Spherical Crystallization for Lean Solid-Dosage Manufacturing (Part II) - Pharmaceutical Technology

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Spherical Crystallization for Lean Solid-Dosage Manufacturing (Part II)
In Part I of this article, which appeard in the March 2010 issue, the authors describe their approach for constructing form spaces for carbamazepine, cimetidine, and phenylbutazone by initial solvent screening to evaluate the feasibility of spherical crystallization. Part II of this article discusses their findings.


Pharmaceutical Technology
Volume 34, Issue 4, pp. 88-103

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).


Table I
Form spaces. To construct the form space for an API, which contains the possible solvent combinations for discovering a new polymorph, the 19 common solvents for scale-up listed in the materials and methods section of Part I of this article were arranged from top to bottom vertically and from left to right horizontally in ascending order of the solvent's Hildebrand value (1). This arrangement resulted in a 19 19 matrix of 361 boxes (see Tables 1(a), 1(b), and 1(c)). Each box represented a specific binary solvent combination except for the 19 boxes located diagonally in the matrix stepping down from the upper left-hand corner to the lower right-hand corner. The 19 diagonal boxes represented the 19 pure-solvent systems. The yellow boxes were the good solvents (i.e, defined as a solvent that gave solubility of ≥ 5 mg/mL at 25 C) and the red boxes the bad solvents (i.e, defined as a solvent that gave solubility of ≤ 5 mg/mL at 25 C) with respect to a particular API. The yellow and red boxes were the materials properties of the API. The gray boxes also were determined experimentally. They represented the immiscible solvent pairs that were independent of the API. Once the locations of the red, yellow, and gray boxes were fixed, the location of the green, blue, and white boxes representing the antisolvent system (i.e., a good solvent and a bad solvent), the good cosolvent system (i.e, a good solvent and a good solvent) and the bad cosolvent system (i.e,. a bad solvent and a bad solvent), respectively, were deduced graphically from the diagonal boxes. Since the 19 19 matrix was symmetrical along the diagonal boxes, the actual possible solvent combinations were reduced from 361 boxes to a total of 190 boxes or less (i.e., derived from 19 + (361 – 19) 2 = 190) because it is impractical to perform experiments in the white-boxed areas.

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).


Table II
The solubility values of carbamazepine, cimetidine, and phenylbutazone in their corresponding solvents at 25 C were listed in Table II. Most of the good solvents of Form III carbamazepine belonged to Class 1 (i.e., a protic hydrogen-bond-donating solvents [Lewis acids]), Class 2 hydrogen-bond-acceptor solvents [Lewis bases]), and Class 3 polar aprotic solvents, which were capable of disrupting the N–H•••O hydrogen bonds and the C–H•••O weak interactions of the carboxamide dimer units existing in the solid state of all forms of carbamazepine (2, 13). The good solvents for Form A cimetidine were mainly Class 1 solvents, which had the capability of interacting readily with the weakly basic imidazole ring and disrupting the N–H•••N hydrogen bonds of the dimer units existing in the solid state of Form A cimetidine (8, 13, 14). The good solvents for Form A phenylbutazone were Classes 1, 2, and 3 solvents, Class 4 chlorocarbon solvents, and Class 5 hydrocarbon solvents. This result implied the intermolecular interactions in the crystal lattice of phenylbutazone were dominated by van der Waals forces (i.e., dipole-dipole interactions and London dispersion force) (15).

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 1: No solid production upon the addition of 10 mL of an antisolvent to 2 mL of an API solution at 25 C
  • Type 2: Dissolution of the solids upon the addition of the bridging liquid at 25 C
  • Type 3: No agglomeration upon the addition of the bridging liquid at 25 C
  • Type 4: Nonspherical agglomeration upon the addition of the bridging liquid at 25 C
  • Type 5: Spherical agglomeration upon the addition of the bridging liquid at 25 C.

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).


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