ISSN 00125008, Doklady Chemistry, 2014, Vol. 456, Part 2, pp. 98–102. © Pleiades Publishing, Ltd., 2014. Original Russian Text © T.P. Shakhtshneider, S.A. Myz’, A.I. Nizovskii, A.V. Kalinkin, E.V. Boldyreva, T.C. Alex, Rakesh Kumar, 2014, published in Doklady Akademii Nauk, 2014, Vol. 456, No. 5, pp. 556–560.
CHEMISTRY
Effect of the Selected Inorganic Carriers on the Properties of Mechanocomposites with Drugs T. P. Shakhtshneider a, b, S. A. Myza, A. I. Nizovskiic, d, A. V. Kalinkinc, E. V. Boldyrevaa, b, T. C. Alexe, and Rakesh Kumare Presented by Academician V.V. Boldyrev January 22, 2014 Received February 4, 2014
DOI: 10.1134/S0012500814060044
replacement of the carrier is associated with a funda mental change of its chemical nature. The formation of hybrid mechanocomposites and the efficiency of the dosage forms prepared using different polymorphs or amorphous forms of the same inorganic compound or samples differing only in the degree of dispersion have not been compared so far. In this communication, we report the first study of this sort in relation to alumi num hydroxides (gibbsite and boehmite) as the inor ganic carrier and two oxicams (piroxicam and meloxi cam) as organic drug substances. For comparison, sys tems with the oxide carrier (γAl2O3) were also studied.
Hybrid core–shell type composites, including organicinorganic composites, possess unique proper ties and, hence, find use in many areas of science and technology, in particular, in pharmacy [1]. Mecha nochemical methods are efficient for the preparation of such materials because they shorten the duration of synthesis and avoid using large amounts of organic sol vents [2]. Rather popular inorganic drug carriers are highly porous alumina, silica, and magnesia [3, 4]. Hydroxides, which are mechanically softer and, due to layered structure, can be more easily mechanically activated are even more promising for the use in phar macy. Drugs can not only interact with their external surface but also enter the space between the layers, which underlies the manufacture of “retard dosage forms” characterized by retarded controlled release of the drug in the body, which is important, for example, for antihypertensive or antidepressant drugs [5]. The selection of the carrier is known to be impor tant for the properties of the formed composite. The
Piroxicam (4hydroxy2methylN(2'pyridyl)2H 1,2benzothiazine3carboxamide1,1dioxide) (I) and meloxicam (4hydroxy2methylN(5'methyl 2'thiazolyl)2Hbenzothiazine3carboxamide1,1 dioxide) (II) are nonsteroidal antiinflammatory drug substances poorly soluble in water. They belong to oxi cam family and have similar molecular structures [6]. 3'
OH O
OH O
4'
N
5'
2'
4
N H N S 2 CH3 O 1 O I 3
N H N S CH3 O O II
N
2'
S
CH3
1'
Piroxicam was synthesized at the Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, meloxicam was provided by the CJSC Altaivitaminy (Biysk), gibbsite Al2O3 ⋅ 3H2O) was manufactured by the National Aluminum Com pany (Bhubaneswar, India). Boehmite (Al2O3 ⋅ H2O) and γAl2O3 were prepared from gibbsite by heating at 350°C for 2.5 h and at 600°C for 1 h, respectively. The mechanical treatment was carried out in a Pulverisette 6 planetary mill (Fritsch, Germany) in 250mL steel
a
Institute of Solid State Chemistry and Mechanochemistry, Siberian Branch, Russian Academy of Sciences, ul. Kutateladze 18, Novosibirsk, 630128 Russia email:
[email protected] b Novosibirsk State University, ul. Pirogova 2, Novosibirsk, 630090 Russia c Boreskov Institute of Catalysis, Siberian Branch, Russian Academy of Sciences, pr. Akademika Lavrent’eva 5, Novosibirsk, 630090 Russia d Omsk State Technical University, pr. Mira 11, Omsk, 644050 Russia e National Metallurgical Laboratory, Jamshedpur, India 98
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drums by steel balls 10 mm in diameter; the sample weight to ball weight ratio was 1 : 30, the rotation velocity was 500 rpm, the duration was 30 min, and the drug substance to carrier ratio was 1 : 3 (by weight). The samples were dissolved at 37 ± 0.5°C in a Varian 705 DS solubility tester certified for pharmaceutical testing. The samples had a definite particle size (125– 315 µm) and contained an excess of the drug substance exceeding its solubility. Distilled water was used as the dissolution medium (pH 6.5). In the case of hydrox ides, pH slightly increased to 6.7 for gibbsite and to 7.2 for boehmite. Boehmite and γAl2O3 obtained by thermal decom position of gibbsite retained the morphology of the initial phase, all samples having similar particle size distributions. However, the surface areas were much greater for boehmite (263.1 m2/g) and γAl2O3 (147.6 m2/g) than for gibbsite (1.4 m2/g), owing to the pores formed upon thermal decomposition [7]. After mechanical treatment, the boehmite surface area decreased (50.1 m2/g), while that of gibbsite increased (43.2 m2/g); as a consequence, the mechanically acti vated carriers had roughly equal surface areas. Both drug substances and carriers became Xray amorphous upon mechanical treatment. However, the degrees of amorphization of gibbsite and boehmite mixed with drug substances were lower than upon separate treat ment of the hydroxides. Presumably, coating of the carrier surface by the organic phase inhibits amor phization. The O and Al maps from Xray photoelectron spectroscopy for mechanically activated mixtures were fully consistent with the S maps, indicating a uniform distribution of the drug substance and the carrier in the composite. The increased S content in the maps attests to possible coating of the boehmite particles by meloxicam giving core–shell type composites. Changes in the IR spectra of piroxicam (Fig. 1a) and meloxicam (Fig. 1b) upon the formation of mech anocomposites with all carriers were similar; thus, the active sites on the gibbsite and boehmite surface are identical, so are the active sites on the alumina surface [4]. The observed changes indicate that the oxicams interact with the surface active sites of inorganic carri ers through C=O and N–H groups. Analogous changes were observed earlier in the spectra of piroxi cam complexes with Cu(II) and Ni(II) due to chela tion of the metal to the amide oxygen and pyridyl nitrogen atoms of piroxicam [8, 9]. The alumina sur face bears terminal and bridging OH groups and Lewis acid and base sites [10]. Presumably, chelate bonds are formed between piroxicam molecules and the Lewis acid sites represented by coordinatively unsaturated aluminum ions on the hydroxide surface, as was DOKLADY CHEMISTRY
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observed previously for piroxicam–alumina compos ites [4]. The Xray photoelectron spectra of the physical and mechanically activated piroxicam and meloxicam mixtures with gibbsite and boehmite were similar and resembled the spectra of mixtures with alumina [4]. The C1s line of the drug substances remained unchanged after the mechanical treatment, which may imply that mechanical treatment does not cause destruction of the covalent bonds in the molecules. In the N1s and S2p3/2–1/2 spectral regions, changes were noted that can be interpreted as being due to interac tion of the piroxicam and meloxicam molecules in the mechanocomposites with the carrier surface involving sulfur and nitrogencontaining groups. Although the mechanical treatment induced amor phization of all of the inorganic carriers even in the mechanocomposites with drug substances formed during this treatment, the difference between them was still manifested in the dissolution of mechano composites. The effect of formation of mechanocom posites on the dissolution of the drug substances in water as compared with the dissolution of individual mechanically activated substances was fundamentally different for piroxicam and meloxicam (Fig. 2). The mechanically activated pure piroxicam exhib ited a characteristic initial solubility peak exceeding 2.5fold the solubility of the starting untreated piroxi cam, which gives a supersaturated solution, and then, as soon as 15 min later, the piroxicam concentration decreased to the equilibrium level. For practical appli cation of piroxicam as a drug substance, 15 min is a too short period, because the substance may precipitate in the body before the drug has been uptaken. In the case of piroxicam mechanically activated with carriers, this initial peak was not observed and the piroxicam con centration in the solution was slightly higher than the equilibrium concentration inherent in the pure piroxi cam. The nature of the inorganic component of the composite did not affect much the piroxicam solubil ity; the maximum dissolution of piroxicam was observed in the composite with boehmite (1.5fold higher than the dissolution of pure piroxicam), Fig. 2a. This is consistent with the fact that initially boehmite had the greatest specific surface area. However, during the dissolution of physical mixtures of both the initial and mechanically activated components, the piroxi cam dissolution rate and concentration in the solution were lower than those for mechanically activated mix tures, even despite the fact that increase in the pH in the presence of hydroxides is expected to increase the piroxicam concentration in the solution [11]. Presum ably, the hydroxides used can sorb the drug substance from solution. Apparently, not only the specific sur
SHAKHTSHNEIDER et al.
νs(SO2)
3
δ(N−H)
ν(N−H)
ν(С=N)
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(b) 1 νs(SO2) δ(N−H)
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ν(С=O)
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4
5 6
3600 3300 3000 2700 2400 2100
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1200 ν, cm−1
Fig. 1. IR attenuated total reflectance spectra of physical (continuous lines) and mechanically activated (MA) (dashed lines) (a) piroxicam–carrier and (b) meloxicam–carrier mixtures: (1, 2) with gibbsite; (3, 4) with boehmite; (5, 6) with alumina. Changes in the MA mixtures are visible in the ν(N–H), ν(С=O), δ(N–H), ν(С=N), νs(SO2) regions.
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EFFECT OF THE SELECTED INORGANIC CARRIERS 0.07
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0.06 1 0.05
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7 9
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Fig. 2. Dissolution curves of (a): (1) MA piroxicam, (2) piroxicam–boehmite MA mixture, (3) piroxicam–γAl2O3 MA mixture, (4) piroxicam–gibbsite MA mixture, (5) initial piroxicam, (6) initial piroxicam–initial gibbsite, (7) initial piroxicam–initial boe hmite, (8) MA piroxicam–MA boehmite, (9) MA piroxicam–MA gibbsite; (b) (1) meloxicam–boehmite MA mixture, (2) meloxicam–γAl2O3 MA mixture, (3) meloxicam–gibbsite MA mixture, (4) MA meloxicam–MA gibbsite mixture, (5) MA meloxicam–MA boehmite, (6) MA meloxicam, (7) initial meloxicam.
face area but also the active site concentration and strength on the surface of the carriers are significant for this process. In the case of meloxicam, no initial supersaturation peak was observed for any of the pure drug substance, physical mixtures, or mechanocomposites. However, the concentration of meloxicam that passed to the solution was much higher for all mechanocomposites than for pure meloxicam; the most pronounced effect (6.5fold) was observed for the mechanocomposite with boehmite (Fig. 2b). In the case of mechanocom posites, the meloxicam concentration in the solution DOKLADY CHEMISTRY
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was higher than for the dissolution of mixtures of sep arately activated components. It is very important for therapeutic use that the increased concentrations of meloxicam in solution observed for the dissolution of mechanocomposites were retained for a long period (at least 4–5 h). Piroxicam is more prone to metal chelation [8, 9] than meloxicam [12]. Therefore, piroxicam and meloxicam may bind to the surface active sites of the carriers in different ways, which results in the forma tion of bonds with different strength and, hence, dif ferent rates of drug release into the solution. The same
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is also indicated by the fact that in the case of meloxi cam, sorption of the drug substance on the carriers does not occur to the same extent as observed for piroxicam and the meloxicam concentration in the solution is higher than the solubility of the initial sub stance. A certain contribution to the increase in the meloxicam solubility in the presence of boehmite and gibbsite can be made by increase in the pH [11]. Meanwhile, in the case of dissolution of physical mix tures with gibbsite or boehmite, both untreated and prepared from components that were separately mechanically treated, the concentration of meloxicam in the solution is lower than in the case of dissolution of mechanocomposites. Thus implies that the forma tion of core–shell composites characterized by enhanced specific surface area of the organic phase makes an additional contribution to the dissolution rate and effective solubility of meloxicam. Thus, we found several nontrivial effects that are important for the development of solubilization meth ods for poorly soluble drug substances by preparation of mechanocomposites with inorganic carriers. Indeed, drug substances having similar molecular structures and corresponding to the same class of oxi cams behave in different ways when dissolved as parts of composites with the same inorganic components. With the same drug substance, the initial differences between the aluminum hydroxide forms used as inor ganic carriers were manifested even upon mechanical activation in which the carrier was partly amorphized. The effect arising upon joint mechanical treatment of the drug substance and the carrier was much higher than upon mixing of the components that were sepa rately mechanically pretreated. These effects are to be taken into account for choosing the excipients and for design of new drugs. ACKNOWLEDGMENTS This work was supported by the Ministry of Educa tion and Science of the Russian Federation, the Rus
sian Foundation for Basic Research–DST (India) (project nos. 09–03–92658_IND and 13–03– 92704_IND), and the program “Fundamental Sci ences for Medicine” of the Russian Academy of Sci ences (project FNM03). REFERENCES 1. Cate, A.T., Eversdijk, J., and van Bommel, K.J.C., in Abstracts of First International Conference on Multifunc tional, Hybrid and Nanomaterials, Tours, 2009, p. A12. 2. Boldyreva, E., Chem. Soc. Rev., 2013, vol. 42, pp. 7719–7738. 3. Shakhtshneider, T.P., Myz, S.A., Mikhailenko, M.A., Drebushchak, T.N., Drebushchak, V.A., Fedotov, A.P., Medvedeva, A.S., and Boldyrev, V.V., Mater. Manufact. Proc., 2009, vol. 24, pp. 1064–1071. 4. Shakhtshneider, T.P., Myz, S.A., Dyakonova, M.A., Boldyrev, V.V., Boldyreva, E.V., Nizovskii, A.I., Ka linkin, A.V., and Kumar Rakesh, Acta Phys. Polon. A, 2011, vol. 119, pp. 272–278. 5. Shen, S.C., Chow, P.S., Chen, F.X., and Tan, R.B.H., J. Crystal Growth, 2006, vol. 292, pp. 136–142. 6. ElGamel, N.E.A., J. Coord. Chem., 2009, vol. 62, pp. 2239–2260. 7. Alex, T.C., Kumar Rakesh, Roy, S.K., and Mehrot ra, S.P., in Light Metals, Warrendale (PA): TMS, 2012. pp. 15–19. 8. Santi, E., Torre, M.H., Lremer, E., Etcheverry, S.B., and Baran, E.J., Vibration. Spectrosc., 1993, vol. 5, pp. 285–293. 9. Cini, R., Giorgi, G., Cinquatini, A., Rossi, C., and Sabat, M., Inorg. Chem., 1990, vol. 29, pp. 5197–5200. 10. Kul’ko, E.V., Ivanova, A.S., Budneva, A.A., and Pauk shtis, E.A., React. Kinet. Catal. Lett., 2006, vol. 88, pp. 381–390. 11. Luger, P., Daneck, K., Engel, W., Trummlitz, G., and Wagner, K., J. Pharm. Sci., 1996, vol. 4, pp. 175–187. 12. Defazio, S. and Cini, R., J. Chem. Soc., Dalton Trans., 2002, vol. 9, pp. 1888–1897.
Translated by Z. Svitanko
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