21 research outputs found
Trehalose Crystallization During Freeze-Drying: Implications On Lyoprotection
Lyoprotectants are stabilizers used to prevent denaturation of proteins during freeze-drying and subsequent storage. In order to be effective, lyoprotectants must be retained amorphous. The physical state of the lyoprotectant is usually characterized by powder X-ray diffractometry of the dried cake. While trehalose is widely used as a lyoprotectant, we report its crystallization during freeze-drying and point out why it may not become evident from characterizing the final lyophile. When an aqueous trehalose solution was cooled to â40 °C, ice was the only crystalline phase observed. However, upon annealing at â18 °C, crystallization of trehalose dihydrate was evident. During drying, the dihydrate dehydrated to substantially amorphous anhydrate. Therefore, analyzing the final dried product will not reveal crystallization of the lyoprotectant during freeze-drying. In light of the observed phase separation of trehalose in frozen solutions, its ability to serve as a lyoprotectant warrants further investigation
Strength of DrugâPolymer Interactions: Implications for Crystallization in Dispersions
We
investigated the influence of the strength of drugâpolymer
interactions on the crystallization behavior of a model drug in amorphous
solid dispersions (ASDs). Ketoconazole ASDs were prepared with each
polyÂ(acrylic acid), polyÂ(2-hydroxyethyl methacrylate), and polyvinylpyrrolidone.
Over a wide temperature range in the supercooled region, the α-relaxation
time was obtained, which provided a measure of molecular mobility.
Isothermal crystallization studies were performed in the same temperature
interval using either a synchrotron (for low levels of crystallinity)
or a laboratory X-ray (for crystallization kinetics) source. The stronger
the drugâpolymer interaction, the longer was the delay in crystallization
onset time, indicating an increase in physical stability. Stronger
drugâpolymer interactions also translated to a decrease in
the magnitude of the crystallization rate constant. In amorphous ketoconazole
as well as in the dispersions, the coupling coefficient, a measure
of the extent of coupling between relaxation and crystallization times
was âŒ0.5. This value was unaffected by the strength of drugâpolymer
interactions. On the basis of these results, the crystallization times
in ASDs were predicted at temperatures very close to <i>T</i><sub>g</sub>, using the coupling coefficient experimentally determined
for amorphous ketoconazole. The predicted and experimental crystallization
times were in good agreement, indicating the usefulness of the model
Physical Stability and Dissolution Behavior of KetoconazoleâOrganic Acid Coamorphous Systems
In an earlier investigation,
coamorphous systems of ketoconazole
(KTZ) prepared with each oxalic (OXA), tartaric (TAR), citric (CIT),
and succinic (SUC) acid, revealed drugâacid ionic or hydrogen
bonding interactions in the solid-state (Fung et al, <i>Mol.
Pharmaceutics</i>, 2018, <i>15</i> (3), 1052â1061).
We showed that the drugâacid interactions in KTZâTAR
were the strongest, followed by KTZâOXA, KTZâCIT, and
KTZâSUC. In this study, we investigated the crystallization
propensity and dissolution behavior of the KTZâacid coamorphous
systems. When in contact with water (either as water vapor or as aqueous
phosphate buffer), while KTZâCIT and KTZâTAR were physically
stable and resisted crystallization, KTZâSUC and KTZâOXA
crystallized more readily than KTZ alone. The dissolution performances
of the coamorphous systems were compared using the area under the
curve (AUC) obtained from the concentrationâtime profiles.
KTZâOXA exhibited the highest AUC, while it was about the same
for KTZâTAR and KTZâCIT and the lowest for KTZâSUC.
The enhancement in dissolution appeared to become more pronounced
as the strength of the acid (OXA > TAR > CIT > SUC) increased.
Coamorphization
with acid caused at least a two-fold increase in AUC when compared
with amorphous KTZ. The decrease in pH of the diffusion layer of the
dissolving solid, brought about by the acid, is at least partially
responsible for the dissolution enhancement. In addition, the particles
of KTZâOXA, KTZâTAR, and KTZâCIT were much smaller
than those of KTZâSUC. The consequent effect on surface area
could be another contributing factor to the initial dissolution behavior
âpH Swingâ in Frozen SolutionsîžConsequence of Sequential Crystallization of Buffer Components
Succinate buffer solutions of different initial pH values and concentrations were cooled. The solution pH and the phases crystallizing from solution were monitored as a function of temperature. In a solution buffered to pH 4.0 (200 mM), the freeze-concentrate pH initially increased to 8.0 and then decreased to 2.2. On the basis of X-ray diffractometry (synchrotron source), the âpH swingâ was attributed to the sequential crystallization of succinic acid, monosodium succinate, and disodium succinate. A similar swing, but in the opposite direction, was seen when a solution with an initial pH of 6.0 was cooled. In this case, crystallization of the basic buffer component occurred first. The direction and magnitude of the pH shift depended on both the initial pH and the buffer concentration. In light of the pH-sensitive nature of a significant fraction of pharmaceuticals (especially proteins), extreme care is needed, both in the buffer selection and in its concentration
The Role of Polymer Concentration on the Molecular Mobility and Physical Stability of Nifedipine Solid Dispersions
We
investigated the influence of polymer concentration (2.5â20%
w/w) on the molecular mobility and the physical stability in solid
dispersions of nifedipine (NIF) with polyvinylpyrrolidone (PVP). With
an increase in polymer concentration, the α-relaxation times
measured by broadband dielectric spectroscopy were longer, which reflects
a decrease in molecular mobility. In the supercooled state, at a given
temperature (between 55 and 75 °C), the relaxation time increased
linearly as a function of polymer concentration (2.5â20% w/w).
The temperature dependence of the relaxation time indicated that the
fragility of the dispersion, and by extension the mechanism by which
the polymer influences the relaxation time, was independent of polymer
concentration. The time for NIF crystallization also increased as
a function of polymer concentration. Therefore, by using molecular
mobility as a predictor, a model was built to predict NIF crystallization
from the dispersions in the supercooled state. The predicted crystallization
times were in excellent agreement with the experimental data
Quantification, Mechanism, and Mitigation of Active Ingredient Phase Transformation in Tablets
Model
tablet formulations containing thiamine hydrochloride [as
a nonstoichiometric hydrate (NSH)] and dicalcium phosphate dihydrate
(DCPD) were prepared. In intact tablets, the water released by dehydration
of DCPD mediated the transition of NSH to thiamine hydrochloride hemihydrate
(HH). The use of an X-ray microdiffractometer with an area detector
enabled us to rapidly and simultaneously monitor both the phase transformations.
The spatial information, gained by monitoring the tablet from the
surface to the core (depth profiling), revealed that both DCPD dehydration
and HH formation progressed from the surface to the tablet core as
a function of storage time. Film coating of the tablets with ethyl
cellulose caused a decrease in both the reaction rates. There was
a pronounced lag time, but once initiated, the transformations occurred
simultaneously throughout the tablet. Thus the difference in the phase
transformation behavior between the uncoated and the coated tablets
could not have been discerned without the depth profiling. Incorporation
of hydrophilic colloidal silica as a formulation component further
slowed down the transformations. By acting as a water scavenger it
maintained a very âdryâ environment in the tablet matrix.
Finally, by coating the NSH particles with hydrophobic colloidal silica,
the formation of HH was further substantially decelerated. The microdiffractometric
technique not only enabled direct analyses of tablets but also provided
the critical spatial information. This helped in the selection of
excipients with appropriate functionality to prevent the <i>in
situ</i> phase transformations
Investigation of Spatial Heterogeneity of Salt Disproportionation in Tablets by Synchrotron Xâray Diffractometry
Tablets which were
binary mixtures of pioglitazone hydrochloride
(PioHCl) with magnesium stearate (MgSt), croscarmellose sodium (CCS),
microcrystalline cellulose, or lactose monohydrate were prepared.
Two sets of experiments, using intact tablets, were performed. (i)
Tablets containing PioHCl (90% w/w) and MgSt were exposed to 25 or
40 °C and 75% RH in a custom-built temperature/humidity chamber.
In situ spatiotemporal mapping of disproportionation was performed
by transmission-mode synchrotron X-ray diffractometry (SXRD; Argonne
National Laboratories). Tablets were scanned in radial direction starting
from the top edge of the tablet and moving, in increments of 300 ÎŒm,
toward the center. There was evidence of disproportionation after
10 min (at 40 °C). The reaction was initiated on the tablet surface
and progressed toward the core. (ii) SXRD of tablets stored for a
longer time (up to 15 days) enabled the simultaneous quantification
of the reactants and products of disproportionation and provided insight
into the reaction progression. The influence of sorbed water and microenvironmental
acidity on the disproportionation reaction was investigated. The most
pronounced reaction was observed in the presence of MgSt followed
by CCS. The transformation was solution-mediated, and the spatial
heterogeneity in disproportionation could be explained by the migration
of sorbed water. There was a good correlation between microenvironmental
acidity (pH<sub>eq</sub>) and extent of PioHCl disproportionation
The Role of DrugâPolymer Hydrogen Bonding Interactions on the Molecular Mobility and Physical Stability of Nifedipine Solid Dispersions
We
investigated the influence of drugâpolymer hydrogen bonding
interactions on molecular mobility and the physical stability in solid
dispersions of nifedipine with each of the polymers polyvinylpyrrolidone
(PVP), hydroxypropylmethyl cellulose (HPMCAS), and polyÂ(acrylic acid)
(PAA). The drugâpolymer interactions were monitored by FT-IR
spectroscopy, the molecular mobility was characterized using broadband
dielectric spectroscopy, and the crystallization kinetics was evaluated
by powder X-ray diffractometry. The strength of drugâpolymer
hydrogen bonding, the structural relaxation time, and the crystallization
kinetics were rank ordered as PVP > HPMCAS > PAA. At a fixed
polymer
concentration, the fraction of the drug bonded to the polymer was
the highest with PVP. Addition of 20% w/w polymer resulted in âŒ65-fold
increase in the relaxation time in the PVP dispersion and only âŒ5-fold
increase in HPMCAS dispersion. In the PAA dispersions, there was no
evidence of drugâpolymer interactions and the polymer addition
did not influence the relaxation time. Thus, the strongest drugâpolymer
hydrogen bonding interactions in PVP solid dispersions translated
to the longest structural relaxation times and the highest resistance
to drug crystallization
Influence of Molecular Mobility on the Physical Stability of Amorphous Pharmaceuticals in the Supercooled and Glassy States
We investigated the correlation between
molecular mobility and
physical stability in three model systems, including griseofulvin,
nifedipine, and nifedipineâpolyvinylÂpyrrolidone dispersion,
and identified the specific mobility mode responsible for instability.
The molecular mobility in the glassy as well as the supercooled liquid
states of the model systems were comprehensively characterized using
dynamic dielectric spectroscopy. Crystallization kinetics was monitored
by powder X-ray diffractometry using either a laboratory (in the supercooled
state) or a synchrotron (glassy) X-ray source. Structural (α-)
relaxation appeared to be the mobility responsible for the observed
physical instability at temperatures above <i>T</i><sub>g</sub>. Although the direct measurement of the structural relaxation
time below <i>T</i><sub>g</sub> was not experimentally feasible,
dielectric measurements in the supercooled state were used to provide
an estimate of the α-relaxation times as a function of temperature
in glassy pharmaceuticals. Again, there was a strong correlation between
the α-relaxation and physical instability (crystallization)
in the glassy state but not with any secondary relaxations. These
results suggest that structural relaxation is a major contributor
to physical instability both above and below <i>T</i><sub>g</sub> in these model systems