principios generales del polimorfismo en fármacos sólidos: una perspectiva supramolecular

PRINCIPIOS GENERALES DEL POLIMORFISMO EN FARMACOS SOLIDOS:

UNA PERSPECTIVA SUPRAMOLECULAR

Alfonso Enrique Ramírez SanabriaGrupo de Catálisis

Departamento de QuímicaUniversidad del Cauca

http://alfonsoeramirezs.wordpress.com

ICESI-Cali, Facultad de Ciencias Naturales, agosto 22/2011

1



www.iyc2011.org3

http://www.iyc2011.org

http://www.iyc2011.org

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L´apéro

L. Yu, Accounts of Chemical Research, September 2010. Polymorphism in Molecular Solids: An Extraordinary System of Red, Orange, and Yellow (ROY) Crystals. ... ROY as a reagent to prepare the schizophrenia drug ...

Polymorphism in Molecular Solids: AnExtraordinary System of Red, Orange, and

Yellow CrystalsLIAN YU*

School of Pharmacy and Department of Chemistry, University ofWisconsinsMadison, 777 Highland Avenue, Madison, Wisconsin 53705

RECEIVED ON MARCH 4, 2010

C O N S P E C T U S

Diamond and graphite are polymorphs of each other: they have the same composition but different structures and prop-erties. Many other substances exhibit polymorphism: inorganic and organic, natural and manmade. Polymorphs are

encountered in studies of crystallization, phase transition, materials synthesis, and biomineralization and in the manufac-ture of specialty chemicals. Polymorphs can provide valuable insights into crystal packing and structure-property relation-ships. 5-Methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile, known as ROY for its red, orange, and yellow crystals, hasseven polymorphs with solved structures, the largest number in the Cambridge Structural Database.

First synthesized by medicinal chemists, ROY has attracted attention from solid-state chemists because it demonstrates theremarkable diversity possible in organic solids. Many structures of ROY polymorphs and their thermodynamic properties are known,making ROY an important model system for testing computational models. Though not the most polymorphic substance on record,ROY is extraordinary in that many of its polymorphs can crystallize simultaneously from the same liquid and are kinetically sta-ble under the same conditions. Studies of ROY polymorphs have revealed a new crystallization mechanism that invalidates thecommon view that nucleation defines the polymorph of crystallization. A slow-nucleating polymorph can still dominate the prod-uct if it grows rapidly and nucleates on another polymorph. Studies of ROY have also helped understand a new, surprisingly fastmode of crystal growth in organic liquids cooled to the glass transition temperature. This growth mode exists only for those pol-ymorphs that have more isotropic, and perhaps more liquid-like, packing.

The rich polymorphism of ROY results from a combination of favorable thermodynamics and kinetics. Not only must therebe many polymorphs of comparable energies or free energies, many polymorphs must be kinetically stable and crystallizeat comparable rates to be observed. This system demonstrates the unique insights that polymorphism provides into solid-state structures and properties, as well as the inadequacy of our current understanding of the phenomenon. Despite manystudies of ROY, it is still impossible to predict the next molecule that is equally or more polymorphic. ROY is a lucky giftfrom medicinal chemists.

IntroductionDiamond and graphite have the same composi-

tion but different structures and properties. This

phenomenon, polymorphism, is known for many

substances, inorganic and organic, natural and

manmade. It is encountered in studies of crystal-

lization, phase transition, materials synthesis, and

biomineralization; it is important in the manufac-

Vol. 43, No. 9 September 2010 1257-1266 ACCOUNTS OF CHEMICAL RESEARCH 1257Published on the Web 06/18/2010 www.pubs.acs.org/acr10.1021/ar100040r © 2010 American Chemical Society

12

Reconocimiento MolecularEnsamble Supramolecular

Reconocimiento MolecularEnsamble Supramolecular

El ejemplo clásico

13

“Química, más allá de las moléculas”. J-M. Lehn (1987)

14

INTRODUCCION

ReconocimientoMolecular

EnsambleSupramolecular

API

15

Polimorfismo en CristalesMateriales con igualcomposición química

pero diferenteCONFORMACION MOLECULAR

ESTRUCTURA DE RED

Existencia de masde un tipo de

SUPERESTRUCTURA DE RED

para un mismo

BLOQUE MOLECULAR

ISOMERISMO SUPRAMOLECULAR

that reflect (1) molecular mobility, such as enthalpyrelaxation, viscosity, and solid-state NMR relaxationtimes and (2) intermolecular interactions such asinfrared and Raman spectroscopies.

5.2. Crystalline

Structurally, crystalline polymorphs are character-ized by varying degrees of changes in conformationand packing arrangement of molecules in the solidstate. Often the key intermolecular interactions, bothweak and strong, are preserved among forms, al-though it is difficult to predict when this will be thecase for a given compound. For cases where obviouschanges in conformation are observed, the designator‘‘conformational polymorph’’ [1,2,29,97–99] is gen-erally used. Differences in the packing of moleculeswith similar conformations have been termed by someinvestigators as ‘‘packing polymorphism’’ [1,29]. It isgenerally recognized that these designations, however,are artificial because virtually all polymorphs exhibitsmall differences in conformation among their mod-ifications. However, it is important to note that poly-morphs, which exhibit large differences in structure,do not necessarily have large differences in stabilityand vice versa.

5.2.1. NabumetoneNabumetone (Relafenk), Fig. 7, is an anti-inflam-

matory, analgesic, and antipyretic therapeutic usuallyprescribed to patients with arthritis. This pharmaceu-tical crystallizes in two polymorphic forms. Thecommercial material (form I) is monoclinic with twounique molecules in the unit cell [48,51,100]. Asecond polymorph forms upon evaporation from smallvolumes of ethanol [48] or crystallization in capillar-ies (Section 7.2.2) [51]. This polymorph is alsomonoclinic, but possess only one asymmetric mole-cule in the unit cell (form II) [48,51]. Similar molec-ular conformations are adopted in both forms.However, the molecules in each structure adopt strik-

ingly different arrangements in the lattice. Form Iassembles in a head-to-tail manner whereas form IIpacks in a tail-to-tail head-to-head fashion, Fig. 8. Inform I weak intermolecular interactions, especiallyCUH: : :O close contacts, dominate the structure.By contrast, form II packs in a herringbone arrange-ment with several CUH: : : k interactions.

5.2.2. CarbamazepineCarbamazepine, Fig. 9, a pharmaceutical used in

the treatment of epilepsy and trigeminal neuralgia, is atetramorphic system possessing nearly identical mo-lecular conformation and strong hydrogen bondingamong its polymorphs. Investigations into the poly-morphism of this drug began in the late 1960s andproduced three forms; two of these were structurally

Fig. 7. Structure of nabumetone. Fig. 9. Structure of carbamazepine.

Fig. 8. Packing diagram of nabumetone polymorphs (top: form I,

bottom: form II).

B. Rodrı́guez-Spong et al. / Advanced Drug Delivery Reviews 56 (2004) 241–274254


5.2. Crystalline









bottom: form II).


Namebutona

16

Pseudo-PolimorfismoFormas cristalinascon moléculas de

solvente como parteintegral de laESTRUCTURA

Solvente comocomponente del

SISTEMA

CO-CRISTAL

in these networks depends on hydrogen bondingbetween OUH: : : O moieties and has been describedfor three solvates of niclosamide: a dihydrate, atetrahydrofuran (THF) solvate and a tetraethyleneglycol (TEG) solvate. The relative strength of hydro-gen bond donor and acceptor groups was correlated tostructural architecture and thermal behavior, indicat-ing desolvation pathways. Caira et al. [130] showedthat in the niclosamide hydrate, water moleculesoccupy a channel and hydrogen bond with surround-ing drug molecules (Fig. 13a). This arrangement falls

into the aforementioned class II structures. Thestrength of this assembly is confirmed by high dehy-dration onset temperatures (173F 5 and 201F 5 jC),and indicates that water and niclosamide are tightlybound. In contrast, the THF solvate undergoes rapiddesolvation from molecular assemblies at 30 jC,which is 36 jC lower than the boiling point of THF.The instability of this system was explained by weakforces forming a continuous channel within the crystalstructure, which facilitates migration of the solventout of the lattice (Fig. 13b). The TEG solvate forms

Fig. 13. Crystal structures and heterosynthons of niclosamide (a) monohydrate, (b) THF solvate, and (c) TEG solvate. Solvent molecules are

represented as cap-stick models for clarity in the molecular packing diagrams. Adapted with permission from reference [13].

B. Rodrı́guez-Spong et al. / Advanced Drug Delivery Reviews 56 (2004) 241–274 259

Niclosamida

17

Auto-Ensamblaje Molecular

• Comportamiento mecánico

• Estabilidad Química y Física

• Solubilidad

• Tasa de disolución

• Biodisponibilidad

API´s OralLipofílico

AumentarDisolución y

Permeabilidaden la Pared Intestinal

Desarrollar Nuevas Formasen su Estado Sólido

Implicaciones del Polimorfismo

18

Nuevas Formas en el ES

• Cambios en el Arreglo Supramolecular de la Red

• Cambios en Componentes Moleculares de la Red

Estado Cristalino Estado Amorfo

Co-Cristales Solventes Sales

Materiales con estados de diferente Energía Libre

Estabilidad y “Liberación”

19

Transformaciones en la Fase Sólida

Reconocimiento MolecularFenómenos controlados no-covalentementeEnsamblajes enlazados por HidrógenoRedes moleculares

CinéticosSupersaturaciónMobilidad molecularNucleación y crecimiento del cristal

TermodinámicosEnergía libre de GibbsEntalpíaEntropíaSolubilidad

Mecánicas

TérmicasQuímicasSolventesAditivosImpurezasHumedad Relativa

20


5.2. Crystalline









bottom: form II).



5.2. Crystalline









bottom: form II).


TERMODINAMICA

• Cual es su estabilidad termodinámica

relativa?

• Cuales son las condiciones y la dirección

necesarias para una transformación?


5.2. Crystalline









bottom: form II).



5.2. Crystalline









bottom: form II).


Cinética

• Cuanto tiempo tomará para que una

transformación alcance el equilibrio?

•


5.2. Crystalline









bottom: form II).



5.2. Crystalline









bottom: form II).


ka

kb

Elementos estructurales delEnsamblaje Molecular

Cristalización

Cinética



•


5.2. Crystalline









bottom: form II).



5.2. Crystalline









bottom: form II).


ka

kb


Cristalización

TERMODINAMICA

• Refleja la diferencia de energía

estructural o de red entre las formas

• Refleja el grado de desorden y

las vibraciones de la red

summary of the methods is presented in the followingsections.

2.1. Free energy diagrams and solid-state stability

The relative thermodynamic stability of solids andthe driving force for a transformation at constanttemperature and pressure is determined by the differ-ence in Gibbs free energy and is given by:

DG ! DH " TDS #1$

The enthalpy difference between the forms, DH,reflects the lattice or structural energy differencesand the entropy difference, DS, is related to thedisorder and lattice vibrations. The relative stabilityis given by the algebraic sign of DG as follows:

1. DG is negative when the free energy decreases. Thetransformation can occur naturally and a changehas the potential to continue to occur as long as thefree energy of the system decreases;

2. DG = 0 when the system is at equilibrium withrespect to the transformation and the free energy ofthe two phases is the same; and

3. DG is positive when the free energy increases andthe transformation is not possible under the specificconditions.

The thermodynamic conditions for equilibriumbetween phases and the possible directions of thetransformations at constant pressure for a singlecomponent system that exists in amorphous andcrystalline states are shown in the Gibbs free energyplot, Fig. 2. This illustrates that polymorph C is morestable than A, since DG =GC"GA is < 0 and thus atransformation from polymorph A to C is possible.Amorphous or disordered solids of the same com-pound have a higher free energy than the crystallinestates due mainly to the higher enthalpy and entropyof the glass and results from the victory of kineticsover thermodynamics [36,37].

In the G versus T diagram, the intersection pointsrepresent phases that coexist in equilibrium, crystaland liquid states corresponding to melting temper-atures, crystalline states at transition temperatures,and amorphous and supercooled liquid states at glasstransition temperatures. In the case of crystalline states

the systems are classified as (1) monotropic (forms Aand C) where one form is more stable than the other attemperatures below the melting temperatures, or (2)enantiotropic (forms A and B) where there is atransition temperature below the melting tempera-tures. Above and below the transition temperaturethe stability order is reversed.

Phase transformations between crystalline statesand between crystalline–liquid states are first-ordertransitions in which there is a discontinuity in thefirst derivative of the free energy, for example (BG/BT)P=" S, (BG/BP)T =V, and B(G/T)/B(1/T)P=H.Amorphous to supercooled liquid transitions are notfirst-order and exhibit a gradual change in slope atTg such that there is a discontinuity in the heatcapacity, (BH/BT)P=CP. Amorphous solids of thesame composition will exhibit different kinetic states,relaxation times and glass properties depending onthe mode of preparation and time of storage [37].This will shift the position of the G versus T curvefor the amorphous solid-state, in contrast to the

Fig. 2. Schematic Gibbs free energy curves for a hypothetical single-

component system that exhibits crystalline and amorphous phase

transitions. Monotropic systems (A and C, A and B), enantiotropic

system (A and B) with a transition temperature Tt, and an amorphous

and supercooled liquid with a glass transition temperature Tg.

Melting points, Tm, for the crystalline phases are shown by the

intersection of the curves for the crystalline and liquid states.

Adapted from the relations developed by Shalaev and Zografi [37].





DG ! DH " TDS #1$





















DG ! DH " TDS #1$


















21

TERMODINAMICA

• Refleja la diferencia de energía

estructural o de red entre las formas

• Refleja el grado de desorden y

las vibraciones de la red




DG ! DH " TDS #1$





















DG ! DH " TDS #1$





















DG ! DH " TDS #1$


















22

Diagramas dG vs T




DG ! DH " TDS #1$


















Monotrópicos

Enantiotrópicos

Termodinámica

23

Ej. Carbamazepina

P-monoclínica = III = A Triclínica = I = B

crystalline states that have well defined G versus Tcurves.

Yu et al. [34,35]have shown that the DG versustemperature diagram provides the most complete andquantitative information about the stability relation-ship of polymorphs. The DG and its temperaturedependence can be obtained from melting data (melt-ing temperature, enthalpy of fusion), enthalpy oftransformation if available, and/or solubility depen-dence on temperature data for the solid-state forms ofinterest (enthalpies of solution from van’t Hoff plot).The melting data method requires less sample weightrelative to the solubility method, however, it exposesthe material to potential chemical degradation. Whilethe solubility method offers the advantage of studyinga range of temperatures and various solvents, there isthe possibility for solution-mediated transformationsor solvate formation during solubility measurement.Thus, instead of an equilibrium method for solubilitymeasurement, a dynamic method is used for estimat-ing the solubility of metastable solid states [38] and isreferred to as metastable or kinetic solubility. Thesolubility can be estimated from the maximum con-centration achieved during dissolution of excess solidin a solvent or from the initial intrinsic dissolution ratemethod [39,40].

The stability relationships for polymorphs of an-hydrous carbamazepine, P-monoclinic and triclinic,can be determined from a DG versus temperaturediagram based on melting and solubility data reportedin the literature, according to the method described byYu [35]. Consider for carbamazepine, P-monoclinic= III = A and triclinic = I = B. The change in freeenergy for the polymorphic transformation from poly-morph A to B is given by:

DG0 ! DH0 " Tm;ADS0 #2$

where the subscript ‘‘0’’ indicates the value of thethermodynamic function at Tm,A, the melting point ofform A. The same nomenclature used by Yu [35] isused in this example. The changes in enthalpy, DH,and entropy, DS, associated with the transformationare calculated from melting data according to thefollowing equations:

DH0 !DHm;A " DHm;B % #Cp;L " Cp;B$#Tm;B " Tm;A$#3$

DS0 !DHm;A

Tm;A" DHm;B

Tm;B% #Cp;L " Cp;B$ln

Tm;B

Tm;A

! "

#4$

where the term (Cp,L"Cp,B) is the difference betweenthe heat capacities of form B and supercooled liquid attemperatures between Tm,A and Tm,B and the differ-ence in heat capacity is assumed to be independent oftemperature in the narrow temperature range typicallyobserved for polymorphs (T < 20 K). Among thevarious methods proposed to calculate the value ofthis parameter [35,41] we will demonstrate the heat oftransition (DHt) calculation since solubility data as afunction of temperature is often available for APIs. IfDHt is independent of T in the range of measurementthen:

DHt ! DH0 #5$

where DHt for a transition from A to B is given by:

DHt ! DH BS " DH A

S #6$

DH SB and DH S

A are the enthalpies of solution forpolymorphs A and B and can be calculated from thesolubility dependence on temperature according to thelinear relationship given by a van’t Hoff plot accord-ing to:

ln#s$ ! " DHS

RT% c #7$

where s is the solubility of a given polymorph at anabsolute temperature T, R is the gas constant, and c is aconstant. The van’t Hoff plot has been successfullyapplied to APIs over narrow temperature ranges. Themodel derived by Grant and coworkers [42] for eval-uation of the heat of solution can be applied over widertemperature ranges when the van’t Hoff plot leads tonon-linearity. These methods have been thoroughlyreviewed elsewhere [28].

The value for (Cp,L"Cp,B) can then be calculatedfrom substitution of DH0 with DHt and rearrangementof Eq. (3), which gives:

#Cp;L " Cp;B$!#DHt"DHm;A%DHm;B$=#Tm;B"Tm;A$#8$





DG0 ! DH0 " Tm;ADS0 #2$



DS0 !DHm;A

Tm;A" DHm;B


Tm;B

Tm;A

! "

#4$


DHt ! DH0 #5$


DHt ! DH BS " DH A

S #6$

DH SB and DH S


ln#s$ ! " DHS

RT% c #7$








DG ! DH " TDS #1$





















DG0 ! DH0 " Tm;ADS0 #2$



DS0 !DHm;A

Tm;A" DHm;B


Tm;B

Tm;A

! "

#4$


DHt ! DH0 #5$


DHt ! DH BS " DH A

S #6$

DH SB and DH S


ln#s$ ! " DHS

RT% c #7$





24

Diagramas de van´t Hoff




DG0 ! DH0 " Tm;ADS0 #2$



DS0 !DHm;A

Tm;A" DHm;B


Tm;B

Tm;A

! "

#4$


DHt ! DH0 #5$


DHt ! DH BS " DH A

S #6$

DH SB and DH S


ln#s$ ! " DHS

RT% c #7$








DG0 ! DH0 " Tm;ADS0 #2$



DS0 !DHm;A

Tm;A" DHm;B


Tm;B

Tm;A

! "

#4$


DHt ! DH0 #5$


DHt ! DH BS " DH A

S #6$

DH SB and DH S


ln#s$ ! " DHS

RT% c #7$








DG0 ! DH0 " Tm;ADS0 #2$



DS0 !DHm;A

Tm;A" DHm;B


Tm;B

Tm;A

! "

#4$


DHt ! DH0 #5$


DHt ! DH BS " DH A

S #6$

DH SB and DH S


ln#s$ ! " DHS

RT% c #7$








DG0 ! DH0 " Tm;ADS0 #2$



DS0 !DHm;A

Tm;A" DHm;B


Tm;B

Tm;A

! "

#4$


DHt ! DH0 #5$


DHt ! DH BS " DH A

S #6$

DH SB and DH S


ln#s$ ! " DHS

RT% c #7$








DG0 ! DH0 " Tm;ADS0 #2$



DS0 !DHm;A

Tm;A" DHm;B


Tm;B

Tm;A

! "

#4$


DHt ! DH0 #5$


DHt ! DH BS " DH A

S #6$

DH SB and DH S


ln#s$ ! " DHS

RT% c #7$





Thus DH0, DS0, and DG0 can be evaluated from Eqs.(8), (3), (4) and (2). By assuming a non-linear or lineardependence of DG on temperature [35], DG for thepolymorphic transition can be determined at othertemperatures. The linear relationship is given by:

DG!T" # DG0 $ DS0!T $ Tm;A" !9"

In this way, a DG–temperature diagram can be ob-tained for a polymorphic pair from melting data.

The difference in the Gibbs free energy associatedwith the transformation of polymorph A to B can becalculated from solubility measurements of the twoforms by the following relation

DG # !GB $ GA" # RT lnSBSA

! "

: !10"

This equation assumes that concentrations can besubstituted for activities if the ratio of the activitycoefficients of the two polymorphs is approximately1. A complete discussion of this method is presentedin other reviews [28,38]. The DG–temperature dia-gram based on the solubility method (Eq. (10)) can becombined and compared with that obtained from themelting data according to Eq. (9). This is shown forcarbamazepine polymorphs below.

2.1.1. DG–temperature diagram for carbamazepinepolymorphs

2.1.1.1. DG– temperature diagram from solubilitydata. Behme and Brooke [41] studied the P-mono-clinic and triclinic carbamazepine polymorphs andmeasured solubilities as a function of temperature in2-propanol. There has been confusion in the nomen-clature of carbamazepine polymorphs in the literatureand in the original report by Behme and Brooke [41];values have been reported for the triclinic form andnot trigonal [43,44]. A transition temperature of 346 K(73 jC) was calculated by extrapolation of the solu-bility lines from a van’t Hoff plot, Fig. 3. Since thistransition temperature is below the melting temper-atures of each polymorph, III and I are enantiotropi-cally related. Below 346 K, III has lower solubilityand is thus more stable than I. The heats of solution in2-propanol calculated from the slopes of the lines are31.54 kJ/mol for III, and 28.01 kJ/mol for I. The heat

of transition is then 3.53 kJ/mol. The DG–tempera-ture diagram was calculated from Eq. (10) and isshown in Fig. 4.

2.1.1.2. DG–temperature diagram from meltingdata. The thermal analysis of carbamazepine poly-morphs I and III [41] shows that form I melts at 189jC and form III at 174 jC. DSC at slow heatingrates shows that III transforms to I endothermicallywith a DHt of 3.3 kJ/mol between 150 and 170 jC.From the melting data, (DHm,I = 26.4 kJ/mol,DHm,III = 29.3 kJ/mol) and from the solubility data,(DHt = 3.53 kJ/mol), the value for (Cp,L$Cp,B) wascalculated from Eq. (8) and DG0 =$ 0.94 kJ/mol wasobtained from Eq. (2). The DG values were calcu-lated at other temperatures from Eq. (9) and areplotted in Fig. 4.

Extrapolation of DG obtained from solubility andmelting data to DG = 0, Fig. 4, shows a transitiontemperature of 353 K (80 jC) from the melt methodcompared with 346 K (73 jC) from the solubilitymethod. This deviation is within the expected rangeof 7% [35].

2.2. Burger–Ramberger rules

Burger and Ramberger have described rules for theassignment of a given polymorphic pair as enantio-tropic or monotropic [33]. Three particularly usefulrules they proposed are the heat of transition, heat offusion, and density rule [33,45,46]. The first two rules

Fig. 3. The van’t Hoff plot for the P-monoclinic (III) and triclinic (I)

forms of carbamazepine in 2-propanol. Adapted from the data

presented by Behme and Brooke [41].


31.54 kJ/mol

28.01 kJ/mol

3.53 kJ/mol 26.4 kJ/mol29.3 kJ/mol

Tt 346K+ estable- soluble

25

Cinética



•


5.2. Crystalline









bottom: form II).



5.2. Crystalline









bottom: form II).


ka

kb


Cristalización

26

Cristalización

• Etter. Moléculas que se acomodan por

medio de fuerzas no covalentes (P. de H)

siguiendo patrones de empaquetamiento

energéticamente adecuados.bonds. A major conclusion of this work was toestablish a connection between the molecular assem-bly processes that precede nucleation and the molec-ular arrays in the crystal state:

Molecule X Molecular assembly X

Molecular network X Crystal

These findings motivated investigations on the supra-molecular aspects of crystallization processes andhave found great utility in explaining the appearanceor disappearance of polymorphs [14], the role thatsolvents and additives have on the directed nucleationof polymorphs [17,27,54], and the kinetic stability ofmetastable forms including amorphous solids [37].

The balance between the kinetic and thermody-namic factors is illustrated by the free energy-reactionprogress diagram (Fig. 5) for a transition from theinitial state Gi, to two different solid forms A or B.Form A is more stable and less soluble than B(GA <GB). Gi may represent a supersaturated solutionin a multiple-component system, liquid or solid (mo-lecular dispersion in amorphous system), or in the

case of a single component system an undercooledliquid (melt) or an amorphous solid. The reactionfollows a path through an energy maximum betweenthe initial and final states. This resistance to thetransition from Gi to GA or GB arises because thereis an energy barrier for molecular diffusion, molecularassemblies, and for the creation of an interface. For achemical reaction in a homogeneous system, thisenergy maximum is the transition state and reflectselementary reactions, bimolecular or trimolecular, thatyield products with new covalent bonds. In compar-ison, a crystallization event or phase transformationleads to heterogeneous systems in which a separatenew phase is created from a supramolecular assemblyby formation of non-covalent bonds.

A transition from the initial state Gi to state A or Bwill depend on the energy barrier and according to thereaction pathway in Fig. 5, the height of the energybarrier for structure A (G*A!Gi) is greater than thatfor B (G*B!Gi). Because the rate of nucleation isrelated to the height of the energy barrier on thereaction path, B will nucleate at a faster rate than Aeven though the change in free energy is greater for A(GA!Gi) than for B (GB!Gi). This is one of thepossible behaviors that could be observed in the orderof appearance of polymorphs and is referred to asOstwald’s law of stages. It states that ‘‘when leavingan unstable state, a system does not seek out the moststable state, rather the nearest metastable state whichcan be reached with loss of free energy’’ [55].However, Ostwald’s law of stages is not universallyvalid because the appearance and evolution of solidphases are determined by the kinetics of nucleationand growth under the specific experimental conditions[27,56,57] and by the link between molecular assem-blies and crystal structure [16,58,59].

Crystallization involves both the nucleation andgrowth of a phase. Because of the key role ofnucleation in the selective crystallization of poly-morphs and the stabilization of metastable states, itwill be discussed in this review. Studies of growthkinetics and crystal morphologies are useful in char-acterizing intermolecular interactions on specific crys-tal planes and as a consequence in identifyingadditives or solvents that may preclude or promotethe crystallization of a particular polymorph. Thereader is referred to references that address theseconcepts and strategies [15,17,18,27,54,60].

Fig. 5. Schematic diagram for a hypothetical transition from the

initial state, Gi, to two different solid forms A or B, with free

energies GA and GB. Form A is more stable and less soluble than B.

A transition from the initial state Gi to state A or B will depend on

the energy barrier and according to this reaction pathway the height

of the energy barrier for structure A, (G*A!Gi) is greater than that

for B, (G*B!Gi). Because the rate of nucleation is related to the

height of the energy barrier on the reaction path, B will nucleate at a

faster rate than A even though the change in free energy is greater

for A (GA!Gi) than for B (GB!Gi).

B. Rodrı́guez-Spong et al. / Advanced Drug Delivery Reviews 56 (2004) 241–274 249bonds. A major conclusion of this work was toestablish a connection between the molecular assem-bly processes that precede nucleation and the molec-ular arrays in the crystal state:



















solventes

aditivos

27

Cinética Vs Termodinámica

bonds. A major conclusion of this work was toestablish a connection between the molecular assem-bly processes that precede nucleation and the molec-ular arrays in the crystal state:



















menos soluble

Ley de las Etapas de Ostwald´s: “Cuando se deja un estado inestable, el sistema no busca el estado mas estable, buscará el estado metaestable que

pueda ser logrado con la menor pérdida de energía libre”

28

Sistemas de un Solo Componente

• Amorfos

• Cristalinos

Sistemas de Múltiples Componentes

• Amorfos

• Cristalinos: i) Co-cristales: Moléculas neutras, Moléculas Cargadas y Solvatos.

29

SSC - Amorfos

• Mejor Biodisponibilidad que los cristalinos

No-Orden Molecular Tri-Dimensional a Larga Distancia

Presentan Estados de Alta Energía

Están más alejados del equilibrio

VDisolución SCinética o Metaestable MAYORES

Propiedades Mecánicas AFECTAN

30

SSC - Amorfos

• EL por una rápida precipitación. Bajas

To, rápida evaporación o enfriamiento

del solvente. Reducción de la MM

• Maceración de SC.

• Desolvatación de MC.

Spray-drying Freeze-drying Melt-extrusion

POLI-AMORFISMO a partir de

31

SSC - Amorfos

than the thermodynamically stable crystalline state,whereas for polymorphs and solvates it could be aboutfour times higher.

Amorphous phases can be prepared under condi-tions very far from equilibrium from various initialstates: (a) the liquid state by fast precipitationachieved at high driving forces and at low temper-atures to reduce mobility (quenching a melt by rapidcooling and fast evaporation or freezing of solvent inliquid solution) [36,37], and from (b) crystalline solidsby milling or grinding at low temperatures [91] and bydesolvation of crystalline materials [92]. Manufactur-ing processes commonly used to prepare amorphousmaterials include spray-drying, freeze-drying and meltextrusion. Pharmaceutical products reported in theUSP/NF and Physician’s Desk Reference containingamorphous components, APIs, and excipients ofteninclude tablets, capsules, suspensions, and powders.Insulin suspensions, for instance, for subcutaneousadministration have been marketed with varying ratiosof amorphous and crystalline insulin to control therate of delivery.

Molecularly disordered solids experience transla-tional motion and molecular mobility that do notoccur in the crystalline state. This enhanced molecularmobility can also lead to physically and chemicallyreactive materials and to changes in pharmaceuticalproperties depending on the methods of preparationand storage as well as storage time. For example, ithas been shown that amorphous cefamandole nafateprepared by freeze-drying and spray-drying has slight-ly different X-ray diffraction patterns [93] and amor-phous tri-O-methyl–cyclodextrin prepared by millingand melt-rapid quench has different relaxation enthal-py rates and crystallization rates although the Tg andheat capacity values are similar [94]. This differencein properties for the same material has raised thequestion of whether there are different amorphousstates. In a recent publication, Shalaev and Zografidiscuss the differences between true polyamorphismand relaxation polyamorphism [37]. To our knowl-edge, true polyamorphism has not been reported forpharmaceutical materials and is defined as the exis-tence of two distinct amorphous states involving afirst-order transition and differs from the frequentlyobserved relaxation states typical of amorphous mate-rials. The latter behavior or relaxation polyamorphismis more frequently observed in pharmaceutical materi-

als and is a result of different kinetic states orcontinuous changes of amorphous systems.

Despite the long-range disorder of amorphous mate-rials it has been found that there are regions of localorder. Information about molecular assemblies and inparticular hydrogen-bond patterns in low molecularweight organic glasses has been obtained by spectro-scopic methods (infrared and Raman) [95]. Similaritiesbetween molecular assemblies in the amorphous andcrystalline states have been related to the instability ofthe amorphous state and to the crystallization of dif-ferent polymorphic forms [37,89]. Indomethacin hasbeen shown to crystallize from the amorphous state ineither the g or a crystal forms depending on thetemperature [96]. Temperatures V Tg produce the gpolymorph whereas T >Tg produce the a form. Ramanand IR studies have shown that hydrogen-bond patternsof indomethacin in the amorphous state lead to crys-tallization of the polymorph with molecular assembliessimilar to those in the glass [24]. Hydrogen-bondmotifs found in crystalline monocarboxylic acids andin the a and g indomethacin polymorphs are shown inFig. 6. The dimer found in the g form is the mostcommon supramolecular synthon for monocarboxylicacid crystals [53].

Recent developments to probe molecular levelinteractions and mobility provide in-depth under-standing of molecular relaxation and recognition pro-cesses that allow for better design and stability ofdisordered pharmaceutical dosage forms. Strategies toassess and predict the long-term stability and perfor-mance of amorphous systems rely on measurements

Fig. 6. Molecular assemblies of the carboxylic acid synthon

(intermolecular connector) illustrating the hydrogen bond patterns

that lead to two supramolecular isomers: (a) dimer and (b) head-to-

tail chain.


Indomethacina Amorfa (gamma y alfa)










tail chain.











tail chain.

B. Rodrı́guez-Spong et al. / Advanced Drug Delivery Reviews 56 (2004) 241–274 253than the thermodynamically stable crystalline state,whereas for polymorphs and solvates it could be aboutfour times higher.









tail chain.


32

SSC - Cristalinos


5.2. Crystalline









bottom: form II).



5.2. Crystalline









bottom: form II).


Namebutona


5.2. Crystalline









bottom: form II).



5.2. Crystalline









bottom: form II).



5.2. Crystalline









bottom: form II).


Anti-inflamatorio

Analgésico

Antipirético

Artritis (Relafen)

33

as at least seven polymorphs. Four of these forms(II–V) have been structurally characterized [105–107]. Polymorphism of this system was first reportedin 1946, [108] when four polymorphs were identi-fied by melting point and a fifth was found byoptical crystallographic properties. Later thermalmicroscopy experiments on sulfapyridine revealedseven polymorphs [109]. However, it was not until1984 that a single crystal structure of this compoundhad been solved [105]. Two additional polymorphs

were structurally characterized in 1985 and anotherwas described in 1988 [106,107]. This system dis-plays conformational polymorphism, which is exem-plified by differences in the NUSUCUC torsionangle in the molecule, Fig. 11, that can be as largeas 39j between forms. A single distinct molecularconformation is present in forms II–IV. However,form V is unique in the fact that it possesses twodifferent conformers in the same unit cell. Thisdifference is also apparent in the packing arrange-ment and hydrogen bonding schemes displayed byeach modification, Fig. 12. Forms II, IV, and Vexhibit a similar NUH: : : N hydrogen bonded di-mer. These dimer units assemble in a differentmanner in each of the three polymorphs, while formIII packs with an NUH: : : O intermolecular hydro-gen bonded dimer.

Fig. 11. Structure of sulfapyridine.

Fig. 12. Packing diagrams of sulfapyridine polymorphs. From top left clockwise: form II, III, IV, and V.












SSC - Cristalinos


5.2. Crystalline









bottom: form II).



5.2. Crystalline









bottom: form II).


Namebutona


5.2. Crystalline









bottom: form II).



5.2. Crystalline









bottom: form II).



5.2. Crystalline









bottom: form II).


Anti-inflamatorio

Analgésico

Antipirético

Artritis (Relafen)

Droga Sulfaanti-bacterialNeumonia











34

Sistemas de un Solo Componente

• Amorfos

• Cristalinos

Sistemas de Múltiples Componentes

• Amorfos

• Cristalinos: i) Co-cristales: Moléculas neutras, Moléculas Cargadas y Solvatos.

Puentes de H, e. iónicos, interacciones de van der Waals y

SMC - Amorfos

• Polietilenglicol (PEG)

• Polivinilpirrolidina (PVP)

• Polivinilalcohol (PVA)

• Polivinilpirrolidina/vinilacetato (PVP/VA)

• Derivados de: celulosa, poliacrilatos y polimetacrilatos

6. Multiple-component systems

Multi-component systems are molecular assem-blies composed of an API and a complementarymolecule (neutral or charged) such as solvent, exci-pients, and other substances. These solid-state super-molecules are assembled from specific non-covalentinteractions between molecules, including hydrogenbonds, ionic, van der Waals and k–k interactions.Supramolecular synthons are the structural units thatconnect molecules to one another via these interac-tions. Thus, intermolecular interactions can be used askey molecular recognition elements in the design ofamorphous or crystalline multiple-component systemsand in the characterization of structures. It is impor-tant to recognize that amorphous and crystalline solidsshare the same intermolecular bonds and differ mainlyin the range of disorder.

Etter derived guidelines for hydrogen bonding incrystals from analysis of hydrogen bond motifs thatapply to the design of molecular assemblies [26,110].The simplest of these rules states that all availableproton donor and acceptor groups will be used in thehydrogen bond patterns of most organic molecules inthe crystalline state [110]. Ideally, the hydrogen bondrules can be used as guidelines for the design ofmolecular assemblies if one is mindful of crystalliza-tion kinetics and thermodynamic properties.

6.1. Amorphous

Multiple-component systems can be prepared asamorphous molecular dispersions. Homogeneous dis-persions of API and other substances offer the advan-tages of the higher energy amorphous state, such asimproved dissolution rates and bioavailability. Com-ponents used in the formulation of solid dispersionsinclude polymers such as polyethylene glycol (PEG)[111,112], polyvinylpyrrolidone (PVP) [24,113–116],polyvinylalcohol (PVA) [117], polyvinylpyrrolidone/vinylacetate (PVP/VA) copolymers [118,119], cellu-lose derivatives [120,121], polyacrylates and polyme-thacrylates [122,123]. In contrast to single-componentamorphous solids, molecular dispersions can bedesigned with optimal stability and function. Forinstance, relaxation times, molecular mobility, andintermolecular interactions can be varied by the choiceof components [37,118].

The stabilizing effects of PVP on amorphousmolecular dispersions of organic substances havebeen explained in terms of hydrogen bonding patterns[24,118,119]. For instance, the ability of PVP toinhibit the crystallization of indomethacin at roomtemperature (30 jC) has been related to molecularmobility and intermolecular interactions. Vibrationalspectroscopy results revealed that the hydrogen bondsresponsible for dimer formation in indomethacin aredisrupted, which are prerequisite to the formation ofcrystal nuclei [24,119]. The carboxylic acid of indo-methacin instead forms a stronger hydrogen bond withthe more basic amide carbonyl of the polymer. Sincethe local structure or heterogeneity of the moleculardispersion is apparently less ordered than that ofamorphous indomethacin due to disruption of thedimer, it can be expected that the time scale forstructural relaxation will be greater for the dispersion[37].

6.2. Crystalline

Crystal engineering offers a rational approach tothe design of new compositions and crystal structures.Much as an organic chemist employs the covalentbond in the design of drug molecules, non-covalentbonds can be exploited in the design of supramolec-ular structures. Hydrogen bonded networks are themost commonly studied since a certain degree ofreliability and predictability exists regarding the in-teraction of donors and acceptors [110]. However,additional interactions that also play significant rolesin the creation of multi-component crystals includevan der Waals, k–k stacking, and electrostatic inter-actions [2,9]. Molecular networks of these kinds areused in building cocrystals, solvates, hydrates, andsalts and will be described herein.

6.2.1. Cocrystals: solvatesThe drug development process exposes pharma-

ceutical solids to solvents, organic and aqueous sol-vents during crystallization, wet granulation, storageand dissolution, that can lead to the formation ofsolvated crystals by design or inadvertently. Crystal-line forms of APIs with included solvent moleculesdiffer in pharmaceutical performance—mechanicalbehavior, stability, dissolution and often bioavailabil-ity—from the unsolvated API crystal [124–126].





6.1. Amorphous



6.2. Crystalline





35

SMC - Amorfos

• Polietilenglicol (PEG)

• Polivinilpirrolidina (PVP)

• Polivinilalcohol (PVA)

• Polivinilpirrolidina/vinilacetato (PVP/VA)

• Derivados de: celulosa, poliacrilatos y polimetacrilatos




6.1. Amorphous



6.2. Crystalline








6.1. Amorphous



6.2. Crystalline





PVP inhibe la cristalización de indometacina a 30oC

Dispersiones

Moleculares

Amorfas

Movilidad Molecular e Interacciones Intermoleculares36

SMC - Cristalinos

5070 Agua,

745 MEOH,

356 ETOH,

309 Acetona,

137 DMSO

274 THF

in these networks depends on hydrogen bondingbetween OUH: : : O moieties and has been describedfor three solvates of niclosamide: a dihydrate, atetrahydrofuran (THF) solvate and a tetraethyleneglycol (TEG) solvate. The relative strength of hydro-gen bond donor and acceptor groups was correlated tostructural architecture and thermal behavior, indicat-ing desolvation pathways. Caira et al. [130] showedthat in the niclosamide hydrate, water moleculesoccupy a channel and hydrogen bond with surround-ing drug molecules (Fig. 13a). This arrangement falls

into the aforementioned class II structures. Thestrength of this assembly is confirmed by high dehy-dration onset temperatures (173F 5 and 201F 5 jC),and indicates that water and niclosamide are tightlybound. In contrast, the THF solvate undergoes rapiddesolvation from molecular assemblies at 30 jC,which is 36 jC lower than the boiling point of THF.The instability of this system was explained by weakforces forming a continuous channel within the crystalstructure, which facilitates migration of the solventout of the lattice (Fig. 13b). The TEG solvate forms

Fig. 13. Crystal structures and heterosynthons of niclosamide (a) monohydrate, (b) THF solvate, and (c) TEG solvate. Solvent molecules are

represented as cap-stick models for clarity in the molecular packing diagrams. Adapted with permission from reference [13].


• Co-cristales:

Solvatados 173+5

30

65-230

Niclosamida

Agua

THF

TEG

37

SMC - Cristalinos

• Co-cristales: Moléculas Neutras

molecular assemblies with fine-tunable pharmacolog-ic activity [10,138].

A supramolecular design strategy was recentlyused to prepare 13 new cocrystals of carbamazepine[13]. The crystal packing of carbamazepine in poly-morphs and solvates shows the formation of dimers,with the carboxamide unit acting as both a hydrogenbond donor and acceptor (Fig. 14). Two designstrategies were utilized using this moiety as theprimary supramolecular synthon where interactions

either retain or disrupt the carbamazepine dimerformation. Fig. 14a–d shows how carbamazepinecan form cocrystals with water, acetone, saccharin,or nicotinamide that retain the carboxamide dimer andhydrogen bond instead with available donor/acceptorgroups. In contrast, formic acid and trimesic acidcocrystals of carbamazepine disrupt dimer formation(Fig. 14e–f). Given that these cocrystals significantlyalter intermolecular associations and modify crystalpacking, physical and pharmaceutical properties may

Fig. 14. Molecular assemblies in multiple-component crystals of carbamazepine: (a) hydrate, (b) acetone, (c) saccharin, (d) nicotinamide,

(e) acetic acid, and (f) 5-nitroisophthalic acid. Adapted from reference [130].


Carbamazepina

Agua

Acetona

Sacarosa

Nicotinamida

Acido Acético

Acido 5-nitroisoftálico

Nicotinamida, VB3, higroscópica y delicuesente

Aductos de la Nicotinamida estables

38

Preparación de Sólidos

• Cristalización (EL al ES)

Fluidos Supercríticos

Libre de Solvente

(mezclado, macerado,

calentamiento, compresado)

Espacios Confinados (Capilares)

Highthroughput

the crystallizing medium, the process relies on thebalance between molecular recognition, kinetics, andthermodynamics, as discussed in earlier sections.

The search and control of solid-state forms hasmotivated the development of new crystallizationmethods from liquid solutions, supercritical fluids,and solids via solvent-free methods. In liquid solu-tions, recent focus has led to the study of crystalliza-tion processes in confined spaces, for example incapillary tubes [51], and to the evolution of high-throughput methods that in addition to employingsmall volumes, test the ability of surfaces to nucleatepolymorphs [68]. Other advances include crystalliza-tion from supercritical fluids where enhanced molec-ular diffusion and ease of solubility, control oftemperature, pressure and solvents provide a meansto carefully control polymorph selection [151]. Sol-vent-free methods have attracted attention in deliber-ately preparing multiple-component crystalline andamorphous phases by grinding, mixing, compressing,or heating. Several groups have reported cocrystalformation by simple grinding of a mixture of solidcomponents. Frankenbach and Etter [53] showed thatcocrystals of 3,5-dinitrobenzoic acid and 4-amino-benzoic acid with an extensive network of hydrogenbonds can be created by grinding. In some cases,crystals formed in solvent do not form by solid-stategrinding and vice versa [152,153]. The use of me-chanical force is attractive because of its low envi-ronmental impact and ease of preparation.

Solid phase transformations of APIs caused bymechanical stress are more frequently associated withthe formation of amorphous states. This has attractedattention in the pharmaceutical area because of theunintentional transitions that occur during processing[1] and the significant increase in metastable, orkinetic, solubility of the amorphous state relative tothe thermodynamically stable solubility of the crys-talline state. The increase in metastable solubility as aresult of amorphous formation by grinding has beenshown for griseofulvin and glibenclamide [154,155].Increases in steady-state concentration (c) relative tothe solubility of the crystalline phase (s), as high as 14for glibenclamide and 5 for griseofulvin, were ob-served by increasing the mass of drug added to thesolvent during solubility measurements, Fig. 15.Awareness of this type of transformation is importantwhen unexpected properties could compromise thera-

peutic outcomes. However, recent advances in under-standing of molecular assemblies and mobility inamorphous states, provide significant opportunitiesto control the stability of disordered delivery systems[37,89,90].

7.2. New approaches

In general, scientists have yet to achieve a satis-factory degree of control over polymorphism and inparticular there is no method to guarantee the produc-tion of even the most thermodynamically stable formof a compound. More problematic, and a commonlyencountered task for pharmaceutical companies, isfinding all forms of a compound that can exist underambient conditions. When the crystal structures ofpolymorphs are already known then design of crystalgrowth accelerators or inhibitors is possible usingadditives [56,60,156] or monolayers [157]. Thesestrategies are in general limited to crystallographicallycharacterized compounds and are often system spe-cific. The ultimate goal in the field is a universalapproach that can produce all energetically reasonablepolymorphs of a compound rapidly. Though a methodfor systematically exploring ‘‘polymorph space’’[158] has not yet been demonstrated there areexciting recent developments in crystallization tech-niques that contribute toward this goal; five of these

Fig. 15. Comparison of plateau supersaturations achieved by in-

creasing the mass of amorphous glibenclamide (.) and griseofulvin

(E) in aqueous suspensions.



• High Throughput

• Crecimiento en Capilares

• Nucleación inducida por Laser

• Heteronucleación en mono-cristales

• Heteronucleación por polímeros

Tendencias


• Cristalización (EL al ES)

Fluidos Supercríticos

Libre de Solvente

(mezclado, macerado,

calentamiento, compresado)

Espacios Confinados (Capilares)

Highthroughput

the crystallizing medium, the process relies on thebalance between molecular recognition, kinetics, andthermodynamics, as discussed in earlier sections.

The search and control of solid-state forms hasmotivated the development of new crystallizationmethods from liquid solutions, supercritical fluids,and solids via solvent-free methods. In liquid solu-tions, recent focus has led to the study of crystalliza-tion processes in confined spaces, for example incapillary tubes [51], and to the evolution of high-throughput methods that in addition to employingsmall volumes, test the ability of surfaces to nucleatepolymorphs [68]. Other advances include crystalliza-tion from supercritical fluids where enhanced molec-ular diffusion and ease of solubility, control oftemperature, pressure and solvents provide a meansto carefully control polymorph selection [151]. Sol-vent-free methods have attracted attention in deliber-ately preparing multiple-component crystalline andamorphous phases by grinding, mixing, compressing,or heating. Several groups have reported cocrystalformation by simple grinding of a mixture of solidcomponents. Frankenbach and Etter [53] showed thatcocrystals of 3,5-dinitrobenzoic acid and 4-amino-benzoic acid with an extensive network of hydrogenbonds can be created by grinding. In some cases,crystals formed in solvent do not form by solid-stategrinding and vice versa [152,153]. The use of me-chanical force is attractive because of its low envi-ronmental impact and ease of preparation.

Solid phase transformations of APIs caused bymechanical stress are more frequently associated withthe formation of amorphous states. This has attractedattention in the pharmaceutical area because of theunintentional transitions that occur during processing[1] and the significant increase in metastable, orkinetic, solubility of the amorphous state relative tothe thermodynamically stable solubility of the crys-talline state. The increase in metastable solubility as aresult of amorphous formation by grinding has beenshown for griseofulvin and glibenclamide [154,155].Increases in steady-state concentration (c) relative tothe solubility of the crystalline phase (s), as high as 14for glibenclamide and 5 for griseofulvin, were ob-served by increasing the mass of drug added to thesolvent during solubility measurements, Fig. 15.Awareness of this type of transformation is importantwhen unexpected properties could compromise thera-

peutic outcomes. However, recent advances in under-standing of molecular assemblies and mobility inamorphous states, provide significant opportunitiesto control the stability of disordered delivery systems[37,89,90].

7.2. New approaches

In general, scientists have yet to achieve a satis-factory degree of control over polymorphism and inparticular there is no method to guarantee the produc-tion of even the most thermodynamically stable formof a compound. More problematic, and a commonlyencountered task for pharmaceutical companies, isfinding all forms of a compound that can exist underambient conditions. When the crystal structures ofpolymorphs are already known then design of crystalgrowth accelerators or inhibitors is possible usingadditives [56,60,156] or monolayers [157]. Thesestrategies are in general limited to crystallographicallycharacterized compounds and are often system spe-cific. The ultimate goal in the field is a universalapproach that can produce all energetically reasonablepolymorphs of a compound rapidly. Though a methodfor systematically exploring ‘‘polymorph space’’[158] has not yet been demonstrated there areexciting recent developments in crystallization tech-niques that contribute toward this goal; five of these

Fig. 15. Comparison of plateau supersaturations achieved by in-

creasing the mass of amorphous glibenclamide (.) and griseofulvin

(E) in aqueous suspensions.


39

Técnicas Estructurales y Analíticas

• Rayos X de monocristal. Diferencias en

el empaquetamiento y conformación

• Análisis Termogravimétricos (TGA)

• Infra-Rojo

• Raman

• Difracción de Rayos X (polvo)

• Microscopía

40

Difracción de Rayos X (Polvo)

• Huella Digital de una Fase Espacios Periódicos de los Atomos en el ES

general, give rise to different peak positions. Further-more, the generally good separation between peaks inthe diffractogram allows for quantitative analysis ofmixtures of polymorphs using PXRD [2]. Unlikesingle crystal X-ray diffraction or vibrational spec-troscopy, there is no chemical information apparent inthe data. However, with additional effort lattice con-stants can often be extracted from the data. The cellvolume can be compared to other crystalline formsand this information can be used to infer the presenceof solvent molecules in the lattice or changes indensity between polymorphs. In exceptional cases,high quality PXRD data can be employed to derivecomplete crystal structures and this technique ofstructure determination from powder diffraction(SDPD) is currently one of the exciting frontiers instructural chemistry [183,184]. Often synchrotrondata is required to obtain satisfactory results withSDPD and the intensities of the peaks are critical[185].

New advances in PXRD technology have made itpossible to obtain data at a rapid rate on smallquantities ( < 1 mg) of sample. Several diffractometermanufacturers have developed systems based on two-dimensional detectors with automated mapping stagesgeared for high throughput screening [186,187]. Fur-thermore, recent innovations have led to the design of

a novel batch crystallizer, which can be used inconjunction with dispersive X-ray diffraction to studysolution crystallization in situ [188].

8.4. Thermal techniques

8.4.1. Differential scanning calorimetry and thermog-ravimetric analysis

The technique of differential scanning calorimetry(DSC) measures the amount of energy absorbed orreleased by a sample as it is heated, cooled or held at aconstant temperature, Fig. 19 [189–193]. This energyis related to the difference in heat flow between astandard sample and the unknown. Integration of thearea under the heat flow curve yields the enthalpy

Fig. 18. PXRD comparison of the four polymorphs of carbamaze-

pine. Dramatic differences in peak position are observed when

comparing diffraction patterns making this an excellent technique

for distinction among forms in a tetramorphic system.

Fig. 19. DSC overlay of the four polymorphs of carbamazepine.

These are readily distinguished by this method. These curves

indicate that forms II, III, and IV transform to form I upon heating.


Carbamazepina


5.2. Crystalline









bottom: form II).


41

Análisis Térmico

• Hot Stage Microscopy

• DSC y TGA

Carbamazepina















Análisis Térmico

• Hot Stage Microscopy

• DSC y TGA

Carbamazepina
















5.2. Crystalline









bottom: form II).


42

Espectroscopía Vibracional

• IR• Raman

vibrational modes associated with the absorption of acompound in the infrared region of the spectrum,whereas, the Raman effect is based on the observationof scattered photons that occur as a result of thepassage of light through a sample. Different selectionrules apply in determining which vibrational modesare observed in each technique, although in the typicalcase of low symmetry molecules bands are observedat the same positions with both techniques and merelyvary in intensity.

Infrared absorption spectroscopy has enjoyed themost use in polymorph investigations primarily be-cause it is a robust technique available in mostlaboratories. Several limitations of the technique areworth considering especially for studies involvingsmall quantities of sample or single crystals. Thesestudies are most conveniently conducted by IR mi-croscopy and this is the method of choice for studieson single crystals. However, an IR transparent sub-strate must be employed and it is difficult to collectspectra of all but the thinnest crystals due to transmit-tance issues. Substrate and sample transmittance issuescan be circumvented by using attenuated total reflec-tion (ATR) or diffuse-reflectance infrared (DRIFT)spectroscopy [177].

Raman spectroscopy provides similar chemicalinformation to IR absorption spectroscopy [178,179].However, when applied to investigations of polymor-phism the Raman method has a number of importantadvantages. The technique is well suited for in situ

studies of polymorphism because it can perform meas-urements both behind glass and in water; conditionsthat cannot be accommodated by IR absorption meas-urements [180,181]. A Raman spectrometer interfacedto a microscope has an additional advantage of beingable to pinpoint small crystalline samples, which donot have to be removed from crystallization vials foranalysis, thus eliminating sample preparation. In addi-tion, the spatial resolution of Raman microscopy (f 1Am) is limited by the wavelength of the visible lightprobe rather than infrared radiation, making this tech-nique suitable for examining minute sample quantitiesin complex matrices. Traditionally Raman spectrom-eters were exotic tools because they required expen-sive parts and exhibited low sensitivity. However,recent advances in detector technology and improvedlasers are bringing this technique into the mainstream.Modern Raman spectroscopy is rapid and applicable todirect analysis in multi-well plates facilitating highthroughput studies.

8.3. Powder X-ray diffraction

One of the most reliable techniques for polymorphdifferentiation is PXRD [182], which yields a finger-print of a phase having numerous peaks whosepositions correspond to periodic spacings of atomsin the solid state, Fig. 18. This experiment is one ofthe most important in the characterization of poly-morphs because different lattice constants will, in

Fig. 16. FT-IR spectra of the two polymorphs of nabumetone. The

carbonyl shift between the two forms is prominent indicating large

differences in intermolecular interactions.

Fig. 17. Raman spectra overlay of selected region of monoclinic

(top) and orthorhombic (bottom) polymorphs of acetaminophen.

The low frequency region is easily accessed with this technique.















Namebutona Acetaminofen

Monoclínico

Ortorombico

Enlaces de H, dieferencias E de vibración (empaquetamientos)

Espectroscopía Vibracional

• IR• Raman



























Namebutona Acetaminofen

Monoclínico

Ortorombico

Enlaces de H, dieferencias E de vibración (empaquetamientos)

Enlaces de H, diferencias en Evibración

43


• High Throughput

44


• High Throughput


• High Throughput


• High Throughput

45

21/08/11 10:39Solid Form Solutions Ltd

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Welcome to Solid Form Solutions Ltd

The solid form pharmaceutical development experts...

Solid Form Solutions Ltd was founded early 2008 by three family members with the aim of providing SolidState Contract Research Services to the pharmaceutical industry. The early continued success of thecompany allowed for rapid growth in a very short period of time, which also positioned Solid FormSolutions as a world leader in Solid–State Services.

After establishing a high quality solid-state screening service, Solid Form Solutions Ltd soon expanded intothe scale-up and process development arena, which has seen the company provide the backbone to severalsuccessful manufacturing campaigns.

The Solid Form Solutions team also recognised early the importance of providing quality assurance andregulatory guidance as part of their service, which has proved extremely valuable to their clients.

The latest addition to SFS's capabilities is synthetic chemistry. This now allows the company to provide acomplete work program for early chemical development.

In the future, Solid Form Solutions aim to build on their early success by launching more innovative andhigh value services that will allow companies to develop APIs more efficiently and cost effectively.

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Physical Properties Testing

Salt Selection

Co-Crystal Screening

Crystallisation Screening

Polymorph Screening

Batch Process Optimisation

Custom Synthesis

http://www.solidformsolutions.co.uk46

http://www.solidformsolutions.co.uk

http://www.solidformsolutions.co.uk

ConclusionesEl entendimiento de los factores termodinámicos y cinéticos que determinan la estabilidad de una fase sólida es esencial para el desarrollo de fármacos

... desde el punto de vista del reconocimiento molecular, la formación de cristales moleculares, depende de la “habilidad” de las MO para participar efectivamente en la formación puentes de hidrógeno...

47

Electroquímica

Materiales

Oleoquímica

Química Fina

En que trabajamos ...

48

Vibrational spectroscopy of

molecules and crystalline solids:

theory and applications

[email protected]

Alejandro Pedro Ayala

Department of Physics

Universidade Federal do Ceará

Fortaleza, Brazil

49

Naı́r Rodríguez-Hornedo. Advanced Drug Delivery Reviews 56 (2004) 241 – 274

GENERAL PRINCIPLES OF PHARMACEUTICAL SOLID POLYMORPHISM:

A SUPRAMOLECULAR PERSPECTIVE

50

IDENTIFICACIÓN DEL EFECTO PROTECTOR DE LA

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