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Rapid amorphization of molecular crystals by absorption of solvent molecules in the presence of hydrophilic matrices
Journal of Alloys and Compounds 483 (2009) 217–221
Contents lists available at ScienceDirect
Journal of Alloys and Compounds journal homepage: www.elsevier.com/locate/jallcom
Rapid amorphization of molecular crystals by absorption of solvent molecules in the presence of hydrophilic matrices S. Nakayama a,b,∗ , T. Watanabe c , M. Senna a,c a
Technofarm Axesz Co., Ltd., 3-45-4 Kamiishihara, Chofu, Tokyo 182-0035, Japan Nara Machinery Co., Ltd., 2-5-7 Jounan-jima, Tokyo 143-0002, Japan c Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Yokohama 223-8522, Japan b
a r t i c l e
i n f o
Article history: Received 30 August 2007 Received in revised form 5 July 2008 Accepted 27 July 2008 Available online 10 February 2009 Keywords: Amorphization Homogenization Molecular crystals Nanocomposites Hydrophilic matrices
a b s t r a c t Two organic molecular crystalline species, ibuprophen (IB) and indomethacine (IM) were subjected to methanol absorption in the presence of hydrophilic organic matrix, hydroxypropyl methylcellulose (HPMC). While spraying of 8–10% methanol or water on the drug–matrix mixture decreased the subsequent milling time for amorphization, absorption of methanol in a closed container caused spontaneous amorphization of IB was observed to give a nanocomposites with macroscopic agglomerates up to 250 m after methanol absorption for overnight. Gentle mechanical homogenization under saturated methanol vapor with a newly developed apparatus, a tandem rotation mill (TRM), brought about homogeneous grains of IB-HPMC nanocomposites with the average particle size, 30 m. We observed amorphous particles of IB in 60 nm regime dispersed in HPMC matrix under a transmission electron microscope (TEM). In the case of IM, mechanical homogenization with TRM was indispensable to obtain similar nanocomposites with HPMC. © 2009 Published by Elsevier B.V.
1. Introduction It is generally recognized that simple milling does not always allow reducing size of solid particles down to nanometer regime. It is particularly the case when we deal with soft solids like organic molecular crystals. Demands on organic nanoparticles, however, are ever glowing, among others in pharmaceutical or biomedical communities. Amorphization attempts of molecular crystals are plenty, in pharmaceutical science and technology in particular [1–3]. Apart from manipulating glass transition [4] or eutectic behaviors [5,6], cogrinding of molecular crystals with appropriate matrices is one of the easily affordable techniques to obtain organic amorphous particles [7–9] or inorganic pharmaceutical excipients [10], often in the form of nanoparticles. However, we are increasingly conscious to save energy to all the milling-related operations, not only from environmental or ecological viewpoints but also, and more importantly, due to preservation of chemical nature with simultaneous prevention of contamination. One of the smart ways to realize
∗ Corresponding author at: Technofarm Axesz Co., Ltd., 3-45-4 Kamiishihara, Chofu, Tokyo 182-0035, Japan. E-mail address: [email protected] (S. Nakayama). 0925-8388/$ – see front matter © 2009 Published by Elsevier B.V. doi:10.1016/j.jallcom.2008.07.236
these concepts is to use chemical spontaneity to a maximum extent [11]. We recently demonstrated rapid amorphization and nanomization of ibuprophen (IB) with the presence of hydroxypropyl methylcellulose (HPMC) to give nanocomposites by mixing clear solution of the individual species and quickly drying [12]. The method was easy and rapid but was restricted to a narrow composition range. We therefore explored smarter way of obtaining similar composites with larger allowance of the composition. This way of preparation for solid dispersion via solvent route is known as a solvent evaporation method [13], where the drying method plays a key role. Karavas et al. [14] observed amorphous nanoparticles after formulating composites comprising felodipine (Felo) and polyvinylpyrrolidone (PVP) via a solvent evaporation route. In the present study, we therefore attempt to give mobility to the organic solids for rapid amorphization and micronization. The objective of the present study is, thus, to obtain IB-HPMC or IM-HPMC nanocomposites by exposing IB or indomethacine (IM) crystals in the saturated vapor of methanol at room temperature in the presence of HPMC. For the purpose of homogenization of the entire mass of the composites, we developed mechanical homogenizer under the saturated methanol vapor, which plays another significant role from the viewpoints of practical application.
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Fig. 1. A schematic image of a tandem rotation mill (TRM).
2. Experimental 2.1. Materials We chose hydroxyprolyl methylcellulose (HPMC, Shin-etsu Chemicals Co., Ltd., Metolose 60SH-15) as a polymeric matrix due to its high hydrophilicity, chemical stability and popularity as an excipient. IB (TCI, Analytical grade, used as purchased) and IM (Sigma), both being popular anti-inflammatory drugs, were used as model drugs.
Fig. 2. XRD profiles of the samples: (a) IB20-PM, (b) IB20-M3 h, (c) IB20-Sm1 h, (d) IB20-Sw3 h, (e) IB20-AB16 h, and (f) IB20-TRM16 h.
3. Results 3.1. Amorphization of IB and IM
2.2. Addition of methanol as vapor to physical mixture of drug and matrix A physical mixture (PM) of the drug and matrix was prepared by mixing them manually in an agate motar. Dry milling was operated using a planetary mill (Fritsch, Pulversitte 5) at rotation and revolution speeds 245 and 196 rpm, respectively, for 3 h. We denote these samples by a letter M. To add small amount of liquids, 10% (to the mixture) of methanol or 8% of water was sprayed through a hand spray onto the surface of the powder mass comprising drug and matrix under continuous stirring by a PTFE paddle. The mixture was subsequently milled with the planetary mill for 1–3 h under the same condition as sample M to obtain sample Sm or Sw for methanol or water, respectively.
2.3. Absorption of methanol in a closed container To add methanol more homogeneously, we spread PM on a filter paper and put it on a sieve in a closed container with saturated methanol vapor at 25 ◦ C up to 16 h. Samples thus prepared were named AB.
2.4. Tandem rotation mill (TRM)
XRD profiles of IB are shown in Fig. 2. Intensities of IB crystalline diffraction peaks were decreased after dry milling with HPMC for 3 h as shown in Fig. 2(b), compared to the physical mixture as shown in Fig. 2(a), but significant portion of IB remained still crystalline. When 9.6% of methanol was sprayed and subsequently milled for 3 h, the XRD peak intensities further reduced and exhibited a state close to amorphous, as shown in Fig. 2(c). When we replaced the solvent to 8% of water, the same effect was recognized as shown in Fig. 2(d). This indicates that addition of a small amount of methanol or water accelerated amorphization of IB. Note that a diffraction peak at around 2 = 17◦ in Fig. 2(b) and (c) is ascribed to the PTFE contamination from the grinding vessel, and the peaks between 22◦ and 28◦ are attributed to the signals from clay to mount the sample mass and not to IB. In contrast, complete amorphization of IB was accomplished after absorption of methanol in a closed container without milling,
To accomplish absorption of the solvent vapor and simultaneous homogenization, a mixing devise shown in Fig. 1 was devised and named as a “TRM”. Two cylindrical vessels with their diameter 95 mm were set coaxially on rotating rolls. Vessels were connected by a flexible short tube with its diameter 6 mm, to keep the entire volume airtight. Fifty milliliters of methanol was inserted in one vessel (A), while 40 nylon-coated steel balls with the diameter 15 mm and the sample with weight 4 g were put into the other vessel (B). Vessel A was warmed to 50 ◦ C in a water bath to enrich the methanol vapor in both vessels. Both of the vessels were then rotated at 144 rpm for up to 16 h. Each sample was named with its drug weight percent, mixing method and a treatment time, e.g. IB20AB15 min.
2.5. Characterization Change in the crystallinity was monitored by conventional X-ray diffractometry (XRD) (Rigaku, RINT 2000). Physical states of grains were observed under an optical microscope (OM) and transmission electron microscopy (FE-TEM, TECNAI F20, TECNAI, with 120 kV acceleration voltage). We exposed the sample to the vapor above a 1% (w/v) aqueous solution of OsO4 for 2 h to acquire better contrast of the micrographs. Chemical states of IB and HPMC, including their interaction, were examined by FT-IR spectroscopy (FT-IR, FTS60A, Varian) by a conventional KBr method.
Fig. 3. XRD profiles of the samples: (a) IM20-PM, (b) IM20-AB16 h, and (c) IM20TRM16 h.
S. Nakayama et al. / Journal of Alloys and Compounds 483 (2009) 217–221
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Fig. 4. Optical microscopic images of the samples: (a) IB20-AB16 h, (b) IB20-TRM16 h, and (c) IB100-AB15 min, and (d) IB20-AB15 min.
as shown in Fig. 2(e). The state of amorphization remains almost unchanged when we exert weak mechanical stressing by TRM, as shown in Fig. 2(f). It is therefore obvious, that methanol sorption to the mixture of IB and HPMC is very effective for amorphization of IB. When we treated with no solvent in a vessel (A), the same TRM treatment did not give rise to IB amorphization. When IM was treated under the same condition, i.e. by exposure to the saturated vapor of methanol at room temperature, spontaneous amorphization did not occur, as shown in Fig. 3(b). IB20-PM was shown in Fig. 3(a) for comparison. It is important to note that amorphization of IM proceeds close to completion by very weak mechanical treatment with TRM in the saturated methanol vapor, as shown in Fig. 3(c). 3.2. Particulate morphology Amorphous mixture comprising IB and HPMC after absorption of methanol vapor for 16 h was highly agglomerated, as shown in
Fig. 4(a). By treating with TRM, however, the mass turned into much more homogeneous, as shown in Fig. 4(b). Although the state of homogeneity does not seem to be significantly different, as far as Xray diffractograms are concerned (Fig. 2(e) and (f)), granulometrical properties the size regime between several to hundreds of micrometers significantly change, as shown in Fig. 4(a) and (b). For IB20-AB shown in Fig. 4(a), highly agglomerated particles over 250 mm are observed and particle size is 260 ± 110 m in the micrographical image, while for IB20-TRM, in Fig. 4(b), particle size is decreased to 34 ± 13 m. We observed the amorphized sample under a TEM. As shown in Fig. 5, the drug particles, as stained by OsO4 , are well-dispersed spherical particles in the size 60 ± 31 nm, which are very close to what we have observed in our previous study on the formation of amorphous nanoparticles of IB obtained via a sol–gel route [12]. Note that OsO4 vapors preferentially adsorb to CHCH bonds, which is imparted to IB but not to HPMC. The texture is similar to what Karavas et al have observed for the Felo–PVP system [14].
Fig. 5. TEM images of IB20-TRM16 h at smaller (a) and larger (b) magnification.
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S. Nakayama et al. / Journal of Alloys and Compounds 483 (2009) 217–221
Fig. 6. FT-IR spectra of C O stretch region: (a) peak separation curves (green) and calculated curve (red) of IB intact (black), and (b) peak separation curves (green) and calculated curve (red) of IB20-TRM16 h (black). Colors are given on the Internet version. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
Fig. 7. FT-IR spectra of C O stretch region: (a) peak separation curves (green) and calculated curve (red) of IM intact (black), and (b) peak separation curves (green) and calculated curve (red) of IM20-TRM16 h (black). Colors are given on the Internet version. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
4. Discussion 4.1. Possible chemical interaction between IB and HPMC FT-IR spectra of C O vibration peak of intact IB, HPMC, and IB20TRM16 h are shown in Fig. 6(a) and (b). Peak separation was done using ORIGIN® by curve fitting with Gaussian basis. Peak number was set to 2 and initial FWHM, settled at 10 cm−1 . Intact IB peak in Fig. 6(a) at 1693 and 1719 cm−1 and signals from phenyl ring at 1507 cm−1 blue-shifted to 1719, 1737 and 1513 cm−1 in IB20TRM16 h, respectively. C O peaks of intact IM and IM20-TRM16 h are shown in Fig. 7(a) and (b). Peak number was set to 3, and initial FWHM, settled at 10 cm−1 for peak separation. The result was summarized in Table 1 as well. C O peaks at 1712 and 1688 cm−1 also blue-shifted to 1717 and 1694 cm−1 , respectively. These FT-IR shifts suggest the recombination of hydrogen bonds of intermolecular IB to the interaction between IB and HPMC. In our previous work, the interaction was also represented as blue shifts of FT-IR peaks [12]. 4.2. Consequences of methanol absorption When IB crystals were exposed to the saturated methanol vapor in a closed container for 15 min, they changed to spherical droplets, as shown in Fig. 4(c). This is a clear indication that IB absorbs a large amount of methanol quickly and turns quickly into the state of a saturated solution of methanol. When we simply heat this droplet and accelerate nuclear formation into dryness, amorphization never occurred. The same simple experiment was carried out under the coexistence of HPMC and observed under the OM. As
shown in Fig. 4(d), spherical aggregates in the same size range to bare droplets were observed. Therefore, chemical interaction between IB and HPMC in the samples IB20-AB and IB20-TRM must have occurred with the coexistence of a liquid phase. 4.3. Comparison between IB and IM As shown above, both IB and IM are amorphized by methanol absorption. However, the effects of methanol on two drugs are different. While IB amorphized spontaneously, IM required TRM treatment for complete amorphization. We observed spontaneous liquefaction of IB upon methanol absorption but not of IM. It is therefore straightforwardly conceivable that insufficient molecular mobility was supplemented by mild mechanical stressing to reduce the drug-excipient distance to recombine hydrogen bonds, necessary for amorphization of IM. Note that the color of IM20-AB16 h turned to pale yellow like IM20-TRM16 h, while no color change was observed for IM20-PM. The authors attribute the difference in the amorphization behavior between IB and IM to the common mechanisms of the present amorphization, i.e.: (i) affinity of the molecular crystals to methanol, represented by their solubility in methanol [15], (ii) quantity and topotaxy of the hydrogen bonds in their crystalline states, and (iii) polarity of hydrogen bonds and associated probability of proton transfer to the matrix, HPMC. 5. Concluding remarks Spontaneous amorphization of IB was observed as nanocomposites after methanol absorption for overnight. Gentle mechanical
S. Nakayama et al. / Journal of Alloys and Compounds 483 (2009) 217–221
homogenization under saturated methanol vapor with a newly developed apparatus, a TRM, brought about homogeneous grains of IB-HPMC nanocomposites and amorphization of IM. We observed amorphous particles of IB in 60 nm regime dispersed in HPMC matrix. The entire amorphization process could well be applied to pharmaceutical field to improve bioavailability of sparing soluble drugs. Acknowledgements The authors thank Shin-etsu Chemical Co., Ltd. for donating HPMC. They appreciate Ms. Katharina Wagner in University Karlsruhe, Germany for experimental support. References [1] B.C. Hancock, G. Zografi, J. Pharm. Sci. 86 (1997) 1–12.
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[2] L. Yu, Adv. Drug Deliv. Rev. 48 (2001) 27–42. [3] T. Watanabe, N. Wakiyama, A. Kusai, M. Senna, Powder Technol. 141 (2004) 227–232. [4] A. Foster, J. Hempenstall, I. Tucker, T. Rades, Int. J. Pharm. 226 (2001) 147– 161. [5] C.S. Yong, S.H. Jung, J.D. Rhee, H.G. Choi, B.J. Lee, D.C. Kim, Y.W. Choi, C.K. Kim, Drug Deliv. 10 (2003) 179–183. [6] S.R. Vippagunta, Z. Wang, S. Hornung, S.L. Krill, J. Pharm. Sci. 96 (2007) 294–304. [7] T.P. Shakhtshneider, M.A. Vasilchenko, A.A. Politov, V.V. Boldyrev, J. Therm. Anal. 48 (1997) 491–501. [8] T. Ozeki, H. Yuasa, Y. Kanaya, Int. J. Pharm. 155 (1997) 209–217. [9] T. Watanabe, S. Hasegawa, N. Wakiyama, A. Kusai, M. Senna, Int. J. Pharm. 250 (2003) 283–286. [10] T. Watanabe, S. Hasegawa, N. Wakiyama, F. Usui, A. Kusai, T. Isobe, M. Senna, J. Solid State Chem. 164 (2002) 27–33. [11] M. Senna, J. Therm. Anal. (2007) doi:10.1007/s10973-007-8483-z. [12] S. Nakayama, K. Ihara, M. Senna, Powder Technol. Submitted for publication. [13] F.I. Kanaze, E. Kokkalou, I. Niopas, M. Georgarakis, A. Stergiou, D. Bikiaris, J. Therm. Anal. Calorim. 83 (2006) 283–290. [14] E. Karavas, M. Georgarakis, A. Docoslis, D. Bikiaris, Int. J. Pharm. 340 (2007) 76–83. [15] S. Gracin, A.C. Rasmuson, J. Chem. Eng. Data 47 (2002) 1379–1383.
Contents lists available at ScienceDirect
Journal of Alloys and Compounds journal homepage: www.elsevier.com/locate/jallcom
Rapid amorphization of molecular crystals by absorption of solvent molecules in the presence of hydrophilic matrices S. Nakayama a,b,∗ , T. Watanabe c , M. Senna a,c a
Technofarm Axesz Co., Ltd., 3-45-4 Kamiishihara, Chofu, Tokyo 182-0035, Japan Nara Machinery Co., Ltd., 2-5-7 Jounan-jima, Tokyo 143-0002, Japan c Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Yokohama 223-8522, Japan b
a r t i c l e
i n f o
Article history: Received 30 August 2007 Received in revised form 5 July 2008 Accepted 27 July 2008 Available online 10 February 2009 Keywords: Amorphization Homogenization Molecular crystals Nanocomposites Hydrophilic matrices
a b s t r a c t Two organic molecular crystalline species, ibuprophen (IB) and indomethacine (IM) were subjected to methanol absorption in the presence of hydrophilic organic matrix, hydroxypropyl methylcellulose (HPMC). While spraying of 8–10% methanol or water on the drug–matrix mixture decreased the subsequent milling time for amorphization, absorption of methanol in a closed container caused spontaneous amorphization of IB was observed to give a nanocomposites with macroscopic agglomerates up to 250 m after methanol absorption for overnight. Gentle mechanical homogenization under saturated methanol vapor with a newly developed apparatus, a tandem rotation mill (TRM), brought about homogeneous grains of IB-HPMC nanocomposites with the average particle size, 30 m. We observed amorphous particles of IB in 60 nm regime dispersed in HPMC matrix under a transmission electron microscope (TEM). In the case of IM, mechanical homogenization with TRM was indispensable to obtain similar nanocomposites with HPMC. © 2009 Published by Elsevier B.V.
1. Introduction It is generally recognized that simple milling does not always allow reducing size of solid particles down to nanometer regime. It is particularly the case when we deal with soft solids like organic molecular crystals. Demands on organic nanoparticles, however, are ever glowing, among others in pharmaceutical or biomedical communities. Amorphization attempts of molecular crystals are plenty, in pharmaceutical science and technology in particular [1–3]. Apart from manipulating glass transition [4] or eutectic behaviors [5,6], cogrinding of molecular crystals with appropriate matrices is one of the easily affordable techniques to obtain organic amorphous particles [7–9] or inorganic pharmaceutical excipients [10], often in the form of nanoparticles. However, we are increasingly conscious to save energy to all the milling-related operations, not only from environmental or ecological viewpoints but also, and more importantly, due to preservation of chemical nature with simultaneous prevention of contamination. One of the smart ways to realize
∗ Corresponding author at: Technofarm Axesz Co., Ltd., 3-45-4 Kamiishihara, Chofu, Tokyo 182-0035, Japan. E-mail address: [email protected] (S. Nakayama). 0925-8388/$ – see front matter © 2009 Published by Elsevier B.V. doi:10.1016/j.jallcom.2008.07.236
these concepts is to use chemical spontaneity to a maximum extent [11]. We recently demonstrated rapid amorphization and nanomization of ibuprophen (IB) with the presence of hydroxypropyl methylcellulose (HPMC) to give nanocomposites by mixing clear solution of the individual species and quickly drying [12]. The method was easy and rapid but was restricted to a narrow composition range. We therefore explored smarter way of obtaining similar composites with larger allowance of the composition. This way of preparation for solid dispersion via solvent route is known as a solvent evaporation method [13], where the drying method plays a key role. Karavas et al. [14] observed amorphous nanoparticles after formulating composites comprising felodipine (Felo) and polyvinylpyrrolidone (PVP) via a solvent evaporation route. In the present study, we therefore attempt to give mobility to the organic solids for rapid amorphization and micronization. The objective of the present study is, thus, to obtain IB-HPMC or IM-HPMC nanocomposites by exposing IB or indomethacine (IM) crystals in the saturated vapor of methanol at room temperature in the presence of HPMC. For the purpose of homogenization of the entire mass of the composites, we developed mechanical homogenizer under the saturated methanol vapor, which plays another significant role from the viewpoints of practical application.
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Fig. 1. A schematic image of a tandem rotation mill (TRM).
2. Experimental 2.1. Materials We chose hydroxyprolyl methylcellulose (HPMC, Shin-etsu Chemicals Co., Ltd., Metolose 60SH-15) as a polymeric matrix due to its high hydrophilicity, chemical stability and popularity as an excipient. IB (TCI, Analytical grade, used as purchased) and IM (Sigma), both being popular anti-inflammatory drugs, were used as model drugs.
Fig. 2. XRD profiles of the samples: (a) IB20-PM, (b) IB20-M3 h, (c) IB20-Sm1 h, (d) IB20-Sw3 h, (e) IB20-AB16 h, and (f) IB20-TRM16 h.
3. Results 3.1. Amorphization of IB and IM
2.2. Addition of methanol as vapor to physical mixture of drug and matrix A physical mixture (PM) of the drug and matrix was prepared by mixing them manually in an agate motar. Dry milling was operated using a planetary mill (Fritsch, Pulversitte 5) at rotation and revolution speeds 245 and 196 rpm, respectively, for 3 h. We denote these samples by a letter M. To add small amount of liquids, 10% (to the mixture) of methanol or 8% of water was sprayed through a hand spray onto the surface of the powder mass comprising drug and matrix under continuous stirring by a PTFE paddle. The mixture was subsequently milled with the planetary mill for 1–3 h under the same condition as sample M to obtain sample Sm or Sw for methanol or water, respectively.
2.3. Absorption of methanol in a closed container To add methanol more homogeneously, we spread PM on a filter paper and put it on a sieve in a closed container with saturated methanol vapor at 25 ◦ C up to 16 h. Samples thus prepared were named AB.
2.4. Tandem rotation mill (TRM)
XRD profiles of IB are shown in Fig. 2. Intensities of IB crystalline diffraction peaks were decreased after dry milling with HPMC for 3 h as shown in Fig. 2(b), compared to the physical mixture as shown in Fig. 2(a), but significant portion of IB remained still crystalline. When 9.6% of methanol was sprayed and subsequently milled for 3 h, the XRD peak intensities further reduced and exhibited a state close to amorphous, as shown in Fig. 2(c). When we replaced the solvent to 8% of water, the same effect was recognized as shown in Fig. 2(d). This indicates that addition of a small amount of methanol or water accelerated amorphization of IB. Note that a diffraction peak at around 2 = 17◦ in Fig. 2(b) and (c) is ascribed to the PTFE contamination from the grinding vessel, and the peaks between 22◦ and 28◦ are attributed to the signals from clay to mount the sample mass and not to IB. In contrast, complete amorphization of IB was accomplished after absorption of methanol in a closed container without milling,
To accomplish absorption of the solvent vapor and simultaneous homogenization, a mixing devise shown in Fig. 1 was devised and named as a “TRM”. Two cylindrical vessels with their diameter 95 mm were set coaxially on rotating rolls. Vessels were connected by a flexible short tube with its diameter 6 mm, to keep the entire volume airtight. Fifty milliliters of methanol was inserted in one vessel (A), while 40 nylon-coated steel balls with the diameter 15 mm and the sample with weight 4 g were put into the other vessel (B). Vessel A was warmed to 50 ◦ C in a water bath to enrich the methanol vapor in both vessels. Both of the vessels were then rotated at 144 rpm for up to 16 h. Each sample was named with its drug weight percent, mixing method and a treatment time, e.g. IB20AB15 min.
2.5. Characterization Change in the crystallinity was monitored by conventional X-ray diffractometry (XRD) (Rigaku, RINT 2000). Physical states of grains were observed under an optical microscope (OM) and transmission electron microscopy (FE-TEM, TECNAI F20, TECNAI, with 120 kV acceleration voltage). We exposed the sample to the vapor above a 1% (w/v) aqueous solution of OsO4 for 2 h to acquire better contrast of the micrographs. Chemical states of IB and HPMC, including their interaction, were examined by FT-IR spectroscopy (FT-IR, FTS60A, Varian) by a conventional KBr method.
Fig. 3. XRD profiles of the samples: (a) IM20-PM, (b) IM20-AB16 h, and (c) IM20TRM16 h.
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Fig. 4. Optical microscopic images of the samples: (a) IB20-AB16 h, (b) IB20-TRM16 h, and (c) IB100-AB15 min, and (d) IB20-AB15 min.
as shown in Fig. 2(e). The state of amorphization remains almost unchanged when we exert weak mechanical stressing by TRM, as shown in Fig. 2(f). It is therefore obvious, that methanol sorption to the mixture of IB and HPMC is very effective for amorphization of IB. When we treated with no solvent in a vessel (A), the same TRM treatment did not give rise to IB amorphization. When IM was treated under the same condition, i.e. by exposure to the saturated vapor of methanol at room temperature, spontaneous amorphization did not occur, as shown in Fig. 3(b). IB20-PM was shown in Fig. 3(a) for comparison. It is important to note that amorphization of IM proceeds close to completion by very weak mechanical treatment with TRM in the saturated methanol vapor, as shown in Fig. 3(c). 3.2. Particulate morphology Amorphous mixture comprising IB and HPMC after absorption of methanol vapor for 16 h was highly agglomerated, as shown in
Fig. 4(a). By treating with TRM, however, the mass turned into much more homogeneous, as shown in Fig. 4(b). Although the state of homogeneity does not seem to be significantly different, as far as Xray diffractograms are concerned (Fig. 2(e) and (f)), granulometrical properties the size regime between several to hundreds of micrometers significantly change, as shown in Fig. 4(a) and (b). For IB20-AB shown in Fig. 4(a), highly agglomerated particles over 250 mm are observed and particle size is 260 ± 110 m in the micrographical image, while for IB20-TRM, in Fig. 4(b), particle size is decreased to 34 ± 13 m. We observed the amorphized sample under a TEM. As shown in Fig. 5, the drug particles, as stained by OsO4 , are well-dispersed spherical particles in the size 60 ± 31 nm, which are very close to what we have observed in our previous study on the formation of amorphous nanoparticles of IB obtained via a sol–gel route [12]. Note that OsO4 vapors preferentially adsorb to CHCH bonds, which is imparted to IB but not to HPMC. The texture is similar to what Karavas et al have observed for the Felo–PVP system [14].
Fig. 5. TEM images of IB20-TRM16 h at smaller (a) and larger (b) magnification.
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Fig. 6. FT-IR spectra of C O stretch region: (a) peak separation curves (green) and calculated curve (red) of IB intact (black), and (b) peak separation curves (green) and calculated curve (red) of IB20-TRM16 h (black). Colors are given on the Internet version. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
Fig. 7. FT-IR spectra of C O stretch region: (a) peak separation curves (green) and calculated curve (red) of IM intact (black), and (b) peak separation curves (green) and calculated curve (red) of IM20-TRM16 h (black). Colors are given on the Internet version. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)
4. Discussion 4.1. Possible chemical interaction between IB and HPMC FT-IR spectra of C O vibration peak of intact IB, HPMC, and IB20TRM16 h are shown in Fig. 6(a) and (b). Peak separation was done using ORIGIN® by curve fitting with Gaussian basis. Peak number was set to 2 and initial FWHM, settled at 10 cm−1 . Intact IB peak in Fig. 6(a) at 1693 and 1719 cm−1 and signals from phenyl ring at 1507 cm−1 blue-shifted to 1719, 1737 and 1513 cm−1 in IB20TRM16 h, respectively. C O peaks of intact IM and IM20-TRM16 h are shown in Fig. 7(a) and (b). Peak number was set to 3, and initial FWHM, settled at 10 cm−1 for peak separation. The result was summarized in Table 1 as well. C O peaks at 1712 and 1688 cm−1 also blue-shifted to 1717 and 1694 cm−1 , respectively. These FT-IR shifts suggest the recombination of hydrogen bonds of intermolecular IB to the interaction between IB and HPMC. In our previous work, the interaction was also represented as blue shifts of FT-IR peaks [12]. 4.2. Consequences of methanol absorption When IB crystals were exposed to the saturated methanol vapor in a closed container for 15 min, they changed to spherical droplets, as shown in Fig. 4(c). This is a clear indication that IB absorbs a large amount of methanol quickly and turns quickly into the state of a saturated solution of methanol. When we simply heat this droplet and accelerate nuclear formation into dryness, amorphization never occurred. The same simple experiment was carried out under the coexistence of HPMC and observed under the OM. As
shown in Fig. 4(d), spherical aggregates in the same size range to bare droplets were observed. Therefore, chemical interaction between IB and HPMC in the samples IB20-AB and IB20-TRM must have occurred with the coexistence of a liquid phase. 4.3. Comparison between IB and IM As shown above, both IB and IM are amorphized by methanol absorption. However, the effects of methanol on two drugs are different. While IB amorphized spontaneously, IM required TRM treatment for complete amorphization. We observed spontaneous liquefaction of IB upon methanol absorption but not of IM. It is therefore straightforwardly conceivable that insufficient molecular mobility was supplemented by mild mechanical stressing to reduce the drug-excipient distance to recombine hydrogen bonds, necessary for amorphization of IM. Note that the color of IM20-AB16 h turned to pale yellow like IM20-TRM16 h, while no color change was observed for IM20-PM. The authors attribute the difference in the amorphization behavior between IB and IM to the common mechanisms of the present amorphization, i.e.: (i) affinity of the molecular crystals to methanol, represented by their solubility in methanol [15], (ii) quantity and topotaxy of the hydrogen bonds in their crystalline states, and (iii) polarity of hydrogen bonds and associated probability of proton transfer to the matrix, HPMC. 5. Concluding remarks Spontaneous amorphization of IB was observed as nanocomposites after methanol absorption for overnight. Gentle mechanical
S. Nakayama et al. / Journal of Alloys and Compounds 483 (2009) 217–221
homogenization under saturated methanol vapor with a newly developed apparatus, a TRM, brought about homogeneous grains of IB-HPMC nanocomposites and amorphization of IM. We observed amorphous particles of IB in 60 nm regime dispersed in HPMC matrix. The entire amorphization process could well be applied to pharmaceutical field to improve bioavailability of sparing soluble drugs. Acknowledgements The authors thank Shin-etsu Chemical Co., Ltd. for donating HPMC. They appreciate Ms. Katharina Wagner in University Karlsruhe, Germany for experimental support. References [1] B.C. Hancock, G. Zografi, J. Pharm. Sci. 86 (1997) 1–12.
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