Journal of Crystal Growth 211 (2000) 122}136
`
`Crystallization processes in pharmaceutical technology
`and drug delivery design
`
`B.Yu. Shekunov!,*, P. York!,"
`
`!Drug Delivery Group, Postgraduate Studies in Pharmaceutical Technology, School of Pharmacy, University of Bradford,
`Bradford BD7 1DP, UK
`"Bradford Particle Design Ltd., 49 Listerhills Science Park, Campus Road, Bradford BD7 1HR, UK
`
`Abstract
`
`Crystallization is a major technological process for particle formation in pharmaceutical industry and, in addition,
`plays an important role in de"ning the stability and drug release properties of the "nal dosage forms. Industrial and
`regulatory aspects of crystallization are brie#y reviewed with reference to solid-state properties of pharmaceuticals.
`Crystallization, incorporating wider de"nition to include precipitation and solid-state transitions, is considered in terms
`of preparation of materials for direct compression, formation of amorphous, solvated and polymorphic forms, chiral
`separation of drugs, production of materials for inhalation drug delivery and injections. Finally, recent developments in
`supercritical #uid particle technology is considered in relationship to the areas discussed. ( 2000 Elsevier Science B.V.
`All rights reserved.
`
`Keywords: Particle technology; Crystallization and precipitation; Pharmaceuticals; Solid drugs and excipients; Supercritical carbon
`dioxide
`
`1. Introduction
`
`Solution crystallization is widely used for manu-
`facturing bioactive drug substances and formula-
`tion excipients during "nal and intermediate stages
`of puri"cation and separation. This process de"nes
`drug chemical purity and physical properties: par-
`ticle habit and size, crystal structure and degree
`of crystal imperfection. Consequently, crystalline
`variations are responsible for a wide range of phar-
`maceutical formulation problems, such as bio-in-
`equivalence, as well as chemical and physical
`instability of the solid drugs in their "nal dosage
`
`* Corresponding author.
`
`forms. The crystallization process requires con-
`siderable time and energy resources and de"nes
`such economical issues as the e$ciency of solvent
`recycling, separation of waste (impurities) and con-
`sumption of raw materials [1]. Over 90% of all
`pharmaceutical products, such as tablets, aerosols,
`capsules, suspensions and suppositories contain
`drug in particulate, generally crystalline,
`form
`[2]. Although the in#uence of the crystallization
`process on the properties of dosage forms and
`products is well documented, particle formation
`and crystallization have often been regarded as
`‘
`a
`a
`low-tech
`area of chemical production. Ad-
`vances of chemical synthesis have achieved control
`over drug identity and purity, but control over the
`physical
`form and crystallinity remains poor.
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`
`123
`
`Chemically equivalent materials are commonly
`found to perform or behave unpredictably and im-
`pair product development or manufacture. For
`example, one-"fth of all plant handling particulate
`material fails to attain more than 20% e$ciency
`[2]. These problems rapidly become recognized on
`scienti"c and technical levels and, because pharma-
`ceutics is a part of health care system, have a pro-
`nounced commercial and social importance. The
`purpose of this mini review is to indicate the variety
`of research directions and industrial crystallization
`problems associated with engineering of solid-state
`properties of drug substances, stability of drug
`products and consistency of crystallization process.
`Crystal growth mechanisms, with reference to
`pharmaceutical systems, have been discussed in re-
`views [3,4].
`
`2. Regulatory aspect
`
`Table 1 summarizes the most important solid-
`state and drug delivery characteristics a!ected by
`crystallization. Pre-formulation and formulation
`drug development stages are associated with manu-
`facturing control, characterization and optimiza-
`tion of
`the
`solids. Pre-formulation concerns
`‘
`rational, science-based requirements for drug sub-
`a
`stances
`and excipients
`[5] which include
`physicochemical stability, consistency and solid
`state-properties (Table 1). This stage begins im-
`mediately after the synthesis and initial toxicity
`screening of a new drug. Formulation research is
`more related to the drug products (e.g. "nal com-
`position of drug and functional excipient substan-
`ces in the dosage form) and focused on stability and
`
`Table 1
`Solid-state properties de"ned by crystallization process and their relationship with speci"c characteristics of drug substances and drug
`products
`
`Solid-state properties
`
`E!ect on drug substance and/or drug product
`
`Structural
`Crystallinity (existence of amorphous and
`semi-crystalline forms)
`
`Polymorphs
`Solvates (hydrates)
`Salts
`Crystal defects
`
`Dimensional
`Particle size distribution
`
`Particle morphology
`Particle surface structure
`
`Physical and chemical stability
`
`%RH pro"le (hygroscopicity)
`Solubility pro"le and dissolution rate
`All aspects of processing
`
`Processing behaviour: bulk density, agglomeration,
`#ow/rheology, compaction
`Particle permeability (i.e. particle adsorption)
`Bioavailability (drug absorption)
`Consistency and uniformity of the dosage form
`
`Chemical
`Organic and inorganic impurities, residual solvent
`and decomposition products
`
`Toxicity
`
`Chiral forms and chiral separation
`Sterility (microbial limits)
`
`Chemical, physical and enantiomeric stability
`
`Mechanical
`Brittle/ductile transitions, fracture stress, indentation hardness,
`stress/strain relaxation, yield pressure, Young’s modulus
`
`Milling and tableting behaviour
`
`Electrical
`Electrostatic charge distribution
`
`Agglomeration and #ow properties
`
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`124
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`
`drug release properties to be carried out through
`Phases I}III (i.e. di!erent degrees of clinical evalu-
`ation) [6]. This development work, combined with
`results of clinical tests, culminates in a New drug
`application (NDA) submitted to a government
`regulatory body such as US Food and Drug Ad-
`ministration (FDA) [6,7]. The newness of a drug
`product may arise not only from a new bioactive
`chemical form, but also from a di!erent solid-state
`form (e.g. polymorphic, amorphous or chiral), com-
`bination with other solids (excipients, carriers,
`coating), di!erent delivery method or even a di!er-
`ent proportion of the drug in this combination.
`New drugs and any associated manufacturing and
`formulation aspects,
`including
`crystallization
`methods for a particular solid-state form, are typi-
`cally protected by patents. These patents guarantee
`the future "nancial security of the company-spon-
`sor and become very sensitive issues as,
`for
`example, occurred during the case concerning the
`di!erent polymorphic forms of the popular ulcer
`drug Zantac [8]. Therefore, screening of all di!er-
`ent solid state forms and the development of corre-
`sponding crystallization techniques should ideally
`be carried out as early as possible.
`The drug substance section of an NDA must
`contain speci"cations related to purity, solubility,
`crystal properties, morphology, particle size and
`surface area. Both drug substance and drug prod-
`uct sections of NDA require detailed investigation
`into the in#uence of structure on stability, in order
`to avoid negative recrystallization phenomena, and
`also into the relationship between structure and
`drug release rate. An NDA also requires complete
`proof of structure on all crystalline drug candi-
`dates, preferably from single-crystal structural data.
`Often, a growth technique will have to be de-
`veloped to produce single crystals, which may
`prove a challenging task for large molecular sub-
`stances or substances with low solubility. If produc-
`tion of single crystals is di$cult, X-ray powder
`di!raction will have to be used to assure crystal and
`solid-state phase identity. Additional requirements
`are imposed on chiral drugs, which may possess
`di!erent toxicological and pharmacological e!ects
`depending on their enantiomeric form. These re-
`quirements consist of identi"cation of enantiomeric
`composition and (optical) purity, resolution (if the
`
`drug is used in a single enantiomeric form) and the
`con"rmation of enantiomeric stability in formula-
`tion.
`The potential impact of changing crystal proper-
`ties during late-stage drug development, in terms of
`both cost and product delay has led to speci"c
`guidelines on the control of physicochemical prop-
`erties according to the NDA requirements and fur-
`ther
`inspections. These guidelines have been
`developed as a result of collaboration between
`regulators, industry and academia [9}11] and pre-
`sented in the form of algorithms. The four types of
`solid-state phases identi"ed according the FDA
`charts are polymorphs, solvates (e.g. hydrates),
`desolvated solvates (pseudopolymorphs) and amor-
`phous compounds. A combined #ow chart is pre-
`sented in Fig. 1. The crystallization process must be
`controllable with respect to the solid form produc-
`ed. Once the properties of these solid forms are
`identi"ed using appropriate analytical techniques
`and these properties are di!erent, control and spe-
`ci"cation procedures should be de"ned to ensure
`consistency and stability of the product. Extended
`international guidelines have been formulated as
`collaboration has grown between di!erent regula-
`tory organizations through the International Con-
`ference on Harmonization (ICH). The standards of
`potency, purity and other physicochemical proper-
`ties and the standard analytical methods for most
`commonly used drugs and drug products are
`given in pharmaceutical compendia such as the
`United State Pharmacopoeia (USP) and British
`Pharmacopoeia (BP). The above
`regulations,
`combined with internationally accepted manufac-
`turing rules covering current good manufacturing
`practices (cGMP) [12] make the crystallization
`process among the most important industrial and
`regulatory recognized issues in pharmaceutical
`development.
`
`3. Crystallization process and design of solid dosage
`forms
`
`3.1. Crystal properties and direct compression
`
`Tablets are still by far the most widely used,
`simple and convenient solid dosage form. A number
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`
`125
`
`Fig. 1. Algorithm for identi"cation of solid forms (following the FDA guidelines).
`
`of di!erent solids, mostly crystalline excipients such
`as bulking and binding agents, lubricants, plas-
`ticizers as well as other ingredients may be included
`in the formulation. The success of any direct-tablet-
`ting procedure and resulting mechanical properties
`of tablets are strongly a!ected by the quality of the
`crystals used in this process. The manufacture of
`tablets by directs compression o!ers advantages
`over conventional wet granulation procedures in
`reducing the number of manufacturing steps (typi-
`cally from six down to two) and the elimination of
`any undesirable exposure to water or solvent and
`elevated temperature [13,14]. Direct compression
`requires good powder #ow properties, uniform
`mixing between the drug and excipients and the
`ability to consolidate and bond under pressure and
`maintain interparticle bonds on ejection from the
`tablet machine. Relevant processing and mechan-
`ical parameters are shown in Table 1. The carrier
`capacity of excipients for drug in tablets is typically
`limited to 25%. However, since about two-thirds of
`the currently marketed tablets contain less than
`100 mg of drug [13], the mechanical properties and
`compressibility of the excipient will be the control-
`ling factor. Because of increased potency of the
`modern drugs, such low dose tablets will dominate
`
`in the future. In the remaining one-third of tablet
`formulations, the mechanical characteristics of the
`drug substance will be important.
`Considerable research e!orts have been made to
`optimize crystals for compression. For example,
`particles with elongated morphology and enhanced
`compression behaviour were obtained by changing
`the solvent polarity during crystallization of nit-
`rofurantoin and ibuprofen [15,16] or pH and
`supersaturation of octotiamine [17]. The tableting
`behaviour of acetaminophen, known by its poor
`compression ability, can be improved by crystalli-
`zing particles of platy morphology with lower hard-
`ness and greater plasticity then those of prismatic
`form [18], changing thermodynamic crystal prop-
`erties [19,20], or crystallizing the recently reported
`orthorhombic polymorph [21]. Studies into modi-
`"cation of crystal structure and crystal shape by
`speci"c additives has shown that an incorporated
`additive increases the crystal free energy and en-
`tropy, reduces the enthalpy of fusion and increases
`the dissolution rate. For example, low levels of
`n-alkanoic acid in adipic acid crystals lead to an
`increase in lattice strain, reducing the energy
`required for plastic deformation which resulted
`in improved tabletting performance
`[22,23].
`
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`126
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`B.Yu. Shekunov, P. York / Journal of Crystal Growth 211 (2000) 122}136
`
`Crystallization of acetaminophen has been studied
`with the structurally related impurity, p-aceto-
`xyacetanilide (PAA) [24,25] and work showed the
`importance of additives in modifying the crystal
`habit and the intrinsic dissolution rate. Lactose,
`perhaps the widest used excipient, exhibits mechan-
`ical properties of which are directly related to the
`crystallization process [26,27]. Relatively slow
`crystallization produces single crystals of a-lactose
`monohydrate, whilst rapid crystallization results in
`aggregates of anhydrous a- and b-lactose micro-
`crystals. On compression, the aggregates undergo
`intensive fragmentation, leading to higher tablet
`crushing strength as compared with a-lactose tab-
`lets. Amorphous lactose can be obtained using a
`spray-drying technique with its superior bonding
`ability attributed to the plastic #ow on compression.
`It should be emphasized, however, that even mi-
`nor changes
`in crystallization conditions,
`for
`example, supersaturation, temperature, impurity or
`cooling rate can produce signi"cant changes in the
`crystal and powder properties, notably particle size,
`shape, purity and defect structure [22}25,28] fol-
`lowed by less pronounced but signi"cant variations
`in thermodynamic and mechanical properties.
`These e!ects have been recognized as the major
`batch-to-batch and source variation problems
`leading to inconsistency of the "nal tablet proper-
`ties. Clearly, the radical solution of these problems
`is to design more advanced crystallization methods
`in order to achieve full control of required charac-
`teristics. Spherical agglomeration [29,30] and
`spherulitic crystallization [31] techniques allow
`production of particles (polycrystalline aggregates
`of characteristic size 100}200 lm) with improved
`#ow characteristics and compressibility. Modi"ca-
`tion of both the crystal structure and crystallization
`process can be achieved by the formation of series
`of salts based on the same parent active drug
`[32,33]. About 95% of all pharmaceutical substan-
`ces are ionizable and such salts as hydrochloride
`(anion), potassium or sodium (cation) are com-
`monly used in pharmaceutical formulation espe-
`cially when intrinsic solubility, crystallinity or
`mechanical properties of the parent drug are inad-
`equate.
`The complexity and variety of crystallization
`problems attributed to pharmaceutical processes
`
`involving mechanical treatment such as milling and
`compression warrant studies of more fundamental
`aspects of particle formation and crystal growth in
`this area. For example, surface kinetics and crystal
`defects, surface energetics, in#uence of additives
`and solvent}surface bonding have been investi-
`gated using laser interferometric technique for acet-
`aminophen crystals [18,25,34]. Theoretical models
`have been developed to obtain ad hoc the crystal
`morphology [35,36], polymorphic form [37] and
`mechanical properties [38] of organic molecular
`solids. However, further work is needed to study
`the relationships between crystallization conditions
`and the formation of defects, to predict the crystal
`properties on the basis of molecular and crystallo-
`graphic structure and to understand in detail the
`mechanism of nucleation and agglomeration pro-
`cesses.
`
`3.2. Amorphous and partly crystalline substances
`
`Di!erent crystallization processes, spray drying
`and lyophilization, and post-crystallization treat-
`ment, such as heating, milling, granulation, com-
`paction and polymer coating,
`leads to various
`degree of disorder in the form of crystal defects and
`amorphous regions [13,39]. Production of highly
`disordered materials is very compound-speci"c.
`Relatively large molecules and molecules with
`a certain degree of rotational #exibility tend to
`form a disordered state even at mild crystallization
`conditions. The quanti"cation of crystallinity is
`critically important in considering both the con-
`trolled modi"cation of pharmaceutical powders
`and the resulting solid-state stability. According to
`the USP, crystallinity is determined by the fraction
`of completely crystalline material in the mixture
`(two-state model). More physically realistic, the
`one-state model incorporates the concept of a grad-
`ual decrease of crystallinity with no sharp distinc-
`tion between the completely crystalline (100%
`crystallinity) and amorphous (0% crystallinity)
`states [40]. The degree of crystallinity is frequently
`characterized using X-ray powder di!raction
`(XRD), di!erential calorimetry (DSC) or water
`sorption (%RH) techniques (Fig. 1). An alternative
`approach involves the measurement of changes in
`entropy, *S, between processed and reference
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`
`127
`
`samples either from enthalpy of fusion or enthalpy
`of solution [41}43], which is directly related to the
`solid-state disorder created by the crystallization
`process or other processing. For example, small
`quantities of Pluronic surfactant caused large dis-
`ruption of phenylbutazone crystals [13]. Di!erent
`crystallization methods were responsible for vari-
`ation of *S and the crystallinity of cephalothin
`sodium by a factor of 10 [13,44], whilst a positive
`linear relationship was observed between *S and
`intrinsic dissolution rate of calcium fenoprofen
`[45]. Concentration of the crystal defects can also
`be assessed using the mosaic spread technique in
`which distortions of the Laue X-ray re#ections are
`monitored for a individual crystal particles as, for
`example, acetaminophen particles doped with PAA
`[25]. Most of this quantitative work is focused on
`the description of the disordered state. The under-
`standing of amorphous phase formation and its
`mechanism related to the molecular and crystal
`structure, still represent an important and major
`scienti"c challenge.
`Partially crystalline and amorphous drugs and
`excipients are much more soluble than highly cry-
`stalline substances and can be used to promote
`therapeutic activity. The classic example of such
`application is the formulation of insulin, described
`in Pharmacopoeias, consisting of various propor-
`tions of amorphous, crystalline and complexed
`forms of insulin to achieve short, intermediate and
`long acting. However,
`formulations containing
`amorphous forms are less stable than their crystal-
`line counterparts and are generally considered at
`signi"cant risk to crystallize at a later stage during
`product shelf life [9]. Such materials are often re-
`active and unstable to mechanical and thermal
`stresses [46] and very sensitive to water sorption
`[47]. This instability is the major factor precluding
`more widespread use of amorphous solids. Thus,
`one of the basic questions of pharmaceutical for-
`mulation is to de"ne what conditions (e.g. temper-
`ature, humidity, composition) make the solid form
`unstable. The
`important
`factor
`is
`the glass
`transition temperature, „
`’, above which the mo-
`lecular mobility (translational di!usion coe$cient)
`and the rate of solid-state reactions increase by
`several orders of magnitude. Above „
`’ the likeli-
`hood of crystallization and chemical degradation
`
`greatly increases. In addition, amorphous solids
`tend to associate water vapour forming an amorph-
`ous solution which further decreases „
`’, accelerates
`crystallization and can initiate chemical degrada-
`tion (e.g. hydrolysis, oxidation or deamidation) in
`its own right [47]. Below „
`’, solid-state crystalliza-
`tion is still important and failure to recognize this
`e!ect over the relatively long life-time of a typical
`pharmaceutical product may lead to signi"cant
`stability problems [46]. In general, understanding
`of crystallization kinetics of the amorphous state,
`particularly at di!erent concentrations of water,
`and in combination with required excipients, would
`provide considerable advantage and direction in
`formulating such drugs.
`
`3.3. Polymorphs and solvates
`
`Gross structural modi"cation such as polymor-
`phism and solvate formation is notably common
`for certain groups of drugs e.g., barbiturates, sul-
`fonamides and steroids. In fact, it is rare when
`a medicinally active substance exhibits only a single
`crystalline structure. Polymorphic forms can have
`remarkably di!erent physical properties including
`solubility and melting point resulting in di!erent
`stability and bioavailability of drug products [48].
`If a mixture of polymorphs occurs in a pharmaceut-
`ical formulation, quantitative control of crystalliza-
`tion is needed to ensure a "xed proportion of forms
`(see Fig. 1). In addition, solid-state recrystallization
`phenomena, which may have conversion times of
`between seconds and years, will have to be sup-
`pressed to maintain integrity during product shelf-
`life. Thus the simplest solution would be to select
`the single, most stable form, provided that there are
`no special requirements on solubility or other phys-
`ical properties (see Table 1). It should be recog-
`nized, however, that processing techniques such as
`milling, drying and compression can also introduce
`polymorphic modi"cations and transformation.
`Investigation into the number of possible poly-
`morphs of a compound typically starts with crystal-
`lization of a drug substance from a number of
`solvents, which includes the solvents frequently
`used in the "nal crystallization steps, formulation
`and processing [9] and, in addition, may also in-
`clude water and other solvents depending on the
`
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`128
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`B.Yu. Shekunov, P. York / Journal of Crystal Growth 211 (2000) 122}136
`
`drugs solubility. The e!ect of a solvent or solvent
`mixture on the formation of stable and unstable
`polymorphs is well recognized. For example, two
`polymorphs of drug sulfathiazole (II and III) can be
`crystallized in water, two other polymorphic forms
`I and IV are obtained from acetone, whilst n-pro-
`panol gives only form I [37]. This selectivity of
`solvent systems was explained by kinetic, rather
`than thermodynamic mechanism because the solu-
`bility of sulphathiazole polymorphs follow the
`same rank order in di!erent solvents [37]. The
`proposed mechanism involves selective adsorption
`on crystal faces followed by inhibition of nucleation
`and growth of particular polymorphic forms.
`Clearly, the e!ect of temperature has both thermo-
`dynamic and kinetic implications, particularly for
`enantiotropic polymorphs which change solubility
`order near the transition temperature. The e!ect of
`supersaturation is largely kinetic, unless it is also
`followed by temperature change, for example by
`cooling saturated solutions. This e!ect has been
`described by the well-known empirical Ostwald’s
`law of stages, according to which the most soluble
`and the least stable form crystallizes "rst. This
`phenomenon can be theoretically explained by
`a surface crystallization mechanism. For example,
`the least stable form has the highest volume free
`energy and the lowest speci"c step free energy and,
`correspondingly, the highest average step velocity
`and crystal growth rate [34,36]. In addition, the
`radius of critical nuclei should be smaller and the
`nucleation rate higher for the least stable form. As
`a result, the crystallization of the least stable form
`should dominate at high supersaturations. This ef-
`fect is also dependent on the solvent}solute interac-
`tions and requires further detailed investigation
`using both surface measurements and computer
`modeling. Understanding of the kinetic mecha-
`nisms of polymorphism will answer many of the
`technological problems experienced with drug de-
`livery systems.
`The above general considerations can also be
`applied for solvated, in most cases hydrated, forms
`of pharmaceutical substances [49]. Solvates re-
`present either "nal or intermediate products of
`crystallization [9,11]. A widely used method of
`controlling the crystallization of hydrates is chang-
`ing the concentration of water in both miscible and
`
`immiscible organic solvents. The presence of sol-
`vent molecules in a crystal lattice gives another
`opportunity for modi"cation of crystal structure
`which a!ects the thermodynamic activity, free en-
`ergy and correspondent physicochemical charac-
`teristics as illustrated in Table 1. Many dosage
`forms such as creams, gels, suspensions are for-
`mulated with water and, therefore, the possible
`formation of di!erent hydrates requires careful
`consideration. Hydrates may be stable within
`a wide range of relative humidity (RH) or otherwise
`transform into higher (or lower) solvates or anhyd-
`‘
`a
`rous
`desolvated
`forms [50]. As a result, partly
`solvated forms with di!erent degrees of crystal-
`linity, stable or unstable crystal structures can be
`obtained.
`
`3.4. Chiral drugs
`
`More than half of the marketed drugs are chiral
`and exist at least in two symmetrical enantiomer
`forms [51]. Drug substances are often administered
`as racemates (racemic mixture) [52] even if the two
`enantiomers exhibit di!erent pharmacological ac-
`tivity pro"les. A well known and tragic example is
`that of racemic drug thalidomide: the thalidomide
`disaster of the 1960’s a!ecting unborn babies was
`caused by the S-enantiomer being highly tera-
`togenic, whilst the R-enantiomer has a sedative
`e!ect. Very often di$culties in separation of chiral
`forms for synthetic drugs make pharmaceutical de-
`velopment of a single enantiomer economically un-
`feasible. Crystallization is the simplest and most
`e$cient method for chiral separation (resolution) of
`enantiomers. In most cases and with the exception
`of solid solutions, crystallization yields either
`a mixture of enantiomorphous crystals (a racemic
`conglomerate) or racemic crystalline material (a
`racemic compound). Racemic conglomerates pro-
`vide the means for direct chiral separation, how-
`ever, only about 10% of all drugs can be resolved in
`this way because the racemic compounds are usu-
`ally more thermodynamically stable than crystals
`of their pure counterparts [52,53].
`Direct resolution of enantiomers by crystalliza-
`tion is termed preferential (or entrainment) crystal-
`lization [54,55] and based on the principle
`whereby a supersaturated solution of both racemic
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`
`129
`
`compounds is seeded with crystals of one of the
`enantiomeric forms, the pure crystals allowed to
`grow in a controlled way without spontaneous nu-
`cleation of undesired enantiomer. This process is
`then repeated in a cyclic manner yielding relatively
`pure (ca. ’90% optical purity) enantiomers. Ma-
`terials which cannot form conglomerates may be
`separated via diastereomer crystallization. This
`method generally involves reaction of the racemate
`and an optically pure acid or base to form a mix-
`ture of diastereomeric salts, which are separated by
`crystallization. Another possibility of separating
`enantiomers involves using optically active solvents
`which create asymmetrical phase behaviours of
`S- and R-compounds. The formation of racemic
`conglomerates is controlled by the kinetics of crys-
`tallization processes. Since these kinetics have not
`been su$ciently studied, the resolution of chiral
`drugs still largely relies on methods of trial and
`error. Other research areas involve crystallization
`of chiral salts and crystal growth in a chiral envi-
`ronment, e.g. in the presence of chiral solvents or
`additives.
`The most important crystallization and pharma-
`ceutical problem associated with chiral drugs is
`related to the purity of the forms obtained. The
`undesirable stereoisomers and, "rst of all, the enan-
`tiomer of opposite enantiomer are present in the
`crystallization medium and incorporated into the
`crystal lattice. The similarity of their molecular
`structure ensures that these impurities are very
`di$cult to remove completely. The formation of
`terminal solid solutions is common [52]. A chiral
`impurity incorporated into crystals gives rise to
`variation of solid-state properties. This problem
`has been investigated for a number of chiral drugs
`such as diastereomeric salts of ephedrine and
`pseudoephedrine bases [56}59]. The in#uence of
`chiral impurity may explain variable dissolution
`rate of some pharmaceutical solids as a function of
`this impurity concentration. Uncontrolled impurity
`content may give rise to unpredictable and erratic
`performance leading to batch-to-batch variations.
`A metastable racemic compound or conglomerate
`in the dosage form will be likely to convert into
`a more stable form and cause signi"cant formula-
`tion problems. The kinetics of this recrystallization
`process has yet to be de"ned.
`
`3.5. Drug-carrier systems
`
`The concept of drug-carrier systems is associated
`with sustained (e.g. prolonged time of action) and
`controlled (e.g. responsive or programmed type of
`action) drug release [60]. In both cases a carrier,
`which is typically a natural or synthetic polymer,
`acts as a barrier to drug release in order to improve
`the therapeutic e!ect or to reduce toxicity. At the
`same time, the polymer protects the drug substan-
`ces from chemical and biological degradation. The
`drug particles are incorporated or encapsulated in
`the polymer forming a dispersion of crystalline ma-
`terial or a solid solution in the form of micro-
`spheres
`and microcapsules,
`formulated
`as
`injectable, aerosol, transdermal and implantable
`systems. Nanoparticles (both spheres and capsules)
`can be designed for targeted delivery by which the
`particles accumulate in speci"c organs and/or tis-
`sues [62,63]. There are also di!erent type of mono-
`lithic devices consisting of a polymer matrix, with
`distributed drug particles, prepared as implants,
`tablets, gels and other forms.
`Particle formation techniques for drug-carrier
`systems depends on the molecular structure and
`solubility for each speci"c drug and carrier com-
`pound [60}63]. This can involve polymerization
`methods, although the product may contain toxic
`monomers and therefore precipitation methods of
`preformed polymers have been preferred. One of
`the most important precipitation method is the
`emulsion technique which involves emulsi"cation
`of drug solution (water) in polymer solution (oil)
`and evaporation of this w/o emulsion leading to the
`formation of micro- or nanospheres. The prepara-
`tion of capsules, with speci"c solubility and par-
`titioning of drugs, may require oil in oil (o/o) or
`multiphase (i.e. w/o/o, w/o/o/o) emulsions [60].
`Other methods include coacervation (phase separ-
`ation in a ternary polymer/solvent/solvent system),
`antisolvent addition, desolvation, salting-out pre-
`cipitation [64], spray-drying [65] and supercritical
`#uid processing (see Section 4).
`The relevance of crystallization and precipitation
`processes in the preparation of drug-carrier systems
`arises from the following facts. The drug particles
`are nucleated and grow within the polymer matrix,
`which may itself form a semi-crystalline material
`
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`
`with distinctive long- and short-range ordering.
`Precipitation mechanism of both polymer and drug
`in solution de"nes the size and surface properties of
`drug-carrier particles and, the crystalline or or-
`dered structure of both the drug and carrier strong-
`ly in#uences the drug release rate and stability of
`such co-formulations. For example, the investiga-
`tion into drug loading and release of water-soluble
`mitomycin [60] from PLGA microspheres in-
`dicated that the release rate was determined by size
`and fractal structure of crystals in the matrix. For
`monolithic devices, the kinetics, duration and rate
`of drug release can be optimized by manipulation
`