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`a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m
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`j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / e j p s
`
`Commentary
`Generic substitution: The use of medicinal
`products containing different salts and
`implications for safety and efficacy
`
`R.K. Verbeeck 1, I. Kanfer
`Faculty of Pharmacy, Rhodes University, Artillery Road, Grahamstown 6140, South Africa
`
`, R.B. Walker
`
`∗
`
`a r t i c l e
`
`i n f o
`
`a b s t r a c t
`
`Article history:
`Received 25 May 2005
`Received in revised form 31 October
`2005
`Accepted 4 December 2005
`Published on line 18 January 2006
`
`Keywords:
`Generic substitution
`Bioequivalence
`Pharmaceutical equivalence
`Therapeutic equivalence
`Pharmaceutical alternative
`
`In their quest to gain early entry of new generic products into the market prior to patent expi-
`ration, one of the strategies pursued by generic drug product manufacturers is to incorporate
`different salts of an approved active pharmaceutical ingredient (API) in a brand company’s
`marketed dosage form and subject such dosage forms to bioequivalence assessment. These
`initiatives present challenges to regulatory authorities where the decision to approve bioe-
`quivalent products containing such pharmaceutical alternatives must be considered in the
`light of safety and efficacy, and more particularly, with respect to their substitutability.
`This article describes the various issues and contentions associated with the concept of
`pharmaceutical alternatives, specifically with respect to the uses of different salts and the
`implications for safety, efficacy and generic substitution.
`© 2005 Elsevier B.V. All rights reserved.
`
`1.
`
`Introduction
`
`Most drugs are either weak organic acids or weak organic bases
`and can therefore exist as different salt forms. Although the
`active pharmaceutical ingredient (API) in these different salts
`is the same, each of these salts may be considered as being
`distinct chemical entities with their own chemical and bio-
`logical profiles which may lead to differences in their clinical
`efficacy and safety (Berge et al., 1977; Gould, 1986; Davies,
`2001; Stahl and Wermuth, 2002a). The term pharmaceutical
`alternatives is used in relation to different salts (or esters)
`of the same active substance in the EU Note for Guidance
`
`as well as in the FDA Guidance for Industry on Bioavailabil-
`ity and Bioequivalence Studies for Orally Administered Drug
`Products (EMEA, 2001; FDA, 2000). According to the EU guide-
`lines “medicinal products are pharmaceutical alternatives if
`they contain the same active moiety but differ in chemical
`form (salt, ester, etc.) of that moiety or in the dosage form or
`strength”. Similarly, the definition of pharmaceutical alterna-
`tives as stated in the FDA’s “Approved Drug Products with Ther-
`apeutic Equivalence Evaluations”, 24th edition (Orange Book,
`2004) is as follows: “Drug products are considered pharmaceu-
`tical alternatives if they contain the same therapeutic moiety,
`but are different salts, esters, or complexes of that moiety,
`
`∗
`
`Corresponding author. Tel.: +27 46 603 8382; fax: +27 46 636 1205.
`E-mail address: I.Kanfer@ru.ac.za (I. Kanfer).
`1 Present address: School of Pharmacy, UCL/PMNT 7369, Av. E. Mounier 73, Brussels, Belgium.
`0928-0987/$ – see front matter © 2005 Elsevier B.V. All rights reserved.
`doi:10.1016/j.ejps.2005.12.001
`
`Merck Exhibit 2196, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`e u r o p e a n j o u r n a l o f p h a r m a c e u t i c a l s c i e n c e s 2 8 ( 2 0 0 6 ) 1–6
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`or are different dosage forms or strengths . . .”. In contrast
`to the issue of pharmaceutical alternatives, the Orange Book
`(2004) also defines the term, pharmaceutical equivalents, as
`follows: “Drug products are considered pharmaceutical equiv-
`alents if they contain the same active ingredient(s), are of the
`same dosage form, route of administration and are identi-
`cal in strength or concentration. Pharmaceutically equivalent
`drug products are formulated to contain the same amount
`of active ingredient in the same dosage form and to meet
`the same or compendial or other applicable standards (i.e.
`strength, quality, purity and identity), but they may differ in
`characteristics, such as shape, scoring configuration, release
`mechanisms, packaging, excipients (including colors, flavours
`and preservatives), expiration time and within certain limits,
`labelling”.
`According to both the FDA (2000) and EMEA (2001)
`guidelines, bioequivalence can be established between two
`medicinal products, which are pharmaceutical alternatives.
`However, the definition of therapeutic equivalence as given
`in the Orange Book (2004) precludes the substitutability of
`pharmaceutical alternatives, as follows: “Drug products are
`considered to be therapeutic equivalents only if they are phar-
`maceutical equivalents and if they can be expected to have
`the same clinical effect and safety profile when administered
`to patients under the conditions specified in the labelling”.
`On the other hand the European Agency for the Evaluation
`of Medicinal Products (EMEA) makes provision for medici-
`nal products which are either pharmaceutically equivalent
`or pharmaceutical alternatives to be declared as therapeu-
`tic equivalents, as follows: “In practice, demonstration of
`bioequivalence is generally the most appropriate method
`of substantiating therapeutic equivalence between medici-
`nal products which are pharmaceutically equivalent or phar-
`maceutical alternatives, provided they contain excipients
`generally recognised as not having an influence on safety
`and efficacy and comply with labelling requirements with
`respect to excipients” (EMEA, 2001). The immediately pre-
`ceding paragraph in the same EMEA guideline confound-
`ingly states that: “A medicinal product is therapeutically
`equivalent with another product if it contains the same
`active substance or therapeutic moiety and, clinically, shows
`the same efficacy and safety as that product, whose effi-
`cacy and safety has been established”. The issue is compli-
`cated by incorporation of the phrase “. . ., clinically, shows
`the same efficacy and safety as that product, whose effi-
`cacy and safety has been established”, in the definition.
`In our view this implies that therapeutic equivalence can-
`not be established between pharmaceutical alternatives on
`bioequivalence data alone. Hence, whereas pharmaceutically
`equivalent products can clearly be considered therapeuti-
`cally equivalent based on a bioequivalence study, additional
`preclinical and/or clinical data may be required for a pharma-
`ceutical alternative to be considered therapeutically equiva-
`lent.
`In this commentary, scientific facts/data will be pre-
`sented to show that establishing bioequivalence between
`oral drug products containing different salts of the same
`active substance, will usually not suffice to claim therapeutic
`equivalence and consequently substitutability/interchange-
`ability.
`
`Active pharmaceutical ingredients and
`2.
`their salts
`
`Converting an API to a particular salt form is a means of mod-
`ifying and sometimes optimising its physicochemical prop-
`erties (Stahl and Wermuth, 2002a,b). However, changing the
`salt form may also affect the biological properties of the
`drug and have significant implications for safety and tox-
`icity (Davies, 2001). The most appropriate salt form of an
`active moiety should ideally be selected at an early stage
`of the development of a New Chemical Entity (NCE) to opti-
`mise the characteristics of the final formulation. Indeed, dif-
`ferent salt forms of a particular API can differ markedly in
`physicochemical properties, such as solubility, hygroscopicity,
`stability, flowability, etc. In addition, the presence of impu-
`rities associated either with the route of synthesis of that
`particular salt or resulting as a consequence of instability and
`the formation of degradation products, can impart toxicity
`and/or undesirable biological activity quite different from the
`drug’s intended clinical use (Bastin et al., 2000; Byrn et al.,
`1995). Hence, it may therefore be possible that substitution
`of one salt form of an API for another can alter therapeu-
`tic efficacy, safety and/or quality. Unfortunately, there is no
`reliable way of predicting the influence of a particular salt
`species on the behaviour of the parent compound in dosage
`forms.
`It is estimated that half of all the active substances used
`in medicinal therapy are administered as salts, and salifica-
`tion of a drug substance has become an essential step in drug
`development (Balbach and Korn, 2004; Gardner et al., 2004).
`Selecting an appropriate salt form of an API is not only an
`important consideration in the early stages of new drug devel-
`opment (Bowker, 2002), it may also play a role in the develop-
`ment of generic drug products as illustrated by the example
`of amlodipine. This calcium channel blocker is marketed by
`Pfizer as the besylate salt (Norvasc®). Pfizer’s original patent
`on amlodipine besylate expired in 2003 but was extended until
`2007 to compensate for a lengthy review process by the FDA
`(Anon., 2004). Pfizer’s original patent attempted to protect both
`the chemical structure of amlodipine besylate and a series
`of other salts of amlodipine. Dr. Reddy’s Laboratories Limited
`developed a generic version of amlodipine in the form of the
`maleate salt and showed that their product (AmVazTM, Reddy
`Pharmaceuticals Inc.) was bioequivalent to Pfizer’s Norvasc®
`(Suh et al., 2004). Dr. Reddy’s Laboratories tried to obtain mar-
`keting authorization arguing that Pfizer’s patent extension
`did not apply to their version of the drug, i.e. amlodipine
`maleate. However, on February 27, 2004 The United States
`Court of Appeals for the Federal Circuit reversed the ear-
`lier New Jersey District Court’s dismissal of Pfizer’s patent
`infringement action against Dr. Reddy’s Laboratories’ generic
`version of Norvasc®, thus effectively preventing the generic
`version from entering the market (Anon.: Pfizer Inc. ver-
`sus Dr. Reddy’s Laboratories, www.ll.georgetown.edu/federal/
`judicial/fed/opinions/03opinions/03-1227.html, visited 05/23/
`05). A short discussion of the properties of amlodipine
`maleate, with particular emphasis on stability and subsequent
`effects on efficacy and safety is presented in Section 3.4 (vide
`infra).
`
`Merck Exhibit 2196, Page 2
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
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`3
`
`Apart from the legal issues, the important question to
`be answered is: what experiments and tests are required
`to ensure that a drug product containing a specific salt
`form of an API has comparable pharmacokinetic, pharma-
`cological, toxicological and safety profiles as the registered
`product containing an alternative salt form of the same
`active substance? Furthermore, what is the likelihood that
`pharmaceutical alternatives which have been shown to be
`bioequivalent will have different clinical safety and efficacy
`profiles?
`
`Development of generic drug products
`3.
`using an alternative salt of the same active
`moiety
`
`The following issues are important when considering whether
`alternative salt forms of the same active moiety can be
`considered therapeutically equivalent and hence have to be
`addressed when developing a generic drug product using an
`alternative salt form of the active substance.
`
`3.1.
`
`Solubility, dissolution and bioavailability
`
`Many examples can be found in the scientific literature
`showing that the water solubilities of alternative salt forms
`of the same active moiety can be quite different. The antide-
`pressant, trazodone, for example,
`is currently marketed
`as the hydrochloride salt. Ware and Lu (2004) prepared a
`number of alternative salts in an attempt to find a salt form
`of trazodone with lower aqueous solubility compared to
`trazodone hydrochloride. Among the salts selected for final
`evaluation, the tosylate and pamoate salts of trazodone
`were less water-soluble than the sulphate and hydrochloride
`salts. The tosylate salt showed the most interesting solu-
`bility profile with values ranging from 3 mg/ml at pH 1.0 to
`0.2 mg/ml at pH 12.0. This characteristic makes it the best
`candidate, compared to the other salts, for the development
`of a prolonged release oral trazodone product to improve
`patient compliance in the elderly. Because of the significantly
`lower (8–10-fold in the pH range 1–5) solubility of the tosylate
`salt compared to the marketed hydrochloride salt, the in vivo
`absorption rate of trazodone following oral administration of
`the tosylate salt may be significantly lower. Consequently, the
`two salts will probably be neither bioequivalent, i.e. having
`a similar rate and extent of absorption, nor therapeutically
`equivalent.
`Following oral administration as a solid dosage form, the
`dissolution rate of the active substance in the gastrointesti-
`nal juices is affected by its aqueous solubility. Therefore,
`solid dosage forms containing alternative salts of the same
`active substance may show different in vivo dissolution
`characteristics. According to the principles underlying the
`Biopharmaceutics Classification System,
`for active drug
`substances with a high intestinal permeability, the in vivo
`dissolution rate will determine the rate and in some cases
`also the extent of absorption (Amidon et al., 1995). For active
`substances with a low intestinal permeability and a relatively
`good aqueous solubility, however, in vivo dissolution is no
`longer the rate-limiting step in the absorption process and
`
`differences in aqueous solubility and dissolution are usu-
`ally not important determinants of bioavailability. Human
`bioequivalence studies comparing salt forms of basic drugs
`have been rather limited and none of them have reported
`significant differences in bioavailability between different salt
`forms due to differences in their aqueous solubilities (Engel et
`al., 2000). Lin et al. (1972), for example, reported no enhance-
`ment in bioavailability when salts of a basic antihypertensive
`agent,
`1-(2,3-dihydro-5-methoxybenzo[b]furan-2-ylmethyl)-
`4-(o-methoxyphenyl)piperazine, having significantly different
`intrinsic dissolution rates, were compared. Walmsley et al.
`(1986) also indicated that they did not observe a difference
`in the extent of bioavailability between oxalate and citrate
`salts of naftidrofuryl, while Jamuludin et al. (1988) saw no
`significant differences in Cmax, Tmax, or AUC of quinine
`following oral administration of the hydrochloride, sulphate
`and ethyl carbonate salts of this antimalarial to healthy
`volunteers. Consequently, it may be concluded that an in
`vivo bioequivalence study is absolutely necessary if thera-
`peutic equivalence between alternative salts of the same
`active drug molecule is being claimed, except when both
`salts are highly soluble and highly permeable, i.e. BCS class
`I compounds. In that case a BCS-based waiver for an in
`vivo BE study for an immediate release oral dosage form
`which exhibits rapid in vitro dissolution can be requested,
`provided a number of additional conditions are met (FDA,
`2000).
`
`3.2.
`
`Toxicity
`
`Toxicity associated with the salt of an active drug molecule
`may be due to the conjugate anion or cation used to form
`the salt (Berge et al., 1977; Stahl and Wermuth, 2002b). For
`example, the nephrotoxicity of pravadoline maleate, which
`was reported to cause renal tubular lesions in the dog, has
`been shown to be the result of the formation of maleic acid
`from the maleate anion (Everett et al., 1993). The need to evalu-
`ate the safety profile of the salt-forming agent depends largely
`on its chemical nature, its biological characteristics, whether
`the agent has been used in other medicinal products, foods
`and beverages or not, as well as the relative ratio of the salt-
`forming component to the active substance. Toxicity studies
`are required for a new salt form of an active substance when
`the salt of that active substance has been prepared by using a
`new salt-forming agent with little or no information on its tox-
`icity profile. Toxicity studies on the salt-forming agent alone
`are also necessary. Monographs on 68 salt-forming acids and
`27 salt-forming bases have been published in the Handbook
`of Pharmaceutical Salts: Properties, Selection and Use, edited by
`Stahl and Wermuth (2002a) as well as a comprehensive list
`of salt-forming acids and bases with information regarding
`their safety/toxicity (Stahl and Wermuth, 2002b; Wermuth,
`2002).
`Potentially toxic chemical impurities formed during the
`preparation of a specific salt of an API may also explain dif-
`ferences found in the toxicity profiles of various salt forms
`of an active drug molecule. It is therefore necessary to eval-
`uate the toxic potential of all impurities found during the
`synthesis of a specific salt form (Bauer et al., 1998). For
`example, methane sulfonic acid is used in the formation of
`
`Merck Exhibit 2196, Page 3
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

`

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`methane sulfonates (also called mesylate salts) of active basic
`drug molecules, such as pergolide, nelfinavir, imatinib and
`amlodipine. Benzene and toluene sulfonates (besylates and
`tosylates, respectively), have also been prepared. Recently, the
`potential health hazards of trace amounts of mesylate esters,
`including methyl methanesulfonate, ethyl methanesulfonate
`and isopropyl methanesulfonate, in pharmaceuticals have
`attracted the attention of health authorities (Anon., 2000).
`These impurities could arise from the reaction of methane
`sulfonic acid with solvents, such as methanol, ethanol and iso-
`propyl alcohol during the manufacture of the mesylate salts
`of active substances. These mesylate esters are known to be
`potent mutagenic, carcinogenic and teratogenic compounds
`(Sega et al., 1986; Morris et al., 1994). In general, it can be
`concluded that when the routes to synthesize or prepare alter-
`native salt forms of the same active moiety result in different
`chemical by-products, the toxic potential of these impurities
`should be evaluated by preclinical testing for each salt form
`synthesized/prepared.
`The specific salt form of an active substance may also
`affect tolerability. Gastrointestinal irritation and ulceration,
`for example, may be dependent upon the aqueous solubil-
`ity and dissolution rate of different salt forms administered
`by the oral route. Olovson et al. (1986) tested the ulcero-
`genic effect of five different salts of alprenolol against placebo
`in a porcine oesophageal test model. The salts with high
`water solubility, such as the hydrochloride and the fumarate,
`gave rise to the highest plasma concentrations of alprenolol
`and evoked serious oesophageal lesions, while the salts with
`low solubility – the benzoate, maleate and sebacate – had
`no irritant effect on the oesophagus. The plasma levels of
`alprenolol were much higher following administration of
`alprenolol hydrochloride in the oesophagus than after an iden-
`tical intraduodenal dose of the same salt possibly because of
`the avoidance of first-pass metabolism during oesophageal
`absorption.
`
`3.3.
`
`Polymorphism
`
`The solid-state properties of a molecule, as well as its proper-
`ties in solution, can be modified by salt formation. Selecting a
`salt suitable for a certain route of administration or a particu-
`lar dosage form of a drug substance requires that all the rele-
`vant solid-state properties of the salt candidates be thoroughly
`investigated. Polymorphism is frequently a critical point in
`determining preferences for one salt or another (Balbach and
`Korn, 2004; Bowker, 2002). Polymorphism can be defined as the
`ability of a drug substance to exist as two or more crystalline
`phases that have different arrangements and/or conforma-
`tions of the molecules in the crystal lattice. Polymorphism is
`a widespread phenomenon observed in more than half of all
`active drug substances. The most critical issue related to drug
`substance polymorphism is equilibrium solubility which is
`an important determinant of dissolution rate and which may
`affect the bioavailability following oral administration of the
`active substance (Huang and Tong, 2004). Clearly, if polymor-
`phism has an effect on the bioavailability of a drug substance,
`a bioequivalence study between two formulations containing
`different polymorphs of the same drug should reveal those
`effects.
`
`Stability and formulation/production
`3.4.
`considerations
`
`As mentioned before, the different salt forms of an active
`drug moiety can vary in a number of physicochemical char-
`acteristics including hygroscopicity. Increased hygroscopic-
`ity may reduce stability of the active drug moiety, even in
`a pharmaceutical dosage form, such as tablets, especially
`when the active drug moiety is susceptible to hydrolytic
`degradation. In addition, thermal stability and degradation
`pathways may be different for alternative salt forms of the
`same active moiety possibly requiring the need to evaluate
`new degradation products by using appropriate toxicological
`studies.
`Amlodipine maleate provides an interesting example
`where instability of this particular salt results in the for-
`mation of a degradation product, which has significant
`implications for safety and toxicity. The maleate salt of
`amlodipine, unlike the besylate salt, suffers from intrinsic
`chemical instability which results in the formation of N-(2-{[4-
`(2-chlorophenyl)-3-(ethoxycarbonyl)-5-(methoxycarbonyl)-6-
`methyl-1,4-dihydro-2-pyridyl]methoxy}ethyl) aspartic acid,
`an impurity with demonstrated biological activity. It is formed
`by an intramolecular reaction of the unsaturated maleic acid
`with the primary amine group of amlodipine. This compound
`has been shown to possess a distinctly different biological
`profile to amlodipine itself (Amlodipine Citizen Petition,
`http://www.fda.gov/ohrms/dockets/dailys/03/Sept03/090303/
`03p-0408-cp00001-08-Tab-G-vol3.pdf, visited 05/23/05). Hence,
`the maleate salt of amlodipine cannot be considered to be
`therapeutically equivalent to the besylate salt since the latter
`does not have this additional clinical effect. The consequences
`of the presence of the biologically active impurity associated
`with amlodipine maleate therefore militates against generic
`substitution between maleate and besylate salts even if
`bioequivalence can be demonstrated. Whereas low levels of
`this impurity may not result in serious clinical consequences,
`the instability of the amlodipine maleate salt suggests that
`relatively high levels would likely result following the manu-
`facture of dosage forms and on prolonged storage. However,
`a case could be made to suggest interchangeability and thus
`permit generic substitution if a stabilised formulation of
`amlodipine maleate is used to show bioequivalence between
`the maleate and besylate salts. Such stabilized formulations
`have been described in a recent patent (Bilotte et al., 2002)
`where it is claimed that the formation of amlodipine aspartate
`can be prevented.
`The choice of a particular salt form can have a profound
`effect on the physicochemical properties, which are critical for
`the optimal formulation of the dosage form and large-scale
`manufacturing. The melting point of a particular salt often
`plays an important role. Generally, drugs with low melting
`points exhibit plastic deformation which can result in caking
`and aggregation of the API which can alter flow properties and
`compression characteristics and subsequently impact nega-
`tively on dose uniformity, friability, disintegration and disso-
`lution rate of solid dosage forms. The formation of plastic
`materials can create problems for size reduction and tablet
`processing due to melting and deposition of drug on milling
`equipment and film formation on tabletting punches with
`
`Merck Exhibit 2196, Page 4
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
`
`

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`5
`
`deleterious consequences for the bulk manufacture of tablets
`(Florence and Attwood, 1988).
`
`4.
`
`Regulatory requirements
`
`The health authorities of the European Union as well as those
`of the USA consider alternative salts of approved drug sub-
`stances as NCEs (Asche et al., 2002). However, the application
`to register medicinal products containing an alternative salt
`of an approved active substance as a generic product may
`be facilitated, under certain conditions, by the use of previ-
`ous knowledge on and clinical experience gained with the
`active moiety approved as a different salt form. Therefore, in
`many cases of salt changes or development of a generic drug
`product on the basis of an alternative salt form of the active
`moiety already marketed, an abbreviated or abridged applica-
`tion may be submitted as long as evidence can be provided
`that the alternative salt form does not lead to a change in the
`pharmacokinetics of the active moiety, nor in its pharmaco-
`dynamic and/or toxicity characteristics, which could change
`the safety/efficacy profile. Notwithstanding the above, in the
`USA, pharmaceutical alternatives which have been shown to
`be bioequivalent to an approved reference product containing
`a different salt and/or dosage form, would not be considered
`to be therapeutically equivalent and generic substitution of
`such products is therefore not permitted.
`
`5.
`
`Conclusions
`
`According to the CPMP Note for Guidance on the Investigation
`of Bioavailability and Bioequivalence, demonstration of bioe-
`quivalence is the most appropriate method of substantiating
`therapeutic equivalence between medicinal products which
`are pharmaceutically equivalent or pharmaceutical alterna-
`tives, such as different salt forms of the same active moiety
`(EMEA, 2001). If bioequivalence between two different salts of
`the same active moiety has been demonstrated, it is clear that
`any differences in physicochemical properties, such as solu-
`bility, between the two salts do not have any significant effect
`on the in vivo bioavailability of the active moiety. However,
`this does not suffice to conclude that these alternative salt
`forms are therapeutically equivalent. Therapeutic equivalence
`between two medicinal products not only implies the same
`efficacy but also the same safety profile. The issues raised
`above related to the possible difference in toxicity and sta-
`bility of two different salt forms of the same active moiety,
`demonstrate that an alternative salt form may have to undergo
`toxicological evaluation, in addition to a valid BE study show-
`ing in vivo bioequivalence, before therapeutic equivalence, for
`example, to a different (marketed) salt form of the same active
`moiety, can be accepted.
`
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