Large-Scale Crystallization of a Pure Metastable Polymorph by

Communication pubs.acs.org/OPRD

Large-Scale Crystallization of a Pure Metastable Polymorph by Reaction Coupling Hung Lin Lee, Hong Yu Lin, and Tu Lee* Department of Chemical and Materials Engineering, National Central University, 300 Jhong-Da Road, Jhong-Li City 320, Taiwan R.O.C. S Supporting Information *

dependent equilibrium saturation concentration, C*, and the initial S0 = C0/C*, where C0 is the initial concentration, (2) the Ostwald’s rule of stages14 that metastable polymorphs are prone to be formed and then transformed rapidly into only one thermodynamically stable polymorph, (3) the nucleation of thermodynamically stable polymorph when S at later times is lower than the initial S0, and (4) instead of going through recrystallization, realistically, the process usually undergoes crystallization immediately after a chemical reaction. Although common techniques such as the addition of antisolvent15 may be used to obtain high S0 initially by lowering all C*’s on the solubility curve without worrying too much about Factor (1) above (but the drawback of this method is to take up additional volume in the batch crystallizer) or the use of viscous solvents may be employed to slow down the effect of Factor (2),16 the aim of this research is to provide an alternative way so that all the above-mentioned key factors can be taken into account and to overcome them simultaneously based on the concept of reaction coupling. Reaction coupling had been employed before to sculpt the hierarchical microstructures of the carbonate−silica system17 and the spherical morphology of calcium−alginate microspheres18 at a larger length scale. The synthesis of acetaminophen (paracetamol) and its crystallization are chosen to demonstrate this particular concept because of the commercial value of the elusive metastable polymorph of acetaminophen and the acquaintance with acetaminophen based on our previous work.19 Acetaminophen is an important analgesic and antipyretic active pharmaceutical ingredient (API) manufactured in several millions of tablets and various dosage forms every year worldwide. So far, three acetaminophen polymorphs have been reported.20−23 The monoclinic Form I acetaminophen is the thermodynamically stable and commercially used polymorph. This form is not suitable for direct compaction into tablets due to its poor densification property and compressibility. Making tablets of Form I generally requires solid-state modifications24−26 such as granulation27,28 and spherical agglomeration29,30 in the pharmaceutical industry. However, granulation involves the tedious blending and drying steps, whereas spherical crystallization depends on the compositions and physicochemical properties of solvent mixtures, which may complicate the downstream operations. For the above reasons, preparation of Form II acetaminophen on large-scale is more appealing economically. Form II is a metastable orthorhombic form in a

ABSTRACT: A maximum of more than 40 g of acetaminophen Form II crystals with a yield of 65 mol % is made reproducibly in a 500 mL reactor by coupling the acetylation of p-aminophenol with the neutralization of acetic acid before the crystallization of acetaminophen Form II crystals. This novel working principle involves a sudden drop of the solubility of acetaminophen from the acetic acid−water environment to the acetate−water system in addition to temperature cooling but without agitation. This particular processing pathway is capable of maintaining a large supersaturation for quite some time for the system to enter the metastable zone of Form II with respect to the acetate−water system. The large amount of Form II crystals so produced are then isolated by filtration and oven drying to prevent Form II crystals in the mother liquor from transforming to the thermodynamically stable Form I crystals by the Ostwald’s rule of stages.

■

INTRODUCTION Molecules, atoms, or ions are often precisely packed in a number of different long-range orders through self-recognition and self-assembly under the influence of intermolecular forces.1 Each of this order at the subnanometer level in the solid-state is termed a crystal polymorph.2 Since each polymorph is a unique material with its physicochemical properties, the discovery, the selection, and the production of a desired polymorph at largescale are essential in many high-valued industries.3 They are especially so in the pharmaceutical arena.4 Metastable polymorphs can often be recrystallized in a small-scale through swift cooling5 and rapid solvent evaporation6 by suddenly raising the relative supersaturation, S,7 and/or broadening of the metastable zone width (MZW),8 or through the solvent effect9 by altering the shape of the solubility curve and MZW,10 or through heterogeneous nucleation11 by lowering the interfacial energy and/or S.12 However, unlike biological environments where a bulk material with a metastable modification can be cleverly induced, confined, and stabilized through the layering and tiling of the organic nucleation templates and nanosized crystals of metastable polymorph,13 large-scale crystal production of metastable polymorph for industrial applications is more difficult to achieve because of the interplay among the four key factors: (1) the time delay in temperature change over the large heat capacity of the solution volume in a vessel even with a good mixing which, in turn, can affect the temperature© 2014 American Chemical Society

Received: January 7, 2014 Published: March 13, 2014 539

dx.doi.org/10.1021/op500003k | Org. Process Res. Dev. 2014, 18, 539−545

Organic Process Research & Development

Communication

Figure 1. (a) View of crystal structure of acetaminophen Form II showing the top view along the b-axis. The directions of the applied shear stress are indicated by the red arrows (cif file obtained from ref 32). (b) SEM and (c) OM images of acetaminophen Form II crystals.

Scheme 1. Acetylation and Neutralizationa

a

1, Acetaminophen; 2, p-aminophenol; 3, acetic anhydride; 4, acetic acid; 5, alkaline; and 6, acetate.

Pcab space group. It possesses slip planes in its crystal structure resulting from the corrugated hydrogen-bonding layers for plastic deformation upon compression (Figure 1a),31,32 which exhibits tablet-forming properties. However, Form II is known to be conventionally obtained only in a milligram-scale either

by slow cooling of molten Form I or cooling an ethanolic acetaminophen solution with seeds of Form II harvested from melt-crystallized acetaminophen.23,31 Several other methods for preparing a small amount of acetaminophen Form II have also been reported recently, such as high-throughput CrystalMax 540



Communication

screening,33 polymer additive,11 monosubstituted halobenzoic acids as templates,32 and swift cooling.5 Although the manufacturing of Form II is desirable, it has been proven difficult to make a large quantity of it.31,34

■

RESULTS AND DISCUSSION Here, we demonstrate a controllable route for large-scale manufacturing of acetaminophen 1 Form II via acetylation of paminophenol 2 with acetic anhydride 3 in water producing acetic acid 4 as a byproduct, coupled with the exothermic neutralization of acetic acid with a strong alkaline 5 (i.e., NaOH, KOH, or NH4OH) to produce acetate ions 6 (Scheme 1). At first, the acetylation of 2 with 3 in water35 is implemented with agitation at 250 rpm at around 80 °C for 30 min in a 500 mL jacketed batch reactor. Only half of the molecule of 3 is used, and the other half acts as a leaving group during the acyl substitution step, producing 4. At the end of the acetylation, a nearly saturated aqueous solution of 5 is immediately added into the clear solution within 2 min with a slower stirring rate at 125 rpm to produce the corresponding acetate ions 6. In addition to the rapid change from the aqueous acetic acid solution to the aqueous acetate solution after neutralization, cooling is undertaken when the reactor jacket is set at 7 °C without agitation over 10 min mainly for decreasing the concentration−temperature slope (i.e., dC/dT) of the crystallization route to obtain a better control in nucleation due to a relatively large supersaturation for 10 min and not so much for the purpose of broadening the metastable zone width of Form II in this particular case. However, in a manufacturing scale, the decrease of dC/dT of the crystallization route may still be achievable under a mild agitation due to the large heat capacity of the mother liquor. Later, agitation is applied in the resulting solution at 250 rpm to reduce the existence of concentration and temperature fluctuations. The temperature profile of this typical process is monitored by a thermocouple and recorded in Figure S1 in the Supporting Information for understanding the crystallization route and quantifying the metastable zone width as a function of time. Acetaminophen Form II crystals are isolated from the mother liquor by filtration and by oven drying at 40 °C overnight to avoid the unfavorable polymorphic transformation according to Ostwald’s rule of stages. However, separate experiments in the Experimental Section are designed to investigate the exact amount of time required for the transformation from Form II to Form I in the mother liquor. The maximum yield of Form II crystals is about 42 g (65 mol %). All experiments and measurements are repeated at least three times. The working principles of the reaction coupling method are best illustrated by the solubility curves in Figure 2 which are measured by the gravimetric method,36 and the schematic diagrams for crystallization routes are included in Figure 3. The gravimetric method is employed because each solubility value can be determined rapidly within 30 min, which significantly minimizes the error induced by polymorphic transformation at high temperatures and in solution. Generally, all solubility curves of Form II crystals are above the ones of Form I crystals, and all solubility values are listed in Table S1 in the Supporting Information. For example, the solubility values of Form I and Form II are 256.0 ± 6.0 and 282.2 ± 6.9 mg/mL in the aqueous solution of acetic acid at 80 °C, respectively; 44.7 ± 1.2 and 52.2 ± 1.3 mg/mL in the aqueous solution of sodium acetate at 80 °C, respectively; and 2.2 ± 0.2 and 2.2 ± 0.2 mg/mL in the aqueous solution of sodium acetate at 7 °C, respectively. The

Figure 2. Solubility curves of acetaminophen Form I and Form II: curve a and curve b in an aqueous solution of acetic acid, curve c and curve d in water, and curve e and curve f in an aqueous solution of sodium acetate, respectively.

success of this reaction coupling method lies in the heart of the sudden drop of the solubility value of acetaminophen from the acetic acid−water system, Caaw*, to the acetate-water system, Caw*, after the instantaneous neutralization. The excessive increase of acetaminophen solubility in acetic acid is thought to be contributed to the complex formation.37,38 Acetaminophen associates molecularly with a suitable complexing agent such as acetic acid. This is evidenced by the solubility diagram obtained according to Higuchi39 showing a dependency between the solubility of acetaminophen and the content of acetic acid as demonstrated in Figure 4a due to the effect of hydrotropy. However, after the acetic acid molecules are neutralized to acetate ions, the solubility value of acetaminophen becomes Caw* which is much less than Caaw*, so that the initial S0 is increased from C0/Caaw* to C0/Caw*. The rather low solubility of acetaminophen in aqueous solution of acetate, Caw*, may well be attributed to the formation of inter- or intramolecular hydrogen bonding among acetaminophen molecules and acetate groups as supported by the solubility diagram39 in Figure 4b showing a relationship between the solubility of acetaminophen and the concentration of acetate ions. Point A in Figure 3 with an initial concentration of 189 mg/ mL at 80 °C, C0, is located way above the solubility curve of Form II, Caw* (Figure 3a) and a large S can be maintained by broadening the MZW through rapid cooling to 7 °C without agitation for 10 min. The maximum MZW of Form II acetaminophen achieved is 169 mg/mL at 53 °C as indicated by Point B in Figure S2 in the Supporting Information, based on the temperature recorded at which the system turns cloudy and the measured solubility curve of Form II in Figure 3a. By taking the processing pathway of A → B → C, the system can enter the metastable zone of Form II now having all Points A, B, and C in the acetate−water system with reaction coupling (Figure 3a) instead of having Points D and E in the metastable zone of Form I in the acetic acid−water system (Figure 3b) without reaction coupling but with agitation throughout. Without stirring, it takes a longer time to decrease the bulk temperature, and the relatively mild decrease of dC/dT over time in Figure 3a can ensure a relatively large supersaturation for quite some time. In Figure 3b, cooling proceeds at a constant concentration until the limit of the metastable zone of 541



Communication

Figure 4. Solubility diagrams of acetaminophen Form I in an aqueous solution at 25 °C of (a) acetic acid and (b) sodium acetate with different concentrations.

the nucleation of Form II. Point C ends up at the solubility value of Form II in an aqueous solution of sodium acetate at 7 °C well above the metastable zone of Form I, and Form II crystals are isolated to avoid Ostwald’s rule of stages. If agitation under cooling is applied throughout in the acetate− water system, the efficient heat transfer will bring down the temperature in a short period of time while C is constantly consumed to produce new crystals shaping a steep dC/dT slope of the crystallization route in addition to a significant reduction of the MZW. The sudden surge of high degree of supersaturation can force the system to go beyond the narrow Form II metastable zone easily and reach the limit of the metastable zone of Form I at Point F. Consequently, the processing pathway of A → F → G is followed with a much lower degree of supersaturation after Point F to produce Form I crystals until Point G is reached (Figure 3c). Notably, the IR spectra in Figures S3 and S4 in the Supporting Information further reveal that Form II crystals can be preserved in an aqueous solution of sodium acetate for up to 6 h at 25 °C and for at least 48 h at 7 °C! This promising stability result of Form II in solution has made the scale-up more feasible because it usually takes about 6 to 8 h to discharge a 4000 L sized vessel. And yet, the thermal behavior of Form II is still controversial. Many have reported that the melting point of Form II is ranging from 155° to 160 °C without prior conversion to Form I.31,34,40 However, the differential scanning calorimetry (DSC)

Figure 3. Schematic diagrams of crystallization routes: (a) after neutralization with cooling and without agitation within 10 min, (b) without neutralization with agitation throughout, and (c) after neutralization with cooling and with agitation throughout. (Only Point A is a real value of 189 mg/mL whereas the other points of B, C, D, E, F, and G are theoretical points for demonstrative purposes).

Form I is reached at Point D, where nucleation of Form I occurs. After which, the concentration and temperature subsequently fall, and the system eventually stops at Point E, which is the saturated value of Form I in an aqueous solution of acetic acid at 7 °C. With respect to the acetate−water system, Point B is at the metastable zone limit of Form II (Figure 3a) yielding only 100% Form II nuclei, and the sufficiently high supersaturation further provides a continuous driving force for 542



Communication

(SXD)32 for verifying its authenticity. Moreover, the scanning electron microscopy (SEM) and optical microscopy (OM) images (Figures 1b,c) also show that the kinetically produced Form II crystals exhibit flaky and fractal habits. Their irreversible properties of plastic deformation and brittleness can definitely promote tableting.45,46 Dissolution rates of 250 μm sized cut acetaminophen Form I and II particles are further compared in Figure 7. Both dissolution profiles followed the

scan in our present work (Figure 5) displays that the melting point of Form II is at 151 °C, the molten Form II recrystallizes

Figure 5. DSC thermogram of acetaminophen Form II (I, Form I; II, Form II; and L, liquid).

at 154 °C and becomes Form I solids with a melting point of 170 °C. Since acetaminophen is a monotropic system1,4,41 based on thermodynamic rules for polymorph transitions according to Burger and Ramberger,42,43 the likelihood for the direct transition from Form II to Form I in the presence of Form I nuclei without going through the melting of Form II can be totally dismissed. The purity of Form II crystals without any trace of Form I crystals is further examined by X-ray diffraction (XRD) (Figure 6 and Figure S5 in the Supporting

Figure 7. Dissolution profiles of acetaminophen crystals at 37.0 °C (blue circle, Form I; black square, Form II).

first-order kinetics,19 and Form II crystals exhibit a faster dissolution rate. The stability of metastable Form II also reveals that it remains unchanged at 40 °C with 75% relative humidity over at least 4 months.47

■

Figure 6. PXRD patterns of acetaminophen (a) Form II and (b) theoretical PXRD of Form II.

CONCLUSIONS In summary, we have demonstrated the concept of reaction coupling with temperature cooling is capable of manufacturing Form II acetaminophen on scale-up for pharmaceutical applications through (1) crystallization followed immediately after acetylation coupled with neutralization, (2) the enhancement of supersaturation by lowering the solubility curves, and (3) the decreasing of dC/dT of a crystallization route and broadening of MZW without agitation by cooling. Besides providing a repeatable and robust scale-up approach for manufacturing the kinetically favored polymorph, reaction coupling may also open a new doorway for understanding the polymorphic control of calcium carbonate in biomineralization.12 Furthermore, the working principle of reaction coupling can be applied to the coformer in cocrystallization48 as a complexing agent for another conjugated reaction.

Information) and IR (Figure S6 in the Supporting Information). IR assignments23 are included in the Supporting Information. The characteristic peak of absorption for pure Form II at 836 cm−1 has been used to differentiate from the one of Form I at 806 cm−1.44 Since, the heat of fusion for Form II here is 8.67 J/g, which is much higher than the one reported by slow evaporation of ethanolic solution of acetaminophen, our Form II crystals exhibit a better crystallinity. Our powder X-ray diffraction (PXRD) pattern of Form II (Figure 6 and Figure S5 in the Supporting Information) is overlaid with the theoretical PXRD pattern from single-crystal X-ray diffraction

EXPERIMENTAL SECTION Experiments. Large-Scale Crystallization with the Coupled Reaction. In total, 45 g of p-aminophenol, 225 mL of water, and 60 mL of acetic anhydride were added into a 500 mL jacketed reactor at 80 °C with agitation at 250 rpm for 30 min. An aqueous solution of sodium acetate was prepared by dissolving 36 g of sodium hydroxide into 60 mL of water and then introduced into the reaction solution at a slower stirring rate of 125 rpm. The resulting solution was cooled to 7 °C with a jacketed water bath without agitation for 10 min, and then the agitation was applied to produce 42 g of metastable Form II

■

543



■

crystals. Filtration, oven drying at 40 °C, and solid-state characterization for Form II crystals were then implemented. The yield is about 65 mol % (practically obtained/theoretical amount = 42 g (0.28 mol)/65 g (0.43 mol) × 100%). Solubility Values Measurement. About 20 mg of solid samples of acetaminophen Form I or Form II were weighed in a 20 mL scintillation vial. Drops of water, 3.22 M acetic acid(aq), and 3.0 M sodium acetate(aq) were titrated carefully by a micropipet into the vial separately with intermittent shaking until all solids were just dissolved. The solubility value of solids in a solvent or solution at a given temperature was calculated as the weight of solids divided by the total volume of solvent or solution added to a vial. Solubility values of solids in a solvent or solution at five different temperatures of 7, 25, 40, 60, and 80 °C were determined in a water bath. Although the gravimetric method36 appeared to have an inherent inaccuracy of about ±10%, its advantages were its robustness, simplicity, without the need of performing any calibration, and the concern of solvate formation. All measurements were repeated at least three times. Solution Complex Effect by Higuchi’s Plot.49 The formation of interaction species was detected by the method of solubility analysis. This method was modified in our study. The solubility values of acetaminophen were measured in 3, 2.5, 2, 1.5, 1, 0.75, 0.5, 0.25, 0.1, 0.05, and 0.01 M aqueous solution of acetic acid and sodium acetate by titration at 25 °C. All measurements were repeated at least three times. Polymorphic Transformation Test. In total, 200 mg of Form II acetaminophen crystals was added into a 20 mL scintillation vial containing 2 mL of 3 M aqueous solution of sodium acetate for 30 min, 1, 2, 3, 5, 6, and 8 h at 25 °C and for 48 h at 7 °C. Afterwards, the crystals were filtrated, oven-dried at 40 °C, analyzed, and monitored by IR spectroscopy. Dissolution Test.50 A dissolution test station (SR6, Hanson Research Corporation, Chatsworth, California) Type II (paddle method) at rotation speed of 50 rpm was used for in vitro testing of the dissolution of Form I and Form II acetaminophen crystals. Dissolution was carried out on an equivalent of 500 mg of acetaminophen. Ultrapure water of pH 1.4 with HCl was used as the dissolution medium. The volume and temperature of the dissolution medium were 900 mL and 37.0 ± 0.2 °C, respectively. Samples of 1 mL were withdrawn at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 5, 10, 15, 20, and 30 min for acetaminophen Form I crystals and 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 5, 10, 20, and 30 min for acetaminophen Form II crystals by a plastic syringe near the stirring paddle. Each sample was filtered by a 0.2 μm PVDF membrane (PALL Corporation, PN), diluted 100 times in a 20 mL scintillation vial with ultrapure water, and then assayed for the concentration of acetaminophen by a UV/vis spectrometer. Stability Test. Approximately, 150 mg of acetaminophen Form II crystals was subjected to incubation studies in an open vial. The sample was introduced into a container which was placed in a capped bottle filled with saturated aqueous solutions of NaCl.47 The bottle was kept in an oven at 40 °C to maintain 75% relative humidity inside a vial. Analyses of the stability of sample were carried out by PXRD at different time points.

■

Communication

AUTHOR INFORMATION

Corresponding Author

*Phone: +886-3-422-7151 ext. 34204. Fax: + 886-3-425-2296. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS This research was supported by the grants from the National Science Council of Taiwan, R.O.C. (Grant 102-2221-E-008071-MY2). We are greatly indebted to Ms. Jui-Mei Huang, Ms. Shew-Jen Weng, and Ms. Ching-Tien Lin for their assistance with DSC, PXRD, and SEM at the Precision Instrument Center in National Central University, Taiwan R.O.C.

■

REFERENCES

(1) Lee, T.; Hung, S. T.; Kuo, C. S. Pharm. Res. 2006, 23, 2542− 2555. (2) Threlfall, T. L. Analyst 1995, 120, 2435−2460. (3) (a) Fryer, P.; Pinschower, K. MRS Bull. 2000, 25, 25−29. (b) Lee, T.; Lin, M. S. Cryst. Growth Des. 2007, 7, 1803−1810. (c) Lee, T.; Chen, J. W.; Lee, H. L.; Lin, T. Y.; Tsai, Y. C.; Cheng, S.-L.; Lee, S.W.; Hu, J.-C.; Chen, L.-T. Chem. Eng. J. 2013, 225, 809−817. (d) Sato, K. Chem. Eng. Sci. 2001, 56, 2255−2265. (4) Myrick, M. L.; Baranowski, M.; Profeta, L. T. M. J. Chem. Educ. 2010, 87, 842−844. (5) Sudha, C.; Srinivasan, K. CrystEngComm 2013, 15, 1914−1921. (6) Moribe, K.; Tozuka, Y.; Yamamoto, K. Adv. Drug Delivery Rev. 2008, 60, 328−338. (7) Lu, J.; Wang, X.-J.; Yang, X.; Ching, C.-B. Cryst. Growth Des. 2007, 7, 1590−1598. (8) Cheon, Y.-H.; Kim, K.-J.; Kim, S.-H. Chem. Eng. Sci. 2005, 60, 4791−4802. (9) Musumeci, D.; Hunter, C. A.; McCabe, J. F. Cryst. Growth Des. 2010, 10, 1661−1664. (10) Therlfall, T. Org. Process Res. Dev. 2000, 4, 384−390. (11) (a) Grzesiak, A. L.; Matzger, A. J. J. Pharm. Sci. 2007, 96, 2978− 2986. (b) Lang, M.; Grzesiak, l.; Matzger, A. J. J. Am. Chem. Soc. 2002, 124, 14834−14835. (c) Lee, A. Y.; Ulman, A.; Myerson, A. S. Langmuir 2002, 18, 5886−5898. (d) Sudha, C.; Nandhini, R.; Srinivasan, K. Cryst. Growth Des. 2014, 14, 705−715. (12) Mann, S. Nature 1988, 332, 119−124. (13) Zaremba, C. M.; Belcher, A. M.; Fritz, M.; Li, Y.; Mann, S.; Hansma, P. K.; Morse, D. E.; Speck, J. S.; Stucky, G. D. Chem. Mater. 1996, 8, 679−690. (14) Ostwald, W. Z. Phys. Chem. 1897, 22, 289−330. (15) (a) Yu, Z. Q.; Chow, P. S.; Tan, R. B. H. Org. Process Res. Dev. 2006, 10, 717−722. (b) Kitamura, M.; Sugimoto, M. J. Cryst. Growth 2007, 257, 177−184. (16) Lee, T.; Chang, G. D. Cryst. Growth Des. 2009, 9, 3551−3561. (17) Noorduin, W. L.; Grinthal, A.; Mahadevan, L.; Aizenberg, J. Science 2013, 340, 832−837. (18) Fundueanu, G.; Esposito, E.; Mihai, D.; Carpov, A.; Desbrieres, J.; Rinaudo, M.; Nastruzzi, C. Int. J. Pharm. 1998, 170, 11−21. (19) Lee, T.; Lin, H. Y.; Lee, H. L. Org. Process Res. Dev. 2013, 17, 1168−1179. (20) Naumov, D. Y.; Vasilchenkom, M. A.; Howard, J. A. K. Acta Crystallogr. 1998, C54, 653−655. (21) Haisa, M.; Kashino, S.; Maeda, H. Acta Crystallogr. 1974, B30, 2510−2512. (22) Perrin, M.-A.; Neumann, M. A.; Elmaleh, H.; Zaske, L. Chem. Commun. 2009, 3181−3183. (23) Martino, P. D.; Conflant, P.; Drache, M.; Huvenne, J.-P.; GuyotHermann, A.-M. J. Therm. Anal. 1997, 48, 447−458. (24) André, V.; da Piedade, M. F. M.; Duarte, M. T. CrystEngComm 2012, 13, 5005−5014.

ASSOCIATED CONTENT

S Supporting Information *

Materials, instrumentations, Figures S1−S6, and Tables S1−S3. This material is available free of charge via the Internet at http://pubs.acs.org. 544



Communication

(25) Delmas, T.; Shah, U. V.; Roberts, M. M.; Williams, D. R.; Heng, J. Y. Y. Powder Technol. 2013, 236, 24−29. (26) Karki, S.; Frišcǐ ć, T.; Fábián, L.; Laity, P. R.; Day, G. M.; Jones, W. Adv. Mater. 2009, 21, 3905−3909. (27) Vogel, S. H. Directly Compressible Acetaminophen Granulation. U.S. Patent 4,439,453, March 27, 1984. (28) Railkar, A. M.; Schwartz, J. B. Drug Dev. Ind. Pharm. 2001, 27, 337−343. (29) Ettabia, A.; Joiris, E.; Guyot-Hermann, A.-M.; Guyot, J.-C. Pharm. Ind. 1997, 59, 625−631. (30) Ålander, E. M.; Uusi-Penttilä, M. S.; Rasmuson, A. C. Ind. Eng. Chem. Res. 2004, 43, 629−637. (31) Nichols, G.; Frampton, C. S. J. Pharm. Sci. 1998, 87, 684−693. (32) Thomas, L. H.; Wales, C.; Zhao, L.; Wilson, C. C. Cryst. Growth Des. 2011, 11, 1450−1452. (33) Peterson, M. L.; Morissette, S. L.; McNulty, C.; Goldsweig, A.; Shaw, P.; LeQuesne, M.; Monagle, J.; Encina, N.; Marchionna, J.; Johnson, A.; Gonzalez-Zugasti, J.; Lemmo, A. V.; Eills, S. J.; Cima, M. J.; Almarsson, Ö . J. Am. Chem. Soc. 2002, 124, 10958−10959. (34) Sacchetti, M. J. Therm. Anal. Cal. 2001, 63, 345−350. (35) Ellis, F. In Paracetamol−a curriculum resource; Osborne, C., Pack, M. Eds.; Royal Society of Chemistry: London, 2002; pp 8−12. (36) Lee, T.; Kuo, C. S.; Chen, Y. H. Pharm. Technol. 2006, 30, 72− 92. (37) Donbrow, M.; Jan, Z. A. J. Pharm. Pharmacol. 1965, 17, 129S− 137S. (38) Poochikian, G. K.; Cradock, J. C. J. Pharm. Sci. 1979, 68, 728− 732. (39) Gans, E. H.; Higuchi, T. J. Am. Pharm. Assoc. 1957, 46, 458− 466. (40) Zimmermann, B.; Baranović, G. J. Pharm. Biomed. Anal. 2011, 54, 295−302. (41) Szelagiewicz, M.; Marcolli, C.; Cianferani, S.; Hard, A. P.; Vit, A.; Burkhard, A.; von Raumer, M.; Hofmeier, U. Ch.; Zilian, A.; Francotte, E.; Schenker, R. J. Therm. Anal. Calorim. 1999, 57, 23−43. (42) Giron, D. Thermochim. Acta 1995, 248, 1−59. (43) Burger, B. Acta Pharm. Technol. 1982, 28, 1−20. (44) Al-Zoubi, N.; Koundorellis, J. E.; Malamataris, S. J. Pharm. Bimed. Anal. 2002, 29, 459−467. (45) Rasenack, N.; Müller, B. W. Int. J. Pharm. 2002, 244, 45−57. (46) Lee, T.; Kuo, C. S. Pharm. Tech. 2006, 30 (3), 110−120. (47) Lee, T.; Wang, Y. W. Drug Dev. Ind. Pharm. 2009, 35, 555−567. (48) Lee, T.; Chen, H. R.; Lin, H. Y.; Lee, H. L. Cryst. Growth Des. 2012, 12, 5897−5907. (49) Gans, E. H.; Higuchi, T. J. Am. Pharm. Assoc. 1957, 46, 458− 466. (50) Lee, T.; Hsu, F. B. Drug Dev. Ind. Pharm. 2007, 33, 1273−1284.

545


Large-Scale Crystallization of a Pure Metastable Polymorph by

Recommend Documents