BIOPHARMACEUTICAL
PERFORMANCE AND STABILITY OF CO-CRYSTAL
INTRODUCTION
As
the Biopharmaceutics Classification System (BCS) class-II drugs exhibits poor
aqueous solubility and high permeability, formulation development of this class
drugs remains a challenge. This class of drugs is currently estimated to
account for about 30% of both commercial and developmental drugs. Numerous
approaches to resolve this issue of poor aqueous solubility and bioavailability
are well reported in scientific literature. These strategies include
micronization,[1-3] use of
salt forms,[4] co-solvent approach,[5] micellar
solubilization, [6] and
complexation with cyclodextrins.[6] Crystal engineering approaches,
which can potentially be applied to a wide range of crystalline materials,
offer an alternative and potentially fruitful method for improving the
solubility, dissolution rate and subsequent bioavailability of poorly soluble
drugs. The challenges of low aqueous solubility provide an ideal situation for
the application of crystal engineering techniques for improving bioavailability.[7]
Solubilization
technologies such as micellar systems are reliant on the acceptable solubility
and compatibility of therapeutic molecules in a limited range of
pharmaceutically acceptable excipients, while the increasing number of weakly
ionizable and neutral molecules entering development phase constrains the
opportunities for salt formation as a method for improving dissolution rate.
Furthermore, it was reported that only increase in dissolution rate is
insufficient to provide adequate enhancement of bioavailability.[9]
So, approaches which can improve the aqueous solubility of the drug would be of
great help for delivering BCS class-II drugs.
Crystal
engineering has evolved in such a manner that it is now synonymous with the
paradigm of supra-molecular synthesis, that is, it invokes self-assembly of
existing molecules to generate a wide range of new solid forms without the need
to break or form covalent bonds. Co-crystals incorporate
pharmaceutically acceptable guest molecules into a crystal lattice along with
the active pharmaceutical ingredient, changing the physical properties of the
solid. Pharmaceutical co-crystals consist of two or more components that
are solid at room temperature. Although this definition may be debatable, it
provides sufficient differentiation from solvates or other two-component
systems. This characterization is therefore well-suited for describing new,
possible solid forms for pharmaceutical applications.[10]
Techniques Used in the
Formation of Co-crystals
Synthesis of a co-crystal from
solution might be thought of as counterintuitive since crystallization is such
an efficient and effective method of purification and as such it is used widely
in the pharmaceutical industry for isolation of single component crystals.
However, if different molecules with complementary functional groups result in
hydrogen bonds that are energetically more favorable than those between like
molecules of either component, then co-crystals are likely to be
thermodynamically (although not necessarily kinetically) favored. Co-crystals
involving these supra molecular synthons are usually synthesized by slow
evaporation from a solution that contains stoichiometric amounts of the
components (co-crystal formers); however, sublimation, growth from the melt,
slurries, and grinding two solid co-crystal formers in a ball mill are also
suitable methodologies.[12, 13] More often than not, the phase that
is obtained is independent of the synthetic methodology. The recently reported
technique of solvent-drop grinding, addition of a small amount of suitable
solvent to the ground mixture to accelerate co-crystallization appears to be a
particularly promising preparation method. Solvent drop grinding avoids
excessive use of crystallization solvent and hence it can be regarded as a “green” process.
Moisture sorptions by hygroscopic materials can also lead to deliquescence,
which may further lead to co-crystal nucleation and growth because co-crystal
solubility and thermodynamic stability are dependent on solution chemistry.[14]
Biopharmaceutical
performance
Solubility: Solubility of the active pharmaceutical ingredient is one of
the important factors taken into consideration while developing its dosage
form. Class-II drugs of BCS need improvement of their solubility so as to
optimize their bioavailability. Co-crystals can be made for ionizable as well
as nonionizable drugs. For ionizable drugs, numbers of suitable co-crystal
formers are available which implies that there is great potential to form
highly soluble and stable pharmaceutical co-crystals.[15] Co-crystal solubility is proven to be
dependent on the concentration of co-former in solution. The dissociation of co-crystal
in solution is described by the solubility product (Ksp),
which is defined as a product of drug and ligand solution concentrations.[16]
Co-crystal solubility is considered as a function of the solubility product
such that high Ksp values equate to high co-crystal
solubility. The co-crystal solubility can be best studied by understanding
following thermodynamic calculations.
Co-crystal solubility (Scc)
and solubility product (Ksp):
Consider a
co-crystal Aα Bβ , where A is drug and B is co-former,
then the solubility of cocrystal and equilibrium constant are given by:
Aα Bβ = αA(soln)
+ βB(soln) (1)
K
= ααA(soln) αβB(soln)
_____________________
αAα Bβ (S)
Keeping
solid co-crystal activity equal unity and assuming the activity coefficients of
A and B equal unity for low solute levels, equation 1 can be rearranged as
Ksp = [A]α
[B]β (2)
where
Ksp = solubility product of the co-crystal.
Co-crystal
solubility (Scc)
and the phase
solubility diagram (PSD):
Phase
solubility diagrams are used to represent the solubility and solution stability
of co-crystals. The phase solubility diagram in Figure-1 illustrates two cases,
where case-1 represents stable co-crystal (low solubility and Ksp) and case-2
represents metastable co-crystal (high solubility and Ksp)
with respect to the pure drug form in a given solvent.
The curves in figure represent co-crystal
solubility product behavior with the drug concentration as a function of ligand
given by [drug]α = / [ligand]β from equation-2. The horizontal line
represents drug solubility which is assumed to be much lower than the ligand
solubility. A dashed line represents stoichiometric solution concentrations of co-crystal in pure solvent and its
intersection with the co-crystal solubility curves (marked by circles)
indicates the maximum drug concentration associated with the co-crystal solubility.
For a metastable co-crystal (case-2), the drug concentration associated with
the co-crystal solubility is greater than the solubility of the stable drug
form (horizontal line). As a metastable co-crystal dissolves, the drug released
into solution can crystallize because of super saturation. This super saturation
is a necessary, but not sufficient condition for crystallization. For both
congruently and incongruently saturating co-crystals a eutectic point,
indicated by X marks in figure, is the point where both solid drug and co-crystal
are in equilibrium with a solution containing drug and ligand. Together the
drug and ligand solution concentrations at the invariant point are referred to
as the transition concentration (Ctr).[17, 18]
Co-crystal solubility and chemical potential at the transition concentration:
Co-crystal solubility is a function of chemical
potential (μ). The chemical potential
expression for the equilibrium of co-crystal with solution is:
Aα Bβ =
αA(soln) + βB(soln)
µAα Bβ
= α (µAsoln)
+ β
(µBsoln)
At
the transition concentration, the solution is saturated with drug (A). The
chemical potential of solid drug and drug in solution are equal because they
are at equilibrium.
µAsoln =
µBsolid
When
we consider only one drug substance, µAsolid remains constant and we can substitute µAsolid = C = µAsoln as
µAα Bβ solid = β
(µBsoln)
+ C
(3)
From the above equation it can be
concluded that co-crystal solubility is proportional to ligand solubility.[8]
Thermal analysis and predictions of co-crystal solubility
(Scc):
Melting temperatures and enthalpies of
pharmaceutical crystals have found prevalent utility as indicators of ideal
solubility. These are readily measurable properties associated with the crystal
lattice energy that must be overcome for dissolution to occur. Among
structurally similar pharmaceutical crystalline drug substances, those with
high melt temperatures are generally recognized to possess lower solubility.
For an ideal solution, the solute solubility, x (mole fraction), is a
function of the heat of fusion, melt temperature, and solution
temperature.
There are a number of considerations
when discussing solubility data. The first is equilibrium versus kinetic (or
apparent) solubility measurements. Kinetic solubility values are approximate
values usually based on one measurement at one time point. For equilibrium
solubility, a number of time points and measurements are taken to ensure that
the solution has reached equilibrium as evidenced by a plateau in the
concentration data. The time required to reach the equilibrium solubility can
also be a factor for development based on the residence time in the stomach and
intestines. It is desirable to have the drug dissolve while it is in the
gastrointestinal tract and very long dissolution times may result in less
absorption of the drug. Thus both equilibrium solubility and dissolution rate
plays their parts in efficacy of Class-II drugs.
Solubility
is a very important parameter to obtain during development of a new compound.
As expected, the limited examples in this section show that solubility may be
improved using co-crystals, but not in all cases.
Dissolution: Dissolution
profile of any active pharmaceutical ingredient (API) represents its
bioavailability pattern. The co-crystal dissolution profile is compared with active
pharmaceutical ingredient of original in crystal form. Particle size is
generally an important and controllable parameter of API forms, including co-crystals,
which influences dissolution behavior. Little is known about the effect of the
particle size on the dissolution and transformation behavior of a co-crystal.
Dissolution studies for pharmaceutical co-crystals were carried out by
preparing different co-crystals of same API with different sizes. Powder x-ray
diffraction (PXRD) and polarization microscopy are used to study the mechanisms
of dissolution improvement from co-crystallization, transformation behavior of
each co-crystal in an aqueous suspension. The paddle apparatus is used to study
dissolution rate in fasted-state simulated fluid (FaSSIF) at 37 oC.
The transformation behavior can be studied by suspending co-crystals of all
sizes in FaSSIF at 37 oC. Intrinsic dissolution tests are conducted
to compare the dissolution rate of a co-crystal with its host crystal. The sink
condition is maintained to study the dissolution rate of API and its co-crystals
of different sizes. According to Noyes Whitney equation, the smaller particle
sizes dissolved at a higher rate.[19] The dissolution rates for all
sizes of co-crystals is nearly similar to that of fine API but variability of
the dissolution of co-crystal is greater than that of API. The dissolution rate
is influenced by transformation of co-crystal to host crystal or by size
reduction or by agglomeration. Particle size reduction increases super saturation
state of fine co-crystal and enhance the absorption. The co-crystals are transformed to the host compound form, which
is analyzed by using PXRD. The super saturation from the fine co-crystal is
faster because of large specific surface area of small particles. While
transformation rate of fine co-crystal is slower than that of larger co-crystals.
There are three major reasons behind it, (1) The fine and large co-crystals
have same surface state i.e. morphology but the larges specific surface area of
fine particles require more time for transformation from co-crystal to host
crystal. (2) The ratio of major to minor crystal surface area is different
between fine and large particles. The large co-crystals mainly consisted of a
surface in which guest molecules easily dissociated from the co-crystal.[3]
The concentration of guest inside the agglomeration of fine co-crystal
increases during co-crystal transformation and guest molecule dissociates.
Bioavailability: Bioavailability
is a measurement of the rate and extent of the active drug that reaches
systemic circulation. A study with both the parent material and the co-crystal
will give a direct assessment of bioavailability improvements due to the co-crystal.
A limited number of animal bioavailability studies have been reported using co-crystals.
One study on the pharmaceutical co-crystal of a mono phosphate salt with
phosphoric acid mentions that excellent in vivo performance was observed, but
no details about the study are given.[21]
Stability
Stability is an extensively studied
parameter during the development of a new chemical entity. Different types of stability
need to be considered depending on the structure and characteristics of the
molecule. Chemical and physical stability data are commonly obtained at
accelerated stability conditions to determine developability and shelf life.
Water uptake is included from a handling and packaging point of view. Thermal
stress studies are also incorporated, and extra work may be warranted for
hydrates or thermally labile materials. In the case of co-crystals and salts,
solution stability may be a factor due to dissociation of the material
resulting in precipitation of the less soluble parent compound or a less
soluble form. Thus stability studies should be conducted for co-crystals before
considering it as viable alternative solid form.
Relative Humidity Stress: Automated
moisture sorption/desorption studies are commonly performed to determine
problem areas and to provide direction for more detailed studies when the need
arises. Significant moisture uptake during the course of the experiment may
warrant longer exposure at a specific relative humidity using a relative
humidity chamber and subsequent analysis of the sample after equilibration. There
is limited water sorption/desorption data present in the literature for co-crystals.
One example for a 1:1 indomethacin/saccharin co-crystal showed minimal uptake
(<0.05% water) up to 95% RH.[24]
The second example for a 1:1 AMG 517/sorbic acid co-crystal again showed a
minimal uptake of 0.7% water at 90% RH.[11] These studies showed
that relative humidity is not a major concern for these co-crystals; however,
longer term studies would be advisable to determine the effects of water under
more equilibrium conditions. The well known example of stability improvement
via co-crystallization is caffeine co-crystals. Caffeine is known to readily
form a hydrate upon exposure to water or water vapor.[25] Six co-crystals were successfully produced: 2:1
caffeine/oxalic acid, 2:1 caffeine/malonic acid, 2:1 caffeine/maleic acid, 1:1
caffeine/maleic acid, and two forms of 1:1 caffeine/glutaric acid. Samples were
placed at four RH conditions and analyzed after 1, 3, and 7 days and 7 weeks.
The 2:1 caffeine/oxalic acid sample was found to be stable at all RH conditions
through 7 weeks. The other co-crystals exhibited behavior similar to caffeine,
and one case was found to be worse than caffeine with evidence of dissociation
and conversion to caffeine monohydrate. Thus it can be concluded that the
strongest acid used (oxalic acid) resulted in the most stable co-crystal, while
the weakest acid (glutaric acid) produced the least stable co-crystal.
Thermal stress: High
temperature stress is a common condition used to determine chemical and
physical stability based on accelerated stability conditions. Very few reports
discuss thermal stress experiments on co-crystals. For the co-crystal of a mono
phosphate salt with phosphoric acid an eight week exposure at 60 oC
resulted in no detectable degradation or form change.[21]
Paracetamol co-crystals of
4,4′-bipyridine, 1,4-dioxane, N-methylmorpholine, morpholine, N,N-dimethylpiperazine,
and piperazine were analyzed by differential scanning calorimetry (DSC).
The paracetamol/4,4′-bipyridine sample was the only co-crystal that did not
lose the guest upon heating and exhibit a melting endotherm corresponding to
the monoclinic form of paracetamol where as all other co-crystals did. These limited reports show that
heating studies can provide valuable information about physical and chemical
stability. Information on elevated temperature transitions can give clues about
possible problems in long-term stabilities and can provide guidance on drying
steps. These results can be translated into a better understanding of the
solid-state system and can help develop more robust compounds and processes.
Chemical stability: Chemical
stability is commonly investigated early in the development of a new compound
and during formulation studies in order to minimize any chemical degradation
that may occur. Very few reports of chemical stability of co-crystals are found
in the literature.
In one example, a pharmaceutical co-crystal
of a mono phosphate salt with phosphoric acid was reported to have no
detectable degradation after 8 weeks of storage at 40 oC/75% RH and 60
oC.[21] Samples of a glutaric acid co-crystal of
2-[4-(4-chloro- 2-fluorphenoxy) phenyl] pyrimidine-4-carboxamide were placed at
the same conditions for 2 months, and HPLC impurity analysis did not show any
significant increases in known degradants.[20]
Physical stability in solution: Solution
stability in this context is defined as the ability of the co-crystal
components to stay in solution and not readily crystallize. A variety of
vehicles can be used to study solution stability, including water, simulated
gastric fluid (SGF), simulated intestinal fluid (SIF), formulation vehicles,
and buffered solutions. In many instances, these experiments can be coupled
with solubility or dissolution experiments to get a complete understanding of
the behavior and the solid form remaining at the end of the experiment. Because
dissociation of a co-crystal can occur, solution stability can be a key
consideration for development. Studies of co-crystals in water can give an
indication of possible dissociation and precipitation of another form such as a
hydrate. In the study of caffeine co-crystals, the 2:1 caffeine/ oxalic acid co-crystal
was found to be stable at all relative humidity up to 98% RH for 7 weeks.[25]
In order to further test the stability,
the material was slurried in water at ambient temperature for 2 days. No change
in physical form was observed, demonstrating the stability of the material. A
solubility study at pH 7.4 and two buffer strengths (60 and 200 mM) was
conducted on an indomethacin/saccharin co-crystal and compared to the γ-form
of Indomethacin.[24] At the 60 mM strength, the co-crystal dissolved
immediately and was followed by a drop in pH to 6.8 and precipitation of an
amorphous material with traces of the α-form of indomethacin. By raising the
buffer strength to 200 mM, the co-crystal rapidly dissolved and remained in
solution for several hours, giving a 50-fold increase in solubility over the
indomethacin γ-form.
Performance comparison of cocrystals of carbamazepine with marketed product
The carbamazepine: saccharin co-crystal
was studied in terms of crystal polymorphism, physical stability, in vitro
dissolution and oral bioavailability, with the goal of comparing carbamazepine:
saccharine co-crystal with the marketed form of carbamazepine (Tegretol®).
Carbamazepine, has a high dose
requirement (>100 mg/day) for therapeutic effect. Carbamazepine poses
multiple challenges for oral drug delivery, including a narrow therapeutic
window, auto induction of metabolism and dissolution-limited bioavailability.[26,
27] Pharmaceutical co-crystals have recently been suggested as promising
materials in drug discovery and development.[28] The carbamazepine:
saccharin co-crystal has been prepared from methanol solutions and
characterized using PXRD, DSC, TGA, microscopy and Raman spectroscopy. The
chemical stability of co-crystal was determined using a gradient HPLC
technique. Dissolution experiments in SGF were performed using USP dissolution
apparatus These studies focused on the initial rate of dissolution, which has
been shown to correlate to increased overall absorption and improved
bioavailability.[29] As
expected, faster initial dissolution was observed with smaller particle size of
carbamazepine: saccharine co-crystal, presumably as a result of increased
surface area. Sieved co-crystal fractions of particles less than 150 µm showed
the fastest initial dissolution. The dissolution rates for sieved fractions
greater than 500 µm are slower than that for 150 µm. It is likely that
conversion to the di-hydrate on the surface of the larger crystals is
responsible for the lower concentrations of carbamazepine observed.
The overall conclusions regarding the
stability of carbamazepine: saccharine co-crystals are that (i) chemical
stability in the solid-state appears to be similar to the marketed form of
carbamazepine, (ii) physical stability of carbamazepine: saccharine co-crystal
is comparable to the anhydrous polymorph form which is found in Tegretol®
tablet, and (iii) carbamazepine: saccharine co-crystal shows a dependence of
dissolution rate on particle size above 150 µm and a resistance of the smaller
particle sizes to conversion to di-hydrate in aqueous suspension on the time
scale of drug absorption.
For the comparison of bioavailability of
carbamazepine: saccharine co-crystal with commercial formulation i.e. Tegretol®
tablet, oral pharmacokinetics of carbamazepine: saccharine co-crystal was
conducted in dogs. For the purpose of this preliminary pharmacokinetic study,
ground 1 (less than 53 µm particle size by microscopy) was mixed with lactose
in a dry blending step and placed in HPMC capsules for dosing. In-vitro
dissolution experiments carried out on formulated co-crystal containing lactose
showed no effect on the rate of dissolution or the concentration of
carbamazepine as a result of adding lactose. As per assumed, the co-crystal
shows higher plasma levels than Tegretol®, however, no statistically
significant differences were observed between pharmacokinetic parameters of
Tegretol® and carbamazepine: saccharine co-crystal, as suggested by calculated p values (Student’s t-test).
Thus from overall studies, the benefits
of carbamazepine: saccharine co-crystal can be summarized as,
·
Relative lack of polymorphism and
equivalent chemical stability to the anhydrous polymorph,
·
Favorable dissolution properties and
suspension stability, and
·
Comparable oral absorption profile in
dogs compared with the commercial immediate release product.[22]
REGULATORY PERSPECTIVE
Solid forms of drugs may exhibit undesirable physical properties, but experimental effort can always reveal new forms with potentially advantageous characteristics.[30, 31] Beyond polymorphs, hydrates, salts, and amorphous solids, a thorough solid form screen today may also include a search for co-crystals.[28] Compared to other classes of solid forms, co-crystals possess particular scientific and regulatory advantages, and alongside these advantages are intellectual property issues which confer co-crystals with unique opportunities and challenges.
Pharmaceutical co-crystals, by contrast,
have not yet been officially addressed from the perspective of generic
regulatory approval. In some respects, co-crystals are intermediate between
hydrates (ANDA-eligible) and salts (ANDA-noneligible). Like hydrates, co-crystals
are nonionic supra molecular complexes; but like salts, co-crystals involve
complexation with substances of greater potential toxicity than water. The
issue of whether a new co-crystal of a marketed API may be eligible for
regulatory approval via the ANDA mechanism will impact the overall utility of
co-crystal technology to the generic pharmaceutical industry, and may possibly
bear on the future market place abundance of pharmaceutical products containing
co-crystals.[32]
FUTURE PROSPECTS
As compared to salt formation,
complexation, micronization, etc. techniques, the co-crystallization is very
little explored area. The future development aspects in this area are, polymorphism
need to be examined for co-crystals and process to produce co-crystals on a
large scale will likely require different approaches, such as those based on
ternary solubility phase diagrams. In particular,
applying the concepts of supra molecular synthesis
and crystal engineering to the development
of pharmaceutical co-crystals represents a
paradigm that offers many opportunities related
to drug development and delivery. It seems
inevitable that pharmaceutical co-crystals will
gain a broader foothold in drug formulation.
CONCLUSION
On the basis of the limited examples
available, it can be concluded on the physicochemical properties of co-crystals
that improved solubility for poorly
soluble compounds has been achieved using co-crystals. Limited studies suggest
that salts will provide a larger increase in solubility if they are available.
For poorly soluble neutral compounds, co-crystals are a very feasible approach
to improving solubility. Co-crystals
can provide higher and lower dissolution rates compared to the API.
Dissociation is an important consideration in analyzing data from these
experiments. It was shown that significant increases in bioavailability are
possible with co-crystals, even when dissociation of the co-crystal is
suspected based on in-vitro studies. Improved
stability, such as resistance to hydrate formation, has been shown for co-crystals.
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Figure- 1
Co-crystal
solubility and the phase solubility diagram[17]
Ctr Transition
concentrations {Measurable for both cases}
Case 1 ≤ Drug solubility {Measurable}
Case 2 ≥ Drug solubility {Not always Measurable}
Case 2 (Supersaturated
State)
Ctr
Ctr
[Drug]
Drug
solubility
Case 1
High solubility crystal
Low solubility crystal
[Ligand]
Table-
1
Biopharmaceutical
performance of co-crystals
API or
DRUG
|
COFORMER
|
BIOPHARMACEUTICAL PERFORMANCE
|
REFERENCES
|
||
SOLUBILITY
|
DISSOLUTION
|
BIOAVAILABILITY
|
|||
Fluoxetin
|
Benzoic acid Hydrocloride,
Fumaric acid,
Succinic acid
|
5.6 mg/ml
11.4 mg/ml
14.8 mg/ml
20.2 mg/ml
|
-
-
-
-
|
-
-
-
-
|
[15]
|
Itraconazole
|
Succinic acid, L-malic acid, L-
tartaric acid
|
4 - 20 fold higher than crystalline
itraconazole
|
-
|
-
|
[11]
|
Piroxicam
|
Saccharin
|
No improvement
|
-
|
-
|
[11]
|
2-[4-(4-chloro-2-fluorphenoxy) phenyl]
pyrimidine-4-carboxamide
|
Glutaric acid
|
-
|
18 times faster than parent compound
|
-
|
[20]
|
Exemestane
|
Malic acid
|
-
|
Same as API
|
-
|
[11]
|
Megestrol acetate
|
Saccharin
|
-
|
3-4 times higher than API
|
-
|
[11]
|
Celecoxib Form IV
|
Nicotinamide
|
-
|
Faster than Celecoxib Form III
|
4 times increased
|
[23]
|
Fluoxetin HCl
|
Succinic acid
|
-
|
3- fold increase over API
|
-
|
[11]
|
Fluoxetin HCl
|
Benzoic acid
|
-
|
Half- that of API
|
-
|
[11]
|
Fluoxetin HCl
|
Fumaric acid
|
-
|
Same as that of API
|
-
|
[11]
|