To evaluate the influence of different variables on tablet formulations containing enalapril maleate and indapamide as active substances, two separate experimental designs were employed: one for evaluating powder properties and the other for tablet characteristics. Because of the low active pharmaceutical ingredient content, it was hypothesized that both powder and tablet properties could be determined only by the characteristics of excipients. In order to test this assumption, both experimental designs were done with placebo mixtures. The optimized formulation was then evaluated both with and without APIs. Results indicated that filler and lubricant percentage, along with compression force, were the most important variables during the formulation study. The optimized formulation showed similar characteristics in both cases for all responses, except for angle of repose and friability where only minor differences were observed. The combination of the applied approaches (using placebo composition and fractional experimental design) proved to be efficient, cost effective and time saving.
1. B. Gil-Extremera and P. Cía-Gómez, Hypertension in the elderly, Int. J. Hypertens.2012 (2012) 859176; DOI: 10.1155/2012/859176.
2. P. W. de Leeuw, Combination perindopril/indapamide for the treatment of hypertension: a review, Expert Opin. Pharmacother.12 (2011) 1827–1833; DOI: 10.1517/14656566.2011.585638.
3. S.-S. Huang, T.-C. Wu, S.-J. Lin and J.-W. Chen, Combination of an ACE inhibitor and indapamide improves blood pressure control, but attenuates the beneficial effects of ACE inhibition on plasma adiponectin in patients with essential hypertension, Circ. J.73 (2009) 2282–2287.
4. S. Kalra, B. Kalra and N. Agrawal, Combination therapy in hypertension: An update, Diabetol. Metab. Syndr.2 (2010) 44; DOI: 10.1186/1758-5996-2-44.
5. C. L. Brown, C. I. Backhouse, J. C. Grippat and J. P. Santoni, The effect of perindopril and hydrochlorothiazide alone and in combination on blood pressure and on the renin-angiotensin system in hypertensive subjects, Eur. J. Clin. Pharmacol.39 (1990) 327–332.
6. S. G. Mallat, H. S. Itani and B. Y. Tanios, Current perspectives on combination therapy in the management of hypertension, Integr. Blood Press. Control6 (2013) 69–78; DOI: 10.2147/IBPC.S33985.
7. L. Cavalieri and G. Cremonesi, Delapril plus indapamide: a review of the combination in the treatment of hypertension, Clin. Drug Investig.27 (2007) 367–380.
8. I. N. Belenkov, F. T. Ageev, I. A. Orolova, O. I. Abrosimova, E. G. Volkova, L. I. Gapon, L. I. Katel’nitskaia, A. O. Kondari, I. F. Patrusheva, I. V Fomin and R. A. Khokhlov, Clinical and vascular effects of ACE inhibitor enalapril in combination with thiaside-like diuretic indapamide in hypertensive outpatients. Results of the multicenter trial POEMA, Ter. Arkh.79 (2007) 33–38.
9. S. C. Sweetman, Martindale: The Complete Drug Reference, 37th ed., Pharmaceutical Press, London 2011.
10. D. C. Montgomerey, Design and Analysis of Experiments, 7th ed., John Wiley & Sons, Hoboken, New York 2009.
11. L. Erikkson, E. Johansson, N. Kettaneh-Wold, C. Wilkström and S. Wold, Design of Experiments: Principles and Applications (Third revised and enlarged edition), MKS Umetrics AB, Umea 2008.
12. A. Curić, R. Reul, J. Möschwitzer and G. Fricker, Formulation optimization of itraconazole loaded PEGylated liposomes for parenteral administration by using design of experiments, Int. J. Pharm.448 (2013) 189–197; DOI: 10.1016/j.ijpharm.2013.03.029.
13. European Pharmacopoeia, 7th ed., Council of Europe, Strasburg 2010.
14. United States Pharmacopoeia, 35th ed., United States Pharmacopeial Convention, Rockville MD 2011.
15. I. Popovici and D. Lupuleasa, Tehnologie Farmaceutica, Vol. 3, Editura Polirom, București 2009.
16. R. C. Rowe, P. J. Sheskey and M. E. Quinn (editors), Handbook of Pharmaceutical Excipients, 6th ed., Pharmaceutical Press, London 2009.
17. L. X. Liu, I. Marziano, A. C. Bentham, J. D. Litster, E. T. White and T. Howes, Effect of particle properties on the flowability of ibuprofen powders, Int. J. Pharm.362 (2008) 109–117; DOI: 10.1016/j.ijpharm.2008.06.023.
18. M. Leturia, M. Benali, S. Lagarde, I. Ronga and K. Saleh, Characterization of flow properties of cohesive powders: A comparative study of traditional and new testing methods, Powder Technol.253 (2014) 406–423; DOI: 10.1016/j.powtec.2013.11.045.
19. C. T.-Y. Pourcelot, Preformulation of five commercial celluloses in drug development: Rheological and mechanical behaviour, Drug Dev. Ind. Pharm.19 (1993) 1947–1964; DOI: 10.3109/03639049309073901.
20. P. Kleinebudde, M. Jumaa and F. El Saleh, Influence of the degree of polymerization on the behavior of cellulose during homogenization and extrusion/spheronization, AAPS PharmSci2 (2000) E21.
21. T. Suzuki and H. Nakagami, Effect of crystallinity of microcrystalline cellulose on the compactability and dissolution of tablets, Eur. J. Pharm. Biopharm.47 (1999) 225–230.
22. G. Thoorens, F. Krier, B. Leclercq, B. Carlin and B. Evrard, Microcrystalline cellulose, a direct compression binder in a quality by design environment-A review, Int. J. Pharm.473 (2014) 64–72; DOI: 10.1016/j.ijpharm.2014.06.055.
23. J. Muzíková and P. Sináglová, Comparison of properties of tablets and energy profile of compaction of two spray-dried lactoses, Acta Pol. Pharm.70 (2013) 129–135.
24. F. Podczeck and Y. Mia, The influence of particle size and shape on the angle of internal friction and the flow factor of unlubricated and lubricated powders, Int. J. Pharm.144 (1996) 187–194; DOI: 10.1016/S0378-5173(96)04755-2.
25. A. Mehrotra, M. Llusa, A. Faqih, M. Levin and F. J. Muzzio, Influence of shear intensity and total shear on properties of blends and tablets of lactose and cellulose lubricated with magnesium stearate, Int. J. Pharm.336 (2007) 284–291; DOI: 10.1016/j.ijpharm.2006.12.013.
26. L. X. Liu, I. Marziano, A. C. Bentham, J. D. Litster, E. T. White and T. Howes, Effect of particle properties on the flowability of ibuprofen powders, Int. J. Pharm.362 (2008) 109–117; DOI: 10.1016/j.ijpharm.2008.06.023.
27. G. Gold, R. N. Duvall, B. T. Palermo and J. G. Slater, Powder flow studies III. Factors affecting the flow of lactose granules, J. Pharm. Sci.57 (1968) 667–671; DOI: 10.1002/jps.2600570429.
28. A. M. N. Faqih, A. Mehrotra, S. V Hammond and F. J. Muzzio, Effect of moisture and magnesium stearate concentration on flow properties of cohesive granular materials, Int. J. Pharm.336 (2007) 338–345; DOI: 10.1016/j.ijpharm.2006.12.024.
29. A. C. Shah and A. R. Mlodozeniec, Mechanism of surface lubrication: Influence of duration of lubricant-excipient mixing on processing characteristics of powders and properties of compressed tablets, J. Pharm. Sci.66 (1977) 1377–1382; DOI: 10.1002/jps.2600661006.
30. M. E. Johansson and M. Nicklasson, Investigation of the film formation of magnesium stearate by applying a flow-through dissolution technique, J. Pharm. Pharmacol.38 (1986) 51–54; DOI: 10.1111/j.2042-7158.1986.tb04466.x.
31. C. F. Lerk, G. K. Bolhuis and S. S. Smedema, Interaction of lubricants and colloidal silica during mixing with excipients. I. Its effect on tabletting, Pharm. Acta Helv.52 (1977) 33–39.
32. V. Nicolas, O. Chambin, C. Andrès, M. H. Rochat-Gonthier and Y. Pourcelot, Preformulation: effect of moisture content on microcrystalline cellulose (Avicel PH-302) and its consequences on packing performances, Drug Dev. Ind. Pharm.25 (1999) 1137–1142; DOI: 10.1081/DDC-100102280.
33. G. E. Amidon and M. E. Houghton, The effect of moisture on the mechanical and powder flow properties of microcrystalline cellulose, Pharm. Res.12 (1995) 923–929; DOI: 10.1023/A:1016233725612.
34. A. Mihranyan, A. P. Llagostera, R. Karmhag, M. Strømme and R. Ek, Moisture sorption by cellulose powders of varying crystallinity, Int. J. Pharm.269 (2004) 433–442; DOI: 10.1016/j.ijpharm.2003.09.030.
35. C. C. Sun, Mechanism of moisture induced variations in true density and compaction properties of microcrystalline cellulose, Int. J. Pharm.346 (2008) 93–101; DOI: 10.1016/j.ijpharm.2007.06.017.
36. I. Jivraj, L. Martini and C. Thomson, An overview of the different excipients useful for the direct compression of tablets, Pharm. Sci. Technolo. Today3 (2000) 58–63; DOI: 10.1016/S1461-5347(99)00237-0.
37. C. Ferrero, N. Muñoz, M. V. Velasco, A. Muñoz-Ruiz and R. Jiménez-Castellanos, Disintegrating efficiency of croscarmellose sodium in a direct compression formulation, Int. J. Pharm.147 (1997) 11–21; DOI: 10.1016/S0378-5173(96)04784-9.
38. N. O. Lindberg, Evaluation of some tablet lubricants, Acta Pharm. Suec.9 (1972) 207–214.
39. A. F. Marais, M. Song and M. M. D. V. Φ, Effect of compression force, humidity and disintegrant concentration on the disintegration and dissolution of directly compressed furosemide tablets using croscarmellose sodium as disintegrant, Trop. J. Pharm. Res.2 (2003) 125–135.