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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.
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.
Table I: Polymorphism and crystal-habit-related processing properties of downstream unit operations in pharmaceutical production.
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).
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).
Figure 1: Solvent miscibility, cosolvent, and antisolvent systems of acetaminophen Form I crystals. (ALL FIGURES ARE COURTESY OF THE AUTHORS)
Materials and methods
Solvents. All materials and methods were the same as in the authors' previous experiments (7). Acetone [CH3COCH3, high-performance liquid chromatography (HPLC)–spectrometry grade, 99.9%, Lot: 601109], n-butyl alcohol [CH3 (CH2)3OH, ACS grade, 99.4%, Lot: 205027], n-heptane [CH3 (CH2)5CH3, HPLC–spectrometry grade, 99.4%, Lot: 111110], isopropyl alcohol (IPA) [(CH3)2CHOH, HPLC–spectrometry grade, 99.8%, Lot: 808907], methanol (CH3OH, HPLC–spectrometry grade, 99.9%, Lot: 703416), methyl tert-butyl ether (MTBE) [(CH3)3COCH3, certified grade, 99.9%, Lot: 712032], and methyl ethyl ketone (MEK) (C2H5COCH3, ACS grade, 99.6%, Lot: 201021) were purchased from Tedia (Fairfield, OH). Chloroform (CHCl3, ACS grade, 99.99%, Lot: E554180), N,N-dimethylformamide (DMF) [HCON(CH3)2, ACS grade, 99.8%, Lot: E705279], tetrahydrofuran (THF) (C4H8O, HPLC–spectrometry grade, 99%, Lot: E704198), and ethanol (CH3CH2OH, HPLC–spectrometry grade, 99.5%) were obtained from Echo (Miaoli, Taiwan). Acetonitrile (CH3CN, analytical grade, 99.96%, Lot: 0043 X29B30), toluene (C6H5CH3, ACS grade, 100%, Lot: B46755), and xylenes [C6H4 (CH3)2, ACS grade, 98.8%, Lot: E03B34) were all received from Mallinckrodt Baker (Phillipsburg, NJ). Benzene (C6H6, ACS grade, 99%, Lot: 310008) and benzyl alcohol (C6H5CH2OH, gas chromatography grade, 99.9%, Lot: 70950) were purchased from Sigma-Aldrich Laborchemikalien (Seelze, Germany). Dimethyl sulfoxide (DMSO) [(CH3)2SO, HPLC grade, 99.8%, Lot: SU0155] was obtained from Scharlau Chemie (Barcelona). N,N-dimethylaniline (DMA) [C6H5N(CH3)2, ACS grade, 99%, Lot: A0213203001], nitrobenzene (C6H5NO2, ACS grade, 99%, Lot: A0195683001), and p-xylene [C6H4 (CH3)2, ACS grade, 99%, Lot: 48754/2) were purchased from Acros Organics (Fair Lawn, NJ). 1,4-dioxane (C4H8O2, ACS grade, 98%, Lot: sp-3432R) was obtained from Showa Chemical (Tokyo). Ethyl acetate (CH3COOC2H5, ACS grade, 99.5%, Lot: G43342) was received from Grand Chemical (Daejeon, South Korea). Reversible osmosis (RO) water was clarified by a water-purification system (Milli-RO Plus, Millipore, Billerica, MA). All solvents were colorless except for the yellowish nitrobenzene. Stock solution of all 100 good cosolvent combinations represented as navy blue boxes in Figure 1 were premixed with a 1:1 volume ratio.
Solubility studies. Approximately 50 mg of acetaminophen Form I crystals were weighed in a 20-mL scintillation vial. From 0.2 to 0.5 mL of cosolvent was titrated carefully by micropipette into the vial with intermittent shaking for 2 min until all API solids were just dissolved. The solubility of the API at a given temperature was calculated as the weight of the API in a vial divided by the total volume of the cosolvent added to a vial (i.e., the gravimetric method) (7, 9). Solubility of the API in the same cosolvent at temperatures of 15, 25, 40, and 60 °C was determined. All temperatures were maintained and controlled by a water bath. Although the gravimetric method appeared to be imprecise, its advantages were its robustness, simplicity, lack of the need for calibration, and lack of solvate formation. Polymorphism, crystallinity, and crystal habits of acetaminophen solids recrystallized by cooling from 60 to 25 °C were fully characterized by differential scanning calorimetry (DSC) and optical microscopy (OM).
Results and discussion
Out of the 100 cosolvent systems, the authors constructed only 92 solubility curves represented as van't Hoff plots because eight cosolvent systems (i.e., THF and N-butyl alcohol, THF and DMF, methanol and DMSO, methanol and 1,4-dioxane, methanol and ethanol, ethanol and 1,4-dioxane, DMSO and benzyl alcohol, and DMF and benzyl alcohol) had exhibited light pink–orange color, thus indicating the possible formation of two side-products of acetaminophen oxidation (i.e., p-benzoquinonemonoimine and p-benzoquinone) (see Table II) (16).
Table II: Theoretical yield, apparent heat of solution, Gibb's free energy of dissolution, aspect ratio, enthalpy of melting, and crystallinity of acetaminophen Form I crystals grown from or dissolved in cosolvent systems.
In general, a cosolvent system was a better solubilizer than a single solvent system (7). The theoretical yield (i.e., the amount of crystalline solids that would result if the saturated solution at 60 °C were cooled to 25 °C) was approximated from each solubility curve using the following equation:
where Sh is the solubility (g/mL) at 60 °C, and SL is the solubility (g/mL) at 25 °C. The cosolvent system of benzyl alcohol and acetonitrile and the cosolvent system of ethanol and acetone gave a maximum theoretical yield of 71.73% and a minimum of 17.94%, respectively (see Table II). These results implied that the interactions between protic benzyl alcohol and polar aprotic acetonitrile were relatively weak and more sensitive to temperature change than the relatively strong interactions between hydrogen-bond donating ethanol and hydrogen-bond accepting acetone (7).
Table II (Continued).
The apparent differential heat of solution, ΔHd, of acetaminophen in the 92 cosolvent systems was calculated from the 92 solubility curves based on the following van't Hoff equation if acetaminophen and the cosolvent system were assumed not to behave ideally (17):
in which x is the mole fraction of acetaminophen solute in the cosolvent solution, T is the solution temperature, R is the gas-enthalpy constant (8.314 J/mol K), ΔHd is the apparent differential heat of solution, which was obtained from the slope of the plot of ln x versus 1/T, and C is a constant. Using the solubility data, the standard Gibbs free energy of the dissolution process, ΔGd, at 25 °C was calculated using the following equation (18):
Because the cosolvent systems were all real systems, the calculated ΔGd at a given temperature T might not equal ΔHd – TΔSd. Therefore, only values of ΔGd and ΔHd are listed in Table II. The positive values of ΔHd indicated that dissolution was an endothermic process. The energy of attraction of acetaminophen-solute molecules with each other and the energy of attraction of cosolvent molecules with each other were lower than the energy attraction of the acetaminophen solute and the cosolvent molecules in the solution. Therefore, the solubility of acetaminophen in different cosolvent systems increased with temperature. The negative values of ΔGd at 25 °C also revealed that dissolution was a spontaneous process at 25 °C. Only three systems seriously deviated from the linearity of Equation 2. They were ethyl acetate and acetone, THF and acetonitrile, and MEK and 1,4-dioxane. These solvent pairs seemed to have a large difference in their Hansen polar parameter values only (8).
Table II (Continued).
Optical micrographs of acetaminophen crystals grown from 88 cosolvent systems were taken because four other systems (i.e., THF and 1,4-dioxane, MEK and acetone, IPA and DMF, and IPA and 1,4-dioxane) had failed to produce acetaminophen solids. Perhaps the high affinity of acetaminophen solutes for those four cosolvent systems through hydrogen bonding more than compensated for their crystal interactions. As expected, increases in temperature generally increased the solubility of acetaminophen solutes in those four cosolvent systems to a lesser extent than in the other 88 cosolvent systems, probably because it reduced the cosolvent–cosolvent interactions in those four cosolvent systems less than it reduced the other cosolvent–cosolvent interactions in the other 88 cosolvent systems (19).
Crystal habits of acetaminophen were classified into four typical shapes of prismatic, rhombohedral, hexagonal, and needle with sizes ranging from 50 μm in the cosolvent system of THF and acetone (see Figure 2a) to 4.5 mm in the cosolvent system of MEK and 1,4-dioxane (see Figure 2b) and aspect ratios, defined as length divided by breadth, ranging from 1.07 in the cosolvent system of nitrobenzene and N-butyl alcohol (see Figure 2c) to 7.33 in the cosolvent system of THF and acetonitrile (see Figure 2d) (20). The composition of solvents is known to influence nucleation and growth rates (21). Because THF, acetone, nitrobenzene, 1,4-dioxane, and MEK are hydrogen-bond accepting solvents, they might have preferentially adsorbed at specific faces, thus inhibiting the growth of acetaminophen crystals, or have similar structures to acetaminophen, thus hindering the regular deposition of oncoming molecular layers (22).
Figure 2: Optical micrographs of crystal habit of acetaminophen Form I crystals grown by cooling in (a) tetrahydrofuran and acetone, (b) methyl ethyl ketone and 1,4-dioxane, (c) nitrobenzene + N-butyl alcohol, and (d) tetrahydrofuran and acetonitrile (scale bar = 500 Î¼m).
All acetaminophen crystals harvested from the 88 cosolvent systems exhibited the same typical DSC melting endotherm of about 171 °C for Form I acetaminophen as shown in Figure 3. No other polymorph was observed, even though a change in the morphology to a needle shape could be a strong indication of the presence of acetaminophen Form II crystals (14). This important case serves as a reminder that a definitive identification of polymorphism must be based on spectroscopy, X-ray diffraction, or thermal analysis, and not on microscopy alone (7).
Figure 3: A typical differential scanning calorimetry scan of acetaminophen Form I crystals grown in nitrobenzene and N,N-dimethylformamide cosolvent systems.
The percent of crystallinity of acetaminophen crystals was quantified by dividing the area of a sample melting endotherm by the largest area of melting endotherm of all samples, which turned out to be the acetaminophen crystals grown in the cosolvent system of nitrobenzene and DMF with the enthalpy of melting, ΔHm, of 195.24 J/g (see Table II). The authors suggest two possible reasons that this particular sample had the highest crystallinity. First, the slope of the solubility curve was not steep, so that cooling recrystallization took place gradually. Second, the molecular structures of nitrobenzene and DMF were similar to that of acetaminophen, which might have slowed down the nucleation and growth rate of acetaminophen crystals to yield high-quality crystals (22).
Cosolvent screening is a useful and beneficial method for finding ideal cosolvent systems to create the desirable processing properties of acetaminophen crystals because cosolvent systems offered a wide range of choices in solubility, theoretical yield, crystal habit, aspect ratio, and crystallinity. Although small crystal sizes are advantageous for decreasing the force exerted on the roll-bearing blocks for roll compaction and for enhancing the dissolution rate because they lower εn and raise S, respectively (see Table I), small crystal sizes can lengthen the drying rate, the filtration rate, the mixing rate, and the growth rate of granules in the nuclear growth region because of the decreases in Rc (which resulted from strong capillary force), Dp, k2, and Xa, respectively (see Table I). Crystals with an aspect ratio higher than 3 have needle shapes that are easily broken into pieces of smaller crystal and fines. Therefore, systems produced relatively large crystal sizes, aspect ratios of ~1, and high theoretical yield such as that of the ethyl acetate and acetonitrile system. The authors will carry out similar investigations in the near future for the antisolvent systems represented by the green boxes in Table II and the scale-up effect on the crystal-size distribution.
This work was supported by a grant from the national Science Council of Taiwan, ROC (NSC 97-2113-M-008-006). Suggestions about DSC from Jui-Mei Huang, at Precision Instrument Center in National Central University are gratefully acknowledged.
Tu Lee* is an associate professor, and Gen Da Chang is a graduate student at the Department of Chemical and Materials Engineering, 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, firstname.lastname@example.org.
*To whom all correspondence should be addressed.
Submitted: Aug. 13, 2009. Accepted: Nov. 20, 2009.
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