This document summarizes principles of polymorphism in solid pharmaceuticals from a supramolecular perspective. It discusses how polymorphs can have the same chemical composition but different structures and properties due to variations in molecular conformation and crystal packing arrangements. It also covers implications of polymorphism for properties like mechanical behavior, chemical and physical stability, solubility, and dissolution rate, which can impact bioavailability. Polymorph transformations are controlled by non-covalent interactions like hydrogen bonding and molecular recognition and are influenced by thermodynamic and kinetic factors.

1. PRINCIPIOS GENERALES DEL
POLIMORFISMO 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

2. 2

3. www.iyc2011.org
3

4. 4

5. 5

6. 6

7. 7

8. 8

9. Erase una vez ...
9

10. Formas Cristalinas
10

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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 pro
s. Many other substances exhibit polymorphism: inorganic and organic, natural and manmade. Polymorphs a
ed in studies of crystallization, phase transition, materials synthesis, and biomineralization and in the manuf
ecialty 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. Reconocimiento Molecular
Reconocimiento Molecular
ElEnsamble Supramolecular
ejemplo clásico
Ensamble Supramolecular
13

14. “Química, más allá de las moléculas”. J-M. Lehn (1987)
14

15. API
15

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 igual
as
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-
e
us
or
n-
de un tipo de
es
SUPERESTRUCTURA DE RED
e
is para un mismo
r,
it BLOQUE MOLECULAR
d- 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. ´
B. Rodrıguez-Spong et al. / Advanced Drug Delivery Reviews 56 (2004) 241–274 259
in these networks depends on hydrogen bonding into the aforementioned class II structures. The
between 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-Polimorfismo
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
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
Formas cristalinas
con moléculas de
solvente como parte
integral de la
ESTRUCTURA
Niclosamida
Solvente como
componente del
SISTEMA
CO-CRISTAL
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].
17

18. Implicaciones del Polimorfismo
Auto-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. 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. 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. 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 of
G 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. temperature and pressureof solids
The relative thermodynamic stability is deter
TERMODINAMICA and is
Free energy diagrams and solid-state stability
the drivingence infor a transformation at const
force Gibbs free energy
he 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 transformation
erature 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 structural
¼ 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 differences
the isentropyby the algebraic sign of DG as follows:
given difference, DS, is related to the
22

23. Diagramas dG vs T
Termodinámica
Advanced Drug Delivery Reviews 56 (2004) 241–274 245
llowing
bility
ids and
onstant
e differ-
Enantiotrópicos
ð1Þ
Monotrópicos
ms, DH,
erences
to the
stability
ws:
ses. The Fig. 2. Schematic Gibbs free energy curves for a hypothetical single- 23

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 transformationsGra
strates 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 so
DG = 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 giv
ults 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 ¼
srug 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;B
t 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 will
supercooled 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. 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 While
here 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:
tudying
oly-
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) 241–274
nment.
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
mations
ubility
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 of
olubility 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 for
m 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 -
from
DH,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 DH
poly-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 by
m;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 activity
perature 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. 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 some
cter- k
investigators as ‘‘packing polymorphism’’ [1,29]. It isb
tion generally recognized that these designations, however,
olid are artificial because virtually all polymorphs exhibit
both 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
Cristalización
gen- packs in a tail-to-tail head-to-head fashion, Fig. 8. In
ules 5.2.1. Nabumetone form I weak intermolecular interactions, especially
ome 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.
hibit
mod-
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. 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 sing
bonds. A major conclusion of de empaquetamiento
establish connection case of a mo
establish 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 from
Molecule 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 p
These findings motivated investigations on the supra- energy maxim
have found great utility in explaining t
molecular 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 products
or disappearance of polymorphs [14], the role that
yield the direc
27

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 discussed
sistema 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. Sistemas de un Solo Componente
• Amorfos
• Cristalinos
Sistemas de Múltiples Componentes
• Amorfos
• Cristalinos: i) Co-cristales: Moléculas
neutras, Moléculas Cargadas y Solvatos.
29

30. 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

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. at low temper- [53]. weight particularglasses has been patterns inby spectro-
ecular fast acid crystals
by precipitation organic hydrogen-bond obtained low molecula
allineby rapidtemper- crystalline states Raman) been related to
aes 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, it
or 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 molecular
Manufactur-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 of
2]. Manufactur- amorphous systems relyshown statecrystallize from the dif
emperatures [91] and by beenamorphous to [37,89]. Indomethacin has a
amor- mance of the on measurements
milling [92]. Manufactur-
erials
are amorphous been shown to crystallize from the amorphous state in has
ferent polymorphic forms [37,89]. Indomethacin
ng and melt either the gshown tog or formscrystal forms d
nthal-
dg to preparemelt
drying and
T and amorphous either or a crystal afrom the amorphousthe in
been the crystallize depending on state
rted 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.
and
pensions, 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 assemblies
dexis- for ratios
ance, powders. similartallization of the polymorph with Hydrogen-bond s
subcutaneous of indomethacin in the molecular assemblies
hing 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 in
rying 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 polymo
and chemically
ysically and chemically RecentRecent developments to probe molecular leve
developments to probe molecular level
32

33. matory, analgesic, and antipyretic therapeutic us
ver,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 s
ure, 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
In
MR 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 structure
nd 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 with
Thethe 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, pharmaceutical
mall upon evaporationof epilepsy and trigeminal neuralgia, is a
here the treatment from
weak tetramorphic systeminteractions,treatment of epilepsy and trigeminal neuralgia, is
orms
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. matory, analgesic, and antipyretic therapeutic usually
nized that these designations, however,
n polymorphs [109]. However, it was not until
however, 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 - Cristalinos
s 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 Structure
ks 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 small
m 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].
been
econtrast,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 by
nt 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
assembles
Carbamazepine, Fig. intermolecularin a different used in
ese dimer units in a tail-to-tail head-to-head fashion, Fig. 8. In
packs assemble
form I weak 9, a pharmaceutical
interactions, especially
n 7, is an anti-inflam- three: Opolymorphs, while form
g. 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. 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) has
lid-state super- molecules are assembled from specific rel
neutras, Moléculas Cargadas y Solvatos. been no
c non-covalent interactions betweenintermolecular intera
mobility and molecules, including
ding hydrogene.bonds, interacciones de vanWaals and kthat in
Puentes de H, iónicos, ionic, van der der revealed –k th
spectroscopy results Waals y
k interactions. Supramolecular synthons are formation in
responsible for dimer the structural
35

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 systems
molecular 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
s
k –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- of
via 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. 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. 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-nitroisoftálico
Nicotinamida, 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. Preparación de Sólidos
• Cristalización (EL al ES)
Preparación de Sólido
nced Drug Delivery Reviews 56 (2004) 241–274 263
Fluidos Supercríticos Tendencias
he
nd
Libre de Solvente
• High Throughput
(mezclado, macerado, Fluidos Supercríticos
has • 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
Highthroughput
gh- • Heteronucleación por polímeros
ng
ate
za-
ec-
of
ans
ol- Fig. 15. Comparison of plateau supersaturations achieved by in- 39

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