Controlling Polymorphism in Pharmaceutical Compounds Using

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Controlling Polymorphism in Pharmaceutical Compounds Using Solution Shearing Stephanie M. Guthrie, Detlef-M. Smilgies, and Gaurav Giri Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b01686 • Publication Date (Web): 04 Jan 2018 Downloaded from http://pubs.acs.org on January 5, 2018

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Crystal Growth & Design

Controlling Polymorphism in Pharmaceutical Compounds Using Solution Shearing Stephanie M. Guthrie,† Detlef-M. Smilgies,§ Gaurav Giri*,† † Department of Chemical Engineering, University of Virginia, Charlottesville, Virginia, 22904, USA § Cornell High Energy Synchrotron Source (CHESS), Wilson Laboratory, Cornell University, Ithaca, New York 14853, USA In this work, two model pharmaceutical compounds, glycine and acetaminophen, were crystallized using a flow coating technique termed solution shearing to create thin films with controllable polymorphism. In pharmaceutical compounds, careful control of crystal polymorphism and solid-state properties can provide optimized solubility and bioavailability, and a complete search of the polymorphic landscape is necessary. Thin films were characterized using cross polarized optical microscopy and grazing incidence X-ray diffraction. Films were shown to crystallize as different polymorphs (α and β for glycine and form I and form II for acetaminophen) by controlling processing temperature and shearing speed. The amorphous phase of acetaminophen was also stabilized, and the kinetic transformation to the metastable form II was studied. We show that one dimensional confinement in the thin film plays a significant role to stabilize metastable polymorphs and amorphous phases. Solution shearing has the potential to be used as a high throughput technique to screen candidate pharmaceutical compound polymorphism in industry. Figure Caption: Polymorphism occurrence in glycine and acetaminophen as a function of solution shearing parameters.

Prof. Gaurav Giri Assistant Professor 102 Engineers’ Way, Room 122 Charlottesville, VA 22904 Phone: (+1) 434-924-1351 Fax: (+1) 434-982-2658 Email: [email protected]

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Controlling Polymorphism in Pharmaceutical Compounds Using Solution Shearing Stephanie M. Guthrie,† Detlef-M. Smilgies,§ Gaurav Giri*,† † Department of Chemical Engineering, University of Virginia, Charlottesville, Virginia, 22904, USA § Cornell High Energy Synchrotron Source (CHESS), Wilson Laboratory, Cornell University, Ithaca, New York 14853, USA ABSTRACT In this work, two model pharmaceutical compounds, glycine and acetaminophen, were crystallized using a flow coating technique termed solution shearing to create thin films with controllable polymorphism. Controlling polymorphism in pharmaceutical compounds can provide optimized solubility and bioavailability. Thin films of glycine and acetaminophen were obtained using a simple flow coating method, and these films were characterized using cross polarized optical microscopy and grazing incidence X-ray diffraction. Films crystallized as different polymorphs (α and β for glycine and form I and form II for acetaminophen) by controlling processing temperature and shearing speed. The amorphous phase of acetaminophen was also stabilized, and the kinetic transformation to the metastable form II was studied. We show that one dimensional confinement plays a significant role to stabilize metastable polymorphs and amorphous phases. Solution shearing has the potential to be used as a high throughput technique to screen polymorphs in industry.


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In the pharmaceutical industry, significant resources are allocated to control the stability and solubility of a drug product, as the drug needs to be stable during processing and storage, and follow predictable dissolution kinetics in the body.1 For small organic molecules, most drug products are stored and ingested as solid forms.2 The crystal morphology and the packing (polymorphism) of the pharmaceutical compound in the solid drug product determines the solubility and the associated bioavailability.3 The bioavailability of many newly developed drug candidates is a concern, as the drugs are practically insoluble.4-5 Making drugs readily available in the body has emerged as a challenge that prevents many newer candidates from being pushed forward in development. If candidate drugs have improved solubility and bioavailability, these candidates can be screened with greater emphasis on their biological efficacy. Numerous methods are being researched or used in industry to increase the biological activity of insoluble drugs, but at the cost of increased complexity during formulation.6 We aim to control the formation of amorphous and metastable crystalline solid-state phases to improve the solubility of the active pharmaceutical ingredient (API).7 Non-equilibrium (including metastable polymorphs and amorphous solid phases) formulations are a promising route for increased solubility since the non-equilibrium solid phase is, by definition, less stable than the equilibrium phase. Not only is it advantageous to obtain polymorphs with increased solubility, but regulatory agencies mandate that (1) polymorphs, solvates, hydrates and amorphous forms of drug compounds are known, (2) potential phase transformations are well characterized and (3) each polymorphic form is patented separately for development.8 Gaining this understanding is important because, while lower stability polymorphs have enhanced dissolution, they may also have reduced shelf life. Controlling kinetics of phase transformations is thus an important area of study.


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The search for polymorphs with better solubility, coupled with regulatory guidelines to characterize all known polymorphs, have pushed pharmaceutical companies to carry out extensive searches in the API development phase to identify as many drug polymorphs as possible. However, there are no generally applicable routes for finding polymorphs. Many different trial-and-error methods are combined and employed to induce polymorphism, including variable solvent input, thermal cycling, and additives (including co-crystals, co-solvents and excipients).9 Other methods to obtain polymorphs are being researched, such as computational structure prediction, vapor exposure, crystallization on treated surfaces, thin films, and capillary crystallization.10-14 Recently, nanoscale confinement methods such as crystallization in controlled pore glass and nano-drops have shown great utility in obtaining or stabilizing polymorphs of numerous pharmaceutical compounds.15-18 These results suggest that there is a fundamental connection between confined environments and metastable crystallization.19 However, these methods do not yield significant amounts of the metastable polymorph for further testing and processing. In the field of organic electronics, polymorphs are also of great importance for reliably and consistently preparing high performance devices. A solution based crystallization technique termed solution shearing has recently been extensively utilized to control the polymorphism of organic semiconductors.20-21 Solution shearing can be scaled up for high-throughput industrial production while preserving lab results.22 Giri et al. have previously showed that in solution shearing, one-dimensional confinement is responsible for obtaining metastable polymorphs of organic semiconductors.23 We build upon this work to understand how one-dimensional confinement can control pharmaceutical solid-state behavior. Previous studies have outlined numerous routes to stabilize various polymorphs of glycine and acetaminophen, making them


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ideal molecules to understand the influence of one-dimensional confinement on API polymorphism.24-25 We show controllable polymorphism in glycine and acetaminophen by changing solution shearing conditions. We also stabilize the amorphous form of acetaminophen and study the transformation to crystalline phases. We foresee that solution shearing will have vast utility in screening candidate drug molecules to determine the polymorphic landscape with minimal material usage. Solution shearing was used to create pharmaceutical thin films of glycine and acetaminophen. In this method, a solution containing the solute of interest is placed between a bottom heated substrate and a top shearing blade. As the top blade is translated, solution is spread across the substrate and an evaporation front is created at the meniscus. As the solvent evaporates, the solution becomes supersaturated and the solute nucleates, and forms a solid thin film (Figure 1). We obtain different crystal thickness and morphologies by varying the temperature and shearing speed. In the conditions used in this study, the solution shearing process operates in the evaporative regime, characterized by decreasing solid film thickness with increasing blade speed (Figure S1).26 In the evaporative regime, the timescales of solution shearing speed (which controls fluid deposition) and evaporation (which controls solid state formation) are similar. Therefore, controlling either the shearing speed or the substrate temperature impacts the resulting solid state thin film thickness. We can vary this thickness from tens of nanometers to microns. A representative case of solution shearing at 90˚C shows the effect of shearing speed on the crystalline morphologies of glycine and acetaminophen (Figure 2). For glycine, crystalline films were formed in all cases. Large, continuous crystalline domains were obtained when the film was cast at speeds of 0.1 mm s-1 or slower (Figure 2a). Conversely, thinner, needle-like


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crystals appeared at faster speeds (Figure 2b). In both cases, the crystals were aligned with the shearing direction (Figure S2). For acetaminophen, either amorphous or crystalline phases could be obtained after solution shearing, with the amorphous phase eventually transforming to a crystalline film over a longer time scale. At slow solution shearing speeds (0.08 mm s-1 and slower, Figure 2c), crystalline films were deposited. The film texture was non-uniform, with stick-slip motion during shearing causing bands of thick and thin crystalline regions.27 Shearing speeds of 0.5 mm s-1 or greater (Figure 2d) produced an amorphous thin film that transformed into a spherulitic crystalline film. These crystalline films were isotropic in the plane of the substrate. Grazing incidence X-ray diffraction was used to determine the crystal polymorph of glycine and acetaminophen. The peak positions are identical to previously obtained polymorphs for the APIs (Figure 3 and Figure S3, S4). For glycine, the α (more stable) and β (less stable) phases were obtained, and the γ polymorph was not isolated in this study.28-29 For acetaminophen, form I (monoclinic, equilibrium) and form II (orthorhombic, metastable) polymorphs were obtained.30-31 It was observed that the amorphous phase formed during solution shearing of acetaminophen preferentially crystallized as form II. We show reproducible formation of equilibrium and metastable polymorphs by varying solution shearing speed (0.027 – 3.0 mm s-1) and temperature (70 – 100 ˚C). The processing diagrams in Figure 4 and Figure S5 show that pure phases are isolated at the slowest and fastest shearing speeds, with intermediate speeds producing both polymorphs.

The transformation

boundary – where the polymorph selection changes – was studied in more detail. For glycine, the films had a tendency to form as pure α or β polymorph. A relationship between the crystal morphology and polymorph could be obtained. Large crystalline domains


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were preferentially composed of the α polymorph, while needle-like crystals were preferentially composed of the β polymorph. No interconversion occurred during solution shearing. However, due to variability in the solution shearing process, both polymorphs could be obtained at the transformation boundary. For acetaminophen, the pure polymorphic films were isolated at conditions characterized by fast/slow shearing speeds. The amorphous films formed by solution shearing at faster speeds consistently crystallized as the form II polymorph, while the acetaminophen films solution sheared at lower speeds crystallized as the form I polymorph. However, the intermediate region (characterized by shearing speeds 0.11 – 0.5 mm s-1) captured a transition between amorphous and crystalline behavior, where films with both forms I and II were observed. It is not surprising for both polymorphs to be present in a film when the samples are processed at intermediate conditions, as nucleation is a stochastic process.32 It is likely that at the transformation boundary, free energies of formation for the metastable form II and the equilibrium form I are similar, giving rise to both polymorphs. For glycine, previous literature has reported that α glycine is more stable than β glycine and for acetaminophen, stability follows as form I > form II > amorphous phase.16,

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Therefore, for both molecules, thinner films, formed at the faster shearing speeds, crystallize as the less stable polymorph. (Figure 4, Figure S1).26 This result supports the hypothesis that the one-dimensional confinement of the film thickness during solution shearing is responsible for the stabilization of metastable polymorphs.23 It is also important to note that the transformation boundary for both glycine and acetaminophen occurs at similar temperatures and shearing speeds, indicating that for these molecules, one-dimensional confinement is significant in directing polymorph selection at similar thicknesses.


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The ability to change processing conditions without changing techniques to create different polymorphs is relevant to the pharmaceutical industry, where it is desirable to screen for the existence of multiple polymorphs quickly. It is convenient that the metastable forms are isolated at faster speeds for both molecules tested. This is ideal both for scaled up processing and high throughput screening for metastable solid phases. Glycine does not deposit as an amorphous film because the timescales for crystal nucleation and growth are similar to the timescale of film deposition. However, for acetaminophen, the timescale for nucleation is slower than for solid film formation at higher shearing speeds. This mismatch enabled us to isolate the amorphous phase. We were also able to obtain amorphous phases of another molecule, carbamazepine (Figure S6). The transient crystallization dynamics of acetaminophen were studied to construct a solid-state transformation diagram (Figure 5) based on the shearing speed. The operating lines specify the beginning of the solid-state change from amorphous to crystalline (marked by the first optical activity under polarized light), and the end of the solid-state phase change (signified by a fully crystalline thin film). The solution shearing technique is a simple and straightforward method to obtain the amorphous phase of APIs, which is of interest because amorphous phases have rapid dissolution dynamics. Further, this technique has utility in obtaining the amorphous phase at elevated temperatures. Normally, the amorphous phase is highly prone to undergoing transformations and is typically controlled using careful temperature control, humidity control, or inclusion of materials (like polymers) that inhibit crystallinity.35-36 Understanding and controlling solid state phase transformations can be utilized to study the balance between molecular mobility, nucleation and growth, as well as study the relative


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phase stability. The transformation diagrams obtained through solution shearing can also provide insight about the crystallization kinetics, similar to how a time temperature transformation diagram is used for undercooled melt systems.37 Solution shearing is an effective tool to sample processing conditions rapidly while utilizing a small amount of material, and is a robust method to isolate equilibrium and metastable polymorphs, as demonstrated in organic semiconductors.21 This work broadens the relevance of solution shearing to include pharmaceuticals. In this study, we show that controlling the shearing speed and temperature allows us to obtain polymorphic phases in glycine and acetaminophen with metastable polymorphs being present in the thinnest films. We hypothesize that confinement is responsible for stabilization of metastable polymorphs. Previous studies have demonstrated that shearing induces polymorphism due to one-dimensional confinement.23 The observed solid-state phase formation of a molecule using solution shearing is highly dependent on the molecular structure, but solution shearing is capable of isolating the amorphous phase in multiple candidate APIs, even those suffering from low aqueous solubility. Moving forward, solution shearing can be adopted as a method to aid in polymorph screening and selection during drug development, with the processing diagrams provided as a starting point to obtain metastable polymorphs. Future studies with this technology will study the utility of solution shearing to produce tunable solubility. ASSOCIATED CONTENT Supporting Information. Supporting Information.pdf AUTHOR INFORMATION Corresponding Author


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*[email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Funding Sources This work was financially supported by the Thomas F. and Kate Miller Jeffress Memorial Trust, Bank of America, Trustee, and the Virginia Space Grant Consortium. This work is based upon research conducted at the Cornell High Energy Synchrotron Source (CHESS) which is supported by the National Science Foundation under award DMR1332208. Notes ORCID Stephanie Guthrie: 0000-0001-7549-9983 Detlef-M. Smilgies: 0000-0001-9351-581X Gaurav Giri: 0000-0002-8504-1033 REFERENCES (1) Parks, C.; Koswara, A.; Tung, H.-H.; Nere, N. K.; Bordawekar, S.; Nagy, Z. K.; Ramkrishna, D., Mol. Pharm. 2017, 14 (4), 1023-1032. (2) Byrn, S.; Pfeiffer, R.; Stephenson, G.; Grant, D.; Gleason, W., Chem. Mater. 1994, 6 (8), 1148-1158. (3) Brittain, H.; Grant, D. J. W., Effects of Polymorphism and Solid-State Solvation on Solubility and Dissolution Rate. In Polymorphism in Pharmaceutical Solids, 2009; Vol. 192, pp 436-480. (4) Kalepu, S.; Nekkanti, V., Acta Pharm Sin B 2015, 5 (5), 442-453.


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(5) Dwyer, L.; Kulkarni, S.; Ruelas, L.; Myerson, A., Crystals 2017, 7 (5), 131. (6) Fahr, A.; Liu, X., Expert Opin. Drug Deliv. 2007, 4 (4), 403-416. (7) Hilfiker, R.; Blatter, F.; Raumer, M. v., Relevance of Solid-state Properties for Pharmaceutical Products. In Polymorphism, 2006; pp 1-19. (8) Newman, A. W.; Byrn, S. R., Drug Discov Today 2003, 8 (19), 898-905. (9) Hilfiker, R.; De Paul, S. M.; Szelagiewicz, M., Approaches to Polymorphism Screening. In Polymorphism, 2006; pp 287-308. (10) Childs, S. L.; Chyall, L. J.; Dunlap, J. T.; Coates, D. A.; Stahly, B. C.; Stahly, G. P., Cryst. Growth. Des. 2004, 4 (3), 441-449. (11) Price, S. L., Adv. Drug Deliv. Rev. 2004, 56 (3), 301-319. (12) Lee, E. H., Asian J. Pharm. 2014, 9 (4), 163-175. (13) Leon, R. A. L.; Badruddoza, A. Z. M.; Zheng, L.; Yeap, E. W. Q.; Toldy, A. I.; Wong, K. Y.; Hatton, T. A.; Khan, S. A., Cryst. Growth. Des. 2015, 15 (1), 212-218. (14) Ehmann, H. M. A.; Werzer, O., Cryst. Growth. Des. 2014, 14 (8), 3680-3684. (15) Jiang, Q.; Ward, M. D., Chem. Soc. Rev. 2014, 43 (7), 2066-2079. (16) Hamilton, B. D.; Hillmyer, M. A.; Ward, M. D., Cryst. Growth. Des. 2008, 8 (9), 33683375. (17) Buanz, A. B. M.; Gaisford, S., Cryst. Growth. Des. 2017, 17 (3), 1245-1250. (18) Trauffer, D. I.; Maassel, A. K.; Snyder, R. C., Cryst. Growth. Des. 2016, 16 (4), 1917-1922. (19) Lee, S.; Feldman, J.; Lee, S. S., Cryst. Growth. Des. 2016, 16 (8), 4744-4751. (20) Becerril, H. A.; Roberts, M. E.; Liu, Z.; Locklin, J.; Bao, Z., Adv. Mater. 2008, 20 (13), 2588-2594. (21) Giri, G.; Verploegen, E.; Mannsfeld, S. C. B.; Atahan-Evrenk, S.; Kim, D. H.; Lee, S. Y.; Becerril, H. A.; Aspuru-Guzik, A.; Toney, M. F.; Bao, Z., Nature 2011, 480 (7378), 504-508. (22) Gu, X.; Zhou, Y.; Gu, K.; Kurosawa, T.; Guo, Y.; Li, Y.; Lin, H.; Schroeder, B. C.; Yan, H.; Molina-Lopez, F.; Tassone, C. J.; Wang, C.; Mannsfeld, S. C. B.; Yan, H.; Zhao, D.; Toney, M. F.; Bao, Z., Advanced Energy Materials 2017, 7 (14), 1602742-n/a. (23) Giri, G.; Li, R.; Smilgies, D.-M.; Li, E. Q.; Diao, Y.; Lenn, K. M.; Chiu, M.; Lin, D. W.; Allen, R.; Reinspach, J.; Mannsfeld, S. C. B.; Thoroddsen, S. T.; Clancy, P.; Bao, Z.; Amassian, A., Nature Communications 2014, 5, 3573. (24) Pilling, S.; Mendes, L. A. V.; Bordalo, V.; Guaman, C. F. M.; Ponciano, C. R.; da Silveira, E. F., Astrobiology 2012, 13 (1), 79-91. (25) Zimmermann, B.; Baranović, G., J. Pharm. Biomed. Anal. 2011, 54 (2), 295-302. (26) Le Berre, M.; Chen, Y.; Baigl, D., Langmuir 2009, 25 (5), 2554-2557. (27) Aranson, I. S.; Tsimring, L. S.; Vinokur, V. M., Phys. Rev. B 2002, 65 (12), 125402. (28) Marsh, R., Acta Crystallogr. 1958, 11 (9), 654-663. (29) Iitaka, Y., Acta Crystallogr. 1960, 13 (1), 35-45. (30) Haisa, M.; Kashino, S.; Kawai, R.; Maeda, H., Acta Crystallogr. Sect. B 1976, 32 (4), 12831285. (31) Thomas, L. H.; Wales, C.; Zhao, L.; Wilson, C. C., Cryst. Growth. Des. 2011, 11 (5), 14501452. (32) Goh, L.; Chen, K.; Bhamidi, V.; He, G.; Kee, N. C. S.; Kenis, P. J. A.; Zukoski, C. F.; Braatz, R. D., Cryst. Growth. Des. 2010, 10 (6), 2515-2521. (33) Peterson, M. L.; McIlroy, D.; Shaw, P.; Mustonen, J. P.; Oliveira, M.; Almarsson, Ö., Cryst. Growth. Des. 2003, 3 (5), 761-765.


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For Table of Contents Use Only Controlling Polymorphism in Pharmaceutical Compounds Using Solution Shearing Stephanie M. Guthrie, Detlef-M. Smilgies, Gaurav Giri

SYNOPSIS Solution shearing is a scalable processing technique that was used to isolate polymorphs for glycine and acetaminophen. Through changing shearing speed and temperature, processing diagrams for isolating each polymorph were developed.


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Figure 1. Conceptual image of the solution shearing technique. 167x81mm (96 x 96 DPI)


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Figure 2. Brightfield and cross polarized optical microscopy (⨂) of glycine (a, b) and acetaminophen films (c, d) Subfigure d) shows amorphous to crystalline transition. All films were formed at 90 ˚C. Shearing direction is indicated with arrow, similar for all images. Scale bars are 100 µm, similar for all images. 164x137mm (96 x 96 DPI)



Figure 3. Representative scans obtained from integrating 2-D grazing incidence X-ray diffraction (GIXD) patterns. Dashed patterns are literature reported data28-31 a) α glycine formed at 70˚C, 0.03 mm s-1, b) β glycine formed at 80˚C and 0.11 mm s-1, c) acetaminophen form I formed at 100˚C, 0.03 mm s-1, d) acetaminophen form II formed at 100˚C and 0.5 mm s-1. 400x382mm (96 x 96 DPI)


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Figure 4. (a) Samples taken at similar conditions were organized and polymorphs were assigned from GIXD and 1D diffraction patterns. Relative frequency of polymorph occurrence was assembled into bar graphs. Bar graphs were organized by temperature and shearing speed to show the relationship between processing conditions and the eventual thin film polymorph, to assemble processing diagrams for b) glycine and c) acetaminophen. Polymorph selection is influenced by the solution shearing speed. Column graphs indicate the relative occurrence of each polymorph in the films. Summation of the bar graphs over 1 for any condition indicates film formation with multiple polymorphs in one sample. 613x376mm (96 x 96 DPI)



Figure 5. Transformation diagram showing how blade speed relates to the timescale of nucleation and overall crystallization for acetaminophen thin films sheared at 90˚C. 225x181mm (96 x 96 DPI)


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Controlling Polymorphism in Pharmaceutical Compounds Using

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