J.L. Terebetski, B. Michniak-Kohn / International Journal of Pharmaceutics 475 (2014) 536–546
537
molecular weight of excipients, viscosity, and the potential for
hydrogen bonding (Warren et al., 2010).
dihydrate sodium salt (Lee et al., 2007 Zhang et al., 2003) as the
supersaturating salt system.
In general, stabilized amorphous systems have a number of
potential formulation limitations when compared to equivalent
formulations of crystalline material, including increased risk of
chemical and physical instability during storage as well as large-
scale manufacturing challenges (Vasconcelos et al., 2007).
Therefore, it is desirable to investigate alternative systems that
can achieve supersaturation following oral administration, such as
salts. Since salts are stable solid phases that can be included in
preclinical and clinical formulations for drug candidates with poor
solubility, it is desirable to try to leverage a salt with a favorable pH
solubility profile and attempt to sustain supersaturation following
oral administration. Although a pharmaceutical salt typically
provides solubility enhancement relative to the free form, salt
disproportionation can occur during oral administration if the pKa
of an ionizable drug is close to the physiological pH conditions
encountered during gastrointestinal (GI) transit (Serajuddin,
2007). Therefore, the solubility enhancement afforded by the salt
may be lost, resulting in decreased drug in solution and
uncontrolled precipitation of the free form. This behavior
could contribute to a reduction in exposure and to an increase in
subject-to-subject variability.
Initial experiments evaluated the dissolution profile of the drug
in various media with HPMC in the solid state and pre-dissolved in
media. Solubility and viscosity evaluations were conducted to
assess the potential for HPMC to play
a physical role in
supersaturation. As a means to evaluate the role of HPMC in
nucleation and crystal growth of ibuprofen, additional dissolution
studies were carried out in the presence and absence of free acid
seed and characterization of isolated solids was conducted. In
order to probe whether specific polymer properties could be
attributed to mechanism of supersaturation, additional dissolution
studies were run with other cellulosic polymers, methylcellulose
(MC) and hydroxypropyl cellulose (HPC). The impact of these
polymers on degree and duration of supersaturation as well as
effect on crystal growth were monitored as a means to assess
whether the varying degree of polymer hydrophobicity played a
role in the mechanism of supersaturation of ibuprofen.
2. Materials and methods
2.1. Materials
Identifying excipients that can prolong the supersaturation
initially achieved by a disproportionating salt through precipita-
tion inhibition is a key mitigation plan to maintain solubility
enhancement provided by a salt and delay precipitation of the
lower solubility free form following disproportionation during GI
transit. Guzmán et al. (2007) have demonstrated that specific
combinations of crystalline salt forms of celecoxib with polymers
and surfactants can provide both enhanced dissolution and high
oral bioavailability; however, a mechanistic understanding into
how these excipients are interacting with celecoxib was not
pursued. Depending on the drug–excipient combinations, it is
anticipated that a variety of mechanisms could contribute to the
prolonged supersaturation.
A significant amount of excipient research has led to the
successful development of formulations that delay salt dispropor-
tionation during dissolution through the physical modulation of
microenvironmental pH at the diffusion boundary layer (Hawley
and Morozowich, 2010). However, additional efforts to identify
systems of salts and polymers that exhibit prolonged supersatura-
tion via chemical interactions following dissolution are, to the
authors’ knowledge, currently lacking in the literature and are the
main focus for this article. Since polymers have variable impact on
precipitation inhibition, this work evaluated several polymers
including HPMC, MC and HPC. HPMC has been classified as a broad-
spectrum precipitation inhibitor for a variety of drugs (Warren
et al., 2010). Although HPMC has been shown to stabilize
supersaturation via a variety of mechanisms, such as increasing
aqueous solubility (Loftsson et al., 1996; Usui et al., 1997), it is the
hydrogen bonding potential of HPMC (Iervolino et al., 2001; Wen
et al., 2005) that offers the greatest prospect for inducing a
chemical interaction during dissolution of an acidic salt.
(R/S)-(ꢀ)-ibuprofen (free acid) was purchased from Sigma
(Sigma–Aldrich, St. Louis, MO, USA) and the (R/S)-ibuprofen
sodium dihydrate was prepared from the free acid and 1.006 molar
equivalents of sodium hydroxide. The crystallization for ibuprofen
sodium dihydrate was based on the procedures outlined by Lee and
Wang (Lee and Wang, 2009), but without the need for cosolvent to
facilitate precipitation. The final form of ibuprofen sodium
dihydrate was confirmed to be the racemic conglomerate (Zhang
et al., 2003).
The hydroxypropyl methylcellulose (HPMC, hypromellose)
used for this work was Pharmacoat 603, purchased from
Shin-Etsu (Tokyo, Japan). Additional polymers included methyl-
cellulose (MC, 400 cPs) purchased from Sigma–Aldrich, USA and
Klucel EXF which is a pharmaceutical grade of hydroxypropyl
cellulose (HPC) from Ashland, USA. Information about polymer
structure and substitution are summarized in Table 1.
All other materials were of analytical grade and used as
received. For dissolution experiments, simulated gastric fluid (SGF)
and 50 mM acetate buffer at pH 5.0 were prepared. The recipe for
SGF was 2 g/L sodium chloride and 1.4 mL/L of 12N hydrochloric
acid in deionized water for a final pH of 1.8.
2.2. Methods
2.2.1. In vitro supersaturation testing and equilibrium solubility
assessment
In order to evaluate the supersaturation behavior of ibuprofen
following disproportionation of the highly soluble sodium salt to
the poorly soluble free acid, dissolution experiments were
performed at 25 and 37 ꢁC in SGF and 50 mM acetate buffer at
pH 5.0. Preliminary supersaturation experiments were conducted
in SGF in order to probe feasibility of supersaturation under
biorelevant conditions. However, the majority of experiments were
conducted in 50 mM acetate buffer at pH 5.0 in order to fully
evaluate potential mechanisms of supersaturation. The pH
5.0 buffer was selected since its pH falls between the pKa of
ibuprofen and the pHmax of the ibuprofen sodium salt, which are
4.5–4.6 (Potthast et al., 2005) and 6.9–7.2 (experimentally
determined) respectively. The intent was to avoid immediate
neutralization of the ibuprofen sodium in the media by selecting a
condition that could have slower kinetics of disproportionation
The present study investigated the role of HPMC in the
supersaturation of ibuprofen, a model BCS II acidic drug (Kasim
et al., 2004; Potthast et al., 2005), during dissolution to simulate
oral administration. Ibuprofen is a well-known non-steroidal anti-
inflammatory drug (NSAID) which is widely used for its analgesic,
antipyretic, and anti-inflammatory effects (Rainsford, 2009). The
commercial form of ibuprofen is the racemic free acid; however,
the neutral phase is practically insoluble (Kasim et al., 2004). Since
ibuprofen has a pKa of 4.5–4.6 associated with its carboxylic acid
(Potthast et al., 2005), salt formation is feasible. However,
disproportionation in the stomach is anticipated for this salt of
an acidic drug. For these studies we used the well-characterized
and would have
a lower degree of supersaturation. For
experiments where the polymer was pre-dissolved in media,