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Triboelectrification of active pharmaceutical ingredients: week acids and their salts
International Journal of Pharmaceutics 493 (2015) 434–438
Contents lists available at ScienceDirect
International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm
Triboelectrification of active pharmaceutical ingredients: week acids and their salts Kenta Fujinumaa,b , Yuji Ishiia , Yasuo Yashihashia , Estuo Yonemochic , Kiyohiko Suganoa,* , Katsuhide Taradaa a b c
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan Generic Pharmaceutical Development Department, Nippon Chemiphar Co., Ltd., 1-22, Hikokawado, Misato, Saitama 341-0005, Japan School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41, Ebara, Shinagawa, Tokyo 142-8501, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 11 May 2015 Received in revised form 27 July 2015 Accepted 2 August 2015 Available online 4 August 2015
The effect of salt formulation on the electrostatic property of active pharmaceutical ingredients was investigated. The electrostatic property of weak acids (carboxylic acids and amide-enole type acid) and their sodium salts was evaluated by a suction-type Faraday cage meter. Free carboxylic acids showed negative chargeability, whereas their sodium salts showed more positive chargeability than the free acids. However, no such trend was observed for amide-enole type acids. ã 2015 Elsevier B.V. All rights reserved.
Keywords: Triboelectrification Active pharmaceutical ingredient Weak acid Sodium salt Zero-charge margin Standard carrier beads
1. Introduction Active pharmaceutical ingredients (API) and excipients are prone to electrostatic charging (triboelectrification) by contacting with other materials such as excipients, containers and manufacturing equipments (Engers et al., 2007; Šupuk et al., 2012; Watanabe et al., 2007). Triboelectrification of API and excipients affects powder flow (Engers et al., 2006; Han et al., 2011), dose uniformity (Hao et al., 2013; Pu et al., 2009), metal sticking (Ghori et al., 2014; Zhu et al., 2007), etc. Therefore, it is important to understand the triboelectrification properties of APIs for the quality-by-design (QbD) approach (Olusanmi et al., 2014; Thoorens et al., 2014; Wu et al., 2011). However, the triboelectrification properties of APIs and excipients have not been well investigated (Engers et al., 2007; Šupuk et al., 2012; Watanabe et al., 2007). In drug discovery and development, API form optimization is usually performed before formulation studies (Lee, 2014; Tarsa et al., 2010). At this stage of pre-formulation, various API forms such as salts, cocrystals, and hydrates, are evaluated for dissolution property (Getsoian et al., 2008), chemical stability (Sonje et al.,
* Corresponding author. Fax: +81 47 472 1344. E-mail address: [email protected] (K. Sugano). http://dx.doi.org/10.1016/j.ijpharm.2015.08.008 0378-5173/ ã 2015 Elsevier B.V. All rights reserved.
2011), physical stability (Kojima et al., 2007), etc. However, the triboelectrification property of an API form is usually not investigated even though the chemical composition of an API form mainly determines the triboelectrification properties of the API particles (Shinohara et al., 1976). Little is known about the chemical composition—triboelectrification property relationship. Recently, Supuk et al., (2013) reported the effect of counter ions on the triboelectrification properties of flurbiprofen using a series of amine counter ions. However, sodium ion is most frequently used as the counter ion of an acid. The purpose of the present study was to investigate the effect of sodium salt formation on the triboelectrification properties of various weak acids. 2. Material and methods 2.1. Materials 2.1.1. Standard carrier beads and standard toner The standard carrier beads (N-1, N-2, P-1 and P-2) (Fig. 1) were purchased from the Imaging Society of Japan (Tokyo, Japan) (Hiraga et al., 2013). The P-01 and P-02 carrier beads were made from magnetite, manganese ferrite, modified silicone resin and carbon black. The N-01 and N-02 carrier beads were made from magnetite, manganese ferrite and acrylic resin. The order of the charge induction ability of the standard carrier beads was (positive
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Table 1 Specific charges of master standard toner induced by contact with each standard carrier beads. Grade of standard carrier beads N-01 Specific charge of master standard toner [mC/g]a a
35.8
N-02
P-01 P-02
22.2 23.9
38.4
Obtained from the Imaging Society of Japan.
Fig. 2. Schematic diagram of aspiration nozzle of EA-02, filter capsule and separating device.
side) P-02 > P-01 > N-02 > N-01 (negative side) (Table 1). These standard carrier beads were calibrated against the master standard toner by the Imaging Society of Japan. The specific charges of the standard toner induced by contact with the standard carrier beads are shown in Table 1. The particle sizes (d50) of all standard carrier beads were greater than about 75 mm (Fig. 1).
Fig. 1. Particle size distribution (PSD) and scanning electron microscope (SEM) images of standard carrier beads. PSD: microtrac-bel, microtrac MT3100II. SEM: KEYENCE, VE-7800.
2.1.2. Powder samples In this study, free acids and their sodium salts (carboxylic acids and amide-enole type acids) were used as model drugs. Salicylic acid, sodium salicylate, palmitic acid, ibuprofen, DL-malic acid, maleic acid, oxalic acid, sodium oxalate, succinic acid, disodium succinate, fumaric acid, sodium hydrogen fumarate, disodium fumarate, citric acid, sodium citrate and trisodium citrate were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). Diclofenac sodium, malonic acid, disodium malonate, glutaric acid, disodium glutarate, disodium DL-malate hydrate, phthalic acid, disodium phthalate, sodium maleate trihydrate, disodium maleate, disodium L-(+)-tartrate dehydrate, sodium succinate, disodium citrate sesquihydrate, dantrolene sodium and omeprazole were purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). Sodium palmitate was purchased from Chem Service, Inc. (Pennsylvania, United States). Benzoic acid, barbital and barbital sodium were purchased from Nacalai Tesque, Inc. (Kyoto, Japan). Sodium benzoate was purchased from SigmaAldrich Corporation (St. Louis, United States). Disodium oxalate was purchased from Junsei Chemical Co., Ltd. (Tokyo, Japan). Tartaric acid was purchased from Miyazawa Yakuhin Co., Ltd. (Tokyo, Japan). Sodium (+)-tartrate dehydrate was purchased from Kanto Chemical Co., Inc. (Tokyo, Japan). Diclofenac free acid was prepared by adding HCl to diclofenac sodium dissolved in water. Ibuprofen sodium was prepared by converting ibuprofen free acid to Na salt by adding NaOH and recrystallized from acetone. Dantrolene was prepared by converting dantrolene sodium to free acid by adding HCl and recrystallized from acetonitrile–ethanol–
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Fig. 3. Calculate plot to calculate the zero-charge margin.
Table 2 Zero-charge margins of powder samples. Powder sample
Zero-charge margin [mC/g]a Free acid
Salicylic acid Palmitic acid Benzoic acid Diclofenac Ibuprofen Malonic acid Glutaric acid DL-Malic acid Phthalic acid Maleic acid Oxalic acid Tartaric acid Succinic acid Fumaric acid Citric acid Barbital Dantrolene Omeprazole a
55.5 0.4 24.6 3.8 20.4 3.7 8.3 0.9 4.2 1.8 23.9 6.1 1.2 7.8 23.9 1.2 46.3 3.9 108.1 24.0 42.6 2.0 17.4 5.3 46.0 8.0 89.4 6.9 49.1 2.2 13.0 6.5 10.8 3.4 65.5 1.3
Monosodium salt 11.6 1.8 31.7 2.0 34.1 1.1 32.4 3.5 30.3 2.0
Disodium salt
Trisodium salt
– – – – –
– – – – – – – – – – – – – –
– – – – 14.5 1.7 81.7 7.1 16.0 2.2 5.0 1.7 21.6 1.8 5.0 1.7 7.3 0.9 39.1 11.4 64.2 2.4
34.4 10.2 42.3 2.8 19.7 3.0 13.4 1.9 14.9 0.5 43.5 6.3 10.1 2.4 26.4 3.3 29.1 3.8 3.9 1.1 – – –
Mean S.D., N = 3.
Fig. 4. Zero-charge margins of monovalent free acids and their sodium salts.
9.5 2.2 – – –
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Fig. 5. Zero-charge margins of multivalent free acids and their sodium salts.
Fig. 6. Zero-charge margins of free acids and sodium salts of barbital, dantrolene and omeprazole.
water. Omeprazole sodium was prepared by converting omeprazole free acid to Na salt by adding NaOH and recrystallized from acetone–isopropanol. As fine powder samples are required for a measurement of triboelectrification, all the powder samples were milled by the agate mortar and pestle for 120 times and sieved through a 150 mesh sieve before use. 2.2. Methods 2.2.1. Measurement of specific charge A suction-type Faraday cage meter EA-02 (U-TEC Corporation, Nara, Japan) was used for the measurement of the charge amount induced by triboelectrification. First, the weight of an empty filter capsule was measured. An aspiration nozzle of EA-02 was equipped with the empty filter capsule (Fig. 2). The powder sample (30 mg) and one of the standard carrier beads (2970 mg) were added to a 25 mL glass vial and shaken by the vortex mixer for 90 s at 5000 rpm. The powder sample and standard carrier beads were poured into a separating device (Fig. 2). The separating device
was covered with a 25 mm mesh, so that only the sample powders were sucked into the aspiration nozzle through the mesh. The suction air flow rate was 13.2 L/min. After recording the charge amount of sample powders, the filter capsule was removed from the aspiration nozzle, and the weight of the filter capsule was measured. The specific charge of a powder sample induced by contact with each standard carrier beads was calculated from the charge amount and the weight of the sample captured by the filter. 2.2.2. Zero-charge margin calculation An example of the standard toner—sample charge plots is shown in Fig. 3. The specific charge of a powder sample induced by contact with the standard carrier beads was plotted against that of the standard toner. The zero-charge margin was calculated as the point of intersection of the approximate straight line and the horizontal axis.
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3. Results
Appendix A. Supplementary data
The zero-charge margins of powder samples are shown in Table 2, Figs. 4–6. When the zero-charge margin of a powder sample shows a negative value, the powder sample tends to be positively charged when contacting with the other material (e.g., the standard toner). The larger the absolute value of the zerocharge margin, the higher is the triboelectrification ability of the powder sample. As shown in Fig. 4, the zero-charge margins of salicylic acid, palmitic acid, benzoic acid, diclofenac, ibuprofen, malonic acid, glutaric acid, DL-malic acid and phthalic acid were positive (negative chargeability). By converting to sodium salts, the zerocharge margin was reduced. As shown in Fig. 5, the zero-charge margins of maleic acid, oxalic acid, tartaric acid, succinic acid, fumaric acid and citric acid were also positive (negative chargeability). In the cases of succinic acid, fumaric acid and citric acid, as the number of sodium ion increased, the negative chargeability decreased. However, in the cases of maleic acid, oxalic acid and tartaric acid, the number of sodium ion and the extent of the reduction in the zero charge margin were not correlated. As shown in Fig. 6, the zero-charge margins of barbital and dantrolene were positive (negative chargeability). However, the zero-charge margin of omeprazole was negative (positive chargeability). Sodium salt formation changed the zero-charge margin, however, to various directs in this type of acids.
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. ijpharm.2015.08.008.
4. Discussion The interaction between powder and carrier particles during mixing is important for triboelectrification. In the preliminary study, we tested the effects of the ratio of sample and standard beads and the mixing time on the charge amount. The specific charge amount (mC/g) was constant between 1 and 3% and 90 to 120 sec, respectively. Therefore, 1.0% and 90 sec was employed for further studies. Glass vials were used to minimize the interaction between powder and walls of the mixing vial. By this mixing procedure, the sample particles were attached to the surface of the carrier beads as primary particles (Supplement Fig. S1). All samples of carboxylic acids showed negative chargeability in this study. The carboxyl group is an electron-withdrawing substituent. Therefore, when an acid receives an electron, the electron can be stabilized on the sample surface. All samples of sodium salts of carboxylic acids showed more positive chargeability than the corresponding free acids. When a carboxylic acid is converted to its sodium salt, the carboxyl group is negatively ionized so that it becomes difficult to stabilize an additional electron on the sample surface. Further consideration is required about the amide-enole type acids. In conclusion, we found, for the first time, that sodium salt formation of carboxylic acid shifts the zero-charge margin to a more negative value. However, this simple rule cannot be applied to the other acidic functional groups.
References Engers, D.A., Fricke, M.N., Newman, A.W., Morris, K.R., 2007. Triboelectric charging and dielectric properties of pharmaceutically relevant mixtures. J. Electrostat. 65, 571–581. Engers, D.A., Fricke, M.N., Storey, R.P., Newman, A.W., Morris, K.R., 2006. Triboelectrification of pharmaceutically relevant powders during low-shear tumble blending. J. Electrostat. 64, 826–835. Getsoian, A., Lodaya, R.M., Blackburn, A.C., 2008. One-solvent polymorph screen of carbamazepine. Int. J. Pharm. 348, 3–9. Ghori, M.U., Šupuk, E., Conway, B.R., 2014. Tribo-electric charging and adhesion of cellulose ethers and their mixtures with flurbiprofen. Eur. J. Pharm. Sci. 65, 1–8. Han, X., Ghoroi, C., To, D., Chen, Y., Davé, R., 2011. Simultaneous micronization and surface modification for improvement of flow and dissolution of drug particles. Int. J. Pharm. 415, 185–195. Hao, T., Tukianen, J., Nivorozhkin, A., Landrau, N., 2013. Probing pharmaceutical powder blending uniformity with electrostatic charge measurements. Powder Technol. 245, 64–69. Hiraga, Y., Sato, Y., Hoshino, K., 2013. Triboelectric charging behaviors of polymer films in contact with standard carrier beads and their explanations using charged-water penetration model. J. Imaging Soc. Jpn. 52, 252–260. Kojima, T., Onoue, S., Katoh, F., Teraoka, R., Matsuda, Y., Kitagawa, S., Tsuhako, M., 2007. Effect of spectroscopic properties on photostability of tamoxifen citrate polymorphs. Int. J. Pharm. 336, 346–351. Lee, E.H., 2014. A practical guide to pharmaceutical polymorph screening & selection. Asian J. Pharm. Sci. 9, 163–175. Olusanmi, D., Jayawickrama, D., Bu, D., McGeorge, G., Sailes, H., Kelleher, J., Gamble, J.F., Shah, U.V., Tobyn, M., 2014. A control strategy for bioavailability enhancement by size reduction: effect of micronization conditions on the bulk, surface and blending characteristics of an active pharmaceutical ingredient. Powder Technol. 258, 222–233. Pu, Y., Mazumder, M., Cooney, C., 2009. Effects of electrostatic charging on pharmaceutical powder blending homogeneity. J. Pharm. Sci. 98, 2412–2421. Shinohara, I., Yamamoto, F., Anzai, H., Endo, S., 1976. Chemical structure and electrostatic properties of polymers. J. Electrostat. 2, 99–110. Sonje, V.M., Kumar, L., Puri, V., Kohli, G., Kaushal, A.M., Bansal, A.K., 2011. Effect of counterions on the properties of amorphous atorvastatin salts. Eur. J. Pharm. Sci. 44, 462–470. Supuk, E., Ghori, M.U., Asare-Addo, K., Laity, P.R., Panchmatia, P.M., Conway, B.R., 2013. The influence of salt formation on electrostatic and compression properties of flurbiprofen salts. Int. J. Pharm. 458, 118–127. Šupuk, E., Zarrebini, A., Reddy, J.P., Hughes, H., Leane, M.M., Tobyn, M.J., Timmins, P., Ghadiri, M., 2012. Tribo-electrification of active pharmaceutical ingredients and excipients. Powder Technol. 217, 427–434. Tarsa, P.B., Towler, C.S., Woollam, G., Berghausen, J., 2010. The influence of aqueous content in small scale salt screening—improving hit rate for weakly basic, low solubility drugs. Eur. J. Pharm. Sci. 41, 23–30. Thoorens, G., Krier, F., Leclercq, B., Carlin, B., Evrard, B., 2014. Microcrystalline cellulose, a direct compression binder in a quality by design environment—a review. Int. J. Pharm. 473, 64–72. Watanabe, H., Ghadiri, M., Matsuyama, T., Ding, Y.L., Pitt, K.G., Maruyama, H., Matsusaka, S., Masuda, H., 2007. Triboelectrification of pharmaceutical powders by particle impact. Int. J. Pharm. 334, 149–155. Wu, H., White, M., Khan, M.A., 2011. Quality-by-design (QbD): An integrated process analytical technology (PAT) approach for a dynamic pharmaceutical coprecipitation process characterization and process design space development. Int. J. Pharm. 405, 63–78. Zhu, K., Tan, R.B.H., Chen, F., Ong, K.H., Heng, P.W.S., 2007. Influence of particle wall adhesion on particle electrification in mixers. Int. J. Pharm. 328, 22–34.
Contents lists available at ScienceDirect
International Journal of Pharmaceutics journal homepage: www.elsevier.com/locate/ijpharm
Triboelectrification of active pharmaceutical ingredients: week acids and their salts Kenta Fujinumaa,b , Yuji Ishiia , Yasuo Yashihashia , Estuo Yonemochic , Kiyohiko Suganoa,* , Katsuhide Taradaa a b c
Faculty of Pharmaceutical Sciences, Toho University, 2-2-1, Miyama, Funabashi, Chiba 274-8510, Japan Generic Pharmaceutical Development Department, Nippon Chemiphar Co., Ltd., 1-22, Hikokawado, Misato, Saitama 341-0005, Japan School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41, Ebara, Shinagawa, Tokyo 142-8501, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 11 May 2015 Received in revised form 27 July 2015 Accepted 2 August 2015 Available online 4 August 2015
The effect of salt formulation on the electrostatic property of active pharmaceutical ingredients was investigated. The electrostatic property of weak acids (carboxylic acids and amide-enole type acid) and their sodium salts was evaluated by a suction-type Faraday cage meter. Free carboxylic acids showed negative chargeability, whereas their sodium salts showed more positive chargeability than the free acids. However, no such trend was observed for amide-enole type acids. ã 2015 Elsevier B.V. All rights reserved.
Keywords: Triboelectrification Active pharmaceutical ingredient Weak acid Sodium salt Zero-charge margin Standard carrier beads
1. Introduction Active pharmaceutical ingredients (API) and excipients are prone to electrostatic charging (triboelectrification) by contacting with other materials such as excipients, containers and manufacturing equipments (Engers et al., 2007; Šupuk et al., 2012; Watanabe et al., 2007). Triboelectrification of API and excipients affects powder flow (Engers et al., 2006; Han et al., 2011), dose uniformity (Hao et al., 2013; Pu et al., 2009), metal sticking (Ghori et al., 2014; Zhu et al., 2007), etc. Therefore, it is important to understand the triboelectrification properties of APIs for the quality-by-design (QbD) approach (Olusanmi et al., 2014; Thoorens et al., 2014; Wu et al., 2011). However, the triboelectrification properties of APIs and excipients have not been well investigated (Engers et al., 2007; Šupuk et al., 2012; Watanabe et al., 2007). In drug discovery and development, API form optimization is usually performed before formulation studies (Lee, 2014; Tarsa et al., 2010). At this stage of pre-formulation, various API forms such as salts, cocrystals, and hydrates, are evaluated for dissolution property (Getsoian et al., 2008), chemical stability (Sonje et al.,
* Corresponding author. Fax: +81 47 472 1344. E-mail address: [email protected] (K. Sugano). http://dx.doi.org/10.1016/j.ijpharm.2015.08.008 0378-5173/ ã 2015 Elsevier B.V. All rights reserved.
2011), physical stability (Kojima et al., 2007), etc. However, the triboelectrification property of an API form is usually not investigated even though the chemical composition of an API form mainly determines the triboelectrification properties of the API particles (Shinohara et al., 1976). Little is known about the chemical composition—triboelectrification property relationship. Recently, Supuk et al., (2013) reported the effect of counter ions on the triboelectrification properties of flurbiprofen using a series of amine counter ions. However, sodium ion is most frequently used as the counter ion of an acid. The purpose of the present study was to investigate the effect of sodium salt formation on the triboelectrification properties of various weak acids. 2. Material and methods 2.1. Materials 2.1.1. Standard carrier beads and standard toner The standard carrier beads (N-1, N-2, P-1 and P-2) (Fig. 1) were purchased from the Imaging Society of Japan (Tokyo, Japan) (Hiraga et al., 2013). The P-01 and P-02 carrier beads were made from magnetite, manganese ferrite, modified silicone resin and carbon black. The N-01 and N-02 carrier beads were made from magnetite, manganese ferrite and acrylic resin. The order of the charge induction ability of the standard carrier beads was (positive
K. Fujinuma et al. / International Journal of Pharmaceutics 493 (2015) 434–438
435
Table 1 Specific charges of master standard toner induced by contact with each standard carrier beads. Grade of standard carrier beads N-01 Specific charge of master standard toner [mC/g]a a
35.8
N-02
P-01 P-02
22.2 23.9
38.4
Obtained from the Imaging Society of Japan.
Fig. 2. Schematic diagram of aspiration nozzle of EA-02, filter capsule and separating device.
side) P-02 > P-01 > N-02 > N-01 (negative side) (Table 1). These standard carrier beads were calibrated against the master standard toner by the Imaging Society of Japan. The specific charges of the standard toner induced by contact with the standard carrier beads are shown in Table 1. The particle sizes (d50) of all standard carrier beads were greater than about 75 mm (Fig. 1).
Fig. 1. Particle size distribution (PSD) and scanning electron microscope (SEM) images of standard carrier beads. PSD: microtrac-bel, microtrac MT3100II. SEM: KEYENCE, VE-7800.
2.1.2. Powder samples In this study, free acids and their sodium salts (carboxylic acids and amide-enole type acids) were used as model drugs. Salicylic acid, sodium salicylate, palmitic acid, ibuprofen, DL-malic acid, maleic acid, oxalic acid, sodium oxalate, succinic acid, disodium succinate, fumaric acid, sodium hydrogen fumarate, disodium fumarate, citric acid, sodium citrate and trisodium citrate were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). Diclofenac sodium, malonic acid, disodium malonate, glutaric acid, disodium glutarate, disodium DL-malate hydrate, phthalic acid, disodium phthalate, sodium maleate trihydrate, disodium maleate, disodium L-(+)-tartrate dehydrate, sodium succinate, disodium citrate sesquihydrate, dantrolene sodium and omeprazole were purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). Sodium palmitate was purchased from Chem Service, Inc. (Pennsylvania, United States). Benzoic acid, barbital and barbital sodium were purchased from Nacalai Tesque, Inc. (Kyoto, Japan). Sodium benzoate was purchased from SigmaAldrich Corporation (St. Louis, United States). Disodium oxalate was purchased from Junsei Chemical Co., Ltd. (Tokyo, Japan). Tartaric acid was purchased from Miyazawa Yakuhin Co., Ltd. (Tokyo, Japan). Sodium (+)-tartrate dehydrate was purchased from Kanto Chemical Co., Inc. (Tokyo, Japan). Diclofenac free acid was prepared by adding HCl to diclofenac sodium dissolved in water. Ibuprofen sodium was prepared by converting ibuprofen free acid to Na salt by adding NaOH and recrystallized from acetone. Dantrolene was prepared by converting dantrolene sodium to free acid by adding HCl and recrystallized from acetonitrile–ethanol–
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Fig. 3. Calculate plot to calculate the zero-charge margin.
Table 2 Zero-charge margins of powder samples. Powder sample
Zero-charge margin [mC/g]a Free acid
Salicylic acid Palmitic acid Benzoic acid Diclofenac Ibuprofen Malonic acid Glutaric acid DL-Malic acid Phthalic acid Maleic acid Oxalic acid Tartaric acid Succinic acid Fumaric acid Citric acid Barbital Dantrolene Omeprazole a
55.5 0.4 24.6 3.8 20.4 3.7 8.3 0.9 4.2 1.8 23.9 6.1 1.2 7.8 23.9 1.2 46.3 3.9 108.1 24.0 42.6 2.0 17.4 5.3 46.0 8.0 89.4 6.9 49.1 2.2 13.0 6.5 10.8 3.4 65.5 1.3
Monosodium salt 11.6 1.8 31.7 2.0 34.1 1.1 32.4 3.5 30.3 2.0
Disodium salt
Trisodium salt
– – – – –
– – – – – – – – – – – – – –
– – – – 14.5 1.7 81.7 7.1 16.0 2.2 5.0 1.7 21.6 1.8 5.0 1.7 7.3 0.9 39.1 11.4 64.2 2.4
34.4 10.2 42.3 2.8 19.7 3.0 13.4 1.9 14.9 0.5 43.5 6.3 10.1 2.4 26.4 3.3 29.1 3.8 3.9 1.1 – – –
Mean S.D., N = 3.
Fig. 4. Zero-charge margins of monovalent free acids and their sodium salts.
9.5 2.2 – – –
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Fig. 5. Zero-charge margins of multivalent free acids and their sodium salts.
Fig. 6. Zero-charge margins of free acids and sodium salts of barbital, dantrolene and omeprazole.
water. Omeprazole sodium was prepared by converting omeprazole free acid to Na salt by adding NaOH and recrystallized from acetone–isopropanol. As fine powder samples are required for a measurement of triboelectrification, all the powder samples were milled by the agate mortar and pestle for 120 times and sieved through a 150 mesh sieve before use. 2.2. Methods 2.2.1. Measurement of specific charge A suction-type Faraday cage meter EA-02 (U-TEC Corporation, Nara, Japan) was used for the measurement of the charge amount induced by triboelectrification. First, the weight of an empty filter capsule was measured. An aspiration nozzle of EA-02 was equipped with the empty filter capsule (Fig. 2). The powder sample (30 mg) and one of the standard carrier beads (2970 mg) were added to a 25 mL glass vial and shaken by the vortex mixer for 90 s at 5000 rpm. The powder sample and standard carrier beads were poured into a separating device (Fig. 2). The separating device
was covered with a 25 mm mesh, so that only the sample powders were sucked into the aspiration nozzle through the mesh. The suction air flow rate was 13.2 L/min. After recording the charge amount of sample powders, the filter capsule was removed from the aspiration nozzle, and the weight of the filter capsule was measured. The specific charge of a powder sample induced by contact with each standard carrier beads was calculated from the charge amount and the weight of the sample captured by the filter. 2.2.2. Zero-charge margin calculation An example of the standard toner—sample charge plots is shown in Fig. 3. The specific charge of a powder sample induced by contact with the standard carrier beads was plotted against that of the standard toner. The zero-charge margin was calculated as the point of intersection of the approximate straight line and the horizontal axis.
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3. Results
Appendix A. Supplementary data
The zero-charge margins of powder samples are shown in Table 2, Figs. 4–6. When the zero-charge margin of a powder sample shows a negative value, the powder sample tends to be positively charged when contacting with the other material (e.g., the standard toner). The larger the absolute value of the zerocharge margin, the higher is the triboelectrification ability of the powder sample. As shown in Fig. 4, the zero-charge margins of salicylic acid, palmitic acid, benzoic acid, diclofenac, ibuprofen, malonic acid, glutaric acid, DL-malic acid and phthalic acid were positive (negative chargeability). By converting to sodium salts, the zerocharge margin was reduced. As shown in Fig. 5, the zero-charge margins of maleic acid, oxalic acid, tartaric acid, succinic acid, fumaric acid and citric acid were also positive (negative chargeability). In the cases of succinic acid, fumaric acid and citric acid, as the number of sodium ion increased, the negative chargeability decreased. However, in the cases of maleic acid, oxalic acid and tartaric acid, the number of sodium ion and the extent of the reduction in the zero charge margin were not correlated. As shown in Fig. 6, the zero-charge margins of barbital and dantrolene were positive (negative chargeability). However, the zero-charge margin of omeprazole was negative (positive chargeability). Sodium salt formation changed the zero-charge margin, however, to various directs in this type of acids.
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. ijpharm.2015.08.008.
4. Discussion The interaction between powder and carrier particles during mixing is important for triboelectrification. In the preliminary study, we tested the effects of the ratio of sample and standard beads and the mixing time on the charge amount. The specific charge amount (mC/g) was constant between 1 and 3% and 90 to 120 sec, respectively. Therefore, 1.0% and 90 sec was employed for further studies. Glass vials were used to minimize the interaction between powder and walls of the mixing vial. By this mixing procedure, the sample particles were attached to the surface of the carrier beads as primary particles (Supplement Fig. S1). All samples of carboxylic acids showed negative chargeability in this study. The carboxyl group is an electron-withdrawing substituent. Therefore, when an acid receives an electron, the electron can be stabilized on the sample surface. All samples of sodium salts of carboxylic acids showed more positive chargeability than the corresponding free acids. When a carboxylic acid is converted to its sodium salt, the carboxyl group is negatively ionized so that it becomes difficult to stabilize an additional electron on the sample surface. Further consideration is required about the amide-enole type acids. In conclusion, we found, for the first time, that sodium salt formation of carboxylic acid shifts the zero-charge margin to a more negative value. However, this simple rule cannot be applied to the other acidic functional groups.
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