Engineering Processing Properties of Acetaminophen by Cosolvent Screening

The authors used common solvents to develop an initial solvent-screening method for laboratory-scale research to determine the solubility, polymorphism, and crystal properties of various active ingredients.
Aug 02, 2010

Table I: Polymorphism and crystal-habit-related processing properties of downstream unit operations in pharmaceutical production.
The solid state of an active pharmaceutical ingredient (API), like that of all materials, possesses functional and processing properties. Although much attention is paid to APIs' functional properties such as aqueous solubility, pharmacokinetics, and bioavailability, many processing properties of the solid state of an API (e.g., solubility in organic solvents, shape factor, and particle size) are also important to the success of pharmaceutical manufacturing operations such as mixing, wet granulation, and tableting (see Table I) (1–4). Therefore, in addition to the two essential roles of crystallization (i.e., a purification-and-separation step for the upstream organic synthesis and an adapting-linkage step for various outsourcing and globalization schemes), one other indispensable role of crystallization is a bottom-up material-fabrication step, from polymorphism in a subnanometer scale to crystal habit at a micrometer level, which determines processing and functional properties and the fate of all of the following downstream steps from filtration to dissolution.

Because solvent-mediated chemical reactions, nucleation, and phase transformation are common bottom-up approaches to traditional batch crystallization, the solvent's effects on API solubility, polymorphism, and crystal habits have become crucial (5). Most of the small-scale and solvent-evaporation-based high-throughput screening methods can provide primary information on solubility and polymorphism. However, data on crystal habits of an API are considered to be secondary (6). To change this perception, the authors developed a scalable initial solvent-screening method for laboratory-scale research using 23 to 25 common solvents to systematically determine solubility, polymorphism, and crystal habits of acetaminophen, (R,S)-(±)-ibuprofen,7 (R,S)-(±)-sodium ibuprofen dihydrate, tris(8-hydroxyquinoline)aluminum(III) (Alq3), and sulfathiazole through cooling crystallization (7–10).

Figure 1: Solvent miscibility, cosolvent, and antisolvent systems of acetaminophen Form I crystals. (ALL FIGURES ARE COURTESY OF THE AUTHORS)
After the success of the three binary and 10 tertiary solvent mixtures in enhancing the solubility and inducing polymorphs of sulfathiazole, the authors decided to continue exploring all 100 cosolvent combinations encompassed by the symmetrical form space of acetaminophen (paracetamol) to see how the solubility, polymorphism, and crystal habits of acetaminophen are affected by the cosolvent systems (7, 10). The cosolvent combinations are shown as navy blue boxes within a red triangle that represents the symmetrical form space of acetaminophen in Figure 1. The authors chose acetaminophen as a model API because of its worldwide commercial value in analgesic and antipyretic therapy, previous experiences with it, and the recent discovery of the thermodynamically metastable Forms II and III crystals (7, 11–15).