Clozapine-carboxylic acid plasticized co-amorphous dispersions: Preparation, characterization and solution stability evaluation

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This study addressed the possibility of forming of co-amorphous systems between clozapine (CZ) and various carboxylic acid plasticizers (CAPs). The aim was to improve the solubility and oral bioavailability of clozapine. Co-amorphous dispersions were prepared using modified solvent evaporation methodology at drug/plasticizer stoichiometric ratios of 1:1, 1:1.5 and 1:2. Solid state characterization was performed using differential scanning calorimetry, X-ray diffraction and infra red spectroscopy. Highly soluble homogeneous co-amorphous dispersions were formed between clozapine and CAPs via hydrogen bonding. The co-amorphous dispersions formed with tartaric acid (1:2) showed the highest dissolution percentage (> 95 % in 20 minutes) compared to pure crystalline CZ (56 %). Highly stable solutions were obtained from co-amorphous CZ-citric and CZ-tartaric acid at 1:1.5 molar ratio. The prepared dispersions suggest the possibility of peroral or sublingual administration of highly soluble clozapine at a reduced dose with the great chance to bypass the first pass metabolism.

1. N. Y. Hasan, M. A. Elkawy, B. E. Elzeany and N. E. Wagieh, Stability indicating methods for the determination of clozapine, J. Pharm. Biomed. Anal. 30 (2002) 35-47; DOI: 10.1016/S0731-7085(02) 00125-5.

2. M. Ackenheil, Clozapine pharmacokinetic investigations and biochemical effects in man, Psychopharmacology 99 (1989) 32-37; DOI: 10.1007/bf00442556.

3. A. A. Ambike, K. Mahadik and A. Paradkar, Spray-dried amorphous solid dispersions of simvastatin, a low Tg drug: in vitro and in vivo evaluations, Pharm. Res. 22 (2005) 990-998; DOI: 10.1007/ s11095-005-4594-z.

4. M. Kluge, A. Schuld, A. Schacht, H. Himmerich, M. A. Dalal, P. M. Wehmeier, D. Hinze-Selch, T. Kraus, R. W. Dittmann and T. Pollmcher, Effects of clozapine and olanzapine on cytokine systems are closely linked to weight gain and drug-induced fever, Psychoneuroendocrinology 34 (2009) 118-128; DOI: 10.1016/j.psyneuen.2008.08.016.

5. D. Douroumis, Orally disintegrating dosage forms and taste-masking technologies, Expert Opin. Drug Delivery. 8 (2010) 665-675; DOI: 10.1517/17425247.2011.566553.

6. V. Venkateswarlu and K. Manjunath, Preparation, characterization and in vitro release kinetics of clozapine solid lipid nanoparticles, J. Control. Release 95 (2004) 627-638; DOI: 10.1016/j.jconrel. 2004.01.005.

7. S. A. Agnihotri and T. M. Aminabhavi, Controlled release of clozapine through chitosan microparticles prepared by a novel method, J. Control. Release 96 (2004) 245-259; DOI: 10.1016/j.jconrel. 2004.01.025.

8. T. Vasconcelos, B. Sarmento and P. Costa, Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs, Drug Discov. Today 12 (2007) 1068-1075; DOI: 10.1016/j. drudis.2007.09.005.

9. O. Almarsson and M. J. Zaworotko, Crystal engineering of the composition of pharmaceutical phases. Do pharmaceutical co-crystals represent a new path to improved medicines?, Chem. Commun. 17 (2004) 1889-1896; DOI: 10.1039/B402150A.

10. K. K. Arora and M. J. Zaworotko, Pharmaceutical co-crystals: A new Opportunity In Pharmaceutical Science for a Long-known but Little Studied Class of Compounds, in Polymorphism in Pharmaceutical Solids (Ed. H. G. Brittain), 2nd ed., Informa Healthcare, London 2009, pp. 281-313.

11. K. J. Crowley and G. Zografi, Cryogenic grinding of indomethacin polymorphs and solvates: assessment of amorphous phase formation and amorphous phase physical stability, J. Pharm. Sci. 91 (2002) 492-507; DOI: 10.1002/jps.10028.

12. E. Gagniere, D. Mangin, S. Veesler and F. Puel, Co-crystallization in Solution and Scale Up Issues, in Pharmaceutical Salts and Co-crystals (Eds. J. Wouters, L. Quere and D. E. Thurston), 1st ed., Royal Society of Chemistry, London 2011, pp. 188-208.

13. N. Blagden, M. de Matas, P. T. Gavan and P. York, Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates, Adv. Drug Deliv. Rev. 59 (2007) 617-630; DOI: 10.1016/j.addr.2007.05.011.

14. K. Lobmann, H. Grohganz, R. Laitinen, C. Strachan and T. Rades, Amino acids as co-amorphous stabilizers for poorly water soluble drugs-Part 1: Preparation, stability and dissolution enhancement, Eur. J. Pharm. Biopharm. 85 (2013) 873-881; DOI: 10.1016/j.ejpb.2013.03.014.

15. Y. Gao, J. Liao, X. Qi and J. Zhang, Coamorphous repaglinide-saccharin with enhanced dissolution, Int. J. Pharm. 450 (2013) 290-295; DOI: 10.1016/j.ij pharm.2013.04.032.

16. A. Shayanfar, H. Ghavimi, H. Hamishekar and A. Jouyban, Coamorphous atorvastatin calcium to improve its physicochemical and pharmacokinetic properties, J. Pharm. Sci. 16 (2013) 577-587.

17. A. Lemmerer, J. Bernstein, and V. Kahlenberg, Hydrogen bonding patterns of the co-crystal containing the pharmaceutically active ingredient isoniazid and terephthalic acid, J. Chem. Crystallogr. 41 (2011) 991-997; DOI: 10.1007/s10870-011-0031-9.

18. M. A. Elbagerma, H. G. M. Edwards, T. Munshi and I. J. Scowen, Identification of a new co-crystal of salicylic acid and benzamide of pharmaceutical relevance, Anal. Bioanal. Chem. 397 (2010) 137-146; DOI: 10.1007/s00216-009-3375-7.

19. B. C. Hancock and M. Parks, What is the true solubility advantage for amorphous pharmaceuticals?, Pharm. Res. 17 (2000) 397-404; DOI: 10.1023/a:1007516718048.

20. S. U. Schilling, C. D. Bruce, N. H. Shah, A.W. Malick and J. W. McGinity, Citric acid monohydrate as a release-modifying agent in melt extruded matrix tablets, Int. J. Pharm. 361 (2008) 158-168; DOI: 10.1016/j.ij pharm.2008.05.035.

21. D. R. Weyna, T. Shattock, P. Vishweshwar and M. J. Zaworotko, Synthesis and structural characterization of cocrystals and pharmaceutical cocrystals: mechanochemistry vs slow evaporation from solution, Cryst. Growth Des. 9 (2009) 1106-1123; DOI: 10.1021/cg800936d.

22. A. Newman, D. Engers, S. Bates, I. Ivanisevic, R. C. Kelly and G. Zografi, Characterization of amorphous API: Polymer mixtures using X-ray powder diffraction, J. Pharm. Sci. 97 (2008) 4840-4856; DOI: 10.1002/jps.21352.

23. C. Guitton, J. M. Kinowski, R. Aznar and F. O. Bressolle, Determination of clozapine and its major metabolites in human plasma and red blood cells by high-performance liquid chromatography with ultraviolet absorbance detection, J. Chromatogr. 690 (1997) 211-222; DOI: 10.1016/s0378-4347 (96)00362-3.

24. M. Vasanthavada, W-Q. T. Tong, Y. Joshi and M. S. Kislalioglu, Phase behavior of amorphous molecular dispersions II: Role of hydrogen bonding in solid solubility and phase separation kinetics, Pharm. Res. 22 (2005) 440-448; DOI: 10.1007/s11095-004-1882-y.

25. Q. Lu and G. Zografi, Phase behavior of binary and ternary amorphous mixtures containing indomethacin, citric acid and PVP, Pharm. Res. 15 (1998) 1202-1206; DOI: 10.1023/a:1011983606606.

26. H. Bley, B. Fussnegger and R. Bodmeier, Characterization and stability of solid dispersions based on PEG/polymer blends, Int. J. Pharm. 390 (2010) 165-173; DOI: 10.1016/j.ij pharm.2010.01.039.

27. J. E. Patterson, M. B. James, A. H. Forster, R.W. Lancaster, J. M. Butler and T. Rades, Preparation of glass solutions of three poorly water soluble drugs by spray drying, melt extrusion and ball milling, Int. J. Pharm. 336 (2007) 22-34; DOI: 10.1016/j.ij pharm.2006.11.030.

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