`Enternationqi Union
`0*" Pure and Appiied Chem
`
`
`Handbmk «3i?
`
`Phamamutémfi EaE‘tg
`
`_ PFOPEB’MESg Seam-”Um” and Use
`
`
`
`
`P.,Heinirici55 Stéhfl, Camiiié G.'Wermuth (Eda) ,
`
`
`
`Verlag Helvetica Chimica Acta - Zijrich
`
`. 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. Problems 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-
`yelopment, 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” sys:
`tems, powder flow-characteristics and mechanics, piezo—electrostatics, 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 crystal-logenesis need to be elucidated since we
`.still .cannotpgedict thesohtbiiity .ofa given 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 enpcgi on the
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`v1 FOREWORD
`
`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.
`
`Prof. Bertrand Castro
`
`Director of the Chemical Development
`8 anofi— 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 of the A/Iediciml Section ofDi'visiorz VI] of ZURaC 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 chug
`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 in 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 of the 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. I and 2), basics and the evaluation of solid—state properties (Chapt. 3),
`safety and biopharmaceutical as well as pharmaceutical-technological 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
`———49Lauthoiéities;is;dealtfiwjthiniC]mpL_9 and 10a wars; are 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
`
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`
`
`Viii PREFACE
`
`of salts presented in the style of model procedures (CT/rapt. If) and a compre—
`hensive annotated compilation of the individual salt—forming acids and bas-
`es with their relevant properties (Chapt. .72): followed by an Appendix con—
`taining tables with the acids and bases sorted alphabetically, and by pKfl 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 esrablish an up—to—date guide and source of information not only
`serving medicinal chemists, but also all the other scientists who are involved
`pin the research and development of 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 F O. Ajayi, H. Asche, and C. Hajj“, 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 Chimicd Acta in the prepar—
`ation of the Volume: Thomas Kolitzua Assistant Editor, for his patient and
`attentive handling of all the practical details of the'e'ditorial process, and
`Dr. M. Volkan Kisakiirek, Managing Director and Editor-in—Chief,. for his
`inspiration and for his untiring scrutiny in bringingvhis considerable com—
`prehensive 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 (HHS) gratefully acknowledges the support
`granted by Novartis AG, Basel, and the permission to use their Scientific
`
`Library facilities.
`
`Camille G. Wermurh and P. Heinrich Siam
`Strasbourg and Freiburg,‘ January 2002'
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`

`Contributei‘s
`
`Funmilaye Or; Ajayi
`Qtfice of Clinical Pharmacology 6': Biopliai‘maceutics, HEB—880
`Office of Pharmaceutical Science
`Center for Drug Evaluation & Research
`Food and Drug Administration
`5600 Fishers Lane, Rockville, MD 20857, U.S.A.
`
`Henning Asche
`Pharma—Service & Consulting
`
`Baiei-gasse 42
`CH—4126 Bettingen, Switzerland
`(E—Inail: h.asche @ dataCommeh)
`
`Michael J. Bowker
`M. J. 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 @btintemet.eom)
`Previous address: Rhone—Poulenc Rorer, Dagenham,
`
`Essex RM10 7X8, UK
`
`Hans-Giinther Foraita
`
`Patent Consulting
`Steingmbenweg 10
`CH—4125 Riehen, Switzerland
`(Tel/fax: +41 61 643 93 24', e—mail: foraita@ dataeomm.ch)
`
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`X
`
`CONTRIBUTORS
`
`Danielle Git-on
`
`Novartis Pharina AG
`
`CHAD — Analytical R851)
`13 uilding WKL—127.4.6O
`CH—4002 Basel, Switzerland ‘
`
`(Tel: +41 61 69 68 170; fax: +41 61 6968 172;
`e-mail: clanielle. giron @pharnianovartis.coni)
`
`David J. ‘W 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: grantOOl @maroon.totnnncclu)
`
`Jun-ichi Kondo
`
`Laboratory of Analytical Science
`Product Development Laboratories
`Sanlcyo Co., Ltd.
`
`2—58, Hiromachi 1-Chome, Shinagawa—ku
`
`Tokyo 140, Japan
`(Tel.: +81 3—3492—3131 ext. 4664; fax: +81 3—5436—8571;
`e—mail: kondou@ shinasankyocojp)
`
`Christian Hoff
`
`Physico-Chimie 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 2EN, UK
`(Tel/fax: +44 1625 42 86 23)
`Previous address: Zeneca Pharmaceuticals, Silk Road Business Park,
`vMacclesfield SKlO 2NA, UK
`(Tet: +44 1625 51 3371; fax: +44 1625 50 O7 80)
`
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`

`CONTRIBUTORS
`
`X1
`
`lvllichael B. Maurin
`Biopharmaceutics & Basic Pharmaceutics,
`DuPont Pharmaceutical Company
`
`P. O. Box 80400
`Wilmington, DE 19880-0400, USA.
`(Tel: +1 (302) 695—9387; fax: +1 (302) 695—3565;
`e—mail: MichaelB .Maurin. @ dupontpharmacom)
`
`Masaliirc N allianc-
`Department of Pharmacy, Kuniamoto University Hospital
`Faculty of Pharmacy
`l-l—l Honjo
`Kumamotc 860—0811, Japan
`(Tel: +81 96—373-58 20; fax: +81 96—373—59 06;
`e—mail: nakano @liaij u.medic .lcumamoto—uac .jp)
`
`_
`
`lFriedlieb Pfannkuch _
`
`Roche Vitamins Ltd.
`
`Human Nutrition and Health
`
`Nutrition Safety (VFHS)
`
`Building 72 / 49b
`P. O. Box
`
`i%
`
`(DH—4070 Basel, Switzerland
`(Tel: +41 (61) 687 07 99; fax: +41 (61) 688 68 19;
`e—mail: fn'edlieb.pfannlcucli@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: madhupudipeddi@phamnanovartiscom)
`Previous address: Bristol~Myers Squibb Co., Pharmaceutics R&D,
`Brunswick, NJ 08903—0191, U.S.A.
`
`‘
`
` (Tel: +41 (61) 603 27 35; fax: +41 (61) 603 27 38',
`
`Harald Rett'ig
`BioVista G.m.b. .H.
`
`Ruechligweg 101
`., (SH—412,5. Riehen, Switzerland
`
`.7
`
`e—mail: rettigh@ivivc.com)
`
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`X11
`
`CONTRIBUTORS
`
`Abu T. M. Sei'ajuddin
`NOVfll'll'lS Pharmaceuticals Corp.
`
`Building 40].
`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 @phzu'mamov artis .com)
`
`1?. Heinrich 8121111
`
`Lerehensu'asse 38
`
`13—79104 Freiburg im Breisgau, Germany
`(Tel: +49 (761) 548 23; fax: +49 (761) 5562 910;
`e—mail: heim‘ichstahljr@t—011line.de)
`
`Camille Gi Wei-mum
`
`Louis Pasteur University, Strasbourg
`
`Faculty of Pharmacy
`74, route du Rhin
`13-67400 lllkirch, 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
`
`intro duction
`
`Camille G. Wermiiiit and P. Heinrich Siahi
`
`Chapter 1 The Physicochemical Background: Fundamentals
`of Ionic Equilibria
`
`Michael B. Maurin, David J. W. Grant,
`
`and P. Heinrich Siahl
`
`Chapter 2
`
`Solubility and Dissolution of Weak Acids, Bases,
`and Salts
`
`Madhu Piidipeddi, Abu T. M. Semjuddin,
`David J. W. Grant, and P. Heinrich Stahl
`
`1...:
`
`9
`
`19
`
`Chapter 3
`
`Evaluation of Solid—State Properties of Salts
`
`‘
`
`41
`
`Danielle Giron and David J. W. Grant
`
`Chapter 4
`
`Pharmaceutical Aspects of the Drug Salt Form
`P. Heinrich Stahl and Masahiro Nakcmo
`
`Chapter 5
`
`Biological Effects of the Drug Salt Form -
`
`Friedlieb Pfamikuch, Harald Retrig,
`and P. Heinrich Smhl
`
`83
`
`117
`
`
`
`Chapter '6'
`
`Salt—selection Strategies
`
`
`"
`"
`'
`”
`'
`”' T35 '
`"
`
`Aim T. M. Semjuddin and Madhu Pudipeddi
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`XIV
`
`Chapter 7
`
`A Procedure for Salt Selection and Optimization
`Michael J. Bowker
`
`3
`
`CONTENTS
`
`161
`
`191
`
`221
`
`237
`
`249
`
`265
`
`329
`
`351
`
`361
`
`Chapter 8
`
`Large—Scale Aspects of Salt Formation: Processing
`of Intermediates and Final Products
`
`Stanley Lee and Christian. Hofi‘
`
`Chapter 9
`
`Patent Aspects of Drug Salt Formation
`
`Hans— Giinthe 7‘ F0 raita,
`
`Chapter 10 Regulatory Aspects of Drug Salts
`Henning Asche, Jun—ichi Kondo,
`and Funmilayo O. Ajayi
`
`Chapter 11 Selected Procedures for the Preparation of
`Pharmaceutically Acceptable Salts
`Camille G. Wermuth and P. Heinrich Stahl
`
`Chapter 12 Monographs on Acids and'Bases
`P. Heinrich Stahl and Camille G. W‘ermuth
`
`Appendix
`
`F. Heinrich Stahl
`
`Subj cot—Index ‘
`
`Substance-Index
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`Introduction
`
`by Camille G. Wermuth and P. Heinrich Stahl
`
`When the first ‘vegetable alkalis’, those nitrogen—containing bases later
`termed alkaloids, were extracted from plant mate1ials, they were isolated and
`punfied as well-crystallizing 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, pilocarpine 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 a1e 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 fo1 the old
`adage‘no medicarnents without nitrogen’. This assertion is certainly exag—
`gerated as it excludes therapeutic agents such as the steroids, the prostaglan-
`dins and their derivatives also the fibrates and acidic anti-inflammatory
`drugs like aspi1in, diclofenac, and ibuprofen. Many of these classes of drugs
`contain a carboxylic function, and, therefore, salt formation can evidently
`also be considered.
`.
`An estimated half of all thedrug molecules used1n medicinal therapy are
`administered as salts and salifioation of a drug substance has become an 63- '
`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
`4 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.
`
`’
`
`‘ Imriroving 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 H30 eases molecular pharmacology screening
`for drug candidates. Thusin-virro studies (receptor binding, enzyme inhibi-
`tion, cell cultures) and studies with isolated organs are facilitated. The com—
`mon pIOCedure1n testing piactically insoluble compounds in such assays is
`to prepare stock solutions in an organic solvent (DMSOWpolyethylene gly-
`col, EtOI—l, etc.) and to p1oceed 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 preparationof injectable sterile aqueous solutions. Fast
`dissolution of the active principle contained in solid dosage forms, 6' g., for
`immediate—release tablets and hard——gelatine capsulesIS also dependent on the
`aqueoussolubility.
`Considering i—n—vivo testing, solubility inl-IZO facilitates all studies in
`I 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 with-an insoluble compound always leaves.
`;
`some doubts as to whether the molecule under studyis non—toxic 'or just in» 1
`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 interestofwaterwsoluble drugs resides
`in the possibility of intravenous administration. Solubilityin H20 represents
`an indispensable requisite for drugsin 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 ,on water—
`soluble active agents: Apart from parenteral injections and infusions, there
`are nasal drops and eye-drops,l-syrups for oral administration, etc. Water-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-twometabolism (e. g., hydroxylation, conjugation).
`However, one must keep inmind that making a drug molecule more
`water-soluble can also be a drawback. There is a general tendency that the
`
`,
`
`,
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`i
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`.
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`’-
`..
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`i
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`
`
`' .PROPERTIES, SELECTION, AND USE 3W
`
`
`
`
`
`
`
`
`“14:52rawfivrqm-acfianew
`53:75:aveflwsmmamrvfl
`
`
`rwetness:
`
`,
`
`more water-soluble a compound is, the more difquible it is. This causes it to
`be less specific. in' its aciivity, and'more liable to rapid elimination and, there- -
`fore, shorter acting.
`I
`'
`'
`"
`'
`,
`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-hke’ character. Suchcompounds can .'
`show a detergent behavior towards numerous membranes, and, in particular,
`they can induce hemolyS‘is‘oferythrOCytes.
`'
`'
`‘
`A
`
`Obtaining .3 Solid Aggregation State andlnCréwing ‘
`Chenfihal-Stabili‘ty‘
`'
`y
`‘
`-
`‘
`r
`
`. Some of the bio—active bases are oiiy'opiowanetnag oliii's‘i‘an-d are liable
`-
`to oxidation. Appropriate? salt'fOImatiorr-can yield pro u
`that arec‘rystal—
`
`line, easy to purify, more resistantvtoWards oxidation,“and;"'ihencei,' generally .
`"havealongershelflife., ‘ _
`'
`,
`*
`,
`"
`
`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'olymorp'hism 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 importan'Ce. 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 (eg, compatibility,
`i. 6., the stability in the presence 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 fun
`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. andobserving
`any changes of their mass ratio over time, thermoanalytical data such as the
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`PHARNLACEUTICAL SALTS:
`4
`__________________—_———————-————-——-———-—-
`
`melting points of the pure polymorphs or the behavi01 of eutectic mixtures
`at reduced temperatures, and enthalpy—tempeiature diagrams [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
`temperatuie 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 realm of polymorphism Crystallizations 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 1ule of stages. However, an
`unstable form is prone to a phase transformation either while the product is
`still in suspension, during workup, or even during storage. The latter case is
`not acceptable, since this would question reproduCibleproduct properties.
`The growing number of chiraldrugsrequiies efficient methods f01 pro?
`ducingthese. Compounds in an en-antiomeiically highly pure form. Despite
`the available alternativetechniques opticalreSolution via diastere'oi'someric
`
`
`
`,diastere01somer1 . 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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`5
`PROPERTIES, SELECTION, AND USE
`JIM
`
`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 formulatiOns, 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.
`.' Because the salt form of an" active compound may modify its biological per-
`formance, in viva, toxicological and safety considerations also play a role in
`Salt selection.
`I
`'
`'
`I
`‘
`p "
`Pharmacokinetic properties. may be modified by choosing salts with dif-
`ferent solubilities. Oral 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 activecation or anion as
`re 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
`manhfacturing 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.g.&the 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 proprietary 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 project 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 marketing approval. However the regulatory treat—
`ment of new salts of approved drugs may relyin some details on the facts al—
`1eady known about the active entity of the new salt within its prior thera-
`peutic use.
`
`Both, different polymorphs and different salts, and again any polymorphs
`of those, may alter the peiformance of a drug. For this reason, the regulato—
`ry authorities require an exhaustive, search for polymorphic forms of a drug 1
`substance. The manufacturer is required to make a Substantiated choice for
`one of the forms, or a defined mixture of forms. Changes in 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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`
`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 prepared by well—timed and coordinated investigations followed
`by the intelligent weighting and comparison ofthe available alternatives. The
`points addressed above make it ciear that all the various disciplines that are
`involved1n the drug development process should likewise participate in the
`salt selection. Moreover, a rational strategy should be followed1n 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 spentgfor repeating
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`7
`,
`.
`.
`PROPERTIES; SELECTION, AND USE
`W!—
`
`preparative work and numerous costly investigations. This faet, in addition.
`underlines the importance of a Careful selection of the most suitable drug salt.
`
`REFERENCES
`
`I
`
`[I]
`
`l'es 'résultats expérimentaux I
`'
`’
`‘
`‘
`'
`’
`I“
`‘
`'
`'
`,
`‘
`_
`‘
`,_
`BgBl'Ole, in Des difficultes de transposer 9:1 honu‘he
`obtenus chez Tanimal’, Actual. Pharmacol., 17eme Sene, Massou & Cie, Fans, 1964,
`. 1—40.
`'
`,
`.
`, _.
`1;. O. Henck, U. I. Griesser, A. Burger, Pharm. Ind. 1997, 59,_165—16_9.
`.[2].
`[3] W. Beckmann, Org. Process Res. Dev. 2000, 4, 372—383.
`
`
`
`5,;
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`
`
`Chapter 3
`
`-
`
`i~ Evaluation of SOIid-State Preperties of Salts-
`
`by Danielle Giron’“ and David J. W. Grant
`
`
`
`
`'1. Introduction
`_ 2. Thermodynamic Background
`
`2.1. Phase Diagram of a Single Component Exhibiting Polymorphism
`
`22. Phase Diagrams of Binaiy Mixtures
`2.3. Amorphous State .
`
`.. ,-c 6: _1T'11_L0_.-ems
`3.1. Melting Point
`V
`7
`3.2. Solubility
`3.3. Dissolution Rate
`
`._
`
`..
`
`,
`
`'. COntents .
`
`,
`
`,
`
`3.4. Heat of Solution
`
`3.5. Interaction with Water Vapor
`
`3.6. Density
`
`99$”?
`
`3.7. Morphology
`Kinetic Aspects
`Study of Transitions between Solid Phases
`Stability Behavior
`Molecular Modelling and Solid—State Prediction
`REFERENCES
`'
`
`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 technically feasible and
`suitable for full—scale production and its solid-state properties maintained
`
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