‘2 rnalof
`
`Apotex Exhibit 1013.001
`
`EBLING LIBRARY.
`UNIVERSITY OF WISCONS! N
`
`JAN7 2008
`
`750 H hland Avenue
`Madison W1 53705
`
`Apotex Exhibit 1013.001
`
`

`

`Journalof
`Medicinal
`Chemistry
`
`Journal of Medicinal Chemistry (ISSN 0022-2623)
`is published biweekly by the American Chemical
`Society at 1155 16th St, N.W., Washington, DC
`20036.Periodicals postage paid at Washington,
`DC, and additional mailing offices. POSTMAS-
`TER: Send address changes to Journal of Medici-
`nal Chemistry, Member & Subscriber Services,
`P.O. Box 3337, Columbus, OH 43210.
`
`American Chemical Society
`1155 16th St., N.W.
`Washington, DC 20036
`(202) 872-4600
`TDD (202) 872-6076
`Fax (202) 776-8264
`
`,
`
`Journal Publications
`American Chemical Society
`" 2540 Olentangy River Road
`P.O. Box 3330, Columbus, OH 43210
`(614) 447-3665
`Fax (614) 447-3745
`E-mail acsproof@acs.org
`
`Member & Subscriber Services
`P.O. Box 3337
`Columbus, OH 43210.
`Members contact:
`(614) 447-3776; (800) 333-9511
`Fax (614) 447-3671
`E-mail service @acs.org
`Agencies & institutions contact:
`(614) 447-3674; (888) 338-0012
`Fax (614) 447-3671
`E-mail liblink @acs.org
`
`Advertising Office
`:
`Centcom, Ltd. .
`676 East Swedesford Road
`Suite 202, Wayne, PA 19087-1612
`(610) 964-8061
`
`Publications Division
`Brian D. Crawford, President
`
`Journal Production & Manufacturing
`Operations
`Anne C. O’Melia, Vice President;
`Teresa K. Lewandowski, Director;
`Diane E. Needham, Journals Editing
`Manager; Loretta.M. Yam, Associate Editor;
`Lisa H. Clay, Assistant Editor;
`Karen S. Geist, Production Assistant
`
`Sales & Marketing/Publications
`Dean J. Smith, Vice President
`Matthew J. Price, Director,
`Product Marketing
`Jonathan J. Morgan, Assistant Director,
`Web Innovation & Production
`
`AX
`yy
`
`Canadian GST Reg. No. 127571347
`Printed in the USA
`
`graphic copying beyond that permitted by Section 107 or 108 of the U.S. Copyright Actis allowed,
`provided that the current per article fee is paid to the Copyright Clearance Center. Tel:
`(978) 750-
`8400. Republication or reproduction for sale of articles or abstracts in this journal is permitted only
`by written permission from the Copyright Office, ACS, Washington, DC. Tel: (202) 872-4368. Fax:
`(202) 776-8112. E-mail: copyright @acs.org.
`EDITORIAL INFORMATION
`
`Guidelines for Authors and Copyright Status Form: Seethe first printed issue of each volume or
`visit the Publications Division Web site (http://pubs.acs.org). Please conform to these, instructions
`when submitting manuscripts.
`.
`.
`\
`\
`
`Manuscript Submission: Submit via the secure ACS Website (http://pubs.acs.org/jmc).
`
`.
`
`Accepted Papers and Proofs: Direct correspondence to Journal Publications, Columbus, OH.Tel:
`(614) 447-3665. Fax: (614) 447-3745. E-mail: acsproof@acs.org.
`
`Journal Policies: The American Chemical Society and its Editors assume no responsibility for the
`statements and opinions advanced bycontributors. Registered names and trademarks, etc., used in this
`publication, even without specific indication thereof,-afe not to be considered unprotected by law.
`Document Number: At the end of each document is a 9- or 14-character code that serves as a link
`between the printed and electronic products and facilitates retrieval of the document in electronic
`form.
`.
`Digital Object Identifier (DOD): The DOI identification system for digital media has been-designed
`to provide persistent andreliable identification of digital objects. Information on the DOI andits gov-
`erning body, the International DOI Foundation, can be found at http://www.doi.org/ In the Web edi-
`tions of ACS journals, the DOI appearsat the top of the HTML version of an article and at the bot-
`tom ofthe first page in its PDF version; in the printed editions, the DOI appears in the samelocation
`as in the PDF version.
`CPC Sales Agreement #2976285: Return undeliverable Canada addresses to: IMEX, PO Box 4332,
`Station Rd., Toronto, ON MSW 334.
`2007 SUBSCRIPTION AND ‘ORDERING INFORMATION
`
`Printed Edition
`
`Members
`Student Members
`: Institutional
`.
`
`.
`
`¢
`
`Outside
`North
`_ North America*
`America i
`$ 471 ,
`;
`$ 253 ,
`$ 190
`me
`$ 408
`
`
`
`
` ‘ $2073 | $2291
`
` Copyright Permission: See copyright status form for certain rights (http://pubs.acs.org). Repro-
`
`85
`$
`85
`$
`Members
`Web Edition?
`* Air service included. ' For Institutional rates, call M&SS Agency & Institutional Customer Service.
`
`Web Edition: This journal is available to subscribers via the Internet. Members may contact Cus-
`tomer Service. Tel: (614) 447-3776 or (800) 333-9511. E-mail: service @acs.org. Institutional sub-
`scribers may contact Agency & Institutional Customer Service. Tel: (614) 447-3674 or (888) 338-
`0012. Fax: (614) 447-3671. E-mail:
`liblink@acs.org. For additional details, visit the Publications
`Division Website (http://pubs.acs.org).
`:
`
`:
`
`182426, Columbus, OH43218-2426.
`
`New and Renewal Subscriptions: Send with payment to American Chemical Society, Pp.OQ. Box
`Subscription Donations: Members may donate/share their Personal subscriptions to/with libraries but
`only after 5 years from the date of publication.
`Change of Address: Notify Member & Subscriber Services, ACS, Columbus, OH.Tel: (614) 447-
`3776 or (800) 333-9511. Fax: (614) 447-3671. E-mail: address @acs.org. Include both old and new
`addresses and a mailing label from a recent issue.
`Microfilm, Microfiche, Back Issue, and Printed Edition Single Issue Orders: Send requests to
`Publications Support Services, ACS, Washington, DC. Tel: (202) 872-4376. Fax: (202) 872-6325.
`E-mail: pss@acs.org. Printed edition not available prior to 2003.
`Bulk Reprint Orders: For quotes and information, contact Cadmus Reprints. Tel: (888) 257-2134 or
`(410) 819-3995. Fax: (410) 820-9765.
`
`Claims for Issues Not Received: Claims will be honored only if submitted within 90 days of the
`issue date for subscribers in North’ America or within 180 days of the issue date for all other sub-
`scribers. Members may contact Customer Service. Tel: (614) 447-3776 or (800) 333-9511. E-mail:
`service @acs.org.Institutional subscribers may contact Agency & Institutional Customer Service. Tel:
`(614) 447-3674 or (888) 338-0012. Fax: (614) 447-3671. E-mail: liblink@acs.org.
`Supporting Information (SD: SI from 1995 to the present is available free of charge from the jout-
`nal’s home page (http://pubs.acs.org/jmc). For information on electronic access, send e-mail [0
`journalhelp@acs.org. SI_prior to 1995 is available, for a fee, from Publications Support Services. Tel:
`(202) 872-4376. Fax: (202) 872-6325. E-mail: pss@acs.org.
`
`© Copyright 2007 American Chemical Society
`
`Apotex Exhibit 1013.002
`
`Apotex Exhibit 1013.002
`
`

`

`'
`
`1
`J. Med. Chem. 2007, 50,°6665-6672
`
`.
`
`. 6665 _
`
`Trends in Active Pharmaceutical Ingredient SaltSelection based on Analysis of the Orange
`Book Database
`
`G. Steffen Paulekuhn,’* Jennifer B. Dressman,* and Christoph Saal**
`.. Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt,Germany, and Institute of Pharmaceutical Technology, Biocenter, Johann Wolfgang
`Goethe University, Max von Laue Street 9, 60438 Frankfurt (Main), Germany
`
`Received August 20, 2007
`
`The Orange Bookdatabase published by the US. Drug and Food.Administration (FDA) was analyzed for
`the frequency of occurrence of different counterions-used 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
`formationofsalts as active pharmaceutical ingredients (APIs), while sodiumions are most widely utilized
`for the formationofsalts starting from acidic molecules. A strong trend toward a wider variety of counterions
`overthe 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 canbe influenced by using a variety of
`pharmaceutically acceptable counterions.8 Even polymorphism
`issues can be resolved in many cases by formation ofsalts. The
`crystal structuré of a salt is usually completely different from
`the crystal structure of the conjugate base or acid andalso 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 pharmacodynamics and
`pharmacokinetics,includingbioavailabilityandtoxicityprofile.'°"°
`Owing to dramatic changes in the techniques applied in
`pharmaceutical discovery programs over the past 20 years, the
`physical chemical properties of development candidates have
`changedsubstantially.’ Drug design based on high-throughput
`screening has in general led to more lipophilic compounds
`exhibiting/low aqueoussolubility.
`{There® are many well-known formulation techniques to
`“Increase aqueoussolubility,’*""“ 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 lowsolubility. Nevertheless,
`formation of salts is almost
`the only chemical
`technique
`available to change aqueous solubility and dissolution rate
`Withoutchanging theAPI molecule. Further options formodify-
`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,
`Athis method is beyond the scopeof 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 .
`
`
`physical chemical properties of pharmaceutical salts-and meth-
`odsfor 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 few.”3 All publica-
`tions known to the authors dealing with occurrence of coun-
`terions for formation of pharmaceuticalsalts 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 examinesthe selection of counterions
`for the formation of salts by analyzing the Orange Book
`Database” published by the U.S. Drug and Food Administration
`(FDA). The Orange Booklists all drug products approved in
`the U.S. Drug products approved after1981 are listedincluding
`their date 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 and.the outcomeofthe overall analysis of the Orange
`Book comparedto 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, 21187 drug
`products werelisted, 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..1000..Da.and.thattheir 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
`II comprises salts formed from acidic species. Finally, category
`Ill 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
`
`* To whom correspondence should be addressed. Phone: +496151727634.
`Fax: +496151723073. E-mail: Christoph.Saal @merck.de.
`T Merck KGaA.
`* Johann Wolfgang Goethe University.
`© 2007 American Chemical Society
`5
`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, No. 26
`
`Table 1. Distribution of FDA Approved APIs among Categories I-III
`overall [982 1982-1986 1987-1991 1992-1996 1997-2001 2002-2006
`(%)
`(%)
`(%)
`(%)
`(%)
`(%)
`(%)
`CategoryI: API Salts Formed of Basic Entities
`42.0
`40.2
`38.0
`40.3
`Category II: API Salts Formed of Acidic Entities
`10.1
`11.1
`13.3
`11.1
`
`© 32.7
`
`14.6
`
`38.6
`
`384
`
`12.8
`
`13.6
`
`48.6
`
`48.0
`
`47.9
`
`Category III: Nonsalt APIs
`48.7
`48.7
`
`48.6
`
`52.7
`
`example, the occurrenceof bromides includes bromides and _
`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 “pre-1982”. The
`period from 1982to 2006 has been dividedinto 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
`moiccules. 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 showsthe corresponding distribution of APIs among
`the three categories used in oral and injectable dosage forms.
`Together, oral and injectable formulations represent the majority
`of FDA-approved formulations. However,
`the requirements
`placed on an API for oral and injectable dosage formsare quite
`different. For oral dosage 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 permeabilityare 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 ofthe solution, osmolarity,
`and solubility in a small volumeare 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 ~
`
`
`
`500
`
`600
`
`numberofAPIs 200
`
`400
`
`300
`
`400
`
`Paulekuhnet al.
`
`
`
`Wm pre-1982
`mmm 1982-1986
`momo 1987-1991
`mam 1992-1996
`me 1997-2001
`2002-2006
`
`
`
`
`
`
`
`
`SE
`
`
`
`
`
`non-salt bases _acids||non-salt bases _acids|inon-salt bases acids
`
`injectable
`”
`oral
`overall
`Figure 1. Classification anddistribution of species in the Orange Book
`according to their type of charge and administration route.
`’ Table 2. Figure’ 2 displays the overall distribution of anions,
`whereas Figure 3 depicts the most recent period, 2002-2006.
`The ariion encountered most frequently in FDA-approved_
`pharmaceutical salts is the chloride ion. ‘The fraction ofchlorides
`increased from 52.9% (pre-1982)to 63.8% (4987-1991),
`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 encounteredwith highest
`frequency after chloride is sulfate. However, it accounts for only
`7.5% of APIs formed from basic molecules. Its peak incidence
`was 12.0% during: the period 1982-1986. Further acidic
`counterions frequently encountered include:‘bromides, with a
`total incidence of 4.6%, as well as maleates and mesylates,both
`i
`/
`with incidences of 4.2%.
`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%.Tartrates exhibited a higher incidence
`~ of 6.7% in 1992-1996than 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 period. In total, there
`are only two anions with an average incidence of more than
`5% over the whole period. Theseare 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 im 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-
`approvedsalts 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 2002to 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 trendtoward increased diversity of anions applied for
`the formation ofsalts in category I. The trend can be explained
`asa consequence of the changes in research techniques
`
`".
`
`Apotex Exhibit 1013.004
`
`Apotex Exhibit 1013.004
`
`

`

`Trends in Salt Selection
`
`Table 2. Distribution of Anions Used in APIs of Category I
`1982-1986 (%)
`overall (%)
`pre-1982 (%)
`3.3
`15
`
`8.0
`
`5
`
`.
`>
`-
`Journalof Medicinal Chemistry, 2007, Vol. 50, No. 26 6667
`f.
`
`1987-1991 (%)
`12.7
`
`1992-1996 (%Y
`
`1997-2001 (%)
`3.5
`L.7
`
`2002-2006 (%)
`2.8
`
`0.4
`5.2
`
`52.9
`
`2.6
`
`2.0 -
`4.0
`
`52.0
`
`2.0
`
`1s 2.0
`
`15
`
`5.5
`2.6
`
`0.7
`
`4.0
`
`2.0
`2.0
`
`8.0
`
`9.6 2 en 12.0--
`
`2.1
`
`638
`
`2.1
`
`2.1
`
`43
`
`2.1
`
`21
`
`2.1
`
`43
`
`2.1
`
`5.2
`
`46.6
`
`5.2
`
`8.6
`
`3.5
`13.8
`
`3.3
`17
`
`63.3
`
`3.3
`
`3.3
`
`17
`
`:
`
`33
`1.7
`
`17
`
`1.7
`
`17
`
`-
`
`wo,
`17
`
`8.3
`
`38.9
`
`2.8
`
`2.8
`
`5.6
`8.3
`
`2.8
`
`2.8
`
`5.6
`
`3.3
`17.
`
`6.7
`LT
`
`17
`BS ge
`
`2.8
`ee SB
`
`:
`
`3.5
`
`832.8
`
`
`
`_ acetate
`benzoate
`besylate
`bromide
`carnphorsulfonate
`chloride
`:
`chlortheophyllinate
`citrate
`ethandisulfonate:
`fumarate
`gluceptate
`gluconate
`glucuronate
`hippurate
`iodide
`isethionate
`lactate
`lactobionate
`laurylsulfate
`malate
`maleate
`mesylate
`~ methylsulfate
`~ naphthoate
`napsylate
`nitrate
`octadecanoate
`" oleate
`oxalate
`pamoate
`phosphate
`polygalacturonate
`succinate
`sulfate -
`sulfosalicylate
`tartrate
`tosylate
`trifluoroacetate
`
`50
`272
`numberofsalts
`47
`
`60.
`
`“5g
`
`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 distribution.of cations insalts formed from.chemical
`entities exhibiting. acidic properties. In Figure 5, the relative
`occurrence during the last period from 2002to 2006is depicted.
`Amongthe cations used to form API salts of acidic molecules,
`the sodium ion strongly dominates with an incidence of 75.3%
`overthe entire period. From 1982 to 1991, the fraction of sodium
`salts was more than 90%. This decreased to 62.5% during the
`
`mem Acetate (1)
`ca Bromide (3)
`
`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 and dissolution rate of new drugcandidates
`over the past.20 years. This in turn has necessitated a more
`.intensive ‘search,for appropriate salts as a tool to improve
`| —physiéal chemical properties, a search typically conducted at
`the end of leadoptimization or during exploratory development.
`mmm Acetate (17)
`@mmm Besylate (4)
`meme Bromide (24)
`Chloride (279)
`SEES Citrate(14)
`Fumarate (9)
`= Gluconate (2)
`mmm jodide (5)
`wamm Isethionate (2)
`seem Lactate (7)
`waa Malate (2)
`|= Maleate (22)
`Mesylate (22)
` Methylsulfate (2)
`gmem Napsylate (2)
`mma Nitrate (9)
`aga Pamoate (4)
`waza Phosphate (14)
`Citrate
`rao Succinate
`Succinate (6)
`Fumarate
`_~~ Phosphate
`Sulfate (39)
`Gluconate
`” Sulfate
`Pamoate
`C=Tartrate (20)
`lodide
`Nitrate
`isethiondte/ Malate veclaa\IN
`
`Mesylate
`Succinate
`mam Tosylate (2).
`Napsylate
`mea Only used once (16)
`
`Lactate Maleate
`Methyisulfate
`
`
`
`\.
`\
`
`©
`
`
`
`
`
`
`Besylate
`Acetate
`
`only used
`once
`
`Tosylate
`Tartrate
`
` amd “Chitoride’(14)"
`
`Citrate (1)
`smam Malate (1)
`
`sama Maleate (2)
`munm [Vlesylate (3)
`Nitrate (1)
`a@mme Oxalate (1)
`Phosphate (2)
`mum Succinate (1)
`emma Sulfate (2)
`mama Tartrate (3)
`== Tosylate (1)
`
`
`
`
`
`Acetate
`
`Citrate
`Malate
`
`Maleate
`
`Figure 2. Overall distribution 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, No. 26
`
`Paulekuhn et al.
`
`Table 3. Distribution of Cations Used in APIs of Category I
`
`
`1987-1991 (%)
`1992-1996 (%)
`1997-2001 (%)
`2002-2006 (%)
`
`1982-1986 (%)
`
`9.5
`
`188°
`
`
`
`ctionbenedenidnainimdemisinianecacecata
`
`
`
`pre-1982 (%)
`1.0
`73
`1.0
`1.0
`1.0
`
`:
`benzathine
`calcium
`cholinate
`diethanolamine
`diethylamine
`lysine
`magnesium
`meglumine
`piperazine
`potassium,
`procaine
`silver
`“Soditm,
`tromethamine
`zinc
`
`:
`
`:
`
`overall (%)
`0.6
`6.9
`0.6
`0.6
`0.6
`0.6
`1.2
`2.9
`0.6
`6.3
`0.6
`0.6
`753
`17
`12
`
`63
`
`63
`
`6.3
`
`.
`
`5.2
`1.0
`6.3
`1.0
`1.0
`72.9
`
`1.0
`
`143
`
`63
`
`—
`
`OLT
`
`8.3
`
`92.3
`LT
`
`66.7
`9.5 .
`
`875
`
`63
`
`62.5
`
`3B 7 16 16
`
`number of salts ©
`“174
`96
`12
`applied mostst
`frequently iin APIsutilized in oral formulationsis_
`chloride.Its fraction increased from 55.8% (pre-1982) through.
`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% _
`over the whole.period: 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 fraction of 3.4% over the whole time period. The
`fifth anion according to frequency ofusage 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 perperiod. 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. All cations encountered’ as counterions for
`> formation of API salts used in’ products: for 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
`
`2002-2006 period. The second most commoncation 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 II 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 anionsis 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 formationof salts from acidic moieties, five
`of which were employed over the past 25 years. The analysis
`showsthat 15 anions and 3 cations were only used once.
`Distribution of Anionic Counterions Used in _ Oral
`Formulations. Relative incidencesof all anions used in FDA-
`approved oral formulations are presented in Table 4, The anion
`Silver Procaine
`Benzathine (1)
`mma Calcium (12)
`Piperazine
`~ Potassium
`
`C= Cholinate (1)
`Megiumine
`gama Diethanolamine (1)
`
`~~ Magnesium
`Diethylamine (1)
`
`.---
`LYSINE Diethylamine
`mmm Lysine (1)
`Diethanolamine
`
`Magnesium (2)
`4
`Cholinate
`mage MVeglumine (5)
`fe
`Calcium
`=> Piperazine (1)
`wmzas Potassium (11)
`sq
`Procaine(1)
`wm Silver (1)
`saa Sodium (131)
`tama Tromethamine (3)
`= Zine @)
`
`fo
`
`
`.
`
`
`
`ia
`
`Calcium (3):
`Lysine (1)
`Magnesium (1)
`Potassium (1)
`Sodium (10)
`
`2, Calcium
`
`
`
`Figure 4. Overall distribution of cations used'in APIs of category IL
`in the Orange Book.
`
`‘Figure 5. Distribution of cations used in APIs of category Il from
`2002 to 2006.
`soe
`
`Apotex Exhibit 1013.006
`
`Apotex Exhibit 1013.006
`
`

`

`Trends in Salt. Selection
`
`Journal of Medicinal Chemistry, 2007; Vol. 50, No. 26 6669 -
`
`Table 4. Distribution of Anions for API Used in Oral Dosage Forms
`overall (%)
` pre-1982 (%)
`1982-1986 (%)
`0.9
`/
`0.6
`17
`acetate
`0.3.
`—
`~ benzoate
`0.6
`_ 0.6
`besylate
`bromide = 41
`5.2
`chloride
`,
`56.6
`55.8
`chlortheophyllinate
`0.3
`, 0.6
`citrate
`34.
`© AL
`ethandisulfonate
`0.3
`0.6
`fumarate
`160
`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
`69
`mesylate
`4.4
`methylsulfate
`0.6
`napsylate
`0.6
`nitrate
`0.6.
`. octadecanoate
`0.3
`oxalate
`0.3 |
`pamoate
`0.9 7
`phosphate
`25
`.
`2.9
`polygalacturonate
`0.3
`0.6
`succinate
`1.9
`1.2
`sulfate
`75
`7.6
`’ tartrate
`2.8
`17
`tosylate
`0.3
`
`:
`
`:
`
`|
`
`-
`
`.
`
`.
`
`:
`oe
`
`—
`
`:
`
`|
`
`my
`
`,
`
`_ 87
`1.7
`1.2
`1.2
`
`0.6
`
`1987-1991 (%)
`
`1992-1996 (%)
`
`1997-2001 (%)
`
`2001-2006 (%)
`
`2.9
`
`65.7
`
`2.9
`
`2.9
`
`5.7
`2.9
`
`2.9
`
`57
`2.9
`5.7
`
`5
`uo
`
`:
`
`“
`
`79.2
`
`4.2
`
`8.3
`
`42
`4.2
`:
`
`25
`
`5.0
`45.0
`‘
`75
`
`5.0
`
`5.0
`15.0
`
`—
`
`.
`
`2.5
`
`2.5
`5.0
`5.0
`
`.
`
`:
`
`8.7
`34.8
`
`4.4
`8.7
`8.7
`
`4.4
`
`8.7
`
`44
`8.7
`44
`44
`
`5
`
`65.4
`
`.
`*
`
`3.9
`
`y
`oy
`ao
`3.9
`
`19.2
`
`
`number ofsalts
`~
`320
`172
`26
`24
`350
`40
`,
`23
`
`ps
`Table5. Distribution of Cations for API Used in Oral Dosage Forms
`overall (%) ‘pre-1982 (%) , 1982-1986 (%)
`1.3
`2.3
`L
`12.0
`11.4
`1.3
`2.3
`27
`1.3
`13.3
`65.3
`- 27
`
`.
`
`2.3.
`- 13.6
`_ 68.2.
`,
`
`100.0
`
`benzathine
`calcium
`cholinate
`magnesium
`piperazine
`potassium
`sodium
`tromethamine
`
`1987-1991 (%)
`
`1992-1996 (%)
`
`1997-2001 (%)
`
`2002-2006 (%)
`
`11.1
`
`,
`
`50.0
`
`83.3.
`16.7
`
`33.3
`a4
`111
`
`W167
`
`7
`889.
`
`16.7
`16.7
`
`
`
`
`
`
`
` 9 9number ofsaits 75 Ag 1 6 6
`
`
`
`
`
`
`
`
`
`fraction ofjat least 68.2% until 1991. This value decreased to
`44.4%- during 1992-1996. During the following period,
`'1997-2001, 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 thesmall 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 appliedin drug products for oral delivery. The free
`acid is not used in FDA-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 dissolutionrates. Finiet
`al.2} have discussed the difference in dissolution behavior
`between these salt forms.
`:
`Salts Used in Injectable Formulations. The 482 APIs used
`for injectable 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 injectable.formulations only aboutone-third wereemployed
`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. An 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.” Typically, the preferred injectable dosage
`form comprises a volume of a few milliliters. If the solubility
`of the APIis too low forthis application, an infusion formulation
`becomes necessary. In many cases, there is a difference of at
`least one order of magnitude with respect to the solubility
`required for the formulation of an API as an injectable versus
`
`Apotex Exhibit 1013.007
`
`Apotex Exhibit 1013.007
`
`

`

`6670
`
`Journal of Medicinal Chemistry, 2007, Vol. 50, No. 26
`
`Table 6. Distribution of Anions for API Used in Injectable Dosage Forms
`
`Paulekuhn et al.
`
`1987-1991 (%)
`1992-1996 (%)
`1997-2001 (%)
`2002-2006 (%)
`overall (%)—pre-1982 (%) 1982-1986 (%)
`
`26.3
`143
`16.7
`acetate
`5.8
`2.3
`5.0
`besylate
`14
`0.8
`5.0
`bromide
`4.3
`3.9
`5.0
`carmmphorsulfonate
`0.5
`0