Article pubs.acs.org/crystal
Two New Polymorphs of Huperzine A Obtained from Different Dehydration Processes of One Monohydrate Qi Zhang and Xuefeng Mei* Pharmaceutical Analytical & Solid-State Chemistry Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China S Supporting Information *
ABSTRACT: Two new polymorphs (forms IV and V) of huperzine A were obtained from the same hydrate form H1, which is currently commercially available, via dehydration processes under different conditions. Notably, the number of reported polymorphs of huperzine A is increased to five and the polymorphs with well-determined structures are increased to four. Forms IV and V were analyzed by single crystal X-ray diffraction (SCXRD) and X-ray powder diffraction (XRPD). In addition, form V was further characterized by Raman spectra, Fourier-transform infrared (FTIR), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and dynamic vapor sorption (DVS). Finally, the mechanism for the two-phase transformation is discussed.
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INTRODUCTION Polymorphism occurs commonly among drugs and different polymorphs always present distinct physical and chemical attributes, such as compressibility, melting point, crystal habit, color, density, dissolution rate, and solubility.1−4 Accordingly, in order to explore the polymorphism landscape and to optimize the solid-state properties, thorough polymorph screening and solid-state characterization of drug candidates are routinely conducted throughout the drug development process.5−8 The most common polymorph screening methods are crystallization from melt,9 vapor10 and cooling,11 evaporating,12 antisolvent,13 and slurrying14 with different solvents and at different temperatures. In addition, dehydration is an effective method for polymorph screening15−20 and some polymorphs can be prepared only by this conversion.21 At present, only a few organic compounds present a remarkable number of polymorphs. Since 2005, the most abundant polymorphic system has been 5-methyl-2-[(2-nitrophenyl) amino]-3-thiophenecarbonitrile (ROY), which has 10 reported polymorphs, and 7 of them are structurally characterized.22−24 Recently, the record for explicitly solved polymorphs was broken by aripiprazole,25 which has 12 reported anhydrous forms and a record-breaking 9 solved crystal structures. In 2012, the third highest number of polymorphs with well-determined structures was 5, and there were only 34 cases with 4 polymorphs and 8 cases with 5 polymorphs with well-determined structures in the Cambridge Structural Database (CSD).26 Therefore, organic compounds exhibiting 4 or more polymorphs with well-determined structures are very rare. If an unstable physical form is selected for development, undesirable phase transformation may occur and lead to a more stable solid form during formulation or storage processes.27 This change could result in serious solubility, stability, or © XXXX American Chemical Society
manufacturing problems in a drug product, and could result in serious losses such as in the case of Ritonavir.28 Consequently, thorough investigation of any potential solid phase transformation for a market form is essential. Solid state phase transformations occur via two different processes: solid-to-solid phase transformation (SSPT) and solvent-mediated phase transformation (SMPT).29−32 The phase transformation can be affected by modifying the conversion conditions, such as temperature, particle size, and solvents.33−39 Compared with reactions in a finite system, e.g., molecules and clusters, solid phase transition is much more complex, because it involves both the collective atom movement and a change of the crystal lattice. Identification of the solid transition pathway and resolution of the mechanism have long been major challenges with regard to both theory and experiment. Up to 1998, there were more than 160 mechanisms reported for solidstate polymorph transitions.40 Two of the most common mechanisms proposed in the literature are (1) nucleation and growth and (2) concerted, or martensitic, transformations. According to the nucleation and growth mechanism, the parent crystals are completely destroyed and the daughter crystals are recrystallized from the amorphous or liquid (melt or solution) state. In comparison, martensitic transformations are first-order crystal−crystal phase transitions that proceed rapidly without diffusion of the atomic or molecular species. However, there is increasing evidence that the transformations thought to be martensitic in nature actually occur via a nucleation and growth.41−43 (−)-Huperzine A (Scheme 1) is found in the plant families Huperziaceae, Lycopodiaceae, and Selaginella.44 It is a highly Received: March 29, 2016 Revised: May 4, 2016
A
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monochromator. Integration and scaling of the intensity data were conducted using the SAINT program.51 The structures were solved by Direct Methods using SHELXS9752 and refinement was carried out by full-matrix least-squares technique using SHELXL97.52 The hydrogen atoms were refined isotropically and the heavy atoms were refined anisotropically. The N−H and O−H hydrogens were located from difference electron density maps and the C−H hydrogens were placed in the calculated positions and refined with a riding model. Data were corrected for the effects of absorption using SADABS. X-ray Powder Diffraction. XRPD was performed on a Bruker D8ADVANCE X-ray diffractometer using a Cu Kα radiation (λ = 1.5418 Å). The voltage and current were 40 kV and 40 mA, respectively. Samples were measured in reflection mode in the 2θ range of 3−40° with a scan speed of 15°/min (step size 0.025°, step time 0.1 s) using a LynxEye detector. All data were acquired at ambient temperature (20 °C). Data were imaged and integrated with RINT Rapid and were peak-analyzed with Jade 6.0 software from Rigaku. Calibration of the instrument was performed using Corindon (Bruker AXS Korundprobe) standard. Fourier-Transform Infrared (FTIR). Fourier-transform infrared (FTIR) spectra were collected with a Nicolet-Magna FT-IR 750 spectrometer in the range of 4000 to 350 cm−1 with a resolution of 4 cm−1 at ambient conditions. Raman. Raman spectra were recorded using a Thermo Scientific DXR Raman microscope equipped with a laser of 532 nm wavelength in the range of 3500 to 50 cm−1. Samples were analyzed directly in a glass sheet using a 10 mW laser power and a 50 μm pinhole spectrograph aperture.
Scheme 1. Structure of Huperzine A
potent, specific, and reversible inhibitor of acetylcholinesterase (AChEI)45,46 and has been extensively evaluated for bioactivity, especially for activity toward cholinesterases and for treatment of Alzheimer’s disease (AD).47 To date, three anhydrous polymorphs, two monohydrates, and four solvates of huperzine A have been reported by us and other groups.48−50 Among these solvates, the hydrate H1 is the market form, and its crystal structure was first reported in 2006. In this work, two new polymorphs (forms IV and V) of huperzine A were obtained from the same hydrate form H1, which is the currently commercially available form, via dehydration under different conditions. Notably, the number of reported polymorphs of huperzine A is increased to 5 and the polymorphs with well-determined structures are increased to 4. Form IV is a transient form obtained via a martensitic process that converts to hydrate H1 quickly when exposed to moisture. Form V is prepared through a SMPT process, is less hygroscopic, and can remain unchanged up to 90% RH. Forms IV and V were analyzed by single crystal X-ray diffraction (SCXRD) and X-ray powder diffraction (XRPD). In addition, form V was further characterized by Raman spectra, Fouriertransform infrared (FTIR), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and dynamic vapor sorption (DVS).
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RESULTS AND DISCUSSION Form IV is a transient form and form V is a metastable polymorph. Form IV is the intermediate state between hydrate H1 and anhydrous form II, whereas form V is an unavoidable intermediate polymorph during the solution-mediated transformation of H1 to form III (Scheme 2). The preparation of
EXPERIMENTAL SECTION Scheme 2. Phase Transformation of Hydrate H1
Materials. Huperzine A raw material (designated as H1) was obtained from Shanghai Nuote Biological Technological Company Limited, with greater than 99% purity. All analytical grade solvents were purchased from Sinopharm Chemical Reagent Company and were used without further purification. Preparation of Form IV. Form IV was prepared by heating hydrate H1 whose particle size was smaller than 50 μm at 130 °C for 24 h. The heated sample was characterized by XRPD immediately; otherwise, it rapidly converted to the initial hydrate H1. Preparation of Form V. Form V was prepared by slurrying hydrate H1 or the amorphous state of huperzine A in n-hexane or nheptane at 50 °C for 3 days. These experiments were monitored carefully because the obtained form V was easily transformed to the more stable form III if the slurry experiments were continued for too long. Thermogravimetric Analysis (TGA). Thermogravimetric analysis was carried out in a Netzsch TG 209F3 equipment, using dry air with a flow of 20 mL/min and a scan rate of 10 °C/min. Differential Scanning Calorimetry (DSC). Differential scanning calorimetry was performed with a PerkinElmer DSC 8500 instrument. Two-point calibration using indium and tin was carried out to check the temperature axis and heat flow of the equipment. Samples weighting 3−5 mg were heated in standard aluminum pans at a scan rate of 10 °C/min under nitrogen gas flow of 20 mL/min. Dynamic Vapor Sorption (DVS). Dynamic vapor sorption experiments were performed on an Intrinsic DVS instrument from Surface Measurement Systems, Ltd. The initial relative humidity was set to 0%. Samples were studied over a humidity range of 0−95% RH at 25 °C. Each humidity step was made if a weight change of less than 0.02% occurred over 10 min, with a maximum hold time of 3 h. Single-Crystal X-ray Diffraction. Single-crystal X-ray diffraction measurements were conducted on a Bruker Smart Apex II diffractometer using Mo Kα radiation (λ = 0.71073 Å) with a graphite
form IV is size dependent. When the particle size of H1 is larger than 100 μm, form IV is not observed during the transformation process from H1 to form II. Form IV can be prepared when the particle size of H1 is smaller than 50 μm. Multiple H1 dehydration experiments were performed, and the results revealed that even if the particle size was well controlled, complete conversion of H1 to IV is still difficult to achieve. In most cases, the resulting material was usually a mixture of both forms. If the mixture was heated to 150 °C or higher, the mixture was finally transformed to the more stable form II (Figure S1). In addition, form IV is unstable at ambient conditions and converted to the initial hydrate H1 within 1 min if exposed to air in the laboratory environment (25 °C and 40% RH). Form V was discovered during the transformation of H1 to form III and is an intermediate state between hydrate H1 and anhydrous form III. This metastable form had reasonable stability compared with the highly hygroscopic form IV. Dynamic vapor sorption/desorption (DVS) showed that form B
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characterized. Due to the different packing motif and hydrogen bonding interactions, form V presents distinct FTIR and Raman spectra from those of the reported polymorphs (Figures S2 and S3). The differences observed in the IR spectra of form V and forms I−III are related to the amide NH and NH2 stretching bands: νass (NH, NH2) = 3250−3500 cm−1, the carbonyl stretching: νass (CO) = 1650−1750 cm−1, and the methyl bending and rocking: νass (CH3) = 1415−1465 cm−1. Compared to that of forms I−III (1666, 1660, and 1668 cm−1, respectively), form V (1656 cm−1) has a lower wavenumber for the CO vibration stretching, which indicates stronger intermolecular interactions in the CO group of form V. This conclusion is consistent with the results of the huperzine A single-crystal structures that are discussed below. The Raman spectra of huperzine A form V and the reported forms I−III are summarized in Figure S3, and the differences are noted with down arrows. In contrast to the FTIR spectra, the most distinct differences observed in the Raman spectra for the four polymorphs related to the C−H stretching bands: νass (CH, CH2, and CH3) = 2750−3150 cm−1, because compared to the IR spectrum, the Raman spectrum is more sensitive to nonpolar groups. The TGA profile of form V is compared with the reported polymorphs in Figure S4. The TGA analysis indicated negligible mass loss prior to decomposition which confirms there are no organic solvents or water molecules involved. In addition, compared to the reported polymorphs, form V exhibits the lowest decomposition temperature, suggesting that form V is the most thermally unstable. Figure S5 shows the DSC results for the four polymorphs heated at 10 K min−1; form V exhibits a much more complex DSC curve. The DSC thermogram of form V has one small broad endothermic peak at T = 192.6 °C and one small broad exothermic peak T = 208.5 °C corresponding to phase transformations, and one endothermic peak at T = 231.0 °C corresponding to form II melting. Single Crystal Structure. Because forms IV and V of huperzine A are metastable polymorphs and can be prepared only by phase transformation methods, high quality single crystals are difficult to prepare. The single crystal of form IV was obtained by single crystal to single crystal transformation (crystal size/mm: 0.08 × 0.10 × 0.15) from H1 under controlled RH conditions. Such conversion was a reversible process; hence, the single crystal of form IV must be strictly isolated from moisture. The single crystal of form V was obtained occasionally by slurrying the amorphous state of huperzine A in heptane at 80 °C for 10 days. The crystallographic data of huperzine A hydrate H1 and the new polymorphs IV and V are summarized in Table 1. Hydrate H1 and form IV both crystallized in a monoclinic system, whereas form V crystallized in an orthorhombic system. The space groups of the three crystals are C2, P21, and P212121, respectively. There is only one huperzine A molecule in the asymmetric unit of H1, but polymorphs IV and V both contain two huperzine A molecules in their asymmetric units (Figure 3). Although the three crystals present distinctly different unit cell parameters, they have very similar hydrogen bonding formations. Similar to that of market hydrate H1, in polymorphs IV and V, the huperzine A molecules are combined by hydrogen bonds N1−H···O2 and N3−H···O1 to form dimeric structures (Figures 2 and S4), which is significantly different from that of the reported polymorphs, in which huperzine A molecules are connected by hydrogen bonds to
V was unchanged up to 90% RH. The material eventually converted to hydrate H1 after the RH reached 95% RH (Figure 1). However, the preparation of form V on a large scale was
Figure 1. DVS curves of huperzine A form V.
challenging. Form V quickly converted to the more stable form III if the time and temperature were not strictly controlled. Therefore, hydrate H1 could be converted to different anhydrous polymorphs via different transient states when distinct phase transformation processes were employed. The different phase transformation processes of hydrate H1 are depicted in Scheme 2. The XRPD patterns of huperzine A new polymorphs IV and V are presented in Figure 2. The results show that the two new
Figure 2. XRPD patterns of huperzine A polymorphs IV and V.
forms have distinguishable differences from the reported forms I−III.50 As reported previously, polymorphs I−III of huperzine A present distinct characteristic peaks at 2θ 7.8°, 9.2°, and 6.8°, respectively. Form IV has its characteristic peaks at 2θ 10.3°, 13.1°, 14.4°, 14.6°, 18.0°, and 21.4°. Form V exhibits some distinct new peaks at 2θ 9.5°, 12.4°, 13.6°, 15.0°, 15.6°, and 23.8°. The XRPD patterns for polymorphs IV and V measured from bulk samples were also compared with those calculated from the single-crystal X-ray data, and the results agreed well. These results confirm the high phase purity for the bulk samples of forms IV and V. Form IV was very unstable and quickly converted to H1 when exposed to air; hence, only form V was further C
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Table 1. Crystallographic Data of Huperzine A Hydrate H1 and New Polymorphs IV and V Formula Crystal system Space group Temperature (K) a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) Cell volume (Å3) Calc. density (g/cm3) Z Z′ μ Unique reflections Rint Rw CCDC number
H149
Form IV
Form V
C15H18N2O·H2O monoclinic C2 rt 14.000(20) 12.350(20) 8.838(14) 90 111.73(1) 90 1419.49 1.218 4 1 / / / / 627639
C15H18N2O monoclinic P21 296(2) 9.034(6) 12.2905(9) 12.2022(8) 90 97.879(5) 90 1342.55(16) 1.199 4 2 0.71073 6169 0.0928 0.1514 1423567
C15H18N2O orthorhombic P212121 296(2) 11.605(3) 14.229(3) 15.618(4) 90 90 90 2617.7(8) 1.248 8 2 0.71073 13606 0.1055 0.1402 1423568
Figure 5. Packing similarity between huperzine A (a) hydrate H1 and (b) form IV.
Figure 3. Asymmetric units of huperzine A forms IV (a) and V (b).
form one-dimensional chains.50 The distances between atoms N and O in the two groups of hydrogen bonds N−H···O in forms IV and V are determined as 2.808, 2.735 and 2.734, 2.788 Å, respectively. Compared to that of reported form II (hydrogen bond lengths: 2.815, 2.790, 2.791, 2.795, 2.817, and 2.810 Å, respectively) and form III (hydrogen bond length: 2.800 and 2.812 Å, respectively), form V has shorter N−H···O hydrogen bonds. Such conclusion is consistent with the FTIR analysis result. The difference is that in H1 the dimers are connected by water molecules (Figure S6), while in forms IV and V the dimers are isolated. Polymorphs IV and V of huperzine A (Figure 4) have very similar hydrogen bonding formations; however, they present significantly different packing patterns. The two-dimensional molecular packing in the crystal structures of huperzine A hydrate H1 and forms IV and V are presented in Figures 5, 6, and 7. The results show that, in the ac layer, H1 and form IV present very similar packing patterns (Figure 5). In H1 and
form IV, the dimers are parallel to the ac layer and are orderly arranged along the a and c axes to form their two-dimensional layers. In addition, the arrangement of huperzine A molecules in the ab layer of form IV is also very similar to that in the bc layer of hydrate H1 (Figure S7). The difference is that in H1 the dimers are arranged to build shelves and the water molecules are included in the shelves (Figure 6a), while in form IV the water is removed and the shelves are collapsed (Figure 6b). In comparison, form V has a distinct packing method (Figure 7). In form V, the dimers are perpendicular to the ac layer and extend sideways and are interlaced along the a and c axes to form a two-dimensional structure. Hirshfeld surface analysis53,54 is also employed to understand and visualize the subtle packing differences among the hydrate H1 and the two new polymorphs of huperzine A. The 2D fingerprint plots of hydrate H1, and polymorphs IV and V, present obviously different shapes (Figure 8a), reflecting the different packing modes of the three crystals, although the structures present similar O···H/H···O contacts, which show up as a pair of sharp spikes in the plots. The most obvious difference among the five plots is the two flanks and the middle part between the two sharp spikes. The plot of molecule A in form IV has two wing angles corresponding to the C···H/H···C contacts while the other plots do not present any wing angles on their flanks. In the fingerprint plots of polymorphs IV and V, some obtuse angles are also visible between these sharp spikes, corresponding to the H···H contacts. In contrast, hydrate H1 has a diffuse pattern of dots in the same region. The relative contributions of each interaction to the Hirshfeld surface are
Figure 4. Dimer structures of huperzine A molecules in form IV (a) and form V (b). D
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Figure 6. Packing difference between huperzine A (a) hydrate H1 and (b) form IV.
Figure 7. Two-dimensional packing pattern of huperzine A form V view along b axis.
depicted in Figure 8b. Each interaction in the three crystal structures presents similar contributions due to the similar intermolecular interactions in the three forms. For all three crystals, the H···H dispersion interactions contribute the most to the Hirshfeld surface. The N−H···O hydrogen bonds have the second greatest contribution, followed by the C···H/H···C interactions. The N···H/H···N contacts have the fourth strongest contributions. There are no other contributions to the Hirshfeld surface in hydrate H1 and form IV. In contrast, form V also has other interactions, e.g., C···C, C···N, N···N. Conversion of H1 to Form IV. To further understand the conversion of H1 to form IV, DVS and DSC experiments of H1 were performed. The DVS profiles of H1 are presented in Figure S8 and the result shows that H1 remains stable across a wide range of humidity (5−95% RH). Dehydration occurs only at a very low relative humidity (RH) level ( form V > form II > form I. Although form V is thermodynamically more stable than forms I and II, based on the DVS results, forms I and II exhibit lower sensitivity to moisture changes than form V.
Figure 9. DSC curves of huperzine A hydrate H1 with different particle sizes.
contrast, when the temperature is higher than 100 °C, part of form IV is further converted to form II and pure form IV is not obtained. As a result, the particle size of hydrate H1 is the key factor of the conversion process. Only when the particle size is small enough (smaller than 50 μm) can the dehydrated H1 be fully converted to form IV at the specific temperature; then, form IV finally can be successfully prepared. Speculations on the Transformation Mechanism. Form V is obtained via a SMPT process which occurs in three steps: (1) dissolution of a metastable form, (2) nucleation of the stable form, and (3) growth of the stable form.31 Form IV is prepared through a SSPT process, which is much more complex. SSPT occurs via three different processes: (1) martensitic transformation, without diffusion of the molecular species, with a portion of the original phase information preserved in the final phase, (2) melting and recrystallization, and (3) gas-induced transformation. Processes (2) and (3) both follow nucleation and growth mechanism and require significant molecular rearrangement. In this paper, the single crystal structure of form IV is very similar to that of hydrate H1, and form IV can be viewed as related to H1 by removing the water molecules and collapsing the huperzine A molecular shelf. It seems that there is no obvious molecular diffusion in the phase transformation from H1 to form IV, and such a transition may occur via a martensitic transformation mechanism. In addition, form IV can be prepared by single crystal to single crystal transformation from H1 which is a distinct characteristic of martensitic transformation. However, several investigations have found that many of these martensitic transformations also occur by nucleation and growth, and two mechanisms have been proposed: (1) the nucleation of the final form (form F) occurs at specific voids in the microstructure of the initial form (form I) and crystal growth proceeds by a “molecule-by-molecule” transfer from form I to form F, without a particular orientational relationship (OR) between the two forms, and (2) the nucleation may occur at oriented cracks, which gives rise to a specific OR during the growth of phase F; the mechanism is thus “epitaxial”.55−57 In comparison, to the present date, there is no evidence that crystal transformations can occur cooperatively in the sense that all molecules of a certain volume or all molecules situated at a certain interface will simultaneously participate in the transition. There is also no indication that a
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CONCLUSION In summary, this work presented two additional new anhydrous polymorphs of huperzine A obtained by dehydration from the commercially available hydrate H1 via two different phase transformation procedures. The two forms are metastable polymorphs. Form IV is a transient form and converts to hydrate H1 when exposed to moisture. Form V is less hygroscopic and can remain unchanged up to 90% RH. Form V is also converted to hydrate H1 when the RH is higher than 95%. The single crystal structures of both forms IV and V are reported here. The two polymorphs present similar hydrogen bonding formation to that of hydrate H1. However, their molecular packing patterns are different. Form IV has a very similar three-dimensional packing to hydrate H1 while form V exhibits a distinctively different packing pattern. Hirshfeld surface analysis showed the differences among the three crystal structures. The mechanism for the two phase transformations is discussed as well. Form IV is obtained via a martensitic transformation process, whereas form V is prepared through a SMPT process. However, the two transformations may both occur through a nucleation and growth mechanism. Finally, the relative stabilities of all the stable polymorphs of huperzine A at room temperature were investigated.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.6b00493. XRPD patterns for the phase transformation, Raman and FTIR spectra, TGA and DSC measurements, hydrogen bonding formation and packing patterns (PDF) F
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CCDC 1423567−1423568 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: + 44 1223 336033.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (Grant Nos. 81273479 and 81402898), the Youth Innovation Promotion Association CAS (Grant No. 2016257), and the CAS Key Technology Talent Program for funding.
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DOI: 10.1021/acs.cgd.6b00493 Cryst. Growth Des. XXXX, XXX, XXX−XXX
Crystal Growth & Design
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DOI: 10.1021/acs.cgd.6b00493 Cryst. Growth Des. XXXX, XXX, XXX−XXX
