Only 10 solvent combinations from a total of 183 combinations produced decent spherical agglomerates of carbamazepine. Only
4 from a total of 100 solvent combinations produced decent spherical agglomerates of cimetidine and 4 of 136 solvent combinations
produced decent spherical agglomerates of phenylbutazone. Water was present in 18 workable combinations as an antisolvent
(i.e., derived from 10 + 4 + 4 = 18). This observation agreed with the many reported experimental conditions that water could
be used as an antisolvent for nonionizable organic compounds (22–43). If only the solvent combinations with water as an antisolvent
were considered, the total number of solvent combinations would have been reduced from 183 to 80 for carbamazepine, from
100 to 40 for cimetidine and from 136 to 80 for phenylbutazone. The criterion of using water as an antisolvent, therefore,
was essential to accelerate the screening activities. The aqueous-solution environment induced the formation of crystal surfaces
with hydrophilic functionalities, which helped to sustain the curvature of the hydrophobic solvents (44). This result may
explain why most of the bridging liquids in the 18 workable solvent combinations were Class-4 chlorocarbon or Class-5 hydrocarbon
Figure 1 (ALL FIGURES ARE COURTESY OF THE AUTHORS)
Solvent combinations for carbamazepine.
The 10 solvent combinations of good solvent, antisolvent, and bridging liquid for carbamazepine were: 1,4-dioxane, water,
and chloroform; acetonitrile, water, and paraxylene; acetonitrile, water, and chloroform; acetonitrile, water, and N,N-dimethylaniline; ethanol, water, and toluene; ethanol, water, and chloroform; ethanol, water, and N,N-dimethylaniline; methanol, water, and xylene; methanol, water and toluene; and methanol, water, and chloroform. All carbamazepine
spherical agglomerates (see Figure 1) were freshly made as the dihydrate, which was the thermodynamically stable form in the
aqueous system (45, 46). They were first oven-dried at 100 °C for 4 h to become Form I before being subjected to characterization
by a scanning electron microscope (SEM), whose high-vacuum system could be contaminated by the dehydration of the dihydrate
form. Although the solubility of Form I carbamazepine was less than the solubility of Form III, it was advantageous to make
Form I carbamazepine spherical agglomerates for several reasons (47). Form I transformed to dihydrate at a slower rate than
Form III did in an aqueous environment, and the solubility of the dihydrate was known to be about 1.3 times less than the
solubility of any of the anhydrous form (48). Also, the difference in the solubility values between Forms I and III was relatively
small, and the area under the curve in bioavailability tests of the forms were in the order of Form I > Form III < dihydrate.
Lastly, Form I was stable below 71 °C (47).
Solvent combinations for cimetidine.The four solvent combinations of good solvent, antisolvent, and bridging liquid for cimetidine were: methanol, water, and
n-heptane; methanol, water, and xylene; methanol, water, and paraxylene; and methanol, water, and toluene. All cimetidine spherical
agglomerates (see Figure 2) were made of Form C crystals as verified by the FTIR spectrum with Form C characteristic bands
at 1066, 1182, 1229, and 1347 cm-1 (5). Even though Form A is thermodynamically less stable than Form C under normal pressure, Form A was preferable for medicine
because of Form C's extraordinarily poor bulk flowability for tableting (4, 6). The feasibility of producing Form C cimetidine
spherical agglomerates, however, might have made the industrial tablet production of Form C cimetidine possible.
Solvent combinations for phenylbutazone.
The four different solvent combinations of good solvent, antisolvent, and bridging liquid for phenylbutazone were: tetrahydrofuran,
n-heptane; 1,4-dioxane, water, and n-heptane; acetonitrile, water, and n-heptane; methanol, water, and n-heptane. Spherical agglomerates (see Figure 2) of the first two cases were made of Form E crystals (see Figure 3), whereas
the last two cases were made of Form A crystals as indicated by DSC. Form A showed only a single melting endotherm at 105
°C for Form A, but the DSC thermogram (see Figure 4) exhibited the first endothermic peak at 92.5 °C , which corresponded
to the melting of Form E (3). This peak was followed by an exothermic peak at 95 °C, which corresponded to the crystallization
of Form E (3). A second endothermic peak at 104 °C corresponded to the melting of Form A (3). Because the equilibrium solubility
and the dissolution rate of the phenylbutazone crystal forms were in the order of Form C > Form E> Form D > Form B > Form
A and Form C > Form E > Form B > Form D > Form A, respectively, spherical agglomeration might offer a way of tuning the dissolution
profile of phenylbutazone by the change of polymorphism in addition to providing good bulk flowability.
The polymorphism of the API solids remained unchanged before and after the addition of a bridging liquid in the previoulsy
described 18 solvent systems. Other powder characteristics of the spherical agglomerates from the 18 solvent systems such
as the percent yield, the length-mean diameter, the apparent density, the population density, the sphericity, and the friability
index were fully analyzed based on the sample weight and digital-camera photographs and were calculated according to Equations
1–6 as follows (22, 26, 40):
where D is agglomerate diameter (cm); D
is length-mean agglomerate diameter (cm); n is number of agglomerates of size D; W is the total weight of solids (g); (D
is length-mean agglomerate diameter (cm) after 30 min, and (D
is length-mean agglomerate diameter (cm) at the beginning of the friability test. The volume of a bridging liquid and the
angle of repose were entirely determined by experiments. The sample sizes varied greatly from numerous powder-like agglomerates
to one large aggregate as revealed clearly in Figures 1, 2, and 3. No replicate was made for each test at this point due to
the limitation of time and materials. All experimental and calculated results are summarized in Table III.
Spherical agglomerates of carbamazepine dihydrate from an acetonitrile–water–paraxylene system, Form C cimetidine from a methanol–water–xylene
system, Form E phenylbutazone from a tetrahydrofuran–water–n-heptane system, and Form A phenylbutazone from an acetonitrile–water–n-heptane system gave relatively high yields, high friability indices (i.e., greater strength) and low angles of repose (i.e.,
good bulk flowability) among the other spherical agglomerates produced by other systems. Therefore, they were first chosen
as candidates for further scale-up or preformulation studies. Rotation in a cylindrical vessel alone did not encourage the
formation of spherical agglomeration because a control experiment confirmed that spherical-shaped agglomerates could also
be produced in a 500-mL sized crystallizer equipped with baffles and an overhead stirrer. The yield of each system was dependent
on the compositional ratios of the solvent combinations. The yield can be easily raised during future process development
by increasing the volume ratio of antisolvent to good solvent to values higher than 5:1.
. SEM images of the cross-section of all spherical agglomerates of carbamazepine dihydrate, Form C cimetidine, Form E phenylbutazone,
and Form A phenylbutazone were categorized into four different typical modes. All primary crystals were needles and were:
tangled with fibrils (see Figure 5(a)); randomly stacked together and linked by solid nodes (see Figure 5(b)); bundled together
in parallel (see Figure 5(c)) and radiated from a center core; and jointed by solid bridges to form many A-shaped or H-shaped ladder structures (see Figure 5(d)) (49).
Because the volume ratio of water (i.e., the antisolvent) to good solvent was fixed at 5:1, the presence of a small amount
of bridging liquid immiscible with water also would be immiscible with the saturated aqueous API solution and the good solvent
as confirmed experimentally. Under a high speed of stirring, the bridging liquid was dispersed in the saturated aqueous API
solution and the good solvent as tiny suspended droplets. These tiny droplets were randomly drawn to near the points of contact
between the preformed needle-like primary crystals by interfacial tension. The fibrils, nodes and joints (see Figures 5 (a)–5
(d)) suggested that the dissolution of API would take place initially at the crystal–bridging liquid interface because of
the relatively higher solubility power of the bridging liquid than the surrounding saturated high water content of the mother
liquor. As the saturated high water content of the mother liquor diffused into the bridging-liquid region, recrystallization
of the API occurred inside the liquid bridges.