
`147.13
`
`132.12
`
`172.08
`
`
`
`A
`
`A
`A
`
`A
`
`A
`A
`
`A
`
`A
`
`A
`
`A
`A
`
`A
`
`A
`
`A
`
`A
`
`+
`
`+
`
`+
`
`#
`
`+
`
`
`
`’
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`Glycolic acid
`
`Hippuric acid
`
`Hydrochloric acid
`DL-Lactic acid
`
`Laurie acid
`
`Maleic acid
`
`(—)-L—Ma1ic acid
`
`Palmitic acid
`
`Phosphoric acid
`Sebacic acid
`
`Stearic acid
`
`Succinic acid
`
`Sulfuric acid
`
`(+)-L-Tartaric acid
`
`76.05
`
`179.17
`
`36.46
`90.08
`
`200.32
`
`1 16.08
`
`134.09
`
`256.42
`
`98.00
`202.25
`
`284.49
`
`118.09
`
`98.08
`
`150.09
`
`A
`
`A
`
`A
`A
`
`A
`
`A
`
`A
`
`A
`
`A
`A
`
`A
`
`A
`
`A
`
`A
`
`Thiocyanic acid
`
`59.09
`
`A
`
`Class 2
`
`Alginic acid
`240 000 _>_ 2.4
`A
`+
`Benzenesulfonic acid
`.
`A
`
`+
`
`Benzoic acid
`
`A
`
`Apotex Exhibit 1022.012
`
`Apotex Exhibit 1022.012
`
`

`

`341
`PROPERTIES, SELECTION, AND USE
`
`Table 4 (cont.)
`
`(+)—Camph0ric acid
`
`200.24
`
`4.716
`
`A 5.83
`
`A
`
`Caprylic acid (octanoic acid)
`
`144.22
`
`4.91
`
`Cyclamic acid
`
`179.24
`
`~ —2.01
`
`Dodecylsulfuric acid
`
`266.40
`
`“0.09
`
`A
`
`A
`
`A
`
`Ethane-1,2-disulf0nic acid
`
`190.20 —2.1
`
`A —l.5
`
`A
`
`~ Ethanesulfonic acid
`
`110.13
`
`2.05
`
`
`
`A
`
`A
`A
`
`Ethanesulfonic acid, 2—hydroxy— 126.13
`Gentisic acid
`154.12
`
`1.66
`2.93
`
`Glutaric acid, 2—oxo—
`
`146.10
`
`2.7
`
`A 4.5
`
`A
`
`Isobutyric acid
`
`Lactobionic acid
`
`Malonic acid
`
`88.11
`
`358.30
`
`4.86
`
`3.2
`
`A
`
`A
`
`104.06
`
`2.826
`
`A 5.696
`
`Methanesulfonic acid
`
`96.10
`
`—1.2
`
`A
`
`Naphthalene-1.5-disulf6nic acid
`
`332.26 —3.37
`
`A —2.64
`
`Napht_halene-2-sulf0nic acid
`
`2—Naphth0ic acid, l-hydroxy-
`Nicotinic acid
`
`208.24
`
`188.17
`123.11
`
`0.17
`
`2.7
`4.85
`
`A
`
`A 13.5
`A 2.07
`
`Oleic acid
`
`282.45
`
`ca. 4
`
`A
`
`5.85
`
`A 8.95
`
`A
`
`A
`
`A
`B
`
`A
`
`
`
`
`
`
`
`Apotex Exhibit 1022.013
`
`Orotic acid
`
`Oxalic acid
`
`156.10
`
`90.04
`
`1.271
`
`A 4.266
`
`Pamoic acid (embonic acid)
`
`388.38
`
`2.51
`
`A 3.1
`
`A
`
`A
`
`Propionic acid
`
`(—)—L—Pyr0g1ulamic acid
`
`74.08
`
`129.11
`
`4.87
`
`3.32
`
`A
`
`A
`
`
`p-Toluenesulfonic acid
`172.21
`—1.34
`A
`
`Class 3
`
`
`
`Acetic acid. 2,2-dichloro-
`
`Benzoic acid, 4-acetamid0-
`
`128.95
`
`179.18
`
`1.35
`
`4.3
`
`' (+)-Camphor~10—sulf0nic acid
`
`232.29
`
`2.17
`
`Caproic acid (hexanoic acid)
`Cinnamic acid
`
`Formic acid
`
`Hydrobromic acid
`
`DL-Mandelic acid
`
`Nitric Acid
`
`Salicylic acid
`
`Salicylic acid. 4-amino-
`
`Undecylenic acid
`(undec— 1 0—enoic acid)
`
`116.16
`148.16
`
`46.02
`
`80.92
`
`152.15
`
`63.02
`
`138.12
`
`153.14
`
`184.27
`
`4.8
`4.404
`
`3.75
`
`< ~6
`
`3.372
`
`41.32
`
`2.97
`
`3.25
`
`4.9
`
`
`
`A
`
`A
`
`A
`
`A
`A
`
`A
`
`A
`
`A
`
`A
`
`A 13.82
`
`A
`
`
`
`A [0
`
`A
`
`A 3.5
`
`Apotex Exhibit 1022.013
`
`

`

`342
`
`PHARMACEUTICAL SALTS:
`
`Table 5. Bases: Alphabetical Order
`
`
`
`Calcium hydroxide
`1
`l
`Choline
`
`2
`Beam]
`
`3 Dielhunolamine
`
`
`
`(2.2'-iminobis(ethnnol))
`
`
`
`2 Diethylamine
`
`2
`
`Ethanol. 2-(diethylamino)—
`
`Elhanolamine (2-aminoethunol)
`
`Ethylenediamine
`
`Glucumine. N—methyl-
`
`l
`
`Lysine
`
`73.14
`
`l 17.|9
`
`61.08
`
`60.10
`
`195.22
`
`596.99
`
`l Magnesium hydroxide
`
`58.33
`
`2 Morpholine. 4-(2-hydroxyethy1)- 131.18
`
`Piperazine
`
`86.14
`
`Potassium hydroxide
`
`Pyrrolidine, 1-(2-hydroxyethyl)-
`
`1
`3
`
`3
`
`
`
`
`3
`l
`
`
`2 Hydrubamine
`
`3
`lH—lmidazole
`
`
`
`3
`
`
`56.11 m. 14
`1
`2
`
`
`Sodium hydroxide
`Tricthanoiamine
`
`
`(2.2'.2"—nitrilotriMethanol))
`Tromethamine
`
`
`Zinc hydroxide
`
`Cluss Base
`
`Mr
`
`l
`
`Ammonia
`
`174.20
`
`
`
`L-Arginine
`l
`2
`Benethamine
`
`2
`Benzuthine
`
`2
`Betuine
`
`
`
`pKul
`
`9.27
`
`13.2
`4,46
`
`9.99
`
`12.16
`
`126
`> 1
`1
`
`8.83
`
`9.28
`
`10.93
`
`9.58
`
`9.50
`
`7.00
`
`8.03
`
`11.92
`7.03
`
`l0.79
`
`I 1.4
`
`7.39
`
`5.68
`
`9.44
`
`ca. 14
`7.82
`
`8.02
`
`m. 14
`
`
`
`
`
`
`
`2.16
`
`9.09
`
`9.39
`
`11.57
`
`10.09
`
`11.32
`
`9.18
`
`9.82
`
`9.64
`
`
`
`WUJCUEUCUEUtUtUCU
`USUJUJCDWCDUUWUUWUJUJCUWCD
`
`DOW
`
`GRAS
`Status
`
`
`
`Apotex Exhibit 1022.014
`
`Apotex Exhibit 1022.014
`
`

`

`PROPERTIES, SELECTION. AND USE
`
`Table 6. Bayes: Sorted by Decreasing pKu Value
`
`343
`
`GRAS
`Status
`
`Class Base
`
`
`
`
`
`2.18
`
`9.64
`
`9.09
`
`1 1.57
`
`11.32
`
`2.16
`
`B B
`
`9.18
`
`9.39
`
`Apotex Exhibit 1022.015
`
`B B
`
`10.09
`
`9.82
`
`
`
`Potassium hydroxide
`
`Sodium hydroxide
`
`Zinc hydroxide
`
`L-Arginim:
`
`Calcium hydroxide
`Bctuine
`
`Hydrubumine
`
`Magnesium hydroxide
`Choline
`
`Dielhy1amine
`
`Lysine
`Benzathine
`
`Ethanol. 2-(diethy1amin01-
`
`Ethanolamine (Z-aminoethunol)
`
`Pyrrolidine. l-(2-hydroxyethyl)-
`Dielhanolamine
`(2;2'-imin0bis(ethan01))
`Ammonia
`
`Deanol
`
`Glucamine, N—methyl—
`Tromethamine
`
`Triethanolamine
`( 2.2‘,2"-nitrilolris(ethanol ))
`
`Morpholine. 4—(2-hydroxyethy1)-
`lH-lmidazole
`
`Ethylenediamine
`
`
`
`mthNv—‘INi—It—NNI—I—m—n—L
`
`Loam—NI-
`Nth-IUN_
`
` ca. 14
`
`('u. 14
`
`('a. 14
`
`13.2
`
`12.6
`
`12.16
`
`11.92
`
`11.4
`
`> 1
`
`l
`
`10.93
`
`10.79
`
`9.99
`
`9.58
`
`9.50
`
`56.1 1
`40.00
`
`99.38
`
`174.20
`
`74.10
`
`117.15
`
`596.99
`
`58.33
`
`121.18
`
`73.14
`
`146.19
`
`240.35
`
`117.19
`
`61.08
`
`115.18
`
`9.44
`
`105.14
`
`9.28
`
`17.03
`
`89.14
`
`195.22
`
`121.14
`
`149.19
`
`9.27
`
`8.83
`
`8.03
`
`8.02
`
`7.82
`
`131.18
`
`7.39
`
`68.08
`
`7.03
`
`60.10
`
`7.00
`
`86.14
`
`wmwmmwwmmwwmmmmm
`
`WWWDJUU
`CUUJWDDW
`
`
`
`5.68
`Piperazine
`
`Benethamine
`197.28 4.46
`
`
`Apotex Exhibit 1022.015
`
`

`

`344
`
`PHARMACEUTICAL SALTS:
`
`Table 7. Bases: Sorted by Increasing Molecular Weight
`
`pKM
`
`pKa:
`
`Ammonia
`
`Sodium hydroxide
`
`Potassium hydroxide
`
`Magnesium hydroxide
`
`Ethylenediamine
`
`Ethanolamine (2-aminoeihanol)
`1H-lmidazole
`
`Diethylflmine
`
`Calcium hydroxide
`
`Piperazine
`Deane]
`
`Zinc hydroxide
`Dielhanolamine
`
`(2,2'-iminobis(ethan01)1
`
`Pyrrolidinc. 1—(2—hydroxyethy1)—
`Betaine
`
`9.27
`17.03
`40.00 m. 14
`
`56.1] ca. 14
`
`58.33
`
`60.10
`
`61.08
`
`68.08
`
`11.4
`
`7.00
`
`9.50
`
`7.03
`
`73.14 10.93
`
`74.10
`
`86.14
`
`12.6
`
`5.68
`
`39.141 8.83
`
`99.38 ca. 14
`
`105.14
`
`115.18
`
`9.28
`
`9.44
`
`117.15 12.16
`
`Ethanol, 2-(diethylamino)-
`Tromethamine
`
`117.19
`
`121.14
`
`9.58
`
`8.02
`
`Choline
`
`Morpholine, 4-(2-hydr0xyethyl)-
`
`Lysine
`Triethanolamine
`
`(2.2',2"-nitrilotris(ethan01))
`
`L-Arginine
`
`Glucamine. N—methyl-
`Benethamine
`
`Benzathine
`
`Hydrabam i n e
`
`
`
`121.18 >11
`
`131.18
`
`7.39
`
`146.19 10.79
`
`149.19
`
`7.82
`
`174.20
`
`13.2
`
`195.22
`
`8.03
`
`197.28
`
`4.46
`
`240.35
`
`9. 99
`
`596.99 11.92
`
`
`
`WLAJNWr—INMUJWI-‘i-l-‘H
`unNn-ANNNN
`NNNb—‘r—
`
`
`
`wwwwWwwmwwwww
`WCUCUUJWUUWUJ
`wwwwm
`
`10.09
`
`11.57
`
`9.82
`
`9.64
`
`9.18
`
`9.09
`
`9.39
`
`11.32
`
`Status
`
` GRAS
`+++a4=
`
`
`
`
`
`
`
`
`
`Apotex Exhibit 1022.016
`
`Apotex Exhibit 1022.016
`
`

`

`PROPERTIES, SELECTION, AND USE
`
`345
`
`Table 8. Bases: Sorted by Class
`
`pKfl:
`
`pKaj
`
`
`
` Class ‘1
`
`
`
`9.27
`B
`
`13.2
`B 9.09
`B 2.18
`
`
`
`B
` Betaine
`
`CUDUUJUUUUUUWUUUJUU
`
`
`
` 10.09
`WWWCUUUCU
`
`Ammonia
`
`L-Arginine
`
`Calcium hydroxide
`Choline
`
`. Glucamine, N-methyl-
`
`Lysine
`
`Magnesium hydroxide
`
`Potassium hydroxide
`
`Sodium hydroxide
`
`
`
`
`Benethamine
`Benzathine
`
`Deanol
`
`Diethylamine
`
`
`
`
`
`12.6
`> 11
`
`8.03
`
`10.79
`
`1 1.4
`
`(a. 14
`
`B 1 1.57
`B
`
`B
`
`B
`
`B 9.18
`
`B 2.16
`
`B
`
`B
`
`
`ca. 14
`B
`
`9.99
`
`12.16
`
`8.83
`
`10.93
`
`9.58
`
`11.92
`
`7.39
`
`9.44
`8.02
`
`EthanoL 2-(diethy1amino)-
`
`Hydrabamine
`
`Morpholine. 4-(2-hydroxyethyl)-
`
`Pyrrolidine. 1-(2-hydr0xyethy1)-
`Tromethamine
`
`1 15.18
`121.14
`
`
`Class 3
`
`Diethanolamine
`
`105.14
`
`9.28
`
`(2.2'-iminobis(ethanol))
`
`Ethanolamine (2-aminoethan01)
`
`61.08
`
`Ethylenediamine
`lH-Imidazole
`
`. Piperazine
`Trieihanolamine
`
`60.10
`
`68.08
`
`86.14
`
`149.19
`
`9.50
`
`7.00
`
`7.03
`
`5.68
`
`7.82
`
`9.82
`
`(2.2',2"-nitrilotris(ethanol))
`
`Zinc hydroxide
`
`99.38
`
`ca. 14
`
`US
`
`9.64
`
`Apotex Exhibit 1022.017
`
`Apotex Exhibit 1022.017
`
`

`

`346
`
`PHARMACEUTICAL SALTS:
`
`3. Diagrams
`
`3.1. Nomographs for Predicting pH Values of Aqueous Solutions of Salts
`
`The following diagrams are designed for quickly estimating the pH of
`aqueous solutions of a salt, if the pKu value of the constituting drug base is
`known. Prediction of pH is particularly useful in cases of intended salts of
`weak and very weak bases. If calculated pKa values [5] are entered into the
`diagrams, the expected aqueous pH values and pH ranges of certain salts can
`be estimated even before a compound is synthesized.
`Diagrams are provided for three of the most frequently used acids for
`salts of basic drug substances: hydrochloric, sulfuric, and maleic acid. The
`
`graphs have been calculated based on exact equations for pH calculation pre-
`
`sented in [7].
`
`As the pH of an aqueous salt solution depends not only on the nature of
`the constituting salt ions but also on their concentrations. the pH functions
`are presented for the molar concentrations 0.01 to 1.0M.
`How to read pH values from the graphs is shown in Fig. 4,a for the sul-
`fates of the weakly basic fungicide econazole as an example, with a calculat-
`ed pKu value of 6.4. For the hydrogen sulfate, Base+- HSOJ. at concentra-
`tions 0.01 -0. l M, the pH would range between 2.2 and 1.55, whereas a 0.05M
`solution of the neutral sulfate, (Base+)2 - 804—. is expected to measure pH 4.3.
`Fig. 3, drawn for hydrochlorides, can also be used for salts of other very
`strong acids with pKa values below —1, e.g., for methanesulfonates. The
`course of the pH curves of the bivalent acids demonstrates the extent of the-
`typical pH—lowering effect of the acid salts (Figs. 4 and 5; hydrogen sulfates.
`hydrogen maleates). The very low dependence of the pH on concentration of
`maleates exemplifies the buffering effect of organic acids of moderate
`strength.
`'
`
`3.2. Aqueous Solutions of Lactic Acid
`
`As described in the monograph on lactic acid in Chapt. 12, the composi-
`tion of aqueous solutions of lactic acid depends on the concentration. Fig. 6
`shows the relationship between free and polymerized lactic acids as a func-
`tion of the water content.
`
`Apotex Exhibit 1022.018
`
`Apotex Exhibit 1022.018
`
`

`

`PROPERTIES, SELECTION, AND USE
`
`347
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`t
`
`
`0
`
`2
`
`I
`
`4
`
`8
`6
`pKa of Base
`
`1O
`
`12
`
`14
`
`I
`
`Hydrochloride
`
`i E
`
`i‘I
`Eiii
`fx
`
`V niifimwmwm---------------~
`
`pKa of Base
`
`Fig. 3. pH of hydrochlorides dependent on the pKu 0f the conjugate base. Top: Base pKu
`range 0— 14; bottom: base pKu range 0—6
`
`Apotex Exhibit 1022.019
`
`Apotex Exhibit 1022.019
`
`

`

`348
`
`PHARMACEUTICAL SALTS:
`
`a)
`
`5 _
`[5m
`-
`7“'#
`_
`4. _____ 0.005 ____________________
`“
`0.010
`4 't— 0.025
`~
`0.050
`
`'
`
`Neutral Sulfate
`
`3
`
`2
`
`1
`
`0
`
`ID
`
`.
`
`
`
`
`
`
`
`
`
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`pKa of Base
`
`
`
`
`Hydrogen Sulfate
`
`pKa of Base
`
`Fig. 4. pH of sulfates and hydrogensul'fates depena'en.r an the pKu of the conjugate base.
`(1) Example of reading pH for the acid sulfate (lines entered: C'=0.0lM and 0.1M, resulting pH:
`2.2 and 1.6) and for the neutral sulfate (line entered: 2c = 0.05M, resulting pH: 4.3) of a weak
`base, pKu=6.4 (e.g., econazole); b) base pK‘1 range 0— 14; c) base pKfl range 0—6.
`
`Apotex Exhibit 1022.020
`
`Apotex Exhibit 1022.020
`
`

`

`PROPERTIES, SELECTION, AND USE
`
`349
`
`I
`
`-
`
`NeutralSulfate I.
`
`
`
`.C)
`
`4
`
`3
`
`10
`
`
`
`
`pKa of Base
`
`Fig. 4 (cont)
`
`
`
`
`
`
`Neutral Maleate
`
`
`
`Hydrogen Maleate
`
`
`
`
`01_1_1_;|_._|__|_|_+_|_1_|_|_+_4_1__41i
`
`Fig. 5. pH of maleates and hydrogenmaleates dependent on the pKa 0f the conjugate base
`
`pKa of Base
`
`Apotex Exhibit 1022.021
`
`Apotex Exhibit 1022.021
`
`

`

`350
`
`120
`
`100
`
`80
`
`4—:
`5
`o
`g 60
`(I)
`a
`E 40
`
`20
`
`o
`100
`
`20
`80
`
`60
`4o
`40
`so
`Mass Per Cent
`
`30
`20
`
`o
`100 LacticAcid
`0 Water
`
`Fig. 6. Lactic acid in aqueous solution: free lactic acid (FLA) and degree of polymerization
`( DP) in relation to the total content of titrated acid (TLA), calculated as lactic acid as a func-
`tion of the water content (drawn from values tabulated in [6])
`
`REFERENCES
`
`[I] L. D. Bighiey, S. M. Berge. D. C. Monkhouse, in ‘Encyclopedia of Pharmaceutical Tech-
`nology', Eds. J. Swarbrick and J. C. Boylan, Vol. 13, Marcel Dekker, Inc.. New York.
`Basel, Hong Kong. 1995. pp. 453—499.
`S. M. Berge, L. D. Bighley, D. C. Monkhouse, J. Pharm. Sci. 1977, 66, 1—19.
`[2]
`[3] Code of Federal Regulations. 2lCFRl70 (Internet source: www.access.gpo.gov/nara/cfr/
`indexahtmi).
`
`[4] Code of Federal Regulations, 2|CFR182,]84 (Internet source: www.access.gpo.gov/nara/
`cfr/inde.t.httnl).
`[5] D. D. Perrin, B. Dempsey, E. P. Serjeant, ‘pKa Prediction for Organic Acids and Bases’,
`Chapman and Hall, London, New York, 198].
`[6] C. H. Holten, Contribut., A. Muller, D. Rehbinder, “Lactic Acid. Properties and Chemis-
`try of Lactic Acid and Derivatives’, Verlag Chemie, Weinheim. 1971.
`[7] C. Bliefert. ‘pH-Wert-Berechnungen’, Verlag Chemie. Weinheim. l978.
`
`-
`
`Apotex Exhibit 1022.022
`
`PHARMACEUTICAL SALTS:
`
`5
`
`4 C
`.9
`a
`':
`3 0’E
`2
`E
`H—
`2 3
`aD}
`
`mD
`
`1
`
`
`
`Apotex Exhibit 1022.022
`
`