Principios Generales del Polimorfismo en Fármacos Sólidos: Una Perspectiva Supramolecular

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Principios Generales del Polimorfismo en Fármacos Sólidos: Una Perspectiva Supramolecular

  1. 1. PRINCIPIOS GENERALES DELPOLIMORFISMO EN FARMACOS SOLIDOS: UNA PERSPECTIVA SUPRAMOLECULAR Alfonso Enrique Ramírez Sanabria Grupo de Catálisis Departamento de Química Universidad del Cauca http://alfonsoeramirezs.wordpress.com ICESI-Cali, Facultad de Ciencias Naturales, agosto 22/2011 1
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  3. 3. www.iyc2011.org 3
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  8. 8. 8
  9. 9. Erase una vez ... 9
  10. 10. Formas Cristalinas 10
  11. 11. !"#$%&"()*+&$*,)-)./*0*#/1-)*+&*$)2*3)1,4%$)2*&"*$)2*Pongale color, pongale ... 31/3(&+)+&2*53,()26*/$/1 !"#"$%&&()&*# 11
  12. 12. School of Pharmacy and Department of Chemistry, University of WisconsinsMadison, 777 Highland Avenue, Madison, Wisconsin 53705 L´apéro RECEIVED ON MARCH 4, 2010 SPECTUS nd and graphite are polymorphs of each other: they have the same composition but different structures and pros. Many other substances exhibit polymorphism: inorganic and organic, natural and manmade. Polymorphs aed in studies of crystallization, phase transition, materials synthesis, and biomineralization and in the manufecialty chemicals. Polymorphs Research, September 2010. Polymorphism incrystal packingAn Extraordinary System of relati L. Yu, Accounts of Chemical can provide valuable insights into Molecular Solids: and structure-property ethyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile,toknown the schizophrenia drug ...orange, and yellow crystals, h Red, Orange, and Yellow (ROY) Crystals. ... ROY as a reagent prepare as ROY for its red,ymorphs with solved structures, the largest number in the Cambridge Structural Database.ynthesized by medicinal chemists, ROY has attracted attention from solid-state chemists because it demonstrates 12
  13. 13. Reconocimiento Molecular Reconocimiento Molecular ElEnsamble Supramolecular ejemplo clásicoEnsamble Supramolecular 13
  14. 14. “Química, más allá de las moléculas”. J-M. Lehn (1987) 14
  15. 15. API 15
  16. 16. unique molecules in the unit cell [48,51,100]. A Carbamazepine, Fig. 9, a pharmac second polymorph forms upon evaporation from small the treatment of epilepsy and trigemina volumes of ethanol [48] or crystallization in capillar- tetramorphic system possessing nearly Polimorfismo en Cristales ies (Section 7.2.2) [51]. This polymorph is also lecular conformation and strong hyd monoclinic, but possess only one asymmetric mole- among its polymorphs. Investigations cule in the unit cell (form II) [48,51]. Similar molec- morphism of this drug began in the l ular conformations are adopted in both forms. produced three forms; two of these w ed Drug Delivery Reviews 56 (2004) 241–274 However, the molecules in each structure adopt strik- y n Materiales con igualas composición química Namebutona Fig. 7. Structure of nabumetone. pero diferente of carbamazepi Fig. 9. Structure r- CONFORMACION MOLECULAR n ESTRUCTURA DE RED d h Existencia de mas l- eusorn- de un tipo dees SUPERESTRUCTURA DE RED eis para un mismo r, it BLOQUE MOLECULARd- Fig. 8. Packing diagram of nabumetone polymorphs (top: form I,y-e, ISOMERISMO SUPRAMOLECULAR bottom: form II). y ingly different arrangements in the lattice. Form I assembles in a head-to-tail manner whereas form II packs in a tail-to-tail head-to-head fashion, Fig. 8. In 16
  17. 17. ´ B. Rodrıguez-Spong et al. / Advanced Drug Delivery Reviews 56 (2004) 241–274 259in these networks depends on hydrogen bonding into the aforementioned class II structures. Thebetween OUH : : : O moieties and has been described strength of this assembly is confirmed by high dehy-for three solvates of niclosamide: a dihydrate, a dration onset temperatures (173 F 5 and 201 F 5 jC), Pseudo-Polimorfismotetrahydrofuran (THF) solvate and a tetraethylene and indicates that water and niclosamide are tightlyglycol (TEG) solvate. The relative strength of hydro- bound. In contrast, the THF solvate undergoes rapidgen bond donor and acceptor groups was correlated to desolvation from molecular assemblies at 30 jC,structural architecture and thermal behavior, indicat- which is 36 jC lower than the boiling point of THF.ing desolvation pathways. Caira et al. [130] showed The instability of this system was explained by weakthat in the niclosamide hydrate, water molecules forces forming a continuous channel within the crystaloccupy a channel and hydrogen bond with surround- structure, which facilitates migration of the solventing drug molecules (Fig. 13a). This arrangement falls out of the lattice (Fig. 13b). The TEG solvate forms Formas cristalinas con moléculas de solvente como parte integral de la ESTRUCTURA Niclosamida Solvente como componente del SISTEMA CO-CRISTALFig. 13. Crystal structures and heterosynthons of niclosamide (a) monohydrate, (b) THF solvate, and (c) TEG solvate. Solvent molecules arerepresented as cap-stick models for clarity in the molecular packing diagrams. Adapted with permission from reference [13]. 17
  18. 18. Implicaciones del PolimorfismoAuto-Ensamblaje Molecular API´s Oral• Comportamiento mecánico Lipofílico• Estabilidad Química y Física Aumentar• Solubilidad Disolución y Permeabilidad• Tasa de disolución en la Pared Intestinal• Biodisponibilidad Desarrollar Nuevas Formas en su Estado Sólido 18
  19. 19. Nuevas Formas en el ES• Cambios en el Arreglo Supramolecular de la Red Estado Cristalino Estado Amorfo• Cambios en Componentes Moleculares de la Red Co-Cristales Solventes Sales Materiales con estados de diferente Energía Libre Estabilidad y “Liberación” 19
  20. 20. Transformaciones en la Fase Sólida Fenómenos controlados no-covalentemente Reconocimiento Molecular Ensamblajes enlazados por Hidrógeno Redes moleculares Solventes Aditivos Impurezas Químicas Térmicas Humedad Relativa Mecánicas Termodinámicos Cinéticos Energía libre de Gibbs Supersaturación Entalpía Mobilidad molecular Entropía Nucleación y crecimiento del cristal Solubilidad 20
  21. 21. ns.2.1. Freereflect (1)driving mobility, solid-state stability energy diagrams and 54 ´ B. Rodrıguez-Spong et al. / Advanced Drug Delivery Reviews 56 (2004) 241–274 that mobility, such as molecular forcesuch as enthalpy hat reflect (1) molecular the enthalpy for a transformation at constant TERMODINAMICA elaxation, viscosity, and solid-state NMR relaxationand solid-state NMR relaxation relaxation, viscosity, The relative thermodynamicpressureof solids and temperature and stability is determined by the differ- mes and (2) intermolecular interactions such as nfrared and Raman spectroscopies. (2) intermolecular interactions such as times and TERMODINAMICA and is given by: Free energy diagrams and solid-state stability .2. Crystalline drivingence in Gibbs free energy at constant the infrared and Raman spectroscopies. force for a transformation eStructurally, crystallineofCrystallinepressure is determined by the differ- temperature and character- 5.2. polymorphs are relative thermodynamic stability of solids and nd packing arrangement of molecules in estabilidad termodinámica • Cualchanges su¼ DH À and is given by: es infree solid zed by varying degrees conformation rivingencekey intermolecular interactions, energy T DS at constant DG crystalline polymorphs are character- in Gibbs a the both tate. Often the force for transformation ð1Þ weak and strong,relativa? are Structurally, forms, al- preserved among et al. / Advanced Drug Delivery Reviews 56 (2004) 241–274 erature andpredict when this willis the of changesby conformation hough it is difficult to pressure degrees h as enthalpy ized by varying be determined in the differ- in Gibbsand are observed, DSenthalpy molecules in the solid DG ¼ DH Refleja 241–274 d Drug Delivery free À T the designator is of • Reviewsenergyla diferencia de energía ð1Þ ase for a given compound. For cases where obvious hanges in conformation packing arrangement given by: 56 (2004) and MR relaxation ons such as The difference between the forms, DH, state. Often theokey intermolecular interactions, both estructural de red entre las formas conformational polymorph’’ [1,2,29,97 – 99] is gen- rally used. Differences in the packing of molecules enthalpy difference lattice or y structural energy differences reflects the between with similar conformations have been strong,some weak and termed by are preserved among forms, al- The •T DS Refleja el grado de desordenthe forms, DH,¼ DH À nvestigators as ‘‘packing polymorphism’’ [1,29]. It is ð1Þ enerally recognized that these designations, however,to predict when this will be the are character- though it is difficult reflects theand thedeentropy difference, DS, is related to the conformation las vibraciones or la red in the solid actions, both lattice structural energy differences re artificial because virtually alla given compound. For cases where obvious case for polymorphs exhibit mall differences in conformation among their mod- Fig. 8. Packing diagram of nabumetone polymorphs (top: form I, changes in conformation bottom: observed, the designator are form II). enthalpy difference difference,the forms, DH, toThe relative stability and the entropy betweenlattice vibrations. the disorder and g forms, al- ications.the s will be However, it is important to note that poly- morphs, which exhibit large differences in structure, DS, is related here obvious ‘‘conformational polymorph’’different arrangements in the gen- Form I [1,2,29,97 – 99] is lattice. the lattice isson las condicionesdifferences of DG ts disorder andorgiven vibrations. The relative stability as follows: • Cuales lattice by the algebraicdirección o not necessarily have large differences in stability he designator ingly nd vicegen- – 99] is versa. of molecules structural energy y la sign erally used. Differences in the packing of manner whereas form II assembles in a head-to-tail molecules 254 ´ B. Rodrıguez-Spong et al. / Advanced Drug Delivery Reviews 56 (2004) 241–274 with similar conformations have tail-to-tail head-to-head fashion, especially packs in a been termedinteractions, Fig. 8. In he isentropyby the algebraic sign of DG as follows: given difference, una transformación? by some med by some necesarias para DS, is related to the .2.1. Nabumetone ’’ [1,29]. It is form I weak intermolecular Cinética ons, however, investigators as ‘‘packingCUH: : : O close contacts,[1,29]. thatis Nabumetone (Relafenk), Fig. 7, is an anti-inflam- orphs exhibit polymorphism’’ dominate It reflect (1) molecular mobility, such as enthalpy the structure.der and lattice1. DG is negative when the free energy decreases. The g their mod- vibrations. The relative stability matory, analgesic, and antipyretic therapeutic usually 8. Packing diagram of recognized that ote that poly- patients form II). arthritis. This pharmaceu- rescribed to bottom: with ment with several CUH relaxation, viscosity, and solid-state NMR relaxation By contrast, form II packs in a herringbone arrange- Fig. generally nabumetone polymorphs (top: form I, these designations, however, : : : k interactions. and (2) intermolecular interactions such as times en 1. DG is negative sign of DG asenergyoccur naturally and a Schematic Gibbs free energySchem by the algebraic when the free follows: calstructure, in s in stability transformation can and a change decreases. The crystallizes in two polymorphicbecause virtually all polymorphs exhibit and Raman spectroscopies. are artificial forms. The ommercial material (form I)arrangements in the lattice. Form I 5.2.2. Carbamazepine ingly different is monoclinic with two infrared Fig. 2. change Fig. 2. curve in the unit cell [48,51,100]. conformation among their mod- transformation can occur naturally assembles in head-to-tail manner whereas packs in a tail-to-tail head-to-head fashion, Fig. 8. In 5.2. Crystalline component nique molecules smalla differences in Aform II Carbamazepine, Fig. 9, a pharmaceutical used in Fig. 8. Packing diagram of nabumetone polymorphs (top: form I, component system that exhibits crystall form I weak intermolecular interactions, especially the treatment of epilepsy and trigeminal neuralgia, is a bottom: form II). econd polymorph forms upon evaporation from small has the when the the potential occur asThe as the potential free energy decreases. long to occur as long as the has to continue to to continue ifications. However, it is important to note that poly- n anti-inflam- ethanol [48] or crystallization in capillar- olumes ofG is negative transitions. Monotropic systems (A and M Structurally, es (Section 7.2.2) [51]. form II packs in a herringbone arrange- lecular differences in structure, bonding degrees of changes in conformation eutic usually morphs,CUH : : : k interactions. which exhibit large conformation and strong hydrogenby varying By contrast, This polymorph is also transitions. C CUH: : : O close contacts, dominate the structure. tetramorphic system possessing nearly identical mo- crystalline polymorphs are character- the system• Cuanto2. systemtomará para que una(A an Fig. tiempo Gibbs B) with a transition temper ized free energy free energy of and a changedecreases; Schematic(A and free energy curves for a hy monoclinic, but ment with several one asymmetric mole- system s pharmaceu- among its polymorphs. Investigations into the poly- possess only forms. The of the system decreases; (form II) necessarily have B. Rodrıguez-Spong et al. / Advanced Drug Delivery Reviews 56 (2004) 241–274 different arrangements in the lattice. Form I ule withthe unit celldo not [48,51]. Similar molec- nsformation can occur naturally in two morphism of this drug began and packing ingly large differences in instability andarrangement of molecules in the solid the late 1960s transformación alcance el equilibrio? a component system that exhibits crystallineglass t and nic 5.2.2. Carbamazepine 254 ´ state. Often the key intermolecular interactions, both andin adopted and trigeminal neuralgia, is a versa. forms. in both 2. DG = 0 2. continue to occur the equilibrium with equilibriumthe with and supercooled liquid with asuperco and lar conformations are viceFig. 9, a pharmaceutical used in produced three forms; two of these were structurally assembles in a head-to-tail manner whereas form II DG = 8,51,100]. A Carbamazepine,s the potential when the 0 andwhenis as long as though it isdifficulttransitions. this will be points, Tm,fashion, Fig. 8.A and torelaxation, viscosity,system NMR relaxationsystem is packs predict when Monotropic systems (Athe crystalline at at to in a tail-to-tail head-to-head for and C, In weak and strong, are preserved among forms, al- However, the molecules of epilepsy on from small n in capillar- the treatment each structure adopt strik- the that reflect (1) molecular mobility, such as enthalpy tetramorphic system possessing nearly identical mo- Melting to times transformationtransformationgivenform molecularfree such obvious ofof curvesMelting poi 254 ´ B. Rodrıguez-Spong et al. / Advanced Drug Delivery Reviews 56 (2004) 241–274 respectthe the and (2) intermolecular interactions such the free energy ofthe (Aintersection a transition temperature Tt, a orph is also system to the respect e energy5.2.1. Nabumetone decreases; of solid-state and as lecular conformation and strong hydrogen bonding case for a compound. For cases where changes inthatand Iare observed, the energy interactions, especially crys conformation weak and designator system mobility, B) with intermolecular the Cinética metric mole- among its polymorphs. Investigations into the poly- for the milar molec- morphism of this drug began in the late 1960s and infrared and Raman spectroscopies. reflect (1) kliquiddominate theintersection as enthalpy the two phases(Relafenk), Fig. 7, is an anti-inflam- used. Differences:intermolecularAdaptedgen- as the relations developed by Nabumetone is the same; and CUH : :supercooled such ‘‘conformational polymorph’’ [1,2,29,97 –NMRisrelaxation relaxation, viscosity, and solid-state 99] a system is at equilibrium same; andand spectroscopies. contacts, with a glassarrange-G = 0 when the 5.2.the two phases is the usually infrared andcontrast, close II packs in a herringbonestructure. from O transition both forms. produced three forms; two of these were structurally e adopt strik- Crystalline with erally interactions from times and (2) in the packing of molecules matory, analgesic, and antipyretic therapeutic increases By Meltingbeen termed byTm, for the crystalline phases ar Raman form Adapted DG is positive when the free energy investigators and with similar conformations have points, some 3. to the transformation and the free energy of as ‘‘packing polymorphism’’ [1,29]. Itb is : : pect k prescribed to patients withpolymorphs arewhen the free Crystallinewith several CUH : curves for the crystalline an DG crystallineof changes in This under generallyspecific these designations, however, and 3. Structurally,isispositiveconformation Fig. 7. Structure of nabumetone. pharmaceu- 5.2. ment arthritis. character- energy increases k interactions. Fig. 9. Structure of carbamazepine. intersection of the thetical crystallizes arrangement polymorphs in the solid I, are artificial Structurally, crystalline polymorphs areexhibit transformationdegreesnotmolecules (top: form ized by varying in two of possible forms. The twoFig. 8. Packingis the of nabumetone phases diagrampacking same; and polymorphic the recognized that all polymorphs character- because virtually and Adapted from the relations developed by Shalaev the transformation is not possible under the specific ized by varying degrees of changes in conformation small differences in conformation among their mod- bottom: formFig. 9. Structure of carbamazepine. key intermolecular interactions, both II). state. Often the 21 Fig. 8. Packing diagram of nabumetone polymorphs
  22. 22. temperature and pressureof solids The relative thermodynamic stability is deter TERMODINAMICA and isFree energy diagrams and solid-state stability the drivingence infor a transformation at const force Gibbs free energyhe relative thermodynamic stability of solids and dif temperature and pressure is determined by the riving force for free DH À and is given by: ence in Gibbs a¼ energy T DS at constant DG transformationerature and pressure is determined by the differ- DG ¼ free À T DSla diferencia de by: in Gibbs• DH Refleja and is given energía energyenthalpy difference betwe The estructural o de red entre las formas reflects the lattice orthe forms, D The enthalpy difference between structural¼ DH À•T DS Refleja el grado de desorden y ð1Þ reflects theand thedeentropy difference, DS las vibraciones or la red lattice structural energy differen and the entropy difference,the forms, DH, toT disorder and lattice vibrations. enthalpy difference between DS, is related ts disorder andorgiven vibrations. The relative stabi the lattice is lattice by the algebraic sign of structural energy differencesthe isentropyby the algebraic sign of DG as follows: given difference, DS, is related to the 22
  23. 23. Diagramas dG vs T Termodinámica Advanced Drug Delivery Reviews 56 (2004) 241–274 245 llowing bility ids and onstant e differ- Enantiotrópicos ð1Þ Monotrópicosms, DH, erences to the stabilityws: ses. The Fig. 2. Schematic Gibbs free energy curves for a hypothetical single- 23
  24. 24. that exists in isamorphous and accordingAbove and The van’t t morph A to B in the literature, given by: tures. to constant. below H the method des in the T Yu free Consider the ð2Þ shown ¼ DH ÀGibbs [35].energy for stability order is reverse carbamazepine, P-m applied to APIs over Ej. Carbamazepina DG0 0 m;A DS0 Phase transformationsGrastrates that polymorph= A and triclinic = I = B. The change C is more = III indicates the value of the model derived by b where the subscript ‘‘0’’ uation of the heat of soDG = GC À GA is < 0 and thus a polymorphic transformation w and between crystalline –li thermodynamic function at Tm,A,the melting point of energy for the temperature ranges fr polymorph Asame C is possible. by Yutransitions non-linearity. there form A. The to nomenclature used is given by: [35] is in which These morphIII =to B A A used solids example. = deredP-monoclínica The changes in enthalpy, DH, in this of the same com- first Triclínica =of = B free[2 derivative I elsewhere reviewed the andenergy thanassociated with the transformation À S, (BG/BP) for (Cp, entropy, DS, the crystalline BT)P = The value free T = of D V, DG0and DH0 accordingAmorphous to substitution are calculated from melting data À Tm;A DS0 ¼ entropy to the from thefollowing equations: higher enthalpy of Eq.supercooled (3), which givults from the victory of kinetics first-order and exhibit a gr where241–274ÀsubscriptÀ ‘‘0’’ indicates p;B Þ¼ðDHt À the Cp;B ÞðTm;B Tm;A Þ the val DH0 ¼srug DeliveryDHm;A À56 (2004)þ ðCp;L [36,37]. Reviews DHm;B ðCp;L À C Tg such that there is a d thermodynamic function at T(BH/BT) = C . A diagram, the intersection points ð3Þ m,A, the melting capacity, P P DHm;A form A. The same same composition will by Y DHm;B nomenclature used exhi Tm;Bt coexist in equilibrium, crystal Cp;B Þln DS0 ¼ À þ ðCp;L À Tm;A used in this example.Tm;A changes in enth Tm;B The rresponding to melting temper- relaxation times and glass ates at transition temperatures, ð4Þ and entropy, DS, associated of preparation a the mode with the trans where the liquid p,L calculated from betweenshift the position (C states at is the This willsupercooled term are À Cp,B) glass differencemelting data accordin crystalline equations: the amorphous solid-es. In the case of followingstates for the heat capacities of form B and supercooled liquid at temperatures between Tm,A and Tm,B and the differ- 24
  25. 25. ff plot). thisvariousDH[35,41] we will demonstrate the heat of value of ted parameter mat- poses where DH(DHt) aþ c proposed solubilityis given a ð7Þ forS calculation since to to B data theby: methods transition from A calculate as Yu [35]. Consider for carbamazepine, P-monoclinic weight lnðsÞ ¼ parameter [35,41] we will demonstrate the heat of transition t À ndbyis While this and triclinic = I = B. The change in = III = A of temperature is often available for APIs. Iffree RT exposes function B (DH )A calculation since solubility data as a where s nic The dying DHtransitionÀpolymorphic transformation from poly- energy independent tof T in the range of measurement ð6Þ DHt ¼ for the DH S is DH S absolute Diagramas de van´t Hoff .con- ree Whilehere is where sAis the is given by:ofis often available for APIs. If constant. function of temperature a given polymorph at an morph to B solubility then: tudyingoly- ations DHand independent of is the the range of measurement applied t solid absolute temperature the T in gas of solution c DH S B t is DH S are T, R enthalpies constant, andforis a A there is DGRodrı´guez-Spong0etÀ /Tm;A DS0 Delivery Reviews 56 (2004) 241–274nment. rate t ¼ DH B. then: DH0 ¼ DH0 al. Advanced and constant. The van’t Drug can behas been successfully model de polymorphs A and B Hoff plot calculated from the 247 ð5Þ ð2Þ mationsubility s DH , DS , andapplied evaluated fromover on temperature according to the DG can be todependence narrow temperature ranges. The solubility APIs Eqs. ‘‘0’’ indicates the value of the uation of rement. 0 0 where the subscript timat- (2). Bywhere DHt for a transition from A to B is given by: 0 fð2Þ and model relationship given by a van’t Hoff plot accord- ð5Þ temperat an- 3), (4) DHt ¼ DH assuming a non-linear or linear linear derived 0by the and isof DG on temperature [35], DG for Grant at Tm,A, the melting point eval- ndence thermodynamic function and coworkers [42] for ofolubility ing to: determined at other linic, transition can be .the The linear relationshipTheÀsame nomenclature be applied over wider non-linea morphic The estimat- uationA. the heat of solution can used by Yu ð6Þ is form ¼of isSgiven DH S DHwhere DH by: Aa transition from A to B is given by: DH B [35] ature peratures. t t form of con- temperature ranges when the van’t in enthalpy,leads to reviewed used in this example. The changes Hoff plot 28.01 kJ/mol tT Þand 0is DS0ðT À TB Þ DH A ð9Þ ] ¼ DG À orted DH, solid and Sentropy, SSB c methods have been thoroughly + estable v The m;A DH ¼ À DH These non-linearity. DS,are theA enthalpies the solution for ð7Þ and ]d is The – temperature diagram can þÀ DH associated with of transformation ty.rate a DG lnðsÞ t ¼ DH be ob- n by DH his way, polymorphsRTdata. B [28]. bedataTt 346K from 31.54 kJ/mol ð6Þ solublesub reviewedmelting and and can calculated A arepair from elsewhere melting calculated Sfrom S according the the to - fromDH,con- m a polymorphic linic d for followingdependence p,L À Cp,B) can then be calculated of Eq. (3 he difference in the Gibbs free energy associated on temperature according to the solubility equations: iontransformation of DHsvalueto for given by a a given polymorph at an for ss solid where relationship (C areof van’t Hoff plot of solution free The B A B can be A of an- the linear S is the DH S polymorphand solubility the enthalpies accord- clinic, following relation temperature DH 3.and can constant, and c is a the ulated ion the the rate fromto: substitution measurements of the two absolute DHpoly-from solubility polymorphs Aof T, R0iswithgas plot andP-monoclinic (III) and triclinic (I) Fig. The van’t Hoff t for the and B the rearrangement s by rature ing DH which gives: of p;L À C in calculated m;A Þ be ÞðTm;B À T from DH0 ¼(3), m;A À DHm;B formsðCcarbamazepine p;B2-propanol. Adapted from the data ðCp;L À C þ of Eq. The dependence plottemperature according to the constant. solubility van’t Hoff onby Behme andbeen [41]. presented has Brooke successfully ported GA Þ ¼ RT ln SB : to DHS 3.53 kJ/mol 29.3 kJ/mol 26.4 kJ/mol ranges. The ¼ ofB À ðG an- applied relationship given temperature Hoff plotð3Þ ð10Þ APIs over narrow by a van’t linear lnðsÞ ¼ ÀSA þc ð7Þ – accord- ð2Þ ed bym;A Þ assumes that concentrations can be t ÀDHdiagram iswas calculated fromThe DG tempera- riclinic, ðCp;L Àderived by GrantturetransitionþDH3.53 [42] for eval-and Þ equation model to: RT ing Cp;B Þ¼ðDH ofand coworkers kJ/mol. m;B ÀTm;A is m;A then m;B Þ=ðT Eq. (10)oclinic activities if the ratio of the activityperature uation of the heat of solution in Fig.be applied over wider fð3Þ for the two polymorphs is approximately tituted the of shown can 4.n free where s is the solubility ofthegiven polymorph at an toð8Þ eported temperature ranges when a van’t Hoff plot leads melting ficients complete poly- DHS nt of discussion of this method is presented 2.1.1.2. DG – temperature diagram from 25
  26. 26. 254 ´ B. Rodrıguez-Spong et al. / Advanced Drug Delivery Reviews 56 (2004) 241–274 Cinética that reflect (1) molecular mobility, such as enthalpy relaxation, viscosity, and solid-state NMR relaxation times and (2) intermolecular interactions such as infrared and Raman spectroscopies. 5.2. Crystalline Structurally, crystalline polymorphs are character- • Cuanto tiempo tomará para que una ized by varying degrees of changes in conformation and packing arrangement of molecules in the solid transformación alcance el equilibrio?anced Drug Delivery Reviews 56 (2004)key intermolecular interactions, both state. Often the 241–274 weak and strong, are preserved among forms, al-alpy though it is difficult to predict when this will be the tion case for a given compound. For cases where obvious as changes in conformation are observed, the designator k ‘‘conformational polymorph’’ [1,2,29,97 – 99] is gen- a erally used. Differences in the packing of molecules with similar conformations have been termed by somecter- k investigators as ‘‘packing polymorphism’’ [1,29]. It isb tion generally recognized that these designations, however, olid are artificial because virtually all polymorphs exhibitboth small differences in conformation among their mod- Fig. 8. Packing diagram of nabumetone polymorphs (top: form I, al- the ifications. However, it is important to note that poly- morphs, which exhibit large differences in structure, Elementos estructurales del bottom: form II). ous ator • do not necessarily have large differences in stability Ensamblaje Molecular II ingly different arrangements in the lattice. Form I and vice versa. assembles in a head-to-tail manner whereas form Cristalizacióngen- packs in a tail-to-tail head-to-head fashion, Fig. 8. In ules 5.2.1. Nabumetone form I weak intermolecular interactions, especiallyome Nabumetone (Relafenk), Fig. 7, is an anti-inflam- CUH: : : O close contacts, dominate the structure. It is By contrast, form II packs in a herringbone arrange- matory, analgesic, and antipyretic therapeutic usually ver, prescribed to patients with arthritis. This pharmaceu- ment with several CUH : : : k interactions.hibitmod- tical crystallizes in two polymorphic forms. The Fig. 8. Packing diagram of nabumetone polymorphs (top: form I, oly- commercial material (form I) is monoclinic with two bottom: form II). 5.2.2. Carbamazepine 26
  27. 27. Cristalización • Etter. Moléculas que se acomodan por Rodrı´guez-Spong B. medio de fuerzas no covalentes (P. deDeliveryof this B. Rodrıguez-Spong et al. / Advanced Drug H) Reviews ´ bonds. A major conclusion siguiendo patronesthis worka was to between the singbonds. A major conclusion of de empaquetamiento establish connection case of a moestablish energéticamente thebly processes that precede nucleation a a connection between adecuados. molecular assem- liquid (melt)bly processes that precede nucleation and the in the crystal follows a path ular arrays molec- state:ular arrays in the crystal state: aditivos the initial and Molecule X Molecular assembly X transition fromMolecule X Molecular assembly X Molecular network X Crystal is an energy ba solventes Molecular network X Crystal These findings motivated investigations assemblies, an chemical reac molecular aspects of crystallization pThese findings motivated investigations on the supra- energy maxim have found great utility in explaining tmolecular aspects of crystallization processes and elementary rea or disappearance of polymorphs [14],have found great utility in explaining the appearance solvents and additives have on productsor disappearance of polymorphs [14], the role that yield the direc 27
  28. 28. initial state Gi, to two different solid forms A or B. barrier for structure A (G Form A is more stable and less soluble than B Cinética Vs Termodinámica for B (G* À Gi). Becaus B ( GA GB). Gi may represent a supersaturated solution related to the height of in a multiple-component system, liquid or solid (mo- reaction path, B will nucl lecular dispersion in amorphous system), or in the even though the change in ( GA À Gi) than for B ( G possible behaviors that co of appearance of polymo Ostwald’s law of stages. an unstable state, a system stable state, rather the nea can be reached with lo However, Ostwald’s law valid because the appeara phases are determined by and growth under the spec [27,56,57] and by the link menos soluble blies and crystal structure Crystallization involve growth of a phase. Be nucleation in the selecti morphs and the stabilizat Ley de las Etapas de Ostwald´s: “Cuando se deja with estado inestable, el in this un free Fig. 5. Schematic diagram for a hypothetical transition from the initial state, Gi, to two different solid forms A or B, will be discussedsistema no busca el estado Bmas estable, buscarásoluble than B. metaestable que energies GA and G . Form A is more stable and less el estado kinetics and crystal morp acterizing intermolecular i pueda A transition from the initial state to ithis state A or B will depend on ser logradoand according G to reaction pathway theenergía libre” the energy barrier con la menor pérdida de height tal planes and as a co * of the energy barrier for structure A, (G A À Gi) is greater than that additives or solvents that for B, (G * À Gi). Because the rate of nucleation is related to the B the crystallization of 28a
  29. 29. Sistemas de un Solo Componente • Amorfos • CristalinosSistemas de Múltiples Componentes • Amorfos • Cristalinos: i) Co-cristales: Moléculas neutras, Moléculas Cargadas y Solvatos. 29
  30. 30. SSC - Amorfos • Mejor Biodisponibilidad que los cristalinosNo-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
  31. 31. SSC - Amorfos POLI-AMORFISMO a partir de• 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 31
  32. 32. at low temper- [53]. weight particularglasses has been patterns inby spectro- ecular fast acid crystals by precipitation organic hydrogen-bond obtained low moleculaallineby rapidtemper- crystalline states Raman) been related toaes and solids developments toprovide molecularunder- have [95]. Similarities ically Recent probe level melt at low and scopic methods (infrared and has been obtained by spectro SSC - Amorfos utical interactions mobility weight in-depth glasses organic[91]solvent by molecular relaxationamorphous state the amorphous and ration and inof rapid g of astandingby nching melt between molecular assembliesand Raman)to the crys the andmethods (infrared in and [95]. Similarities scopic recognition pro- ple, itor freezingsolids allowcrystalline states have been related toin the amorphous and ystallinecesses solvent infor better design and stability of assemblies the instability of of that between molecularManufactur-pharmaceutical dosagestabilityStrategieshave beencrystallizationinstability oI nafate disordered om (b) crystalline predictthe long-term ferentforms.state perfor- to the related to the of dif- res [91] and by solidsthe amorphous states slight- assess and polymorphic forms [37,89]. crystalline and and to amorphous ferent polymorphic forms and to the crystallization of2]. Manufactur- amorphous systems relyshown statecrystallize from the difemperatures [91] and by beenamorphous to [37,89]. Indomethacin has a amor- mance of the on measurementsmilling [92]. Manufactur-erials are amorphous been shown to crystallize from the amorphous state in has ferent polymorphic forms [37,89]. Indomethacinng and melt either the gshown tog or formscrystal forms d nthal-dg to preparemeltdrying andT and amorphous either or a crystal afrom the amorphousthe in been the crystallize depending on staterted in the melt temperature [96]. Temperatures onV T , freeze-drying and temperature [96]. gTemperatures V T produce the g the erence eported in the d the either the or a crystal forms depending g oducts reported in the nce containing temperature T produce the V Tg produce the polymorph whereas[96].TTemperatures a form. Raman g kcontaining Reference containing polymorph whereas T Tg produce th phous g polymorph whereas T Tg produce the a form. Raman xcipients often ografi and IR studies have shown that hydrogen-bond patterns s, and excipients often and IR studies have shown that hydrogen-bond patterns ients often of indomethacin in the inhave shown that hydro phism nowl- powders. andpensions, and powders. and indomethacin amorphous state state lead to crys of IR studies the amorphous lead to crys-r subcutaneous ed for tallization of the polymorph with molecular assembliesdexis- for ratiosance, powders. similartallization of the polymorph with Hydrogen-bond s subcutaneous of indomethacin in the molecular assemblieshing a with varying ratios varying amorphous to those those inglass glass [24]. Hydrogen-bond in the the [24]. eted similar to bcutaneous assemblies ofmotifs in crystalline monocarboxylic acidsacids and uentlycontrol control the to to the insulin Fig. 6. Molecular motifs found foundof crystalline monocarboxylic and tallizationacidin the polymorph with mol the carboxylic synthon mate- (intermolecular connector) the a andhydrogen bond patterns in illustrating the g indomethacin polymorphs are shown in inrying ratios supramolecular isomers: (a) a (gamma y alfa)the glass [24]. phism that lead to two similar and g indomethacin in the dimer to(b) those in polymorphs are shown Indomethacina Amorfa The dimer found ingthe g form is mostmos and head-to-erience transla-materi-experience transla- lids tail chain. Fig. 6. Fig. 6. The dimer found in the form is the the control that do not motifs found in crystallinemonocarboxylic ymobility the that do not common supramolecular synthon for monocarb common supramolecular synthon for monocarboxylic nced molecular the a and g acid crystals [53]. his enhanced molecular in acid crystals [53]. indomethacin polymoand chemicallyysically and chemically RecentRecent developments to probe molecular leve developments to probe molecular level 32
  33. 33. matory, analgesic, and antipyretic therapeutic usver,that these designations, however, prescribed to patients with arthritis. This pharma virtually all polymorphs exhibit SSC - Cristalinos bit tical crystallizes in two polymorphic forms. od- Fig. 8. among their of nabumetone polymorphs (top: form I, nabumetone (form I) is monoclinic with conformation Packing diagram mod- commercial material Fig. 8. Packing diagram of polymorphs (top: form unique molecules in the unit cell [48,51,100 ly-is important formnote that poly- it bottom: to II). bottom: form II). second polymorph forms upon evaporation from sure, large differences in structure, bit volumes of ethanol [48] or crystallization in cap ave large differences inarrangements in the different arrangements possess only onepolymorph ism ity ingly different stability ingly lattice. Form I(Sectionbut in [51]. This asymmetric ies monoclinic, 7.2.2) the lattice. Form et al. / Advanced Drug Delivery Reviews 56 (2004) 241–274 assembles in a head-to-tail manner whereas a head-to-tail manner whereas Similar m assembles in form II in the unit cell (form II) [48,51]. form I cule h as enthalpy packs in a tail-to-tail head-to-head fashion,tail-to-tail head-to-head fashion, Fig. 8. fo packs in a Fig. 8.ular conformations are adopted in both In InMR relaxation However, the molecules in each structure adopt s cking diagram ons such as form I of nabumetone polymorphs (top: form I, weak intermolecular interactions, especially form I weak intermolecular interactions, especially afenk), CUH: : isO close contacts, dominate : the structure. m- II). Fig. 7, : an anti-inflam-orm CUH: : O close contacts, dominate the structurend antipyretic therapeutic usually in aBy contrast, form II packs in a herringbone arrange lly By contrast, form II packs herringbone arrange- s character- ment with several CUH : : : k interactions. several CUH : : : k interactions. eu- are with arthritis. This pharmaceu- ment withThethe solid arrangements in the lattice. Form I ifferent conformation intwo polymorphic forms. The Fig. Namebutona wo in I)5.2.2. Carbamazepine es botha is monoclinic with two whereasCarbamazepine actions, (form head-to-tail manner 5.2.2. form II 7. Structure of nabumetone. g forms, al-nnAthe the Carbamazepine, Fig.A9,fashion, Fig. 8.used in 9, aAnti-inflamatorio used in s will tail-to-tail head-to-head a obvious cell [48,51,100]. be unit a pharmaceutical In Fig. Carbamazepine, pharmaceuticalmall upon evaporationof epilepsy and trigeminal neuralgia, is a here the treatment from weak tetramorphic systeminteractions,treatment of epilepsy and trigeminal neuralgia, isorms he designator intermolecular small ar- isor crystallization in capillar- – 99] gen- the especially nearly identical mo- Analgésico possessingtetramorphic system possessing nearly identical mo [48] : molecules lecular conformation and of O close contacts, dominate the structure. Antipirético lso by someThis polymorph is also strong hydrogen bonding and strong hydrogen bonding med[51]. lecular conformation ’’ [1,29]. It is among its polymorphs. Investigations into the poly- Artritis (Relafen) rast,only oneIIasymmetric mole- le- sess ons, however, form packs in a herringbone arrange- among its polymorphs. Investigations into the poly ec- exhibit morphism of : : drug began in the late 1960s and : thisk interactions. ith several CUH of nabumetone polymorphs (top:morphism of this drug began in the late 1960s and orphs (form II) [48,51]. Similar molec-ms. mod- produced II).diagram forms; two of these were structurally g their three Fig. 8. Packing form I,s arepoly- bottom: form both forms. ote that adopted in produced three forms; two of these were structurally ik-structure, in ulesstability ingly different arrangements in the lattice. Form I s in in each structure adopt strik-Carbamazepinein a head-to-tail manner whereas form II assembles packs in a tail-to-tail head-to-head fashion, Fig. 8. In amazepine, Fig. intermolecular interactions, especially used in form I weak 9, a pharmaceutical 33
  34. 34. matory, analgesic, and antipyretic therapeutic usually nized that these designations, however, n polymorphs [109]. However, it was not untilhowever, manner in each of the three polymorphs, while form prescribed to patients with arthritis. This pharmaceu-4 that a virtually all polymorphs compound cause single crystal structure of this exhibit III packs with an NUH : : : O intermolecular hydro- SSC - Cristalinoss exhibit tical crystallizes in two polymorphic forms. The es in solved/ Advanced8.Drug Delivery polymorphs (2004)gen bonded dimer. form I, nabumetone (form I) is monoclinic withI,two been Spong et al.eir mod- [105]. Two additional Reviews 56 Fig. among their of nabumetone polymorphs (top: commercial material polymorphs (top: form conformation Packing diagram mod- 241–274 Fig. 8. Packing diagram of unique molecules in the unit cell [48,51,100]. A ever, it is important formnote that poly-hat poly- bottom: to II). bottom: form II). second polymorph forms upon evaporation from small tructure, large differences in structurally characterized in 1985 and another [48] or crystallization in capillar- exhibit were structure, volumes of ethanol rily have(2004) 241–274was inarrangements in [106,107]. This system dis- possess only onepolymorph ismole- stability large differences described in 1988 the different arrangements in [51]. This asymmetric I views 56 ingly different stability ingly lattice. Form I(Sectionbut ies monoclinic, 7.2.2) the lattice. Form also assembles in a head-to-tail manner whereas form is the unit cell (form II) [48,51]. Similar molec- plays conformational polymorphism, a head-to-tail manner whereas form II uez-Spong et al. / Advanced Drug Delivery Reviews 56 (2004) 241–274 assembles in whichII exem- cule in lity, such as enthalpy packs in a tail-to-tail differencespacks in NUSUCUC head-to-head fashion, Fig. 8. forms. plified by head-to-head fashion, Fig. 8.ular conformations are adopted in both in the a tail-to-tail torsion In In cturally characterized in in the molecule, Fig. 11, that can However,large state NMR relaxation yridine. angle 1985 and another be as the molecules in each structure adopt strik- 8. Packing as form I of nabumetone polymorphs (top: form I, interactions such diagram weak intermolecular interactions, especially one form I weak intermolecular interactions, especially ribed in 1988 [106,107]. between forms. dis- : the distinct contacts, dominate the structure. -inflam- II). CUH: : isO close This system pies. : as 39j contacts, dominate : O structure. (Relafenk), Fig. 7, conformation is present in forms close However, an anti-inflam- CUH A single : molecular m: form formational By contrast, form usually in aBy contrast, II – IV. II packs in256 herringbone Rodrı´guez-Spong et al. / Adv usuallyantipyretic therapeutic II packs is exem- polymorphism, which herringbone form arrange- B. ic, and ur of these forms form V is unique: in the fact that it possesses two a arrange-y differences –in withdifferent CUH : : k torsion same unit CUH : : : k interactions. aracterized arthritis. the NUSUCUC lattice. Form I cell. This morphs are character- ment rmaceu- atients with [105 several This pharmaceu- interactions. conformers ment with several y different arrangements can the as in the the inmolecule, Fig. 11, forms. in also apparent in the packing arrange- 7. Structure of nabumetone.ms. inconformation nges es Thethe reported was intwo polymorphic that is be olecules first solid difference The large orphs (formal- is terial were I) etween head-to-tail distinct whereas form displayed by Namebutona of sulfapyridine.with two in identi-monoclinic and hydrogen bonding Carbamazepine ular interactions, botha5.2.2. Carbamazepine mbles forms. A single with two molecular schemes II ment manner 5.2.2. Fig. ed among forms, Fig. 12.in Packing diagrams Fig. 11.sulfapyridine polym of Structureks in isthe the by cell head-to-head9,fashion, Fig. 8.usedIV, and VAnti-inflamatorio used in 100].inA found Carbamazepine, Fig.A a Fig. Carbamazepine, Fig. 9, a pharmaceutical when wasa tail-to-tail [48,51,100]. each modification, pharmaceutical In th this will be unit in forms II – IV. However, Forms II, les tionwhere obvious the treatment of epilepsy and trigeminal neuralgia, is a present 12.rphsmall upon evaporation from similar NUH : :treatment of epilepsy and trigeminal neuralgia, is a these fo m Later exhibit a interactions, : N hydrogen bonded di- as Analgésico cases weakin the fact system possessingthe especially es. Iforms thermal served, the designator intermolecular smallm unique gen- tetramorphicthat it possesses nearly identical mo- s two at least seven polymorphs. Four of capillar- or crystallization in capillar-apyridine 1,2,29,97 – 99] isrevealed anol:[48] : molecules lecularthe same unit cell. tetramorphic bonding : also packing of O close contacts, dominate the structure. Droga Sulfa (II –V) have been structurally characterized [1 mer. These dimer units assemble system different 107]. nearly identical mo- first repo in a possessing Polymorphism of this system was Antipirético four polymorphs were id H was some until conformationalso the lecular conformation and strong hydrogen bonding conformers in r,isittermed bynot This polymorph in each ofstrong hydrogen manner is and This .2.2) [51]. beenecontrast,only oneIIasymmetric mole- NUH : : : O arrange- orphism’’ [1,29]. It is among its polymorphs. Investigations into the poly- also form c isthis compound of three polymorphs, while form in 1946, [108] when mole- apparent packs in with an arrange- its polymorphs. Investigations into the apoly- found anti-bacterial Artritis melting point and fifth was fied by (Relafen) III packs a herringbone intermolecular hydro- optical crystallographic properties. Later the in the packing tesignations, however, possess among microscopy Neumonia on hydrogen [48,51]. of : : molec- polymorphs CUH : this interactions. rll molec- exhibit morphismgen bonded dimer. in the late 1960s and tional(form II)bonding Similarkdrug began morphism of this drug began in the experiments on sulfapyridine reve with mod- Fig. polymorphs cell schemes displayed bynt among theirseveral 8. Packing diagram of nabumetone polymorphs (top: form I, late 1960s and seven polymorphs [109]. However, it was not forms. produced three forms; two of these were structurally dification, ant to note are adopted form II).Formsforms. tions that poly-Fig. 12. both II, IV, and V bottom: in produced three forms; two of1984been a were structurally polymo had these solved [105]. Two additional compo that single crystal structure of this pt strik- fferences in structure,moleculesstability ingly : N hydrogen the lattice. Form di- ifferences in in each : : different arrangements in bonded I similar NUH structure adopt strik- 2. Carbamazepinein a head-to-tail manner whereas form II assemblesCarbamazepine, Fig. intermolecularin a different used inese dimer units in a tail-to-tail head-to-head fashion, Fig. 8. In packs assemble form I weak 9, a pharmaceutical interactions, especiallyn 7, is an anti-inflam- three: Opolymorphs, while formg. each of the CUH: : close contacts, dominate the structure.treatment of epilepsy and : trigeminalarrange- By contrast, form II packs in a herringbone neuralgia, is a with an NUH : :withO intermolecular hydro- ment : several CUH : : k interactions. ic therapeutic usually itis. This pharmaceu-amorphicThe morphic forms. system possessing nearly identical mo- ed dimer.two Packing diagrams of sulfapyridine polymorphs. From top left clockwise: form II, III, IV, and V. monoclinic with Fig. 12. 5.2.2. Carbamazepine 34
  35. 35. Sistemas de un Solo Componente • Polietilenglicol (PEG)g et • /Polivinilpirrolidina (PVP) ´guez-Spong • Amorfos Delivery Reviews 56 B. Rodrı241–274 et a al. Advanced Drug (2004) • Cristalinos 6. Multiple-component systems • Polivinilalcohol (PVA) The stabilizing effects of PV Sistemas de Múltiples Componentes molecular dispersions are organic Multi-component systems of molecul ecular Polivinilpirrolidina/vinilacetatoa (PVP • assem- been explainedan API and hydroge blies composed of in terms of comp • Amorfos [24,118,119].omplementary molecule (neutral or For instance, as solv the a charged) such • Derivados inhibitother substances. These solid-s de: celulosa, poliacrilatos y solvent,• exci- pients, and the crystallization of indo Cristalinos: i) Co-cristales: Moléculas polimetacrilatos temperature (30 jC) haslid-state super- molecules are assembled from specific rel neutras, Moléculas Cargadas y Solvatos. been noc non-covalent interactions betweenintermolecular intera mobility and molecules, includingding hydrogene.bonds, interacciones de vanWaals and kthat in Puentes de H, iónicos, ionic, van der der revealed –k th spectroscopy results Waals yk interactions. Supramolecular synthons are formation in responsible for dimer the structural 35
  36. 36. SMC - Amorfos D • Polietilenglicol (PEG) M i o ong et • /Polivinilpirrolidina (PVP) ´ s 257 B. Rodrıguez-Spong et al. / Advanced Drug Delivery R al. Advanced Drug Delivery Reviews 56 (2004) 241–274 l A p 6. Multiple-component systems e m The • Polivinilalcohol (PVA) The stabilizing effects of PVP on amorphouso e c molecula of molecular assem- r been molecular dispersions are organic substances have exp • Polivinilpirrolidina/vinilacetato (PVP/VA) patterns r Multi-component systemsmolecular assem- blies been explainedan API and hydrogen bonding s [24,118, u composed of in terms of a complementary l f [24,118,119]. charged) such the ability of i complementary molecule (neutral or For instance, as solvent, exci- PVP inhibit t to as solvent, exci- pients,de: celulosa, poliacrilatos y super- at rooma • Derivados inhibitother substances. These solid-state and the crystallization of indomethacin o temperat a solid-state super- molecules are assembled from specific related to molecular s polimetacrilatostemperature (30 jC) has been non-covalent n mobility r ific non-covalent interactions betweenintermolecular interactions. Vibrational mobility and molecules, including hydrogen e spectrosc e luding hydrogen bonds, ionic, van der Waals and kthat interactions. bonds spectroscopy results revealed –k the hydrogen responsib s sk –k interactions. Supramolecular synthons are formation in units that responsible for dimerindometacinaindomethacin disrupted PVP inhibe la cristalización de the structural a 30oC are uctural units that connect molecules to one another via thesethe formationcrystal n disrupted, which are prerequisite to interac- ofvia these Movilidad Molecular e Interacciones Intermoleculares indo- interac- tions. crystalintermolecular interactions can be used as of methacin Thus, nuclei [24,119]. The carboxylic acid key molecular recognition elements in the design of the more 36
  37. 37. for three solvates of niclosamide: a dihydrate, a dration onset temperatures (173 F 5 and 201 F 5 jC), tetrahydrofuran (THF) solvate and a tetraethylene and indicates that water and niclosamide are tightly glycol (TEG) solvate. The relative strength of hydro- bound. In contrast, the THF solvate undergoes rapid SMC - Cristalinos gen bond donor and acceptor groups was correlated to desolvation from molecular assemblies at 30 jC, structural architecture and thermal behavior, indicat- which is 36 jC lower than the boiling point of THF. ing desolvation pathways. Caira et al. [130] showed The instability of this system was explained by weak that in the niclosamide hydrate, water molecules forces forming a continuous channel within the crystal occupy a channel and hydrogen bond with surround- structure, which facilitates migration of the solvent ing drug molecules (Fig. 13a). This arrangement falls out of the lattice (Fig. 13b). The TEG solvate forms• Co-cristales: Solvatados 173+5 5070 Agua, 745 MEOH, 356 ETOH, 30 309 Acetona, 137 DMSO 274 THF Niclosamida Agua THF 65-230 TEG Fig. 13. Crystal structures and heterosynthons of niclosamide (a) monohydrate, (b) THF solvate, and (c) TEG solvate. Solvent molecules are 37
  38. 38. ic activity [10,138]. formation. Fig. 14a – d shows how carbamaze A supramolecular design strategy was recently can form cocrystals with water, acetone, sacch used to prepare 13 new cocrystals of carbamazepine or nicotinamide that retain the carboxamide dime [13]. The crystal packing of carbamazepine in poly- hydrogen bond instead with available donor/acc SMC - Cristalinos morphs and solvates shows the formation of dimers, groups. In contrast, formic acid and trimesic with the carboxamide unit acting as both a hydrogen cocrystals of carbamazepine disrupt dimer form bond donor and acceptor (Fig. 14). Two design (Fig. 14e – f). Given that these cocrystals signific strategies were utilized using this moiety as the alter intermolecular associations and modify cr primary supramolecular synthon where interactions packing, physical and pharmaceutical properties• Co-cristales: Moléculas Neutras Carbamazepina Agua Acetona Sacarosa Nicotinamida Acido Acético Acido 5-nitroisoftálicoNicotinamida, VB3, higroscópica y delicuesente Aductos de la Nicotinamida estables Fig. 14. Molecular assemblies in multiple-component crystals of carbamazepine: (a) hydrate, (b) acetone, (c) saccharin, (d) nicotina (e) acetic acid, and (f) 5-nitroisophthalic acid. Adapted from reference [130]. 38
  39. 39. Preparación de Sólidos • Cristalización (EL al ES) Preparación de Sólidonced Drug Delivery Reviews 56 (2004) 241–274 263 Fluidos Supercríticos Tendenciashend Libre de Solvente • High Throughput (mezclado, macerado, Fluidos Supercríticoshas • Crecimiento de Solvente Libre en Capilares on calentamiento, compresado) (mezclado, macerado,ds, • Nucleación inducida por Laser lu- Espacios Confinados (Capilares) calentamiento, compresado) Espacios Confinados (Capilares)za- in Highthroughput • Heteronucleación en mono-cristales Highthroughputgh- • Heteronucleación por polímeros ngateza-ec- ofans ol- Fig. 15. Comparison of plateau supersaturations achieved by in- 39
  40. 40. 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

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