Part 1 of this article, which appeared in the March 2010 issue of Pharmaceutical Technology, described a robust miniaturized screening strategy to accelerate the preparation and characterization of spherical agglomerates produced by spherical crystallization (1). This approach can be readily adopted or automated using only a small amount of active pharmaceutical ingredient (API), so spherical crystallization can be performed before the submission of a new drug application. The authors described their approach for constructuring form spaces for the nonionizable APIs, carbamazepine, cimetidine, and phenylbutazone by initial solvent screening of 19 common organic solvents to evaluate the feasibility of spherical crystallization. The materials and methods for this study were outlined in Part I of this article (1). Part II of this article discusses the results.
Results and discussion
Identification tests. The differential-scanning-calorimetry (DSC) identification-test scan of the purchased carbamazepine exhibited the first endothermic peak at 170–174 °C, which corresponded to the melting of Form III (2). An exothermic peak at 175 °C followed, which corresponded to the crystallization of Form I (2). A second endothermic peak at 193 °C corresponded to the melting of Form I (2). The DSC identification-test thermogram of the purchased phenylbutazone displayed a single endothermic peak around 105 °C, which corresponded to the melting of Form A (3). The polymorphism of the purchased carbamazepine and phenylbutazone, therefore, were Form III and Form A, respectively, at room temperature. The identification test for cimetidine was performed using Fourier transform infrared (FTIR) spectroscopy instead of DSC because the melting points of the different forms of cimetidine were very close to each other (4).The FTIR spectrum showed four significant infrared peaks for Form A cimetidine at 1204, 1156, 1077, and 954 cm-1 and two well-resolved characteristic peaks at 1243 and 1228 cm-1, which indicated the polymorphism of the purchased cimetidine at room temperature was Form A (5–7). Two cimetidine molecules formed a dimer unit in Form A with an eight-member ring through the hydrogen bonds between N(10)H of one molecule and the N(12) of the other molecule (1). The cimetidine molecule could absorb water at the N(1)H group (8). The imidazolium peaks were at 1204 and 954 cm-1 (8, 9). The peak at 1077 cm-1 was attributed to a CH deformation and a ring deformation (8, 10). The peak at 1156 cm-1 was either a coupled ring and a CH-bending mode or the deprotonation of the N(1)H group on the complexation with a water molecule (8, 10).
The actual form space of carbamazepine had 13 yellow, 6 red, 69 green, 78 blue, 14 gray, and 10 white boxes (see Table I (a)). The actual form space of cimetidine contained 5 yellow, 14 red, 66 green, 10 blue, 14 gray and 81 white boxes (see Table I (b)). The actual form space of phenylbutazone was composed of 17 yellow, 2 red, 22 green, 135 blue, 14 gray and 0 white boxes (see Table I (c)). The actual form spaces would have been expanded significantly if various solvent compositions of binary mixtures, temperatures, and ternary solvent systems were considered (10–12).
Spherical crystallization . The spherical agglomeration (SA) method was used in spherical crystallization. Because all miscible pairs of a good solvent and a bad solvent (i.e., an antisolvent) were represented by the green boxes and all immiscible pairs of a bad solvent and a bridging liquid were designated by the gray boxes in the actual form space of each API, the total number of combinations of a good solvent and a bad solvent and a bridging liquid was equal to (the sum of the number of green boxes in each column with a red box × the number of gray boxes in the same column) and (the number of green boxes in the bottom row with a red box × the number of gray boxes in the same bottom row), if water were also a bad solvent symbolized by a red box situated at the bottom right-hand corner of the actual form space.
The number of combinations for the SA method based on Table 1(a) for carbamazepine is 183 (i.e., derivied from 10 × 4 + 12 × 2 + 13 × 1 + 13 × 1 + 13 × 1 + 8 × 10 = 183). The number of combinations for the SA method based on Table 1(b) for cimetidine is 100 (i.e., derived from 3 × 4 + 4 × 2 + 5 × 1 + 5 × 1 + 5 × 1 + 5 × 1 + 5 × 1 + 5 × 1 + 5 × 1 + 5 × 1 + 4 × 10 = 100). The number of combinations for the SA method based on Table 1(c) for phenylbutazone was 136 (i.e., derived from 14 × 4 + 8 × 10 = 136).
Using the SA method, five types of behavior were observed:
Type-3 behavior was not observed with phenylbutazone.
In Type-1 and Type-2 behaviors, the solubility and the width of a metastable zone of an API solid were profoundly related to the molecular interactions among API solutes and solvents in a real solution system, which were dependent on the molecular structure of an API, the physical nature of a solvent, temperature, and compositional ratios of the solvent combinations (10, 12, 16, 17). In Type-3, Type-4, and Type-5 behaviors, the agglomeration process was intricately related to the balance between the drag force and the liquid-bridge strength (18, 19). The drag force was dependent on the speed of agitation, the viscous force, and the growing diameter of an agglomerate (18, 19). The liquid-bridge strength relied on the low pressure in the bridging-liquid phase led by the curvature of the bridging-liquid interface. The curvature of the bridging liquid was a function of: the interfacial tension of the bridging liquid and the mother liquor; the surface tension between the API crystals and the bridging liquid; the solubility of the API at the interface between the bridging liquid and the mother liquor; and the geometry of the API crystals (18–21).