Spherical Crystallization for Lean Solid-Dose Manufacturing (Part 1)

In Part I of this article, the authors describe the materials and methods used in developing a screening strategy to accelerate the preparation and characterization of spherical agglomerates by spherical crystallization.
Mar 02, 2010
Volume 34, Issue 3

Pharmaceutical manufacturing typically lags behind other industries in process efficiencies because production processes for new drug products are quickly developed in a laboratory for producing clinical-trial materials to enable the rapid submission of a new drug application (NDA) (1). The NDA locks in the documented manufacturing steps with a regulatory commitment and leaves no chance for the full optimization of processing steps such as crystallization, filtration, drying, dry blending, granulation, drying, and tableting (2). Granulation is the slowest of these processing steps, but by applying cross-performance relationships and mixing rules, the efficiency of granulation can be enhanced significantly (2–4). To achieve lean solid-dose manufacturing, the granulation step can be replaced with spherical crystallization in a common stirred tank at the crystallization step (5–26). This change may reduce the time-consuming and labor-intensive steps in solid-dose manufacturing for a high-dose formulation to only a few unit operations of spherical crystallization, filtration, drying, dry blending, and tableting.

To the best of our knowledge, no literature has laid out a systematic way to identify the best solvent combinations for spherical crystallization. This article presents a robust miniaturized screening strategy to accelerate the preparation and characterization of spherical agglomerates produced by spherical crystallization. This strategy can be readily adopted or automated using only a small amount of active pharmaceutical ingredient (API), thus enabling spherical crystallization to be performed before the NDA submission.

Spherical crystallization

Spherical crystallization is a well-studied, solvent-based method that directly produces spherically agglomerated crystals to afford free flowability, uniform packability, and good compressibility for mixing, filling, direct tableting, and even burning characteristics (17–19). Spherical crystallization is categorized into two methods: emulsion solvent diffusion (ESD) and spherical agglomeration (SA) (13, 22, 24, 26). Both methods use a good solvent (i.e., a solvent that gave solubility of ≥ 5 mg/mL at 25 °C ) to dissolve the API and a bad solvent (i.e., a solvent that gave solubility of < 5 mg/mL at 25 °C) miscible with the good solvent (i.e., the antisolvent) to generate the required supersaturation. For the ESD method, the solution containing the dissolved API is dispersed into the bad solvent to produce emulsion droplets. Crystals are generated inside the suspended droplets by the counterdiffusion of the good and bad solvents at the droplet interface (26). However, for the SA method, the formation of agglomerates is promoted by the addition of a small amount of the third solvent, namely the bridging liquid, which is immiscible with the bad solvent and drawn preferentially in the interstitial space between the newly formed API crystals (26).

Spherical crystallization is a very versatile method. The operating conditions involve either: the recrystallization of a near-saturated solution by cooling (10, 12, 13, 15, 16, 19, 21, 22, 25, 26), by seeding (14), or by an antisolvent (7, 8, 10–13, 15, 16, 19–26) with (7, 8, 10–13, 15, 20–26) or without (19, 22) the presence of a bridging liquid or with the addition of an emulsifying agent (13, 15, 18) or a cross-linking agent (16, 23); or secondly, the dispersion of solids with the addition of a bridging solution (5, 6, 11, 17). The addition order of the antisolvent and the bridging liquid to the near-saturated solution can vary (11, 26).

Spherical crystallization relies on the form space (or the solvent-miscibility plot) derived from an initial solvent-screening method performed in 20-mL scintillation vials (27–31). Because the composition ratio of an antisolvent to a good solvent at the time of nucleation determines the polymorphism of the API crystals, the solvents were added by a specific SA pathway (11, 12, 30). The antisolvent was first added to the near-saturated API solution to ensure the occurrence of recrystallization in a binary solvent system. The bridging liquid was introduced at the end point of recrystallization to induce the agglomeration of the existing primary crystals. The polymorphism of the primary crystals before and after spherical agglomeration was monitored by either differential scanning calorimetry (DSC) or transmission Fourier transform infrared (FTIR) spectroscopy. The volume of a bridging liquid used, the percent yield, the length-mean diameter, the apparent density, the population density, the sphericity, the angle of repose, and the friability index of spherical agglomerates were carefully measured and calculated (5, 9, 13, 23). The internal microstructures of spherical agglomerates were examined by scanning electron microscopy (SEM).

Figure 1: Molecular structures of (a) carbamazepine,(b) cimetidine, and (c) phenylbutazone. (FIGURE I IS COURTESY OF THE AUTHORS.)
The feasibility of spherical crystallization by initial solvent screening was tested with three model APIs (32–42) (see Figure 1). These APIs were: carbamazepine (5H-dibenze (b, f) azepine-5-carboxamide), an anticonvulsant used to treat epilepsy and trigeminal neuralgia; cimetidine (N"-cyano-N-methyl-N'-[2-[[5-methyl-1H-imidazol-4-yl]methyl]thio]ethyl)guanidine), a specific competitive histamine H2-receptor antagonist used to treat human peptic ulcers; and phenylbutazone (1,2-diphenyl-4-n-butyl-3,5-pyrazolidinedione), a nonsteroidal antiinflammatory drug with antipyretic and analgesic activity. These APIs were chosen because of several key properties: their nonionizable nature between pH of 6 and 7; their worldwide commercial value; the abundance of characterization information in the literature; the lack of extensive solvent studies on their solubility, polymorphism, crystallinity, and crystal habits; and the variety of their naturally occurring polymorphs, hydrates, and/or solvates.

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