Communication pubs.acs.org/crystal
Mechanism for Polymorphic Transformation of Artemisinin during High Temperature Extrusion Chaitrali Kulkarni,† Adrian Kelly,† John Kendrick,‡ Tim Gough,† and Anant Paradkar*,† †
Centre for Pharmaceutical Engineering Science, University of Bradford, Bradford BD7 1DP, U. K. Department of Chemistry and Forensic Science, School of Life Sciences, University of Bradford, BD7 1DP, U. K.
‡
S Supporting Information *
ABSTRACT: A novel, green, and continuous method for solid-state polymorphic transformation of artemisinin by high temperature extrusion has recently been demonstrated. This communication describes attempts to understand the mechanisms causing phase transformation during the extrusion process. Polymorphic transformation was investigated using hot stage microscopy and a model shear cell. At high temperature, phase transformation from orthorhombic to the triclinic crystals was observed through a vapor phase. Under mechanical stress, the crystalline structure was disrupted continuously, exposing new surfaces and accelerating the transformation process.
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conveying material along the barrel; the extent of shear and residence time in the process depends on the screw configuration, screw speed, set temperature, and properties of the material. The barrel is divided into several zones and the temperature of each zone can be independently controlled.10 The extruder has been used as a reactor to cause grafting of the polymers. Solvent-free cocrystallization (SFCC) using a melt extruder involves processing of stoichiometric amounts of cocrystallizing components at their eutectic point or melting point of the lower melting component.11 We have previously demonstrated the transformation of artemisinin (art) from the orthorhombic to the triclinic form by high temperature extrusion (HTE).12 In this process, the temperature was maintained at 140 °C, significantly below the melting point of art. The metastable triclinic form obtained by this technique was found to be stable for two years. It is difficult to generate and stabilize the triclinic form of art because it undergoes solvent-mediated transformation. Solvent mediated polymorphic transformation has been observed for many drugs such as sulfamerazine, nitrofurantoin, artemisinin, etiracetam, benzamide, and buspirone hydrochloride.13−18 Our previous work explored the reasons why the triclinic form of art produced by solvent-free processing was less susceptible to solvent-mediated polymorphic transformation than methods using solvents. The aim of this work is to provide a mechanistic understanding of the polymorphic transformation which occurs during HTE. The two primary factors responsible for causing this transformation are temperature and shear. Polymorphic transformations induced by high temperature or pressure are
harmaceutical processing has the potential to disrupt the crystal lattice of APIs and has thus gained considerable attention.1,2 Different molecular arrangements can provide diverse physical and chemical properties in pharmaceutical substances, thus altering solubility, density, stability, and bioavailability.3 Several unit operations employed to prepare solid dosage forms, such as grinding, milling, drying, and compression may induce solid-state polymorphic transformation.4 Some elegant examples which utilize such process induced transformation are described in pharmaceutical research. Tablet compression has been reported to cause a polymorphic transition in drugs such as acetaminophen, piroxicam, carbamazepine, phenylbutazone, and chlorpropamide. This transformation alters the physicochemical properties of these drugs and influences the dissolution rate and bioavailability of the final products.5 Grinding can also induce polymorphic transitions in caffeine, theophylline, and famotidine.6 Recently various solvent free technologies have been investigated which cause complete polymorphic transformations. Trask et al. demonstrated the application of solventassisted grinding to achieve polymorphic transformation in anthranillic acid and succinic acid.7 Our group reported a solvent free, scalable thermo-mechanical technology for continuous crystalline transformation using a hot melt extruder.8,9 Hot melt extrusion (HME) has been widely used in the plastics industry and is now being increasingly applied to pharmaceutical processing, commonly for compositions containing a molten thermoplastic polymer. A twin screw hot melt extruder comprises a feeder, a heated barrel containing two corotating or counter rotating screws, and a die at the end of the barrel. The screws provide a shearing action while © 2013 American Chemical Society
Received: June 12, 2013 Revised: November 12, 2013 Published: November 18, 2013 5157
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Figure 1. Microscopy images during isothermal heating of orthorhombic crystals at 140 °C for (a) 0, (b) 45, and (c) 90 min; during isothermal heating of orthorhombic crystals at 140 °C and with 0.5 s−1 shear rate for (d) 0, (e) 8, and (f) 15 min.
Figure 3. Experimental PXRD patterns of orthorhombic form, sublimed crystals, and crystals collected from the lower vessel.
Figure 2. Polymorphic transformation of artemisinin crystals by sublimation.
and triclinic polymorphs indicated that the ratio of peak intensities at 2θ = 9.95 and 7.80, respectively, could be used to estimate the fraction of triclinic polymorph present. The PXRD pattern of the product showed a small peak at 2θ = 9.95, characteristic of the triclinic form but was otherwise dominated by orthorhombic peaks. An orthorhombic to triclinic phase transformation was observed to occur slowly on a hot stage when isothermal conditions were maintained at 140 °C. Fine orthorhombic crystals were seen to disappear gradually, while thicker, plateshaped crystals started to appear during polymorphic transformation. After a longer period at 140 °C, the orthorhombic crystals underwent sublimation. Recorded images are shown in Figure 1 (panels a−c). During this process of transformation, an intermediate vapor phase was observed as the triclinic plates were growing at the expense of contracting orthorhombic fine crystals (images are provided in the Supporting Information). Similar vapor phase polymorphic transformation has been observed in the case of venlafaxine hydrochloride.21 The intensity of the thick, platelike crystals increased, and there was a partial transformation into the triclinic form. Complete polymorphic transformation was not achieved at higher temperatures; in fact, many pharmaceutical materials subjected to higher temperatures over a long period of time are likely to suffer degradation. In order to confirm that polymorphic transformation was taking place through vapor phase
well-known. Louer et al. generated a metastable piracetam polymorph at room temperature. Form I of piracetam was formed by heating form III to 410 K at ambient pressure for 30 min in a glass capillary followed by quenching to room temperature.19 Boldyreve et al. demonstrated pressure-induced transformation of paracetamol in a diamond anvil cell. No change was observed in a single monoclinic crystal until the pressure was increased up to 4.5 GPa.20 The transformation was also observed when pressure was slowly decreased after an initial increase. This transformation is dependent on the API and the procedure of increasing/decreasing pressure. Lin et al. discussed the role of mechanical stress and rise in temperature during processing in polymorphic transformation using a grinding method.7 We performed isothermal hot stage microscopy (Axioplan 2 imaging) experiments to determine whether thermal treatment alone can cause complete polymorphic transformation in art crystals. Orthorhombic crystals of art were subjected to isothermal heating at 140 °C on a hot stage for 90 min and changes in form were recorded. Images were collected periodically using AxioCam MRc5 camera, and the product at the end of the experiment was collected and characterized by Powder X-ray Diffraction (PXRD). A Bruker D8 diffractometer (wavelength of X-rays 0.154 nm Cu source, voltage 40 keV, and filament emission 40 mA) was used to characterize the crystalline components. PXRD results for the orthorhombic 5158
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Table 1. SEM Images of the Samples Collected from Different Zones of Extruder and Schematic Presentation of the Proposed Transformation Mechanism
lization. The structural dynamics of complex fluids can be directly monitored via a standard optical microscope while subject to precisely controlled temperature and various shear modes. Shear cell microscopy was performed using a Linkam shear cell (CSS450) coupled with a polarized light microscope connected to a video capture system. The orthorhombic form was loaded between the top and bottom of highly polished quartz windows of the shear cell, and the gap between the two plates was reduced to 30 μm by slowly lowering the upper glass plate of the Linkam device. The sample was isothermally heated at 140 °C and for 15 shear cycles of one min each at the steady shear rate of 0.5 s−1, samples were collected after each cycle and analyzed by PXRD. Interestingly, complete transformation to the triclinic form was observed after only 13 min. The captured images are shown in Figure 1 (panels d−f). No polymorphic transformation was observed at lower shear rates (details are provided in the Supporting Information). It was not possible to track individual crystals of art since the continuous shear, the breakdown of crystals, and vapor phase transformation occurred simultaneously. In this process, the applied mechanical shear stress continually disrupts the crystalline structure, which leads to the formation of new surfaces being continuously exposed to high temperatures. The process of transformation is therefore accelerated under temperature and shear. We extended this concept using a combination of controlled temperature and shear and explored application of HTE to induce polymorphic transformation. The commercially available orthorhombic form of art was processed in a twin screw extruder (Pharmalab, Thermo Scientific, UK) having screw
Figure 4. Experimental PXRD patterns of the material collected from different zones of extruder.
sublimation, experiments were carried out using a sublimation unit. Orthorhombic crystals were heated at 145 °C. After 90 min, a new crystal phase started growing on the condensing surface (shown in Figure 2). The PXRD patterns confirmed that the collected sublimed crystals were the triclinic form. The PXRD pattern of the powder collected from the lower vessel showed partial transformation to the triclinic form (Figure 3). The combination of shear and temperature was considered necessary in order to achieve complete polymorphic transformation. The next set of experiments was performed to investigate the effect of temperature and shear using a shear cell microscopy. This provided an opportunity to study the material state under model shear conditions and has been widely used in polymer research to study flow and shear-enhanced crystal5159
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Figure 5. Orthorhombic and triclinic crystal structures, viewed in the (a) (200) plane and (b) (100) plane, respectively.
the amorphous phase. The obtained data suggested that no amorphous phase was involved during the HTE experiment. Complete transformation was observed in the next stage (zones 6−8), where the high shearing configuration caused further densification of the material, forming slightly larger agglomerates. Agglomerates conveyed into the final zone (8− 10) were observed to break down into smaller agglomerates, which may be due to shearing between the screw and barrel wall. This study has provided an understanding of polymorphic transformation of art through the vapor phase which occurs in high temperature extrusion and a complex process of agglomeration and deagglomeration. In our previous study concerning the formation of cocrystals in extrusion, similar observations were made whereby cocrystallization occurred via melt and eutectic phase assisted agglomeration induced by high shear stress.10 The suitability of solid-state polymorphic transformation by melt extrusion is currently being explored for a range of pharmaceutical applications. Otsuka and Matsuda reported polymorphic interconversion of chlorpropamide during compaction and proposed the formation of an unstable noncrystalline material during compaction, which spontaneously recrystallizes to provide different crystal forms.22 The same authors reported that the extent of polymorphic transformation is enhanced with repeated compaction cycles and reaches a plateau. It was also shown that increase in temperature of the die to 45 °C affected polymorphic transformation. Wildfong et al. investigated polymorphic transformation of chlorpropamide during the compression process to explore mechanistic understanding. It was proposed that the shear components of the applied stress causes lattice distortion and molecular rearrangements leading to polymorphic interconversion.23 The computational analysis was carried out to understand molecular arrangements in the crystal lattice and slip planes in the orthorhombic and triclinic crystals of artemisinin using the Morphology module in Material Studio 4.1.014.24 The 3D
Table 2. Results of Growth Morphology Calculations crystal orthorhombic
triclinic
surface {hkl}
total facet area (%)
attachment energies (Eatt total) (kcal/mol)
200 110 101 100 001
58.3 47.4 20 55.4 21.8
−37.53 −101.77 −162.48 −38.84 −68.47
diameter 16 mm and a length-to-diameter ratio of 40:1. A screw rotation speed of 20 rpm was applied. Full details of screw configuration and set temperature profiles are included in the Supporting Information. To examine the transient transformation further, samples of art from different zones along the extruder barrel were collected and characterized by SEM and PXRD. The results are shown in Table 1 and Figure 4. Observation of the collected samples revealed that agglomerated material occurred in the later section of the process. Within the extruder barrel, material passes through three stages: preheating, which occurs when the material passes through initial conveying zones and its temperature is raised to 100 °C. During this state no significant decrease in particle size or change in crystal form was observed. In the next zone, mixing paddles in the extruder screws were set up to impart higher shear and the set temperature was raised to 140 °C. Also in this region, forward conveying of the material is slowed by the mixing elements so the residence time is increased. It is assumed that art in this region of the extruder undergoes vapor phase transformation and significant reduction in size due to the high shearing stresses imparted by the screws. Samples taken from this zone did not show complete transformation to the triclinic form, although a considerable portion of orthorhombic API had already been converted. To obtain further insight about a specific transformation, the samples collected from each zone were analyzed by DSC for 5160
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ABBREVIATIONS HME- Hot Melt Extrusion; HTE- High Temperature Extrusion; PXRD- Powder X-ray Diffraction; art- artemisinin
crystal structure was obtained from the Cambridge Structural Database (CSD) with code QNGHS. A number of force fields and charge models were used to perform geometry optimization, and the calculated values of the unit cell dimensions were compared with experimental values. Full details of these calculations are provided in the Supporting Information. The PCFF force field25 with QEq charges26 was found to calculate lattice parameters in closest agreement with experimental data, and this force field was used in all further calculations. The cohesive strength of crystal planes is related to their attachment energies.23 Therefore, growth morphologies of the polymorph were calculated using the Morphology module, during which attachment energies of all low index faces were calculated. The calculated crystal habit was dominated by the {200} faces for the orthorhombic form and {100} for the triclinic form with percentage areas of 58.3% and 55.4%, respectively (Table 2). The molecular arrangement at the possible slip planes of the orthorhombic and triclinic forms are shown in Figure 5. It clearly shows that the molecular density is higher on the (100) surface of the triclinic form compared to the (200) surface of the orthorhombic crystal. In contrast, the slip plane surfaces of chlorpropamide demonstrated significant similarity in the molecular arrangement at the slip plane of two polymorphs, which was considered to be responsible for interconversion of these polymorphs.23 The difference in molecular arrangements of surfaces may have been responsible for transformation of orthorhombic to triclinic rather than interconversion under applied shear. During the HTE process, the crystalline material is subjected to shearing between two screws and between the barrel and screw surface with intermittent decompression. As compared to compaction, small portions of crystalline materials are repeatedly subjected to different shear regions across the barrel with maximum shear in the mixing zone where screw elements are arranged in different angles. Therefore, this process is more efficient in continuously disrupting crystal lattice at the slip planes. High shear and high temperature accelerate the process of transformation via sublimation. To conclude, the application of controlled temperature and shear has been demonstrated to produce a high purity, metastable triclinic form of art.
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ASSOCIATED CONTENT
S Supporting Information *
Hot stage microscopy experiment images, PXRD patterns of the material treated by hot stage and shear cell, screw configuration, temperature profile of extrusion experiment, and computational analysis. PXRD patterns of the orthorhombic and triclinic form of art are adapted from the Cambridge Crystallographic Database. Purity of the triclinic form obtained by HTE was analyzed by HPLC−MS, and details of the experiments, and DSC thermograms of the samples collected from different zones of extruder are provided. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest. 5161
dx.doi.org/10.1021/cg400891b | Cryst. Growth Des. 2013, 13, 5157−5161
