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AAPS PharmSciTech. 2007 June; 8(2): E32–E39.
Published online 2007 April 20. doi:  10.1208/pt0802031
PMCID: PMC2750370

Effect of interactive ternary mixtures on dispersion characteristics of ipratropium bromide in dry powder inhaler formulations


The purpose of this investigation was to evaluate the effect of mixing order and the influence of adding fines on in vitro performance of ipratropium bromide (ITB) dry powder inhaler formulations. Coarse lactose (CL) in varying mass ratio with or without addition of micronized lactose (ML) and ITB in different mixing sequences was used to formulate ternary mixtures. A binary mixture composed of CL and ITP served as control. The in vitro deposition of ITB from these formulations was measured using an Andersen cascade impactor (aerosolization at 39 L/min) employing a HandiHaler as the delivery device. It was observed that mixing order has a significant effect (P<.05) on in vitro deposition of ITB. Formulations with preblending of CL and ITB produced similar deposition profiles as the control, regardless of the added ML. In contrast, formulations without preblending resulted in significantly higher fine particle dose (FPD) as compared with the control. In addition, an increased quantity of ML generally resulted in an increase in drug deposition. The results show that the effect of ML on dispersion of ITB is highly dependent upon the mixing order. The evaluation of atomic force measurement (AFM) to forecast drug detachment and predict the aerodynamic characteristics resulted in similar attraction forces for the different pairs lactose/lactose (42.66±25.01 nN) and lactose/ITB (46.77±17.04 nN).

Keywords: Ternary interactive mixture, mixing order, atomic force microscopy, interparticle forces, dry powder inhaler, lactose

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
1. Ganderton D. The generation of respirable clouds from coarse powder aggregates. J Biopharm Sci. 1992;3:101–105.
2. Hersey JA. Ordered mixing: a new concept in powder mixing practice. Powder Technol. 1975;11:41–44. doi: 10.1016/0032-5910(75)80021-0. [Cross Ref]
3. Louey MD, Stewart PJ. Particle interactions involved in aerosol dispersion of ternary interactive mixtures. Pharm Res. 2002;19:1524–1531. doi: 10.1023/A:1020464801786. [PubMed] [Cross Ref]
4. Louey MD, Razia S, Stewart PJ. Influence of physico0chemical properties on the in vitro aerosol deposition from interactive mixtures. Int J Pharm. 2003;252:87–98. doi: 10.1016/S0378-5173(02)00621-X. [PubMed] [Cross Ref]
5. Flament MP, Leterme P, Gayot A. The influence of carrier roughness, content uniformity and the in vitro deposition of terbutaline sulphate from dry powder inhalers. Int J Pharm. 2004;275:201–209. doi: 10.1016/j.ijpharm.2004.02.002. [PubMed] [Cross Ref]
6. Srichana T, Martin GP, Marriott C. On the relationship between drug and carrier deposition from dry powder inhalers in vitro. Int J Pharm. 1998;167:13–23. doi: 10.1016/S0378-5173(98)00037-4. [Cross Ref]
7. Zeng XM, Martin GP, Tee SK, Marriott C. The role of fine particle lactose on the dispersion and deaggregation of salbutamol sulphate in an air stream in vitro. Int J Pharm. 1998;176:99–110. doi: 10.1016/S0378-5173(98)00300-7. [Cross Ref]
8. Zeng XM, Pandal KH, Martin GP. The influence of lactose carrier on the content homogeneity and dispersibility of beclomethasone dipropionate from dry powder aerosols. Int J Pharm. 2000;197:41–52. doi: 10.1016/S0378-5173(99)00400-7. [PubMed] [Cross Ref]
9. Islam N, Stewart P, Larson I, Hartley P. Lactose surface modification by decantation: are drug-fine lactose ratios the key to better dispersion of salmeterol xinifoate from lactose-interactive mixtures? Pharm Res. 2004;21:492–499. doi: 10.1023/B:PHAM.0000019304.91412.18. [PubMed] [Cross Ref]
10. Steckel H. Inhalation powders—a simple dosage form for pulmonary delivery? Swiss Pharma. 2002;24:15–28.
11. Zeng XM, Martin GP, Marriott C, Pritchard J. The influence of carrier morphology and drug delivery by dry powder inhalers. Int J Pharm. 2000;200:93–106. doi: 10.1016/S0378-5173(00)00347-1. [PubMed] [Cross Ref]
12. Podczeck F. Adhesion forces in interactive powder mixtures of a micronized drug and carrier particles of various particle size distributions. J Adhes Sci Technol. 1998;12:1323–1339.
13. Tsukada M, Irie R, Yonemochi Y, et al. Adhesion force measurements of a DPI size pharmaceutical particle by colloid probe atomic force microscopy. Powder Technol. 2004;141:262–269. doi: 10.1016/j.powtec.2004.03.008. [Cross Ref]
14. Zeng XM, Martin GP, Tee SK, Ghoush AA, Marriott C. Effect of particle size and adding sequence of fine lactose on the deposition of salbutamol sulphate from a dry powder formulation. Int J Pharm. 1999;182:133–144. doi: 10.1016/S0378-5173(99)00021-6. [PubMed] [Cross Ref]
15. Bérard V, Lesniewka E, Andrès C, Pertuy D, Laroche C, Pourcelot Y. Affinity scale between a carrier and a drug in DPI studied by atomic force microscopy. Int J Pharm. 2002;247:127–137. doi: 10.1016/S0378-5173(02)00400-3. [PubMed] [Cross Ref]
16. Begat P, Morton DAV, Staniforth JN, Price R. The cohesive-adhesive balances in dry powder inhaler formulations I: Direct measurements by atomic force microscopy. Pharm Res. 2004;21:1591–1597. doi: 10.1023/B:PHAM.0000041453.24419.8a. [PubMed] [Cross Ref]
17. Begat P, Morton DAV, Staniforth JN, Price R. The cohesive-adhesive balances in dry powder inhaler formulations II: Influence on fine particle delivery characteristics. Pharm Res. 2004;21:1826–1832. doi: 10.1023/B:PHAM.0000045236.60029.cb. [PubMed] [Cross Ref]
18. Council of Europe . European Pharmacopoeia. 5th ed. Strasbourg, France: Council of Europe; 2006. 2.9.18. Preparation for Inhalation: aerodynamic assessment of fine particle; pp. 3103–3315.
19. Dufner J, Jensen J, Schumacher E. Statistik mit SAS. Stuttgart, Germany: BG Tuebner Studienbücher; 1992.
20. Little RC, Milliken GA, Stroup WS, Wolfinger RS. SAS System for Mixed Models. Cary, NC: SAS Institute Inc; 1996.
21. Lucas P, Anderson K, Staniforth JN. Protein deposition from dry powder inhalers: fine particle multiplets as performance modifiers. Pharm Res. 1998;15:562–569. doi: 10.1023/A:1011977826711. [PubMed] [Cross Ref]

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