PLUS:
`
`Expanding
`the Cold Chain
`
`Optimizing
`Adjuvant Filtration
`
`Regulatory
`Scientists’ Future
`
`February 2012
`
`Volume 36
`
`Number 2
`
`The Authority on Drug Development & Manufacturing
`
`PharmTech.com
`
`Applying QbD
`Principles to Drug
`
`Substance
`Development
`and Manufacture:
`Inside ICH Q11
`
`CQAs
`
`Material
`Selection
`
`Control and
`Validation
`
`PEER-REVIEWED: Evaluating Impurities
`
`Outsourcing Outlook: Biomanufacturing on the Rise
`
`Volume 36 Number 2
`
`PHARMACEUTICAL TECHNOLOGY
`
`February 2012 pharmtech.com
`
`IPR2020-00770
`United Therapeutics EX2024
`Page 1 of 7
`
`

`

`Impurities
`
`Evaluating Impurities in Drugs
`Part I of Part III
`
`Kashyap R. Wadekar, Mitali Bhalme, S. Srinivasa Rao, K. Vigneshwar Reddy,
`L. Sampath Kumar, and E. Balasubrahmanyam
`
`To ensure the quality of APIs and finished drug prod-
`
`ucts, impurities must be monitored carefully dur-
`ing process development, optimization, and process
`changeover. The isolation, characterization, and con-
`trol of impurities in pharmaceutical substances are being
`reviewed with greater attention based on national regulatory
`and international guidelines. In Part I of this article, the au-
`thors examine the different types and sources of impurities
`with specific examples.
`
`Definition and sources of impurities
`An impure substance may be defined as a substance of in-
`terest mixed or impregnated with an extraneous or usually
`inferior substance. The greatest financial impact on the cost
`of a drug substance often is found in the final preparation
`process. Product yield, physical characteristics, and chemical
`purity are important considerations in the manufacture of the
`active ingredient, the formulation of the dosage form, and the
`manufacture of the finished drug product. Processes to con-
`trol the preparation of the drug substance and drug product
`must be disclosed to FDA as part of a new drug application. If
`production batches do not meet the purity and impurity speci-
`fications required, the manufacturer must attempt to upgrade
`materials by rework procedures, which are costly because they
`consume drug substance and resources and prevent the prepa-
`ration of other batches of drug substance. The sources and
`types of impurities can be illustrated by considering a general
`flow scheme for manufacturing drugs. The formation of im-
`purities is interconnected with each stage as shown in Figure 1.
`In short, any material that can affect the purity of an API
`or finished drug product is considered an impurity. Impuri-
`ties arise from various sources, which commonly include
`starting material(s), intermediates, penultimate intermedi-
`ates, byproducts, transformation products, interaction prod-
`ucts, related products, degradation products, and tautomers.
`
`Starting material(s)
`Impurity control in starting materials used to manufacture
`APIs has long been expected by regulatory agencies (1). An
`API starting material is a raw material, intermediate, or API
`that is used in the production of an API and that is incorpo-
`rated as a significant structural element into the API. API
`
`AdAM GAuLT/ OJO IMAGeS/GeTTy IMAGeS
`
`To ensure the quality of APIs and finished drug
`products, impurities must be monitored carefully
`during process development, optimization, and
`process changeover. This three-part article series
`examines the types of impurities, their sources,
`and strategies for the isolation, characterization
`and control of impurities. In Part I of this article,
`the authors discuss what constitutes an impurity
`and the potential sources of such impurities,
`such as vendor scheme, solvents, and reagents
`for key starting raw material(s).
`
`Kashyap R. Wadekar, PhD,* is a research
`scientist (II), Mitali Bhalme, PhD, is an associate
`research scientist, S. Srinivasa Rao is a research
`associate, K. Vigneshwar Reddy is a research
`associate, L. Sampath Kumar is a research chemist,
`and E. Balasubrahmanyam is a research chemist, all
`with Neuland Laboratories, 204 Meridian Plaza, 6-3-
`854/1, Ameerpet, Hyderabad, India, tel. 91 40 30211600,
`kashyapwadekar@neulandlabs.com.
`
`*To whom all correspondence should be addressed.
`
`Submitted: Sept. 19, 2011; Accepted Nov. 28, 2011.
`
`46 Pharmaceutical Technology February 2012 P h a r mTe c h . c o m
`
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`

`

`the produced drug substance,
`the following framework has
`been offered for the selection
`of starting materials:
`• Appropriate, discriminat-
`ing methodology is used
`to determine the quality of
`the starting material.
`• Specifications are appropriate
`to ensure quality of the API.
`• The impact of the starting
`material quality on API
`quality is understood and
`controlled.
`• The starting material is
`available commercially and
`is incorporated into the new
`drug substance as an im-
`portant structural element.
`• The starting material is
`characterized, and stabil-
`ity is well understood.
`• The starting material is a
`compound whose name,
`chemical structure, chemical
`and physical characteristics
`and properties, and impu-
`rity profile are well defined
`in the chemical literature (4).
`Because of the starting
`materials’ potential impact
`on the quality of an API,
`stricter requirements for a
`starting material arise based
`on the proximity in the API
`synthesis of the starting ma-
`terial to the final API. For ex-
`ample, fluoronitrobenzene is
`a key starting material for the
`API olanzapine. If the 2-4-
`difluoronitrobenzene impu-
`rity is present in the key start-
`ing material, the same will
`be converted under reported
`conditions to 8-fluoro-olan-
`zapine, a nonpharmacopeial impurity (US Pharmacopeia [USP]
`method, relative retention time [rrt] 1.07). The 2,4-difluoroni-
`trobenzene is carried forward along with the fluoronitroben-
`zene, resulting in analogous compounds up to the final stage .
`In another example, N-[6-(4-phenylbutoxy)hexyl)]
`benzenemethanamine (see Figure 2) is a drug master file
`(DMF) starting material for the selective long-acting β-2-
`adrenoreceptor agonist salmeterol. The drug is used clini-
`cally as an inhaled bronchodilator for treating asthma and
`chronic bronchitis (5, 6).
`
`Intermediate 1
`
`O
`
`N
`
`Compound 2
`
`O
`
`as known process
`
`No Reaction
`
`Pharmaceutical Technology February 2012 47
`
`OH H
`
`N
`
`HO
`
`HO
`
`O
`NaBH4, Methanol
`Pd/C, Hydrogen
`
`O
`
`Salmeterol
`
`Figure 1: Schematic representation of impurity-formation pathways for APIs and finished drug
`products. DMF is drug master file.
`
`Metabolite - Impurities
`
`DMF
`Starting Raw Material (s)
`
`Drugs / APIs
`(Generic Drugs)
`
`Non-DMF Stages
`
`Kew Starting Raw Material (s)
`
`Starting Material (s) - Impurities
`Penultimate Intermediate - Impurities
`Byproduct - Impurities
`Transformation Products - Impurities
`Interaction Products - Impurities
`Related Products - Impurities
`Degradation - Impurities
`Tautomer - Impurities
`
`Formulation - Impurities
`
`Polymorphic - Impurity
`
`Genotoxic - Impurities
`
`Figure 2: Reaction scheme of salmeterol and impurities. EP is the European Pharmacopoeia. NaH
`is sodium hydride. TBAB is tetra-n-butylammonium bromide DMSO is dimethyl sulfoxide. NABH
` is
`sodium borohydride. Pd/C is palladium on carbon.
`
`4
`
`OH H
`
`N
`
`O
`
`Salmeterol impurity B (EP)
`
`HO
`
`HO
`
`HO
`
`HO
`
`OH H
`N
`
`O
`
`Methyl Salmeterol impurity
`(Nonpharma impurity)
`
`HO
`
`OH
`
`OH
`
`(A)
`4-Phenyl butanol
`
`HO
`
`HO
`
`HO
`
`HO
`
`OH H
`N
`
`O
`
`Salmeterol impurity C (EP)
`
`OH H
`N
`
`O
`
`Salmeterol impurity E (EP)
`
`1,6-Dibromohexane, NaH
`Toluene, TBAB
`
`(A)
`
`O
`
`Br
`
`Intermediate 1
`DMSO, Benzylamine
`Triethylamine
`
`Benzyl amine
`base
`
`No Reaction
`
`O
`
`O
`
`Compound 1
`
`HO
`
`HO
`
`HO
`
`HO
`
`HO
`
`HO
`
`Benzylamine
`
`(A)
`
`OH H
`N
`
`Compound 4
`
`N-N-diisopropyl ethylamine
`
`Methyl ethyl ketone
`
`OH H
`N
`
`O
`
`Compound 3
`
`Cyclohexyl salmeterol impurity
`
`O
`
`H
`
`HO
`
`O
`
`Intermediate 2
`O
`
`H
`
`HO
`
`
`
`OO
`
`N
`
`NH
`
`O
`
`Br
`
`Intermediate 3
`
`starting materials normally have defined chemical properties
`and structure (2). An FDA draft guidance, Drug Substance:
`Chemistry and Manufacturing Controls Information, reflects
`the concern that starting materials should be selected and
`controlled such that any potential future changes to the
`quality of the starting material would have an insignificant
`impact on the safety, identity, purity, or quality of the drug
`substance (3). Based upon the principles outlined in this FDA
`draft guidance and ICH guidelines for process understanding
`and control over potential adverse effects on the quality of
`
`ALL FIGureS Are COurTeSy OF THe AuTHOrS
`
`IPR2020-00770
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`

`

`Impurities
`
`Figure 3: Linezolid (e.g., oxazolidinones class) and pemetrexed disodium tautomer impurity. EP is
`the European Pharmacopoeia. RRT is relative retention time.
`
`N H
`
`O
`
`O
`
`N
`
`O
`
`NH
`
`O
`
`R
`
`F
`
`N
`
`H2N
`
`O
`
`N
`
`H
`
`NH
`
`2
`
`O
`
`N
`
`O
`
`R
`
`F
`
`O
`
`HN
`
`N H
`
`O
`
`O
`
`N
`
`O
`
`OH
`
`N
`
`Part - I
`
`O
`
`N
`
`O
`
`N
`
`O
`
`F
`
`Linezolid
`
`Part - II
`
`NH
`
`O
`
`O
`
`N
`
`F
`
`N
`H
`2
`
`N
`
`NH
`2
`
`N
`H
`2
`
`N
`
`NH
`
`2
`
`2,4-Diamino-6-hydroxy-pyrimidine
`
`O
`
`COONa
`
`OH
`
`H
`
`N
`
`O
`
`O
`
`COOH
`
`H2N
`
`N
`
`O
`
`O
`
`COOH
`
`NH
`
`Impurities due to rearrange-
`ment. Developing practical
`synthetic routes to render
`high-yield products in shorter
`stages or in a one- or two-pot
`reaction generally involves
`formation of rearranged inter-
`mediates that ultimately give
`the required final product.
`As an example, the cycliza-
`tion of bromonitrostyrene in
`the API ropinirole involves the
`rearrangement of the interme-
`diate cyclic ion to give the in-
`dole ring with the formation
`of hydroxamic ester and chlo-
`rooxime acetate as impurities.
`Impurities due to in situ reac-
`tions. Advances in synthetic
`chemistry have enabled a
`number of stages in a reac-
`tion to be carried out in just
`one or two pots without the
`need to isolate intermedi-
`ates. The downside of such
`reactions is the unexpected
`and numerous impurities
`that form because interme-
`diates and reagents are not isolated.
`As an example, the alkylation of the key starting material
`(S)-2-amino butyramide for the API levetiracetam with chlo-
`robutyrylchloride using potassium hydroxide in the presence
`of tetra-n-butylammonium bromide gives an intermediate
`that eventually cyclized into levetiracetam. This intermediate,
`however, is present in the final product as an USP impurity A.
`Nonreactive intermediates. Nonreactive intermediates are
`impurities formed in some intermediate stage by the reac-
`tion of reagents used in the next stages due to carryover.
`Such impurities remain nonactive in the later stages.
`For example, 4-phenyl butanol is a key raw material for the
`synthesis of salmeterol Intermediates 1 and 2 (see Figure 2).
`Intermediate 1 reacts with 4-phenyl butanol in the presence
`of sodium hydride and toluene to yield Compound 1, which
`is a nonreactive impurity in further stages. Intermediate 2
`reacts with the trace amounts of Intermediate 1 and in the
`same conditions react to form Compound 2 (see Figure 2).
`Reactive intermediates. Reactive intermediates, as the name
`implies, are byproducts or impurities resulting from the in-
`termediate stages of the reaction that have the potential to
`react with the reagents or catalysts used in later stages. They
`are carried forwarded in every stage up to the final API as
`a reactive intermediate.
`During the process development of salmeterol, an un-
`known impurity was detected at 2.08 RRT at a level of 0.11%
`and later identified after isolation to be Compound 3 (see Fig-
`
`Cl
`
`Cl
`
`O
`
`O
`
`OH
`
`N
`
`Dichloro, starting material impurity
`
`O
`
`O
`
`OH
`
`N
`
`Cl
`
`N
`
`HN
`
`Chloro impurity (RRT 2.1)
`(EP method)
`
`In the case of salmeterol, 4-phenyl butanol reacts with
`1,6-dibromohexane to give Intermediate 1, which in turn
`reacts with benzylamine in the presence of dimethyl sulf-
`oxide and triethylamine to yield N-[6-(4-phenyl butoxy)
`hexyl)] benzenemethanamine, a DMF starting material for
`salmeterol (see Figure 2). The compound 4-phenyl butanol
`is commercially available and prepared from benzene with
`succinic anhydride (7–11). If the benzene has a trace amount
`of toluene, the toluene is converted to 4-(4-methylphenyl)-
`1-butanol. The compound 4-(4-methylphenyl)-1-butanol is
`present in 4-phenyl butanol as a starting material impu-
`rity, which undergoes further reaction, similar to 4-phenyl
`butanol, to afford the methyl salmeterol impurity (see Fig-
`ure 2). Similarly, the presence of 2-phenylethanol, 3-phenyl-
`1-hydroxypropane, and 4-phenyl-2-hydroxybutane in the
`4-phenyl butanol will yield known salmeterol Impurities B,
`C, and E, respectively.
`Similarly, 6-hydroxy and dichloro impurities, if present
`in the DMF starting material of ciprofloxacin, will be con-
`verted to European Pharmacopoeia impurity F and nonphar-
`macopeial impurity (chloro ciprofloxacin) at 2.1 RRT.
`
`Intermediates
`Organic compounds formed during the synthesis of APIs
`are termed as intermediates. The compound in the synthetic
`chain before the production of the final desired compound
`is called the penultimate intermediate.
`
`48 Pharmaceutical Technology February 2012 P h a r mTe c h . c o m
`
`COOH
`
`NH
`
`Structure in
`draft EP monograph
`
`O
`
`O
`
`OH
`
`N
`
`HO
`
`N
`
`HN
`
`Hydroxy impurity F (EP, RRT 0.5)
`
`N
`
`H
`
`O
`
`OH
`
`NH
`
`H2N
`
`N
`
`COONa
`
`NH
`
`COOH
`
`Structure in
`literature / patents
`pemetrexed disodium
`
`NH
`
`NH
`
`H2N
`
`N
`
`N
`
`Part - III
`
`O
`
`O
`
`F
`
`Cl
`
`OH
`
`N
`
`HO
`
`O
`
`O
`
`OH
`
`Cl
`
`N
`
`O
`
`N
`
`F
`
`N
`
`HN
`
`Cipro(cid:0)oxacin starting material
`
`6-Hydroxy, starting material Impurity
`
`Cipro(cid:0)oxacin
`
`IPR2020-00770
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`

`

`sired chroman product is ac-
`companied by the generation
`of a furan byproduct in succes
`sively increasing amounts (15).
`In the ropinirole synthesis,
`a somewhat similar case is ob-
`served in the final step. The re-
`action between the ropinirole
`precursor 4-(2-bromoethyl)-
`13-dihydro-2H-indol-2-one
`and di-n-propyl amine in
`water produces ropinirole in
`modest yield (57%), together
`with styrene as the major by-
`product (38%) (16).
`In another example, thio-
`phenes are important het-
`erocyclic compounds that
`are widely used as build-
`ing blocks in many agro-
`chemicals and pharmaceu-
`ticals (17). The synthesis of
`2-amino-5-methylthiopene-3-carbonitrile is achieved by
`reacting a mixture of sulfur, propionaldehyde, malononi-
`trile, and dimethylformamide using triethylamine (18–26).
`The reaction of propionaldehyde with malononitrile and
`sulfur resulted in formation of two unknown impurities
`up to 7%, which were isolated and confirmed by 1H NMR
`(nuclear magentic resonance spectroscopy), correlation
`spectroscopy, nuclear Overhauser effect spectroscopy, and
`single X-ray crystallography to be Impurity 1 (see Figures 4
`and 5). These impurities are further found to react with
`2-fluoro nitrobenzene to give next-stage impurities and
`which are controlled by purification in the respective stages.
`Impurity 1 (see Figure 5) is a novel tricarbonitrile bicyclic
`compound, and as of the writing of this article, it is not known
`in the literature. Prediction of cLogP is 0.65, drug linkness
`is 4.04, and the drug score is 0.45 as determined by OSIRIS
`Property Explorer, software used to calculate various drug-
`relevant properties of chemical structures. Structure–activity
`relationship, quantitative structure–activity relationship, and
`drug design with other modified organic/inorganic hetrocyclic
`moieties could give some biological activity. The molecular de-
`signing of Impurity 1 for specific and unspecific purposes (e.g.,
`DNA-binding, enzyme inhibition, anticancer efficacy) is based
`on the knowledge of molecular properties, such as the activity
`of functional groups, molecular geometry, and electronic struc-
`ture, and on information cataloged on analogous molecules.
`The compound 2,6-diamino-7-ethyl-8-methylbicyclo[2.2.2]
`octa-2,5-diene-1,3,5-tricarbonitrile could be coupled with an
`active or nonactive peptide to check the biological activity as a
`prodrug or drug. The potential therapeutic and prophylactic
`activities of antimalarials, antimitotics, and antitumor agents
`could also be performed. This bicyclic compound may be used
`alone as a single agent or in combination with any organic or
`
`Figure 4. Propionaldehyde with malanonitrile reactions. CAS refers to Chemical Abstracts Service,
`No. is number, and NA is not available. Conditions: (a) with piperidine in pyridine, heating (Ref. 27);
`(b) with piperidine in pyridine, heating, cyclization (Ref. 28); (c) with piperidine, 1,4-dioxane
`(Ref. 29–30); (d) With [C
`DABCO][BF
`] in water, Time = 0.0166667 h, T = 20 °C, Knoevenagel
`condensation or with aluminum oxide in dichloromethane, T= 20 °C, Knoevenagel condensation
`aldol-condensation (Ref. 31–33).; and with morpholine in ethanol, T = 20 °C, Knoevenagel
`condensation (Ref. 34–37).
`
`4
`
`4
`
`N N
`
`N
`
`O
`
`NH
`
`N
`
`N
`
`NH2
`
`N
`
`N
`
`N
`
`CAS No. NA
`
`CAS No. 90323-61-8
`
`CAS No. 52833-34-8
`
`Pharmaceutical Technology February 2012 49
`
`CN
`
`NH2
`
`CN
`
`e
`
`CAS No. 55525-92-3
`
`b
`
`a
`
`H
`
`c
`
`O
`
`d
`
`NC
`
`CN
`
`N N
`
`CAS No. 38091-73-5
`
`Propionaldehyde Malanonitrile
`
`ure 2). The impurity formed in the final API due to presence
`of N-benzyl-6-(4-cyclohexylbutoxy)hexan-1-amine in Inter-
`mediate 2 leads to the salmeterol cyclohexyl impurity (12).
`The reactive intermediate, N-benzyl-4-phenylbutan-1-
`amine is present in Intermediate 2 (see Figure 2). It is formed
`by the reaction of 4-phenyl butanol with benzyl amine and
`competes in all reaction stages with Intermediate 2 to form
`Compound 4 (see Figure 2).
`A main challenges faced in developing the olefination
`route of the API aprepitant was a subsequent reaction of the
`vinyl ether intermediate with dimethyltitanocene to form
`an ethyl impurity (13).
`Bis-compound impurities. The formation of new or unknown
`impurities can occur when scaling up a process, even with
`successful runs at a smaller scale. Examining the molecular
`weight of such impurities often reveals the compound is ex-
`actly double the weight of that being formed in that reaction
`step. Such dimeric derivatives are called bis-compound im-
`purities. Two bis-compound impurities were formed in the
`intermediate and final stages in the synthesis of linezolid,
`to be discussed in Part III of this article.
`
`Byproducts
`In synthetic organic chemistry, getting a single end prod-
`uct, 100% pure, seldom occurs because of the change into
`byproducts, which can be formed through a variety of side
`reactions, such as incomplete reactions, overreactions, isom-
`erization, or unwanted reactions between starting materi-
`als, intermediates, chemical reagents, or catalysts. For ex-
`ample, in the bulk production of paracetamol, diacetylated
`paracetamol may form as a byproduct (14).
`In the Claisen rearrangement of the aryl propargyl ether in
`diethylaniline at elevated temperatures, formation of the de-
`
`IPR2020-00770
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`

`

`Impurities
`
`Figure 5: Reaction scheme of olanzapine impurities. DMF is dimethylformamide. TEA is
`triethylamine. Addn is addition. RT is room temperature. CAS is Chemical Abstracts Service, No. is
`number, and NA is not available.
`
`(1)
`
`DMF/TEA
`
`addn at 28 to 32 °C
`
`N
`
`N
`
`O
`
`H
`
`NC
`
`CN
`
`Propionaldehyde Malanonitrile
`
`Overnight RT
`
`OR
`
`(2) DMF/TEA
`
`addn at -5 to 10 °C
`
`Overnight RT
`
`H2N
`
`N
`
`NH2
`
`OR
`
`Impurity 1
`
`Condition 1
`
`formed compound
`
`CAS No. NA
`
`15 - 20 °C, 1 h
`
`Sulfur
`
`DMF/TEA
`
`NC
`
`H2N
`
`S
`
`CAS No. 138564-58-6
`
`Olanzapine
`
`CN
`
`NH2
`
`CN
`
`Impurity 2
`
`Condition 2
`
`formed compound
`
`CAS No. 55525-92-3
`
`NO2
`
`CN
`
`NH
`
`CN
`
`N
`
`N
`
`N
`
`N
`
`H2N
`
`N
`
`NH
`
`NO2
`
`NH
`
`N
`
`NO2
`
`NO2
`
`NH
`
`Nonpharmacopeial impurities
`
`Interaction products
`The term interaction product
`deals with the interaction of
`two or more intermediates/
`compounds with various
`chemicals, intentionally or
`unintentionally. An interac-
`tion product is slightly more
`comprehensive than byprod-
`ucts and transformation
`products. Two types of inter-
`action products that are com-
`monly encountered are drug
`substance–excipient interac-
`tions and drug substance–
`container/closure interactions.
`
`Related products
`The term related products
`means that the impurity
`has similar structure as that
`of the drug substance and
`may exhibit similar biologi-
`cal activity. This structural
`similarity by itself, however,
`does not provide any guar-
`antee of similar activity. An
`example of a related product
`is 8-fluoro olanzapine.
`
`C12
`
`C10
`
`C14
`
`C11
`
`C13
`
`C2
`
`C7
`
`C1
`
`N1
`
`N5
`
`C6
`
`C5
`
`C9
`
`N4
`
`C3
`
`C8
`
`N2
`
`C4
`
`N3
`
`N
`
`H2N
`
`N
`
`NH2
`
`Impurity 1
`
`inorganic salts in chemotherapy or in combination with other
`chemotherapeutic agents after in vivo and in vitro testing.
`
`Transformation products
`Transformation products deal with theorized and nontheo-
`rized products produced in a reaction. They can be synthetic
`derivatives of byproducts and are closely related to byproducts.
`A reaction where transformation products occur is the for-
`mation of chloro acetyl derivative of salicylaldehyde during
`the acylation reaction of salicylaldehyde with bromo acetyl
`bromide using methylenedichloride (MDC) and aluminum
`chloride (AlCl3). Mechanistically, the formation of chloroacetyl
`derivative using bromoacetyl bromide could not be expected,
`but hypothetically, it could occur as a transformation reaction
`due to halogen exchange. During Friedel–Craft acylation with
`Lewis acid AlCl3 in methylene dichloride, the Lewis acid forms
`an ionized complex [Cl–AlCl2–Br]–, which eventually undergoes
`halogen exchange with the bromo acylium ion to yield the chloro
`acetyl derivative. Formation of this impurity in reaction is as
`high as 7–20%, which is an uncontrolled impurity in the manu-
`facturing process. Nevertheless, this impurity would not affect
`the purity of the final drug substance because the reaction of
`the transformed impurity with 2 (see Figure 6, Part I) forms the
`desired product, salmeterol. The presence of the chloro impurity
`also has been confirmed by experiment (see Figure 6, Part II).
`
`50 Pharmaceutical Technology February 2012 P h a r mTe c h . c o m
`
`Degradation products
`Impurities formed by decomposition or degradation of the
`end product during manufacturing of the bulk drug are
`called degradation products. The term also includes deg-
`radation products resulting from storage, formulation, or
`aging. Parts II and III of this article will discuss the types
`and sources of the degradation products in further detail.
`
`Tautomer impurities
`Tautomers are readily interconvertible constitutional isomers
`that coexist in equilibrium. For APIs or drug molecules that ex-
`hibit tautomerism, there has been a confusion in identifying the
`two tautomeric forms. If one tautomer is thermodynamically
`stable and is the major form, the other tautomer should be con-
`sidered as an impurity or simply termed as a tautomer of the API
`or drug molecule. To the best of the authors’ knowledge, there
`has been no literature relating to the isolation, synthesis, or char-
`acterization of a tautomeric impurity(-ies) from the final API.
`Linezolid is an treatment for nosocomial infections involv-
`ing gram-positive bacteria. Oxazolidinones possess a unique
`mechanism of bacterial protein synthesis inhibition (38–39).
`Linezolid has an N-acetyl group (–NH–CO–CH3) due to
`that lactam–lactim tautomerism, which may occur during
`the synthesis but also may be stable. An effective analytical
`method needs to be developed to identify both tautomers.
`
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`

`

`Figure 6: Chloro impurity-formation scheme of salmeterol. HPLC is high-performance liquid
`chromatography. MDC is methylenedichloride; AlCl
` is aluminum chloride.
`
`3
`
`OH
`
`O
`
`MDC / AICI 3
`
`H
`
`Br
`
`OH
`
`O
`
`H
`
`Br
`
`O
`
`Br
`
`O
`
`Bromo acetyl derivative
`
`Salicylaldehyde
`
`5-(Bromoacetyl)-2-hydroxybenzaldehyde
`
`OH O
`
`H
`
`Cl
`
`O
`
`Chloro acetyl derivative
`5-(Bromoacetyl)-2-hydroxybenzaldehyde
`2
`
`Part-I
`
`Part-II
`
`Pathway as per Figure: 2
`
`HOH
`N
`
`HO
`
`HO
`
`O
`
`Salmeterol
`
`OH
`
`O
`
`H
`
`OH O
`
`H
`
`MDC / AICI 3
`Re(cid:0)ux 24 h
`
`OH
`
`O
`
`H
`
`Br
`
`O
`
`Cl
`
`O
`
`MDC / water
`
`Br
`
`O
`
`Bromo acetyl derivative
`
`Chloro acetyl derivative
`
`HPLC purity 90.43%
`
`HPLC purity 9.53%
`
`Bromo acetyl derivative
`
`HPLC purity 87.27%
`
`1
`
`2
`
`1
`
`OH O
`
`H
`
`Cl
`
`O
`
`Chloro acetyl derivative
`
`HPLC purity 12.73%
`
`2
`
`Salmeterol
`
`3. FDA, Draf t Guidance for
`Industry: Drug Substance:
`Chemistry Manufacturing and
`Controls Information (Rock-
`ville, MD, Jan. 2004).
`4. T. Cupps et al., Pharm. Tech-
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`tia Pharm. 77, 579–587 (2009) .
` 13. J.J. Hale et al., J. Med. Chem. 41 (1), 4607–4614 (1998).
` 14. K.M. Alsante, Amer. Pharm. Rev. 4 (1) 70–78 (2001).
` 15. J. Zsindely et al., Helv. Chim. Acta 51, 1510 (1968).
` 16. J.D. Hayler et al., Org. Process Res. Dev. 2 (1), 3–9 (1998).
` 17. J. Swanston, “Thiophene” in Ullmann’s Encyclopedia of Industrial
`Chemistry, (Wiley-VCH, Weinheim, Germany, 2006).
` 18. Tel-Aviv University, “Novel Psychotropic Agents Having Gluta-
`mate NMDA Activity,” WIPO Patent WO2008/50341, May 2008.
` 19. Watson Pharmaceuticals, “2-Methyl-thieno-benzodiazepine Pro-
`cess,” WIPO Patent WO2004/94390, Nov. 2004.
` 20. Shastri et al., “Process for Producing Pure Form of 2-Methyl-4-(4-
`Methyl-1-Piperazinyl)-10H-Thieno[2,3-b] [1,5]Benzodiazepine,”
`US Patent 2009/5556, Jan. 2009.
` 21. Eli Lilly, “Process for Preparing 2-Methyl-thieno-benzodiaze-
`pine” US Patent 6008216, Dec. 1999.
` 22. Lilly Industries, “2-Methyl-thieno-benzodiazepine,” US Patent
`5229382, July 1993.
` 23. Eli Lilly, “2-Methyl-thieno-benzodiazepine,” US Patent 5605897,
`Feb. 1997.
` 24. X He et al., J. Pharm. Sci. 90 (3) 371–388 (2001).
` 25. V.P. Shevchenko, Russian J. Bioorg. Chem. 31 (4), 378–382 (2005).
` 26. V.P. Shevchenko, Bioorganicheskaya Khimiya 31 (4) 420–424
`(2005).
` 27. J.C. Dunham et al., Synthesis, 4, 680–686 (2006).
` 28. A.H. Elgandour et al., Indian J. Chem. Sec. B: 36 (1) 79–82 (1997).
` 29. R. Mariella and A. Roth, J. Org. Chem. 22 (9), 1130 (1957).
` 30. Hart and Freeman, Chemistry and Industry, p. 332 (1963).
` 31. Da-Zhen Xu et al., Green Chem. 12 (3) 514–517 (2010).
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`1–12 (1990).
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`(4), 567–576 (2006).
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` 38. D.L.K. Marotti et al., AntiMicrob. Agents Chemother. 41 (10),
`2132–2136 (1997).
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`
`A key starting raw material of pemetrexed disodium
`2,4-diamino-6-hydroxy-pyrimidine shows the keto-enol
`form occurring in different ratios and which will be converted
`to the final drug using a known synthesis (see Figure 3).
`Tautomers vary in their kinetic and thermodynamic stabil-
`ity, thereby making it difficult to determine whether they could
`be separated, isolated, or analyzed. Keeping this in mind, the
`use of the term impurity for tautomers in a final API/drug moi-
`ety presumably will be an important discussion in near future.
`
`Conclusion
`Part I of article highlights the origination and classification of
`impurities and provides a perspective on impurities in drug
`substances and drug products. The impurity profile of a drug
`substance is on increasing importance for ensuring the quality
`of drug products. Whatever the class of impurity, its identifica-
`tion and adequate control is a tremendous challenge for process-
`development chemists. Because no two drugs are alike, neither
`are two development pathways. Each drug candidate poses a
`different challenge in terms of impurities, and establishing ef-
`ficient ways for the isolation and control of impurities is a key
`task in process development.
`Part II of this article, to be published in the March 2012
`issue of Pharmaceutical Technology, will discuss chiral and
`polymorphic impurities. Part III, to be published in the
`April 2012 issue of Pharmaceutical Technology, will discuss
`genotoxic and stability impurities.
`
`References
`1. FDA, Guideline for Submitting Supportive Documentation in Drug
`Applications for the Manufacture of Drug Substances (Rockville,
`MD, Feb. 1987).
`2. ICH, Q7 Good Manufacturing Practice Guide for Active Pharma-
`ceutical Ingredients, Step 5 (Nov. 2000).
`
`Pharmaceutical Technology February 2012 51
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