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S Supporting Information
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INTRODUCTION
Development of supersaturating drug delivery systems to
enhance oral bioavailability of poorly water soluble drugs has
been of interest for many decades.1 In these systems, two
essential steps need to be considered: the drug in a high energy
form, e.g., amorphous forms, crystalline salts, or cocrystals,
should dissolve rapidly to generate a high concentration above
the saturation solubility and then this supersaturated solution
must be maintained for a reasonable period to allow for
signicant absorption and eventually sucient bioavailability.
This has been referred to as a spring and parachute
approach.2 As a supersaturated drug solution is thermodynamically unstable and has the tendency to return to the equilibrium
state through drug crystallization, extensive work has been
carried out to delay the drug crystallization by inclusion of
dierent excipients as eective crystallization inhibitors in
formulations.3 For example, signicant progress has been made
in amorphous solid dispersion formations by using polymeric
crystallization inhibitors to maintain the solid drug in an
amorphous state and also maintain the drug supersaturation
after dissolution.4,5 It has been found that inhibition of the drug
crystallization is a result of the polymers interfering in the
nucleation and/or crystal growth stages of the more stable
phase, through physical or chemical interactions between the
2016 American Chemical Society
July 6, 2016
August 4, 2016
August 5, 2016
August 5, 2016
DOI: 10.1021/acs.molpharmaceut.6b00612
Mol. Pharmaceutics 2016, 13, 32923307
Article
Molecular Pharmaceutics
Table 1. Structure and SP Values of FFA, NIC, TP, and Polymers
DOI: 10.1021/acs.molpharmaceut.6b00612
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Molecular Pharmaceutics
DOI: 10.1021/acs.molpharmaceut.6b00612
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Solubility Parameter (SP), Supersaturation Ratio (SR), and
Supersaturation Parameter (SSP). Solubility parameter (SP) is
used to compare the relative hydrophobicity of polymers, FFA,
and coformers in solution. The SP of an organic compound is
estimated by Fedors34 as
SP =
i ei
i vi
EV
V
SSP =
C
Ceq
AC0CR(t )C0(t )
100%
(3)
(1)
SR =
RESULTS
Solid Characterization of FFA I, NIC, TP, and FFA
Cocrystals. Figure 2a shows the XRPD patterns of individual
(2)
DOI: 10.1021/acs.molpharmaceut.6b00612
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Figure 3. Solubility test results: (a) apparent equilibrium solubility; (b) DSC results of solid residues; (c) images of solid residues.
DOI: 10.1021/acs.molpharmaceut.6b00612
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Molecular Pharmaceutics
Table 2. Nucleation Induction Time (s)
SR = 1.36
SR = 2.72
SR = 5.44
FFA
FFA-NIC CO
FFA-TP CO
FFA
FFA-NIC CO
FFA-TP CO
FFA
FFA-NIC CO
FFA-TP CO
cosolvent
92
15 7
24 10
N/A
N/A
N/A
N/A
N/A
N/A
176 37
288 172
218 161
N/A
N/A
N/A
N/A
N/A
N/A
no crystal appeared
no crystal appeared
no crystal appeared
658 47
555 93
510 166
N/A
N/A
N/A
appeared
appeared
appeared
appeared
appeared
appeared
DOI: 10.1021/acs.molpharmaceut.6b00612
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needle shape morphology of FFA crystals from both the FFANIC CO and pure FFA solution was similar. In contrast, the
FFA crystals from the FFA-TP CO solution were signicantly
smaller and rod-shaped. In the presence of PEG in solution, the
FFA crystals precipitated from the three test samples became
smaller. In the presence of PVP or PVP-VA in solution, all
crystals precipitated from three test solutions were a similar
shape, lacking any distinctive crystal morphology.
Eect of Polymers on the FFA Crystal Growth in
Solution. Due to the variation of the initial FFA concen-
Cnorm(t ) =
C(t )
C0 + Cstock
(4)
DOI: 10.1021/acs.molpharmaceut.6b00612
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Figure 5. continued
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DOI: 10.1021/acs.molpharmaceut.6b00612
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Figure 5. Seeded desupersaturation curves in the absence or presence of polymers: (a) cosolvent; (b) cosolvent with predissolved PEG; (c)
cosolvent with predissolved PVP; (d) cosolvent with predissolved PVP-VA; (e) comparison of supersaturation parameters; (f) FTIR data of solids.
DOI: 10.1021/acs.molpharmaceut.6b00612
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Figure 6. continued
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Figure 6. Unseeded desupersaturation curves in the absence or presence of polymers: (a) cosolvent; (b) cosolvent with predissolved PEG; (c)
cosolvent with predissolved PVP; (d) cosolvent with predissolved PVP-VA; (e) comparison of supersaturation parameters; (f) FTIR data of solids.
DOI: 10.1021/acs.molpharmaceut.6b00612
Mol. Pharmaceutics 2016, 13, 32923307
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Molecular Pharmaceutics
Figure 7. IR spectroscopic investigation of molecular interaction in solution: (a) FFA interaction with NIC and polymers; (b) NIC interaction with
FFA and polymers; (c) TP interaction with FFA and polymers.
DOI: 10.1021/acs.molpharmaceut.6b00612
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stretching.35 When a component of NIC, PVP, or PVP-VA was
added in the solution, this FFA characteristic peak was shifted
to a smaller wavelength number of 1684 cm1, indicating an
intermolecular interaction between them in solution. In
contrast, there is no change in the FFA CO peak in the
PEG solution, suggesting no interaction between these two
components. NIC can interact with FFA or PVP in solution,
demonstrated by a change in the characteristic peak of NIC at
1625 cm1, corresponding to NH stretching,36 to 1617 cm1
in the presence of FFA and to 1631 cm1 in the presence of
PVP in Figure 7b. Surprisingly there is no interaction between
NIC with PVP-VA or PEG in solution, conrmed by no change
in the characteristic peak of NIC at 1625 cm1. The IR
characteristic peak of TP at 925 cm1, corresponding to NH
symmetric stretching,39 has been shifted to a lower wavenumber by inclusion of PVP or PVA-VA and to a higher
wavenumber by adding PEG or FFA in solution, indicating TP
can interact with any of the components, FFA, PEG, PVP, or
PVP-VA in solution.
DISCUSSION
Eect of a Polymer on the Apparent FFA Equilibrium
Solubility of FFA I, FFA-NIC CO, and FFA-TP CO in
Cosolvent. There is widespread acceptance that the crystalline
nature of pharmaceutical cocrystals can oer advantages over
amorphous materials to formulate drug compounds with
limited solubility and bioavailability, due to superior thermodynamic stability and purity. Although signicant advances in
design and discovery have been made, little work has been
conducted to formulate cocrystals into a drug product.
Therefore, the behavior of a cocrystal in a formulated product
is largely unknown. In order to oer the most desired in vivo
performance with the highest bioavailability for many life-saving
drugs with poor biopharmaceutical properties, a fundamental
understanding of the critical factors that control the dissolution
and absorption performance of a cocrystal formulated product
is required. In this work, the focus was on understanding the
parent drug crystallization kinetics from a supersaturated
cocrystal solution in the presence of a polymeric excipient. It
aimed to provide the mechanistic understanding of the
properties of a polymer as a good inhibitor of crystallization
for a given drug cocrystal. Two FFA cocrystals, FFA-NIC CO
and FFA-TP CO, were chosen due to signicant dierences in
their physicochemical properties. The low polymer concentration of 200 g/mL used in the investigation was based on
the rational consideration of a 500 mg tablet containing 250 mg
of stabilizing polymer, in which 20% of the polymer was
released in 250 mL of the GI tract at the beginning stage of
dissolution. According to the equilibrium solubility results in
Figure 3a, the FFA concentrations of FFA I, FFA-NIC CO, or
FFA-TP CO were constant in solution in the absence and
presence of 200 g/mL polymer of PEG, PVP, or PVP-VA,
indicating that the impact of a polymer on FFA crystallization
in a supersaturated solution was not caused by a change in the
level of supersaturation. Furthermore, due to the low molecular
weight of the polymer used in the study, the viscosity of the 200
g/mL polymer solution was essentially the same as that of the
dissolution medium without a predissolved polymer. Therefore,
the interplay of API-coformer, API-polymer, and coformerpolymer elucidated in this study was not aected by the
changes of the solution bulk properties of solubility and mass
transport.
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DOI: 10.1021/acs.molpharmaceut.6b00612
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DOI: 10.1021/acs.molpharmaceut.6b00612
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acceleration ability for FFA in solution, indicating that the rate
of desupersaturation was reduced dramatically in the presence
of PVP or PVP-VA. The desupersaturation behavior of FFA
cocrystal solutions in the presence of PVP or PVP-VA depends
on dierent interaction mechanisms of the polymer and
coformer and on the competition eect of the polymer and
coformer for formation of hydrogen bonding with FFA
molecules, in which PVP-VA was a good crystallization
inhibitor for FFA-NIC CO solution.
It is worth noting that the study has shown the coformers
and polymers have been integrated in the solid particles
recovered from the seeded and unseeded experiments based on
the measured IR spectra. However, the IR data cannot quantify
the relative proportion of coformer/polymer coprecipitated in
the desupersaturated solids, which could be determined by
solid state NMR or other techniques. In the meantime, more
fundamental research is required to guide the selection of
polymers in cocrystal formulation systems through understanding the parent drug crystallization kinetics.
AUTHOR INFORMATION
Corresponding Author
ACKNOWLEDGMENTS
The authors would like to thank Dr. Simon Roberts from
Ashland Specialty Ingredients for providing materials for this
study.
REFERENCES
CONCLUSIONS
Development of enabling formulations is a key stage when
demonstrating the eectiveness of pharmaceutical cocrystals
and is applied to maximize the oral bioavailability for poorly
water soluble drugs. Inhibition of the drug crystallization from a
supersaturated cocrystal solution through a fundamental
understanding of the nucleation and crystal growth is
important. In this study, the inuence of the three polymers
PEG, PVP, and PVP-VA on the FFA crystallization in three
dierent supersaturated solutions of the pure FFA and two
cocrystals of FFA-NIC CO and FFA-TP CO has been
investigated by measuring nucleation induction times and
desupersaturation rates in the presence and absence of seed
crystals. It was found that the competition of intermolecular
hydrogen bonding among drug/coformer, drug/polymer, and
coformer/polymer was a key factor responsible for maintaining
the supersaturation through nucleation inhibition and crystal
growth modication in a cocrystal solution. The supersaturated
cocrystal solutions with predissolved PEG demonstrated
eectiveness at stabilizing supersaturated solution compared
to pure FFA in the presence of the same polymer. In contrast,
the two cocrystal solutions in the presence of PVP or PVP-VA
did not perform as well as pure FFA with the same predissolved
polymer. The study suggested that the selection of a polymeric
excipient in a cocrystal formulation should not be solely
dependent on the interplay of the parent drug and polymer
without considering the coformer eects.
ASSOCIATED CONTENT
S Supporting Information
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DOI: 10.1021/acs.molpharmaceut.6b00612
Mol. Pharmaceutics 2016, 13, 32923307
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