TAILORING DRY POWDER INHALER PERFORMANCE BY - RCPE

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768 Maas et al. Already at this point, it has to be mentioned, the scale of the surface asperities is in the same range as the particle size of the active. This is important because the scale of the asperities in relation to the size of the drug particles is decisive for the contact area between the carrier and the active (Young et al., 2008), with smaller-scale asperities leading to a decrease of the contact area and the interparticle interactions, whereas larger-scale asperities result in an increase. 3.3 Metered Mass and Uniformity of Metered Mass The metered mass is defined as the mass of the formulation metered by the built-in metering system of the inhalation device. The uniformity of the metered mass, re- mass / mg 40 20 spectively, dosing was examined by discharging 50 doses from the Novolizer multidose inhaler using the experimental setup described in the European Pharmacopoeia monograph (Ph. Eur., 2008b). Each metered mass was determined by weighing the inhaler before and after the discharge (Fig. 2). Three batches (A, B, C) of each formulation (mannitol 60 ◦ C, 90 ◦ C, 120 ◦ C) were examined, and the mean of the mass (mean mass) of the 50 doses was calculated for each batch. The mean and the standard deviation of the mean mass of the three batches (A, B, C) of each formulation (mannitol 60 ◦ C, 90 ◦ C, 120 ◦ C) were calculated. They are given in Fig. 3. There is no significant difference between the formulations, the mean of the mean mass having values of 8.0 mg for formulations containing mannitol 60 ◦ C, 6.6 mg for formulations containing mannitol Mannitol 120 °C Mannitol 90 °C Mannitol 60 °C 0 0 10 20 30 40 50 number of the dose discharged FIG. 2: Metered mass of three batches of each formulation containing mannitol carrier particles spray dried at 60◦C, 90◦C, and 120◦C. mean of the mass / mg 12,00 10,00 8,00 6,00 4,00 2,00 0,00 Mannitol 60°C Mannitol 90°C Mannitol 120°C FIG. 3: Mean of the metered mass of 50 single doses of formulations containing mannitol carrier particles spray dried at 60◦C, 90◦C), and 120◦C; n = 3, mean ± standard deviation. Begell House Digital Library, http://dl.begellhouse.com Downloaded 2011-3-4 from IP 129.27.117.213 by Technische Universitaet Graz Atomization and Sprays
Tailoring Dry Powder Inhaler Performance 769 90 ◦ C, and 8.9 mg for formulations containing mannitol 120 ◦ C. In addition, the uniformity of dosing was evaluated by calculating the coefficient of variation of the mass of each batch (A, B, C). The mean and the standard deviation of the three coefficients of variation of each formulation (mannitol 60 ◦ C, 90 ◦ C, 120 ◦ C) were calculated. The coefficients of variation are given in Fig. 4. Despite the differences in surface topography, there is no significant difference between the formulations, the coefficient of variation showing values of 27.1% for ordered mixtures with mannitol 60 ◦ C, 36.2% for ordered mixtures with mannitol 90 ◦ C, and 21.3% for ordered mixtures with mannitol 120 ◦ C. Therefore, even if there was a difference of the flowability of the pure carriers prior to mixing of the carriers with the active, the attachment of the drug particles to variation coefficient of the mass / % 50,0 40,0 30,0 20,0 10,0 the carrier surface must have influenced the surface properties to such an extent that a similar powder flowability and dosing was finally obtained. 3.4 Delivered Dose The delivered dose is defined by the dose of active delivered to the patient by the inhalation device. In this study, it was determined by discharging 10 doses from the Novolizer multidose inhaler using the experimental setup described in the European Pharmacopoeia (Ph. Eur., 2008b). In contrast to what is described in Pharmacopoeia, 10 subsequent doses were examined, each consisting of five puffs in order to ensure the proper quantification of the drug. The dose of active delivered was determined by HPLC (Fig. 5). 0,0 Mannitol 60°C Mannitol 90°C Mannitol 120°C FIG. 4: Variation coefficient of the metered mass of 50 single doses of formulations containing mannitol carrier particles spray dried at 60◦C, 90◦C, and 120◦C; n = 3, mean ± standard deviation. delivered dose / µg 0 0 0 0 1 2 3 4 5 6 7 8 9 10 number of the dose discharged FIG. 5: Delivered dose of three batches of each formulation containing mannitol carrier particles spray dried at 60◦C, 90◦C, and 120◦C. Volume 20, Number 9, 2010 Begell House Digital Library, http://dl.begellhouse.com Downloaded 2011-3-4 from IP 129.27.117.213 by Technische Universitaet Graz Mannitol 120 °C Mannitol 90 °C Mannitol 60 °C
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TAILORING DRY POWDER INHALER PERFORMANCE BY - RCPE

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