`
`of Pure and Applied Ch
`
`international Union
`
`Handbook of
`
`Pharmaceutical Salts
`Properties, Selection, and Use
`
`P. Heinrich Stahl, Camille G. Wermuth (Eds.)
`
`
`
`
`
`Verlag Helvetica Chimica Acta - Ziirich
`
`Y) 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 beén with us for nearly 10 years at the interface between the
`disciplines essential to the development of new drugs: chemical process de-
`velopment, analytical chemstry, 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.
`oo
`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 notyet 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-elecirostatics, the
`physics of complex micellar systems, efc.
`-
`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 whoare often reticentto 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 knowledgeis still lacking. For instance,
`the mechanisms involved in crystallogenesis need to be elucidated since we
`still cannot:predict thesolubility of.a given salt. Will it be. oily or solid? Will
`it show several polymorphs? Thecrystal chemistry of crystalline surfaces —
`regulated by specific interactions between functional groups exposed on the
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`VI
`
`FOREWORD
`
`surfaces and very small amounts of impurities —- impacts with other factors
`on the preferential development of one face rather than another, butis still in
`limbo. Westill 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
`Sanofi-Synthelabo
`
`
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`Preface
`
`The origin of this book goes back to a proposition made by one of us
`(C. GW.) at a meeting of the Medicinal Section of Division Vil of IUPAC to
`write useful handbooks for medicinal chemists. Amongthe 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 priorto the initiation of dosage form development has
`become a decision point if 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 moaterial. 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. 1 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 ofsalt production, and
`the significance of salt formation in industrial processing. The involvement
`__-of_authorities-is-dealt_within.Chapt..9and.10,whichare 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
`
`
`
`sasaramesnorenannncenninntbamrentma
`
`
`
`
`osesousatitSachetspeopcerereree-PnenapanenMeretetoPot
`
`
`sonicsXmasIPRTeAEAACSREAopeerentENO
`
`
`
`
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`Vit
`
`PREFACE
`
`of salts presented in the style of model procedures (Chapt. J/) and a compre-
`hensive annotated compilation of the individual salt-forming acids and bas-
`es with their relevant properties (Chapt. 12), followed by an Appendix con-
`taining tables with the acids and bases sorted alphabetically, and by p&, val-
`ues and supplemented with other useful facts and data.
`Altogether, these chapters reflect the multidisciplinary character of for-
`mation and selection of suitabie salt forms of drug substances. An attemptis
`made to establish an up-to-date guide and source of information not only
`serving medicinal chemists, but also all the other scientists who are involved
`. in the research and development of drugs and their pharmaceutical dosage
`Torms.
`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 im the process of drug-salt for-
`mation and selection for pharmaceutical products in an mdustrial environ-
`ment. The editors wish to thankall 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 £ O, Ajayi, H. Asche, and C. Hoff, who acceptedto contribute to the
`book in the very last moment. The editors wish to acknowledge the smooth
`andexcellent cooperation with Verlag Helvetica Chimica Acta in the prepar-
`ation of the volime: Thomas Kolitzus, Assistant Editor, for his patient and:
`attentive handling of all the practical details of the editorial process, and
`Dr. M. Volkan Kisakiirek, Managing Director and Editor-in-Chief, for his
`inspiration and for his untiring scrutiny in bringing ‘his considerable com-
`prehensive knowledge into this project: Thanks aré also expressed to Larry
`Lesko of the U.S. Food and Drug Administration for establishing helpful
`contacts. Oneof the editors (PH. S.) gratefully acknowledges the support
`granted by Novartis AG, Basel, and the permission to use their Scientific
`Library facilities.
`
`Camille G. Wermuth and P. Heinrich Stahl
`Strasbourg and Freiburg,January 2002
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`

`Contributors
`
`Funmilaye QO. Ajay!
`Office of Clinical Pharmacology & Biopharmaceutics, HFD-886
`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
`Baiergasse 42
`CH-4126 Bettingen, Switzerland
`(E-mail: h.asche @ datacomm.ch)
`
`Michael J. Bowker
`M. J. Bowker Consulting Limited,
`36, Burses Way,
`Hutton, Brentwood,
`Essex CM13 2PS,; UK
`(Tel.: +44 (0)1277 228029, fax: +44 (0)1277 262899,
`e-mail: mjbconsulting @btinternet.com)
`Previous address: Rhéne-Poulenc Rorer, Dagenham,
`Essex RM10 7XS, UK
`
`Hans-Giinther 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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`a
`
`CONTRIBUTORS
`
`Danielle Giron
`Novartis Pharma AG
`CHAD — Analytical R&D
`Building WKL-127.4.60
`CH-4002 Basel, Switzerland —
`(Tel.: +41 61 69 68 170; fax: +41 61 69 68 172;
`e-mail: danielle. giron @pharma.novartis.com)
`
`
`
`.
`David J. W. Grant
`University of Minnesota
`College of Pharmacy
`Dept. of Pharmaceutics
`Minneapolis, MN 55455-0343, U.S.A.
`(Tel.: +1 (612) 624-3956; fax: +1 (612) 625-0609;
`e-mail: grant00] @maroon.tc.ummn.edu)
`
`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 3-5436-8571,
`e-mail: kondou @shina.sankyo.co jp)
`
`Christian Hoff
`Physico-Chimie des Procédés
`Sanofi-Synthelabo
`Route d’ Avignon
`F-30390 Aramon, France
`(Tel.: +33 (0) 466 57 71 71; fax: +33 (0) 466 57 72 91)
`
`Stanley Lee
`4 Manor Crescent
`Macclesfield SK10 2EN, UK
`(Tel./fax: +44 1625 42 86 23)
`Previous address: Zeneca Pharmaceuticals, silk Road Business Park,
`~Macclesfield SK10 2NA, UK
`(Tel.: +44 1625 513371; fax: +44 1625 50 07-80)
`
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`

`AL
`CONTRIBUTORS
`
`
`Michael B. Maurin
`Biopharmaceutics é& Basic Pharmaceutics,
`DuPont Pharmaceutical Company
`P. O. Box 80400
`Wilmington, DE 19880-0400, U.S.A.
`(Tel.: +1 (302) 695-9387; fax: +1 (302) 695-3565;
`e-mail: Michael.B.Maurin @ dupontpharma.com)
`
`Masahiro Nakane
`Department of Pharmacy, Kumamoto University Hospital
`Faculty of Pharmacy
`{-1-1 Honjo
`Kumamoto 860-0811, Japan
`(Tel: +81 96-373-58 20; fax: +81 96-373-59 06;
`e-mail: nakano @kaiju.medic.kumamoto-u.ac.jp)
`
`Friedlieb Pfannkuch |
`Roche Vitamins Ltd.
`Human Nutrition and Health
`Nutrition Safety (VFHS)
`Building 72 / 49b
`P.O. Box
`CH-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
`Bast Hanover, NJ 07936-1080, U.S.A.
`(Tel.: +1 (973) 781-7385; fax: +1 (973) 781-4556;
`e-mail: madhu.pudipeddi @ pharma.novartis.com)
`Previous address: Bristol-Myers Squibb Co., Pharmaceutics R&D,
`Brunswick, NJ 08903-0191, U.S.A.
`
`Harald Rettig
`BioVista G.m.b. H.
`Ruechligweg 101
`_ CH-4125Richen, Switzerland
`(Tel.: +41 (61) 603 27 35; fax: +41 (61) 603 2738; i
`e-mail: rettigh @ivive.com)
`
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`
`
`erinteennmeTSENEATERMETEHR
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`XxH
`
`CONTRIBUTORS
`
`Abu T. M. Serajuddin
`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)
`
`P, Heinrich Stahl
`Lerchenstrasse 28
`D-79104 Freiburg im Breisgau, Germany
`(Tel.: +49 (761) 548 23; fax: +49 (761) 5562 910;
`e-mail: heinrich.stahl_fr @t-online.de)
`
`Camille G. Wermuth
`Louis Pasteur University, Strasbourg
`Faculty of Pharmacy
`74, route du Rhin
`F-67400 Illkirch, 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. Wermuth and P. Heinrich Stahl
`
`Chapter 1
`
`‘The Physicochemical Background: Fundamentals
`of Ionic Equilibria
`Michael B. Maurin, David J. W. Grant,
`and P. Heinrith Stahl
`
`Chapter 2
`
`Solubility and Dissolution of Weak Acids, Bases,
`and Salts
`
`Madhu Pudipeddi, Abu T: M. Serajuddin,
`David J. W. Grant, and P. Heinrich Stahl
`
`Chapter 3
`
`Evaluation of Solid-State Properties 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 Pfannkuch, Harald Rettig,
`and P. Heinrich Stahl
`
`Jew
`
`19
`
`4
`
`83
`
`117
`
` Chapter 6
`Salt_Selection Strategies — —~-
`Abu T. M. Serajuddin and Madhu Pudipeddi
`
`“B57
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`

`XIV
`
`Chapter 7
`
`Chapter 8
`
`
`CONTENTS
`
`A Procedure for Salt Selection and Optimization
`Michael J. Bowker
`
`i614
`
`Large-Scale Aspects of Salt Formation: Processing
`of Intermediates and Final Products
`Stanley Lee and Christian Hoff
`
`191
`
`221
`
`237
`
`249
`
`265
`
`329
`
`351
`
`361
`
`Chapter 9
`
`Patent Aspects of Drug Salt Formation
`Hans-Giinther Foraita
`
`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. Wermuth
`
`Appendix
`
`.
`P. Heinrich Stahl
`
`Subject-Index —
`
`Substance-Index
`
`
`
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`Introduction
`
`by Camille G. Wermuth and P. Heinrich Stabl
`
`When the first ‘vegetable alkalis’, those nitrogen-containing bases later
`termed alkaloids, were extracted from plant materials, they were isolated and
`purified 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 compoundsas 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 endogenousbiological 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 exag-
`gerated as it excludes therapeutic agents such asthe steroids, the prostaglan-
`dins 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.
`An estimated half of all the.drug 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 suitablesalt form is important, and salt selection may have far-
`reachingconsequences and can open new opportunities. In modern pharma-
`ceutical research and development, a variety of objectives are pursuedin the
`formation ofsalts. The most important of these objectives and points to be
`considered, as they becomesignificant along the pathway ofthe development .
`of anew drug, are reviewed here.
`
`.
`
`| Improving 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 H,O eases molecular pharmacology screening
`for drug candidates. Thus. in-vitro 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 aqueousdilutions. In doing so,
`there is often the risk that the compound canprecipitate 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 H.O, whereas
`many of the corresponding salts render the drug substances ionized in H,O,
`and, as a consequence, water-soluble. Salts that are soluble in H,O are also
`ideally suited for the preparation.of injectable sterile aqueous solutions. Fast
`dissolution of the active principle contained in solid dosage forms, e.g., for
`immediate-release tablets and hard--gelatine capsules is also dependent on the
`aqueous solubility.
`Considering in-vivo testing, solubility in H,© facilitates all studies in
`which parenteral administration is required. In pharmacokinetics, reliable
`determination of absolute peroral. bioavailability is possible in comparison
`with the amount.administered 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.
`: 3 |
`some doubts as to whether the molecule under study3is non-toxic or just in-. 3
`completely absorbed.
`Finally, one.has to remember that the pharmacological effects of hydro-
`philic compounds are much more comparable.from one animal species to the
`other than those of lipophilic substances[1]. .
`.
`;
`Onthe therapeutic level, themajor interestofwater-soluble drugs resides
`in the possibility of intravenous administration. Solubility in H,O represents
`an indispensable requisite for drugs in emergency treatments permitting ther-
`apeutic plasmalevels 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, syrups for oral administration, ec. Water-sol- .
`“uble drug entities should a priori also. be less toxic. Thanksto 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 in-mind that making a drug molecule more’
`water-soluble can also be a drawback. There is a general tendency that the
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`
`
` | :PROPERTIES, SELECTION, AND USE 3
`
`
`
`
`
`more water-soluble a compoundis, the more diffusible it is. This causes it to
`be less specific inits activity, and-more liable torapid elimination and, there-
`fore, shorter acting.
`—
`-
`Tt may also be pointed out here that the simultaneous presence of an
`‘ionized hydrophilic group on one end ofa nonpolar lipophilic chain confers
`“to the molecule an amphiphilic, ‘soap-like’ character. Such-compoundscan .
`show a detergent behavior towards numerous membranes, and,in particular,
`they can induce hemolysisoferythtocytés. ,
`“ Be
`
`Obtaining a Solid AggregationState and. Increasing .
`ChemicalStability)
`. eee
`
`: Someof the bid-active basésare ‘oilyorlow-meltingsolidsaid are liable
`
`to oxidation. Appropriate’ saltformationcan yieldproducts:
`‘at arécrystal-
`line, éasy to purify, moreresistant'towards oxidation; and;hence; generally
`°
`have a longer shelf life. 7 re .
`
`Polymorphism
`Selecting a salt suitable for a certain route of administration or aparticu-
`lar dosage form of a drug substance requires that all therelevant solid-state
`properties of the salt candidates be thoroughly investigated. Polymorphism
`and pseudopolymorphism are frequently critical points in determining pref-
`erences for one salt to another. Polymorphism is a widespread phenomenon
`observed in more than halfof all drug substances [2]. The choice of the most
`appropriate solid-state form is of considerable importance. Here, the most
`prominentaspect to be consideredis stability. First of all, this means thermo-
`dynamic stability of the solid-state form, but also chemical stability and re-
`activity (e.g., compatibility, ie., the stability in the. presence of excipients)
`may vary from one polymorphto the other. In mostcases, the modification
`thermodynamically stable at room temperature is the most appropriate one.
`This is the solid-state form into which, sooner orlater, 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 observing
`any changes of their mass ratio over time, thermoanalytical data such as the
`
`
`
`a
`"!
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`
`4 PHARMACEUTICALSALTS:I
`melting points of the pure© polymorphs or the behavior of eutectic mixtures
`at reduced temperatures, and enthalpy—temperature diagrams [3]. A variety
`of techniquesis 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 Meansto Industrial Processing
`
`Salt formation is an established means for the isolation and purification
`of substances. This applies not only forthe 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.
`Aswith 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 Ostwala’s rule of stages. However, an
`unstable formis prone to a phase transformation either while the productiis
`still in 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-
`ducing,these compounds in an enantiomerically highly pure form. Despite
`theavailablealtemative.techniques, optical resolution via diastereoisomeric
`salt.formation remains themost widely-used method forpreparing pure enan-
`
`1.-be ‘separated from,racemic drug substances or
`
`long -s' nithetic.routes by. fractional érystallization of suitable
`; intermediates
`diastereoisomeric,salts.
`
`Adaptationto the Therapeatic {Use andPharmaceutical
`
`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. T’he
`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 citcumstances 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 suchdrugs.. The design of implants, sustained-release
`oral formulations, dermal and transdermal products can benefit from use of
`‘Jesssoluble or more lipophilic salts.
`
`Safety Aspects and Modification of Biological Properties
`‘Nil nocere’ is one of the oldest and the topmost requirementsfor a ther-
`apeutic treatment. For this reason, the step next to the detectionof a desired
`biological activity of a new chemical: entity is to initiate toxicological and .
`pharmacological investigations on the safety of a potential drug candidate.
`* Because the salt form of arf active compound may modify its biological per-
`formancein vivo, toxicological and safety considerations also play a role in
`salt selection.
`;
`:
`.
`Pharmacokinetic properties may be modified by choosing salts with dif-
`ferent solubilities. Oral absorption may so be accelerated or retarded as com- —
`pared to a.reference form. Selection of a sparingly soluble salt can be an al-
`ternative to complicated release retardation. by technological measures.
`“With proper choice of a pharmacodynamically active cation or anion as
`ne counter-ion for an ionizable drug molecule, it is sometimes possibleto
`achieve a synergistic effect. to counteract side effects or to facilitate the de-
`toxification of the mainactive principle.
`;
`_ Finally, salt formation sometimes offerssolutions to biopharrhaceutical
`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.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 nghts. 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 accountright at the initiation of a de-
`velopmentproject 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 rely in some details on the facts al-
`ready 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, mayalter the performance of a drug. Forthis reason, the regulato-
`ry authorities require an exhaustivesearch for polymorphic forms of a drug |
`substance. The manufacturer is required to make a substantiated choice for
`oneof 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- i
`tion process, also requiring thereproducible crystallization of a certain solid-
`.
`.
`
`state form.
`
`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 availablealternatives. The
`points addressed above makeit clear that all the various disciplines that are
`involved in the drug development process. shouldlikewise participate in the
`salt selection. Moreover, a rational strategy. should be followed in order to
`guide the selection process in an economic way, and thefinal decision should
`be made transparent and acceptableto all units involved downstream the de-
`velopment path. The present-day situation of industrial 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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`preparative work and numerous costly investigations. This fact, in addition,
`underlines the importance of a careful selection of the most suitable drugsalt.
`
`REFERENCES
`les résultats expérimentaux
`lho
`A
`1
`iffic
`‘
`in
`.
`ie,
`in ‘Des difficultés de transposer a homme e
`B. Brodie,
`obtenus chez l’animal’, Actual. Pharmacol., 17éme Série, Masson & Cie, Paris, 1964,
`mM
`. 1-40. |
`;
`i O. Henck, U. J. Griesser, A. Burger, Pharm. Ind. 1997, 59,165-169.
`[2]
`[3] W. Beckmann, Org. Process Res. Dev. 2000, 4, 372-383,
`
`4
`
`PROPERTIES,SELECTION,ANDPSF
`
` PROPERTIES, SELECTION, AND USE —
`
`
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`
`Chapter 3
`
`Evaluation of Solid-State Properties of Salts
`
`by Danielle Giron* and David J. W. Grant
`
`Contents
`
`“1. Introduction
`2, Thermodynamic Background
`2.1. Phase Diagramof a Single Component Exhibiting Polymorphism
`2.2. Phase Diagrams of Binary Mixtures
`.
`2.3. Amorphous State -
`
`
`
`PhysicochemicalProperties
`
`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
`4, Kinetic Aspects
`5. Study of Transitions between Solid Phases
`. Stability Behavior
`. Molecular Modelling and Solid-State Prediction
`REFERENCES
`
`6 7
`
` =
`
`}. 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 drag molecule must be technically feasible and
`suitable for full-scale production and its solid-state properties maintained
`
`5 aa E
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`42
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`PHARMACEUTICAL SALTS:
`
`batchwise