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 (11 of them inorganic).
`A survey in the 1995 issue of Index Nominumled to the followingresults:
`
`
`Numberof drugsalts
`with counter-ion
`
`
`acidic
`basic
`
`14
` Total
`
`Total
`
`Percentage
`
`1820
`
`1346
`
`73.96%
`
`474
`
`26.04%
`
`Involved numberof different
`
`acids (anions)
`
`cations (bases}
`
`organic
`
`inorganic
`
`101
`
`x
`
`L108
`
`23
`
`37
`
`The surveys make apparent that acids by far outnumberthe 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 pharmacodynamicactivities, and indeed the majority of
`drug substancesare 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 morerealistic 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:
`
`with counter-ion
`
`acidic
`
`Total
`
`Percentage
`
`820
`
`612
`
`74.63%
`
`Involved numberofdifferent
`
`acids (anions)
`
`organic
`
`46
`
`inorganic
`g
`[ Total $5
`
`
`
`Interestingly, although the numberof drug salts is less than half of the
`numberlisted in a cumulative drug inventory, the ratio of basic to acidic drug
`substancesis identical. The frequency of the most relevant acids and basesis
`shown graphically in Figs. / and 2.
`
`
`
`Hydrochloride
`
`
` Numberofdrugsalts
`Fumarate
`
`Sulfate
`
`Hydrobromide
`Tartrate
`
`Mesylate
`Maleate
`Citrate
`
`Phosphate
`Acetate
`Pamoate/Embonate
`
`Hydroiodide
`Nitrate
`
`Lactate
`stake
`ethylsulfate
`
`i
`i
`black, mineral acid
`shaded, organic acid
`
`0
`
`10
`
`20
`
`30
`
`40
`
`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
`
`Sodium
`
`Benzathine
`
`Magnesium
`Megiumine
`Ammonium
`Aluminum
`Zinc
`
`Piperazine
`Tromethamine
`Lithium
`Choline
`
`Diethylamine
`4-Phenylcyclohexylamine
`
`Seee
`black, mineral bases
`’
`shaded, organic bases
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`60
`
`Frequency of Salt-Forming Bases [%]
`
`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, Bighley,
`and Monkhouse [1] [2] are frequently referred to when the formation ofsalts
`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 numberof 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 revisedlist
`of useful salt-forming acids and bases.
`In the following tables, an attempt has been madeto groupthe salt-form-
`ing acids and bases into classesoffirst, second, and third choice. The follow-
`ing criteria for assignment to the respective classes were applied.
`
`|. 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 usefre-
`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 readeris also referred to Chapt. 5, Sect. 3.3.3, for further comments
`on the classification, also to the remarks on individual acids and basesin the
`monographs of Chapt. 12.
`It is recommendedto search for the latest safety records in the RTECSin-
`ventory and in literature at the time when a Class 3 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 ADJ for man, expressed on a body weight basis, is the amountof a |
`food additive that can be taken daily in the diet, even overa lifetime, with-
`out risk.
`An ADIis 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 AD/is limiting for the use of additives in food, it has no legal
`significance for the use in drug preparatioris. 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 1—8: A: indicates an acidic pK,; B: indicates a
`basic pK,; M,: relative molar mass; ADI: accepted daily intake (WHO); n.s.:
`ADI not specified; GRAS: +: ‘generally regarded as safe’, #: some ofthe salts
`are GRAS. Values given in italics were estimated with PALLAS pKaltc 3.2
`(CompuDrug Chemistry Inc.).
`
`Apotex Exhibit 1022.005
`
`Apotex Exhibit 1022.005
`
`

`

`Hippuric acid
`
`wNMNMNwNw
`ypvoo-_= Gentisic acid
`spam Glycolic acid
`
`
`
`rrrrrrPrrrrrrPrPrrerPD
`
`>rrrrrPrprrrrrPprprs
`
`D-Glucuronie acid
`
`Glutamic acid
`
`Glutaric acid
`
`Glutaric acid, 2-oxo-
`
`Glycerophosphoric acid
`
`Hexanoic acid (see caproic acid)
`
`Apotex Exhibit 1022.006
`
`334
`
`Class |Acid
`
`PHARMACEUTICALSALTS:
`
`Table 1. Acids: Alphabetical Order
`
`Acetic acid
`
`Acetic acid, 2,2-dichloro-
`
`Adipic acid
`
`Alginic acid
`L-Ascorbie acid
`
`L- Aspartic acid
`Benzenesulfonic acid
`
`Benzoic acid
`
`Benzoic acid, 4-acetamido-
`
`(+)-Camphoric acid
`
`(+}-Camphor-10-sulfonic acid
`
`Capric acid (decanoic acid)
`
`Caproic acid (hexanoic acid)
`
`Caprylic acid (octanoic acid)
`Carbonic acid
`
`Cinnamic acid
`
`Citric acid
`
`Cyclamic acid
`
`Decanoic acid (see capric acid)
`
`Dodecylsulfuric acid
`Ethane-1,2-disulfonic acid
`
`Ethanesulfonic acid
`
`Ethanesulfonic acid, 2-hydroxy-
`Formie acid
`
`Fumaric acid
`
`Galactaric acid
`
`bD-Glucoheptonic acid
`D-Gluconic acid
`
`1 3 1 2 1 1 2 z 3 2 3 1 3 a 1 3 i 2
`
`Apotex Exhibit 1022.006
`
`

`

`
`
`
`
`isBeeom=Beeeee
`Ceeeaaaaaaaod
`
`memeaeNOONOOUOUD
`>FrPFPFPrerrPerPeererrerPePP
`
`
`Hydrobromic acid
`Hydrochloric acid
`
`Isobutyric acid
`DL-Lactic acid
`
`Lactobionie acid
`
`Laurie acid
`
`Maleic 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 galactaric acid}
`
`Naphthalene-1,5-disulfonic acid
`
`|332.26
`
`Naphthalene-2-sulfonic acid
`
`2-Naphthoic acid, }-hydroxy-
`Nicotinic acid
`
`Nitric Acid
`
`Octanoie acid (see caprvlic acid)
`Oleic acid
`
`
`
`Orotie acid
`
`Oxalic acid
`
`Palmitic acid
`
`Pamoic acid (embonic acid)
`
`Phosphoric acid
`
`Propionic acid
`
`(—)-L-Pyroglutamie acid
`
`Salicylic acid
`
`Salicylic acid, 4-amino-
`
`Sebacic acid
`
`Stearic acid
`
`Succinic acid
`
`Sulfuric acid
`
`(+)-L-Tartaric acid
`
`Thiocyanic acid
`
`p-Toluenesulfonic acid
`
`Undecylenic acid
`(undec-10-enoic acid)
`
`PROPERTIES, SELECTION, AND USE
`
`Class} Acid
`
`Table | (cont.)
`
`>Fr>PS
`
`208.24
`
`188.17
`[233.11
`
`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
`
`335
`
`GRAS
`Status
`
`
`
`Apotex Exhibit 1022.007
`
`Apotex Exhibit 1022.007
`
`

`

`Decanoic acid (see capric acid)
`Hexanoic acid (see capreic acid)
`
`rrrrrrmrmrmrmhUmLUm upto|Status
`
`>PrPrrrrPrrrrrrrerrr
`
`Mucic acid (see galactaric acid)
`
`Octanoic acid (see caprylic acid)
`
`Hydrobromic acid
`
`Hydrochloric acid
`
`Naphthalene-1,5-disulfonic acid
`Sulfuric acid
`
`Ethane-1,2-disulfonic acid
`
`Cyclamice acid
`
`p-Toluenesulfonic acid
`
`Thiocyanic acid
`Nitric Acid
`
`Methanesulfonic acid
`
`Dodecylsulfuric acid
`
`Naphthalene-2-sulfonic acid
`Benzenesulfonie acid
`
`Oxalic acid
`
`Acetic acid, 2,2-dichloro-
`
`Glycerophosphoric acid
`
`Ethanesulfonic acid, 2-hydroxy-
`
`L-Aspartic acid
`Maleic acid
`
`Phosphoric acid
`Ethanesulfonic acid
`
`(+)-Camphor-10-sulfonic acid
`Glutamic acid
`
`Alginic acid
`
`Pamoic acid (embonic acid)
`
`Glutaric acid, 2-oxo-
`
`2-Naphthoic acid, 1-hydroxy-
`Malonic acid
`
`Gentisic acid
`
`Salicylic acid
`
`(+)-L-Tartaric acid
`
`Fumaric acid
`
`
`
`3 1 Z 1 2 2 2 1 3 2 2 2 2 2 3 1 2 1 1 1 2 3 1 2 2 2 2 2 2 3 1 1
`
`336
`
`PHARMACEUTICAL SALTS:
`
`Table 2. Acids: Sorted by Increasing pK,, Value
`
`
`
`Apotex Exhibit 1022.008
`
`Apotex Exhibit 1022.008
`
`

`

`PROPERTIES, SELECTION, AND USE
`
`337
`
`Table 2 (cont.)
`
`M, ADI|GRASpKa
`
`
`upto|Status
`[mg/kg]
`
`
`
`Galactaric acid
`
`210.14|3.08 A |3.63 A
`
`Citric acid
`192.13
`3.128
`A|4.761
`A/6.396
`A]
`ns.
`+
`
`b-Glucuronic acid
`
`Lactobionic acid
`
`194.14
`
`13.18
`
`358.30
`
`a2
`
`A
`
`A
`
`153.14|3.25 A| 10 A} 3.5 B
`
`
`
`
`
`
`
`
`Salicylic acid, 4-amino-
`
`Glycolic acid
`
`76.05|3.28 A
`
`D-Glucoheptonic acid
`
`(—}-L.-Pyroglutamic acid
`DL-Mandelic acid
`
`129.11|3.32 A
`
`152.15
`
`|3.372
`
`A
`
`226.18
`
`3.3
`
`A
`
`(—)-L-Malic acid
`
`134.09
`
`|3,459
`
`A {5.097
`
`A
`
`ns.
`
`“
`
`179.17)|3.55 A
`
`
`Hippuric acid
`Formic acid
`
`
`46.02|3.75 A
`
`DL-Lactic acid
`
`
`90.08|3.86 A +
`
`
`
`D-Gluconic acid
`
`196.16
`
`|3.76
`
`A
`
`50
`
`Oleic acid
`
`282.45
`
`|cea. 4
`
`A
`
`
`
`
`
`L-Ascorbic acid 176.13|4.17 A|11.57 A
`
`
`
`Benzoic acid
`
`Succinic acid
`
`122.12
`
`|4.19
`
`A
`
`+
`
`118.09
`
` |4.207
`
`A {5.635
`
`A
`
`n.s
`
`4.3
`
`A
`
`CdmemesmeNememmaeemeeNeeaNSe
`
`
`
`
`
`
`
`
`
`Benzoic acid, 4-acetamido-
`
`179.18
`
`Glutaric acid
`Cinnamic acid
`
`132.12
`
`|4.34
`
`A|5.27
`
`A
`
`148.16
`
`[4.404
`
`A
`
`
`
`
`
`
`
`
`
`146.14|4.44 A|5.44 A 5 +
`
`
`| Adipic atid
`Sebacic acid
`
`
`202.25|4.59 A|5.59 A
`
`A
`4.8
`{116.16
`Caproic acid (hexanoic acid)
`
`123.11|4.85 A |2.07 B +
`Nicotinic acid
`
`(+)-Camphoric acid
`Acetic acid
`
`200.24
`
`14.716
`
`A/5.83
`
`A
`
`60.05
`
`[4.756
`
`A
`
`n.s.
`
`
`
`Isobutyric acid
`
`Propionic acid’
`
`Capric acid (decanoic acid)
`Lauric acid
`
`Palmitic acid
`
`Stearic acid
`
`Undecylenic acid
`(undec-10-enoie acid)
`
`88.11
`
`74.08
`
`172.27
`200.32
`
`256.42
`
`284.49
`
`184.27
`
`4,86
`
`4.87
`
`49
`49
`
`4.9
`
`49
`
`4.9
`
`A
`
`A
`
`A
`A
`
`A
`
`A
`
`A
`
`DLS.
`
`ns
`ns
`
`n.s
`
`ns.
`
`+
`
`
`
`+
`
`+
`
`
`
`Caprylic acid (octanoic acid) [144.22|4.91 A ns. -
`
`
`Orotic acid
`
`156.10|5.85 AI8.95 A
`
`Carbonic acid
`
`44.01 A|ae + 6.46 A|10.3
`
`
`
`Apotex Exhibit 1022.009
`
`Apotex Exhibit 1022.009
`
`

`

`
`
`1|Thiocyanic acid $9.09 —1,33 A
`
`
`1|Acetic acid 60.05 4.756 - A ns. +
`
`
`
`
`
`
`
`
`
`
`
`3|Nitric Acid 63.02 -1.32 A
`
`
`
`338
`
`PHARMACEUTICALSALTS:
`
`Table 3. Acids: Sorted by Increasing Molecular Weight
`
`Decanoic acid (see capric acid)
`Hexanoic acid (see caproic acid)
`
`Mucic acid (see galactaric acid)
`
`Octanoic acid (see caprylic acid)
`
`1
`
`1
`
`3.
`
`|Hydrochloric acid
`
`|Carbonic acid
`
`|Formic acid
`
`36.46
`
`44.0]
`
`46.02
`
`-6
`
`6.46
`
`3.75
`
`[mg/kg]
`
`.
`
`A
`
`A }10.3
`
`A
`
`A
`
`pKaa
`
`ADI
`up to
`
`ns
`
`ns
`
`2
`
`1
`
`3.
`
`2
`2
`
`1
`
`2
`
`1
`
`1
`
`|Propionic acid
`
`|Glycolic acid
`
`|Hydrobromic acid
`
` |Isobutyric acid
`|Oxalie acid
`
`|DL-Lactic acid
`
`|Methanesulfonic acid
`
`|Phosphoric acid
`
`{Sulfuric acid
`
`74.08
`
`76.05
`
`80.92
`
`88.11
`90.04
`
`90.08
`
`96,10
`
`98.00
`
`98.08
`
`4.87
`
`3.28
`
`<-6
`
`4.86
`L271
`
`3.86
`
`-1.2
`
`1.96
`
`3
`
`n.s.
`
`+
`
`A
`
`A
`
`A
`
`A
`A |4.266
`
`A
`
`A
`
`A
`
`A 7.12
`
`A}1.92
`
`+
`
`+
`
`+
`
`A}12.32
`
`A
`
`A
`
`A
`
`ns.
`
`|2.826
`
`A {5.696
`
`
`
`
`
`1 133.11|1.88|L-Aspartic acid A 3.65 Aj9.60 B
`
`
`
`
`
`3 A|13.82{Salicylic acid 138.12 [2.97 A
`
`
`
`
`
`
`
`1
`
`|(—)-L-Malic acid
`
`134.09
`
`|3.459
`
`A |5.097
`
`A
`
`ns
`
`a
`
`2
`2
`
`|Caprylic acid (octanoic acid)
`|Glutaric acid, 2-oxo-
`
`144.22
`146.10
`
`|4.91
`2¢
`
`A
`A| 4.5
`
`A
`
`ns.
`
`+
`
`
`
`
`
`
`
`1|Adipic acid 146.14 |4.44 A}5.44 A 5 +
`
`
`
`
`
`
`
`Apotex Exhibit 1022.010
`
`
`
`2
`
`|Malonic acid
`
`104.06
`
`
`
`
`
`
`
`2|Ethanesulfonic acid 110.13 |2.05 A
`
`1
`
`1
`
`3
`1
`
`2
`
`2
`
`|Fumaric acid
`
`|Maleic acid
`
`|Caproic acid (hexanoic acid)
`|Succinic acid
`
`|Benzoic acid
`
` |Nicotinic acid
`
`116.08
`
`116.08
`
`116.16
`148.09
`
`122.12
`
`123.11
`
` |3.03
`
`{1.92
`
`4.8
`|4.207
`
`|4,19
`
`14.85
`
`A
`
`A|6.23
`
`A
`A}5.635
`
`A
`
`A |2.07
`
`A
`
`A
`
`A
`
`B
`
`6
`
`ns.
`
`+
`
`+
`
`+
`
`A
` |/.66
`[126.13
`|Ethanesulfonic acid, 2-hydroxy-
`2
`
`3|Acetic acid, 2,2-dichloro- 128.95 11.35 A
`
`
`
`2
`1
`
`|(—)-L-Pyroglutamic acid
`|Glutaric acid
`
`129.1]
`132.12
`
`3.32
`|4.34
`
`A
`A}5.27
`
`A
`
`
`
`
`
`
`
`
`
`Apotex Exhibit 1022.010
`
`

`

`oad
`PROPERTIES, SELECTION, AND USE
`
`Table 3 soni)
`
`a .
`
`Glutamic acid
`Cinnamicacid
`
`147.13
`
`148.16
`
`as
`
`(+)-L-Tartaric acid
`
`DL-Mandelic acid
`
`Salicylic acid, 4-amino-
`Gentisic acid
`
`Orotic acid
`
`Benzenesulfonic acid
`
`Glycerophosphoric acid
`
`p-Toluenesulfonic acid
`
`Caprice acid (decanoic acid)
`L-Ascorbic acid
`
`Hippuric acid
`
`Benzoic acid, 4-acetamido-
`
`Cyclamic acid
`
`Undecylenic acid
`(undec-10-enoic acid)
`
`2-Naphthoic acid, 1-hydroxy-
`
`
`
`150.09
`
`3.02
`
`($2.15
`
`3.372
`
`153.14
`
`£54.12
`
`156.10
`
`158.18
`
`172.08
`
`AS)
`
`293
`
`5.85
`
`0.7
`
`1.47
`
`172.21
`
`—1.34
`
`172.27
`
`176.43
`
`179.47
`
`179.18
`
`179,24
`
`184.27
`
`188.17
`
`4.9
`
`4.17
`
`B35,
`
`4.3
`
`~-2.0!
`
`4.9
`
`2h
`
`—2.]
`
`Status
`
`7
`
`4.25
`
`4.36
`
`10
`
`11.57
`
`13.5
`
`CameetOt
`weONRONONOetet
`
`Ethane-1,2-disulfonic acid
`
`Citric acid
`
`D-Glucuronic acid
`
`D-Gluconic acid *
`(+)-Camphoric acid
`Lauric acid
`
`Sebacic acid
`
`Naphthatene-2-sulfenic acid
`Galactaric acid
`
`D-Glucoheptonic acid
`
`(+)-Camphor-10-sulfonie acid
`Palmitic acid
`Dodecylsulfuric acid
`Oleic acid
`
`Stearic acid
`
`Naphthalene-1,5-disulfonic acid
`Lactobionic acid
`
`Pamoic acid (embonic acid)
`
`Alginic acid
`
`190.20
`
`192.13
`
`194.14
`
`196.16
`
`200.24
`
`200.32
`
`202.25
`
`208.24
`
`240 000
`
`210.14
`
`226.18
`
`232.29
`
`256.42
`
`266.40
`
`282.45
`
`284,49
`
`332.26
`
`358.30
`
`388.38
`
`A GRAS
`
`
`
`>> 6.396
`
`>PPrrr>PerPrrePePePP
`>PFPrPrPrPPrerPrPrPrererPrerPrPPPS
`
`af
`
`4.76}
`
`339
`
`3.63
`
`3.128
`
`3.18
`
`3.76
`
`4.716
`
`4.9
`
`4.59
`
`0.17
`
`3.08
`
`33
`
`2.17
`
`4.9
`
`-0.09
`
`ca. 4
`
`4.9
`
`—3.37
`
`3.2
`
`251
`
`> 24
`
`Apotex Exhibit 1022.011
`
`Apotex Exhibit 1022.011
`
`

`

`340
`
`“
`
`PHARMACEUTICAL SALTS:
`
`Table 4. Acids: Sorted by Class
`
`
`
`GRAS
`Status
`
`Decanoic acid (see capric acid)
`Hexanoic acid (see caproic acid)
`
`Mucic acid (see galactaric acid)
`
`Octanoic acid (see caprvlic acid)
`
`L-Ascorbic acid
`
`L-Aspartic acid
`
`Capric acid (decanoic acid)
`Carbonic acid
`
`Citric acid
`
`Fumaric acid
`
`Galactaric acid
`
`D-Glucoheptonic acid
`D-Gluconic acid
`
`D-Glucuronic acid
`
`Glutamic acid
`
`Glutaric acid
`
`Glycerophosphoric acid
`
`Glycolic acid
`
`Hippuric acid
`
`Hydrochloric acid
`DL-Lactic acid
`
`Lauric acid
`Maleic acid
`
`(—)-L-Malic acid
`
`Palmitic acid
`
`Phosphoric acid
`Sebacic acid
`
`Stearic acid
`
`Succinic acid
`
`Sulfuric acid
`
`(+)-L-Tartaric acid
`
`
`
`60.05
`
`146.14
`
`176.13
`
`133.11
`
`172.27
`44.01
`
`192.13
`
`116.08
`
`210.14
`
`226.18
`196.16
`
`194.}4
`
`147.13
`
`132.12
`
`172.08
`
`76.05
`
`179.17
`
`36.46
`90.08
`
`200.32
`116.08
`
`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
`
`A
`
`A
`
`A
`
`A
`A
`
`A
`A
`
`A
`
`A
`
`A
`A
`
`A
`
`A
`
`A
`
`A
`
`+
`
`+
`
`#
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`+
`
`
`
`Thiocyanie acid
`59.09
`A
`
`Alginic acid
`240 000|> 2.4
`A
`+
`Benzenesulfonic acid
`A
`
`Class 2
`
`+
`
`Benzoic acid
`
`A
`
`Apotex Exhibit 1022.012
`
`Apotex Exhibit 1022.012
`
`

`

`
`
`
`
`Dodecylsulfuric acid 266.40=|--1.09 A
`
`
`
`341
`PROPERTIES, SELECTION, AND USE
`
`Acid
`
`Table 4 (cont.)
`
`(+)-Camphoric acid 200.24=|4.716 A/5.83 A
`
`
`Caprylic acid (octanoic acid)
`144.22
`|4.91
`A
`
`Cyclamic acid
`
`179.24
`
`|~-2.0/)
`
`A
`
`
`
`Ethane-I,2-disulfonic acid
`
`-{Ethanesulfonic acid
`
`190.20
`
`HO:T3
`
`|-2.]
`
`|2.45
`
`Aj-/.5
`
`A
`
`A
`
`Ethanesulfonic acid, 2-hydroxy- |126.13|/.66 A
`
`
`Gentisic acid
`154.12
`42.93
`A
`
`A
` |-1.2
`96.10
`Methanesulfonic acid
`A
`A |-2.64
`|-3.37
`|332.26
`Naphthatene-1,S-disuifonic acid
`
`
`Naphthalene-2-sulfonic acid 208.24=|0.17 A
`
`Glutarie acid, 2-oxo-
`
`Isobutyric acid
`
`Lactobionic acid
`
`Malonic acid
`
`146.10
`
`88.11
`
`358.30
`
`2:7
`
`4.86
`
`42
`
`A| 4.5
`
`A
`
`A
`
`A
`
`104.06
`
`|2.826
`
`A 15.696
`
`A
`
`2-Naphthoie acid, |-hydroxy-
`Nicotinic acid
`
`188.17
`123.11
`
`af
`|4.85
`
`A|I3.5
`A |2.07
`
`Oleic acid
`
`Orotic acid
`
`Oxalic acid
`
`282.45
`
`|ca. 4
`
`A
`
`156.10
`
`5.85
`
`A 18.95
`
`90.04
`
`1.27]
`
`A |4.266
`
`A}
`
`3.1
`
`A
`B
`
`A
`
`A
`
`A
`
`
`
`
`
`Pamoic acid (embonic acid)
`
`Propionic acid
`
`(—)-L-Pyroglutamic acid
`
`p-Toluenesulfonic acid
`
`388.38
`
`74.08
`
`129.11
`
`172.21
`
`12.51
`
`4.87
`
`}3.32
`
`|-1.34
`
`A
`
`A
`
`A
`
`Class 3
`
`
`
`Acetie acid, 2,2-dichloro-
`Benzoic acid, 4-acetamido-
`
`128.95
`179.18
`
`‘|(+)-Camphor-10-sulfonic acid
`
`232.29
`
`Caproic acid (hexanoic acid)
`Cinnamic acid
`
`Formic acid
`
`Hydrobromic acid
`
`DL-Mandelic acid
`
`Nitric Acid
`
`Salicylic acid
`
`116.16
`148.16
`
`46.02
`
`80.92
`
`13215
`
`63.02
`
`138.12
`
`|1.35
`4.3
`
`(217
`
`4.8
`14.404
`
`3.75
`
`<-6
`
`3.372
`
`|-1.32
`
`|2.97
`
`A
`A
`
`A
`
`A
`A
`
`A
`
`A
`
`A
`
`A
`
`A |13.82
`
`A
`
`Salicylic acid, 4-amino- 153.14=|3.25 A| 10 Al} 35
`
`
`
`
`
`
`
`
`
`
`
`
`
`Undecylenic acid
`(undec-10-enoic acid)
`
`184.27
`
`4.9
`
`A
`
`Apotex Exhibit 1022.013
`
`
`
`Apotex Exhibit 1022.013
`
`

`

`342
`
`PHARMACEUTICAL SALTS:
`
`Table 5. Bases: Alphabetical Order
`
`Class|Base M, pKa
`
`GRAS
`
`Status
`
`
`
`
`
`
`1
`|Ammonia
`17.03
`13.2
`1
`|L-Arginine
`174.20
`
`
`2 197,28|4.46|Benethamine
`
`
`
`9.39
`2 240.35|G99|Benzathine
`
`
`
`2 17.15|12.16|Betaine
`
`
`
`
`26
`1
`jCalcium hydroxide
`74.10
`
`
`
`I 121.18|>11{Choline
`
`
`
`2
`|Deanol
`89.14
`
`
`
`3 105.14|9.28|Diethanolamine
`
`
`(2,2'-iminobis(ethanol))
`
`
`2
`|Diethylamine
`
`
`2
`
`
`3
`
`
`1 195.22|8.03|Glucamine, V-methyl-
`
`
`PL32
`
`2 596.99|71,92|Hydrabamine
`
`
`3|1 A-Imidazole 68.08 7.03
`
`
`
`9.18
`2.16
`1 146.19|10,79|Lysine
`
`
`
`
`1
`|Magnesium hydroxide
`
`2 |Morpholine, 4-(2-hydroxyethyl)- 131.18|7.39
`
`9.82
`
`
`
`
`9.27
`
`8.83
`
`73.14
`
`10.93
`
`117,19
`
`[61.08
`
`60.10
`
`O58
`
`9.50
`
`7.00
`
`58.33
`
`[14
`
`9.09
`
`11.57
`
`10.09
`
`rmnmonmnwmwnehww&
`
`Damnmomwmenrnenmemenmtemremwemewemewehw
`
`
`
`
`
`ca. 14
`7.82
`
`
`1|Potassium hydroxide 56.11 fea. 14
`
`
`2 |115.18|944|Pyrrolidine, 1-(2-hydroxyethyl)-
`
`
`1
`3
`
`3|Piperazine 86.14 5.68
`
`
`
`|Ethanol, 2-(diethylaming)-
`
`3
`
`|Ethanolamine (2-aminoethanol)
`
`|Ethylenediamine
`
`
`
`
`
`
`
`
`
`
`
`|Sodium hydroxide
`|Friethanolamine
`(2,2',2"-nitrilotris(ethanol))
`
`Tromethamine
`
`Zine hydroxide
`
`
`
`
`
`
`
`
`oo
`
`8.02
`
`ca. 14
`
`9.64
`
`Apotex Exhibit 1022.014
`
`Apotex Exhibit 1022.014
`
`

`

`Class|Base
`GRAS
`Status
`
`
`
` ca. 14
`
`Potassium hydroxide
`Sodium hydroxide
`
`Zine hydroxide
`
`L-Arginine
`
`Calcium hydroxide
`Betaine
`
`Hydrabamine
`
`Magnesium hydroxide
`Choline
`
`Diethylamine
`
`Lysine
`Benzathine
`
`Ethanol, 2-(diethylamino)-
`
`Ethanolamine (2-aminoethanol)
`
`|-(2-hydroxyethy])-
`Pyrrolidine,
`Diethanolamine
`(2;2'-iminobis(ethanol))
`Ammonia
`
`Deanol
`
`Glucamine, N-methyl-
`Tromethamine
`
`Triethanolamine
`(2,2',2"-nitrilotris(ethanol))
`Morpholine, 4-(2-hydroxyethy1)-
`1H-Imidazole
`
`Ethylenediamine
`
`
`
`56.11
`40.00
`
`99,38
`
`174.20
`
`74.10
`
`117.15
`
`596.99
`
`58.33
`
`121.18
`
`73.14
`
`446.19
`
`240.35
`
`1TE49
`
`61.08
`
`115.18
`
`ca. 14
`
`ca. 14
`
`[3:2
`
`T236,
`
`12.16
`
`TE92
`
`11.4
`
`> Il
`
`10.93
`
`10.79
`
`9.99
`
`9.58
`
`9.50
`
`9.44
`
`105.14
`
`9.28
`
`17.03
`
`89.14
`
`195.22
`
`121.14
`
`149.49
`
`9.27
`
`8.83
`
`8.03
`
`8.02
`
`782
`
`7,39
`
`7.03
`
`7.00
`
`weBwltNRRmORONmeet
`
`CdNet
`NmBSBBH&bh.
`
`5.68
`Piperazine
`Benethamine
`4.46
`
`
`PROPERTIES, SELECTION, AND USE
`
`343
`
`Table 6. Bases: Sorted by Decreasing pK, Value
`
`
`
`
`Dmmnwnwrwrwnwtrinrneoewnwnetwewneeeaeoae
`
`nammwmD
`nuwTwowwD
`
` 9.64
`
`O09
`
`11.57
`
`L1:32
`
`9.18
`
`9:39
`
`10.09
`
`9.82
`
`
`
`ive]
`
`wo
`
`B
`
`Apotex Exhibit 1022.015
`
`Apotex Exhibit 1022.015
`
`

`

`344
`
`PHARMACEUTICALSALTS:
`
`Table 7. Bases: Sorted by Increasing Molecular Weight
`
`M.
`
`pKa
`
`ittobWmONOWOe
`w=N=NMNHWHWN
`Ln
`
`Ammonia
`
`Sodium hydroxide
`
`Potassium hydroxide
`
`Magnesium hydroxide
`
`Ethylenediamine
`Ethanolamine (2-aminoethanol)
`LA-Imidazole
`
`Diethylamine
`
`Calcium hydroxide
`
`Piperazine
`Deanol
`
`Zinc hydroxide
`Diethanolamine
`
`(2,2'-iminobis(ethanol))
`Pyrrolidine, 1-(2-hydroxyethyl)-
`Betaine
`
`Ethanol, 2-(diethylamino)-
`Tromethamine
`
`Choline
`
`Morpholine, 4-(2-hydroxyethyl)-
`
`Lysine
`Triethanolamine
`(2,2',2"-nitrilotris(ethanol))
`L-Arginine
`
`Glucamine, V-methyl-
`Benethamine
`
`Benzathine
`
`Hydrabamine
`
`
`
`17.03
`40.00
`
`56.11]
`
`58.33
`
`60.10
`
`61.08
`
`68.08
`
`73.14
`
`74.10
`
`9,27
`ca. 14
`
`ca. 14
`
`11.4
`
`7.00
`
`9.50
`
`7.03
`
`10.93
`
`12.6
`
`86.14
`5.68
`89.14) 8.83
`
` ca. 14
`
`99.38
`
`105.14
`
`115.18
`
`117.15
`
`117,19
`
`121.14
`
`121.18
`
`131.18
`
`146.19
`
`149.19
`
`9.28
`
`9.44
`
`12,16
`
`9.58
`
`8.02
`
`>11
`
`7.39
`
`10.79
`
`7.82
`
`174.20
`
`13.2
`
`195.22
`
`8.03
`
`197.28
`
`240.35
`
`4.46
`
`9.99
`
`596.99
`
`11.92
`
`DunwreumwtuontemwnwoeeTwewoe
`DBowuwwmmwa
`aaowwy
`
`
`
`pKa2
`
`10.09
`
`LL.S¢
`
`9:82
`
`9.64
`
`9.09
`
`9.39
`
`11,32
`
`Status
`
` GRAS
`+++
`
`
`
`
`
`
`
`
`
`Apotex Exhibit 1022.016
`
`Apotex Exhibit 1022.016
`
`

`

`PROPERTIES, SELECTION, AND USE
`
`345
`
`Table 8. Bases: Sorted by Class
`
`ADI
`
`up to
`[mg/kg]
`
`
`Class 1
`
`
`
`
`
`
`
`
`9.27
`
`13.2
`
`12.6
`>1l
`
`8.03
`
`10.79
`
`11.4
`
`ca. 14
`
`B
`
`B {9.09
`
`BjI1.57
`B
`
`B
`
`B |9.18
`
`B
`
`B
`
`B }2.18
`
`B
`
`B /2.16
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Ammonia
`
`L-Arginine
`
`Calcium hydroxide
`Choline
`
`|Glucamine, V-methyl-
`
`Lysine
`
`Magnesium hydroxide
`
`Potassium hydroxide
`
`Sodium hydroxide
`
`
`ca. 14
`B
`
`
`B
`
`B
`
`
`
`
`Betaine 117.15|12.16 B
`
`Class 2
`
`Benethamine
`Benzathine
`
`240.35
`
`9.99
`
`Deano!
`Diethylamine
`
`Ethanol, 2-(diethylamino)-
`
`89.14
`73.14
`
`117.19
`
`8.83
`10.93
`
`9.58
`
`B
`B
`
`B
`
`Hydrabamine 596.99|71.92 B
`
`
`Morpholine, 4-(2-hydroxyethyl-
`)131.18 Fs
`B
`
`Pyrrolidine, 1-(2-hydroxyethyl)- |115.18|944 B
`
`
`
`
`Tromethamine 124.14|8.02 B
`
`Class 3
`
`Diethanolamine 105.14|928 B
`
`
`
`(2,2'-iminobis(ethanol))
`
`Ethanolamine (2-aminoethanol)
`
`161.08
`
`9.50
`
`B
`
`B
`B |10.09
`7.00
`60.10
`Ethylenediamine
`
`
`1H-Imidazole 68.08|7.03 B
`
`| Piperazine
`
`86.14
`
`5.68
`
`B /9.82
`
`B
`
`Triethanolamine 149.19|7.82 B
`
`
`
`(2,2',2”-nitrilotris(ethanol))
`Zine hydroxide
`
`~
`
`199.38
`
`lea. 14
`
`B |9.64
`
`B
`
`#
`
`Apotex Exhibit 1022.017
`
`Apotex Exhibit 1022.017
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`

`

`346
`
`3. Diagrams
`
`PHARMACEUTICAL SALTS:
`
`3.1. Nomographsfor 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 pK, value of the constituting drug baseis
`known. Prediction of pH is particularly useful in cases of intended salts of
`weak and very weakbases. If calculated pK, values [5] are entered into the
`diagrams, the expected aqueous pH values and pH ranges ofcertain salts can
`be estimated even before a compoundis 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.
`Howto 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 pK, value of 6.4. For the hydrogen sulfate, Base* - HSOj,at .concentra-
`tions 0.01 —0.1M, the pH would range between 2.2 and 1.55, whereas a 0.05M
`solution of the neutral sulfate, (Base”), - SO4”, is expected to measure pH 4.3.
`Fig. 3, drawn for hydrochlorides, can also be used for salts of other very
`strong acids with pK, values below —1, e.g., for methanesulfonates. The
`course of the pH curvesof 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 dependenceof 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 onlactic acid in Chapt. 12, the composi-
`tion of aqueous solutions of lactic acid depends on the concentration. Fig. 6
`showsthe 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`0
`
`2
`
`|
`
`4
`
`8
`6
`pk, of Base
`
`10
`
`12
`
`14
`
`Hydrochloride
`
`{|
`
`|
`
`j |
`
`5i
`ijif
`ii
`
`fofinn|
`
`c (M
`
`0.01 mo
`
`pk, of Base
`
`Fig. 3. pH of hydrochlorides dependent on the pK, of the conjugate base. Top: Base pK,
`range 0-14; bottom: base pK, range 0-6.
`
`Apotex Exhibit 1022.019
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`Apotex Exhibit 1022.019
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`

`

`348
`
`PHARMACEUTICAL SALTS:
`
`4)
`
`pH
`
`
`
`Neutral Sulfate
`
`
`
`
`5
` aLA
`
`
`=ehigAwadKYp +b
`
`
`
`
`
`
`
`pk, of Base
`
`
`
`
`0
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`14
`
`pk, of Base
`
`Fig. 4. pH of sulfates and hydrogensulfates dependent on the pK,, of the conjugate base.
`a) Example of reading pH for the acid sulfate (lines entered: c=0.01m and 0.1M, resulting pH:
`2.2 and 1.6) and for the neutral sulfate (line entered: c = 0.05M, resulting pH: 4.3) of a weak
`base, pK, =6.4 (e.g., econazole); b) base pK, range 0— 14; c) base pK, range 0-6.
`
`Apotex Exhibit 1022.020
`
`Apotex Exhibit 1022.020
`
`

`

`
`
`
`pK, of Base
`
`Fig. 4 (cont.)
`
`
`
`Neutral Maleate
`
`
`
`
`PROPERTIES, SELECTION, AND USE
`
`349
`
`3
`
`
`
`
`
`
`Qoptte tt
`
`
`
`Hydrogen Maleate
`
`Fig. 5. pH of maleates and hydrogenmaleates dependent on the pK, of the conjugate base
`
`pk, of Base
`
`Apotex Exhibit 1022.021
`
`Apotex Exhibit 1022.021
`
`

`

`350
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`MassPerCent
`
` 5
`
`0
`100
`
`20
`80
`
`60
`40
`40
`60
`Mass Per Cent
`
`80
`20
`
`0
`100 Lactic Acid
`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
`
`[1]
`
`[2]
`[3]
`
`[4]
`
`[5]
`
`[6]
`
`[7]
`
`L. D. Bighley, 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.
`Code of Federal Regulations, 21CFR170 (Internet source: www.access.gpo.gov/nara/cfr/
`index.html).
`Code of Federal Regulations, 21CFR182,184 (Internet source: www.access.gpo.gov/nara/
`cfrfindex.htnl).
`D. D. Perrin, B. Dempsey, E. P. Serjeant, ‘pK, Prediction for Organic Acids and Bases’,
`Chapman and Hall, London, New York, 1981.
`C. H. Holten, Contribut., A. Miiller, D. Rehbinder, “Lactic Acid. Properties and Chemis-
`try of Lactic Acid and Derivatives’, Verlag Chemie, Weinheim, 1971.
`C. Bliefert, ‘:pH-Wert-Berechnungen’, Verlag Chemie, Weinheim, 1978.
`
`Apotex Exhibit 1022.022
`
`PHARMACEUTICALSALTS:
`
`4 c
`
`S5
`
`s
`5
`ae
`>
`a
`26
`oO
`®DD
`wo
`QO
`
`1
`
`Apotex Exhibit 1022.022
`
`