Influences of Crystal Anisotropy in Pharmaceutical Process Development
I n f l u e n c e s o f C r y s t a l A n i s o t r o p y i n P h a r m a c e u t i c a l Process Development
Eftychios Hadjittofis 0 1
Mark Antonin Isbell 0 1
Vikram Karde 0 1
Sophia Varghese 0 1
Chinmay Ghoroi 0 1
Jerry Y. Y. Heng 0 1
0 DryProTech Laboratory, Chemical Engineering, Indian Institute of Technology Gandhinagar , Palaj, Gandhinagar, Gujarat 382355 , India
1 Surfaces and Particle Engineering Laboratory (SPEL), Department of Chemical Engineering, Imperial College London , South Kensington Campus, London SW7 2AZ , UK
2 Jerry Y. Y. Heng
Crystalline materials are of crucial importance to the pharmaceutical industry, as a large number of APIs are formulated in crystalline form, occasionally in the presence of crystalline excipients. Owing to their multifaceted character, crystals were found to have strongly anisotropic properties. In fact, anisotropic properties were found to be quite important for a number of processes including milling, granulation and tableting. An understanding of crystal anisotropy and an ability to control and predict crystal anisotropy are mostly subjects of interest for researchers. A number of studies dealing with the aforementioned phenomena are grounded on oversimplistic assumptions, neglecting key attributes of crystalline materials, most importantly the anisotropic nature of a number of their properties. Moreover, concepts such as the influence of interfacial phenomena in the behaviour of crystalline materials during their growth and in vivo, are still poorly understood. The review aims to address concepts from a molecular perspective, focusing on crystal growth and dissolution. It begins with a brief outline of fundamental concepts of intermolecular and interfacial phenomena. The second part discusses their relevance to the field of pharmaceutical crystal growth and dissolution. Particular emphasis is given to works dealing with mechanistic understandings of the influence of solvents and additives on crystal habit. Furthermore, comments and Guest Editors: Tony Zhou and Tonglei Li perspectives, highlighting future directions for the implementation of fundamental concepts of interfacial phenomena in the rational understanding of crystal growth and dissolution processes, have been provided.
anisotropy; crystal engineering; crystal growth; dissolution; surface properties
γTotal Total surface energy (mJ/m2).
γLW van der Waals surface energy (mJ/m2).
γAB Acid-base surface energy (mJ/m2).
γ+ Acid component of surface energy (mJ/m2).
γ− Alkaline component of surface energy (mJ/m2).
γSL Solid-liquid interfacial energy (mJ/m2).
γhkl Surface energy of facet hkl (mJ/m2).
Δμ Chemical potential difference (J/mol).
ΔGh*kl Activation free energy for the incorporation of a
solute molecule on the facet hkl (J/mol).
Crystalline materials are ubiquitous in several sectors
including electronics, cosmetics and pharmaceuticals,
contributing significantly to the development of a wide
range of products. Within the pharmaceutical industry,
crystalline materials remain at the epicentre of most
formulations. Understanding the processes underpinning
the growth and dissolution of crystalline materials is
therefore of crucial importance in the development of
more efficient drug formulations.
Crystals are multifaceted entities, with each facet carrying
different properties depending on the orientation of the
molecules in the crystal lattice. This leads to the concept of crystal
anisotropy, which holds true for several properties of
crystalline materials, including optical, magnetic, and surface
properties. The concept of anisotropy was extensively studied in
the electronics industry towards the late nineteenth century
), notably for semi-conductors. For crystalline
pharmaceutical solids, experimental evidence of facet specific properties
has also been established (
). Nevertheless, the importance
of crystal anisotropy in pharmaceutical process development
remains omitted, mainly owing to the lack of a sufficiently
developed framework for the implementation of anisotropic
properties in mechanistic modelling of pharmaceutical
processes. The emphasis of this review is on the importance of
crystal anisotropy in crystal growth and dissolution, two
processes of major concern for pharmaceutical industry.
Especially for the former, it is critical to understand the
importance of controlling crystal habit during crystallization;
crystal anisotropy is critical in processes downstream of
). Obtaining a desired crystal habit upstream
could potentially allow the optimization or even elimination of
downstream operations such as milling and granulation.
These processes modify the crystal habit, but their output
heavily relies on the crystal habit of the input material.
Thus, understanding the rise of different crystal habits during
crystallization is definitely not a subject of strict academic
interest. It is a topic that could, potentially, transform the design
of pharmaceutical processes.
This review is aimed at an audience with little to no
exposure in the development of rational crystal engineering
approaches for the design and production of particles with
tailored properties. It begins with an overview of the
aforementioned theoretical concepts associated with the performance of
pharmaceutical crystals, with an emphasis on surface energy
anisotropy. Following that, the importance of the latter in
crystal growth is discussed. Numerous theoretical and
computational studies, highlighting the importance of anisotropic
surface interactions in the determination of crystal habits,
are introduced. The interactions of different crystal facets with
solvents and additives are examined, and experimental studies
are presented. The review, also, discusses several concepts
related to crystal dissolution. Particular emphasis is given on
topics such as crystal polymorphism, the importance of surface
energy anisotropy and the influence of surface coatings. Both
modelling and experimental approaches are reviewed.
The authors also provide their own perspectives on the
field following the review. They highlight the differences
between crystal growth and dissolution, two processes
which are not reversible nor opposites. Furthermore the
need for a thorough understanding of the dissolution and
growth media, which includes all the components of surface
energy including the importance of surface active agents, is
CONCEPTS IN CRYSTAL GROWTH
The ability of the constituent components (atoms, ions or
molecules) of a solid substance to arrange themselves to more than
one crystalline phases is defined as polymorphism. This
concept was officially introduced by Professor Eilhard
) in 1826, when he presented evidence for
the existence of monoclinic and rhombic crystals of sulphur.
Based on his results he called this phenomenon dimorphism.
Earlier, in 1825, he reported, for the first time, experimental
proof for the different physical and structural properties of
different polymorphs. Polymorphs of calcium carbonate were
used in this study. Intriguingly, in these studies Mitscherlich
identified, probably for the first time, scientific evidence for
the anisotropic nature of crystals, reporting different rates of
expansion/contraction of different crystal facets.
From a thermodynamic standpoint, for a certain
compound at a set paired temperature and pressure, there is only
one stable polymorph. The rest of the polymorphs are
considered metastable, and tend to transform to the stable form by
means of a solid-state transformation. The Gibbs free energy
of a solid, as depicted in Fig. 1, is the thermodynamic
parameter used to assess the stability of each polymorph and is
calculated, for a polymorph i, according to the equation:
Gi ¼ H i −TSi
As the conditions change, a shift in the relative magnitude of
the value of the Gibbs free energy of two polymorphs can
occur, leading to a change in the order of stability called
enantiotropic behaviour. On the other hand, some solids
exhibit only a single stable polymorph which is called monotropic
behaviour. In this case all the other polymorphs appear as
metastable. These phenomena are illustrated in Fig. 2.
Owing to the kinetic nature of crystallization, certain
polymorphs can be exhibited at temperatures where they are
considered metastable. Thus, the system would start to exhibit a
behaviour associated with the Ostwald rule of stages, applied
to the context of crystallization (
) by the following excerpt
from the original body of work (
BAt a sufficiently high supersaturation the first form that
crystallizes is the most soluble form. This transient state
then transforms to the more stable form through a process
of dissolution and crystallization.^
In other words, since the activation barrier for the metastable
polymorph is lower, the higher rates of the reaction may
Fig. 1 Diagram showing the variation of Gibbs free energy, enthalpy, and
entropy with temperature for a crystalline solid material. The slope of the
enthalpy curve gives the value of heat capacity and the value of the Gibbs free
energy slope gives the value of entropy. For pharmaceuticals, the importance
of pressure is usually omitted, since the operations are performed in
conditions where the influence of pressure is considered negligible
favour the nucleation of the metastable polymorph. The
metastable polymorph would then tend to transform to the
most stable form over time.
A vast array of experimental techniques are currently
implemented for the identification of polymorphs in the
pharmaceutical industry. Polarised optical microscopy
), differential scanning calorimetry (DSC) (
Xray diffractometry (XRD) (
), infrared (IR) and
Raman spectroscopy (
), inverse gas
chromatography (IGC) (19), and nuclear magnetic resonance
) are just some of the techniques used in
polymorph identification. Despite all of the tools
offered, quantifying polymorphic content is not always
straightforward, and often requires complex
Carbamazepine and mefenamic acid are two clear
examples, highlighting the limitations of some of the
aforementioned techniques. For instance, it is well reported that crystals
of mefenamic acid form I, crystallized from a supersaturated
toluene solution (
) are needle shaped, similar to crystals of
mefenamic acid form II (
). Similarly carbamazepine
polymorphs II, III and IV have been isolated as needle shaped
crystals as well (
). The occurrence of crystals of the same
molecule, but of different polymorphic form, with the same
crystal habit poses limitations for the identification of the
different polymorphs by means of optical microscopy.
Additionally, the study of carbamazepine’s polymorphism
exposes the limits of both DSC and FTIR as means of
polymorph identification. For instance, the melting temperatures
of polymorphs I, II and III are 193.5, 192.1 and 193.2°C
respectively; and all three polymorphs have very similar
FTIR spectra. In this context, it is not a coincidence that
XRD is seen as the most reliable technique for polymorph
Computational tools have been used extensively for the
prediction of the different polymorphic forms (
tools are predicting a large number of polymorphic structures,
though the existence of some of these predicted structures has
not been confirmed experimentally as of yet. These simulation
studies showcase the importance of different parameters
(conformational flexibility, functional groups, etc.) in the
determination of the free energy of a crystal lattice. Given the
framework determining polymorphism, the next step is to
understand how different species manifest themselves at a
macroscopic level in the form of crystals. The first step is to
understand how crystal growth from first principles.
Defects in Crystalline Materials
In a footnote in his pioneering essay on the BEquilibrium of
Heterogeneous Substance^, published in 1878, Professor J.W.
) made the following statement highlighting the
possibility for the growth of perfect crystals (where the term
‘perfect’ refers to crystals where their only defects are their
BSingle molecules or small groups of molecules may indeed
attach themselves to the side of the crystal but they will
speedily be dislodged, and if any molecules are thrown
out from the middle of a surface, these deficiencies will also
soon be made good; nor will the frequency of these
occurrences be such as greatly to affect the general smoothness
of the surfaces, except near the edges where the surfaces
fall off somewhat, as before described. Now a continued
growth on any side of a crystal is impossible unless new
layers can be formed.^
A number of pioneers on crystal growth has developed
theoretical approaches for the growth of perfect crystals, via
the nucleation of two dimensional layers. However, it was
soon realised that in the supersaturation range where
crystals usually grow, two dimensional nucleation is not easily
achievable. An extensive series of studies conducted by
researchers such as Frenkel, Burton, Cabrera, and Frank,
revealed the importance of topographical defects in crystal
growth, suggesting that these features are necessary for a
more coherent explanation of crystal growth at low
As mentioned, crystal defects are an inherent part of crystal
growth, but they can also be induced on crystals, by thermal or
mechanical stresses. Generally speaking, they are
characterised as having a higher free energy than the bulk of
the material and thus are preferential reaction sites (either via
Lifshitz-van der Waals or chemical interactions).
Defects are distinguished into three large categories on the
basis of their nature:
1. Point defects: This case includes situations where atoms or
molecules are missing from a point on the crystal lattice
creating a vacant point, or when an extra atom appears at
a random position on the lattice.
2. Line defects: This is when a group of atoms/molecules
is misplaced in the lattice creating screw or edge
3. Plane defects: In this case defects appear in the region
between two homogeneous crystal planes.
Atomic force microscopy (AFM) is, usually, employed for
the study of defects in crystalline materials. The technique
allows for very accurate studies, even though the nature of
the experiment means the AFM tip may affect the sample
being investigated, both in dry or wet conditions.
Adsorption based techniques, such as IGC, appear to have
the potential to provide quantitative data on the number of
surface defects present in crystalline materials, along with
the surface energies associated with them (
). Such defects
are the basis from which all crystal growth occurs and allow
us to better understand how facets of crystals are exhibited.
These facets can be best studied and understood through
their changing surface energies.
Surface energy (γ) arises from the anisotropic interactions at the
surface of a substance, as shown in Fig. 3. Considering the
range of functional groups and the associated types of
interactions, surface energy has been proposed to be
) in two major components, a Lifshitz-van
der Waals (γLW) component and an acid-base (γAB) component.
The former term includes London (
), Debye and Keesom
interactions. On the other hand, the acid-base component can
be further deconvoluted to an acid (γ−) and a base (γ+)
component. This analysis, developed by van Oss, Chaudhury and
Good, has been named after the initials of its founders as
) and proposes a geometric mean relation between
the acid and the base components. Its mathematical
formulation is given as follows:
γ ¼ γLW þ γAB ¼ γLW þ 2 γþγ−
On the same grounds, the work of adhesion between two
surfaces, here 1 and 2, is described by the following equation:
qffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi qffiffiffiffiffiffiffiffiffiffi qffiffiffiffiffiffiffiffiffiffi
W 12 ¼ 2* γ1LW γ2LW þ γ1þγ2− þ γ1−γ2þ ð3Þ
One should note that if the two surfaces are identical, the
term work of adhesion becomes work of cohesion.
Despite the fact that the work of adhesion is usually
considered to be reversible, meaning that it’s equal in absolute
magnitude to the work of separation between the two objects,
this has not been verified experimentally. In fact,
) performed both on solid-solid and the
solidliquid interfaces reveal that a number of different factors
contributing to an inherent irreversibility of the process of
adhesion-separation; meaning that it is not the experimental
procedure that leads to the irreversible behaviour, but the
nature of the process per se.
The concept of the Lifshitz-van der Waals component of
surface energy is quite well established. However, the exact
nature of the acid-base component is a field of active
discussion. The geometric mean approximation, used to describe
acid-base interactions, does not have a solid theoretical
background and it has been adopted on the basis that it has a
theoretical meaning for the Lifshitz-van der Waals
component. The harmonic mean approximation has been employed
instead of the geometric mean one; however, there is no
theoretical explanation for why acid-base interactions can be
modelled using the harmonic mean approximation.
Each crystal facet possesses different surface energy values.
This means that all the processes associated with surface
energy, including crystal growth and dissolution, are facet
specific. Therefore, a mechanistic understanding of these
processes requires an understanding of the facet specific surface
energy. Depending on the nature of the material of interest,
different experimental techniques can be used to measure
the surface energy of solids. All of them use a number of
different solvents to measure the interactions between the solid
and the particular solvents. Then, the different models,
proposed in literature, were used to calculate the values of surface
energy, or the acid-base work of adhesion.
In the past ten years, a number of investigators have
managed to grow macroscopic crystals of different compounds of
pharmaceutical interest and calculate the surface energies of
individual facets using contact angle goniometry. X-ray
photoelectron spectroscopy has been used as a complimentary
technique to confirm anisotropic surface properties. More
recently IGC measurements and computational models for
deconvolution have been developed enabling the link between
contact angle and IGC measurements (
understood how we measure and study surface energy, we can now
see how this is reflected in exhibited crystalline facets
specifically, otherwise known as crystal habits.
The fundamentals behind crystal growth, surface energy,
and the parameters that govern them were discussed in the
previous section. Crystal habit refers to the shape of the
crystal, determined by the facets present. Here, the concept
of crystal habit, or in other words, the facets that are
exhibited macroscopically are discussed. Crystalline facets
are related to unit cell lattices and are usually assigned
using Miller’s Indices, based on the following notation
(hkl). They are numbered relative to their orientation in
the crystalline plane as integers such as , ,
. As mentioned earlier, control of crystal habit during
crystal growth and the associated anisotropy could play a
crucial role in guiding pharmaceutically relevant processes
or unit operations like dissolution, milling, compaction,
flow and granulation. Hence, both the thermodynamic
and mechanical aspects allied to the anisotropy in
crystalline materials should be given diligent attention during
pharmaceutical formulation and development process.
As with a lot of the work in this field, Gibbs would be the
first to formally approach this topic (
introducing the crucial idea that, thermodynamically, the crystal habit
should seek to minimize total surface energy in anisotropic
particles. The minimization of the total surface free energy
of the crystal-medium interface, is calculated as the sum of
the surface energies (γ) by surface area (A), for each facet
exhibited (i or hkl). Wulff, and later Chernov, would suggest
that each facet quantity was proportional to a vector
normal to the facet from the centre of the crystal, called
the Wulff-Chernov construction (
). Thus crystal habits
are dictated by the growth rates of particular facets,
with the slow growing ones being more exhibited at
Several models were later proposed to predict crystalline
habits, with the two below being considered the original
1. The first true predictive approach would come from the
Bravais-Friedel-Donnay-Harker (BFDH) model (
founded upon the Bravais relationship where the
perpendicular growth rate of a facet (Rhkl) is inversely
proportional to its interplanar spacing (dhkl). The model is purely
crystallographic in its nature and therefore the simplest
given the limited amount of data required to make
2. The next model is from Hartman & Perdok (
claimed that the faster the growth rate was, the higher
the bond energy of that facet. Similar to the model above,
the perpendicular growth rate is therefore predicted to be
proportional to the bond attachment energy, i.e. the bond
energy released for each molecule becoming a part of the
surface (EhAkEl ).
Bond attachment energy (EhAkEl ) is separate from the surface
energy (γhkl) of a facet. The former is specifically the energy
released per molecule when a uniform molecular layer with
interplanar spacing (dhkl) bonds to the facet. As evident from
the definition it is specific to layered growth, unlike surface
energy which lacks this molecular directionality, related to
Both of them lack any microscopic understanding of
the growth mechanisms and do not account for any
hydrodynamic phenomena, and have been known to
give unreliable predictions at times. Therefore more
mechanistic models, accommodating a more molecular
approach, have been developed, notably with the
furthered understanding of the important role of surface
defects discussed in the next section, dealing with crystal
growth. Having gone through the fundamentals of
crystalline anisotropy, we can now look to see how this was
observed at the molecular level; in other words the
actual formation of such crystals.
Crystal growth, in liquid, is the step following
nucleation where a crystalline solid will form and continue
to grow until equilibrium is achieved with the
surrounding liquid phase (
). This only occurs if the free energy
of the molecules in the solid is lower than that of those
in the solution. This step involves the addition of solute
molecules onto the crystal surface and becoming a part
of the lattice. Chronologically it typically involves the
following four steps, typically called Kossel model,
illustrated in Fig. 4:
1. The bulk transport of the solute to the facet
2. The surface diffusion of the solute on the solid surface
across the crystal facet
3. The desolvation of both the site and the solute molecule
4. The bond attachment of the molecule onto the facet
One of the first points understood on crystal growth is
that surface diffusion is typically the rate limiting step
during growth, in the range of supersaturations usually
employed. Furthermore, it was shown that the attachment
frequency of a molecule onto a perfectly flat surface would
be very slow and by extension so would the growth process.
Once a molecule was attached, it would form the defects
that would greatly diminish the energetic cost and so speed
growth. These preferred attachment points are the defects
mentioned earlier in the review, and are shown and
described as kink sites in the Fig. 4. Though this process of
layered growth, 2D nucleation, has a low likelihood if the
degree supersaturation is not high enough, as mentioned in
the section on defects in crystalline materials (
however experimental data showed that growth would occur
despite low degrees of supersaturation.
This understanding allowed researchers such as Frenkel
) to realize that monolayers will naturally become rough
and therefore seek to maximize the number of such kinks. One
major mechanism for the formation of such sites is spiral
growth where a plane dislocation forms a step that will fully
regenerate. This mechanism was utilized by Burton,
Carbrera, and Frank in their BCF model (
). The concept
of intrinsic defects, or that crystalline materials are not perfect,
allowed them to better predict crystal growth of various facets.
They determined the perpendicular growth rate to be equal to
the height of the step (hs), multiplied with the step velocity (v),
and lastly the interstep distance (y). All three of these
parameters are variable depending on the conditions imposed. The
BCF model links crystal growth to the crystalline habit.
Rhkl ¼ hsv=y
The BCF model has been refined by several researchers,
most notably by Chernov who moved away from the Kossel
crystal lattice assumption (
). The Kossel model, used in Fig.
4, assumes all monomers to be cubic blocks and isotropic, and
therefore removes most molecular distinctions.
One notable development within this model was the
observation of a critical length (Lc) for the step. It was
experimentally determined that for a step to flow outwards (parallel to
the facet), it had to be of a certain length. Without this, the
spiral mechanism would not take place as a new edge would
not be present. This is notably seen in the works of Rimer and
), who showed that it was related to the
chemical potential difference (Δμ) which provides a measurement
for the supersaturation, the liquid-solid interfacial tension (γ),
and the volume occupied by one molecule in a crystal (ω). The
inclusion of chemical potential difference and the liquid-solid
interfacial tension means that a wide variety factors are
subsumed under them. These include but are not limited to
supersaturation, viscosity, solvent, temperature, which gives this
model a tremendous amount of flexibility.
Lc ¼ γω=Δμ
An alternative take on the crystal growth modelling
problem focusing on kinetics and the solid-liquid interface was
pioneered by both Boek and Bennema (
). The BCF
model was modified to include the diffusion of the solute
molecules from the solution to the kinks. Furthermore, on the
same work the authors incorporated on the BCF model the
concepts of desolvation for the solute to become incorporated
at the solid interface, in Fig. 4 it is the 3rd step. Effectively
Boek and Bennema split the activation free energy (ΔGh*kl ) into
two steps, the desolvation and the incorporation into the kink.
Ultimately the concept of molecule attachment frequency was
introduced, to account for the time required for molecules to
appropriately orient themselves prior to be adsorbed,
becoming a part of the lattices.
Further developments still, have revolved around
molecular simulations with the work by Gilmer and Bennema (
using a Monte Carlo simulation being one of the first. Good
agreement was found with the known mechanistic rationales
of the time, though only at set conditions notably at low
supersaturations. Later improvements have come from
Molecular Dynamics, notably from Boek (
investigating the influence of the water shell surrounding the urea
molecule. This work by Boek showed that the arrangement of
water molecules depended in part on the facet exhibited by
the crystal at the interface, reaffirming the need for a strong
molecular mechanistic rationale (
).The above sections were
a dense review of the fundamentals of crystalline anisotropy,
how they are observed, studied and formed. Within the
context of pharmaceuticals, their importance lies in how they will
be consumed by the patients, their dissolution performances.
This next section deals with these fundamentals and seeks to
connect the growth of anisotropic crystals to their dissolution.
Thermodynamic Basis for Dissolution Processes
Dissolution performance of a dosage form is a critical quality
control criterion in the pharmaceutical industry (
Typically, the in-vitro dissolution performance is used as a
surrogate for in vivo bioequivalence testing. In general, the
different sequential steps involved in the dissolution of orally
administered pharmaceutical solid dosage form follows the
wetting of the solid surface by the liquid, with the subsequent
disintegration and deaggregation of the solids in the medium
(solvation, referred to as a surface reaction), and finally the
diffusion of the solute into the bulk fluid. Thus, the solvation
of the drug molecules is a pre-requisite to the dissolution
process into the bulk solution.
Dissolution processes are governed by the second law of
thermodynamics. Dissolution results in the disruption of
intermolecular bonding between the solute molecules and forms
new solute-solvent interactions causing an increase in the
degree of disorder. The mass transfer of drug molecules into the
dissolution medium occurs by diffusion and convection
mechanisms, depending on the features of the system. Diffusive
mass transfer takes place due to the chemical potential
gradients of the molecular species, and the random thermal motion
of the molecules. In other words, the mass transfer is said to be
dependent on the concentration gradient. The concept of
drug dissolution is generally examined in the context set by
the regulatory agencies of each country. For example, for the
United States Pharmacopoeia (USP), one could look to
chapters <711>, <724>, <1088>, <1090> and <1092> (
Owing to the nature of in vivo dissolution process, diffusion
based models are usually employed by regulatory bodies in
order to assess drug solubility. In addition, it is worth noting
that convective phenomena are also involved in dissolution
In 1855, Adolf Fick (
), with his intuitive analogy between
the molecular diffusion and conduction of heat and electricity,
provided a fundamental equation to describe the diffusion
mechanism which would be later known as Fick’s law of
diffusion. Fick’s first law of diffusion states that, the rate of mass
transfer ( J ) through a unit area (A) in a direction (x) is directly
proportional to the concentration gradient (dC/dx), as shown
J ¼ −D
Where, J is mass transfer per unit area, also known as flux, C
stands for the concentration, and D is the diffusion coefficient, a
property which depends on the solute, fluid medium, and
temperature of the system. It is important to understand that as the
dissolution proceeds, the amount of solute in the bulk liquid
increases and thus the driving force for dissolution and mass flux
decreases. Despite the fact that in vivo dissolution is goverened by
a combination of convection and diffusion mechanisms, Fick’s
first law remains the most popular in predicting the dissolution
rate and process in pharmaceutical systems.
In 1897, Noyes –Whitney (
) provided an empirical
equation for the dissolution of a planar surface of constant surface
area exhibiting Fick’s diffusion mechanism. It was proposed
that, at constant surface area of a dissolving solid, the rate of
dissolution (dQ/dt) is directly proportional to the solubility
(Cs) and bulk concentration (Cb). Furthermore, for soluble
solids this process can be considered zero order if the bulk
concentration does not change.
dt ¼ k ðC s−C bÞ
Here k is the dissolution rate constant (mass transfer
coefficient). This model is simplistic and does not provide a
physical meaning for the rate constant ‘k’. Subsequently, a more
sophisticated version of the model was given by Nernst–
) which proposed that rapid equilibrium occurs
initially at the solid-liquid interface followed by the formation
of a stagnant hydrodynamic diffusion layer. The dissolution
rate then depends on the mass transfer through the diffusion
layer into the bulk solution. The dissolution rate constant (k)
could now be related to the thickness of the diffusion layer (h),
the diffusion coefficient (D) in the layer, and the surface area
(A), assuming that the concentration gradient across the
diffusion layer was constant. Thus, according to Nernst-Brunner
model the dissolution rate (dQ/dt) is given by the
concentration gradient from the surface of the exposed solid, and the
diffusivity across a hydrodynamic boundary layer of thickness
dt ¼ DA ðC s−C bÞ
Such transport controlled dissolution models are presumed
superior and are very popular amongst pharmaceutical
scientists. Based on it, Higuchi proposed a model which included
the rate of release of solute from a matrix tablet (
model considers the drug dispersed in solid matrix and for
planar geometry, is given by the corresponding equation:
M ¼ A½D C sð2C 0−C sÞt 1=2
Where, M is the total mass released in time t and C0 is the
initial drug loading. This model was later extended to other
geometries and porous systems (
Predictive Modelling for Dissolution
To improve pharmaceutical drug design and development,
substantial efforts have been expended towards modelling
and predicting wetting, solubility, and dissolution behaviours.
To elucidate and predict wettability and liquid-solid phase
interactions during dissolution, MD simulations, involving
classical force-field approximations, like statistical associating
fluid theory (SAFT), have been used in the past couple of
). Recently, tools like COSMO-RS resulting
from the efforts of Klamt and co-workers, have gained
considerable attention for the prediction of different
thermodynamic and physiochemical properties, including wettability
and solubility of small to medium sized molecules (71).
Further improvements, in the form of the COSMOfrag
method, now make it possible to screen large numbers of potential
molecules for drug design applications (
In addition to simulating the dissolution process,
researchers have now started to look a step further, by predicting
the dissolution and oral absorption of drugs through
mathematical models incorporating both dissolution and
precipitation theories (
). These models could address the
complexity in predicting the bioavailability of various drugs by
describing complex kinetic dissolution-precipitation
behaviour through physiological based modelling. Eventually, the
introduction of anisotropy in crystalline solids and the
resulting complex dissolution behaviours, to these theoretical
and computational models, could be the next step towards a
more accurate description and prediction of the dissolution
process in crystalline materials. Figure 5 is a qualitative figure
which shows how greater wettability of a facet favours its
A Brief Overview of Current Research into Nucleation
Prior to crystal growth, nucleation must occur to give rise to a
solid from the previous all liquid system. In this review, we do
not approach the topic in depth, but it is crucial in the
development of a mechanistic description of crystallization and in
understanding which polymorphs are manifested (
formation of this liquid-solid interface is not energetically
spontaneous and is affected by many of the same factors that
affect crystal growth (77). Nuclei, in the classical sense, are
defined by a critical diameter below which it is energetically
unfavourable and wants to dissolve, and above which the
nucleus will spontaneously grow. In other words, a nucleus on its
critical size is just as likely to dissolve as to grow.
Nucleation was first modelled according to classical
nucleation theory. While the concepts behind it, including a
thermodynamic critical size, are still useful in helping us
understand the phenomenon, there are severe limitations to it.
Notably, the theory was found inadequate to describe
crystallization kinetics, and therefore changes and even newer
equations have been adapted to more accurately predict nucleation.
Vekilov et al. introduced a phenomenological model which
suggested an intermediate step in nucleation (
). A highly
dense metastable pre-nucleation liquid droplet within which
nuclei would form, was proposed. The model was reliable for
proteins and corroborated with experimentally determined
Fig. 5 Schematic depicting the
diffusion layer for two facets A and B
of crystal S. From the legend it can
be seen that the work of adhesion
between facet A and the bulk liquid
is bigger than the work of adhesion
between facet B and the bulk liquid
nucleation rates. Other academics such as Gebauer et al. and
Sleutel et al. have offered evidence to support the presence of
such pre-nucleation clusters for alternative systems to proteins
). However, computational molecular simulations from
Zahn and structural sampling techniques from Parinello
suggest that such clusters may actually impede nucleation in
certain cases (
). Other groups, such as Yoreo and Rimer
et al., have offered an alternative approach following particle
attachment theory. Their body of work has been to subsume
various theories into an encompassing branch of particle
attachment, including the pre-nucleation clusters, though their
work was developed from crystal growth. Another major
advancement in modelling nucleation has focused on the effect of
diffusive interfaces in the phase transformation, first presented
by Cahn et al. (
). It remains unclear, whether the solution
conditions influence the crystal anisotropy of the fundamental
crystalline particle. This means that despite the advancements,
the mechanism dictating the rise of a faceted entity from an
amorphous one is still unknown.
The Influence of Solvent in Crystal Growth
Snowflakes were probably the first system for which crystal
habit was extensively investigated as a function of different
parameters. From the early seventeenth century, scientists
were already investigating their crystal habits, but it was not
until 1932 that a systematic study was performed. At that time,
Professor Ukichiro Nakaya (
) started examining the crystal
habit of snowflakes produced at different temperatures and
different values of water vapour saturation. His results were
tabulated in the Nakaya diagram.
In the field of industrial crystallization, the crystal habit of
) was one of the first to be studied. A publication in
1936 documented that the urea produced in the USA,
crystallized in alcohol, was rhombus like, contrary to the
needle shaped imported urea, crystallized in water. The
rhombohedral crystal habit offered a great advantage in terms of
flowability. Using arguments similar to those outlined in the
crystal habit section of the theory section, one can claim that
certain facets interact favourably with water molecules,
slowing down their growth rates. Thus, these facets dominate
compared to the faster growing facets. In the case of water, the
rate of growth of each facet, described by this simple
formalism, is such that it gives rise to needle shaped crystals.
The first attempts to understand this behaviour were done
with the aid of a mechanistic model based on the
BurtonCabrera-Frank approach. The model was parameterized
using the results from force field simulations and it was able
to capture the needle shaped structure of urea crystals grown
in water and the cuboid habit of crystals grown in polar
). A similar model was successfully implemented for
the study of amino acids (
The breakthrough in the field was achieved with the
implementation of the concept of the solid-liquid interfacial
interactions in the modelling methodology, as referenced in the crystal
growth section earlier. Molecular dynamic (MD) (
simulations were performed on individual facets with respect to
different solvents, enabling the development of a library containing all
the necessary information. These were later fed into a model,
based on the Wulff-Chernov (42) formalism, to construct
diagrams accurately predicting the crystal habit for different solvents
at different supersaturations (
). Even though the process
employed for the prediction of the crystal habit of urea offers
accurate results, it has many bottlenecks; the most notable being
the length of time required for MD simulations. This makes it
difficult to implement the influence of additives in the system, as
simulations including molecular additives would significantly
increase the computation time.
The understanding of the rate of attachment/detachment
) on kink sites, was accompanied by the development of
formalisms on the study of spiral growth on individual facets, and
on the influence of solvents (
). The advancements enabled
by the development of mechanistic models for the prediction of
the crystal growth. In these studies, the concept of periodic bond
chains, introduced by Hartman and Perdock (
), was used in
order to describe the anisotropic rates of attachment and
detachment associated with the spiral growth. It was shown that during
the spiral growth process, the most time consuming part for each
revolution was the lengthening of the edges. AFM images verified
that the spiral structure, predicted by computational models,
were expressed on the crystal facets.
The efforts, towards an integrated computational
framework for the prediction of crystal habit, culminated in the
development of the ADDICT algorithm. ADDICT was tested
and found to successfully capture the crystal habits of
molecules of pharmaceutical interest such as acetaminophen,
lovastatin, δ-mannitol, and glycine in a number of solvents (
These mechanistic approaches, appear to be versatile tools
for the determination of crystal habit under various
conditions. In the latest versions, the surface energies of both the
solvent and the solid surface are a key component of the
algorithm. These models have several assumptions, the most
notable one being that in the absence of hydrogen bonds, the
whole acid-base component of the surface energy is assumed
to be zero. However, given the empirical character of the
geometric mean approximation for the acid-base interactions,
doubts arise about the range of results that can be obtained,
suggesting areas of improvement. In addition, certain aspects
of the behaviour of fluids at interfaces could be implemented
). This could include the formation of Bclathrate cages^ by
water molecules around hydrophobic molecules where the
average number of hydrogen bonds is higher than in the bulk.
Finally, an experimental validation of the proposed values for
both the surface energies of individual facets, as well as their
corresponding work of adhesions with different solvents, could
provide guidelines for the enhancement of the currently
Shah et al. (
) used mefenamic acid form I as a model
compound to experimentally study the influence of solvent
on crystal habit. Using a range of solvents, it was shown that
mefenamic acid can crystallize in a broad spectrum of crystals,
ranging from needles to thick plates. In this study, it was
possible to correlate the aspect ratio of the crystals with the polar
component of the solubility parameter of the solvent. The
work did not investigate the influence of degree of
supersaturation, which may affect the interfacial properties.
More detailed studies (
) were performed on the crystal
habit of acetaminophen for solvents with different polarities.
For polar protic solvents, it was found that their affinity
towards facets favouring hydrogen bonding slowed the growth
rate of those facets, since the sites were less prone to interact
with solute molecules. For polar aprotic solvents, where
hydrogen bonding was weaker, there was more ambiguous
relationship. These results highlight that simulation tools and/or
complimentary techniques (such as XPS) are paramount for
understanding crystal growth.
The above findings complimented studies (
performed on carbamazepine dihydrate, a hydrophobic channel
hydrate, which usually crystallizes as needles. Investigations on
the structure of the compound suggest that the elongation is
driven by the formation of a hydrogen bond network, owing
to the presence of water in the crystal lattice. Thus, in this case,
hydrogen bonding drives the crystal growth in one axis. This
easily explains why the crystals grow into needles in pure
water; though aqueous alcohol mixtures are more often used to
crystallize carbamazepine dihydrate. It has been observed,
that the more protic the alcohol is, the higher the aspect ratio
of the crystals.
Attempts have been made to understand the importance of
more exotic phenomena like π-π stacking in crystal nucleation
and habit, where hybrid modelling – experimental
approaches have been employed (
). The α polymorph
of para-amino benzoic acid (α-PABA) was picked as the model
compound because its structure gives rise to π-π stacking. The
results suggest that the nucleation is governed by hydrogen
bonding, whilst π-π stacking governs crystal growth, therefore
determining the crystal habit. The authors claim that the
crystal growth of α-PABA is driven by a poly-nucleation
roughening mechanism, in which solute molecules diffuse on the [011 ]
facet and attach to it by means of π-π interactions. This
mechanism appears to dominate the process independently of the
supersaturation. Even though the exact nature of π-π stacking
is still a matter of debate (104), one can argue that beyond π-π
stacking, a number of other parameters could be involved in
crystal growth, including the effect of different solvents at the
interface with particular facets.
The Influence of Additives in Crystal Growth
There is a solid framework for the prediction of crystal habits
for pharmaceutical compounds, from first principles, for
different solvents and supersaturations. However, for the robust
design of pharmaceutical formulations, it is important to
understand crystal growth in environments containing many
solute additives (
); additives influence crystal growth,
interacting with individual crystal facets. It has also been
shown that the majority of impurities incorporated into the
crystal lattice are solute molecules and not solvent
). The key to understanding the influence of
additives in crystal growth, is to appreciate that the additive
molecules interact anisotropically with different facets,
competing with the molecules of the solvent and the other solutes.
Thus, they can adsorb on specific facets, limiting their growth.
), Cabrera (
), and Vermilyea (
extensively studied the influence of impurities on the
development of surface dislocations on crystals and therefore crystal
growth. Those studies set the groundwork for the
development of a mechanistic framework (
) for the
prediction of the influence of additives in crystal growth in
the context of the infamous BCF model, mentioned earlier.
It has been shown that additives posing similar structure with
the molecules of the crystal can be used as effective crystal
habit modifiers. The extent of their influence appears to be a
function of the additive concentration. Molecules of
pharmaceutical interest have been employed in these studies to verify
the importance of structural similarity; glycine was grown in
the presence of another amino acid, alanine, and
acetaminophen was grown in the presence of p-acetoxyacetanilide (113).
For the amino acids, alanine shows an affinity to the 
facet, whereas p-acetoxyacetanilide seems to be attracted to
) facet of acetaminophen. Furthermore, using similar
mechanistic approaches, the results obtained from the
combination of MD and the Wulff-Chernov formalism, in
the context of the earlier urea-biuret system, have been
Modelling attempts, grounded on the mechanistic models
discussed in the previous section have been developed.
Interestingly, urea was one of the molecules of interest. MD
simulations, verified that the biuret additives interact
anisotropically with different facets (
). The results were again
implemented in the modelling framework which managed to
predict accurately the crystal habit in the presence of biuret.
This concept, of structurally similar additives as crystal
growth inhibitors, has been successfully implemented for the
development of therapeutic approaches against kidney stones
). A combination of experimental, modelling, and
theoretical studies were employed to select the most
appropriate molecular imposters from a library of candidate
compounds. The growth velocities of the individual facets have
been investigated with the aid of AFM. Interestingly, a case
of crystal growth acceleration owing to the presence of
additives was reported in this study. Comparable results have been
reported for the growth of l-alanine in the presence of l-valine.
The acceleration has been attributed to the enhanced
solvation of the crystal by water because of the strongly
hydrophobic nature of the additive (
Similar approaches have also been used to tackle malaria
). The structure of hemozoin, the inert crystal that
malaria parasites crystallize in their digestive vacuole to
accommodate for the toxicity of heme, crystals was resolved
enabling the determination of the facet specific attachment
energies. In this context, it was possible to develop a rationale
for understanding the action of quinoline based drugs. More
in depth studies lead to the development of screening
) for the selection of optimum drug candidates
based on growth inhibitor activity (
The hitherto presented approaches are based on the use of
small molecule additives. However, it has been demonstrated
that polymeric and surfactant additives can influence crystal
). Going a step further, Rimer et al. (
studied the influence of ionic polymers in the inhibition of
kidney stones. In these studies, it was highlighted that
polyanions were interacting much better with crystal surfaces
compared to polycations. Furthermore, it was shown that
beyond crystal growth, polymeric additives contribute to the
aggregation of crystals. In fact, it was demonstrated that in
mixtures of polyanions with polycations, the protein
aggregates formed were mediating the formation of crystal
The use of seed crystals is a key method used for the control
of crystallization processes industrially (
). From the
hitherto analysis, and from an intuitive understanding of
crystal growth mechanisms, it is obvious that as long as crystal
growth is allowed to reach equilibrium, the crystal habit of
the seeds does not influence the crystal habit of the final
product. This concept has been proved experimentally, using
succinic acid as the model compound. It was shown that for
single crystal growth, the equilibrium crystal habit is
independent of the seed’s habit (
). However, as the concept of
seeding is expanded in the field of industrial crystallization,
precautions should be taken in order to minimize the
influence of homogeneous nucleation. Excessive homogeneous
nucleation would shift the heterogeneous nucleation controlled
system to a homogeneous nucleation controlled one. This
would eliminate any potential advantages offered by seeding
Factors Affecting Crystal Dissolution
Different physicochemical characteristics of crystalline solids
can influence the dissolution rate. These characteristics
include crystal defects, habit, surface area to volume ratio,
surface chemistry, surface energetics, and physiochemical
stability (polymorphism and the propensity of forming hydrates or
solvates) to name a few, all of which were covered in the
fundamental section of the review. The influence of these
material characteristics on dissolution behaviour often overlap.
The following sections will seek to isolate and develop these
points from the perspective of their effect on crystal
Anisotropy and Wetting of Crystalline Solids
As stated earlier, surface wetting is a prerequisite for the
dissolution of materials. The process of surface wettability can be
quantified in terms of fundamental concepts of work of
adhesion and surface energy. Hence for the purpose of simplicity,
some of the studies discussed here are from the perspective of
wettability changes and involve surface energetics.
The surface energy of crystalline pharmaceutical materials,
as has been shown throughout this review, is anisotropic (
Considering facet specific surface energy of a crystalline
material, it is postulated that surface energetics of the bulk
crystalline material depends on the relative surface energy
contributions of different crystal facets. For acetaminophen, Heng
et al. reported that when milled, the dispersive component of
surface energy increases with decreasing particle size and it
was attributed to the surface energy of the weakest attachment
energy plane for the acetaminophen crystals (
). Along similar
lines, different studies have reported the facet specific wetting
behaviour due to surface energy anisotropy of different
crystalline facets. Lippold and Ohm reported that the surface
wettability is correlated to the dissolution rate of solids
through the effective surface area in contact with liquid at
constant experimental conditions, notably constant agitation
speeds. The wettability of the drugs was assessed by measuring
contact angles with isopropanol –water mixtures and
surfactant solutions (
). In the studies performed by Modi et al.
), using celecoxib as the model compound, the
influence of crystal anisotropy in dissolution was assessed and it was
found that systems that exhibited more facets with higher
surface energies showed greater bioavailability.
Despite the promising and reasonable conclusions, one
should note that the contact angle measurements employed
in the studies by Modi and Lippold were on powder compacts.
During compaction, process breakages and defects arise on
the crystals, as can be seen from relevant SEM images. It
should be noted that the extent of the influence of these
mechanically induced features are themselves heavily influenced
by the crystal habit, meaning that different crystal habits will
be modified differently under identical compaction
conditions. This phenomenon, stemming from the concept of
anisotropic mechanical properties of crystalline materials, casts
doubts on the accuracy of the correlations between the contact
angle surface energy measurements and wettability. From a
theoretical perspective, it would be better for contact angle
measurements on powder compacts to include notions based
on the Wenzel and Cassie-Baxter eqs. (
Crystalline Defects and Dissolution
The mechanisms underpinning the influence of defects on
dissolution are multifaceted. Considering that defects,
depending on their type, can influence both surface and bulk
properties, one could expect that obtaining correlations for
the influence of defects is not a straightforward process. In
the absence of any defects, it is expected that crystal habit
greatly determines dissolution; however, investigators have
shown that this was not the case for acetaminophen. In fact,
the dissolution rate trend for the facets was not in line with the
attachment energy trend (
) used in the Hartman and
Perdok predictive model. Thus, X-ray topography was
employed to investigate the effect of defect induced strain on
the crystal. Acetaminophen crystals with two distinct crystal
habits were used: columnar crystals, obtained at low
supersaturations, and prismatic shaped crystals, at elevated ones. The
results suggest that the abundance of defects incorporated
within the crystal lattice create a strain which enhances
dissolution. They did not suggest a primary mechanism of defect
formation, though, as discussed earlier in the review, we know
that the inclusion of defects is an integral part of crystal
growth. The effect of defects induced solely by mechanical
processing is more often discussed since it appears to be more
Particular attention is given to milling, a process used
extensively downstream of crystallization. It typically induces
disorder into the crystal lattice, which varies depending on
the material. DSC and PXRD are not always adequate to
quantify this disorder, and solution calorimetry (
been employed as a more accurate quantification method.
Shah et al. investigated the behaviour of recrystallized brivanib
alaninate, milled at both cryogenic and ambient temperatures
). It was found that milling at cryogenic temperatures
lead to higher disorder upon milling. This phenomenon
suggests that the mechanical properties of crystals change in
cryogenic temperatures, leading to more brittle structures. It
should be noted that extensive mechanical processing can lead
to partial amorphization of the material, especially on the
vicinity of the surface. The lack of long range order, associated
with amorphous materials, leads to higher reactivity. Thus,
wettability, the first step of dissolution, becomes faster.
Effect of Polymorphism on Dissolution
Polymorphism in crystalline solids and its effect on the
performance of pharmaceutical products, has been the subject of
extensive research over several years. The ability of a molecule
to exist in different crystal forms influences the saturation
solubility (Cs) parameter affecting the dissolution rate; it can
drastically alter the dissolution behaviour of an API or the
formulation and its bioavailability (
A well-known industrial case study for an unexpected and
unwanted polymorphic transformation was that of Ritonavir,
an antiretroviral medication. After a couple of years of its
commercialization, a new and previously unknown
metastable polymorph was discovered, with poorer bioavailability
than the corresponding original crystalline form (
). In a
way, such case studies showcase the importance of
polymorphic transformations in crystalline solids as related to
therapeutic efficacy. Metastable polymorphs can be used to
enhance the dissolution rate; however, enhanced dissolution
with such polymorphs does not always translate into improved
The anhydrous form of a crystalline solid is generally more
aqueous soluble than the so called pseudopolymorphic
hydrate, such as in carbamazepine dihydrate from earlier.
Therefore, hydrate formation can influence the solubility
and the dissolution of solids. This could be a substantial issue
in the case of moisture sensitive substances where the
transformation from anhydrous to hydrous form occurs with the
uptake of moisture from the environment. Bartolomei et al.
documented a decrease in the intrinsic dissolution rate of
hydrated diclofenac sodium, formed on exposure to humid
conditions, than that of the corresponding anhydrous diclofenac
sodium salt. Moreover, the transformation of metastable
polymorph to its stable form may occur during the dissolution
process. Often this is influenced by the dissolution medium
as suggested by several studies on solvent mediated
solidstate transformation of certain APIs (
). An interesting
study by Lehto et al. reports the complex dissolution behaviour
of molecules susceptible to hydrate formation, by studying
simultaneous dissolution and crystal growth processes of
carbamazepine form III and carbamazepine dihydrate
respectively using in situ analytical techniques. They reported solvent
mediated crystal habit changes of the carbamazepine
dihydrate crystals in the dissolution media of normal
simulated intestinal fluid (SIF) and SIF containing surfactants, and the
corresponding changes in the dissolution kinetics. These
crystal habit changes were attributed to hydrogen bonding effects
between the carbamazepine dihydrate and surfactant
CRYSTAL ENGINEERING FOR FAVOURABLE
Poor water solubility is evidently linked to poor dissolution
which could consequently result in worsening bioavailability.
Therefore, extensive efforts and resources are being invested
in both the solubility and dissolution enhancements of drugs.
It is important to mention that this section deals with
approaches strictly pertaining to the engineering of crystals for
dissolution improvement, and omits literature studies where
formulation factors are responsible in improving dissolution.
Both bottom up (during crystal growth), and top down
(processing of crystalline materials, or nano/micro- crystallization)
approaches can be used in conjunction with cocrystallization.
Crystal Habit Modification
The significance of surface area in dissolution kinetics, makes
crystal habit and crystal size critical factors during the
dissolution process. Solvents, crystal growth inhibitors, and
), as discussed earlier in the review (20), have
been proven to be particularly successful at controlling crystal
dissolution rates (
Although variable dissolution rate changes, due to crystal
habit, can be correlated to surface area, sometimes the
physicochemical changes in surface characteristics, such as defects
and surface chemistry, may contribute to such behaviour.
Adhyayiman and Basu reported the improvement in the
dissolution rates of dipyridamole crystals, based on their crystal
habits. Two different crystallization setups were used. The first
involved the use of different solvents, whereas the second used
additives such as Tween-80, PEG, and PVP (
). It was
previously reported that the relative exposure of different
crystal facets is related to the degree of wettability, and subsequent
dissolution, of an API (
). Modi et al. studied the influence of
plate and acicular crystals of celecoxib on their intrinsic
dissolution rates (IDR). The IDR of the plates were about 50%
greater than that of acicular ones in a phosphate buffer. The
greater wettability of the plates, as compared to acicular
shaped crystals, was found to be responsible for the variation
). Sometimes a combination of factors, such as surface
area and surface chemistry, can improve the dissolution rate
of the crystals. Chow et al. reported an increase in the IDR of
doped phenytoin crystals, where the habit was controlled, by
varying the specific surface area alongside the increased
density of surface polar groups at the facets (
Dissolution is an inherently dynamic process during which
the size of the crystal decreases along with its habit. The
process is driven by the preferential removal of lattice components
from the edges of the crystal. Inevitably, this leads to the
appearance of new facets, as the crystal shrinks from the edges.
In other words, the crystal becomes smaller but more
heterogeneous, exposing more facets. This is different to crystal
growth where the fastest growing facets tend to disappear so
less are exhibited (
). However, experimental studies,
performed in the absence of convective mass transfer, show that
as the dissolution process progresses, crystals take a more
rounded shape (
). This suggests the presence of many more
crystal facets being exhibited than as predicted from
simulations. This behaviour has been attributed to the effects of local
roughening on each facet. This roughening is associated with
the growth mechanisms brought forth by Burton, Cabrera,
and Frank; however, their effects are often omitted in favour
of better simulation performances. In experiments performed
in the presence of some sort of stirring, this rounding
phenomenon occurs for larger crystals than when observed in purely
diffusional experiments. The shear stress associated with
stirring further enhances the formation of local defects and
roughening on individual facets, promoting this rounding
Owing to the heterogeneous nature of crystalline materials,
researchers are exploring numerous strategies to tailor particle
surfaces for controlling properties such as surface wettability
and solubility. Since the physicochemical nature of surfaces is
critical in determining these properties, the emphasis remains
on the development of technologies which can ensure that
changes occur only at the particle surface, keeping the particle
bulk properties intact. This section deals with the
postcrystallization treatments of surfaces to produce tailored
crystalline materials to improve dissolution properties (
Gaining control over surface chemistry appears to be the
preferred method for controlling the wetting and dissolution
characteristics of pharmaceutical materials. Surface
functionalized coating of pharmaceuticals is the most popular
technique employed in the industry to modify the dissolution
profile of APIs. Functional polymeric coatings from solvents are
the most commonly used approach to obtain APIs with
desirable dissolution properties (
). Profiles for the latter may
include increased dissolution rates as well as controlled release
). Moreover in the future, applications of potential
surface functionalization techniques, like surface silanization,
could be explored to modify the surface chemistry (
wettability, to alter the dissolution behaviour of crystalline
Apart from solvent based methods, dry coating methods
have, also, been used by various researchers for particle
surface modification to improve dissolution (
wettability, as well as powder properties. In this technique, the
coating of guest (fine) particles over host (coarse) particles is
achieved by mechanical forces as depicted in Fig. 6.
Recently, Han et al. reported a simultaneous micronization
and surface modification technique for improving the
dissolution of ibuprofen. This was achieved by co-grinding the
drug with a water soluble hydrophilic polymer in a
continuous fluid energy mill (FEM) to obtain surface modified
particles. The dissolution rate enhancement in ibuprofen was
ascribed to the resulting improvement in the wettability of
the dry coated API (165). Generally, with proper operation
control, co-grinding allows for enhanced dissolution without
changing the crystalline form of the drug (
another similar study, Tay et al. performed the mechanofusion
of poorly water-soluble indomethacin with MgSt and NaSt.
An increase in the dissolution rate of the NaSt coated API,
attributed to the combination of its ability to act as a
surfactant and both promote drug wettability and drug dispersion
in the dissolution medium, was observed. The dissolution
profile was modelled using a non-linear least squares
regression analysis with a bi-exponential eq. (166). Furthermore,
Karde and Ghoroi showed that depending on the nature of
the guest particle (hydrophilic and hydrophobic) employed
for coating, modulation in the wetting behaviour of host
surfaces is possible. Thus, dry coating using silica nano-particles
Fig. 6 Schematic of dry particle coating
(guest) with diverse functionalities led to wettability variation
in several pharmaceutical excipient (host) surfaces (
Largely, such solventless dry particle coating technique offer
several advantages over the conventional wet or solvent
based techniques for surface modification and dissolution
enhancement of powders.
One crystal engineering approach, which has become popular
these past few decades, for improving the solubility,
dissolution, and bioavailability of drugs is co-crystal formation. Its
popularity as a pharmaceutical dosage form design strategy
is obvious by the numerous reviews and studies on the topic, as
well as an ever-growing number of patent applications
). A co-crystal can be defined as a crystalline
material that consists of different molecular species held
together by hydrogen bonds or non-covalent forces (
the terms ‘co-crystal’ and ‘molecular complexes’ are used
) to describe the hydrogen bonded
molecular arrangements between two separate molecular entities,
however some may disagree (
). Interestingly, one of the
earliest studies on co-crystallization was by Ito and Sekiguchi
), focusing on two sulphonamide drugs (sulfathiozole and
sulphanilamide), reported this mixture as a ‘molecular
compound’. These unclear terminologies for describing
cocrystals have given rise to some other conflicting views whereby
solvates, hydrates, and inclusion complexes (
sometimes considered co-crystals.
Pharmaceutical co-crystals can improve bioavailability of
poorly water soluble drugs by enhancing the solubility (
and dissolution (
) of the crystalline APIs. Several
studies have investigated the intrinsic dissolution rates of
co-crystals. Lee et al. investigated the dissolution characteristics of an
acetaminophen/theophylline (AT) co-crystal (
dissolution rates for various AT co-crystals compared to their
individual components and physical mixtures, were observed.
In another instance the IDR of a poorly soluble API was
drastically increased by a factor of 18 via co-crystallization
with coformer glutaric acid (
Due to their superior physicochemical properties (
cocrystals provide a suitable alternative to salts, hydrates,
solvates, and polymorphs of APIs in the development of dosage
form, thus circumventing some of the limitations associated
with the latter compounds. For pharmaceutical applications,
co-crystals can be formed between the active and a non-active
co-crystallizing agent (co-former) (
), or between two
active ones to combine their therapeutic effects (186). Crystal
packing structures and lattice energies should be considered
during co-crystallization. Molecules that can arrange
themselves in alternative packing patterns whilst forming hydrogen
bond networks are preferred molecules for co-crystallization
. Thus, finding polymorphs which are not energetically
locked into single packing modes and exhibit structural
flexibility, are good candidates for co-crystal formation (
The two most popularly used methods for preparing
cocrystals include the evaporation of a heteromeric solution, or
co-grinding the components together, called neat grinding
). Caira et al. prepared co-crystals of sulphamidine with
aromatic carboxylic acids using neat grinding. From their study
on the preference for co-crystal formation (competitive
experiments), they inferred that it is favoured by the decreased
intermolecular interactions in homomer crystals as compared to the
heteromers. As an alternative to the neat co-grinding process for
co-crystallization, Jones and co-workers suggested a process
called liquid-assisted grinding (LAG), in which the addition of
small amounts of a liquid can dramatically increase the
cocrystallization yield. However, in some cases the use of solvents
prompted the formation of solvates. In subsequent work, it was
claimed that greater control of the outcome could be achieved
by using a solvent of appropriate polarity (189). This was further
corroborated by Fischer et al. (
) with their work on
theophylline and benzamide co-crystallization using LAG over a range
of solvents. To avoid the possibility of solvate formation during
co-crystallization, Jones et al. recently introduced polymer
assisted grinding (POLAG) that provides advantages
comparable to the conventional liquid-assisted process along with better
control over the particle size of co-crystals (
Apart from the above mentioned approaches for crystal
engineering to enable better dissolution, a popular top-down
approach of micronization through milling, is widely
employed in the pharmaceutical industry to improve the
dissolution of crystalline material (
). The reduction in particle
size and consequentially the increase in surface area due to
micronization is thought to be main factor responsible for
dissolution improvement. As discussed in the earlier sections
of this review, mechanically induced defects generation in
crystalline solids also play a crucial role in this process.
However, it is worth mentioning that co-crystals are not
always more soluble, i.e. dissolve in greater amounts than their
corresponding coformers. This could happen because of the
rapid precipitation of the poorly soluble drug, which could
form a layer of precipitate on the soluble co-crystal and thus
affect the formers dissolution. Recently, Yamashita and Sun
showed that this precipitation phenomenon, of the low soluble
entity of co-crystals, could be reduced by adding excess
coformer to the dissolution medium, which they have named
the ‘common coformer effect’ (
COMMENTS AND PERSPECTIVES
Crystal Growth and Dissolution Are Not Reversible
This review highlights the importance of crystal habit in both
crystal growth and dissolution in solution. These two
processes, of crucial importance in the pharmaceutical
industry, are inherently different and they should not be
approached as opposites nor reversible. It is crucial to
understand that the underlying mechanisms for these two processes
are unique as has been highlighted in this review.
Dissolution is initiated by the wetting of a solid by the
undersaturated bulk fluid. As long as the wettability is
established, a diffusion layer is formed. The rate of dissolution
is then established, where the process is governed by the size of
the diffusion layer, the magnitude of the diffusion coefficient,
and the concentration gradient between the bulk and the
surface. The different surface chemistries of individual facets
leads to anisotropic wettability, changing the time needed
for the dissolution to be initiated on each facet. Similarly,
the rate of detachment of molecules from the surface of the
crystal during dissolution is also facet specific.
On the other hand, crystal growth takes place in a
supersaturated solution. It is well established that the degree of
supersaturation is one of the key parameters driving it.
However, interfacial phenomena, linked with crystal habit,
are also of crucial importance. The concept of critical step
length, as mentioned earlier, is the ratio linking interfacial to
bulk phenomena. The solid-liquid interfacial (γSL) tension, on
the numerator of the equation describing critical step length, is
facet dependent. In the case of strong affinity between the
solvent and the facet, the magnitude of γSL is large leading
to a large critical step length. The bigger it is, the greater the
force limiting the influence of supersaturation in crystal
). In other words, if the liquid and the solid have
a strong affinity, more energy is required to form a new solid
surface area. Hence, wettability counterbalances the effects of
Unfortunately, there is a dearth of studies in the
literature discussing the importance of the different components
of surface energy in crystal growth. From a theoretical
perspective, the step size should vary for different solvents and
different values of pH. In any case, a strong understanding
of the interactions, both electrostatic and specific,
associated with individual facets is required. However, for
a wide range of materials, including proteins, contact angle
goniometry and XPS measurements as those proposed in
the literature (
) are not experimentally feasible, where
similar issues limit the applicability of IGC (
force microscopy (CFM), could be a promising tool
) as it enables the measurement of the interactions
of a specific facet with a functionalized AFM tip.
Combining many functionalization groups against a
specific facet, could provide a good understanding of the
interactions associated with that facet. The Quartz crystal
microbalance (QCM), may provide a useful platform to study
facet specific interactions with different functional groups.
In this direction, some progress has, already, been achieved
in the use of QCM to study crystal growth (
It should be appreciated that during crystal growth,
especially at low supersturations, there is an interplay between
attachment and detachment frequencies of molecules on
different facets. Molecules can attach or detach from the crystal
facets, though because of the nature of the process, the former
will dominate the latter as is evident in all the MD studies.
The Importance of Surface Active Additives in Growth and Dissolution
The presence of additives in solution, giving rise to surface
activity, changes its wettability. In the presence of surface
active agents such as polymers (
), and surfactants
), the wettability mechanism is driven by their
tendency to migrate towards the three phase contact line (
This influence has been highlighted in a very detailed way in
the concept of carbamazepine dihydrate (129). The
interactions of the hydrophilic components of sodium taurocholate
with the (
) facet of the carbamazepine dihydrate, via
hydrogen bonds, limits the growth of that facet, leading to
crystals with smaller aspect ratios. Similar studies were conducted
with aspirin (
) and nifedipine (
Similar arguments apply for the importance of specific
surface interactions with additives in the dissolution process. The
influence of a wide range of polymers in the dissolution of
crystalline pharmaceutical materials has been investigated. It
is evident that there is a lag time between the contact of a
tablet with a solvent and the start of drug release (
This lag phase is influenced by the wetting mechanism of the
drug by the surrounding solvent. Higher wettability, linked
with lower surface tension of the liquid surrounding the drug,
would decrease this lag phase. Increasing the amount of
polymer used and its physicochemical properties alters the surface
tension and therefore the lag time. One should be careful
when performing or assessing such experiments with tablets,
since residual powder on the surface of the tablet should be
removed, as it dissolves quite fast and thus makes the lag phase
difficult to be identified. This lag behaviour can also be seen in
The interpretation of the impact of additives on the
components of the surface tension, the Lifshitz-van der Waals and
the acid-base ones, remains unclear. It is not unreasonable to
speculate that the solubility parameters could provide a metric
enabling us to quantify the impact of additives by these
individual components. Further studies should also be conducted
to understand the changes in the solvent properties by the
addition of additives.
Particle Sizing Is Crucial
The reader should appreciate that when considering the size
of the particles used in drug formulation, usually in the micron
and submicron scale, interfacial phenomena tend to be of
increasing importance. One should also note that there is a
tendency towards the introduction of smaller particles in
pharmaceutical formulations (
). This tendency for smaller
particles will, therefore shift the balance towards interfacial
phenomena. The advantages of using particles in the
nanometre scale are extensive and many of them can be easily
conceptualized in terms of the fundamental interfacial
phenomena outlined in the theoretical development part of this
Working at the nanoscale poses challenges for researchers.
Therefore, it is of crucial importance to further the
development of bottom-up and top-down techniques for the synthesis
of nanoparticles with specific engineered properties.
Especially for top-down approaches, the importance of crystal
habit and crystal anisotropy in milling and breakage cannot be
understated. The production of smaller particles should be
accompanied by the development of theoretical,
computational and experimental approaches for the understanding of
interfacial phenomena at the nanoscale. This should go
beyond the well-established concepts of Ostwald-Freundlich
theory. It could focus on the influence of the decrease in size in
the lattice properties giving rise to surface energy. Finally, the
implementation of nanoparticles in process development and
their storage could be challenging, considering the variety of
undesired phenomena associated with them, including
coalescence upon storage and extensive cohesiveness.
In addition, traditional pharmaceutical unit operations,
like spray drying, can be used to modify the microstructure
of crystalline materials. A study published by Rasenack et al.
demonstrated that the dissolution enhancement of poorly
water-soluble drugs could be achieved by the formation of
microcrystals using precipitation techniques and spray drying.
The crystals could be produced with high specific surface
areas and higher surface hydrophilicity with stabilising
protective polymer facilitating dissolution (
Crystal growth and dissolution remain key phenomena in
pharmaceutical process development and they will probably
retain this status for the foreseeable future. Their study
requires a strong understanding of the interplay between surface
and bulk properties of materials. The focus of this work has
been on interfacial phenomena and crystal anisotropy. It is
evident that the combined use of theoretical, computational
and experimental approaches is paramount to the
development of predictive tools for crystal growth and dissolution.
The shift towards sub-micron/nano particles, for the
enhancement of bioavailability, makes the importance of
interf a c i a l p h e n o m e n a m o r e p ro m i n e n t in t h e f ie l d of
pharmaceutics. Interfacial phenomena can be exploited for
the development of strategies for the improvement of the rate
of dissolution of crystalline materials. However, it is becoming
evident, that there are still big discrepancies associated with
the quantitative understanding of interactions at the
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