1) Compound A is a poorly water soluble compound that enhances sweetness but dissolves slowly, hindering its use. 2) Solid dispersions using sugar alcohols were developed through co-melting and spray freezing to form intimate mixtures. 3) These solid dispersions showed dissolution times of only seconds for Compound A, much faster than physical mixtures or pure compound. However, recrystallization at the surface slowed further dissolution.

1. Sugar alcohol based solid dispersions for delivery of a taste-active compound
M. Sillick and C.M. Gregson
Firmenich, Inc, Princeton, NJ, 08536, USA
matthew.sillick@firmenich.com
ABSTRACT SUMMARY EXPERIMENTAL METHODS
Compound A is a heterocyclic compound that Simple physical mixtures of Compound A and fine
interacts with the receptor protein hT1R2 to dramatically sucrose were prepared by placing measured quantities
enhance the perceived sweetness of certain natural into a vial and mixing the powders with a spatula. Sugar
sweeteners. Unfortunately, Compound A is also poorly alcohol/ Compound A solid dispersions were co-melted at
water soluble and dissolves slowly at concentrations near 190°C. The melt was then sprayed via a pressure nozzle
its solubility limit. Thus effective delivery during to form droplets which landed and quickly solidified
consummation presents a distinct formulation challenge. within an immiscible quench fluid (limonene at 0°C). The
Powder formulations were prepared by two hardened particles were collected and laid on a paper
strategies: i) simple physical mixtures with food-relevant towel overnight to allow the quench fluid to evaporate off.
carriers and ii) co-melting with a sugar alcohol followed Measurements of dissolution rate were performed in
by spray freezing to form intimately mixed solid 25°C deionized water by the USP2 paddle method within
dispersions. Physical mixtures noticeably improved a Distek 2100B dissolution apparatus using 1 L vessels
wetting and reduced aggregation. The time to 50% release stirred at 200 rpm. The concentration of Compound A in
was reduced to as little as several minutes compared to 45 solution was monitored as a function of time with a
minutes for the pure form. The solid dispersions proved UV/VIS spectrometer probe (measuring absorbance at
potentially even more effective. Microscopy, x-ray 324 nm) inserted directly into the dissolution vessel.
diffraction and calorimeter suggest that an intimate Sufficient quantities of each physical mixture or solid
active/carrier mixture was achieved. This allowed dispersion were added to achieve a theoretical dose of 20
dissolution in as little as few seconds. ppm of Compound A. Dissolution rates were summarized
by t50 and t90, the times required to achieve 50% and 90%
INTRODUCTION respectively of the plateau absorbance. Reported values
Food applications can provide an even greater are the mean of duplicate measurements.
challenge with regard to dissolution rate than
pharmaceutical actives. In the latter case, the timescale RESULTS AND DISCUSSION
requirement is typically on the order of tens of minutes. Pure Compound A has a fine particle size (~20μm)
Powdered beverages, on the other hand, may require and therefore high surface area. Nonetheless, dissolution
dissolution times less than 2 minutes. There are other is slow. Fig. 1 shows that only one quarter of the 20 ppm
even more demanding applications, such as frosted dose is brought into solution within the first 20 minutes.
cereals, where the active may need to dissolve to a When the pure powder is poured into still or gently stirred
significant extent within the timescale that the product is water (such as in a dissolution test or as might be done to
held in the mouth (i.e. in seconds). For certain poorly prepare a beverage), the product does not fully wet but
soluble solid flavoring ingredients, such as Compound A, tends to float of the surface and form “rafts”. The rafting
it is necessary to consider delivery options that enhance behavior reduces dissolution rate by reducing the
dissolution rate. effective surface area of the dissolving crystal.
Solid dispersions of poorly soluble drugs and freely
soluble carriers have been extensively investigated in the
aim of enhancing dissolution.[1-3] In marketed products,
the carrier is typically a polymer such as polyethylene
glycol, polyvinyl acetate, hydroxypropylmethylcellulose
or polyvinylpyrolidone.[4] Such materials find only
limited use in foods. Sugar alcohol carriers, mannitol in
particular, have also been shown to form effective solid
dispersions[5, 6] and are more broadly accepted in the
food industry. This report describes creation of several
solid dispersions of Compound A with a sugar alcohol.
The resulting powders were characterized by dissolution
testing and physical methods (XRD, DSC, and
microscopy).
Figure 1
Example dissolution profiles of Compound A in pure, physical mixture,
and solid dispersion forms.

2. a) b)
Figure 2 d)
c)
Schematic summarizing the time required for 50% and 90% dissolution.
All results are for the equivalent of a 20ppm dose of Compound A added Figure 3
to deionised water. Photomicrographs of a) pure Compound A and Compound A /sugar
alcohol complexes after heating to 190°C followed by cooling at
Physical mixtures of Compound A and dry sucrose b)~10°C/minute, c)~1°C/sec and d) very rapidly by spray freezing into a
were effective at hastening dissolution. Fig. 2 describes chilled immiscible fluid. Evidence of a liquid-liquid phase separation
(small circular domains) are seen in b and c, but not d.
that sucrose-rich mixtures had faster dissolution rates
despite the larger overall powder to water dosing. Wetting One way to avoid recrystallization was to decrease
is likely enhanced due to the surrounding powder dragging the degree of supersaturation. Formulations with lower
the active below the water surface, thereby overcoming active to carrier ratios successfully avoided
surface tension. Dispersion is aided by separating and recyrstallization and indeed dissolve very fast (t50 was as
preventing aggregation of the particles. short as 6 seconds). A second successful tactic blended
DSC, thermal stage microscopy and XRD were used the solid dispersion particles with a second powder, such
to assess the potential of the solid dispersion approach. as dry glucose. The goal of such formulations was to
Calorimetry experiments on Compound/ sugar alcohol reduce the degree to which recrystallizartion caused
mixtures showed two endothermic events. First, the sugar powder agglomeration.
alcohol melted near its normal melting point. The second
endotherm spanned from 160°C to 190°C and ended well CONCLUSION
below the normal melting point of Compound A (~230°C), As can be the case for drugs, certain poorly soluble
which suggests that it undergoes dissolution into the sugar flavoring ingredients require strategic delivery in order to
alcohol melt. By thermal microscopy, the co-melt indeed ensure efficacy. Compound A is one such case because
appeared as a single phase liquid. However, the mixture the pure form dissolves too slowly for the intended
was prone to phase separate under certain cooling applications. Physical mixtures, which helped to wet and
conditions. Only by the very fast quenching and disperse the active, successfully reduced the dissolution
solidification afforded by the spray freezing technique was times to several minutes. To further hasten release, melt-
the intimate active/carrier mixture preserved. (See fig. 3.) processed solid dispersions with a sugar alcohol were
An XRD pattern collected from the solid dispersion prepared. These compositions provided very fast release
powder showed only peaks corresponding to the sugar so long as recrystallization was avoided.
alcohol carrier. Even with 10 wt% loading, crystalline
domains of the active ingredient were not large or REFERENCES
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dispersion was high.
Observations of hydration within a microscope cell
demonstrated that while solid dispersions dissolved rapidly
at first, they then showed a propensity for recrystallization
of Compound A within the boundary layer. Extensive
recrystallization to coat and agglomerate adjacent particles
dramatically hindered further dissolution.