theory and practice with solution systems

Respiratory Drug Delivery IX, 2004 – Lewis et al.

THEORY AND PRACTICE WITH SOLUTION SYSTEMS D.A. Lewis, D. Ganderton, B.J. Meakin, and G. Brambilla Vectura Ltd., Chippenham, UK, Chiesi Farmaceutici SpA, Parma, Italy

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KEYWORDS: hydrofluoroalkane, HFA, pressurized metered dose inhaler SUMMARY e pharmaceutical industry’s development of the cascade impactor as a controlled performance testing methodology has allowed reliable comparison of formulations under standardised protocols. e knowledge base created by application of these standardised protocols to drug delivery has allowed two fundamental delivery performance indicators of ethanol-based solution HFA pMDIs, mass median aerodynamic diameter (MMAD), and ex-valve fine particle fraction (FPF), to be characterised by two semi-empirical equations. e independency of the equations allows target MMAD and ex-valve FPF to be selected and achieved independently by ‘armchair’ consideration of formulation and device. INTRODUCTION Since its development in the s, the pMDI has become popular with both patients and clinicians, and it is now available to deliver virtually all drugs used in the treatment of asthma. e Montreal Protocol () has led to the replacement of chlorofluorocarbon (CFC) propellants by the hydrofluoroalkanes HFA a and HFA ea which, although safe toxicologically, have significantly different physico-chemical properties to CFCs, making the transition more complex than was initially anticipated (,). e addition of ethanol as a low vapour pressure co-solvent within the HFA system has become widespread, initially due to its ability to solubilise traditional surfactants used in the formulation of CFC suspensions, but more significantly because ethanol-based systems can dissolve many active substances, allowing the formulation of solutions. Although such solution formulations and the use of ethanol as a co-solvent are not new, interest in solution pMDI technology has grown. is is because high vapour pressure HFA propellants are able to maintain atomisation efficiency even when a substantial amount of ethanol is added to the system (). Furthermore, solution formulations offer predictably good reproducibility of batch manufacture and pMDI metering performance, resulting in excellent inter/intra-can dosage uniformity and spray characteristics throughout product use-life. e inherent performance consistency of solution pMDIs means that once the delivery characteristics for one individual solution pMDI system have been quantified and metering consistency confirmed, performance characteristics for any active substance at a dose which is soluble within that formulation vehicle can generally be inferred, allowing intelligent formulation if a database is available. Such knowl109

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edge was unavailable to the pharmaceutical industry at the introduction of the HFA propellants and was further confused by the lack of compatible metering valves, canisters, and actuator designs. However, a significant amount of information has been accumulated over recent years allowing a knowledge base for ethanol-HFA solution systems to be established. e introduction of a standardised methodology for evaluating pMDI delivery characteristics has allowed reliable comparison of formulations under defined protocols. is paper brings together a number of factors observed over recent years. Issues relating to devising a chemically stable solution are outside the scope of this paper; neither will attention be given to container and valve formulation compatibility. What will be discussed is the ability to predict and control the delivery performance of a solution pMDI with regard to the delivery efficiency and particle size distribution as measured by the standardised pharmacopoeial methodology. A semi-empirical approach has been employed, allowing the variables available to the formulator to be placed into context with regard to the ethanol based solution HFA pMDI. Modulation of particle size distributions of solution HFA pMDI formulations has been previously described (, ). However, the effects of propellant and actuator orifice choice have not yet been fully explored. is paper will elaborate further upon the ability to modulate particle size by control of the formulation’s non-volatile components (NVC), i.e., the drug and any additional non-volatile excipients. METHODOLOGIES In vitro drug deposition characterisation was obtained for a number of pMDI formulations and actuator orifice designs using a cascade impactor (Apparatus , USP ) at a sampling flow rate of . L/min. All cascade impactor drug deposition profiles were quantified using validated HPLC assay methods. pMDI efficiency was defined as the fine particle dose (FPD ≤ . µm) represented as a fraction of the ex-valve dose, i.e., that fraction having aerodynamic properties potentially allowing lung deposition following inhalation. FPD, mass median aerodynamic diameter (MMAD), and geometric standard deviation (GSD) were calculated for all drug delivery profiles using CITDAS software (Copley Scientific, UK). pMDIs were fitted with Bespak BK  µL,  µL,  µL, or  µL metering valves and discharged through Bespak BK series actuators with orifice sizes ., ., ., or . mm. For investigation of smaller orifice diameters Bespak BK series actuator housings were adapted to hold aluminium valve-stem seating blocks with laser drilled orifices with diameters of . or . mm and lengths of . mm (). e sump volumes of the Bespak and aluminium actuator pieces were  µL and  µL, respectively. MASS MEDIAN AERODYNAMIC DIAMETER MMAD Upon actuation, the solution formulation atomises and the volatile excipients rapidly evaporate such that particles are formed before reaching the cascade impactor stages. e particle morphology of any resultant solid particles is independent of the preferred crystal habit of the raw material (). Remaining liquid NVC containing either drug in solution or as particulates can be approximated to droplet spherical geometry, allowing its diameter, d, to be related to volume (V) by Equation : d = (6V/π) 1/3 (Equation 1)

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If atomisation patterns remain unchanged, the particle size may be increased from a baseline value of d to d by increasing the volume of the NVC from V to V (Equation ). d1 = d0 (V1/V0) 1/3 (Equation 2) For a given combination of drug, excipients, and propellant (assuming density changes are small as the percentage composition varies and that spray patterns are unchanged), volume may be replaced by mass of NVC (m) and the diameter specified as the MMAD, giving Equation . is predicts the MMAD is proportional to the cube root of the NVC mass or its weight percent within the pMDI formulation. MMAD1 = MMAD0 (m1/m0) 1/3 (Equation 3) Figure  shows this later relationship, defined by Equation , holding for forty-seven combinations of ethanol-based HFA a formulation/actuator orifice diameters. In all cases, pMDIs were fitted with  µL metering valves. e data encompasses nine active materials, dose range - µg/actuation, five actuator orifice diameters (.-. mm), twenty formulations with an HFA a content of . ± .% w/w, and twenty-seven with an HFA a content of . ± .% w/w. MMAD134a = 2.31 (%w/w NVC) 1/3 (Equation 4) When the data for the two propellant levels were analysed separately, no significant difference (p = .) was observed in the slopes confirming that the MMAD of an ethanol-based HFA a solution formulation is independent of both actuator orifice size and HFA a content over the range of HFA a levels investigated. However, the spread of the pMDI particle size distributions is broader for formulations with the lower HFA a content (. ± .% w/w), geometric standard deviations (GSD) being .-. compared to .-. for formulations containing (. ± .% w/w) HFA a .

Figure 1: Mass median aerodynamic diameter (MMAD) as a function of the cube root

Figure 1.

Mass median aerodynamic a ethanol function of HFA the cube of non-volatilediameter component (MMAD) content (NVC),asfor based 134a root of non-volatile component content (NVC), for ethanol based HFA 134a formulations discharged through 0.14formulations discharged through 0.14 – 0.42mm actuator orifices. 0.42 mm actuator orifices. The same functional relationship between MMAD and NVC content holds for ethanol based HFA227ea formulations. Figure 2 which leads to Equation 5 is compiled from twenty-two data sets involving three actives, dose range 17 - 250µg/actuation, five actuator orifice diameters (0.18 – 0.42mm) and HFA content within the range 74.4 – 97.2%w/w. Again the pMDIs were fitted with 50µl metering valves.

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e same functional relationship between MMAD and NVC content holds for ethanolbased HFAea formulations. Figure  which leads to Equation  is compiled from twenty-two data sets involving three actives, dose range - µg/actuation, five actuator orifice diameters (.-. mm) and HFA content within the range .-.% w/w. Again the pMDIs were fitted with  µL metering valves. MMAD227ea = 3.26 (%w/w NVC) 1/3 (Equation 5)

Figure 2: Mass median aerodynamic diameter (MMAD) as a function of the cube root

Figure 2.

Mass median aerodynamic diametercontent (MMAD) as ethanol a function the cube root of non-volatile of non-volatile component (NVC), for based of HFA 227ea component content (NVC), for ethanol based HFA 227ea formulations discharged through formulations discharged through 0.18 – 0.42mm actuator orifices. 0.18-0.42 mm actuator orifices. PRESSURISED METERED DOSE INHALER EFFICIENCY PRESSURISED METERED DOSE INHALER EFFICIENCY The portability, apparent simplicity and convenience of the pMDI have led to its

widespread acceptance and by patients and clinicians. The clinical value of current e portability, apparent simplicity, convenience of the pMDI have led to its widespread acpMDIs is largely attributed to the efficacy of the active compounds rather its ceptance by patients and clinicians. e clinical value of current pMDIs is largely attributed to the with respect to delivering highly respirable cloud. Nevertheless, an efficacy of the activeefficiency compounds rather its effia ciency with respect to delivering a highly respirable cloud. Nevertheless,understanding an understanding of pMDI effiwhether ciencydesigning is essential designing an HFA of pMDI efficiency is essential an HFA whether pMDI to pMDI to match thematch in vitro performance existing CFC producttheordelivery optimising the delivery of the in-vitro performance ofof anan existing CFC product or optimising a new active substance to active the lower airways. of a new substance to the lower airways. e efficiency of a pMDI to produce a respirable cloud may be characterised by its ability to produce particles capable of passing through the cascade impactor’s throat and reaching the 7 impactor stages which capture particles ≤  µm aerodynamic diameter. Loss of -% of a pMDI’s delivered dose to the impactor throat is not uncommon. An understanding of why some particles deposit within the throat and others remain entrained by the airflow is essential if an understanding of pMDI efficiency is to be obtained. Stein and Gabrio () investigated the throat deposition of two pMDIs discharged through actuators with a range of orifice diameters and concluded that throat deposition occurs within the first - cm of the throat, rather than by inertial impaction at the bend. is is consistent with computational fluid dynamic modelling which reports deposition mainly via turbulent dispersion within the horizontal section of the throat, which is found to decrease at increased sampling flow rates (). Particle image velocimetry (PIV) techniques have also reported induced regions of turbulence, recirculation, and large velocity mismatches between the sampling airflow and the pMDI plume. In this case, the particle velocities at the inlet of the throat were

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found to be an order of magnitude above that of the average sampling airflow, inducing instabilities at the inlet, and a choked flow profile which results in dose ‘loss’ via throat deposition (). Calculations give the Reynolds numbers within the throat as  at . L/min, increasing to  at  L/min, and  at  L/min; the respective average velocities within the throat are calculated to be ., ., and . m/s. e reported decrease in throat deposition at the respective increased flow rates implies that lowering the velocity mismatch between the plume and the sampling airflow will reduce the turbulence induced by flow interactions, the dominant factor influencing throat deposition. us, it is clear that the rate at which a pMDI introduces a dose into the throat is of fundamental importance in regard to the ability of the dose to pass through the throat and reach the lower impaction stages. In order to predict throat deposition and the resultant respirable dose, consideration was given to three pMDI parameters; actuator orifice diameter, metered dose volume and propellant content, all of which were known to influence pMDI atomisation performance (). PIV measurements also identified they all significantly affected the plume velocity at the throat inlet. Utilising the now established knowledge base and applying multiple regression analysis, the empirical functional relationship between ex-valve FPF and the device parameters, actuator orifice (a, mm) and metering chamber volume (v, µL), was obtained (Equation ). FPF = 12.7 a-1.5 v -0.25 (Equation 6) Figure  illustrates the goodness of fit of the experimental data to Equation  by plotting the ex-valve FPF (≤  µm) determined experimentally by cascade impaction, against the predicted value for beclomethasone dipropionate formulations in a vehicle comprising HFA a containing -% w/w ethanol and .% w/w glycerol. e slope of . ± .% is close to unity with an R value of .. Equation  predicts that smaller metered dose volumes delivered through smaller orifices result in an increase in pMDI delivery efficiency to the lower cascade impactor stages. By inference, therefore, such device manipulations will induce lower turbulence within the cascade impactor throat.

Figure 3.

Figure 3: Experimental ex-valve FPF versus ex-valve FPF predicted from Equation

Experimental ex-valve FPF versus ex-valve FPF predicted from Equation 6 for beclomethasone for beclomethasone dipropionate containing HFA 134a solution formulations dipropionate HFA6 134a solution formulations 13-15% w/w ethanol, and 1.3% w/w glycerol (actuator orifi ce diameter = 0.22-0.42 mm, metering – 100 µL). containing 13 - 15%w/w ethanol, and 1.3%w/w glycerolvolume (actuator 25 orifice diameter = 0.22 - 0.42mm, metering volume 25 - 100µl).

For significant changes in formulation vehicle composition, the effect of the HFA 134a content, C134a also needs to be considered, formulations having higher HFA 134a and hence lower ethanol content being observed to have an enhanced efficiency.

Multiple regression analysis of knowledge base data gives the final

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For significant changes in formulation vehicle composition, the effect of the HFA a content, Cª also needs to be considered, formulations having higher HFA a and, hence, lower ethanol content being observed to have an enhanced efficiency. Multiple regression analysis of knowledge base data gives the final functional relationship (Equation ) which describes the delivery efficiency of an ethanol based solution HFA a pMDI system. FPF = 2.1x10-5 a-1.5 v -0.25 C134a3 (Equation 7) Figure 4 exemplifies the goodness of fit to Equation 7 for nine different active Figure  exemplifi es the goodness of fit to Equation  for nine different active materials, dose range with 19 - 1000µg/actuation, with 60 – 98% HFA 134a -.% content, 0 –w/w non-volatile addidose range -materials, µg/actuation, -% HFA a content, 1.8%w/w non-volatile additive, 2 – 40%w/w ethanol, and involving four tive, -% w/w ethanol, and involving four actuator orifice diameters actuator (.-. mm) - metering orifice diameters (0.22 (50µl) is combinations. The slope volume ( µL) combinations. e- 0.42mm) slope -ofmetering .volume ± .% again close to unity with an R value 2 of .. of 0.999 ± 1.6% is again close to unity with an R value of 0.8906.

Figure 4:

Figure 4.

Observed ex-valve FPF versus ex-valve FPF predicted from Equation

Observed FPF versus ex-valve FPF predicted fromdiameter Equation 7 forex-valve ethanol based HFA 134a solution formulations (actuator orifice = 0.227 for ethanol based HFA 134a solution formulations (actuator orifice diameter = 0.22-0.42mm, metering volume 50 µL). - 0.42mm, metering volume 50µl).

us, Equation  allows prediction of the ex-valve FPF for a wide range of formulations Thus Equation 7 allows of prediction of theparameters ex-valve FPF enables for a wideconceptual range of and device variations. e simplicity the input formulations to be formulations and device variations.‘in Thethe simplicity of the input parameters enables rapidly screened for therapeutic potential armchair.’ When developing new ethanol based solution pMDI systems, selection to for achieve both required conceptual formulationsoftoformulations be rapidly screened therapeutic potential ‘in the MMAD and ex-valve FPF by the application of Equations - allows the requirement for time consuming cascade impactor analysis to be markedly curtailed thereby enabling resources to be11focused upon plausible therapeutic delivery opportunities. CONCLUSIONS By considering non-volatile content, actuator orifice diameter, valve metering volume and HFA content, equations have been derived that relate the MMAD and ex-valve FPF of ethanol-based HFA solution pMDIs to device hardware and formulation variable, the influence of ethanol and other co-solvent content being an inverse function of HFA content. ese equations allow these two fundamental pMDI delivery performance indicators to be independently selected by choice of formulation and device. MMAD was observed to be proportional to the cube root of formulation non-volatile component content for a wide range of HFA content (-% w/w), and actuator orifice diameters

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(.-. mm). For formulations containing an equivalent % w/w of non-volatile component, the MMAD of HFA ea formulations were observed to be . times greater than that of HFA a formulations. Particle size distributions were generally broader for formulations with lower HFA content. e ex-valve FPF predictability was developed from initial consideration of the rate at which the pMDI plume enters the cascade impactor’s throat; pMDIs with smaller orifices and metering volumes and high HFA contents were found to have the highest ex-valve FPFs. e versatility of the ethanol-based solution pMDI allows drugs with suitable solubility to be delivered according to predetermined characteristics, making this system ideal for matching in vitro performance of existing CFC pMDI products or delivering new active substances to the respiratory system in a highly efficient manner. REFERENCES 1.

Meakin, B.J., Lewis, D.A., Ganderton, D., and Brambilla, G. (2000), “Countering challenges posed by mimicry of CFC performance using HFA systems,” Proc. Respiratory Drug Delivery VII, Serentec Press, Raleigh, NC, 99-107.

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Byron, P.R. and Vervaet, C. (1999), “Drug-surfactant-propellant interactions in HFAformulations,” Int. J. Pharm., 186, 13-30.

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Ganderton, D., Lewis, D., Davies, R., Meakin, B., Brambilla, G., and Church, T. (2002), “Modulite: A means of designing the aerosols generated by pressurized metered dose inhalers,” Resp. Med., 96 (Sup D), S3-S8.

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Meakin, B.J., Ganderton, D., Davies, R.J., and Lewis, D.A. (2003), “Pressurized metered dose inhaler (pMDI) actuators with laser drilled orifices,” WO 03053501.

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McKenzie, L. and Oliver, M.J. (1999), “Evaluation of the particle formation process after actuation of solution MDIs,” Proc. Drug Delivery to the Lungs X X, 9-12.

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Stein, S.W. and Gabrio, B.J. (2000), “Understanding throat deposition during cascade impactor testing,” Proc. Respiratory Drug Delivery VII, Serentec Press, Raleigh, NC, 287-290.

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Versteeg, H.K., Hargrave, G., Harrington, L., Shrubb, I., and Hodson, D. (2000), “e use of computational fluid dynamics (CFD) to predict pMDI air flows and aerosol plume formation,” Proc. Respiratory Drug Delivery VII, Serentec Press, Raleigh, NC, 257-264.

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Davies, R.J., Lewis, D.A., Ganderton, D., Meakin, B.J., Brambilla, G., Murphy, S.D., and Nicholls, T.R. (2002), “Velocity profiling of a new HFA budesonide pMDI,” Proc. Respiratory Drug Delivery VIII, Davis Horwood International Publishing, Raleigh, NC, 759-762.

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