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Hsiang Yu Hsieh is a graduate student at National Central University, 300 Jhong-Da Rd., Jhong-Li City 320, Taiwan, ROC.
Yan Chan Su is a graduate student at National Central University, 300 Jhong-Da Rd., Jhong-Li City 320, Taiwan, ROC.
Hung Ju Hou is a graduate student at National Central University, 300 Jhong-Da Rd., Jhong-Li City 320, Taiwan, ROC.
The authors describe the importance of a rapid and an abbreviated screening strategy in initial solvent screening. This article contains bonus online-exclusive material.
In Part 1 of this article, which appeared in the May 2009 issue of Pharmaceutical Technology, the authors described characterization methods for the functional properties and the process-dependent polymorphic flow charts of the three soft pharmaceutical materials: carbamazepine, cimetidine, and phenylbutazone. This part presents several indispensable processing properties (i.e., solubility, polymorphism, crystallinity, and crystal habit) of those three active pharmaceutical ingredients. The underlying principles can be easily extended to other nonconventional sytems such as metal–organic framework materials, infinite coordination polymer particles, and cocrystals.
NICHOLAS RIGG/GETTY IMAGES
Results and discussion
Use tests. The differential scanning calorimetry (DSC) use-test scan of carbamazepine in Figure 1 exhibited the first endothermic peak at 170–174 °C, which corresponded to the melting of Form III, followed immediately by an exothermic peak at 175 °C, which corresponded to the crystallization of Form I, and a second endothermic peak at 193 °C, which corresponded to the melting of Form I (1). The DSC use-test thermogram of phenylbutazone in Figure 2 displayed a single endothermic peak around 105 °C, which corresponded to the melting of Form A (2). Thus, the polymorphisms of carbamazepine and phenylbutazone were Form III and Form A, respectively, at room temperature. The use test for cimetidine was performed by Fourier transform infrared spectroscopy (FTIR) because the melting points of the different forms of cimetidine are close to each other (3).
Figure 1: Differential scanning calorimetry scan of the carbamazepine. (ALL FIGURES ARE COURTESY OF THE AUTHORS)
The FTIR spectrum in Figure 3 showed four significant infrared peaks for Form A cimetidine at 1204, 1156, 1077, and 954 cm-1 and two well-resolved characteristic peaks at 1243 and 1228 cm-1 (4–5). Therefore, the polymorphism of cimetidine at room temperature was Form A. The cimetidine molecule has three hydrogen-donor centers (i.e., N1H, N10H, and N13H) and three hydrogen acceptor centers (i.e., N3, N12, and N17) (see Figure 4) (6). Two cimetidine molecules formed a dimer unit in Form A with an eight-member ring through the hydrogen bonds between N10H of one molecule and N12 of the other. The cimetidine molecule absorbed water at the N1H group (6). Cimetidine was weakly basic, and its reported pKa values were 6.80 and 6.93. The imidazolium peaks were 1204 and 954 cm-1 (6). The peak at 1077 cm-1 was attributed to a CH deformation and a ring deformation (6, 7). The peak at 1156 cm-1 could either be a coupled ring and a CH bending mode or the deprotonation of the N1H group on the complexation with a water molecule (6, 7). Two imidazole tautomers coexisted in the cimetidine structure: one with a hydrogen atom bound to the N1 atom and the other with the hydrogen atom bound to the N3 atom (see Figure 4). However, only the N1-H form was present in the crystal states of cimetidine and its monohydrates. In the solution, cimetidine also assumed two staggered (E, Z) configurations of the cyanoguanidine group (8).
Figure 2: Differential scanning calorimetry scan of the phenylbutazone.
Form spaces. To construct the form space for an active pharmaceutical ingredient (API), which contains the possible solvent combinations for discovering a new polymorph, 19 common solvents for scale-up were first arranged vertically and horizontally in ascending order of the solvent's Hildebrand value. This arrangement resulted in a 19 x 19 matrix of 361 boxes (see Tables I–III). Each box represented a specific binary-solvent combination, except for the 19 boxes descending diagonally from the upper left corner to the lower right corner. These 19 boxes represented the 19 pure solvent systems. The yellow boxes were the good solvents, and the red boxes the bad solvents, with respect to a particular API. The yellow and red boxes were the material properties of an API. Besides the red and yellow boxes, the gray boxes were also determined experimentally. They represented the immiscible solvent pairs that were independent from the nature of an API. Once the locations of the red, yellow, and gray boxes were fixed, the location of the green, blue, and white boxes representing the antisolvent system (i.e., a good solvent and a bad solvent), the good cosolvent system (i.e., a good solvent and a good solvent), and the bad cosolvent system (i.e., a bad solvent and a bad solvent), respectively, could be deduced graphically. Since the 19 x 19 matrix was symmetrical along the diagonal boxes, the actual possible solvent combinations were reduced from 361 boxes to a total of 19 + (361 – 19) ÷ = 190 boxes or fewer because it is normally impractical to perform experiments in the white-boxed areas.
Figure 3: Fourier transform infrared spectrum of the cimetidine.
The form space of carbamazepine had 13 yellow, 6 red, 69 green, 78 blue, 14 gray, and 10 white boxes (see Table I); the form space of cimetidine had 5 yellow, 14 red, 66 green, 10 blue, 14 gray, and 81 white boxes (see Table II); and the form space of phenylbutazone had 17 yellow, 2 red, 22 green, 135 blue, 14 gray, and 0 white boxes (see Table III). The actual form spaces would have been significantly bigger if various solvent compositions of binary mixtures,temperatures, and ternary solvent systems had been considered (9–11).
Solubility studies. When the locations of the 19 solvents were assigned within the 3-D Hansen plot of a dispersion-force component (δd), a polar component (δp), and a hydrogen-bonding component (δh) by their corresponding coordinates (δd, δp, and δh) and all the good solvents and bad solvents were represented by yellow and red, respectively, based on the colors of the diagonal boxes in the form space of a given API, a cluster of yellow domains was formed. The contour of these yellow domains outlined a 3-D volume of solubility in space that excluded all the bad solvents by a solubility sphere with center coordinates (δd, API, δp, API, δh, API) and an interaction radius (RS–API) (12). For the solubility sphere of Form III carbamazepine at 25 °C, δd, API = 21.4 MPa1/2 , δp, API = 17.2 MPa1/2 , δh, API = 13.1 MPa1/2 , and RS–API = 17.6 MPa1/2 . For the solubility sphere of Form A cimetidine at 25°C, δd, API = 26.3 MPa1/2 , δp, API = 17 MPa1/2 , δh, API = 23.8 MPa1/2 , and RS–API = 24.8 MPa1/2 . Finally, for the solubility sphere of Form A phenylbutazone at 25°C, δd, API = 15 MPa1/2 , δp, API = 10 MPa1/2 , δh, API = 10 MPa1/2 , and RS–API = 12.7 MPa1/2 , whose center coordinates (δd, API, δp, API, δh, API) were close to the reported values of 17.5, 12.5, and 10.7 MPa1/2 , respectively, measured by dissolution calorimetry (13).
Table I: Solvent systems of carbamazepine.
With the solubility sphere of an API at hand, the solubility power of any new solvent other than the 19 solvents used with known values of δd, δp, and δh can be predicted instantly. If the coordinates of a new solvent (δd, δp, δh) are located inside the solubility sphere of an API, it is a good solvent with respect to that API. Otherwise, it is deemed a bad solvent. To verify the validity of the solubility sphere, each sphere of an API was tested with n-propanol (δd = 16 MPa1/2 , δp = 6.8 MPa1/2 , δh = 17.4 MPa1/2 ) and cyclohexane (δd = 16.8 MPa1/2 , δp = 0 MPa1/2 , δh = 0.2 MPa1/2 ). Calculations showed n-propanol to be located inside the Form III carbamazepine's solubility sphere (because D S - API = 17.4 MPa1/2 for n-propanol < R S - API = 17.6 MPa1/2 for Form III cambamazepine), inside the Form A cimetidine's solubility sphere (because D S - API = 23.8 MPa1/2 for n-propanol < R S - API = 24.8 MPa1/2 for Form A cimetidine), and inside the Form A phenylbutazone's solubility sphere (because D S - API = 8.30 MPa1/2 for n-propanol < R S - API = 12.65 MPa1/2 for Form A phenylbutazone). These calculations agreed well with the experimental observations that n-propanol was a good solvent at 25 °C for Form III carbamazepine (solubility = 14.18 mg/mL), for Form A cimetidine (solubility = 13.7 mg/mL) and for Form A phenylbutazone (solubility = 31.46 mg/mL).
Table II: Solvent systems of cimetidine.
However, cyclohexane was calculated to be situated outside the Form III carbamazepine's solubility sphere (because D S - API = 23.8 MPa1/2 for cyclohexane > R S - API = 17.6 MPa1/2 for Form III cambamazepine), outside the Form A cimetidine's solubility sphere (because D S - API = 34.7 MPa1/2 for cyclohexane > R S - API = 24.8 MPa1/2 for Form A cimetidine), and outside the Form A phenylbutazone's solubility sphere (because D S - API = 15.74 MPa1/2 for cyclohexane > R S - API = 12.65 MPa1/2 for Form A phenylbutazone) (12). Once again, the experimental results supported the calculations that cyclohexane was a bad solvent at 25 °C for all three APIs with a solubility of < 1 mg/mL.
Table III: Solvent systems of phenylbutazone.
Most of the good solvents of Form III carbamazepine belonged to Class 1 protic or hydrogen-bond donating solvents (i.e., Lewis acids), Class 2 hydrogen-bonding acceptor solvents (i.e., Lewis bases), and Class 3 polar aprotic solvents, which disrupted the N-H···O hydrogen bonds and the C-H···O weak interactions of the carboxamide dimer units existing in the solid state of all forms of carbamazepine (1, 14). The good solvents for Form A cimetidine were mainly Class 1 solvents that interacted readily with the weakly basic imidazole ring and disrupted the N-H···N hydrogen bonds of the dimer units existing in the solid state of Form A cimetidine (6, 8, 14). Finally, the good solvents for Form A phenylbutazone were Classes 1 to 3 solvents, Class 4 chlorocarbon solvents, and Class 5 hydrocarbon solvents. This result implied that the intermolecular interactions in the crystal lattice of phenylbutazone were dominated by van der Waals forces (dipole–dipole interactions and London dispersion force) (15).
Figure 5: Solubility curves of Form III carbamazepine in 13 solvents.
Figure 6: Solubility curves of Form A cimetidine in five solvents.
The solubility curves of Form III carbamazepine in 13 single good solvents, Form A cimetidine in five single good solvents, and Form A phenylbutazone in 17 single good solvents are shown in Figures 5, 6, and 7, respectively. The solubility of all three APIs in different solvents increased with temperature. The enthalpy of dissolution (ΔHd) and the entropy of dissolution (ΔSd) of an API in a particular good solvent could be approximated from the slope and the y-intercept of a straight line, respectively, when the solubility curve of the API in that particular good solvent was replotted in the form of the van 't Hoff equation (16).
Figure 7: Solubility curves of Form A phenylbutazone in 17 solvents.
Solids characterizations. All API solids generated from the saturated solutions of their corresponding good solvents by temperature cooling were isolated and analyzed with optical microscopy, DSC, thermogravimetric analysis (TGA), and FTIR. Optical micrographs of carbamazepine, cimetidine, and phenylbutazone solids are illustrated in Figures 8, 9, and 10, respectively. The crystal habits, the aspect ratios, the polymorphism, and the crystallinity of carbamazepine, cimetidine, and phenylbutazone solids grown from the 13 good solvents are summarized in Table IV.
Most of the carbamazepine solids exhibited the typical DSC thermograms for Form III and Form I crystals, respectively. Unlike Form III carbamazepine crystals, Form I crystals showed no transformation and only one sharp melting endotherm at 190 °C (17). A carbamazepine acetone solvate produced in acetone agreed with this observation (18). The TGA scan (see Figure 11) further showed that the carbamazepine acetone solvate had a 1:1 stoichiometric ratio and the DSC curve (see Figure 11) demonstrated the removal of acetone from the solvate at 50–88 °C and a phase change of the material to Form I with a melting endotherm at 190 °C (17, 19).
In contrast with the previous observations that solvents with low dielectric constants yielded Form I crystals and those with high dielectric constants yielded Form III crystals, the authors obtained Form I needles not only from solvents such as chloroform and 1,4-dioxane with low dielectric constants, but also from acetonitrile with a high dielectric constant (see Figures 8c, 8g, and 8j) (1, 18, 20, 21). Form III prisms were also harvested from a solvent such as isopropyl alcohol with a low dielectric constant when enough aging time was given for the transformation of Form I to Form III according to Ostwald's Rule of Stages (see Figure 8i). The rest of the good solvents generated the thermodynamically stable Form III prisms (see Figures 8a, 8b, 8d, 8e, 8f, 8h, 8k, 8l, and 8m) (1, 20, 21). Isopropyl alcohol tended to give a mixture of needled and prismatic carbamazepine solids (see Figure 8i). The interplay between thermodynamics and kinetics made concomitant crystallization possible (22). The DSC curves of the physically isolated needles and prisms by a pair of tweezers were resolved to Form I (see Figure 1) and Form III crystals, respectively.
Table IV: Crystal habits, aspect ratios, polymorphism, and crystallinity of solids of carbamazepine, cimetidine, and phenylbutazone generated from their corresponding good solvents.
Apparently, the needle or prism crystal habit of carbamazepine was affected only by polymorphism and not by microscopic properties such as the Hansen parameters and the dielectric constants of the solvents. The dominant factor that influenced the crystallization outcomes could have been the degree of supersaturation imposed by temperature cooling, which placed the crystallization under either kinetic or thermodynamic control (22). This inference was supported by the feasibility of a one-solvent polymorph screen of carbamazepine and the appearance of the metastable Form I carbamazepine from a high degree of supersaturation, either by a sudden drop of the solubility through the introduction of an antisolvent or by cooling the system with a relatively steep solubility curve such as chloroform and acetonitrile (see Figure 5) (11). The drive for structures that could be formed more quickly than others might override the drive for settling with structures of the maximum decrease in energy. However, this speed seldom affected the crystallinity, as was seen by the relatively high percent crystallinity of Form I carbamazepine crystals.
Figure 11: Differential scanning calorimetry and thermogravimetric analysis scans of 1:1 carbamazepine acetone solvate made from acetone.
The cimetidine solids showed the two typical FTIR spectra in Figure 3 and Figure 13 as Form A and Form B crystals. The FTIR spectrum in Figure 13 displayed the six characteristic infrared peaks for Form B cimetidine at 1375, 1230, 1192, 1184, 1176, and 1066 cm-1 (4, 23). The thermodynamically Form A cimetidine was formed in Class 1 solvents such as n-butyl alcohol and in isopropyl alcohol as rods (see Figures 9a and 9b) (3). Isopropyl alcohol yielded Form A cimetidine (3). However, the steep slope for the solubility curves of Form A cimetidine in solvents of Classes 1 and 2 such as N,N-dimethylformamide, methanol, and ethanol produced metastable Form B cimetidine needled crystals (see Figures 9c, 9d, and 9e) without the need of adding and seeding crystals because of the high degree of supersaturation created by temperature cooling (see Figure 6) (3). Apparently, the crystal habits for Forms A and B cimetidine depended on the solvents and the polymorphs, respectively.
Figure 12: Differential scanning calorimetry thermogram of Form I carbamazepine crystals grown from chloroform.
Almost all of the phenylbutazone solids exhibited the typical DSC scan in Figure 2 for Form A long-needled crystals (see Figures 10a–k and 10m–q). However, the phenylbutazone solids grown from n-butyl alcohol could be a newly discovered Form F (see Figure 10l) because its DSC thermogram in Figure 14 showed two endothermic peaks at 85 and 103 °C, and its TGA scan showed no weight loss at 85 °C. Therefore, the first and second endothermic peaks corresponded to the heat of transformation from Form F to Form A and the melting of Form A, respectively. Despite the many forms of phenylbutazone, phenylbutazone revealed only the ketoform in all polymorphs (24). Furthermore, two solvates were produced. Rather than a phenylbutazone solvate to tetrahydrofuran ratio of 2:1, a ratio of 3:1 (see Figure 10h) was obtained when the isolated solids crystallized from tetrahydrofuran were oven dried at 40 °C for 9 h instead of the crystal surface being blotted with filter paper (15). DSC and TGA thermograms in Figure 15 showed the desolvation endotherm from 70 to 90 °C and the sharp melting of Form A phenylbutazone at 103 °C under a heating rate of 8 °C/min. However, the stoichiometric ratio of 2:1 of phenylbutazone solvate with 1,4-dioxane (see Figure 10k) oven dried at 40 °C for 9 h remained the same as that prepared by blotting the crystal surface with filter paper (15). DSC and TGA thermograms in Figure 16 illustrate the desolvation endotherm from 80 to 84 °C and the sharp melting of Form A phenylbutazone at 103 °C under a heating rate of 8 °C/min (15).
Figure 13: Fourier transform infrared spectrum of Form B cimetidine produced from methanol.
Obviously, given the moderate slope of the solubility curve of phenylbutazone Form A in n-butyl alcohol, the degree of supersaturation could not explain the production of Form F in n-butyl alcohol. Since the b-axis of phenylbutazone is > 5.1 Å, it belongs to the a-type structure (24). The molecule is stabilized more uniformly by a larger number of near neighbors (24). The molecular coordination is between 6 and 10. The C-H···O interaction, especially in the n-butyl side chain of phenylbutazone, plays an important role in stabilizing the crystal packing in addition to the stacking of the benzene rings (24). The authors hypothesized that the similar molecular structures of n-butyl alcohol and the n-butyl side chain of phenylbutazone and the interference of the hydroxyl group of n-butyl alcohol with the C-H···O interaction might have induced the formation of a thermodynamically metastable Form F nucleus and perturbed the crystal lattice order, as reflected by the low crystallinity of 61%. Since needle-shaped crystals were obtained from all good solvents, it seemed that solvents did not play a dominant role in the induction of the habits characteristic of the crystals, but rather the processing conditions and the polymorphism did (24).
Figure 14: Differential scanning calorimetry thermogram of Form F phenylbutazone grown from n-butyl alcohol.
The form space constructed from the common organic solvents by initial solvent screening provided information not only about materials properties such as solubility curves, solubility spheres, crystallinity, crystal habits, and a possible solvent combination for discovering a new polymorph, but also about a systematic way of finding the ideal combination of a good solvent, an antisolvent, and a bridging liquid for solvent-based processes in a miniaturized scale. Initial screening by common laboratory tools could be easily integrated by automation and be applied to other compounds as well.
Figure 15: Differential scanning calorimetry and thermogravimetric-analysis scans of 3:1 phenylbutazone tetrahydrofuran solvate.
This work was supported by a grant from the National Science Council of Taiwan, R.O.C. (NSC 95-2113-M-008-012-MY2). Suggestions about DSC from Jui-Mei Huang, assistant at National Central University's Precision Instrument Center, and about scanning electron microscopy from Ching-Tien Lin, assistant at National Central University's Precision Instrument Center, are gratefully acknowledged.
Figure 16: Differential scanning calorimetry and thermogravimetric-analysis scans of 2:1 phenylbutazone 1,4-dioxane solvate.
Tu Lee* is an associate professor in the Department of Chemical and Materials Engineering and the Institute of Materials Science and Engineering, Yan Chan Su and Hung Ju Hou are graduate students at the Department of Chemical and Materials Engineering, and Hsiang Yu Hsieh is a graduate student at the Institute of Materials Science and Engineering, 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, firstname.lastname@example.org.
*To whom all correspondence should be addressed.
Submitted: July 8, 2008. Accepted: Sept. 15, 2008.
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