Phenomena and Kinetics of Solid-State Polymorphic Transition of

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DOI: 10.1021/cg901405h

Phenomena and Kinetics of Solid-State Polymorphic Transition of Caffeine

2010, Vol. 10 2916–2920

Yoshifumi Kishi and Masakuni Matsuoka* Department of Chemical Engineering, Tokyo University of Agriculture and Technology, 24-16 Naka-cho 2, Koganei, Tokyo 184-8588, Japan Received November 10, 2009; Revised Manuscript Received April 27, 2010

ABSTRACT: In situ AFM observation of polymorphic transition of caffeine form I (stable at high temperatures) to form II (stable at room temperature) was conducted to obtain fundamental information on the mechanism with which the solid state transition progresses. From the observation of formation of projections of a new phase (form II) followed by their growth inward, the crystalline body of form I was found. On the basis of this observation, the kinetics was analyzed by the penetration model proposed by Matsuo and Matsuoka,1 and the transition was found to be well expressed by the model.

1. Introduction Many compounds can exist as more than one crystal structure with different molecular packing or conformation, thus exhibiting polymorphism. Each polymorph has in general different physical and chemical properties such as melting point,2,3 solubility, dissolution rate, stability,4 morphology, and bioavailability;5 therefore, controlling polymorphism is crucial for the production of, in particular, pharmaceuticals. In addition, polymorphic transition from an unstable or metastable to more stable polymorphs can occur, and this has been a serious concern to the pharmaceutical industry.6,7 Major factors affecting polymorphic transition kinetics, such as temperature, humidity, mechanical stress, and compression, are related one another in a complicated manner.8,9 Pirttim€aiki et al.10 reported that the polymorphic transition of anhydrous caffeine readily took place during mechanical treatment and tableting compression and that the transition started in only 1 min of grinding, while in the case of tableting, the surface conversion to form II was faster than the ground tablets, indicating that the transition occurred mainly near the surface of the tablet. Matsuo and Matsuoka investigated the transition of theophylline fine particles from form III to form II and found that humidity accelerated the transition.11 They proposed a mechanism of transition that moisture penetrating into the mother crystalline particles drove the transition, and from the kinetic analysis, they found that both temperature and humidity were important factors for the transition.12 In addition, they also measured polymorphic transition of caffeine from form I to form II at various temperature and humidity levels. For this transition, humidity had no effect on the kinetics but temperature was important, and the kinetics were well explained by the penetration.1 Note that the molecular structure of caffeine is similar to that of theophylline. In general, phenomena of solid state polymorphic transition are observed with PXRD, DSC, FT-IR, FT-Raman, optical microscope, or SEM.2,3,7-9 However, because of resolution limitations, these tools have difficulty detecting changes in structures at nanolevels occurring on the crystal *To whom correspondence should be addressed. Phone: þ81-42-3887059. Fax: þ81-42-387-7944. E-mail: [email protected]. pubs.acs.org/crystal

Published on Web 05/25/2010

surface. Actually, the beginning of a transition, i.e., nucleation of a new solid phase, would occur at such levels so that the validity of the models introduced would be difficult to examine. From this point of view, AFM observation of transition processes would be advantageous for verifying the transition mechanism.13 In the present study, we aim to make clear the mechanism of solid state transition of caffeine, C8H10N4O2, 1,3,7-trimethylxanthine, from form I (stable at higher temperature) to form II (stable at room temperature). The transition is known to be enantiotropic.1,14-19 An in situ AFM observation technique is used, and we analyze the transition kinetics quantitatively. 2. Experimental Methods 2.1. Preparation of Caffeine Form I and Form II Particles. To prepare caffeine form II particles, which are stable at room temperature, special grade caffeine, purchased from Wako Pure Chemicals Co., >98.5% pure, was first dissolved in distilled water at 358 K to saturation and was naturally cooled to room temperature to yield caffeine hydrate crystals. The crystals were dried in a vacuum dryer at 353 K to obtain form II particles and were gently crushed with a stainless steel mortar because the obtained particles were too large and were needle-like. Form I was then prepared by keeping the form II particles in an electric furnace at 423 K for 3 or 16 h. The form I particles thus prepared were sieved, and the fraction in the size range of 38106 μm was used. For AFM observation, relatively large crystals of form I were prepared by keeping form II crystals at 493 K on a hot-plate for 30 min. For the observation of surface morphology and structures and for the measurement of particle size of the prepared polymorphic crystals of form I and form II, an optical microscope (Olympus BX333) and a scanning electron microscope (JEOL, JSM-5310LV) were used. 2.2. In Situ AFM Observation of Solid-State Polymorphic Transition from Form I to Form II. AFM observation was conducted using an AFM (NanoScope III, Digital Instruments) in contact mode. The prepared crystals of form I were fixed gently on an AFM specimen stage with a double-face adhesive tape, and measurement was started. It was kept at a constant temperature of 303 K, and AFM images were recorded in situ during the observation. The observed area was 1.0 μm  1.0 μm, and the scan rate was 2.0 Hz. 2.3. Transition Experiments. About 0.110 g of form I crystalline powders mounted on a sample holder was maintained in thermostat ovens controlled at 313, 333, and 353 K with silica gel for the purpose of desiccation, and the polymorphic composition was r 2010 American Chemical Society

Article measured with PXRD (MiniFlex, Rigaku Co., operating conditions, target Cu, filter Ni, voltage 30 kV, current 15 mA, scanning speed 3/min and 0.01/ step) at predetermined time intervals. The conversion at time t, Rt defined by eq 1 as the extent of transition from form I to form II, was calculated from the relative increase in the peak areas of the characteristic form II peak at approximately 27.5 < 2θ < 29.0 in accordance with the previous studies.1,19 integrated intensity at time t ð1Þ Rt ¼ integrated intensity of pure form II sample

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3. Results and Discussion

Figure 1. PXRD patterns of caffeine form I and form II: (top) form II; (bottom) form I.

3.1. Characterization of Polymorphic Forms. The PXRD patterns of prepared caffeine form I and form II particles are shown in Figure 1, and they are in good agreement with the PXRD patterns in the literature.15-19 Because of the recrystallization and storage at high temperature, intense peaks were obtained. Relatively large single crystals of caffeine form I prepared to observe the changes in surface morphology during the transition from form I to form II were transparent and had flat faces as shown in Figure 2. In order to determine the crystal faces, form I crystals were measured by PXRD. From the PXRD patterns, the peaks corresponding to the (2 -1 0) and (4 -2 0) were clearly intense compared with other peaks, indicating these faces were selectively developed. Therefore, we concluded that the measurement faces were identified as the {2 -1 0} faces by reference to a previous report.15 Figure 3 shows a series of AFM images during the transition. At the beginning of observation, the crystal surface was smooth, but as time elapsed, the surface morphology started to change by the penetration of projections from the outer area where AFM tip did not make contact. The projections became gradually larger (Figure 3a). The neighboring projections coalesced onto each other, and the boundaries disappeared. Similar phenomena were observed to occur in different areas (Figure 3b), and the transition was considered to have taken place from the surface with the projections as the starting point which appeared in the crystal surface suddenly.

Figure 2. Photomicrograph of caffeine form I by holding form II at 493 K.

Figure 4. Changes in PXRD patterns for transition of caffeine from form I to form II during storage at 353 K.

Pure form II particles were prepared by the method mentioned in section 2.1 (at 353 K for 16 h), and a calibration curve of integrated intensity versus mass was prepared.

Figure 3. AFM deflection images (1.0 μm  1.0 μm, scan rate of 2.0 Hz) of a crystal surface during the polymorphic transition from form I to form II.

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Kishi and Matsuoka

Figure 5. Solid state transition from form I to form II.

Figure 6. Optical microscope and scanning electron microscope images: (column a) optical microscope; (columns b-d) scanning electron microscope; (row 1) initial material as purchased; (row 2) crushed form II; (row 3) form I; (row 4) after transition. Scale is a follows: (a) 100 μm; (b) 10 μm; (c) 5 μm; (d) 1 μm.

3.2. Transition Experiments. In Figure 4 continuous changes of PXRD patterns during the transition at 353 K from form I to form II are illustrated. The transition was found to progress with the simultaneous changes of the characteristic peaks. The single characteristic peak at 2θ = 26.6 for form I broke into bimodal peaks specific to form II. The effect of the temperature on the transition kinetics is compared in Figure 5, showing that the conversion is significantly dependent on the temperature but that the holding time of the particles in the oven has no effect on the transition kinetics. It was also found that both the particle size and the appearance of particles changed significantly by the transition as shown in Figure 6. It contains optical and SEM photomicrographs of the particles of form II

(Figure 6, rows 1, 2, 4) and form I (Figure 6, row 3) at different magnifications. The particle size was different between the steps of experiments. Figure 6, row 1, shows the initial particles of caffeine form II as purchased. Figure 6, row 2, shows crushed form II particles after drying hydrate. Figure 6, row 3, shows form I after the transition at 423 K. The comparison of the optical and scanning electron microscope images reveals that form I crystals clearly became larger than initial particles (Figure 6, row 1). Because caffeine is sublimable, the Ostwald ripening occurred to increase the particle size with consuming smaller particles. From the AFM and optical microscope observations, the crystal surface of form I was smooth; however,

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Figure 7. Solid state transition from form I to form II and fitting results by the penetration model.

SEM images were different (Figure 6, images 3b,c,d) and there were some projections on the crystal surface. As previous studies1,19 mentioned and our experimental data (Figure 5) show, caffeine form I can readily undergo transition to form II even at room temperature, although the transition rate at lower temperature would be low. This means that transition has occurred even during pretreatment for SEM observation, in particular during Au-coating where local temperature would be higher; thus, the surface morphology has changed. Moreover, the observed morphology of the surface of form I; particles (Figure 6, image 3d) and the size were almost the same as those observed in AFM images (Figure 3). After completion of the transition, form II particles became smaller and the morphology was completely different (Figure 6, rows 3 and 4). To examine whether the transition at 353 K was completed or not, the samples after the experiment were analyzed with DSC, and the heat of transition from form II to form I was compared with that of pure form II. The result indicates that the values of heat of transition agreed well each other; therefore, the transition was understood to have been completed.14-16 3.3. Kinetics of Transition. As mentioned above, from the AFM observations, it was considered that the transition progressed as the form II structure propagated inward from the crystal surface. Therefore, the penetration model, eq 2, which was reported to describe well the transition kinetics of caffeine from form I to form II,1 was applied to the present case, and the results are shown in Figure 7. Rt ¼ 1 -

¥ 6 X 1 - n2 kd t e 2 π n ¼ 1 n2

Table 1. Kinetic Coefficients in the Penetration Model temp (K)

run

kd (S-1)

R2

353 353 333 333 313 313 353 353 333 333 313 313

16 h, run 1 16 h, run 2 16 h, run 1 16 h, run 2 16 h, run 1 16 h, run 2 3 h, run 1 3 h, run 2 3 h, run 1 3 h, run 2 3 h, run 1 3 h, run 2

3.22  10-6 3.15  10-6 4.35  10-7 4.14  10-7 1.33  10-7 1.08  10-7 3.82  10-6 3.33  10-6 5.69  10-7 5.09  10-7 1.21  10-7 1.46  10-7

0.985 0.970 0.931 0.932 0.852 0.900 0.974 0.968 0.952 0.919 0.898 0.873

Figure 8. Arrhenius plot of kd for the transition of caffeine from form I to form II.

4. Conclusions ð2Þ

The values of kinetic coefficients kd determined are given in Table 1, and the activation energy was calculated to be 73.8 kJ/mol (Figure 8). The value was almost comparable with that for the transition of caffeine from form I to form II,1 and the value of activation energy was considered to be reasonable, since those of many solid state transitions are, in general, of the order of tens to hundreds in kJ/mol. The model adopted here was first used to analyze the kinetics of solid state transition of theophylline; therefore, it can be concluded that the mechanism of transition of caffeine form I to form II is very similar to the one of theophylline form III to form II.12

Phenomena and kinetics of polymorphic solid-state transition of caffeine anhydrate from form I (stable at high temperatures) to form II (stable at room temperature) were investigated. The surface phenomena during the transition were observed using an atomic force microscope (AFM), and projections of different morphologies were observed to appear and to grow on the flat surface. The transition kinetics were well described by the penetration model in which the transition progressed as the form II structure propagated inward from the crystal surface. The activation energy of the transition was determined to be 73.8 kJ/mol. Acknowledgment. The authors gratefully acknowledge the financial support provided by the Grant-in-Aid for Scientific Research (A) (2007-2008, Grant 19206082) and Research (B)

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(2009-2011, Grant 21360378) Japan Society for the Promotion of Science (JSPS). Y.K. appreciates the support by the Human Resource Development Program for Scientific Powerhouse of Tokyo University of Agriculture and Technology.

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