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`i
`
`r
`
`J. Med. Chem. 2007, 50f‘6665—6672
`
`y 6665 ..
`
`Trends in Active Pharmaceutical Ingredient Salt-”Selection based on Analysis of the Orange
`Book Database
`
`G. Steffen Paulekuhnf’i Jennifer B. Dressman} and Christoph Saal*’l
`. Merck KGuA, Frankfurter Strasse 250, 64293 Damstadty'G/ermany, and Institute of Pharmaceutical Technology, Biocenter, Johann Wolfgang
`Goethe University, Max yon Laue Street 9, 60438 Frankfurt (Main), Germany
`*
`
`Received August 20, 2007
`
`The Orange Book database published by the U.S. Drug and FoodAdministration (FDA) was analyzed for
`the frequency of occurrence of different counterionsbused for the formation of pharmaceutical salts. The
`data obtained from the present analysis of the Orange Book“ are compared to reviews of the Cambridge
`Structural Database (CSD) and of the Martindale “The Extra Pharmacopoeia”. As well as showing overall
`distributions of counterion usage, results are broken down into 5—year increments to identify trends in
`‘ counterion selection. Chloride ions continue to be the most frequently utilized anionic counterions for the
`formation of salts as active pharmaceutical ingredients (APIs), while sodium ions are'most widely utilized
`for the formation of salts starting from acidic molecules. A strong trend toward a wider variety of counterions
`over the past decade is observed. This trend can be explained by. a stronger need to improve physical chemical
`properties of research and development compounds.
`
`
`
`Introduction
`
`Salt formation is a well-known technique to modify and
`optimize the physical chemical properties of an ionizable
`research or development compound. Properties such as solubil-
`ity, dissolution rate, hygroscopicity, stability, impurity profiles,
`and crystal habit can: be influenced by using a variety of
`pharmaceutically acceptable counterions.“8 Even polymorphism
`issues can be resolved in many cases by formation of salts. The
`crystal structure of a salt is usually completely different from
`the crystal structure of the conjugate base or acid and also differs
`from one salt to another. The modification of physical chemical
`properties, mainly solubility and dissolution rate, may also lead
`to changes in biological effects such as pharrnacodynamics and
`phannacokinetics, includingbioavailability andtOXicityprofile.1’9'1°
`Owing to dramatic changes in the techniques applied in
`pharmaceutical discovery progranis over the past 20 years, the
`physical chemical propertiespof development candidates have
`changed substantially.11 Drug design based on high—throughput
`screening has in general led to more lipophilic compounds
`exhibiting/low aqueous solubility.
`a.“
`There are many well—known formulation techniques to
`increase aqueous solubilityfz‘14 e.g., micronization, nanosizing,
`or complexation with cyclodextrins. The use of solid solutions
`and solid dispersions is another way to improve bioavailability
`for development candidates with low‘ solubility. Nevertheless,
`formation of salts is almost
`the only chemical
`technique
`available to change aqueous solubility and dissolution rate
`without Changing the'API mbleér’llef Further Options for 'r‘nddify—
`ing these properties comprise the choice of the polymorphic
`form including solvates and formation of cocrystals. Although
`cocrystals in particular are an innovative way of designing APIs,
`\ this method is beyond the scope of this publication. An overview
`\of this topic can be found in ref 15‘. Salt selection remains an
`important step at the interface between pharmaceutical research
`and development. A large number, of publications covering .
`
`* To whom correspondence should be addressed. Phone: +496151727634.
`Fax: +49615l723073. E—mail: Christoph.Saal@merck.de.
`T Merck KGaA.
`i Johann Wolfgang Goethe University.
`
`physical chemical properties of pharmaceutical salts-and meth-
`ods for salt screening exist, e.g., refs 4, 16—19 and references
`included therein. On the other hand, publications giving an
`overview of approved salt forms are very fewd“3 A11 publica-
`tions known to the authors dealing with occurrence of coun-
`terions for formation of pharmaceutical salts list the counterions
`and their distribution in the respective data set only at a given
`point in time. Neither the- distribution trends over timenor the
`causes for these have been analyzed to date.
`The present contribution examines the selection of counterions
`for the formation of salts by analyzing the Orange Book
`Databasezo published by the U.S. Drug and Food Administration
`(FDA). The Orange Book lists all drug products approved in
`the U.S. Drug products approved after 1981 are listedvincluding
`theirdate of approval. This enables an analysis of the changes
`in frequency of usage of the different counterions with time.
`Trends in salt selection over the past 25 years can thus be
`identified andthe outcome of the overall analysis of the Orange
`Book compared“ to resultsbased on other sources.
`-
`»
`»;
`
`Study Design
`
`The data were compiled from the FDA Orange Book
`Database as of the end of 2006. At this date, 21 187 drug
`products were listed, including 1356 chemically “well—defined”
`APIs. “Well defined” for the purpose of our analysis means
`that the API molecules are small chemical entities with a defined
`molar .mass, typically below...l_0.0,0, Da , and that their chemical
`structure is completely known. Dosage forms containing
`multiple APIs, peptide hormones, biological APIs like antibod—
`ies, enzymes, extracts, and proteins, metal complexes, polymeric
`salt forms, inorganic APIs, and markers were excluded from
`our analysis. The APIs were classified into three categories:
`Category I consists of salts formed from basic molecules
`containing at least one atom suitable for protonation. Category
`11 comprises salts formed from acidic species. Finally, category
`III is represented by APIs that are used as nonsalt forms. This
`class also includes zwitterions. Counterions are reported ac-
`cording to their type of charge as cations and anions. The
`stoichiometry of the salts is not discussed separately: for'
`
`.
`
`© 2007 American Chemical Society
`10.1021/jm701032y ccc: $37.00
`Published on Web 12/01/2007 .
`
`Apotex Exhibit 1013.003
`
`Apotex Exhibit 1013.003
`
`

`

`6666
`
`Journal of Medicinal Chemistry, 2007, Vol. 50, N0. 26
`
`Table 1. Distribution of FDA Approved APIs among Categories Ijlll
`
`overall 113982 1982—1986 1987—1991 1992—1996 1997—2001 2002—2006
`(%)
`(%)
`(%)
`(%)
`(%)
`(%)
`(%)
`Category 1: API Salts Formed of Basic Entities
`42.0
`40.2
`38.0
`40.3
`
`38.6
`
`38.4
`
`f 32.7
`
`12.8
`
`13.6
`
`Category II: API Salts Formed of Acidic Entities.
`10.1
`11.1
`13.3
`11.1
`
`48.6
`
`48.0
`
`47.9
`
`Category III: Nonsalt APls
`48.7
`48.7
`
`48.6
`
`14.6
`
`52.7
`
`example, the occurrence of bromides includes bromidesand g
`dibromides. Furthermore, the APIs were arranged by year of
`approval to analyze how trends in the choice of salt forms have
`changed in recent decades. Prior to 1981, no date of approval
`is given in the Orange Book. Therefore,
`the drug products
`approved before 1982 are summarized under “pro-1982”. The
`period from 1982‘ to 2006 has been divided into five intervals,
`each comprising 5 years. After completion of the analysis of
`all chemically well—defined APIs, a separate assessment of the. .
`subset of APIs of oral (844 APIs) and injectable (482 APIs)
`- dosage forms was made. Our analysis shows how the route of
`administration influences the choice of a specific salt form. This
`Observation can be assigned to the different requirements of
`the two routes of administration. For example, for the two basic
`compounds biperiden and pentazocine, the chloride salts are
`used for oral dosage forms, whereas the lactate salts are used
`for injectable dosage forms.
`
`Results and Discussion
`
`- Distribution of API Salts Formed of Basic and Acidic
`Molecules and APIs in Nonsalt Forms. The 1356 chemically
`well—defined APIs listed in the Orange Book comprise 659
`(48.6%) APIs in nonSalt forms, 523 (38.6%) salts formed from
`basic compounds, and 174 (12.8%) salts formed from acidic
`molecules. Thirty-eight different anions and 15 cations are used
`as counterions for the formation of salts. Thereof, 16 anions
`and 8 cations were only used once. During the past 25 years,
`25 anions and 7 cations have been used to form salts. The ratios
`
`of APIs obtained by salt formation ofmolecules exhibiting basic
`properties, API salts obtained from acidic species, and APIs in
`nonSalt forms have remained virtually constant. This is shown
`in Table 1. During 2002—2006, there has been some decrease
`in the percentage of APIs obtained as salts of basic compounds.
`This leads to a small increase in both of the other categories
`Figure 1 shows the corresponding distribution of APIs among
`the three categories used1n oral and injectable dosage forms.
`Together, oral and1nJectable formulations represent the majority
`of FDA-approved formulations. However,
`the requirements
`placed on an API for oral and injectable dosage forms are quite
`different. For oraldosage forms, a key prerequisite of the API
`is a certain minimum solubility in the pH range of the
`gastrointestinal
`tract. An adequate diSsolution rate and a
`sufficient permeability are also important If these requirements
`are not fulfilled, bioavailability will be insufficient to achieve
`the desired therapeutic effect. In the case of solutions for
`injection, considerations such as pH of the solution, osmolarity,
`and solubility in a small volume are important for efficient and
`pain—free administration.
`In many cases,
`this can lead to
`situations where a considerably higher solubility is required for
`injectables than for oral formulations.
`Distribution of Anionic Counterions Used To Form
`
`\
`
`Pharmaceutical Salts. A summary of all anions used along »
`with their distribution during different time periods is given in ‘
`
`’
`
`Paulekuhn et al.
`
`— ore-1982— 1982-1986
`- 1987—1991
`m- 1992-1995
`’f‘“ 1997-2001
`2002-2006
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`M1
`
`
`
`
`
`600
`
`500
`
`400
`
`numberofAPIs 200
`
`300
`
`100
`
`non—salt bases acids non-salt bases acids non—salt bases acids
`overall ‘
`oral
`‘
`injeetable
`
`Figure 1. Classification and distribution of species in the Orange Book
`according to their type oféharge and administration route.
`
`' Table 2. Figure 2' displays the overall distribution of anions,
`Whereas Figure 3 depicts the most recent period, 2002—2006.
`The anion encountered most frequently in FDA—approved
`pharmaceutical salts1s the chlorideron. The fraction of chlorides
`increased from 52.9% (pre—1982)
`to 63. 8% (1987—1991),
`remained almost constant at 63.3% over the next 5 years
`(1992—1996) and decreased significantly to 38.9% (2002—2006)
`over the past 10 years. The anion encountered, .with highest
`frequency after chloride is sulfate. However, it accounts for only
`7 5% of APIs formed from basic molecules Its peak incidence
`was 120% during the period 1982—1986. Further acidic
`counterions frequently encountered includebromides, with a
`total incidence of 4.6%, as well as maleates and mesylates, both
`with incidences of 4.2%.
`.
`r‘
`.
`There appears to be some tendency for “fashions” in anionic
`counterion selection, with certain counterions showing a notice-
`ably higher occurrence during one period compared to their
`overall usage. For example, nitrates represented 8.0% of anionic
`counterions during the 1982—1986 period. The average usage
`of nitrates is only 1.7%. Further examples include acetate with
`a maximum incidence of 12.7% during 1987—1991 and an
`overall usage of 3.3%.J’Tartrates exhibited a higher incidence
`‘ of 6.7% in 1992—1996 than the average of 3.8%. Fumarates
`showed most frequent utilization during ,1997—2001, contributing
`8.6% of FDA-approved salts formed of basic molecules during
`this period. They yielded an average fraction of 1.7%. For
`mesylates, the same is true with a peak occurrence of 13.8%
`during the same period and an average incidence of 4.2%. The
`number of anions used to form salts has varied during the past
`25 years between 11 and 15 per 5—year periodln total, there
`are only two anions with an average incidence of more than
`5% over the whole period. These are the chlorides and sulfates.
`Nevertheless, during the individual 5—year intervals, there are
`several anions reaching fractions of more than 5%. For example,
`in the pre-1982 period these are bromides and maleates. From
`1982 to 1986, acetates and nitrates are encountered in more
`than 5% of the APIs of category I. From 1987 to 1991, acetate
`and from 1992 to 1996 tartrate are the only anions other than
`chloride that were used to form more than 5% of the FDA-
`
`approved salts of basic molecules. After 1996, a broader variety
`of anions has reached an incidence of more than 5% usage
`_ During 1997—2001 five anions exhibit an occurrence of more
`than 5%: bromides, chlorides, citrates, fumarates, and mesylateS
`From 2002 to 2006, seven different anions including bromides,
`chlorides, maleates, mesylates, phosphates, sulfates, and tartrates
`had an incidence of’5% or more. These figures indicate a strong,
`recent trend toward increased diversity of anions applied for
`the formation of salts in category I. The trend can be explained
`as: a consequence of the changes'in research techniques
`
`,
`
`Apotex Exhibit 1013.004
`
`Apotex Exhibit 1013.004
`
`

`

`Trends in Salt Selection
`
`-
`
`Jaurnal’ofMedicinal chemistry, 2007, Vol. 50, No. 261 6667
`r5" .
`
`7
`
`Table 2. Distribution of Anions Used in APIs of Category I
`
`1987—1991 (%)
`overall (%)
`pre—1982 (%)
`1982—1986 (%)
`1992—1996 (%)”1
`1997—2001 (%)
`2002—2006 (%)
`3.3
`1.5
`8.0
`3.5
`2.8
`0.2
`1.7
`0.8
`4.6
`0.2
`531.4
`0.2
`2.7
`0.2
`1.7
`0.2
`0.4
`0.2
`0.2
`1.0
`0.4
`1.3
`0.2
`0.2
`0.4 ‘
`4.2
`4.21
`0.4
`0.2
`0.4
`1.7
`0.2
`0.2
`0.2
`0.8
`27
`0.2
`1.2
`7.5
`1 0.2
`‘ 3.8 '
`0.4
`0.2
`
`, acetate
`benzoate
`besylate
`bromide
`camphorsulfonate
`chloride
`,
`chlortheophyllinate
`citrate
`ethandisulfonate
`fumarate
`‘
`gluceptate
`gluconate
`glucuronate
`hippurate
`iodide
`isethionate
`lactate
`lactobionate
`laurylsulfate'
`malate
`maleate
`mesylate
`' methylsulfate
`- naphthoate
`napsylate
`nitrate
`octadec'anoate
`1 oleate
`oxalate
`pamoate
`phosphate
`polygalacturonate
`succinate
`..
`sulfate
`sulfosalicylate
`tamate
`tosylate
`trifluoroacetate
`
`.
`
`1‘1
`
`2.0 1
`4.0
`
`'
`
`52.0
`1
`
`2.0
`
`2.0
`2.0
`4.0
`
`2.0
`2.0
`
`8.0
`
`712.0 .
`
`..
`
`0.4
`5.2
`. 0.4
`52.9
`0.4
`2.6
`0.4
`0.4
`0.4
`0.7
`
`0.4
`1.5
`0.4
`1.5
`0.4
`0.4
`0.4
`5.5
`2.6
`0.7
`
`0.7
`0.7
`0.4
`
`-
`
`1.1
`3.3
`0.4
`0.7 _
`-.19.6 .
`0.4
`3.7.
`. 0.41;
`1
`
`12.7
`
`2.1
`
`63.8
`
`.
`
`2.1
`
`'
`
`2.1
`
`—
`
`_
`
`4.3
`
`2.1
`
`2.1
`
`2.1
`
`...4.3
`
`2.1
`
`3.3
`1.7
`
`63.3
`
`3.3
`
`3.3
`
`1.7
`
`'
`g 3.3
`1.7
`
`1.7
`
`1.7
`
`1.7
`
`3.3
`1.7,
`
`6.7
`
`17
`
`5.2
`.
`46.6
`
`5.2
`
`8.6
`
`35
`13. 8
`
`,
`
`1.7 .
`1.7
`
`1.7
`3.5
`
`3.5
`
`8.3
`
`38.9
`
`2.8
`
`2.8
`5.6
`8.3
`
`2.8
`
`2.8
`
`5.6
`
`1
`
`2.8
`. 5.6
`
`8.3
`12.8
`
`1
`
`1 9?
`1L
`
`1111:1:1
`1111111
`11'1”
`
`1
`
`1
`1;
`1"
`
`
`
`
`
`
`
`
`
`50 — 47 _ 60 58 .272' 523number of salts 36
`
`
`
`
`
`
`
`
`
`Distribution of Cationic Counterions Used To Form
`Pharmaceutical Salts. All cationic counterions together with
`their respective incidences are listed in Table 3. Figure 4 shows
`the overall distributionof cations in' salts formed fromchemical
`entities exhibiting acidic properties. In Figure 5, the relative
`occurrence during the last period from 20021 to 2006 is depicted.
`Among the cations used to form API salts of acidic molecules,
`the sodium ion strongly dominates with an incidence of 75.3%
`over the entire period. From 1982 to 1991, the fraction of sodium
`salts was more than 90%. This decreased to 62.5% during the
`
`III—I Acetate (1)
`we Bromide (3)
`
`Citrate
`Malate
`
`Maieaie
`
`
`
`Mesyiaie
`Succinate
`
`hosphate
`Oxalate
`
` ,
`
`’
`
`
` —-’ Chloride (1~4)‘
`
`Citrate (1)
`—- Malate (1)
`
`.
`a Maleate (2)
`_ Mesylate(3)
`Nitrate (1)
`- Oxalate (1)
`Phosphate (2)
`— Succinate (1)
`~1 Sulfate (2)
`— Tartrate (3)
`m Tosylate (1)
`
`employed by the pharmaceutical industry. The extensive use
`of combinatorial Chemistry and high-throughput screening in
`drug discovery has led to higher lipophilicity and commensurate
`loWer solubility anddissolution rate- of new drug candidates
`over the past 20 years. This in turn has necessitated a more
`intensive search for appropriate salts as a tool to improve
`'physical chemical properties a search typically conducted at
`the end of lead1optimization or during exploratory development.
`— Acetate (17)
`— Besylate (4.)
`— Bromide (24)
`Chloride (279)
`Am Citrate-(14)
`Fumarate (9)
`=1 Gluconate (2)
`— Iodide (5)
`— lsethionate(2)
`— Lactate (7)
`m Malate (2)
`.fil Maleate (22)
`Mesylate (22)
`:I Meihyisulfate (2)
`— Napsylaie (2)
`_ Nitrate (9)
`— Pamoate (4)
`m Phosphate (14)
`Succinate (6)
`Sulfate (39)
`:‘ Tanrate (20)
`— Tosylate (2).
`— Only used once (16)
`
`
`
`Besylate
`Acetate
`
`only used
`once
`
`Tosylate
`Tartrate
`
`
`
`Citrat
`Fumarate
`Gluconate
`
`-——- Succinate
`\ Phosphate
` Pamoate
`Nitrate
`\\\Napsylate
`
`
` Lactate Maleate
`Methylsulfate
`
`\
`\
`
`‘
`
`
`
`
`Figure 2. Overall distributibn of anions used in APIs of category I in
`the Orange Book.
`
`Figure 3. Distribution of anions used in APIs of category I from 2002
`to 2006.
`
`Apotex Exhibit 1013.005
`
`Apotex Exhibit 1013.005
`
`

`

`6668
`
`Journal of Medicinal Chemistry, 2007, Vol. 50, N0. 26
`
`Paulekul’m er al.
`
`
`
`
`
`
`Table 3. Distribution of Cations Used in APls of Category I
`1997—2001 (%)1992—1996 (%) 2002—2006 (%)
`1987—1991 (%)
`overall (%)
`pre—1982 (%)
`1982—1986, (%)
`‘
`0.6
`1.0
`benzathine
`calcium
`6.9
`7.3
`cholinate
`0.6
`1.0
`diethanolarnine
`0.6
`1.0
`diethylamine
`0.6
`1 .0
`lysine
`0.6
`magnesium
`1.2
`meglumine
`2.9
`piperazine
`0.6
`potassium
`6.3
`procaine
`0.6
`silver
`0.6
`V‘stodium
`75.3
`Iromethainine
`1.7
`zinc
`1.2
`
`-
`
`,
`
`.
`
`5.2
`1.0
`6.3
`1.0
`_ 1.0
`72.9
`
`1.0
`
`91.7
`
`8.3
`
`92.3
`7.7
`
`9.5
`
`14.3
`
`66.7
`9.5
`
`6.3
`
`6.3
`
`/
`
`’
`
`87.5
`
`,
`
`18.8 ‘
`
`r\
`
`6.3
`
`6.3
`
`6.3
`
`62.5
`
`
`
`
`
`..“a“...Rama...*Mw‘ml
`
`12
`96
`~ 174
`number of salts '
`.13 16 ~21 ' ‘ 16
`
`
`
`
`
`
`
`
`
`
`
`
`
`2002—2006 period. The second most commOn cation is calcium
`with an average incidence of 6.9%. Its peak frequency of 18.8%
`was reached during 2002~2006. Another cation with frequent
`usage is potassium. On average, 6.3% of the FDA-approved
`drugs of category 11 are potassium salts. Potassium salts show
`their highest relative occurrence during 1992—1996, yielding.
`14.3% of API salts obtained from acidic entities. Benzathine,
`cholinate, diethanolamine, diethylamine, meglumine, piperazine,
`procaine, and silver have not been used over the past 25 years.
`They were only used once each during the time frame before
`. end of 1981,. Lysine and magnesium were both introduced as
`counterions during the 'past 10 years.
`Only two basic counterions were utilized in each of the two
`5-year periods 1982—1986 (sodium, zinc) and 1987—1991
`(sodium, tromethamine). This number increased from three in
`the period 1997—2001 to five in the period 2002—2006. This
`analysis indicates that the trend toward a Wider diversity of
`counterions observed for usage of anions is also occurring with
`catiOns.
`‘
`‘
`.
`Salts Used in Oral Formulations. Of the 1356 chemically
`well—defined APIs listed in the Orange Book, 844 are used for
`oral delivery. A total of 449 (53.2%) of them are nonsalt forms,
`320 (37.9%) salts are formed from molecules exhibiting basic
`properties, and 75 (8.9%) are salts formed from entities with
`acidic behavior. A total of 30 different anions have been used,
`17 of them during the past 25 years. Only eight cations have
`been employed for formation of salts from acidic moieties, five
`of which were employed over the past 25 years. The analysis
`shows that 15 anions and 3 cations were only used once.
`Distribution of Anionic Counterions Used in 1 Oral
`Formulations. Relative incidences of all anions used inFDA-
`approved oral formulations are presented in Table 4. The anion
`Silver Procaine
`Benzathinem)
`_ Calcium (12)
`fiotassium
`\ /
`
`
`1:1 Cholinate (1)
`- Diethanolamine(1)
`— ysme
`piethyizrgine (1)
`Magnesium (2)
`— Meglumine (5)
`1:1 Piperazine (1)
`_ Potassium (11)
`
`"
`Procaine (1)
`— Silver(1)
`Sodium (131)
`nu Tromethamine (3)
`=1 Zinc (2)
`
`
`
`»
`
`P' eraz‘ne
`1p Meglluinine
`Magnesium
`~
`-
`a
`5
`//'-YS‘“e Diethylamine
`
`gfitfilfiamme
`
`C [
`~
`'
`‘ac1um
`.
`,
`Benzaihine
`Zinc
`
`\Tromethamine
`
`
`applied most frequently in APIs utilized in oral formulations is7
`chloride. Its fraction increased from 55.8% (pm—1982) thidu‘ghx
`65.4% (1982—1986) to 79.2% (1987—1991). After this period,
`there was a continuous decrease from 65.7% (1992—1996)
`through 45.0% (1997—2001)
`to 34.8% (2002—2006). Other
`important anions for oral delivery comprise sulfate with an
`incidence of 7.5%, maleate with 6.9%, and mesylate with 4.4% 7
`over the wholeperiod; Mesylate salts exhibited a peak incidence
`of 15.0% during 1997—2001. Citrate salts were also frequently
`encountered during the same period, with 7.5% compared. to
`an average fractibn of 3.4% over the whole time period. The
`fifth anion according to frequency of\usage ranking is bromide
`with an average value of 4.1% and a peak occurrence of 8.7%
`. in 2002—2006.
`During each of the periods from 1982 to 1986 and 1987—1991,
`salts containing five different anions were approved in oral
`formulations. Between 1992 and 1996, 10 different anions were
`used in API salts in newly approved drug products intended
`for oral use. During the two last periods of 1997—2001 and
`. 2002—2006, 11 anions were applied per period. Thus, the overall
`‘ trend toward a higher variety of acids and bases used for
`formation of salts is reflected in APIs for oral applicatiOn.
`Distribution of Cationic Counterions USed in [Oral
`Formulations. A11 cations encountered as counterions for
`formation of API salts used in’ productsfor oral delivery are
`. summarized in Table 5. Sodium represents the most common
`cation of this category. Its average frequency of occurrence
`during the Whole time period analyzed is 65.3%..It strongly
`fluctuates during the different '5-year time periods with a relative
`
`Magnesium Lysine
`.
`Potassium
`
`
`
`‘\ Calcium
`
`Calcium (3) ‘
`- Lysine (1)
`Magnesium (1)
`Potassium (1)
`men‘- Sodium (10)
`
`
`
`
`
` —
`
`Figure 4. . Overall distribution of cations used'in APIs of category II
`in the Orange Book.
`
`Figure 5. Distribution 'of cations used in APls of category 11 from
`2002 to 2006.
`1..
`
`Apotex Exhibit 1013.006
`
`Apotex Exhibit 1013.006
`
`

`

`Trends in Salt. Selection
`
`Journal of Medicinal Chemistry, 2007; Vol. 50, N0. 26/ 6669 .
`
`_
`
`
`
`'
`
`‘
`
`5
`
`*
`
`"
`
`‘
`
`,
`
`,
`
`‘
`
`I
`
`,
`
`»
`
`'
`
`‘
`
`8.7
`1.7
`1.2
`1.2
`
`0.6
`
`‘
`
`\
`
`65.4
`
`79.2
`
`4.2
`
`2.9
`
`65.7
`
`2.9
`
`2.9
`
`.
`
`‘
`~ V
`
`3.9
`
`\
`
`‘
`3.9
`
`\
`
`'
`
`'
`
`p
`
`/
`
`8.3
`
`p
`‘_"
`
`.
`
`'
`
`V
`
`5.7
`2.9
`
`2.9
`
`2.5
`
`5.0
`45.0
`'
`7.5
`
`5.0
`
`. 5.0
`15.0
`
`,
`
`8.7
`34.8
`
`4.4
`8.7
`8.7
`
`
`Table 4. Distribution of Anions for API Used in Oral Dosage Forms
`1992—1996 (%) 1997—2001 (%) 2001—2006 (%)
`1987—1991 (%)
`overall (%)
`pre-1982 (%)
`1982—1986 (%)
`0.9
`L
`0.6
`7.7
`acetate
`’ benzoate
`0.3.
`'
`besylate
`0.6
`y 0.6
`, g
`bromide
`_ 4.1
`5.2
`'
`chloride
`56.6
`55.8
`chlortheophyllinate
`0.3
`, 0.6
`citrate
`3.4
`4.1
`ethandisulfonate
`0.3
`0.6
`furnarate
`1.6
`0.6
`gluconate
`0.3
`0.6
`hippurate
`0.3
`0.6
`iodide
`0.3
`0.6
`lactate -
`0.3
`0.6
`laurylsulfate
`0.3
`0.6
`malate
`0.3
`maleate
`6.9
`mesylate
`4.4
`methylsulfate
`0.6
`napsylate
`‘
`0.6
`nitrate
`0.6 .
`. octadecanoate
`0.3
`oxalate
`0.3 _
`pamoate
`0.9
`phosphate
`2.5
`polygalacturonate
`0.3
`succinate
`1.9
`sulfate
`7.5
`‘ tartrate
`2.8
`tosylate
`0.3
`
`19.2
`
`4.2
`4.2
`_
`
`2.5
`
`2.5
`5.0
`5.0
`
`.
`
`5.7
`2.9
`5.7
`
`'
`
`4.4
`
`8.7
`
`4.4
`8.7
`4.4
`4.4
`
`,
`
`,
`
`.
`
`‘
`
`‘
`
`’
`
`p
`
`1.7
`2.9
`0.6
`1.2
`7.6
`1.7
`
`
`number of salts
`.1
`320
`172
`26
`24
`35
`‘
`4o
`'
`23
`
`. '
`
`/,
`
`Tables. Distribution of Cations for API Used in Oral Dosage Forms
`1987—1991 (%)
`overall (%)
`‘
`ipre—l982 (%) ,
`. 1982—1986 (%)
`1992—1996 (‘7 )
`1997—2001 (%)
`2002—2006 (%)
`benzathine
`1.3
`2.3
`1
`-
`calcium
`12.0
`11.4
`cholinate
`’ 1.3
`2.3
`magnesium
`' 2.7
`piperazine
`1.3
`potassium
`13.3
`.
`sodium ‘
`65.3
`trometharnine
`2.7
`
`.
`
`2.3 .
`, 13.6
`, 68.2,
`'
`
`‘
`
`.-
`
`11.1
`
`.
`
`33.3
`. 44.4
`11.1
`
`~
`
`'
`
`'
`
`.
`
`.
`
`11.1
`‘
`
`.
`
`88.9.
`
`50.0
`
`’
`
`.
`
`”16.7
`
`. 16.7
`16.7
`
`100.0
`
`83.3,
`16.7
`
`,
`
`
`number of salts
`75
`'
`44
`1
`6
`_ ,9
`’
`9
`6
`
`I
`
`fraction of/at least 682% until 1991. This value decreased to
`44.4%jduring 1992—1996. During the following period,
`._;_1—9~97'—*2'001, there was an increase to 88.9% followed by a huge
`drop to just 16.7% during 2002—2006. The strong fluctuations
`are caused by the small absolute numbers of approved drug
`products containing salts formed from acidic entities. There were
`a maximum of nine drugs approved in this category for oral
`usage during each of the 5—year periods. The second common
`cation is potassium with an average fraction of. 13.3% over the
`whole period and a peak of 33.3% in 1992—1996. The third
`important cation for oral dosage forms, which accounted fora
`total frequency of 12.0% and a peak of 50.0% during the last
`\ period from 2002 to 2006,
`is calcium. Thus, calcium and
`\potassium have changed positions in usage ranking for oral
`dosage forms in recent times.
`A good example of how the counterion affects the physical
`chemical properties of an API in oral formulations is diclofenac
`and its salts. There are both sodium and potassium salts of
`diclofenac applied. in drug products for oral delivery. The free
`acid is not used in RDA-approved drug products. Only the
`diclofenac sodium salt is utilized for extended and delayed
`release tablet dosage forms. In contrast, the diclofenac potassium
`salt is used for immediate release tablets. This suggests that
`
`,the different salt forms may influence dissolution rates. Fini et
`al.21 have, discussed the difference in dissolution behavior
`between these salt forms.
`‘
`
`Salts Used in Injectable Formulations. The 482 APIs used
`for inj ectable formulations consist of 171 (35.5%) nonsalt forms,
`208 (43.2%) API salts. of basic molecules, and 103 (21.4%)
`salts of acidic entities, whereas in APIs utilized in oral
`formulations about half of the APIs were used as nonsalt forms;
`in injectableformulations .only .abczutenerthirdwereemployed
`as noncharged forms. This shows that formation of salts is even
`more. important for injectable dosage forms than for oral
`formulations. The mOre frequent usage of salt forms in injectable
`formulations can be explained by the need for even higher
`solubility compared to oral formulations. A'n oral dosage form
`needs to completely dissolve in 250 mL of aqueous media in
`the physiological relevant pH range of 1—8 to be classified as
`highly soluble with reference to the Biopharmaceutical Clas—
`sification System.22 Typically, the preferred injectable dosage
`form comprises a volume of a few milliliteIs. If the solubility
`