ELSEVIER
`
`Advanced Drug Delivery Reviews 48 (2001) 3-26
`
`Advanced
`DRUG DELIVERY
`Reviews
`
`www .elsevier.com/locate/ drugdeliv
`
`Crystalline solids
`Sudha R. Vippagunta\ Harry G. Brittainb, David J.W. Granta·*
`
`Department of Pharmnceutics, College of Pharmncy, University of lvfinnesota, Weaver-Densford Hall, 308 Harvard Street S.E.,
`Minneapolis, MN 55455, USA.
`6Center for Phannaceutical Physics, 10 Charles Road, Milford, NJ 08848, USA
`
`Received 18 October 2000; accepted 21 December 2000
`
`Abstract
`
`Many drugs exist in the crystalline solid state due to reasons of stability and ease of handling during the various stages of
`drug development. Crystalline solids can exist in the form of polymorphs, solvates or hydrates. Phase transitions such as
`polymorph interconversion, desolvation of solvate, formation of hydrate and conversion of crystalline to amorphous fonn
`may occur during various phannaceutical processes, which may alter the dissolution rate and transport characteristics of the
`drug. Hence it is desirable to choose the most suitable and stable form of the drug in the initial stages of drug development.
`The current focus of research in the solid-state area is to understand the origins of polymorphism at the molecular level, and
`to predict and prepare the most stable polymorph of a drug. The recent advances in computational tools allow the prediction
`of possible polymorphs of the drug from its molecular structure. Sensitive analytical methods are being developed to
`understand the nature of polymorphism and to characterize the various crystalline forms of a drug in its dosage form. The
`aim of this review is to emphasize the recent advances made in the area of prediction and characterization of polymorphs and
`solvates, to address the current challenges faced by pharmaceutical scientists and to anticipate future developments.
`© 2001 Elsevier Science B.V. All rights reserved.
`
`Keywords: Crystallinity; Polymorphs; Hydrates; Solvates; Formulation; Drug substance; Phase transformation; Characterization
`
`Contents
`
`1. Introduction .. ........ ..... .... .... ..... .... ........ ..... ......... .... .... .... ......... ......... .... .... .... ......... ..... ... ......... ... . .... ..... .... .... ..... .... .... ..... .... .... ...
`2. Recent advances in the identification, prediction and characterization of polymorphs .. .. ...... ... ... . . .... .. .. .... .. ... ... . . ... ... .. ... ... . . ... ... .. ...
`2.1. Types of polymorphism....................................................................................................................................................
`2.2. Packing polymorphism .. . . . . .. . . . . . . . . . . . . .. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. . . . . . . . . . . . . .. . . . . .. . . . . . . .. .. . . . . .. . . . . . . .. . . . . . . .. . . . . . . . . . . . . .. .. . . . . . . . . . . . . . .
`2.3. Conformational polymorphism..........................................................................................................................................
`2.4. Phase transformations in the solid state..............................................................................................................................
`2.5. Prediction of polymorphs ................................ ........ ...................... ................. .................................. ...................... ........ ...
`2.6. Directing the crystallization of specific polymorphs ......................................... ...................... ........ ........ .............................
`2.7. Characterization ofpolymorphs using a combination of analytical techniques.......................................................................
`3. Recent advances in the identification and characterization of hydrates and solvates ... ...................... ........ .....................................
`3.1. Introduction to solvates and hydrates.................................................................................................................................
`3.2. Structural aspects.............................................................................................................................................................
`
`4
`6
`6
`7
`8
`9
`11
`12
`13
`15
`15
`15
`
`*Corresponding author. Tel.: + 1-612-6243-956; fax: + 1-612-6250-609.
`E-mnil address: grantOOl@tc.umn.edu (D.J.W. Grant).
`
`0169-409X/0l/S - see front matter © 2001 Elsevier Science B.V. All rights reserved.
`PII: S0169-409X(0l)00097-7
`
`Argentum EX1027
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`SR. Vippagunta et al. I Advanced Drug Delivery Reviews 48 (2001) 3-26
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`3.3. Phase transformation of hydrates and solvates .. ........ ...................... ................. ............. ..................... .............................. ...
`3.4. Prediction of the formation of hydrates and solvates ...........................................................................................................
`3.5. Characterization of hydrates and solvates ...........................................................................................................................
`4. Current challenges and future directions....................................................................................................................................
`4.1. Origins of the challenges .. .... .. .. .... .. ... ... . . ... ... .. .... .. .. ...... ........ .... .... ... . . . .. ..... .... .. .. ...... ... ... . . .... .. . . .... .. .. .... .. ... ... . . ... ... .. .... .. .. ...
`4.2. Phase transformations during processing............................................................................................................................
`4.3. Degree of crystallinity .................................... ........ ...................... ................. .................................. ...................... ........ ...
`4.4. Characterization of mixtures of polymorphs .......................................................................................................................
`5. Conclusions............................................................................................................................................................................
`References . . . .. . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . .. .. . . . . . . . . . . . . .. . . . . . . . . . . . . .. .. . . . . .. . . . . . . .. . . . . .. .. . . . . .. .. . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. .. . . . . . . . . . . . . .. . . . . .. .. . . . . .
`
`17
`18
`18
`18
`18
`19
`21
`21
`23
`24
`
`1. Introduction
`
`Most orgamc and inorganic compounds of phar(cid:173)
`maceutical relevance can exist in one or more
`crystalline fonns. When applied to solids, the adjec(cid:173)
`tive, crystalline, implies an ideal crystal in which the
`termed unit cells, are repeated
`structural units,
`regularly and indefinitely in three dimensions in
`space. The unit cell has a definite orientation and
`shape defined by the translational vectors, a, b, and
`c, and hence has a definite volume, V, that contains
`the atoms and molecules necessary for generating the
`crystal. Each crystal can be classified as a member of
`one of seven possible crystal systems or crystal
`classes that are defined by the relationships between
`the individual dimensions, a, b, and c, of the unit cell
`and between the individual angles, a, /3, and y of the
`unit cell [1,2]. The structure of a given crystal may
`be assigned to one of the seven crystal systems, to
`one of the 14 Bravais lattices, and to one of the 230
`space groups [1]. All the 230 possible space groups,
`their symmetries, and the symmetries of their diffrac(cid:173)
`tion patterns are compiled in the International Tables
`for Crystallography [3].
`The common crystalline forms found for a given
`drug substance are polymorphs and solvates. Crys(cid:173)
`talline polymorphs have the same chemical com(cid:173)
`position but different internal crystal structures and,
`therefore, possess different physico-chemical prop(cid:173)
`erties. The different crystal structures in polymorphs
`arise when the drug substance crystallizes in differ(cid:173)
`ent crystal packing arrangements and/ or different
`conformations. The occurrence of polymorphism is
`quite common among organic molecules, and a large
`number of polymorphic drug compounds have been
`noted and catalogued [ 4-7].
`Solvates, also known as pseudopolymorphs, are
`
`crystalline solid adducts contammg solvent mole(cid:173)
`cules within the crystal structure, in either stoichio(cid:173)
`metric or nonstoichiometric proportions, giving rise
`to unique differences in the physical and pharma(cid:173)
`ceutical properties of the drug. If the incorporated
`solvent is water, a solvate is termed a hydrate.
`Adducts frequently crystallize more easily because
`two molecules often can pack together with less
`difficulty than single molecules. While no definite
`explanations can be given, possible reasons include
`adduct
`symmetry,
`adduct-induced confonnation
`changes, and the ability to form hydrogen bonds
`through the solvent molecules [2,8,9]. Desolvated
`solvates are produced when a solvate is desolvated
`and the crystal retains the structure of the solvate
`[10]. Desolvated solvates are less ordered than their
`crystalline counterparts and are difficult to character(cid:173)
`ize, because analytical studies indicate that they are
`unsolvated materials (or anhydrous crystal fonns)
`when, in fact, they have the structure of the solvated
`crystal forn1 from which they were derived [ 11].
`Because different crystalline polymorphs and sol(cid:173)
`vates differ in crystal packing, and/ or molecular
`conformation as well as in lattice energy and en(cid:173)
`tropy, there are usually significant differences in
`their physical properties, such as density, hardness,
`tabletability, refractive index, melting point, enthalpy
`of fusion, vapor pressure, solubility, dissolution rate,
`other thermodynamic and kinetic properties and even
`color [12]. Differences in physical properties of
`various solid forms have an important effect on the
`processing of drug substances into drug products
`[13], while differences in solubility may have impli(cid:173)
`cations on the absorption of the active drug from its
`dosage fonn [14], by affecting the dissolution rate
`and possibly the mass transport of the molecules.
`These concerns have led to an increased regulatory
`
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`SR. Vippagunta et al. I Advanced Drug Delivery Reviews 48 (2001) 3-26
`
`5
`
`interest in understanding the solid-state properties
`and behavior of drug substances. For approval of a
`new drug, the drug substance guideline of the US
`Food and Drug Administration (FDA) states that
`"appropriate" analytical procedures need to be used
`to detect polymorphs, hydrates and amorphous forms
`of the drug substance and also stresses the impor(cid:173)
`tance of controlling the crystal form of the drug
`substance during
`the various stages of product
`development [11]. It is very important to control the
`crystal form of the drug during the various stages of
`drug development, because any phase change due to
`polymorph interconversions, desolvation of solvates,
`formation of hydrates and change in the degree of
`crystallinity can alter the bioavailability of the drug.
`When going through a phase transition, a solid drug
`may undergo a change in its thermodynamic prop(cid:173)
`erties, with consequent changes in its dissolution and
`transport characteristics [ 15].
`Various phannaceutical processes during drug
`development significantly influence the final crys(cid:173)
`talline fonn of the drug in the dosage fonn. The
`various effects of pharmaceutical processing on drug
`polymorphs, solvates and phase transitions have been
`described in detail by Brittain and Fiese [ 16] and will
`be discussed in later chapters. Briefly, processes such
`as lyophilization and spray drying may lead to the
`formation of the amorphous form of drug, which
`tends to be less stable and more hygroscopic than the
`crystalline product. Also, processing stresses, such as
`drying, grinding, milling, wet granulation, oven
`drying and compaction, are reported to accelerate the
`phase transitions in phannaceutical solids. 1l1e de(cid:173)
`gree of polymorphic conversion will depend on the
`relative stability of the phases in question, and on the
`type and degree of mechanical processing applied.
`Keeping these factors in mind, it is desirable and
`usual to choose the most stable polymorphic form of
`the drug in the beginning and to control the crystal
`form and the distributions in size and shape of the
`drug crystals during the entire process of develop(cid:173)
`ment. The presence of a metastable form during
`processing or in the final dosage form often leads to
`instability of drug release as a result of phase
`transformation [ 17].
`Crystallization plays a critical role in controlling
`the crystalline form and the distribution in size and
`shape of the drug. The significance of crystallization
`
`mechanisms and kinetics in directing crystallization
`pathways of pharmaceutical solids and the factors
`affecting the formation of crystals have been re(cid:173)
`viewed in detail by vaiious researchers [12,18,19]. A
`crystalline phase is created as a consequence of
`molecular aggregation processes in solution that lead
`to the formation of nuclei, which achieve a certain
`size during the nucleation phase to enable growth
`into macroscopic crystals to take place during the
`growth phase. The factors affecting the rate and
`mechanisms by which crystals are formed are:
`solubility, supersaturation, rate at which supersatura(cid:173)
`tion and desupersaturation occur, diffusivity, tem(cid:173)
`perature, and the reactivity of surfaces
`towards
`nucleation. The various forces responsible for hold(cid:173)
`ing the organic crystalline solids together, such as
`nonbonded interactions and hydrogen bonding, have
`been discussed in detail by Byrn et al. [2] and Etter
`[20].
`Various analytical methods are being currently
`used to characterize the crystalline form of the drug
`during the vai·ious steps of processing and develop(cid:173)
`ment. 1l1ese methods have been reviewed recently in
`detail by many authors [7,10,21-25]. The single
`most valuable piece of information about the crys(cid:173)
`talline solid, including the existence of polymorphs
`and solvates, is the molecular and crystalline struc(cid:173)
`ture, which is determined by single-crystal X-ray
`diffractometry
`[2]. Powder X-ray diffractometry
`provides a "fingerprint" of the solid phase and may
`sometimes be used to determine crystal structure.
`Once the existence of polymorphism ( or solvate
`formation) is definitely established by single-crystal
`and powder X-ray diffractometry, spectral methods,
`such as Fourier transform infrared absorption (FTIR)
`spectroscopy, Fourier transfonn Raman scattering
`(FT Raman) spectroscopy, solid-state nuclear mag(cid:173)
`netic resonance (SSNMR) spectroscopy, ultraviolet
`and visible (UV-Vis) and/ or fluorescence spectros(cid:173)
`copy [23] may be employed for further characteriza(cid:173)
`tion. Of special significance are thermal methods,
`such as differential scanning calorimetry (DSC),
`thermogravimetric analysis (TGA) and optical micro(cid:173)
`scopy using a hot stage [24]. These methods are
`almost always employed for further characterization.
`Modulated
`(temperature)
`differential
`scanning
`calorimetry (MDSC) in combination with DSC and
`optical microscopy are able to identify the glass
`
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`SR. Vippagunta et al. I Advanced Drug Delivery Reviews 48 (2001) 3-26
`
`transition of amorphous forms with much greater
`clarity and allow unique insights into the glass
`transitional and polymorphic behavior of drug sub(cid:173)
`stances [26].
`Because solid-state NMR spectroscopy can be
`used to study crystalline solids, as well as pharma(cid:173)
`ceutical dosage forms,
`this powerful method
`is
`finding increasing application in deducing the nature
`of polymorphic variations [27], such as variations in
`hydrogen bonding network and molecular confonna(cid:173)
`tions among polymorphs [28,29] and for the de(cid:173)
`tennination of molecular conformations and mobility
`of drugs in mixtures and dosage forms [2]. Solid(cid:173)
`state 13C-NMR in conjunction with the techniques,
`known as high power proton decoupling, cross
`polarization (CP), and magic-angle spinning (MAS)
`offers information not obtained readily by other
`13C-solid(cid:173)
`techniques. Recently,
`two-dimensional
`state NMR spectroscopy has been used to study the
`three conformational polymorphs of 5-methyl-2-[(2-
`nitrophenyl)amino]-3-thiophenecarbonitrile [30]. Use
`of two-dimensional NMR and total suppression of
`spinning side bands (TOSS) pulse sequences allowed
`the separation of isotropic and anisotropic chemical
`shifts for the three forms. This is a very powerful
`method for analyzing differences in the chemical
`environment and is finding increased application in
`the study of conformational polymorphism.
`With advances in analytical methods, the current
`focus of research in the solid-state area is to under(cid:173)
`stand polymorphism and pseudopolymorphism at the
`molecular level. Knowledge of the crystal packing
`arrangements and the various intermolecular forces
`involved in the different packing arrangements will
`help in the prediction and preparation of the most
`stable polymorphs of a given compound well in
`advance, to avoid surprises during product develop(cid:173)
`ment. A current emphasis is on the development of
`software to predict crystal structures of polymorphs
`from molecular structures. A thorough understanding
`of the physicochemical properties of polymorphs and
`solvates (hydrates) is of primary importance to the
`selection of a suitable crystalline form and develop(cid:173)
`ment of a successful pharmaceutical product. Bray et
`al. [31] have shown that, by thorough characteriza(cid:173)
`tion of four different crystalline forms of L-738,167,
`a fibrinogen receptor antagonist by various analytical
`
`techniques, it was possible to determine the suitabili(cid:173)
`ty of one or two forms for the development of
`pharmaceutical oral dosage forms.
`The present review aims to emphasize the recent
`advances made in the area of prediction and charac(cid:173)
`terization of polymorphs and solvates, attempts to
`address the current challenges and problems faced by
`pharmaceutical scientists and intends to anticipate
`future development. This review does not attempt to
`provide solutions to the problems but attempts to
`review comprehensively the advances made in recent
`years to help address these problems.
`
`2. Recent advances in the identification,
`prediction and characterization of polymorphs
`
`2.1. Types of polymorphism
`
`Based on differences in the thermodynamic prop(cid:173)
`erties, polymorphs are classified as either enantio(cid:173)
`tropes or monotropes, depending upon whether one
`form can transform reversibly to another or not. In
`an enantiotropic system, a reversible transition be(cid:173)
`tween polymorphs is possible at a definite transition
`temperature below the melting point. In a mono(cid:173)
`tropic system, no reversible transition is observed
`between the polymorphs below the melting point.
`Four useful rules have been developed by Burger and
`Ramburger [32,33]
`to determine qualitatively the
`enantiotropic or monotropic nature of the relation(cid:173)
`ship between polymorphs. These rules are the heat of
`transition rule, heat of fusion rule, infrared rule and
`density rule.
`If, by use of the above rules, it is established that
`the polymorphs of a particular drug are enantiotropic
`or monotropic, then the next goal is to define the
`thermodynamically stable (or metastable) domain of
`each crystalline phase of a substance as a function of
`temperature. The plot of the Gibbs free energy
`difference, !:::.G, against the absolute temperature, T,
`gives the most complete and quantitative information
`on the stability relationship of polymorphs [22], with
`the most stable polymorph having the lowest Gibbs
`free energy. The !:::.G between the polymorphs may
`be obtained using several techniques operating at
`
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`SR. Vippagunta et al. I Advanced Drug Delivery Reviews 48 (2001) 3-26
`
`7
`
`different temperatures, such as solubility [34] and
`intrinsic dissolution rate. Yu [35] has derived thermo(cid:173)
`dynamic equations to calculate /j,G between two
`polymorphs and its
`temperature slope from
`the
`melting data. This method is essentially an extension
`of the heat of fusion rule, which is based on
`statistical mechanics. Extrapolating /j,G to zero gives
`an estimate of the transition temperature, from which
`the existence of monotropy or enantiotropy is in(cid:173)
`ferred. The integration of different types of data
`provides the /j,G vs. T curve over a wide temperature
`range and allows the consistency between techniques
`to be checked [22]. Another approach to establish the
`order of stability among various polymorphs has
`been studied using pressure versus temperature plots,
`e.g., for sulfanilamide and piracetam [36]. This
`approach is based upon Ostwald's principle of least
`vapor pressure, according to which the stable poly(cid:173)
`morph exhibits
`the
`lowest vapor pressure. The
`accuracy of this approach to establish the stability
`hierarchy among the polymorphs has been shown to
`be very much dependent on the accuracy of the
`experimental data.
`In recent years, the main focus of research has
`been the characterization of polymorphs arising from
`structural differences in the crystal lattice. It has
`been established for some time that organic mole(cid:173)
`cules are capable of forming different crystal lattices
`through two different mechanisms. One of the mech(cid:173)
`anisms is termed packing polymorphism, and repre(cid:173)
`sents instances where conformationally relatively
`rigid molecules can be assembled into different
`three-dimensional structures through the invocation
`of different intermolecular mechanisms. The other
`mechanism is termed confonnational polymorphism
`and arises when a nonconfonnationally rigid mole(cid:173)
`cule can be folded into different arrangements, which
`subsequently can be packed into alternative crystal
`structures. The distinction between packing poly(cid:173)
`morphism and conformational polymorphism
`is
`somewhat artificial because different packing ar(cid:173)
`rangements impose different conformations on the
`molecules, however slight, and different conforma(cid:173)
`tions will inevitably pack differently. The structural
`aspects associated with polymorphs have been re(cid:173)
`viewed recently [2], as have the analogous features
`of solvate and hydrate systems [9]. In the next
`
`section, the results of some more recent investiga(cid:173)
`tions are discussed.
`
`2.2. Packing polymorphism
`
`An investigation into the structures and charge
`densities of two polymorphs of p-nitrophenol has
`been performed with the aim of deducing the differ(cid:173)
`ent modes of inter-molecular hydrogen bonding that
`lead to the formation of the two structures shown in
`Fig. la and b [37]. A detailed analysis of the charge
`density of the two forms indicates charge migration
`from
`the benzene ring region to
`the nitro and
`hydroxyl groups that accompanies the transfonnation
`of one form into the other. In addition, polarization
`of the oxygen lone-pair electrons was found to be
`substantially larger in the crystal forms than in the
`free molecule, resulting in considerably larger dipole
`moments in the solid state.
`During the study of a new crystal form (fonn I) of
`
`Fig. 1. Molecular packing diagrams of the (a) [3 polymorph of
`p-nitrophenol, (b) a polymorph of p-nitrophenol, showing 50%
`probability displacement ellipsoids ([37], reproduced with the
`permission of the American Chemical Society).
`
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`8
`
`SR. Vippagunta et al. I Advanced Drug Delivery Reviews 48 (2001) 3-26
`
`chlordiazepoxide, it was found that the heat of
`transition between the two forms (forms I and II) is
`rather modest, and kinetic factors permit the exist(cid:173)
`ence of the metastable phase [38]. Both structures
`contain four crystallographically independent mole(cid:173)
`cules linked in dimers through hydrogen bonding,
`but the dimers are packed differently to yield the two
`crystal forms. Because the dimers in the fundamental
`units are spaced differently in the two forms, it was
`proposed that the solid-state enantiotropic trans(cid:173)
`formation entailed rearrangement of the dimer units.
`A different approach has been taken during an
`evaluation of the different structures fanned by
`sulfathiazole [39]. Using a graph set approach to
`classify the known structural differences and simi(cid:173)
`larities among the various fonns, it became possible
`to identify packing motifs common to three of the
`four crystal structures. Fig. 2 shows the unit cells of
`the polymorphs I, II, III and IV, where molecules are
`paired as hydrogen-bonded dimers. At the end of the
`process, the authors were able to deduce possible
`links between the observed patterns of hydrogen
`bonding, processes of nucleation, and the crystal
`growth observed from a number of solvent systems.
`Interestingly, the analysis did not indicate a relation(cid:173)
`ship between the appearance of a particular poly(cid:173)
`morph from solution and the growth of its fastest
`
`growing surface. Rather, it appeared as if the differ(cid:173)
`ent solvents affected the process of polymorph
`formation through their effects on nucleation of the
`various forms.
`
`2.3. Conformational polymorphism
`
`The conformational polymorphism of the two
`forms of piroxicam pivalate has been studied in
`detail [40]. This compound is distinctive in that the
`high-melting form (polymorph 1) contains an un(cid:173)
`anticipated array of associated molecules bound as
`centrosymmetric dimers through hydrogen bonding,
`with the amido nitrogen atom acting as the donor and
`the pyridine nitrogen as the acceptor (Scheme 1,
`structure I). The low-melting form (polymorph 2)
`contains molecules of two distinct conformational
`states coexisting in the same crystal (Fig. 3), but
`linked through different hydrogen bonding arrange(cid:173)
`ments. This latter finding represents another unusual
`aspect of the crystallography of the substance.
`The inclusion of different solvent molecules in a
`crystal lattice can lead to the existence of different
`packing patterns, and has also been found to in(cid:173)
`fluence the molecular conforn1ation of paroxetine
`hydrochloride in two solvate forms [41]. One form
`
`N
`d_'I
`
`N02 H
`
`~~--r\
`s---{
`V
`
`C
`
`:
`
`0
`
`(a) Form I
`
`CH3
`
`II
`
`(b) Form II
`Fig. 2. r nit cells of four polymorphs (I, II, III and IV) of
`sulfathiazole showing hydrogen bonds, with the dimer structure
`clearly discernible ([39], reproduced with the permission of the
`Royal Society of Chemistry).
`
`Ill
`
`Scheme 1. Molecular structure of piroxican1 pi valate (I) [ 40],
`(II)
`5-methyl-2- [2-( nitropheny l )an1ino ]-3-thiophenecarbonitri le
`[30], 2' -acetamido-4' -[N,N-bis(2-methylcarbonylethyl)amino]-4-
`nitroazobenzene (III) [48].
`
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`SR. Vippagunta et al. I Advanced Drug Delivery Reviews 48 (2001) 3-26
`
`9
`
`hemihydrate phase. Crystals of the isopropanol sol(cid:173)
`vate decomposes in the open air at room tempera(cid:173)
`ture, because the isopropanol molecules are released
`easily through
`the channel. The hemihydrate is
`relatively stable.
`In an impressive fundamental study, the poly(cid:173)
`morphism of 5-methyl-2-[2-(nitrophenyl)amino]-3-
`thiophenecarbonitrile (Scheme l, structure II) has
`been catalogued [42,43] and discussed in detail [2].
`This compound was crystallized as six solvent-free
`polymorphs, each of which differed in the mode of
`packing and in molecular conformation. The differ(cid:173)
`ent confonners yielded sufficient perturbations on the
`respective molecular orbital so that a variety of
`crystal colors (red, orange, and yellow) were ob(cid:173)
`served. To obtain a more detailed evaluation of the
`relative stability, the authors considered a partition(cid:173)
`ing of polymorphic energy differences into lattice
`and conformational contributions, and were able to
`deduce general trends that appeared valid in the
`absence of hydrogen bonding. The act of crystalliza(cid:173)
`tion was found to feature an interplay of opposing
`forces, with perpendicular molecular conformations
`being favored in fluid solutions, while a preference
`for planar /high dipole conformers existed in most
`crystal forms, as shown in Fig. 4 [42]. The unusual
`polymorphism displayed by this system may result
`from one or more of the following factors:
`the
`preference for perpendicular conformations in solu(cid:173)
`tions, the preference for planar /high dipole confor(cid:173)
`mers in crystals, the formation of inter- and in(cid:173)
`tramolecular hydrogen bonds, and the thermody(cid:173)
`namic tendency towards low energy and high en(cid:173)
`tropy.
`
`2.4. Phase transformations in the solid state
`
`Studies of phase transfonnations in the solid state
`are important, because the sudden appearance or
`disappearance of a crystalline form can threaten
`process development, and can lead to serious phar(cid:173)
`maceutical consequences if the transformation occurs
`in the dosage forms. Hence, an understanding of the
`kinetics and mechanism of phase transformations is
`of practical importance. The rearrangement of mole(cid:173)
`cules into a new structure during phase transforma(cid:173)
`tion may or may not involve a solvent or vapor
`phase. To explain the mechanism of solid-solid
`
`Fig. 3. Conformations of the two independent molecules of
`piroxicam pi valate (I) in polymorph 2. Thermal ellipsoids are
`drawn at the 40% probability level. and H atoms are shown as
`spheres of arbitrary size ([40]. reproduced with the permission of
`the American Pharmaceutical Association).
`
`was obtained as a hemihydrate, and the other as the
`solvate of isopropanol (2-propanol). In the unit cell
`of the hemihydrate, one finds two protonated parox(cid:173)
`etine and two chloride ions together with one water
`molecule. Interestingly, the two paroxetine molecules
`are conformationally nonequivalent, and exhibit a
`number of different bond angles and torsion angles.
`In the other form, the unit cell contains one proton(cid:173)
`ated paroxetine molecule, one chloride ion, and one
`isopropanol molecule disordered along a molecular
`channel. Furthermore, the conformation of the parox -
`etine molecule in the isopropanol solvate is different
`from either molecular conformation observed in the
`
`Page 7
`
`

`

`10
`
`SR. Vippagunta et al. I Advanced Drug Delivery Reviews 48 (2001) 3-26
`
`Free
`molecules
`
`Cryatals
`
`More planar{
`
`high-dipole
`
`No intermolecular
`
`ON
`OP
`
`6
`
`4
`
`2
`
`0
`
`-2
`
`15
`.€ -,
`.:II!
`.;..
`0
`cS
`C
`UJ
`
`_..;.;.; __ ~ i . - - -~ ;Jm
`---
`
`Perpendicular YN
`low-dipole
`y
`
`Stabilized by inter-
`' - - - -Y
`molecular H bonds
`-4..._ __ _____________ __ _
`Free molecules Polymorphic crystals
`
`Fig. 4. Comparison of conformational energies and crystal ener(cid:173)
`the various polymorphs of 5-methyl-2-[2-(nitro(cid:173)
`gies of
`phenyl)arnino]-3-thiophenecarbonitrile (II). Form R (red prisms,
`m.p. 106.2°C). form Y (yellow prisms, m.p. 109.8°C), form OP
`(orange plates, m.p. 112.7°C), form ON (orange needles, m.p.
`114.8°C), form YN (yellow needles, m.p. not measurable) ([42],
`reproduced with the permission of the American Chemical Socie(cid:173)
`ty).
`
`physical transition, four steps have been proposed:
`(a) molecular loosening in the initial phase; (b)
`formation of an intermediate solid solution; (c)
`nucleation of the new solid phase and (d) growth of
`the new phase
`[2].
`In an
`interesting
`study,
`Skwierczynski [44] has proposed a two-environment
`model to describe the decomposition reaction kinet(cid:173)
`ics of a crystalline solid, aspartame. The decomposi(cid:173)
`tion reaction of aspartame is a simple unimolecular
`thermally-induced aminolysis and
`the
`reaction
`proceeds under anhydrous conditions, i.e., water is
`not a reactant [45]. This model links the chemistry of
`the solid-state reaction with the molecular mobility
`of the reactant as the reaction proceeds. The advan(cid:173)
`tage of this model is that it can be used to determine
`the shelf life of a product from kinetic data gathered
`at elevated temperatures. Apart from sol