HIV Drug

CRYSTAL GROWTH & DESIGN

Polymorphic Behavior and Crystal Habit of an Anti-Viral/HIV Drug: Stavudine Mahmoud

Mirmehrabi†

and Sohrab Rohani*

Department of Chemical and Biochemical Engineering, The UniVersity of Western Ontario, London, Ontario, Canada, N6A 5B9

2006 VOL. 6, NO. 1 141-149

K. S. Keshava Murthy and Bruno Radatus Apotex PharmaChem Inc., 34 Spalding DriVe, Brantford, Ontario, Canada N3T 6B8 ReceiVed June 1, 2005; ReVised Manuscript ReceiVed August 8, 2005

ABSTRACT: Different characterization methods (optical microscopy, Karl Ficher titration (KF), XRPD, and solid-state FTIR) were used to identify the two polymorphs and one hydrate of stavudine. The two forms are monotropically related, and form 1 is the stable polymorph. The effects of solvent, impurities, supersaturation, and mixing on the polymorphic occurrence of stavudine are investigated in detail. Hydrogen bonding analysis is employed to qualitatively predict the role of the solvent and structurally related impurities (thymine and thymidine) on polymorphism and crystal habit of stavudine crystals. The impurities showed significant changes in the crystal habit and crystal bulk density of stavudine but had no influence on the polymorphic structure. Depending on the degree of supersaturation at T ) 25 °C, a specific polymorph or a mixture of forms 1 and 2 was obtained concomitantly. Introduction Stavudine (Zerit) is an anti-viral drug that is used for the treatment of HIV/AIDS.1 The chemical formula of stavudine, 2′,3′-didehydro-3′-deoxythymidine, is C10H12N2O4 with the chemical structure2 depicted in Scheme 1. The stavudine molecule was initially synthesized3 at the Michigan Cancer Foundation in 1966, but Lin and Prusoff4 at Yale University discovered the capability of this molecule in treating HIV/AIDS. Later, Bristol Myers Squibb (BMS) collaborated in developing the molecule for clinical trial and largescale production and obtained the permit for selling this drug. Stavudine has two known polymorphs in which form 1 is the more stable one and form 2 is the metastable polymorph, one hydrate,5 and a few solvates.6,7 The physicochemical properties and thermodynamics of two polymorphs and the hydrate form were studied by Gandhi et al.5 Polymorph 1 of stavudine is the marketed form. The solubility data of stavudine polymorphs 1 and 2 over the temperature range of 23 to 45 °C did not show any crossing, which means that the two polymorphs are monotropically related in the studied temperature range 8. The stavudine molecule is produced from thymidine, which has a structure similar to stavudine. Before crystallization, a series of reactions take place to obtain stavudine6,9. Thus, the crystallization medium contains impurities of thymine, thymidine, threo-thymidine, 3,5-anhydrothymidine, and 5′-O-[stavudine-5′′′-y1]-threo-thymidine.6 Each of these impurities can interact with the stavudine molecule through hydrogen bonding and could lead the molecular arrangement toward a specific crystal structure or polymorph. These impurities can also influence the crystal habit, as they are able to be adsorbed on a particular face of the crystal and inhibit its growth. The reactions and the thymine impurity are shown in Figure 1. In the present work, the characterization methods for identifying the two polymorphs and the hydrate form of stavudine are * To whom correspondence should be addressed. Tel.: 519-661-4116; Fax: 519-661-3498. E-mail: [email protected]. † Present address: Wyeth Pharmaceuticals, Montreal, Canada.

Scheme 1.

Chemical Structure of Stavudine

discussed. XRPD, solid-state FTIR, and optical microscopy were performed. Hydrogen bonding analysis will be used to interpret the polymorphic outcome and crystal habit of stavudine. The effects of supersaturation, agitation rate, and impurity on the polymorphic outcome are also studied experimentally. Experimental Section Materials. Form 1 of stavudine with 99.5 wt % purity, thymine, and thymidine were provided by Apotex PharmaChem Inc. (Brantford, ON). Solvents were purchased from Sigma-Aldrich (Milwaukee, WI). Deionized water was available in our laboratory (CCPL-Western). Preparation of Form 1, Form 2, and Hydrate. Initially, form 1 was dissolved in 2-propanol (IPA) solvent at 50 °C and was cooled to 25 °C with a linear cooling profile at a rate of 0.1 °C/min while agitating the solution to recrystallize the stavudine. The FTIR analyses confirmed that pure form 1 of stavudine was produced. To produce form 2, the stavudine form 1 was dissolved in 2-propanol at 48 °C and cooled to 25 °C in 10 min (approximately linearly) without mixing. The final product was identified as pure form 2 with FTIR. The hydrate form was obtained with the same procedure as form 1, with the exception that the solvent was deionized water instead of 2-propanol. KF and FTIR confirmed the identity of the hydrate form.

Analytical Methods Optical Microscopy, Water Content, and Spectral Characterization. An optical microscope (ZEISS) equipped with a digital camera along with Northern Eclipse image analysis software were used. A Mettler Toledo Karl Fischer DL38 (London, ON) was used to measure the water content of the solution. A Vector 22 solid-state attenuated total reflection

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142 Crystal Growth & Design, Vol. 6, No. 1, 2006

Mirmehrabi et al.

Figure 1. Synthesis route of stavudine and thymine impurity that exist in the crystallization media.

Figure 2. Optical images of three solid forms of stavudine.

Fourier transform infrared spectrometer, ATR-FTIR (Bruker, Milton, ON), was employed for quantification of each form. The samples were analyzed in absorption mode through a zinc selenide crystal. Thirty-two scans with the resolution of 2 cm-1 in the range of 600 to 4000 cm-1 were performed. The background was collected in the same range for air. Approximately 2 to 4 mg of sample was poured on the zinc selenide crystal for each analysis.

X-ray Powder Diffraction. Powder X-ray diffraction (XRPD) was done with Cu KR radiation (λ ) 1.5418 Å) on a DISCOVER D8 diffractometer (Bruker, Germany) with 500 µm beam size and general area diffraction detector system (GADDS). The XRPD data were collected at 40 kV and 40 mA and in the 2θ range of 4 to 90 °. Samples were positioned using a xyz sample stage with video microscope. DIFFRAC plus EVA 7.0 software was employed in data analysis.

Characterization of Stavudine

Crystal Growth & Design, Vol. 6, No. 1, 2006 143 Table 1. Partial Charge of the Atoms Participating in Hydrogen Bonding in Stavudine Molecule

Figure 3. FTIR calibration curve for quantifying the two stavudine polymorphs.

atom

partial charge

atom

partial charge

O(1) O(7) N(8)

-0.288 -0.289 -0.135

N(10) O(14) O(15)

-0.098 -0.230 -0.196

ered as 0.25 wt %, 0.5 wt %, and 1 wt % of the total consumed stavudine in crystallization. For each impurity concentration, the experiments were replicated three times. The supersaturation and crystallization conditions were similar to those in the solvent effects experiments. All the impurity experiments were performed in 2-propanol. 2-Propanol and acetonitrile were used for studying the effect of supersaturation on the polymorphism of stavudine. Supersaturations in the range of S ) 1.7 to 2.5 were employed with the cooling rate of 1 °C/min and nucleation temperature of 25 °C. Two sets of experiments were performed for studying the effect of mixing. In the first set, a stirring rate of 100 rpm was used during the whole process. In the second set, mixing was stopped before cooling the clear solution. Once the temperature reached 25 °C, mixing was resumed at 100 rpm. Results and Discussions

Figure 4. FTIR spectra of forms 1 and 2 in the range of 800 to 1000 cm-1.

Experimental Setup Crystallization was carried out in a 50 mL Bellco jacketed flask (Vinelan, NJ) in which a Neslab RTE digital plus 740 circulating water bath (Portmouth, NH) provided heating and cooling. A Teflon-coated thermocouple was used for reading the temperature (Labcor, Concord, ON). For mixing, a topmounted two-bladed flat electromagnetically driven stirrer was employed. The stirrer blades were Teflon in order to reduce the corrosion and particle breakage. For data monitoring and recording, a National Instrument data acquisition system (Austin, TX) as an interface between the system and the computer and version 6i Labview software (Austin, TX) were employed. Experimental Procedures Effect of Solvent, Impurity, Supersaturation, and Mixing on Polymorphism and Crystal Habit. To study the effect of solvent on polymorphism and crystal habit, a moderate degree of supersaturation was chosen for recrystallization of stavudine at 25 °C. Supersaturation (S) was calculated using the ratio of the activities at supersaturated and saturated solutions. The activity was calculated from the semiempirical activity coefficient (γ) models8 and the experimental solubility data (x). For this set of experiments, the supersaturation was around S ) 1.7, that is, a moderate supersaturation for organic molecules. In mineral systems, this would be a high supersaturation. A constant cooling rate of 1 °C/min was employed for all experiments. Thymine and thymidine were used as two impurities in the crystallization media. The amounts of impurities were consid-

Crystal Habit. All three solid forms (form 1, form 2, and hydrate) are rodlike, but depending on the operating conditions of the crystallization the aspect ratios are different. Figure 2 shows the optical images of the three solid forms. Solid-State FTIR. The IR characteristic peaks of each polymorph were found using a solid-state ATR-FTIR. Form 1 showed unique peaks at 865 and 3425 cm-1. Form 2 exhibited peaks at 975 and 3485 cm-1. The hydrate also showed a peak at 3510 cm-1. These peaks comply with the results reported by Gandhi et al.5 The entire FTIR spectra of three solid forms in the range of 600 to 4000 cm-1 is available on request from the authors. For quantitative analysis of forms 1 and 2, the method suggested by Mirmehrabi et al.10 was used. The precise binary composition (based on weight) were prepared in small HPLC vials and mixed manually with a needle. Since the particle size distribution can affect the absorbance intensity, an inert peak should be chosen as a reference. Forms 1 and 2 show a similar absorbance at 820 and 818 cm-1. The absorbance at either of these wavelengths can be used as the inert peak. The characteristic peak of form 1 at 865 cm-1 was chosen for quantitative analysis. For more detailed information on quantitative analysis the readers are referred to Mirmehrabi et al.10 In the development of the calibration curve, each binary mixture was analyzed three times, and then the average was taken for analysis. The baseline of the FTIR spectra was corrected using the OPUS software (Bruker, Milton, ON). The ratio of the height of the inert peak to the height of the characteristic peak was plotted against the wt % of form 1 in the mixture of the two polymorphs. The result was a line with R2 ) 0.954 that is shown in Figure 3. The repeatability of the data as shown by the small error bars in Figure 3 was good. There was a certain degree of scatter in the calibration curve, which could be attributed, by and large, to the sample preparation. Figure 4 illustrates the FTIR spectra of two polymorphs in the range of 800 to 1000 cm-1. X-ray Powder Diffraction. The XRPD patterns of the two polymorphs and the hydrate over the range of 2θ ) 8° to 24° were obtained. The characteristic peak of form 1 is at 2θ ) 19.1°, the characteristic peaks of form 2 are at 2θ ) 18.6° and


Mirmehrabi et al.

Figure 5. Possible hydrogen bonding between stavudine molecules.

20.2°, and the hydrate has peaks at 2θ ) 15.5° and 22.7°. These data are consistent with the Gandhi et al.5 results. Hydrogen Bonding Analysis of Stavudine Molecule. There are many factors affecting the nucleation of organics at molecular levels. The pioneering work of Weissbuch et al.11 and Anthony et al.12 discuss a host of parameters on the mechanism of nucleation. Among these parameters, the interand intra-hydrogen bonding among solute, solvent, and impurity molecules plays an important role in the polymorphic outcome of the solute.13 Mirmehrabi and Rohani14 developed a novel technique to predict the ability of a molecule to participate in the formation of hydrogen bond either as a donor or an acceptor. The technique is based on the calculation of the partial charge of oxygen and nitrogen atoms existing in the molecule that participates in hydrogen bonding. Their approach agreed well with the rigorous molecular modeling technique based on quantum mechanics.14 Using the method developed by Mirmehrabi and Rohani,14 the partial charge of the hydrogen bonding sites of stavudine are calculated and listed in Table 1. The ability of constituent atoms of stavudine molecule to form hydrogen bonding as a donor or an acceptor, expressed by log(KR) and log(Kβ), respectively, can be calculated by

log(KR) ) 11.294 × PC(N) + 3.0413 ) 1.94 for N(10) log(KR) ) 11.567 × PC(O) + 4.9776 ) 1.64

for O(1)

log(Kβ) ) -13.087 × PC(N) - 0.1202 ) 1.65 for N(8) where PC is the partial charge of the participating atom in forming the hydrogen bond. Note that O(1) and O(7) are quite negative (Table 1) and can accept strong hydrogen bonding.

N(10) is a very strong hydrogen bond donor. A series of possible intermolecular hydrogen bondings are shown in Figure 5. Among these patterns, molecular arrangements III and IV possess the strongest hydrogen bondings and can be present in the crystal structure. The hydrogen bonding between stavudine molecules before and during cluster formation may influence the molecular arrangement toward a specific polymorph. The single-crystal X-ray diffraction8 revealed that the structures IV and V were the predominant hydrogen bonding patterns in the crystal structure of polymorph 1 (Figure 6). Attempts to produce single crystals of form 2 and hydrate failed so that the crystal data were not available for comparison with form 1. Choosing a strong hydrogen bond donor or acceptor solvent for crystallization of stavudine can influence the polymorphism and/or crystal habit. The structurally compatible impurity molecules, such as thymine, may also affect the crystal structure and/or crystal habit. Solvent Effect on Polymorphism of Stavudine The hydrogen bonding ability of stavudine is appreciably high. Therefore, the hydrogen bonding between solvent and stavudine should be stronger or close to the hydrogen bonding between stavudine molecules in order that the solvent could interfere in the cluster formation. Table 2 presents the dipolar properties of a few solvents with the various hydrogen bonding abilities that have been obtained from Mirmehrabi and Rohani.14 Among these solvents, water offers the strongest hydrogen bonding donor capability and dipole-dipole interaction expressed in terms of the polarity index (PI). However, its hydrogen bonding ability is not as strong as between the stavudine molecules (which is larger than 1.64). Water may


Crystal Growth & Design, Vol. 6, No. 1, 2006 145 Table 2. Solvents with Different Hydrogen Bonding Abilitya

a

PI Is the polarity index (please refer to Mirmehrabi and Rohani14 for details).

Figure 6. Observed hydrogen bonding in the crystal structure compatible with patterns IV and V of Figure 5.

establish a type of hydrogen bonding with stavudine, which may lead toward hydrate formation. Using KF, a hydrate with 3:1 stoichiometric ratio of stavudine/water was observed in this study and also reported in the literature.5 However, if the crystallization process were very slow, then the stavudine molecules would have enough time to form a hydrogen bonding pattern and not let the water molecules attach to the stavudine molecules to form a hydrate. This phenomenon was observed in the production of single crystals.8 All of the single crystals that were grown in water turned out to be form 1 and not the hydrate. Single crystals were produced using long-term evaporation of an undersaturated water solution at 25 °C. On the contrary, all of the powders that were produced by cooling crystallization, with water as the solvent, contained water in their lattice. The rest of the chosen solvents can offer weaker hydrogen bonding than the stavudine molecules so that they may not be very effective in polymorphic manipulation. This was confirmed by performing experiments with the chosen solvents. Solvent Effect on Crystal Habit of Stavudine. The angles between faces of the single crystal were found to be 90°, the same as the angles between the unit cells in the orthorhombic system. In general, the growth of a crystal is usually along the smallest unit cell axis. For the stavudine form 1, a is the shortest axis so that the smallest face was indexed as (100) and the two other faces should be (010) and (001) family. Figure 7 shows the functional groups exposed on each plane of the stavudine form 1 crystals. The most important functional groups of stavudine that establish strong hydrogen bonding are exposed on face (100). Thus, crystal growth should be fast along the direction perpendicular to (100) face (along a axis) because

stavudine molecules easily attach themselves to this face by hydrogen bonding. The other two faces (010) and (001) do not have hydrogen bonding sites perpendicular to the surface. This is the reason that these two latter faces are morphologically important and dominant in the crystal habit and face (100) is small. Using solvents that can interact with the hydrogen bondings at (100) face may inhibit the fast growth of this face and decrease the aspect ratio. An aspect ratio close to unity is ideal. Figure 8 illustrates the product crystal habit obtained with various solvents. All of the illustrated solids were form 1, except the one that precipitated in water and led to hydrate formation. In general, the solvents, such as acetonitrile and MEK, that possess strong hydrogen acceptor sites, led to a smaller aspect ratio but the products of the other three solvents (water, methanol, and 2-propanol) were longer. This is due to the fact that the hydrogen acceptor solvents can stick to N(10) through hydrogen bonding and disrupt the fast buildup of the stavudine molecules on face (100) through hydrogen bonding. The worst crystal shape was obtained with methanol and 2-propanol as solvents. An important observation was that all cases resulted in high density slurry that made the mixing difficult. However, the slurry with acetonitrile as solvent was relatively better in terms of mixing. Effect of Impurity on Polymorphism and Crystal Habit of Stavudine. In the production of active pharmaceutical ingredients (APIs), the crystallization process usually occurs after the reactions. Therefore, the solution may contain the reactants, byproducts and intermediate chemicals that are structurally compatible with the molecular structure of the API. These impurities, especially when they exhibit the same hydrogen bond formation ability as the API molecule, can influence the crystal structure and crystal habit of the final product. The attachment of these chemicals to the API molecule at cluster formation stage may lead to the formation of a specific polymorph, while, during crystal growth, the attachment to a particular face of the crystal can inhibit the growth of that face and affect the crystal habit. Figure 1 presents the chemical structure of two molecules that exist in the crystallization media and can act as structurally compatible impurities. Both of these molecules can easily interact with the stavudine molecule both at cluster formation stage and during crystal growth. Since crystallization of stavudine in 2-propanol always led to the formation of needle-like crystals with a thick slurry and low dry solid bulk density, it was chosen as a suitable solvent for the study of impurities. The results of the use of thymine as impurity in IPA were very interesting, as the crystallization slurry was very thin at all three levels of tested impurities. The filtration was very fast


Figure 7. Functional groups and the available hydrogen bonding on each face of the stavudine crystal.

Mirmehrabi et al.


Crystal Growth & Design, Vol. 6, No. 1, 2006 147

Figure 8. Solvent effect on the crystal habit and aspect ratio of stavudine.

compared to the results without using the impurity. Figure 9 shows the crystallization results using thymine as impurity at three different concentrations. The image of the product from pure 2-propanol is also presented for comparison. Thymidine was not as effective as thymine in changing the crystal habit (Figure 9) and solid bulk density. The slurry was thicker than the case with thymine as an impurity, but still better than the case with no impurity. This shows that the interaction between the impurity and the stavudine molecule that inhibits the fastest growing face is mainly through the thymine ring, which agrees with our prediction and interpretation. None of the impurities resulted in a change in polymorphic structure, and in all cases just form 1 precipitated. Table 3 compares the solid bulk density of the discussed cases. The results of pure solvent have also been presented. Results reported in Figure 9 and Table 3 suggest that the crystal size and the average bulk density of stavudine go through maxima at the intermediate impurity concentration level. Effect of Supersaturation and Mixing Regime on Polymorphism of Stavudine. Ostwald’s rule of stages states that

in a supersaturated solution the least stable polymorph crystallizes first followed by relaxation to more stable ones. However, this relaxation (conversion) can be kinetically inhibited, which stabilizes the metastable form. Mixing is also very important in distributing the supersaturation in the solution. Local high supersaturations are in favor of the production of the metastable form. Figures 10 and 11 show the effect of supersaturation and mixing in the production of stavudine polymorphs. The spontaneous crystallization with mixing always led to the formation of polymorph 1 at all supersaturations. We should note that form 1 is the more stable polymorph. For the highest supersaturation (S ) 2.52), the nucleation started before the solution was cooled to 25 °C. Almost the same range of supersaturation (S ) 1.8 to 2.45) was employed for the experiments with no mixing during cooling and prior to reaching 25 °C. In all cases, the spontaneous nucleation initiated a few minutes after mixing was started. The induction time was inversely related to the supersaturation. Depending on the degree of supersaturation at T ) 25 °C, a


Mirmehrabi et al.

Figure 9. Effect of impurity on the crystal habit of stavudine precipitated in 2-propanol.

specific polymorph or a mixture of forms 1 and 2 was obtained. In 2-propanol, below S = 2.05, only pure form 1 was obtained and above S = 2.12, pure form 2 was the product. Between S = 2.05 and S = 2.12, a mixture of the two polymorphs was produced concomitantly. These experiments showed that supersaturation is a critical factor in isolating the two polymorphs of stavudine. At a particular supersaturation, the kinetic factors favor the arrangement of stavudine molecules to form the highest energy crystalline form, which is form 2 stavudine. The only difference between the results obtained from the two solvents was the onset of supersaturation for isolating the

polymorphs. Acetonitrile required a lower supersaturation than 2-propanol to produce form 2. This observation shows that the hydrogen acceptor solvents favor formation of the metastable polymorph of stavudine. However, the solvent effect is not a major controlling factor for stavudine and definitely the role of supersaturation is more important. Conclusions Stavudine, which is a typical API with a few hydrogen bonding sites, has two known polymorphs, one hydrate, and a


Crystal Growth & Design, Vol. 6, No. 1, 2006 149

Figure 10. Effect of supersaturation and mixing on isolation of stavudine polymorphs in 2-propanol. Table 3. Average Solid Bulk Density and Tap/Bulk Density Ratio of Stavudine in Various Solvents and in the Presence of Impurities

methanol water MEK acetonitrile IPA IPA + 0.25 wt % thymidine IPA + 0.5 wt % thymidine IPA + 1 wt % thymidine IPA + 0.25 wt % thymine IPA + 0.5 wt % thymine IPA + 1 wt % thymine

average bulk density, g/mL

average tap/bulk density ratio

0.14 ((0.02) 0.15 ((0.02) 0.16 ((0.02) 0.17 ((0.01) 0.17 ((0.02) 0.20 ((0.02) 0.27 ((0.02) 0.20 ((0.01) 0.26 ((0.01) 0.31 ((0.02) 0.27 ((0.01)

1.45 ((0.1) 1.38 ((0.08) 1.30 ((0.09) 1.32 ((0.02) 1.23 ((0.04) 1.26 ((0.09) 1.23 ((0.04) 1.35 ((0.05) 1.21 ((0.01) 1.10 ((0.02) 1.27 ((0.03)

few known solvates. The quantitative procedure based on solidstate ATR-FTIR was also used for quantifying the two polymorphs without grinding the samples. Hydrogen bonding ability of various sites of stavudine molecule was calculated using the partial charge distribution suggested by Mirmehrabi and Rohani.14 Using theoretical hydrogen bonding analysis, the effect of solvent on polymorphism and crystal habit was interpreted in agreement with the experimental results. Two impurities, thymine and thymidine, which are structurally compatible with the stavudine molecules, were used to determine the effect of impurities on polymorphism and crystal habit. The impurities showed significant changes on crystal habit and crystal bulk density of solid stavudine but no influence on the polymorphic structure. The effect of supersaturation was also studied on the stavudine polymorphic compound. The results were in agreement with Ostwald’s rule of stages, in which the least stable polymorph crystallizes first. It was also observed that mixing favors formation of the more stable polymorph as it distributes the supersaturation in the solution and prevents local peaks in supersaturation. The range of supersaturation that is suitable

Figure 11. Effect of supersaturation and mixing on isolation of stavudine polymorphs in acetonitrile.

for isolating polymorphs or producing the two forms concomitantly was also determined. Acknowledgment. The authors are grateful to the Natural Sciences and Engineering Research Council of Canada for the financial support of this project through a Collaborative Research and Development Grant CRDPJ 306118-3. References (1) Canadian Pharmacological Association. Compendium of Pharmaceuticals and Specialties; Webcom Ltd: Toronto, 2000; pp 17721774. (2) Harte, W. E.; Starrett, J. E.; Martin, J. C.; Mansuri, M. Biochem. Biophys. Res. Commun. 1990, 175, 298-304. (3) Horwitz, J. P.; Chua, J.; Rooge, M. A. D.; Noel, R.; Klundt, I. L. J. Org. Chem. 1966, 31, 205-211. (4) Lin, T. S.; Prusoff, W. H. U.S. Patent 4710492, 1987. (5) Gandhi, R. B.; Bugardus, J. B.; Bugay, D. E.; Perrone, R. K.; Kaplan, M. A. Int. J. Pharm. 2000, 201, 221-237. (6) Radatus, B. K.; Murthy, K. S. K. U.S. Patent 6635753B1, 2003. (7) Skonezny, P. M.; Eisenreich, E.; Stark, D. R.; Boyhan, B. T.; Baker, S. R. EP Patent 0653435A1, 1995. (8) Mirmehrabi, M. Characterization and Control of Polymorphism in Pharmaceutical Solids. Ph.D. Thesis, University of Western Ontario, Ontario, Canada, 2005. (9) Garofalo, P. M.; Marr, T. R.; Perrone, R. K.; Kaplan, M. A. EP Patent 0749969A2, 1996, or EP 0749969A3, 1997. (10) Mirmehrabi, M.; Rohani, S,; Murthy, K. S. K.; Radatus, B. Int. J. Pharm. 2004, 282, 73-85. (11) Weissbuch, I.; Addadi, L.; Lahav, M.; Leiserowitz, L. Science 1991, 253 (5020), 637-45. (12) Anthony, A.; Desiraju, G. R.; Jetti, R. K. R.; Kuduva, S. S.; Madhavi, N. N. L.; Nangia, A.; Thaimattam, R.; Thalladi, V. R. Cryst. Eng. 1998, 1 (1), 1-18. (13) Davey, R. J.; Allen, K.; Blagden, N.; Cross, W. I.; Lieberman, H. F.; Quayle, M. J.; Righini, S.; Seton, L.; Tiddy, G. J. T. Cryst. Eng. Comm. 2002, 4, 257-264. (14) Mirmehrabi, M.; Rohani, S. J. Pharm. Sci. 2005, 94 (7), 1560-1576.

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