Solubility, polymorphism, crystallinity, and crystal habit of acetaminophen and racemic (+/-)-ibuprofen were determined by initial screening of 23 solvents for scale-up. Solubility curves were constructed, and solubility at 25 degrees Celsius was plotted against the dielectric constants of various solvent as a fingerprint for solute identification. The total "form space" for acetaminophen and racemic (+/-)-ibuprofen were calculated to be 222 and 257, respectively. Various crystal habits and sizes for ibuprofen and acetaminophen were observed.
Solubility, polymorphism, crystallinity, and crystal habit of an active pharmaceutical ingredient (API) play critical roles in the value chain of pharmaceutical development, manufacturing, and formulation (1–3). The solubility of an API in solvents and solvent mixtures has a considerable influence on the choice of solvents and the course of operation in solvent-based processes such as chemical reaction, extraction, crystallization, filter cake washing, and wet granulation (4–9). The polymorphism of an API determines its packing, thermodynamic, spectroscopic, kinetic, surface, and mechanical properties in the solid state (10). The crystallinity of an API contributes to the mechanical properties of a compact, an API's stability, and the dissolution rate (11–15). The crystal habit of an API also has profound effects on the rate at which the API can be processed in filtering, washing, and drying, and the success of the API in powder flow, blending, direct compaction, roller compaction, wet granulation, and dissolution rate (16–19).
Because solubility, polymorphism, crystallinity, and crystal habit are all solvent dependent, solvent screening is of fundamental and foremost importance to many chemical process industries, especially the pharmaceutical industry (4, 20–22). Recently, there has been increased interest in performing high-throughput polymorph screening in miniaturized scales using solvent evaporation (23–25). Because of the course of solid generation from a supersaturated solution by evaporation and the relatively small amount of the API used, however, these methods may not always correlate directly with the scale-up conditions in crystallization (e.g., a relatively large volume of solvent, temperature cooling, and stirring) and do not provide direct information about other simultaneous effects brought about by the solvent such as an API's solubility, crystallinity, and crystal habit.
This article promotes an alternative solvent-screening strategy that is tailor-made for the drug development and design of API solids processes. Under this initial screening strategy of pure-solvent systems, 23 kinds of solvent mostly useful for scale-up were chosen (26). The solubility of the API solute in each solvent at 15, 25, 40, and 60 °C was measured by gravimetric titration. The enthalpy and the entropy of solution for each solvent system were calculated. The solubility of the API in each solvent at 25 °C was plotted against the dielectric constant of various solvents, resulting in a characteristic solubility pattern that might serve as the fingerprint to identify a particular API. Although only pure-solvent systems were being considered in this study, the total "form space" for each API—that is, the total number of solid generation experiments in pure-solvent, cosolvent, and antisolvent systems— was also calculated on the basis of the number of good solvents for the API from the solubility studies and the number of miscible and immiscible solvent pairs from the miscibility investigations.
Solid generation of the API solute in each pure solvent was achieved by gently shaking a 20-mL scintillation vial and by temperature cooling from 60 to 25 °C under an ambient condition (27). The cooling rate of a solution with a volume <20 mL was almost independent from the volume and the nature of solvent. The cooling profile could be approximated by a quadratic equation determined experimentally as T = 0.64t2– 7.35t + 59.3 in which T is the temperature (°C) and t is the time (min). The relatively rapid decrease in temperature serves as an ideal way to induce a polymorph that normally does not occur thermodynamically. In addition, temperature cooling is a common method in crystallization scale-up.
Differential scanning calorimetry (DSC) was used to determine the polymorphism and the crystallinity of the API solid samples (28). Optical microscopy (OM) was used for crystal habit imaging. Two well-known APIs were selected for our solvent screening strategies: acetaminophen (4-acetamidophenol) and racemic (±)-ibuprofen (α-methyl-4- [isobutyl] phenylacetic acid) (see Figure 1), because of their worldwide commercial values in analgesic and antipyretic therapy, their abundant information in the literature (4,11,17, 29–44), and the lack of extensive solvent studies on their solubility, polymorphism, crystallinity, and crystal habit (29–31).
Figure 1: Active pharmaceutical ingredient solute molecules.
Materials and Methods
Solvents. The following solvents were used in this study: cetone (CH3COCH3, HPLC–Spectro grade, 99.5%, boiling point [bp] = 56 °C, molecular weight [MW] = 58.08, lot 411050), acetonitrile (CH3CN, ACS grade, 99.96%, bp = 81.6 °C, MW = 41.05, lot 812045), benzene (C6H6, ACS grade, 99%, bp = 80 °C, MW = 78.11, lot 310008), benzyl alcohol (C6H5CH2OH, certified grade, 99.9%, bp = 205 °C, MW = 108.14, lot 809010), n-butyl alcohol (CH3(CH2)3OH, ACS grade, 99.4%, bp = 117.7 °C, MW = 74.12, lot 205027), chloroform (CHCl3, HPLC–Spectro grade, 99.9%, bp = 60.5–61.5 °C, MW = 119.38, lot 401059), dimethyl sulfoxide (DMSO) ((CH3)2SO, HPLC–Spectro grade, 99.8%, bp = 189 °C, MW = 78.13, lot 202060), N,N-dimethylformamide (DMF) (HCON(CH3)2, ACS grade, 99.8%, bp = 153 °C, MW = 73.10, lot 020505), n-heptane (CH3(CH2)5CH3, HPLC– Spectro grade, 99.4%, bp = 98 °C, MW = 100.21, lot 111110), isopropyl alcohol (IPA) ((CH3)2CHOH, HPLC–Spectro grade, 99.8%, bp = 82.4 °C, MW = 60.1, lot. 310067), methanol (CH3OH, HPLC–Spectro grade, 99.9%, bp = 64.7 °C, MW = 32.04, lot. 411070), methyl tert-butyl ether (MTBE) ((CH3)3COCH3, certified grade, 99.9%, bp = 55.2 °C, MW = 88.15, lot 712032), methyl ethyl ketone (MEK) (C2H5COCH3, ACS grade, 99.6%, bp = 81.6 °C, MW = 72.11, lot 201021), tetrahydrofuran (THF) (C4H8O, HPLC–Spectro grade, 99%, bp = 65–67 °C , MW = 72.11, lot 411013), toluene (C6H5CH3, HPLC–Spectro grade, 99.8%, bp = 110.6 °C, MW = 92.14, lot 406050), and xylene (C6H4(CH3)2, ACS grade, 98.5%, bp = 137–144 °C, MW =106.17, lot 305065). These solvents were obtained from Tedia Company (Fairfield, OH).
The following were obtained from Acros Organics (Morris Plains, NJ): N,N-dimethylaniline (DMA) (C6H5N(CH3)2, ACS grade, 99%, bp = 193 °C, MW = 121.18, lot A0213203001), nitrobenzene (C6H5NO2, ACS grade, 99%, bp = 210–211 °C, MW = 123.11, lot A019568301) and p-xylene (C6H4(CH3)2, ACS grade, 99%, bp = 138 °C , MW = 106.17 °C, lot 48754/2).
The following were obtained from Showa Chemical Co., Ltd. (Tokyo, Japan): 1,4-dioxane (C4H8O2, ACS grade, 98%, bp = 100–102 °C, MW = 88.11, lot sp-3432R). Ethanol (CH3CH2OH, HPLC–Spectro grade, 99.5%, bp = 78 °C, MW = 46.7 ) was obtained from Echo Chemical Co. Ltd. (Taipei, Taiwan). Ethyl acetate (CH3COOC2H5, ACS grade, 99.5%, bp = 76.5–77.5 °C, MW = 88.11, lot G43342) was obtained from Grand Chemical Co. Ltd. (Daejeon, South Korea). Reversible osmosis water was clarified with a water-purification system (Milli-RO Plus, Millipore, Billerica, MA).
Active pharmaceutical ingredients. Acetaminophen (4-acetamidophenol, CH3CONHC6H4OH, MW = 151.17, lot S23272-444) and racemic (±)-ibuprofen (α-methyl-4-[isobutyl] phenylacetic acid, C13H18O2, MW = 206.3, lot 26H1368) were obtained from Sigma-Aldrich (Steinheim, Germany).
Solubility studies. Approximately 10 mg of the API were weighted in a 10-mL scintillation vial. Drops of solvent were titrated carefully with a micropipette into the vial with intermittent shaking 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 solvent added to a vial. Solubility of the API in the same solvent at 15, 25, 40, and 60 °C was determined. All temperatures were maintained and controlled by a water bath. Despite the inherent inaccuracy of this method in volume measurements by eye, it provided a rapid and robust way for process scale-up.
Solvent miscibility studies. Out of the 23 solvents, approximately 1-mL portions of each solvent comprising a pair were shaken together for ~1 min in a 20-mL scintillation vial. If no interfacial meniscus was observed after the contents of the vial were allowed to settle, the solvent pair was considered to be miscible. If a meniscus was observed without apparent change in the volume of either solvent, the pair was regarded as immiscible.
Polymorph, crystallinity and crystal habit studies. Saturated API solutions of each solvent were prepared in a 20-mL scintillation vial in accordance with the solubility values at 60 °C that were determined from the experiments described in the previous section. Solids were generated by cooling from 60 to 25 °C in an ambient condition with intermittent shaking. Solids were filtered with a strong vacuum and vacuum-oven dried at 55 °C overnight. Polymorphism, crystallinity, and crystal habits were determined by DSC and optical microscopy, respectively.
DSC. A differential scanning calorimeter (DSC 7, Perkin Elmer, Norwalk, CT) was used to monitor the thermal events during heating. The instrument was calibrated with indium (8–10 mg, 99.999% pure, extrapolated melting onset at 156.6 °C). All samples were run in sealed aluminum pans under a constant nitrogen purge. Each sample was heated at 10 °C/min.
Optical microscopy. An optical microscope (SZII, Olympus, Tokyo, Japan) equipped with a CCD camera (SSC-DC50A, SONY, Tokyo, Japan) was used to take images of crystal habit.
Results and discussion
The solvents were categorized into five classes according to their functional group (26):
Acetaminophen dissolved well in 15 of the solvents (labeled as "good solvents") and only slightly dissolved in 8 of the solvents (labeled as "bad solvents") with a solubility <1 mg/mL at 25 °C. The bad solvents for acetaminophen were mainly solvents of Classes 2, 4, and 5 and included MTBE, DMA, chloroform, benzene, n-heptane, toluene, p-xylene, and xylene. Therefore, only 15 solubility curves of acetaminophen in 15 good solvents of Classes 1 and 3 at 15, 25, 40, and 60 °C (50 °C was used in cases in which a solvent's boiling point is close to 60 °C) were constructed and grouped by their similar solubility ranges for comparison (see Figure 2). As for racemic (±)-ibuprofen, all classes of solvents were good solvents except for water at 25 °C. Therefore, solubility curves of racemic (±)-ibuprofen in 22 good solvents at 15, 25, 40, and 60 °C (either 50 or 55 °C was used in cases in which a solvent's boiling point is close to 60 °C) were constructed and grouped by their similar solubility ranges as well (see Figure 3). Using scattered published results (29, 45) to check the accuracy of our data in Figures 2 and 3, the error percentage was within ±20%.
Figure 2: Solubility curves of acetaminophen in 15 kinds of solvent.
If the solute and the solvent were assumed to form an ideal solution, the solubility could be predicted from the van't Hoff equation:
in which x is the mole fraction of the API solute in the solution, T is the solution temperature (K), R is the gas enthalpy constant (8.314 J/mol K), ΔHd is the enthalpy of dissolution, and ΔSd is the entropy of dissolution (46). Extracting x and its corresponding T from each solubility curve and performing linear-curve fitting to ln x versus 1/T, ΔHd, and ΔSd of the API in each solvent could be approximated from the slope and intercept of a straight line. The values of ΔHd and ΔSd for acetaminophen and racemic (±)-ibuprofen are summarized in Tables I and II.
Table I: Dielectric constants of solvents versus enthalpies and entropies of acetaminophen and racemic (Â±)-ibuprofen solutions.
The positive values of ΔHd in Table I indicate that the energy of attraction of the API solute molecules with each other and the energy of attraction of the solvent molecules with each other are lower than the energy of attraction of the API solute and the solvent molecules in the solution. Therefore, heat was absorbed to make the API solute dissolve in the solvent. In this case, the solubility of the API solute increased with temperature. Furthermore, the positive values of ΔSd in Table I showed that the API solute–solvent systems became less ordered as the API solute dissolved into the solution.
Table II: Solvent miscibility table, cosolvent and antisolvent systems of acetaminophen.
When the solubility values of acetaminophen and racemic (±)-ibuprofen at 25 °C were plotted against the dielectric constant of various solvents (see Table I) in which the APIs were soluble, the APIs' characteristic "solubility pattern" was produced (see Figures 4 and 5). Nonetheless, there were no direct correlations between the dielectric constants of the solvents and the APIs' solubility values (see Figures 4 and 5) or between the dielectric constants of the solvents and the APIs' ΔHd values, nor between the dielectric constants of the solvents and the ΔSd values (see Table I).
Figure 3: Solubility curves of racemic (Â±)-ibuprofen in 22 kinds of solvent.
The implication is that the solubility was profoundly influenced by various intermolecular interactions. Besides the Coulombic (ion–ion or ion–dipole) interactions, other effects such as the Keesom force (rotating dipole–dipole force), the Debye force (dipole–induced-dipole force), the London force (induced-dipole–induced-dipole force), and the hydrogen bonding should all be considered. The high solvation power of the two "polar aprotic solvents"—DMF and DMSO—in the two solubility patterns (see Figures 3 and 4) suggested that solid generation might be difficult to carry out in extremely good solvents.
Figure 4: Solubility spectrum of acetaminophen.
Based on the solvent miscibility studies of the solvent pairs of the 23 kinds of solvent, there were 18 immiscible pairs (36 gray boxes divided by 2) (see Tables II and III). It was necessary to divide the number of boxes by 2 when a particular solvent i was not the same as another solvent j because the solvent pair of i,j was the same as the solvent pair of j,i. Again, there were no direct correlations between solvent dielectric constants (see Table I) and solvent miscibility values (see Tables II and III). For example, 1,4-dioxane with a dielectric constant of 2.2 was miscible with all other solvents in Tables II and III, but xylene (dielectric constant 2.0) was immiscible with DMF, DMSO, and water. Similar to solute–solvent solubility, the solvent–solvent miscibility also was profoundly influenced by the many aforementioned intermolecular interactions.
Table III: Solvent miscibility table, cosolvent and antisolvent systems of racemic (Â±)-ibuprofen.
The pure-solvent systems were represented as the 23 diagonal boxes of the solvent pair of i,i in the solvent miscibility tables (see Tables II and III). The "form space" of the pure-solvent systems for our initial solvent screening was limited to the number of good pure solvents (i.e., indicated by the yellow boxes in Tables II and III) for each API. Therefore, the form space for acetaminophen and racemic (±)-ibuprofen was 15 and 22 respectively (see Tables II and III). If the good co-solvent systems (i.e., the binary mixtures of good solvents) were taken into account, however, the form space of the good cosolvent systems was extended to the number of blue boxes in the solvent miscibility table divided by 2 (see Tables II and III). Therefore, the form space under these particular conditions for acetaminophen and racemic (±)-ibuprofen was 102 and 224 respectively (see Tables II and III).
Table IV: Form space of acetaminophen and racemic (Â±)-ibuprofen.
In addition, if the antisolvent systems (i.e., binary mixtures of a good and a bad solvent) also were considered, the form space of the antisolvent systems was calculated as the number of green boxes in the solvent miscibility table divided by 2 (see Tables II and III). The form space under these circumstances for acetaminophen and ibuprofen was 105 and 11, respectively (see Tables II and III) and the total form space for acetaminophen and racemic (±)-ibuprofen should then be at least equal to 222 and 257, respectively (see Table IV).
Figure 5: Solubility spectrum of racemic (Â±)-ibuprofen.
The total form space should expand dramatically if various solvent compositions of binary mixtures, temperatures, and ternary solvent systems are taken into account (23). Solid generation by temperature cooling can be applied in the yellow and blue regions in the solvent miscibility table (see Tables II and III). Nonetheless, a constant temperature must be maintained if solid generation was achieved by the addition of an antisolvent in the green domain (see Tables II and III). In general, no attempts are made for solid generation in the regions of immiscible solvent pairs (gray boxes), bad solvents (orange boxes), and cosolvents of bad solvents (i.e., binary mixtures of any two bad solvents) in the solvent miscibility table (see Tables II and III). In addition, references of other miscible solvent pairs from organic solvents other than the 23 kinds of solvent listed in Tables II and III are available in the literature (48, 49).
Figure 6: Differential scanning calorimetry thermogram of a typical sample of acetaminophen.
Out of the 15 good solvents, acetaminophen solids were generated in only 14 of them. N,N-dimethylformamide was so good a solvent that acetaminophen was unable to crystallize out by temperature cooling. All 14 isolated white solids were analyzed by DSC, resulting in a sharp endotherm at ~171 °C, which is the melting point of Form I crystals (see Figure 6) (37). This result clearly verified that acetaminophen powders solidified from all 14 solvents were the thermodynamically stable Form I crystals at 25 °C. As for the racemic (±)-ibuprofen, the white powders could only be generated from 18 out of the 22 good solvents. Racemic (±)-ibuprofen supersaturated solutions of acetone, benzyl alcohol, dimethyl sulfoxide, and xylene were unable to produce solids by temperature cooling. Nonetheless, the 18 isolated solid samples showed a typical endotherm around the solid–liquid melting point of 77 °C (see Figure 7) (30, 32). Apparently, there was no new polymorph and the fact that the racemic (±)-ibuprofen is isomorphic once again was verified (18).
Crystallinity of all crystals harvested from solvent screening was approximated by (50):
Table V: Crystallinity of acetaminophen and racemic (Â±)-ibuprofen formed from various solvents.
All of the DSC endotherms (melting peaks) for acetaminophen crystals produced from 12 different solvents were compared with the DSC endotherm for acetaminophen crystals grown from ethyl acetate, with the highest heat of melting of 188.84 J/g. On the other hand, all of the DSC endotherms for racemic (±)-ibuprofen crystals produced from the 17 solvents were referred to the DSC endotherm of racemic (±)-ibuprofen crystals grown from DMF, with the highest heat of melting of 217.35 J/g as a standard (see Table V). DSC was selected on a regular basis rather than powder X-ray diffraction (PXRD) for the crystallinity characterization because DSC required less amount of sample, the peak intensity of PXRD was more susceptible to sample preparation, and the orientation effect. And yet, a couple of samples were cross-checked using PXRD, and the diffraction intensity exceeded 1000 on the average for acetaminophen crystals and 500 for most of the ibuprofen crystals.
Figure 7: Differential scanning calorimetry thermogram of a typical sample of racemic (Â±)-ibuprofen.
No specific correlation between the dielectric constants of solvents and crystallinity was observed. The relatively low crystallinity of racemic (±)-ibuprofen could be attributed to the chiral nature of the molecule itself. Although racemic (±)-ibuprofen was a racemic compound, three types of hydrogen-bonded dimer might coexist in the solution: two composed of the same enantiomers of R-R and S-S and the racemate of R-S (51). When they were adsorbed onto the growing  close-packed face, the enantiomeric dimers might have incorporated with the racemate in the crystal lattice because dimers were particularly not labile. Lattice strain might have been induced. Nonetheless, in a polar solvent of DMA, racemic (±)-ibuprofen existed predominantly as more mobile monomers, thereby facilitating the normal growth of the racemate (51)
The crystal habit and shape factor of particle length to breath of acetaminophen and racemic (±)-ibuprofen crystals produced from pure solvents are illustrated in Figures 8–10 (52). For acetaminophen, solvents such as benzyl alcohol, n-butyl alcohol, and water tended to give platy crystals (see Figure 8). Solvents such as acetonitrile, 1,4-dioxane, isopropyl alcohol, methanol, MEK, and tetrahydrofuran gave prismatic, parallelepiped crystals. Solvents such as acetone, dimethyl sulfoxide, and ethyl acetate produced relatively small-sized crystals. Shape factors of all crystals ranged from 1.06 to 2.38, except for those grown in nitrobenzene (see Figure 9). Intriguingly, they were needle-shaped, with a shape factor of 7.17, and yet they were Form I crystals based on DSC results.
Figure 9: Optical micrographs of needle-shaped acetaminophen crystals with a shape factor of 7.17 grown in nitrobenzene (scale bar = 1 mm) by cooling.
Although needle-shaped acetaminophen crystals are usually associated with Form II crystals (42), as reminded by this important case, the definitive way for doing polymorph screening ought to be coupled with spectroscopy, X-ray diffraction, or thermal analysis. One cannot rely on the crystal morphology taken by microscopy alone (53). For racemic (±)-ibuprofen, all crystals were elongated, thin hexagonal plates (see Figure 10). Agglomeration was commonplace. The shape factors of crystals were ranged from 1.6 to 6.5.
Figure 10: Optical micrographs of crystal habit of racemic (Â±)-ibuprofen grown in various solvents by cooling with various shape factors (in square brackets) (scale bar = 200 Âµm): (a) acetonitrile [2.5], (b) benzene [5.0], (c) n-butyl alcohol [2.0], (d) chloroform [2.2], (e) N,N-dimethylaniline [4.0], (f) N,N-dimethylformamide [1.6], (g) dimethyl sulfoxide [6.5], (h) 1,4-dioxane [3.6], (i) ethanol [2.9], (j) ethyl acetate [3.3], (k) n-heptane [4.3], (l) isopropyl alcohol [2.3], (m) methanol [3.1], (n) methyl tert-butyl ether [4.3], (o) methyl ethyl ketone [3.1], (p) tetrahydrofuran [2.6], (q) toluene [4.5], and (r) p-xylene [5.3].
Noticeably, small-sized crystals and agglomerates were usually formed in solvents whose solubility curves had a relatively steep slope, such as the cases of acetaminophen in DMSO and racemic (±)-ibuprofen in most of the solvents. This result was attributed to the fact that the degree of supersaturation could be increased drastically with a small drop of temperature during cooling, which would in turn increase the rate of nucleation. Besides this thermodynamic effect, other kinetic effects from solvent-crystal surface interactions (20, 51, 54), inhibiting a specific surface growth also could play a key role in the morphogenesis of crystals as suggested by the cases of:
The success of a large-scale preparation of fine chemicals and the manufacture of pharmaceuticals in particular depends heavily on the full knowledge of solubility, polymorphism, crystal habit, and crystallinity of solid compounds and of the active pharmaceutical ingredients. The initial solvent screening strategy coupled with crystallization by temperature cooling in 20-mL scintillation vials and solid characterization by differntial scanning calorimetry and optical microscopy provided a general method of using miniaturized tools on a routine basis to predict an API's performance, maximizing the screens from a minimum quantity of drug product, and providing a data bank of very insightful and informative material properties for process chemistry and process development work. The strategy closely simulates scale-up conditions and is easy to implement in the laboratory. In principal, the initial solvent screening strategy can be readily extended to and integrated with the food, explosives, optoelectronics, agricultural, and ceramics industries.
This work was supported by a grant from the National Science Council of Taiwan, R.O.C. (NSC 93-2119-M-008-030 and NSC 94-2119-M-008-001). Suggestions from Ms. Jui-Mei Huang in DSC at National Central University Precision Instrument Center and High Valued Instrument Center are gratefully acknowledged.
Tu Lee, PhD, is an assistant professor at the Department of Chemical and Materials Engineering and Institute of Materials Science and Engineering, National Central University, 300 Jhong-Da Rd, Jhong-Li City 320, Taiwan, R.O.C. tel. +886 3 422 7151, ext. 34204, fax +886 3 425 2296, firstname.lastname@example.orgChung Shin Kuo and Ying Hsiu Chen are graduate students at the Department of Chemical and Materials Engineering, National Central University.
Submitted: June 13, 2006. Accepted: July 19, 2006.
Keywords: active ingredients, material characterization, scale-up
1. E. Tedesco, D. Giron, and S. Pfeffer, "Crystal Structure Elucidation and Morphology Study of Pharmaceuticals in Development," Cryst. Eng. Comm. 4 (67), 393–400 (2002).
2. N. Blagden and R.J. Davey, "Review: Polymorph Selection—Challenges for the Future?" Cryst. Growth Des. 3 (6), 873–885 (2003).
3. D. Winn and M.F. Doherty, "Modeling Crystal Shapes of Organic Materials Grown from Solution," AIChE J. 46 (7), 1348–1367 (2000).
4. A. Gracin and A.C. Rasmuson, "Solubility of Phenylacetic Acid, p-Hydroxyphenylacetic Acid, p-Aminophenylacetic Acid, p-Hydroxybenzoic Acid, and Ibuprofen in Pure Solvents," J. Chem. Eng. Data 47 (6), 1379–1383 (2002).
5. V. Elango et al., "Method for Producing Ibuprofen," US Patent 4,981,995 (1991).
6. E.G. Zey et al., "Method for Purification of Ibuprofen Comprising Mixtures," US Patent 5,151,551 (1992).
7. J.R. Fritch et al., "Production of Acetaminophen," US Patent 5,155,273 (1992).
8. W.L. McCabe, J.C. Smith, and P. Harriott, Unit Operations of Chemical Engineering (McGraw Hill Co., New York, NY, 6th ed., 2001), p. 1017.
9. Handbook of Pharmaceutical Granulation Technology, D.M. Parikh, Ed. (Marcel Dekker, Inc., New York, NY, 1997).
10. Polymorphism in Pharmaceutical Solids, H.G. Brittain, Ed. (Marcel Dekker, Inc.: New York, 1999).
11. N. Rasenack and B.W. Müller, "Properties of Ibuprofen Crystallized Under Various Conditions: A Comparative Study," Drug Dev. Ind. Pharm. 28 (9) 1077–1089 (2002).
12. B.C. Hancock et al., "Comparison of the Mechanical Properties of the Crystalline and Amorphous Forms of a Drug Substance," Int. J. Pharm. 241 (1), 73–85 (2002).
13. S.J. Byard et al., "Studies on the Crystallinity of a Pharmaceutical Development Drug Substance," J. Pharm. Sci. 94 (6), 1321–1335 (2005).
14. H. Egawa et al., "Solubility Parameter and Dissolution Behavior of Cefalexin Powders with Different Crystallinity," Chem. Pharm. Bull. 40 (3), 819–820 (1992).
15. J.W. McGinity, P. Maincent, and H. Steinfink, "Crystallinity and Dissolution Rate of Tolbutamide Solid Dispersions Prepared by the Melt Method," J. Pharm. Sci. 73 (1), 1441–1444 (1984).
16. V. Labhasetwar, S.V. Deshmukh, and A.K. Dorle, "Studies on Some Crystalline Forms of Ibuprofen," Drug Dev. Ind. Pharm. 19 (6), 631–641 (1993).
17. P.D. Martino et al., "Influence of Crystal Habit on the Compression and the Densification Mechanism of Ibuprofen," J. Crys. Growth 243 (2), 345–355 (2002).
18. N. Rasenack and B.W. Müller, "Crystal Habit and Tableting Behavior," Int. J. Pharm. 244 (1–2), 45–57 (2002).
19. T. Lee and J. Lee, "Particle Attrition by Particle-Surface Friction in Dryers," Pharm. Technol. 27 (5), 64–72 (2003).
20. M. Lahav and L. Leiserowitz, "A Stereochemical Approach that Demonstrates the Effect of Solvent on the Growth of Polar Crystals: A Perspective," Crys. Growth Des. 6 (3), 619–624 (2003).
21. C.H. Gu, V. Young Jr., and D.J.W. Grant, "Polymorph Screening: Influence of Solvents on the Rate of Solvent-Mediated Polymorphic Transformation," J. Pharm. Sci. 90 (11), 1878–1890 (2001).
22. N. Rasenack and B.W. Müller, "Ibuprofen Crystals with Optimized Properties," Int. J. Pharm. 245 (1–2), 9–24 (2002).
23. M.L. Peterson et al., "Interactive High-Throughput Polymorphism Studies on Acetaminophen and an Experimentally Derived Structure for Form III," J. Am. Chem. Soc. 124 (37), 10958–10959 (2002).
24. M. Lang, A.L. Grzesiak, and A.J. Matzger, "The Use of Polymer Heteronuclei for Crystalline Polymorph Selection," J. Am. Chem. Soc. 124 (50), 14834–14835 (2002).
25. A.Y. Lee et al., "Crystallization on Confined Engineered Surfaces: A Method to Control Crystal Size and Generate Different Polymorphs," J. Am. Chem. Soc. 127 (43), 14982–14983 (2005).
26. N.G. Anderson, Practical Process Research & Development (Academic Press, New York, NY, 2000), pp. 81–111.
27. W. Beckman, "Seeding the Desired Polymorph: Background, Possibilities, Limitations, and Case Studies," Org. Proc. Res. Dev. 4 (5), 372–383 (2000).
28. L. Yu, S.M. Reutzel, and G.A. Stephenson, "Physical Characterization of Polymorphic Drugs: an Integrated Characterization Strategy," PSTT 1 (3), 118–127 (1998).
29. H. Cano, N. Gabas, and J.P. Canselier, "Experimental Study on the Ibuprofen Crystal Growth Morphology in Solution," J. Cryst. Growth 224 (3–4), 335–341 (2004).
30. L.C. Garzón and F. Martínez, "Temperature Dependence of Solubility for Ibuprofen in Some Organic and Aqueous Solvents," J. Sol. Chem. 33 (11), 1379–1395 (2004).
31. A.J. Romero, L. Savastano, and C.T. Rhodes, "Monitoring Crystal Modifications in Systems Containing Ibuprofen," Int. J. Pharm. 1993, 99 (2–3), 125–134.
32. A.J. Romeo and C.T. Rhodes, "Approaches to Stereospecific Preformulation of Ibuprofen," Drug Dev. Ind. Pharm. 17 (5), 777–792 (1991).
33. K. Skankland et al., "Structure Solution of Ibuprofen from Powder Diffraction Data by the Application of a Generic Algorithm Combined with Prior Conformational Analysis," Int. J. Pharm. 165 (1), 117–126 (1998).
34. G.L. Perlovich et al., "Thermodynamics of Sublimation, Crystal Lattice Energies, and Crystal Structures of Racemates and Enantiomers: (+)- and (±)- Ibuprofen," J. Pharm. Sci. 93 (3), 654–666 (2004).
35. A.H. Nada, S.M. Al-Saidan, and B.W. Mueller, "Improving the Physical and Chemical Properties of Ibuprofen," Pharm. Technol. 29 (11), 90–101 (2005).
36. F. Giordano et al., "Thermal Behavior of Paracetamol-Polymeric Excipients Mixtures," J. Therm. Anal. Calor. 68 (2), 575–590 (2002).
37. S-L. Wang, S-Y Lin, and Y-S Wei, "Transformation of Metastable Forms of Acetaminophen Studied by Thermal Fourier Transform Infrared (FT-IR) Microspectroscopy," Chem. Pharm. Bull. 50 (2), 153–156 (2002).
38. N. Al-Zoubi, J.E. Koundourellis, and S. Malamataris, "FT-IR and Raman Spectroscopic Methods for Identification and Qualification of Orthorhombic and Monoclinic Paracetamol in Powder Mixes," J. Pharm. Biomed. Anal. 29 (3), 459–467 (2002).
39. M. Szelagiewicz et al., "In Situ Characterization of Polymorphic Forms, The Potential of Raman Techniques," J. Therm. Anal. Calor. 57 (1), 23-43 (1999).
40. P. Espeau et al., "Polymorphism of Paracetamol: Relative Stabilities of the Monoclinic and Orthorhombic Phases Inferred from Topological Pressure-Temperature and Temperature-Volume Phase Diagrams," J. Pharm. Sci. 94 (3), 524–539 (2005).
41. P.D. Martino et al., "Preparation and Physical Characterization of Forms II and III of Paracetamol," J. Therm. Anal. Calor. 48 (3), 447–458 (1997).
42. G. Nichols and C.S. Frampton, "Physiochemical Characterization of the Orthorhombic Polymorph of Paracetamol Crystallized from Solution," J. Pharm. Sci. 87 (6), 684–693 (1998).
43. M.L. Peterson et al., "Crystallization and Transformation of Acetaminophen Trihydrate," Cryst. Growth Des. 3 (5), 761–765 (2003).
44. R.I. Ristic et al., "Macro- and Micromorphology of Monoclinic Paracetamol Grown from Pure Aqueous Solution," J. Phys. Chem. B. 105 (38), 9057–9066 (2001).
45. R.A. Granberg and A.C. Rasmuson, "Solubility of Paracetamol in Pure Solvents," J. Chem. Eng. Data 44 (6), 1391–1395 (1999).
46. J.W. Mullin, "Solutions and Solubility," in Crystallization (Butterworth Heinemann, UK, 3d ed., 1992), pp. 93–94.
47. D.J.W. Grant and T. Higuchi, "Solubility, Intermolecular Forces, and Thermodynamics," in Techniques of Chemistry Volume XXI: Solubility Behavior of Organic Compounds (John Wiley & Sons, New York, NY, 1990), pp. 62–82.
48. J.S. Drury, "Miscibility of Organic Solvent Pairs," Ind. Eng. Chem. 44 (11), 2744 (1952).
49. W.M. Jackson and J.S. Drury, "Miscibility of Organic Solvent Pairs," Ind. Eng. Chem. 51 (12), 1491–1493 (1959).
50. P.J. Haines, "Differential Thermal Analysis and Differential Scanning Calorimetry" in Thermal Methods of Analysis: Principles, Applications and Problems (Blackie Academic & Professional, New York, NY, 1995), p. 89.
51. J.M.E. Bunyan, N. Shankland, and D.B. Sheen, "Solvent Effects on the Morphology of Ibuprofen," AIChE Symposium Series 284 (87), 44–54 (1991).
52. P.W.S. Heng and L.W. Chan, "Drug Substance and Excipient Characterization" in Handbook of Pharmaceutical Granulation Technology, D.M. Parikh, Ed. (Marcel Dekker, Inc., New York, NY, 1997), p. 28.
53. M. Lang, A.L. Grzesiak, and A.J. Matzger, "The Use of Polymer Heteronuclei for Crystalline Polymorph Selection," J. Am. Chem. Soc. 124 (50), 14834–14835 (2002).
54. T. Beyer, G.M. Day, and S.L. Price "The Prediction, Morphology, and Mechanical Properties of the Polymorphs of Paracetamol," J. Am. Chem. Soc. 123 (21), 5086–5094 (2001).