Chiral discrimination by a cellulose polymer: differential crystallization inhibition of enantiomers in amorphous dispersions

Article abstract of DOI:10.1039/c5ce00810g

With the goal of better understanding how polymers inhibit crystallization in amorphous solid dispersions, crystal growth rates of the R and S enantiomers of a model chiral compound in the presence of chiral and achiral polymers were evaluated. The crystal growth rates of enantiomers in undercooled melts were inhibited to different extents by the same mass fraction of a chiral polymer, hydroxypropylmethyl cellulose acetate succinate. This is most likely due to differences in the ability of each enantiomer to form hydrogen bonding interactions with the polymer, which in turn impacts the crystallization behavior of the low molecular weight organic compound. In contrast, the achiral polymer polyvinylpyrrolidone, and the chiral polymer, hydroxypropylmethylcellulose phthalate showed the same inhibitory impact on each enantiomer.

Full text of DOI:10.1039/c5ce00810g

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Chiral discrimination by a cellulose polymer:
differential crystallization inhibition of
Cite this: CrystEngComm, 2015, 17,
enantiomers in amorphous dispersions†
5046
a
Takafumi Satoab and Lynne S. Taylor
*
With the goal of better understanding how polymers inhibit crystallization in amorphous solid dispersions,
crystal growth rates of the R and S enantiomers of a model chiral compound in the presence of chiral and
achiral polymers were evaluated. The crystal growth rates of enantiomers in undercooled melts were
inhibited to different extents by the same mass fraction of a chiral polymer, hydroxypropylmethyl cellulose
acetate succinate. This is most likely due to differences in the ability of each enantiomer to form hydrogen
bonding interactions with the polymer, which in turn impacts the crystallization behavior of the low
molecular weight organic compound. In contrast, the achiral polymer polyvinylpyrrolidone, and the chiral
polymer, hydroxypropylmethylcellulose phthalate showed the same inhibitory impact on each enantiomer.
Received 25th April 2015,
Accepted 9th June 2015
DOI: 10.1039/c5ce00810g
www.rsc.org/crystengcomm
the drug, and by forming specific drug-polymer interactions
and thus restricting the mobility at the local scale.5,7,8,11
Introduction
Many new drug candidates have very low aqueous solubilities,
and hence there is increased interest in solubility enhancing
formulation approaches, including amorphous solid disper-
sions.1 Because the amorphous form is a high energy state, it
temporarily exhibits a higher dissolution rate and solubility
which can enhance the absorption of the drug in vivo.2,3 How-
ever, because of its high energy state, it tends to transform to
the thermodynamically stable crystalline phase during storage
and dissolution, and the advantage of the amorphous form is
lost.4 Therefore, the crystallization of the amorphous formula-
tion needs to be prevented over the product shelf life and dur-
ing delivery of the formulation.
One strategy to prevent crystallization of an amorphous
drug is to add polymers. There are numerous examples illus-
trating that improved physical stability can be achieved
through the use of polymers.5–9 The stabilizing effect of poly-
mers in terms of preventing crystallization of the drug is cur-
rently not fully understood, and several mechanisms are
suggested to be of importance. These include increasing the
glass transition temperature (Tg) of the system thereby reduc-
ing the molecular mobility at the storage temperature,10 by
acting as a diluent thus decreasing the chemical potential of
Many drugs contain one or more chiral center(s) and
increasingly, enantiomerically pure products are being devel-
oped since typically one stereoisomer has greater pharmaco-
logical activity.12 Enantiomers have the same chemical and
physical properties apart from the fundamental difference of
being three dimensional mirror images. Thus conventional
chromatography or other separation processes are incapable
of distinguishing them. For separation of enantiomers, chiral
high performance liquid chromatography (HPLC) columns
are typically used.13,14 These have a chiral stationary phase
that has a differing affinity for each of the enantiomers, and
as a result, differing retention times. Derivatives of amylose
or cellulose polymers are widely used to produce chiral sta-
tionary phases since these natural polymers are chiral,
forming the basis for their differential interaction with
enantiomers.15,16
Cellulose derivatives such as hydroxypropyl cellulose,
hypromellose,
hypromellose
acetate
succinate
and
hypromellose phthalate, which are all chiral polymers, are
widely used to produce amorphous solid dispersions. There-
fore, with the goal of better understanding how polymers
inhibit crystallization in amorphous solid dispersions, crystal
growth rates of the R and S enantiomers of a model chiral
compound in the presence of chiral and achiral polymers
were evaluated. The hypothesis to be tested in this study is
that variations in interactions between enantiomers and chi-
ral polymers in the amorphous system will lead to the poly-
mer having a different crystallization inhibitory impact for
each enantiomer.
a Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue
University, West Lafayette, Indiana 47907, USA. E-mail: lstaylor@purdue.edu;
Fax: +765 494 6545; Tel: +765 496 6614
b Drug Formulation Research and Development Laboratories, Kyowa Hakko Kirin
Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8731, Japan
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5ce00810g
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Materials and methods
the racemic mixture and polymer (HPMCAS HF grade and
PVP) were prepared as described above.
IJS)-IJ−)-2-amino-1,1,3-triphenyl-1-propanol
IJATPIJS))
and
IJR)-IJ+)-2-amino-1,1,3-triphenyl-1-propanol IJATPIJR)) were pur-
chased from Sigma-Aldrich (St. Louis, MO, USA). Hydroxy-
propyl methylcellulose acetate succinate (HPMCAS, grade LF
and HF) and hydroxypropylmethylcellulose phthalate
(HPMCP, grade HP-55) were obtained from Shin-Etsu
chemicals (Niigata, Japan). Polyvinylpyrrolidone K-12 (PVP,
Mw 2000–3000 g mol−1) was acquired from BASF Chemicals
(New Jersey, USA). Polyhydroxybutyrate (PHB, Mw 50 000) was
purchased from Advanced Polymer Materials (Montreal, QC,
Canada). The chemical structures of the model compound
and polymers are given in Fig. 1.
Growth rate measurements
Crystal growth rate measurements were performed by melting
approximately 3 mg of sample between two clean coverslips at
around 5 °C above the melting point of the compound
followed by immediate quenching of the melt to room tem-
perature to yield a clear film. The samples were confirmed to
be non-crystalline by visual observation under cross-polarized
light using a microscope (Nikon Eclipse E600 POL micro-
scope, Nikon Corp, Tokyo, Japan). The samples were heated
to and maintained at different temperatures using a hot
stage (Linkam THMS 600, Surrey, UK). The growth of the
spherulite was recorded by time lapse photography. The size of
the spherulite (Fig. 2) was plotted as a function of time. A linear
relationship was obtained between spheurlite size and time,
and the growth rate was determined from the slope of this data
by applying linear regression analysis. This procedure was
performed in triplicate for each temperature and polymer.
Sample preparation
ATP–polymer mixtures were prepared at a 5% w/w polymer
concentration by first dissolving the compound and polymer
in an organic solvent (acetone for HPMCAS and PVP,
dichloromethane for PHB and
a
1 : 1 mixture of
dichloromethane and ethanol for HPMCP) followed by sol-
vent removal using rotary evaporation and light trituration of
the resultant powder in a mortar and pestle. A racemic mix-
ture IJATPIJRS)) of ATPIJR) and ATPIJS) was prepared by first
mixing an equal amount of ATPIJR) and ATPIJS) in a mortar
and pestle and then cryomilling for 10 min in a 6750 freezer
mill (Spex Sampleprep, Metuchen, New Jersey). Mixtures of
Fourier transform infrared (FTIR) spectroscopy
FTIR spectroscopy was performed in transmission mode using
a Bio-Rad FTS 6000 spectrometer (Bio-Rad, Cambridge, MA).
The samples were prepared by one of two methods: either a
mixture of ATP and the polymer was melted by heating
between a KRS-5 substrate and a coverslip, quenched imme-
diately to room temperature, followed by removal of the
Fig. 1 Chemical structures of (a) ATPIJR), (b) ATPIJS), (c) PVP, (d) PHB,
(e) HPMCAS and (f) HPMCP. For (e) and (f) oligoIJhydroxypropyl)
substituents are also possible.24 *indicates chiral center.
Fig. 2 Photomicrographs of ATPIJR) without polymer (a), with 5%
HPMCAS HF (b), with 5% PVP (c), with 5% HPMCP (d) and with 5% PHB
(e). The scale bar is 20 μm.
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coverslip or ATP and the polymer were dissolved in acetone
followed by spin coating onto a KRS-5 substrates using a
KW-4A spin coater (Chemat Technology Inc., Northridge, CA)
at spin rate about 2000 rpm. The fast spinning action resulted
in a thin film and quick evaporation of the solvent. The spec-
tra were then obtained by coadding 128 scans over the
wavenumber region of 4000–400 cm−1 while maintaining ~0%
RH with a dry air purge.
Thermal analysis
Thermal analysis of ATP and its mixtures was performed
using a differential scanning calorimeter (DSC) (TA Q2000,
TA Instruments, New Castle, DE, USA) attached to a refriger-
ated cooling system. Dry nitrogen was used as the purge gas
and was maintained at a flow rate of 50 mL min−1. The
instrument was calibrated for temperature using indium and
tin, and enthalpy was calibrated using indium, at the heating
rate used. The samples were placed in sealed aluminum pans
with a pinhole in the lid. Determination of the glass transition
temperature (Tg) was performed by cooling the melt at 10 °C
min−1 and then reheating at 10 °C min−1. The melting temper-
ature was measured for physical mixtures of ATP and the poly-
mer at a heating rate of 10 °C min−1. The glass transition tem-
perature, recrystallization temperature during heating and the
melting temperature are reported as the onset value.
Fig. 4 DSC thermograms of (a) ATPIJS) with 5% PVP, (b) ATPIJR) with
5% PVP and (c) ATPIJRS) with 5% PVP.
The Tg was comparable to that of the enantiomers, in spite of
the higher melting point, and upon recrystallization of the
amorphous form, a crystal with the same melting characteris-
tics of the original form was obtained.
The glass transition temperatures of ATP enantiomers
with and without polymers were very similar, presumably
because of the relatively low polymer concentration (5%).
Although the polymers did not influence the Tg, they did
impact the temperature at which recrystallization was
observed. In the absence of a polymer, ATP enantiomers crys-
tallized at around 59 °C upon heating of the amorphous
material. PVP delayed the recrystallization to around 62 °C
(onset), with no difference seen for the two enantiomers. In the
case of HPMCAS, the recrystallization temperature was even
higher and a difference was observed for the two enantiomers.
Thus recrystallization commenced at 77 °C for the ATP-S
Results
Thermal analysis
Thermal analysis of ATP enantiomers and racemate with and
without polymer was carried out. DSC thermograms of each
sample are shown in Fig. 3–5 and values of pertinent thermal
events are summarized in Table 1.
enantiomer and around 82 °C for the
R enantiomer,
Pure ATPIJR) or ATPIJS), as received, melted at around 145
°C, and underwent partial crystallization during cooling.
However, a glass transition event (Tg) at around 16–17 °C
could be observed on reheating, followed by recrystallization
to at least one different polymorph with the predominant
form melting at 120 °C. The racemate melted at a higher
temperature, and did not show crystallization during cooling.
suggesting that HPMCAS-HF is more effective at inhibiting
crystallization of the latter enantiomer.
Growth rate kinetics
The growth rates of each enantiomer alone and in the pres-
ence of HPMCAS, HPMCP, PHB and PVP are summarized in
Fig. 3 DSC thermograms of (a) ATPIJS), (b) ATPIJR) and (c) ATPIJRS).
Black is first heating, blue is cooling and red is reheating.
Fig. 5 DSC thermograms of (a) ATPIJS) with 5% HPMCAS HF, (b) ATPIJR)
with 5% HPMCAS HF and (c) ATPIJRS) with 5% HPMCAS HF.
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Table 1 Glass transition temperatures (Tg), onset recrystallization tem-
peratures (during heating, Tc) and onset melting point temperatures (Tm)
was equally effective for both of the enantiomers. The chiral
polymer, HPMCP was even more effective at inhibiting
growth, but showed no differential effect on the enantiomers.
HPMCAS, which is also chiral, showed a similar extent of
growth inhibition as HPMCP, but a difference in growth rates
was observed for the two enantiomers. This result is shown
in more detail in Fig. 7 and 8, where the change in size of
the crystals as a function of time in the presence of HPMCAS-
LF (Fig. 7) and HPMCAS-HF (Fig. 8) at 60 °C is shown for
each enantiomer.
In the presence of HPMCAS-HF, ATPIJR) grew twice as fast
as ATPIJS). In contrast, in the case of HPMCAS LF grade,
ATPIJS) had a growth rate twice as fast as the R enantiomer.
Thus HPMCAS clearly has a differential impact on each
enantiomer.
a
measured at 10 °C min−1
Sample
Tg (°C)
Tc (°C) onset
Tm (°C) onset
ATPIJS)
ATPIJR)
ATPIJRS)
ATPIJS) HF5
ATPIJR) HF5
ATPIJRS) HF5
ATPIJS) PVP 5
ATPIJR) PVP 5
ATPIJRS) PVP5
17.0
16.3
16.0
16.3
15.6
14.3
18.2
18.4
15.7
58.1
59.0
61.3
77.2
81.6
83.3
63.6
61.5
72.2
119.2IJ144.0)
116.0IJ142.7)
145.8IJ144.6)
106.1
102.0
134.6
116.7
116.6
137.6
a
Melting point during first heating is shown in parentheses.
Fig. 6. As expected, growth rates decrease with decreasing
temperature. ATPIJR) and ATPIJS) showed almost exactly the
same growth rate for the temperature range studied, as
expected. However, ATPIJR) and ATPIJS) appear to grow as dif-
ferent polymorphs depending on the growth temperature.
The crystal images obtained at temperatures between 40 °C
to 90 °C versus those obtained at temperatures over 100 °C
were clearly different. Furthermore, the growth rates of the
enantiomers as a function of temperature showed a disconti-
nuity between 90 °C and 100 °C. Based on the DSC data and
confirmed by IR measurements of crystallized films, the poly-
morph that grows below 100 °C is the low melting point poly-
morph, while at 100 °C and above, it is the higher melting
point polymorph that grows. Certainly, at 120°, the lower
melting point polymorph would not show any growth since
melting has commenced at this temperature.
Limited growth rate studies were performed on the race-
mate and results are summarized in Fig. 9. The racemate has
a lower growth rate at a given temperature than the enantio-
mers. Interestingly, PVP and HPMCAS-HF had similar effec-
tiveness as growth rate inhibitors, in contrast to the enantio-
mers, where HPMCAS-HF was considerably more effective
than PVP. However, for each polymer, the overall extent of
inhibition was less than for the enantiomer. Thus HPMCAS-
HF reduced the growth rate of the racemate by a factor of
two (Fig. 9), while for the S-enantiomer, this polymer reduced
the growth rate by a factor of 50 (Fig. 6).
FTIR spectroscopy
Infrared spectra were obtained for various samples. Fig. 10
shows a comparison of the spectra of the crystalline and
amorphous forms of ATPIJS) in the NH/OH stretching region.
ATP contains NH and OH groups and the crystal structure
can be used to identify hydrogen bonding patterns and to aid
in the interpretation of the IR spectrum. In the crystal of the
high melting point polymorph (Fig. 11), the molecules form
The impact of the polymers on the growth rate of the
enantiomers depended both on the polymer and the enantio-
meric form under study. The chiral polymer, PHB had mini-
mal impact on the growth rate of either enantiomer. The
achiral polymer, PVP was effective at inhibiting growth, but
Fig. 6 Growth rates of each enantiomer with and without polymer.
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Fig. 7 Change in size of crystals as a function of time at 60 °C for
each enantiomer in the presence of HPMCASIJLF).
Fig. 9 Growth rates of racemate with and without polymer.
hydrogen-bonded dimers between the OH group (donor) of
one molecule and the N (acceptor) of the NH2 group of a dif-
ferent molecule. Thus the protons of the NH2 group are not
involved in hydrogen bonding. The spectrum of the crystal
shows sharp asymmetric and symmetric NH stretching vibra-
tions at 3365 and 3307 cm−1 respectively which are super-
imposed on the broad OH stretching peak.
at a lower wavenumber. Changes in the carbonyl region of
the spectrum, where only the polymer has peaks, were consis-
tent with the formation of a hydrogen bonding interaction
between the NH2 group of ATP (Fig. S1†) and the polymer
carbonyl. Specifically, the pure polymer has a carbonyl peak
at 1727 cm−1, and in the dispersion with ATP, a new peak at
1699 cm−1 evolves. However, while evidence of ATP–polymer
hydrogen bonding interactions were observed, the spectra of
dispersions prepared from either R or S-ATP with HPMCP
were identical, suggesting that each enantiomer interacts to a
similar extent with HPMCP.
Spectra obtained from the R and S-ATP enantiomers with
30% HMPCAS-LF are shown in Fig. 13. A new NH peak is
seen 3290 cm−1 and the OH peak is shifted slightly to a
higher wavenumber, indicating the formation of ATP–poly-
mer interactions of the type described above. However, the
changes in the spectrum are more pronounced for the
S-enantiomer, suggesting that more ATP–polymer inter-
molecular interactions are formed in this system, relative to
the R-enantiomer. The differences are particularly evident
from the peak at 3390 cm−1. This peak is present in the pure
amorphous spectrum and is assigned to asymmetric NH2
This hydrogen bonding motif appears to persist in the
amorphous phase, since the IR spectrum is similar in the
NH/OH region (Fig. 10); the peaks are broadened and shifted
to higher wavenumbers in the amorphous spectrum as com-
pared to the crystalline spectrum which most likely indicates
that the hydrogen bonding is weaker in the amorphous form.
Mixtures of HPMCP with ATP were evaluated to determine
the nature of ATP–polymer interactions in a system where
the polymer was an effective growth rate inhibitor. A 30%
polymer level was used in order to obtain sufficient spectral
changes for evaluation of the interactions. Focusing on the
NH/OH region, it is apparent that both the OH and NH peaks
of ATP are modified by the addition of the polymer. The OH
peak shifts to a slightly higher wavenumber, however, much
larger changes are seen in the NH peaks, with the appearance
of a new peak at 3253 cm−1. This is consistent with the NH2
ATP group acting as a donor, forming hydrogen bonds with
acceptor groups on the polymer, in particular the carbonyl
groups, which leads to the NH stretching vibration occurring
Fig. 8 Change in size of crystals as a function of time at 60 °C for
each enantiomer in the presence of HPMCASIJHF).
Fig. 10 Infrared spectra of (a) amorphous and (b) crystalline forms of
ATPIJS) in the NH/OH stretching region.
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Fig. 13 Infrared spectra of (a) amorphous of pure ATPIJS), (b) ATPIJS)
with 30% HPMCAS LF and (c) ATPIJR) with 30% HPMCAS LF in the NH/
OH stretching region. The blue arrow shows the decrease in intensity
of the peak at 3390 cm−1
, while the green arrow shows the
appearance of a new peak at 3290 cm−1, in the presence of the
HPMCAS LF.
Fig. 11 Crystal structure of ATPIJS) showing hydrogen bonding
between OH and N. CCDC deposition # 1401488.
stretch. In the presence of the S-enantiomer, this peak is
drastically reduced in intensity, but in the R-enantiomer dis-
persion spectrum, it is present to a greater extent, indicating
that more of the original ATP–ATP interactions persist in this
system at the expense of ATP–polymer interactions.
Discussion
Understanding how polymers inhibit crystallization of amor-
phous compounds is important in the context of delivering
poorly water soluble compounds as amorphous solid disper-
sions. The hypothesis under investigation in this study was
that the crystallization behavior of the R and S enantiomers
of the model compound, ATP, would be similarly impacted
by an achiral polymer, but would be different in the presence
of a chiral polymer. The hypothesis is based on the expecta-
tion that each enantiomer will have a different interaction
with a chiral polymer and that this will consequently impact
the observed crystallization behavior. This concept is well
established in the area of chiral separations where cellulose
derivatives are widely used as the stationary phase material
under normal phase conditions; under normal phase
For the HPMCAS-HF dispersions, the opposite trend was
observed whereby the 3390 cm−1 peak was more intense for
the S-ATP enantiomer (20% polymer dispersion, Fig. 14),
suggesting that this enantiomer forms less interactions with
HPMCAS-HF, than the corresponding R enantiomer.
IR spectroscopy was also used to compare the overall crys-
tallization behavior of each enantiomer with 5% HPMCAS-
HF. Fig. 15 shows spectra of the NH/OH region obtained at
40 °C at different time points for the two systems. While
ATPIJS) appears to have completely crystallized within 15 h,
ATPIJR) is clearly a mixture of crystalline and amorphous
material. These results are in agreement with the growth rate
studies.
Fig. 14 Infrared spectra of (a) amorphous of pure ATPIJS), (b) ATPIJS)
with 20% HPMCAS HF and (c) ATPIJR) with 20% HPMCAS-HF in the NH/
OH stretching region. The blue arrow shows the decrease in intensity
of the peak at 3390 cm−1, while the green arrow shows the appearance
of a new peak at 3290 cm−1, in the presence of HPMCAS-HF.
Fig. 12 Infrared spectra of (a) amorphous of pure ATPIJS), (b) ATPIJS)
with 30% HPMCP and (c) ATPIJR) with 30% HPMCP in the NH/OH
stretching region. The appearance of a new peak at 3253 cm−1 in the
presence of the polymer is noted by the arrow.
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Fig. 15 Infrared spectra of ATPIJS) (left) and ATPIJR) (right) with 5% HPMCAS HF (3000–3700 cm−1) stored at 40 °C for different periods of time.
conditions, interactions such as π–π, dipole–dipole and
hydrogen bonding between the stationary phase and the ana-
lyte are promoted and if the interactions are different
between each enantiomer, the retention time is altered.17–20
Furthermore, it has been noted that chiral polymers differen-
tially impact the crystallization kinetics of nitrendipine
enantiomers, with the effect being attributed to a difference
in the nucleation rate for each enantiomer when combined
with HPMCP, whereas no difference in crystal growth rates
were observed.21
(Fig. 7 and 8). Given that all other properties of the system
apart from the chirality are identical, this result strongly sup-
ports previous reports that highlight the importance of inter-
molecular interactions between a low molecular weight
organic compound and a polymer as being critical determi-
nants of the polymer effectiveness as a crystal growth rate
inhibitor.11,22,23 The switch in effectiveness of HPMCAS-LF
and HPMCAS-HF for the two enantiomers is not readily
explainable without more detailed studies of the key inter-
molecular interactions in the systems, but is most likely
linked to the different degree of substitution of each polymer
grade with respect to the acetate and succinoyl groups and
the involvement of these groups in intermolecular interac-
tions with ATP.
For the polymers studied herein, as expected, PVP, which
is an achiral polymer, showed no difference in its ability to
inhibit the crystal growth of the R and S enantiomers of ATP.
However, out of the three chiral polymers studied, only
HPMCAS showed a differential effect on the crystallization
behavior of the enantiomers. Since PHB was ineffective as a
growth inhibitor, it is unsurprising that no differences were
observed with this polymer – presumably it had minimal
interactions with either enantiomer. However, while both
HPMCAS and HPMCP were effective inhibitors, only HPMCAS
influenced the growth rates of the enantiomers to different
extents. In considering the differences between these two
polymers, it is perhaps relevant to consider the functional
groups present and potential interaction sites between the
polymers and ATP. The IR data presented above, strongly sug-
gests that both HPMCAS and HPMCP interact with ATP
through hydrogen bonding interactions of the carbonyl
groups present on both polymers with the ATP amino group.
Both HPMCP and HPMCAS are chiral polymers however, in
the case of HPMCP, the functional groups that interacts with
ATP are adjacent to the rigid, achiral phthalate function. This
may minimize the interaction of ATP with the chiral cellulose
backbone and other chiral groups, yielding little discrimina-
tion in interactions between the two enantiomers with the
polymer, consistent with the IR data shown in Fig. 12. For
HPMCAS, some of the carbonyl groups (the ester linkages)
are in closer proximity to the cellulose backbone and it is
clear that this polymer interacts differently with the R and S
ATP enantiomers. This differential interaction leads to a fac-
tor of two variation in the crystal growth rate of the enantio-
mers in the presence of an equivalent amount of polymer
Conclusions
The crystal growth rates of ATP enantiomers in undercooled
melts were inhibited to different extents by the same mass
fraction of a chiral polymer, hydroxypropylmethyl cellulose
acetate succinate. This is most likely due to differences in the
ability of each enantiomer to form hydrogen bonding interac-
tions with the polymer, which in turn impact the crystalliza-
tion behavior of the low molecular weight organic compound.
In contrast, the achiral polymer polyvinylpyrrolidone, and the
chiral polymer, hydroxypropylmethylcellulose phthalate
showed the same inhibitory impact on each enantiomer. For
these polymers, it is suggested that both enantiomers interact
to the same extent with the polymer due either to the lack of
chirality (PVP), or because interacting polymer functional
groups are distant from chiral centers (HPMCP). These insights
are important for understanding amorphous solid disper-
sions and inhibition of drug crystallization, an increasingly
important topic in the formulation of poorly water soluble
compounds.
Acknowledgements
We acknowledge the financial support provided by Kyowa
Hakko Kirin Co., Ltd. (Tokyo, Japan). Dr. N. S. Trasi is greatly
appreciated for discussions.
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