Initial Solvent Screening of Carbamazepine, Cimetidine, and Phenylbutazone: Part 1 of 2

May 2, 2009
Tu Lee, PhD

Hsiang Yu Hsieh

Hsiang Yu Hsieh is a graduate student at National Central University, 300 Jhong-Da Rd., Jhong-Li City 320, Taiwan, ROC.

Yan Chan Su

Yan Chan Su is a graduate student at National Central University, 300 Jhong-Da Rd., Jhong-Li City 320, Taiwan, ROC.

Hung Ju Hou

Hung Ju Hou is a graduate student at National Central University, 300 Jhong-Da Rd., Jhong-Li City 320, Taiwan, ROC.

Pharmaceutical Technology, Pharmaceutical Technology-05-02-2009, Volume 33, Issue 5

The authors describe the importance of a rapid and an abbreviated screening strategy by initial solvent screening in 20-mL scintillation vials.

Many recent important solvent-based processes such as spherical crystallization, the spreading of cube-shaped particles, monodispersed double emulsions, microemulsions, and organic nanocrystal fabrication, involve combinations of two or three solvents (1–26). However, to the authors' knowledge, no literature has laid out a systematic way to identify the best solvent combinations, even though the composition ratio of the solution at the time of nucleation profoundly determines the solubility, polymorphism, and crystal habits of organic compounds functioning as in the case of the active pharmaceutical ingredients (APIs) (7, 8, 27).


This article will re-emphasize the importance of a rapid and abbreviated screening strategy by initial solvent screening in 20-mL scintillation vials. The screen provides engineering information in solubility curves, solubility spheres, polymorphs, crystallinity, form spaces (also known as solvent miscibility plots), and crystal habits of a given compound for solvent-based processes (see Figure 1) (28–31). The attractiveness of this strategy is its ability to be adopted or automated by common laboratories with only a small amount of chemical compounds. The probable solvent combinations of a good solvent, an antisolvent, and a bridging liquid for solvent-based processes are summarized systematically in the form space and can be graphically deduced.

Figure 1: Initial solvent screening in a 20-mL scintillation vial provides engineering information about (counterclockwise from top) solubility curves, polymorphism, solubility spheres, crystal habits, and form space for solvent-based processes. (ALL FIGURES ARE COURTESY OF THE AUTHORS)

Initial solvent screening was thoroughly tested using three model APIs: carbamazepine (5H-dibenze[b,f]azepine-5-carboxamide), an anticonvulsant used to treat epilepsy and trigeminal neuralgia (see Figure 2a); 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 in the treatment of human peptic ulcers (see Figure 2b); and phenylbutazone (1,2-diphenyl-4-n-butyl-3,5-pyrazolidinedione), a nonsteroidal anti-inflammatory drug with antipyretic and analgesic activity (see Figure 2c). These compounds were studied because of their commercial value; their abundant characterization information in the literature (see Table Ia–c); the lack of extensive solvent studies on their solubility, polymorphism, crystallinity, and crystal habits; and the variety of their naturally occurring polymorphs, hydrates, and solvates (see Figure 3) (32–69).

Figure 2: Molecular structures of (a) carbamazepine (5H-dibenze[b,f]azepine-5-carboxamide), (b) cimetidine (N"-cyano-N-methyl-N'-[2-[[5-methyl-1H-imidazol-4-yl]methyl]thio]-ethyl]-guanidine), and (c) phenylbutazone (1,2-diphenyl-4-n-butyl-3,5-pyrazolidinedione).

Although carbamazepine has numerous polymorphs and solvates, it has four main polymorphs and two hydrates: Forms I–IV, and Dihydrates I and II (36, 43, 44). Forms I–III are enantiotropic with respect to each other (34, 36). The stability of carbamazepine is in the order of Form III, Form I, Form IV, Form II, based on the density rule, and the initial dissolution rate of carbamazepine is in the order of Form III, Form I, Dihydrate III (38, 43). Cimetidine has four polymorphs and three monohydrates: Forms A–D, and Monohydrates 1–3 (53). Forms A–D are monotropic (57). Although Forms A and D are virtually isoenergetic crystals, the stability of Form D is slightly higher than that of Form A (58). The solubility of Form A is greater than that of Form B, and Form C (54). Phenylbutazone has six polymorphs and six solvates: Forms α, β, γ, δ, ε, and ζ, and phenylbutazone 2:1 solvates with benzene, cyclohexane, 1,4-dioxane, tetrahydrofuran, tetrachloromethane, and chloroform (62, 63, 65, 69). Forms β and δ are monotropic. Forms α and β, and Forms α and δ are enantiotropic (66).

Table Ia: Characterization methods for four polymorphs and two dihydrates of carbamazepine.

Materials and methods

APIs. Carbamazepine, white crystalline prismatic powders (C15H12N2O, MW: 236.67 g/mol, melting point (mp) = 191–192 °C, reagent grade, Lot: 036k1219) and cimetidine, white crystalline rodlike powders (C10H16N6S, MW: 252.34 g/mol, mp = 141–143 °C, reagent grade, Lot: 088H1317) were purchased from Sigma-Aldrich (St. Louis, MO) and used as received. Phenylbutazone, white crystalline needle-shaped powders (C19H20N2O2, MW: 308.38 g/mol, mp = 106–108 °C, 99+% purity, Lot: A0230775), was purchased from Acros Organics (Morris Plains, NJ) and used as received. Use tests for carbamazepine and phenylbutazone were carried out by differential scanning calorimetry (DSC). However, the use test for cimetidine was performed by Fourier transform infrared spectroscopy (FTIR) instead because DSC was unable to clearly distinguish the polymorphs of cimetidine (57).

Table Ib: Characterization methods for four polymorphs and three monohydrates of cimetidine.

Solvents. Out of the 23 common solvents useful for scale-up, only the following 19 environmentally benign solvents were employed: n-heptane, xylene, p-xylene, ethyl acetate, toluene, methyl tert-butyl ether (MTBE), methyl ethyl ketone (MEK), chloroform, tetrahydrofuran (THF), N,N-dimethylaniline (DMA), acetone, 1,4-dioxane, n-butyl alcohol, isopropyl alcohol (IPA), acetonitrile, N,N-dimethylformamide (DMF), ethanol, methanol, and water (28–30). Two other solvents, n-propanol and cyclohexane, were used to verify the solubility sphere in the three-dimensional (3-D) Hansen plot.

Table Ic: Characterization methods for six polymorphs and six solvates of phenylbutazone.

Initial solvent screening. Under the initial solvent screening, the 19 solvents for scale-up previously listed were chosen (28–30, 70). About 5 mg of the API powders were weighed in a 20-mL scintillation vial the first time. Drops of a given solvent were titrated carefully by a micropipette into the vial with 1–2-min intermittent shaking until all the API powders were just dissolved at 25 °C, maintained by a water bath. The solubility of the API powders in that particular solvent was approximated as the weight of the API powders in the vial divided by the total volume of the solvent added to the vial (i.e., the gravimetric method). A good solvent was defined as a solvent that gave a solubility of ≥ 5 mg/mL at 25 °C and was designated by a yellow color. A bad solvent was designated by a red color later in the form space. The solubility of the API in the good solvent at 15, 40, and 60 °C (or 50 °C if the boiling point of a solvent is close to 60 °C) was measured by the gravimetric method assuming the volumes of solvents were the volumes of solution and the volumes of solvents did not change significantly with temperature. Although the gravimetric method appeared to be imprecise, its advantages were its robustness, simplicity, the low amount of API required, the lack of necessity for calibration, and the absence of solvate and hydrate formation.

Figure 3a: Polymorphic flow chart showing the preparation methods for the four anhydrous polymorphs of carbamazepine, the thermal transition of Forms II–IV to Form I, and relationships (in blue) between carbamazepine Form I and Dihydrate I, and Form III and Dihydrate III.

Solvent-miscibility studies. Of the 19 solvents, about 1-mL portions of each solvent in a pair were intermittently shaken together for about 1–2 min in a 20-mL scintillation vial (28–30). The solvent pair was considered to be miscible if no interfacial meniscus was observed after the contents of the vial were allowed to settle. Otherwise, the pair was regarded as immiscible and designated by a gray color later in the form space.

Figure 3b: Polymorphic flow chart showing the preparation methods for the four anhydrous polymorphs of cimetidine; the mechanical, thermal, and solution transition among Forms A–D; the preparation methods of the three monohydrates; and thermal transition (in blue) of cimetidine Monohydrate I to Forms A–C.

Solids generation. Based on the predetermined solubility curves, solids generation of the API in each good solvent was achieved separately in a 20-mL scintillation vial by cooling the saturated API solution at 60 °C and by moving the vial from a 60 °C water bath to a 25 °C water bath with intermittent shaking (28–30). The crystal habits of all solids were characterized by optical microscopy (OM) inside the vial under a slurry state. All solids were filtered, oven-dried under mild conditions at 40 °C overnight, and characterized for their purity, polymorphism, solvates, and crystallinity by DSC, thermal gravimetric analysis (TGA), and transmission FTIR.

Figure 3c: Polymorphic flow chart showing preparation methods for the six anhydrous polymorphs of phenylbutazone; the thermal transition and the solution transformation among Forms α, β, δ, ε, and ζ; the methods of preparation of six solvates; and thermal transition (in blue) to Form δ.

OM. An optical microscope (SZII, Olympus, Tokyo) equipped with a charged-coupled device (CCD) camera (SSC-DC50A, Sony, Tokyo) was used to take images of crystal habit.

DSC. Thermal analytical data of 3–5 mg of solids placed in perforated, aluminum-sealed 60-µL pans were collected on a calorimeter (DSC-7, Perkin Elmer Instruments, Shelton, CT) with a temperature-scanning rate of 10 °C/min from 50 to 200 °C for carbamazepine 5 °C/min from 50 to 170 °C for cimetidine (mainly for the crystallinity measurements), and 8 °C/min from 50 to 130 °C for phenylbutazone using nitrogen 99.990% as a blanket gas (36, 43, 57, 62). The temperature axis was calibrated with indium 99.999 % (Perkin Elmer Instruments) with a melting onset at 156.6 °C. DSC provided the thermodynamic relationship between different polymorphs (i.e., forms) and information about crystallinity and the melting point of the API solids. The percent of crystallinity was calculated by dividing the area of a sample melting peak by the largest melting peak area of all samples.

TGA. TGA analysis was carried out by TGA heating balance (TGA 7, Perkin Elmer Instruments) to monitor sample weight loss as a function of temperature. The heating rate was 10 °C/min from 50 to 200 °C, 5 °C/min from 50 to 170 °C, and 8 °C/min from 50 to 130°C for carbamazepine, cimetidine, and phenylbutazone, respectively (36, 43, 57, 62). Weight loss was usually associated with either solvent evaporation close to the boiling point of a solvent, as in the case of solvates, or sample decomposition. The open platinum pan and stirrup were rinsed by ethanol and burned by a spirit lamp to remove all impurities. All samples were heated under nitrogen atmosphere to avoid oxidization. About 3 mg of sample were placed on the open platinum pan suspended in a heating furnace.

Transmission FTIR spectroscopy. Transmission FTIR spectroscopy was used to measure purity, detect bond formation, and verify chemical identity. Transmission FTIR spectra were recorded on a spectrometer (Spectrum One, Perkin Elmer Instruments). Approximately 1 mg of sample was ground gently with 99 mg of 50 °C oven-dried KBr in an agate mortar and pestle to avoid polymorphic transition induced by extended grinding. The round KBr sample disk was prepared by a uniaxial press with a pressure of 7 tons. The disk was scanned with a scan number of 8 from 450 to 4000 cm-1, with a resolution of 2 cm-1.


This work was supported by a grant from the National Science Council of Taiwan (NSC 95-2113-M-008-012-MY2). Suggestions from Jui-Mei Huang, of the Precision Instrument Center in National Central University, about DSC and from Ching-Tien Lin, also of the Precision Instrument Center in National Central University, about SEM are gratefully acknowledged.

Tu Lee* is an associate professor, and Yan Chan Su, Hung Ju Hou, and Hsiang Yu Hsieh are graduate students, all at National Central University, 300 Jhong-Da Rd., Jhong-Li City 320, Taiwan, ROC, tel. +886 3 422 7151 ext. 34204, fax 886 3 425 2296,

*To whom all correspondence should be addressed.

Submitted: July 8, 2008. Accepted: Sept. 15, 2008.


The results and related discussion will be included in Part 2 of this article, which will appear in the June issue of Pharmaceutical Technology.

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