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` Advanced Drug Delivery Reviews 48 (2001) 3—26
`
`-
`
`Advanced
`DRUG DELIVERY
`Reviews
`
`,
`5
`
`www.elsevier.com/ locate/ drugdeliv
`
`Crystalline solids
`
`Sudha R. Vippaguntaa, Harry G. Brittainb, David J.W. Granta’*
`
`“fl‘epa,rtment of Pharmaceutics, College of Pharmacy, University of Minnesota, Weaver~Densf0rd Hall, 308 Harvard Street S.E.,
`Minneapolis, MN 55455, USA
`[Center for Pharmaceutical 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
`polyinorph interconversion, desolvation of solvate, formation of hydrate and conversion of crystalline to amorphous form
`may occur during various pharmaceutical 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; Characte1'ization
`
`Contnts
`
`4
`6
`6
`7
`8
`9
`ll
`l2
`13
`15
`15
`l5
`
`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.
`7 5. Prediction of polymorphs ............
`................................................... ..
`2.6. Directing the crystallization of specific polymorphs ................................... ..
`2.7. Characterization of polymorphs using a combination of analytical techniques
`3. 1.ecent advances in the identification and characterization of hydrates and solvates .................................................................... ..
`3.1. Introduction to solvates and hydrates ............................................................................................................................... ..
`3.2. Structural aspects ........................................................................................................................................................... ..
`
`
`
`
`,
`
`*Co1‘responding author. Tel.: + l—6l2—6243-956; fax: + l-612-6250-609.
`Lv-mail address.‘ grant00l@tc.umn.edu (D.J.W. Grant).
`
`0169-409X/01/$ — see front matter © 2001 Elsevier Science B.V. All rights reserved.
`P11: S0169-409X(0l)00097—7
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`4
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`S.R. Vippagrmta at al.
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`/ Advanced Drug Delivery Reviews 48 (2001) 3-26
`
`-><a.:>—«.—~c>ocoooo<>c\I
`
`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 .................................................................................... . .
`
`
`
` . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . A . . . . . . . . . . . . . . . . . . . . . . . l . . . . . . . . . . . . . . . . . . . . . . . . ..
`
`
`
`
`
`1. Introduction
`
`Most organic and inorganic compounds of phar-
`maceutical
`relevance can exist
`in one or more
`
`crystalline forms. When applied to solids, the adjec-
`tive, crystalline, implies an ideal crystal in which the
`structural units,
`termed unit cells,
`are repeated
`regularly and indefinitely in three dimensions in
`space. The unit cell has a definite orientation and
`shape defined by the translational vectors, cz,
`la, 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, CL, b, and c, of the unit cell
`and between the individual angles, aa, [3, and 7 of the
`unit cell [1,2]. The structure of a given crystalmay
`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-
`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-
`talline polymorphs have the same chemical com-
`position but different internal crystal structures and,
`therefore, possess, different physico—chemical prop-
`erties. The different crystal structures in polymorphs
`arise when the drug substance crystallizes in differ-
`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 containing solvent mole-
`cules within the crystal structure, in either stoichio-
`
`metric or nonstoichiometric proportions, giving rise
`to unique differences in the physical and pharma-
`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
`conformation
`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 Cl'1dl‘2tCt@1‘“,,
`ize, because analytical studies indicate that they are
`unsolvated materials (or anhydrous crystal fums)
`when, in fact, they have the structure of the solvated
`crystal form from which they were derived [11].
`Because different crystalline polymorphs and S01-
`vates differ in crystal packing, and/ or molecular
`conformation as well as in lattice energy and 611'
`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 propertiefi Of
`Various solid forms have an important effect on the
`processing of drug substances into "drug productfi
`[13], while differences in solubility may have impli‘
`cations on the absorption of the active ,drug from its
`dosage form [14], by affecting the dissolution rate
`and possibly the mass transport of the molecu1‘>-5'
`These concerns have led to an increased 1*egul'1t0YY‘
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`S.R. Vippagtmta at al.
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`
`5
`
`in understanding the solid—state properties
`interest
`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
`“zip-i:ropriate” analytical procedures need to be used
`to detect polymorphs, hydrates and amorphous forms
`of the drug substance and also stresses the impor-
`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,
`fern ation 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—
`erties, with consequent changes in its dissolution and
`transport characteristics [15].
`_Various pharmaceutical processes during drug
`development significantly influence the final crys—
`talline form of the drug in the dosage form. The
`Vari sus 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
`crygtalline product. Also, processing stresses, such as
`drying, grinding, milling, wet granulation, oven
`drying and compaction, are reported to accelerate the
`phase transitions in pharmaceutical solids. The de-
`gree of polymorphic conversion will depend on the
`relative stability of the phases in question, and on the
`type and degree of niechanicalprocessing 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
`dun‘; crystals during the entire process of develop-
`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—
`viewed in detail by various researchers [l2,18,l9]. 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 a11d
`mechanisms by which crystals are formed are:
`solubility, supersaturation, rate at which supersatura—
`tion and desupersaturation occur, diffusivity,
`tem-
`perature, and the reactivity of surfaces
`towards
`nucleation. The various forces responsible for hold-
`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 Various steps of processing and develop—
`ment. These methods have been reviewed recently in
`detail by many authors
`[7,10,21—25]. The single
`most valuable piece of information about the crys—
`talline solid, including the existence of polymorphs
`and solvates, is the molecular and crystalline struc-
`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 transform Raman scattering
`(FT Raman) spectroscopy, solid—state nuclear mag-
`netic resonance (SSNMR) spectroscopy, ultraviolet
`and visible (UV—Vis) and/or fluorescence spectros-
`copy [23] may be employed for further characteriza-
`tion. Of special significance are thermal methods,
`such as differential scanning calorimetry (DSC),
`thermogravimetric analysis (TGA) and optical micro-
`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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`
`6
`
`S.R. Vippagimta 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-
`stances [26].
`.
`
`Because solid-state NMR spec_troscopy can be
`used to study crystalline solids, as well as pharma-
`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 conforma-
`tions among polymorphs [28,29] and for the de-
`termination of molecular conformations and mobility
`of drugs in mixtures and dosage forms [2]. Solid-
`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
`techniques. Recently,
`two—dimensional
`“C-solid-
`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-
`
`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-
`ment. A current emphasis is on the development of
`software to predict crystal structures of polymorphs
`from molecular s_tructures. A thorough understanding
`of the physicochcmical properties of polymorphs and
`solvates (hydrates) is of primary importance to the
`selection of a suitable crystalline form and develop-
`ment of a successful pharmaceutical product. Bray et
`al.
`[31] have shown that, by thorough characteriza-
`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-
`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-
`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.]. Types of polymorphism
`
`Based on differences in the thermodynamic firep-
`erties, polymorphs are classified as either enantio-
`tropes or monotropes, depending upon whether one
`form can transform reversibly to another or not. In
`an enantiotropic system, a reversible transition be-
`tween polyinorphs is possible at a definite transition
`temperature below the melting point. In a mono-
`tropic system, no reversible transition is robrarvedg
`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-
`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 enantit/tropic
`or monotropic,
`then the next goal
`is to define th6———~—~
`thermodynamically stable (or metastable) domain Of
`each crystalline phase of a substance as a function 0f
`temperature. The plot of the Gibbs free energy
`difference, AG, against the absolute temperatures T1
`gives the most complete and quantitative information
`on the stability relationship of polymorphs [2212 with
`the most stable polymorph having the lowest GibbS
`free energy. The AG between the polymorplw. may
`be obtained using several
`techniques operating at
`
`
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`
`7
`
`different temperatures, such as solubility [34] and
`intrinsic dissolution rate. Yu [35] has derived thermo~
`dynamic equations to calculate AG 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 AG to zero gives
`an estimate of the transition temperature, from which
`the existence of monotropy or enantiotropy is in-
`ferred. The integration of different
`types of data
`provides the AG vs. T curve over a wide temperature
`range and allows the consistency between techniques
`to be checked [22]. Another approach to establish the
`ordir 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-
`inorph 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.
`the main focus of research has
`In recent years,
`been the characterization of polymorphs arising from
`structural differences in the crystal
`lattice. It has
`been established for some time that organic mole-
`cules are capable of forming different crystal lattices
`through two different mechanisms. One of the mech~
`anlsms is termed packing polymorphism, and repre-
`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 conformational polymorphism
`and arises when a nonconformationally rigid mole
`cule can be folded into different arrangements, which
`subsequently can be packed into alternative crystal
`stactures. The distinction between packing poly-
`morphism and conformational polymorphism is
`scmewhat artificial because different packing ar~
`rangements impose different conformations on the
`molecules, however slight, and different conforma-
`tions will inevitably pack differently. The structural
`aspects associated with polymorphs have been re-
`viewed recently [2], as have the analogous features
`of solvate and hydrate systems
`[9].
`In the next
`
`the results of some more recent investiga-
`section,
`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-
`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 transformation
`of one form into the other. In addition, polarization
`of the oxygen lone—pair electrons was found to be
`substantially larger in thecrystal forms than in the
`free molecule, resulting in considerably larger dipole
`moments in the solid state.
`
`During the study of a new crystal form (form I) of p
`
`Fig. 1. Molecular packing diagrams of the (a) B polymorphi of
`p—nitrophenol,
`(b) (1 polymorph of p—nitrophenol, showing 50%
`probability displacement ellipsoids ([37], reproduced with the
`permission of the American Chemical Society).
`
`DEFs-JT(Daru) 046724
`
`Janssen Ex. 2021
`
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`|PR2015-01030
`
`(Page 7 of 26)
`
`

`
`8
`
`S.R. Vippagimta et al.
`
`/ Advanced Drug Delivery Reviews 48 (2001) 3~26
`
`the heat of
`it was found that
`chlordiazepoxide,
`transition between the two forms (forms I and II) is
`rather modest, and kinetic factors permit the exist-
`ence of the metastable phase [38]. Both structures
`contain four crystallographically independent 1nole—
`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—
`formation entailed rearrangement of the dimer units.
`A different approach has been taken during an
`evaluation of
`the different structures formed by
`sulfathiazole [39]. Using a graph set approach to
`classify the known structural differences and simi—
`larities among the Various forms, 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-
`ship between the appearance of a particular poly-
`morph from solution and the growth of its fastest
`
`growing surface. Rather, it appeared as if the difler~
`ent
`solvents affected the process of polymorph
`formation through their effects on nucleation of Ithe
`various forms.
`'
`
`2.3. Conformational polymorphism
`
`the two
`The conformational polymorphism of
`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-
`anticipated array of associated molecules bounti as
`centrosymmetric dimers through hydrogen bonding,
`with the amide 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-
`ments. This latter finding represents another unusual
`aspect of the crystallography of the substance.
`The inclusion of different solvent molecules in a
`
`_
`
`7
`
`crystal lattice can lead to the existence of different
`packing patterns, and has also been found to in-
`fluence the molecular conformation of paroxetine
`hydrochloride in two solvate forms [41]. One iorrn
`
`/ l
`\
`
`Ois/O CH
`\N’
`/
`9
`
`V
`
`N02
`3
`/N
`NH
`/J
`O Q \ i
`
`I
`
`/N[
`/C”
`['4
`N\[%>\/
`5
`
`CH3
`
`n
`
`(‘)0
`C(CH3)s
`
`'
`
`_
`
`\
`
`/
`
`~
`
`H—N
`
`/COCH3
`
`“N N(CH2CH2CO2CH3)2
`
`
` (b) Form II
`((1) Form I
`Fig. 2. Unit 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 l. Molecular structure of piroxicam pivalate (I) [40]'
`5-methyl—2—[2—(nitrophenyl)amino]—3—thiophenecarbonitrile
`(H) V
`[30],
`2’-acetamido—4’-[N,N-bis(2-methylcarbonylethyl)a1T1iI10l'4'
`nitroazobenzene (III) [48].
`
`
`
`DEFS-JT(Daru) 046725
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`
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`(Page 8 of 26)
`
`

`
`
`
`the two independent molecules of
`Fig.’ 3. Conformations of
`piroxicam pivalate (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-
`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-
`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
`frcm either molecular conformation observed in the
`
`S.R, Vipjmgunm at al.
`
`/ Advanced Drug Delivery Reviews 48 (2001) 3-26
`
`9
`
`hemihydrate phase. Crystals of the isopropanol sol-
`vate decomposes