`
`
`
`V internationei Union
`of Pure arré A piied “h
`
`Handbeek ef
`
`Pharmaceutieei Saitg
`
`. Prepemiesfl Seiectieng and Use
`
`
`P. Heinrich Stahi, Camille ewermuth [Edsj
`
`.
`
`
`
`Verlag Helvetica Chimica Acta - Z'Lirich
`
`>. WILEY-VCH
`
`Weinheim - New York - Chichester
`Brisbane - Singapore - Toronto
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`Foreword
`
`The surprise with this very first book on Pharmaceutical Salts is that it
`has appeared so late.
`lE’Jroblems concerning the physical form of drug sub
`stances have been with us for nearly 10 years at the interface between the
`disciplines essential to the development of new drugs: chemical process de-
`velopment, analytical chemistry pharmaceutical sciences, pharmacokinetics,
`toxicology, and clinical studies. These problems have for many years figured
`‘ prominently in the nightmares of industrial chemists and pharmacists, not to
`mention those of their quality assurers, regulatory writers, and project man-
`agers.
`’
`.
`The answer to the question ‘Why has this book appeared so late?” may
`perhaps. have something to do with the fact that pharmaceutical crystal and
`powder engineering should be founded on crystal and powder science. But
`such a science does not yet exist as a single concept since knowledge in this
`field is scattered among different disciplines such as crystallogenesis, crys-
`tallography, the physical chemistry and thermodynamics of multiphase'syse
`terns, powder flow characteristics and mechanics, piezo—electrostatic‘s, the
`physics of complex rnicellar systems, etc.
`-
`,
`'
`Academics, Whose vocation it is to edit this type of book, therefore, heard
`about the specific problems related to pharmaceutical crystal and powder
`engineering fairly late from industrial colleagues who are often reticent to air
`their difficulties in public. Thus, it is only now that efforts at unification have
`begun.
`This book is perhaps an attempt to found such a science, but in the sen~
`se, of a market—driven effort bringing together contributions from academics
`and industry. The book deals not only with the problems raised by salt selec-
`tion strategies and process scale-up, but also with the industrial property and
`regulatory aspects at the heart of the highly regulated pharmaceutical indus—
`try.
`.
`I cannot end without emphasizing that further exploration is required in
`areas where theoretical and practical knowledge is still lacking. For instance,
`the mechanisms involved in crystallogenesis need to be elucidated since we
`still cannotpiedict thesolnbility ofagiven salt. Will it be, oily or solid? Will
`it show several polymorphs? The crystal chemistry of crystalline surfaces -
`regulated by specific interactions between functional groups emtied on the
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`VI
`
`FOREW 0RD
`
`surfaces and very small amounts of impurities — impacts with other factors
`on the preferential development of one face rather than another, but is still in
`limbo. We still know nothing, precise about the factors governing the electro—
`statics of drug substances. We are still unable to predict the relations between
`crystalline forms and the compressibility of powders. I hope that the prelim—
`inary basis of an answer to some of these questions will be found in a future
`version of this book.
`
`?rof. Bertrand Castro
`
`Director of the Chemical Development
`S an ofi—Synthelabo
`
`
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`Preface
`
`The origin of this book goes back to a proposition made by one of us
`(C, G. W.) at a meeting or" the Medicinal Section ofDii-Iision VI] of IUPAC to
`write useful handbooks for medicinal chemists. Among the topics suggested,
`the preparation of pharmaceutically acceptable salts was rapidly considered as
`important and timely. As a matter of fact, an estimated half of all drug mole-
`cules used in medicine are administered as salts. The salt formation of drug
`candidates has. been recognized as an essential preformulation task, as the se—
`lection of a suitable salt prior to the initiation of dosage form development has
`become a decision point iii the netplans of the Preclinical Phase of modern
`drug development. Surprisingly, however, a chemist in search of a book deal—
`ing with the preparation, significance, and selection of pharmaceutically ac—
`tive salts will fail to find one, and also the scientific literature on this topic is
`rather limited and scattered across many journals and patents. On the other
`hand, the majority of medicinal chemists working in the pharmaceutical in—
`dustry are organic chemists whose main conCern is to design and to synthe-
`size novel compounds as future drug entities. While they focus on this chal-
`lenging primary goal, salt formation is often restricted to a marginal activity
`with the short term aim of obtaining nicely crystalline material. Moreover,
`chemists are not explicitly trained in the various aspects of pharmaceutical salts
`and their inherent opportunities. By bringing together the necessary theoreti-
`cal foundations and a lot of practical experience, the objective ofthe present -
`book is to fill this long felt gap in the pharmaceutical bibliography.
`’
`A concise introduction reviewing the various objectives pursued in form~
`ing salts is followed by contributions presenting the theoretical background
`of salt formation: dissociation and ionic equilibria, solubility and .dissolution
`(Chapt. J and 2), basics and the evaluation of solid~state properties (Chapt. 3),
`safety and biopharmaceutical as well as pharmaceutical—technologica1 as-
`pects (Chapt. 4 and 5). Chapt. 6, 7, and 8 reflect the practice of salt forma-
`tion in an industrial research and development environment. They describe
`salt selection strategies, industrial large scale aspects of salt production, and
`the significance of salt formation in industrial processing. The involvement
`_—4of;authoritiesds_dealt_wiih_in~_CJ2apL_9_and_J_Q,_whn2Me devoted to patent
`and regulatory issues, respectively. Addressing the practitioners at the lab
`bench, the last chapters of the book feature practical examples of preparation
`
`“mimwwiwmm
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`

`V LU
`
`PREFACE
`
`of salts presented in the Style of model procedures (Chapt. 1]) and a compre—
`hensive annotated compilation of the, individual salt-forming acids and bas-
`es with their relevant properties (Chapz. J2)r followed by an Appendix con—
`taining tables with the acids and bases sorted alphabetically, and by pleH val—
`ues and supplemented with other useful facts and data.
`Altogether, these chapters reflect the multidisciplinary character of for—
`mation and selection of suitable salt forms of drug substances. An attempt is
`made to establish an up—to-date guide and source of information nor only
`serving medicinal chemisrs, but also all the other scientists who are involved
`pin the research and development or" drugs and their pharmaceutical dosage
`forms.
`
`.
`
`A book dealing with such a truly interdisciplinary subject relies on con-
`tributions of a well—coordinated team of authors from industry and academia
`
`representing the various disciplines involved in the process of drug-salt for-
`mation and selection for pharmaceutical products in an industrial environ—
`ment. The editors Wish to thank all the authors for their engaged cooperation
`and their patience during the revision procedures that were necessary .to
`arrive at this comprehensive and well—balanced handbook; Thanks are also
`due to E O. Ajayi, H. Asche, and C. H017“, who accepted to contribute to the
`book in the very last moment. The editors wish to acknowledge the smooth
`and excellent cooperation with Verlag Helvetica Chimica Acm in the prepar—
`ation of the volume: Thomas .Kolirzus, Assistant Editor, for his patient and.
`attentive handling of all the practical details of the'e'ditorial process, and
`Dr. M. Volkcm Kisaki-lrek, Managing Director and Editor-in—Chief,, for his
`inspiration and for his untiring scrutiny in bringinghis considerable corn—
`prehe'nsive knowledge into this project. Thanks are also expressed to Larry
`Lesko of the US. Food and Drug Administration for establishing helpful
`contacts. One of the editors (P. *H. S.) gratefully acknowledges the support
`granted by Novartis AG, Basel, and the permission to use their Scientific
`Library facilities.
`
`Camille G. Wermurh and P. Heinrich Srahl
`Strasbourg and Freiburg,-Janu'ary 2002'
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`

`Contributors
`
`Eunmilayo 0.; Ajayi
`Office of Clinical Pharmacology 5': Eiopharmaceutics, limo—880
`Office of Pharmaceutical Science
`Center for Drug Evaluation & Research
`Food and Drug Administration
`5600 Fishers Lane, Rockville, MD 20857, USA.
`
`Henning Asche
`Pharma—Service & Consulting
`
`Baiergasse 42
`CH—4l26 Bettingen, Switzerland
`(E—mail: h. asche @ datac‘ommeh)
`
`Michael J. Bowker
`
`M. l. Bowker Consulting Limited;
`36, Burses Way,
`Hutton, Brentwood,
`Essex CM13 2P8; UK
`(Tel; +44 (0)1277 228029; fax: +44 (0)1277 262899;
`e—mail: mjbconsulting @btinternet.com)
`Previous address: Rhone—Poulenc Rorer, Dagenham,
`
`Essex RM10 7X3, UK
`
`Hans-Gunther Foraita
`
`Patent Consulting
`
`Steingrubenweg 10
`CH—4125 Riehen, Switzerland
`(Tel/fax: +41 61 643 93 24; e—mail: foraita@ datacomm.ch)
`
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`

`X
`
`CONTRIBUTORS
`
`Danielle Giron
`Novartis Pharma AG
`
`CHAD — Analytical R8513
`Building WKL—127.4.60
`CPI—4002 Basel, Switzerland '
`
`(Tel: +41 61 69 68 170; fax: +41 61 69 68 172;
`e-niail: danielletgiron @pharmanovartis .com)
`
`David 11 i
`
`‘14" Grant
`
`,
`
`
`
`University of Minnesota
`College of Pharmacy
`
`Dept. of Pharmaceutics
`Minneapolis, MN 55455—0343, USA.
`(Tel.: +1 (612) 624—3956; fax: +1 (612) 625—0609;
`email: grant001 @maroon.tenmnedu)
`
`Jun-ichi Kondo
`
`Laboratory of Analytical Science -
`Product Development Laboratories
`Sankyo Co., Ltd.
`
`2—58, Hiromachi 1-Chome, Shinagawa—ku
`Tokyo 140, Japan
`(Tel: +81 3-3492—3131 ext. 4664; fax: +81 3—54-36—8571;
`e—rnail: k011dou@shinasankyocojp)
`
`Christian Hoff
`
`Physico~Chi1nie des Procédés
`Sanofi—Synthelabo
`,
`Route d’AVignon
`F—3039O Aramon, France
`
`(Tel: +33 (0) 466 57 71 71; fax: +33 (0)466 57 72 91)
`
`Stanley Lee
`4 Manor Crescent
`
`Macclesfield SKlO ZEN, UK
`(Tel/fax: +44 1625 '42 86 23)
`Previous address: Zeneca Pharmaceuticals, Silk Road Business Park,
`‘wMacclesfie'ld SKlO ZNA, UK
`
`(Tel; +44 1625 51 33 ‘71; fax: +44 1625 50 07 80)
`
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`
`
`CONTRlBUTORS X1
`
`Michael 18. Maurin
`Biopharmaceutics & Basic Pharmaceutics,
`DuPont Pharmaceutical Company
`B O, Box 80400
`
`Wilmington, DE 19880—0400, USA.
`(Tel: +1 (302) 695—9387; fax: +1 (302) 6953565;
`e—mail: MichaelB .Maurin. @ dupontpharma.com)
`
`h/llasahim N alcanc
`Department of Pharmacy, Kumamoto University Hospital
`Faculty of Pharmacy
`1—l—1l-lonjo
`Kumamoto 860-0811, Japan
`(Tel: +81 96—373—58 20; fax: +81 96-373—59 06;
`e—mail: iiakano @kaiju.1neclic .kumamoto—u.ac.jp)
`
`_
`
`Fi'iedlieb Pfannkuch _,
`Roche Vitamins Ltd.
`Human Nutrition and Health
`
`Nutrition Safety (VFHS)
`
`Building 72 / 49b
`P. O. Box
`
`01-1—4070 Basel, Switzerland
`(Tel: +41 (61) 687 07 99; fax: +41 (61) 688 68 19;
`e—mail: friedlieb.pfannkuch@roche.com)
`
`Madhu Pudipeddi
`Novartis Pharmaceuticals Corp.
`
`Building 401
`1 Health Plaza
`
`East Hanover, NJ 07936-1080, USA.
`(Tel: +1 (973) 781-7385; fax: +1 (973) 781—4556;
`e—mail: madhu.pudipeddi @phaimanovartiscom)
`Previous address: BristOl—Myers Squibb Co., Pharmaceutics R&D,
`Brunswick, NJ 08903—0191, USA.
`
`Harald Rett'ig
`BioVista G.m.b. H.
`
`Ruechligweg 101
`.. (EH-412.51 Riehena Switzerland
`
`..
`
`(Tel: +41 (61) 603 27 35; fax: +41 (61) 603 27 38',
`e—mail: rettigh@iv.ivc.com)
`
`
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`
`
`X11 CONTRIB UTORS
`
`Arbu T. M. Serajuddiu
`Novartis Pharmaceuticals Corp.
`
`Building 401
`1 Health Plaza
`
`East Hanover, NJ 07936-1080, U.S.A.
`
`(Tel: +1 (973) 781—39 95; fax: +1 (973) 781—5378;
`e—mail: abu .serajuddin @pharma.novartis .com)
`
`PE Heinrich Stahl
`Leroheustrasse 2.8
`
`13-79104 Freiburg im Breisgau, Germany
`(Tel: +49 (761) 548 23; fax: +49 (761) 5562 910;
`e—mail: heinrich.stahl_fr@t—ouliue.cle)
`
`Camille G. Wei-mirth
`
`Louis Pasteur University, Strasbourg
`Faculty of Pharmacy
`74, route du Rhin
`F-674OO lllkiroh, France
`(Tel: +33 388 67 37 22; fax: +33 388 67 47 94;
`e—mail: wermuth@aspirine.u—strasbg.fr)
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`

`Contents
`
`introduction
`
`Camille G. Wermati’t and P Heinrich Stahl
`
`Chaptei" l
`
`The Physicochemical Background: Fundamentals
`of Ionic Equilibria
`
`Michael B. Mam‘in, David J. W. Grant,
`
`and P. Heinrich Smhl
`
`Chapter 2
`
`Solubility and Dissolution of Weak Acids, Bases,
`and Salts
`
`19
`
`Madhu Padipeddi, Abu T. M. Serajudclin,
`David J. W Grant, and P. Heinrich Stahl
`
`Chapter 3
`
`Evaluation of Solid—State Preperties of Salts
`Danielle Giron and David J. W. Grant
`
`Chapter 4
`
`Pharmaceutical Aspects of the Drug Salt Form
`
`P. Heinrich Stahl and Masahiro Nakano
`
`Chapter 5
`
`Biological Effects of the Drug Salt Form
`
`Friedlieb Pfannkach, Harald Rettig,
`and P. Heinrich Stahl
`
`41
`
`83
`
`117
`
`
`
`Chapter 6
`
`Salt—S'election Strategies
`
`" T35 "
`
`Aba T. M. Serajaddz‘n and Madhu Padipeddi
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`
`CONTENTS
`XIV
`
`Chapter 7
`
`A Procedure for Salt Selection and Optimization
`Michael J. B owker
`
`161
`
`Chapter 8
`
`Large—Scale Aspects of Salt Formation: Processing
`of Intermediates and Final Products
`
`Stanley Lee and Christian. Hajj:
`
`Chapter 9
`
`Patent Aspects of Drug Salt Formation
`Hems—Gilli l'her Foraim.
`
`Chapter 10 Regulatory Aspects of Drug Salts
`Henning Ase/1e, Jun—ichi Konclo,
`and Fmeilayo O. Ajayi
`
`Chapter“ 11 Selected Procedures for the Preparation of
`Pharmaceutically Acceptable Salts
`
`Camille G. Wermuth and P. Heinrich Srahl
`
`Chapter 12 Monographs on Acids and Bases
`P. Heinrich Stahl and Camille G. Wermuth
`
`Appendix
`
`R Heinrich Stahl
`
`Subject—Index '
`
`Substance-Index
`
`191
`
`221
`
`237
`
`249
`
`265
`
`329
`
`351
`
`361
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`introduction
`
`by Camille G. Wermuth and P. Heinrich Stahl
`
`When the first ‘Vegetable allcalis’, those nitrogen-containing bases later
`termed alkaloids, were extracted from plant materials, they were isolated and
`purified as wechrystalliZing salts. In contrast to the free bases, the salts were
`found to be water-soluble and also more stable. Such properties qualified the
`salts of these biologically highly active compounds as the preferred forms for
`use as therapeutic agents (morphine hydrochloride, atropine sulfate, quinine
`sulfate, pilocaipine nitrate, codeine phosphate, to name only a few of them).
`If we turn to endogenous biological agents, we see that almost all neurotrans-
`mitters, which are biogenetically derived from amino acids, are also nitro—
`genous bases able to form salts. Nitrogenous functional groups are present in
`many synthetic drugs that mime the neurotransmitters and account for the old
`adage ‘no medicaments without nitrogen’. This assertion is certainly exaga
`gerated as it excludes therapeutic agents such as the steroids, the prostaglan—
`dine and their derivatives, also the fibrates and acidic anti—inflammatory
`drugs like aspirin, diclofenac, and ibuprofen. Many of these classes of drugs
`contain a carboxylic function, and, therefore, salt formation can evidently
`also be considered.
`g
`.
`,
`,
`.
`An estimated half of all thedrug molecules used in medicinal therapy are
`administered as salts, and salification of a drug substance has become an es-
`sential step in drug development. The solid-state properties of a drug, as well
`as its properties in solution, can be modified by salt formation. Therefore, the
`search for a suitable salt form is important, and salt selection may have far—
`reaching. consequences and can open new opportunities. In modern pharma—
`ceutical research and development, a variety of objectives are pursued in the
`formation of salts. The most important of these objectives and points to be
`considered, as they become significant along the pathway of the development
`of a new drug, are reviewed here. '
`'
`
`’
`
`«
`
`_-
`
`I ImIiroving Solubility .
`
`' Before undergoing pharmacological evaluation and other preclinical
`studies, synthetic or natural active principles must usually be dissolved. In '
`the majority of cases, the objective is to render the compound water-soluble.
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`2 .
`
`PHARMACEUTICAL SALTS:
`
`Sufficiently high solubility in H20 eases molecular pharmacoldgy screening
`for drug candidates. Thus. in-vz‘tro studies (receptor binding, enzyme inhibi-
`tion, cell cultures) and studies with isolated organs are facilitated. The com—
`mon proCedure in testing practically insoluble compounds in such assays is
`to prepare stock solutions in an organic solvent (DMSO\polyethylene gly—
`col, EtOH, etc.) and to proceed to appropriate aqueous dilutions. In doing so,.
`there is often the risk that the compound can precipitate during dilution, and
`precipitation may even go unnoticed .if the assay is performed in plastic tubes
`where the precipitate can adhere to the tube wall.
`Most organic acids and bases are only poorly soluble in H20, whereas
`many of the corresponding salts render the drug substances ionized in H20,
`and, as a consequence, water-soluble. Salts that are soluble in H20 are also
`ideally suited for the preparation. of injectable sterile aqueous solutions. Fast
`dissolution of the activeprinciple contained in solid dosage forms, 6 g for
`immediate—release tablets and hard——gelatine capsulesis also dependent on the
`aqueous solubility
`Considering in--vivo testing, solubility inHzO facilitates all studies in
`which parenteral administration is required. In pharmacokinetics, reliable
`determination of absolute peroralbioavailability is possible in comparison
`with the amountadministered intravenously, because a .dose entering the sys—.
`tem by this parenteral route is a precisely known reference. Aqueous solubil-
`ity .becomes particularly important in acute and in chronic toxicity studies
`where the gavage of the animal withan insoluble compound always leaves.
`some doubts as to whether the molecule under studyis non-toxic 'or just in—.
`completely absorbed.
`'
`.
`.
`Finally, one has to remember that the pharmacological effects of hydro-
`philic compounds are much more comparablefrom one animal species to the
`other than those of lipophilic substances [1].
`I
`.
`On the therapeutic level, themajor interestofwatervsoluble drugs resides
`in the possibility of intravenous administration Solubilityin H2O represents
`an indispensable requisite for drugs in emergency treatments permitting ther-
`apeutic plasma levels to be reached within one minute. This route is imposed
`when the oral route is excluded, as in patients undergoing surgery or lying in
`coma. Finally, several other pharmaceutical dosage forms are based onwater—
`soluble active agents: Apart from parenteral injections and infusions, there
`are nasal drops and eye-drops, syrups for oral administration, etc. Waiter-sol- .
`‘ uble drug entities should a priori also be lesstoxic. Thanks to their easier re—
`. nal clearance they have a lesser propensity for accumulation in the organism
`and thus avoid an overload of the hepatic microsomes responsible for phase-
`one and phase—two metabolism (e. g., hydroxylation, conjugation).
`However, one must keep inmind that making a drug molecule more
`water-soluble can also be a dravaack. There is a general tendency that the
`
`,
`
`.
`
`; 5‘
`.
`
`;
`1
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`

` ’qPROPERTIES, SELECTION, AND USE 3_
`
`
`
`
`
`
`
`more water-soluble a compound is, the more diffusible it is. This causes it to
`be less specific in‘ its aclivity, andmOre liable to rapid elimination and, there—
`fore, shorter acting;
`'
`'
`p
`'
`'
`H
`.
`~It may also be pointed out here that-the Simultaneous presence of an
`‘ ionized hydrophilic group on one end of'a 'nonpolar lipophilic chain confers
`' to the molecule an amphiphilic, ‘Soap-like’ character. Suchcompounds- can .
`show ‘a detergent behavior towards numerous membranes, and, in particular,
`they can induce- hemolysis' oferythrocytes. '
`"
`‘
`‘
`'
`
`Obtaining a Solid Aggregation State" and Iner‘ea'Sin‘g
`ChemiCal'Stahili’ty'
`-'
`.
`-
`.»
`.
`
`id- '-i’and are liable
`* Some of the bio-active bases are ‘oily"0r='loW'—me'l’tifig“=
`ts: at are Crystal—
`to oxidation. Appropriate?salt"'formatiori:~can-y-ield~*'p’r6dt
`line, easy to purify, more resistantr'towards oxidation;-‘and';'*hence; generally
`' have alonger'shelf life;
`‘
`. q
`,
`.
`.
`.-
`J
`.1
`F
`
`,
`
`Polymorphism
`
`Selecting a Salt suitable for a certain route of administration or a'particu-
`lar dosage form of a drug substance requires that all the relevant solid-state
`properties of the salt candidates be thoroughly investigated. Polymorphism
`and pseud-op‘olymorphism are frequently critical points in determining pref-
`erences for one salt to another. Polymorphism is a widespread phenomenon
`observed in more than half of all drug substances [2']. The choice of the most
`appropriate solid—state form is of considerable importance. Here, the most
`prominent aspect to be considered is stability. First of all, this means thermo—
`dynamic stability of the solid—State form, but also Chemical stability and re—
`activity (e.g., compatibility,
`i. 2., the stability in thepresence of excipients)
`may vary from one polymorph to the other. In most cases, the modification
`thermodynamically stable at room temperature is the most appropriate one.
`This is the solid—state form into which, sooner or later, all other forms Will
`eventually transform. However, high—energy mechanical processes. such as
`milling or compression can induce transformation to a form not stable at
`room temperature. Such transformation processes may lead to either another
`crystalline form or result in an amorphous material and do not necessarily run
`to completeness. Several techniques have been proposed and are applied to
`determine the thermodynamically stable form. These include measurement of
`solubility, equilibration of a mixture of forms in suspension. and'ohserving
`any changes of their mass ratio over time, thermoanalytical data such as the
`
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`

`PHARMACEUTICAL SALTS:
`‘
`4
`____________________.—————-——-———-—————-
`
`melting points of the pure polymorphs or the behav101 of eutectic mixtures
`at reduced temperatures and enthalpy—temperature diag1anis [3]. A variety
`of techniques is at hand for characterizing and identifying polymorphs: X——ray
`powder diffraction IR and Raman spectra. solid—state NMR, and various
`temperature scanning techniques.
`
`Salt Formation as a Means to Industrial Processing
`
`Salt formation is an established means for the isolation and purification
`of substances. This applies not only for the final step in the synthesis of a
`drug. Also, along a synthetic route, salt formation can afford an economic
`means to separate an intermediate from side products.
`As with crystallization in general, also crystallization of salts is associated
`with the 1ea'1m of polymorphism. Ciystallizations in the pharmaceutical indus—
`try are mostly carried out batch--wise The techniques used are cooling, evap—
`oration, drowning--out, and reaction crystallization. Normally, the process will
`be carried out as unseeded crystallization relying on spontaneous nucleation
`and the modification it entails. In a large number of cases, this will be an un-
`°stable modification, as is predicted by Ostwal‘d’s iule of stages. However, an
`unstable form15 prone to a phase transformation either while the product is
`still1n suspension, during workup, or even during storage. The latter case is
`not acceptable, since this would question reproduCible product properties.
`The growing number of chiral drugs requires efficient methods for pro!
`ducingthese compounds .in an eriantiomerically highly pure form. Despite.
`the available alte1nat1ve techniques opticalresolution via diaste1e'oiSomeric
`saltformauon r
`ainsthe most Widely usedmethod for preparing pure enan—
`
`‘
`__;b_e separated from- racemic drug substances or
`
`Izg'thetic routes by fractional Crystallization of Suitable
`
`rdlaSteICOISOIIleI‘lC salts.
`
`Adaptationto the Therapeutic Use and Pharmaceutical
`
`. Dosage Form
`
`For a new chemical entity considered for development as a drug candi— .
`date, it is important to achieve optimal physical and chemical stability. The
`form to be chosen must be chemically and physically compatible with exci—
`pients and adjuvants in a pharmaceutical formulation it must be able to resist
`the micro--environmental and macro--environmental factors during processing
`and storage, and must have properties compatible with the technology applied
`in the manufacture of the corresponding dosage form.
`
`'
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`PROPERTIES, SELECTION, AND USE 5
`
`Although a substantial aqueous solubility is generally a highly appreciat—
`ed quality for a drug substance, there are certain circumstances in which lipo—
`solubility may be desirable. Highly ionized drug substances usually lack suf—
`ficient lipophilicity for good penetration of biological membranes. Formation '
`, of salts with lipophilic salt—forming counter-ions may be a means of obtain-
`ing better absorption of such drugs. The design of implants, sustainederelease
`oral formulatibns, dermal and transdermal products can benefit from use of
`'less' soluble or more lipophilic salts.
`’
`
`Safety Aspects and Modification of Biological Properties
`
`‘Nil nocere‘ is one of the oldest and the topmost requirements for a ther-
`apeutic treatment. For this reason, the step next to the detection‘of a desired
`biological activity of anew chemical entity is to initiate toxicological and ,
`' pharmacological investigations on the safety of a potential drug candidate.
`I Because the salt form of arf active compound may modify its biological per—
`formance in viva, toxicological and safety considerations also play a role in
`salt selection.
`'
`,
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`.
`‘
`Pharmacokinetic properties may be modified by choosing salts with dif—
`ferent solubilities. 0ral absorption may so be accelerated or retarded as com— '
`pared to areference form. Selection of a sparingly soluble salt can be an al—
`ternative to complicated release retardation. by technological measures.
`1 With proper choice of a pharmacodynamically active cation or anion as
`16 counter-ion for an ionizable drug molecule, it is sometimes possible to
`achieve a synergistic effect» to counteract side effects or to facilitate the de-
`toxification of the main active principle.
`.
`_ Finally, salt formation sometimes offers solutions to biopharmaceutical
`problems such as suppression of pain on injection, avoidance of local irrita—
`tion, taste—masking (bitterness etc.) or avoiding causticity (e.g., corrosion of
`manufacturing equipment).
`
`Extension of the Patent Protection
`
`As already mentioned above, the salt form, as well as a particular solid-
`state form of a drug substance, can influence a variety of important proper—
`ties, e. gakthe solubility and rate of dissolution, the chemical stability or com—
`patibility with excipients, etc. A new salt of a drug substance already in use
`may, for example, allow a simpler manufacturing procedure of the dosage
`form or may be more stable than the salt hitherto in use; it may have a pro—
`file of properties that make it suitable for a new route of administration, or
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`6 PHARMACEUTICAL SALTS:
`
`the new salt may even open a new field of therapeutic application. Any
`one of such advantages may, therefore, constitute new claims for an exten-
`sion of prop1ieta1y rights. The same can apply for the detection of a new
`polymorph
`
`Regulatory Considerations
`
`Along the route of a new drug product to the market, the final step is to
`obtain marketing approval from the regulatory authorities. Nevertheless, the
`regulatory aspects need to be taken into account right at the initiation of a de-
`velopment pr‘oject involving a new salt. A new salt of an approved drug sub-
`stance is, in principle, a new chemical entity which would require a full dos—
`sier to be submitted for maiketing approval. However the regulatory treat
`ment of new salts of approved drugs may relyin some details on the facts al—
`ready known about the active entity of the new salt within its prior thera-
`peutic use.
`Both d1ffe1ent polymorphs and different salts and again any polymorphs
`of those, may alter the pe1fo1mance of a drug. F01 this reason, the regulato—
`ry authorities require an exhaustive search for polymorphic forms of a drug ,
`substance. The manufacturer is required to make a substantiated choice f01
`one of the forms, or a defined mixture of forms Changesin the polymorphic
`- form of the batches produced are seen as indicative of changes in the produc—
`tion process, also requiring the reproducible crystallization of a certain solid:
`state form.
`
`.
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`.
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`p
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`Salt selection .
`
`Many aspects need to be considered when a salt of a drug substance is
`selected for the development of a drug candidate. Such a decision must be
`thoroughly prepa1ed by well—timed and coordinated investigations followed
`by the intelligent weighting and comparison of.the available alternatives The
`points addressed above make it ciear that all the various disciplines that are
`involvedin the drug development process should likewise participate in the
`salt selection. Moreover, a rational strategy should be followedin order to
`guide the selectionprocess in an economic way, and the final decision should
`be made transparent and acceptable to all units involved downstream the de-
`velopment path. The present-day situation ofindustrial drug development
`makes the salt-decision an almost irreversible one, because a change of the
`salt form during later stages of the development of a drug candidate entails
`high additional expenses and loss of valuable time to be spent for repeating
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`7
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`preparative work and numerous costly investigations. This fact, in addition,
`underlines the importance of a Careful selection of the most suitable drug salt.
`
`REFERENCES
`
`[1]
`
`in ‘Des diffieultés de trafisposer a l’homme 1'es 'résultats expérimentaux
`B.-Brodie,
`Tame Série, Massdn & Cie, Paris, 1964',
`obtenus chez l’animal’, Actual. Pharmacol., 1
`p. 1—40.
`‘
`J. o. Henck, U. I. Griesser, A. Burger, Phai-m. Ind. 1997, 59465—169.
`.[2]
`ess Res. Dev. 2000, 4, 372—383,
`[3] W. Beckmann, Org. Proc
`
`
`
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`Chapter 3
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`-
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`7 Evaluation of Solid-State Properties of Salts
`
`by Danielle Giron‘“ and David J. W. Grant
`
`COntents
`
`_
`
`‘1. Introduction
`2. Thermodynamic Background
`2.1. Phase Diagram of a Single Component Exhibiting Polymorphism
`2.2. Phase Diagrams of Binary Mixtures
`'
`'
`2.3. Amorphous State ~
`7
`77'- ,l,o_emi11’,-ertlers
`
`
`3.1. Melting Point
`3.2. Solubility
`3.3. Dissolution Rate
`3.4. Heat of Solution
`3 .5. Interaction with Water Vapor
`3.6. Density
`
`3.7. Morphology
`Kinetic Aspects
`Study of Transitions between Solid Phases
`Stability Behavior
`. Molecular Modelling and Solid—State Prediction
`REFERENCES
`'
`
`“9‘5”?"
`
`1. Introduction
`
`The properties of the solid state are critical factors that determine the
`choice of an appropriate salt form of a drug molecule, especially because
`most pharmaceutical products are solids, in particular, tablets and capsules.
`A satisfactory salt form of a drug molecule must be technidally feasible and
`suitable for full—scale production and its solid-state properties maintained
`
`ia
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`;
`ita
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`g:
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`Te
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`|PR2020-007