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The chlorofluorocarbon to hydrofluoroalkane transition: The effect on pressurized metered dose inhaler suspension stability
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The chlorofluorocarbon to hydrofluoroalkane transition: The effect on pressurized metered dose inhaler suspension stability Anne Brindley, BPharm, MRPharmS, PhD Leicestershire, United Kingdom The phase out of chlorofluorocarbon (CFC) propellants has necessitated the reformulation of pressurized metered dose inhalers (pMDIs) with hydrofluoroalkane (HFA) propellants. One of the main challenges has been that conventional surfactants used for CFC-based pMDIs were not soluble in HFAs. Since one of the main aims of a pMDI is to deliver a reproducible dose of medication to the patient, it is vital that, for suspension-type pMDI formulations, the suspension is stabilized sufficiently for a reproducible dose to be delivered. A new technique has been developed that measures suspension stability more objectively than before. This technique, optical suspension characterization, was used to compare the performance of different formulations of respiratory drugs in HFAs. The optical suspension characterization data were correlated with conventional analytic techniques for the determination of the stability of the suspension formulation. (J Allergy Clin Immunol 1999;104:S221-6.) Key words: Metered dose inhaler, formulation, suspension, stability hydrofluoroalkane
The Montreal Protocol1 came into force in 1989 and initiated the transition of the propellants essential for the operation of pressurized metered dose inhalers (pMDIs) from chlorofluorocarbons (CFCs) to hydrofluoroalkanes (HFAs). The HFA propellants, which have no chlorine atoms in their structure, have zero ozone depleting potential and also a reduced global-warming potential compared with CFC propellant 11.2 Two HFA propellants were soon selected by pharmaceutical companies to use for reformulation of their CFC-based products. These were HFA-134a (1,1,1,2-tetrafluoroethane) and HFA-227 (1,1,1,2,3,3,3heptafluoropropane). However, it soon became apparent that a direct switch of propellant was not straightforward; 10 years later, there are only 3 HFA-based pMDI products marketed in the United Kingdom (Airomir; 3M, marketed 1995; Qvar; 3M, marketed 1998; and Ventolin Evohaler; Glaxo Wellcome, marketed 1998) and one product in the United States (Proventil; Schering). There were significant hurdles to overcome before a suitable replacement product could be marketed. These hurdles spanned all aspects of product development. The major
From AstraZeneca R&D Charnwood, Leicestershire, United Kingdom. Reprint requests: Anne Brindley, AstraZeneca R&D Charnwood, Bakewell Rd, Loughborough, Leicestershire, LE11 5RH United Kingdom Copyright © 1999 by Mosby, Inc. 0091-6749/99 $8.00 + 0 1/0/102782
Abbreviations used OSCAR: Optical suspension characterization pMDI: Pressurized metered dose inhaler
formulation issues that arose as a result of the transition are detailed in Table I. This article will concentrate on how one of these issues (the fact that conventional CFC surfactants were not soluble in the HFA propellants) impacted on product performance particularly in light of the fifth issue listed in Table I: the tightening of regulatory requirements for dose uniformity from inhaled products.
SUSPENSION STABILITY AND PRODUCT PERFORMANCE Surfactants were used in CFC-based pMDI formulations to stabilize micronized drug particles (<10 µm) in a propellant mixture. The surfactants used to suspend the drug particles in CFCs (oleic acid, lecithin, and sorbitan trioleate) were soluble in the CFC propellants; and by adsorbing to the drug particles, the surfactants were therefore able to stabilize the drug particles to form relatively stable suspensions. However, these surfactants are virtually insoluble in the HFA propellants and therefore are not dispersed sufficiently to adsorb onto the drug particles.3 Solutions were sought by pharmaceutical companies, resulting in a variety of approaches to overcome the same problem. Most drug suspensions undergo destabilization over time (eg, flocculating, settling out, or creaming [movement to the surface]), even when surfactants are used to form the suspension.4 Metering valves used in pMDIs operate by sampling a volume of suspension from the bulk, which is retained in the metering chamber of the valve. Fig 1 shows a schematic diagram of the movement of suspension within the metering chamber when a pMDI is actuated.5 Briefly, when the patient actuates the pMDI, this volume of suspension in the metering chamber exits the inhaler through the valve stem and actuator into the patient’s mouth (or nose). At the same time as the dose is released, the metering chamber refills with the next dose. In suspension formulations of pMDIs, the suspension must remain stable between the time when the patient shakes the inhaler before taking a dose and the S221
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FIG 1. The operation of a pMDI valve. (Adapted from Purewal TS. Formulation of metered dose inhalers. In: Purewal TS, Grant DJW, editors. Metered dose inhaler technology. Buffalo Grove, Ill.: Interpharm Press Inc, 1998. p. 9-68. © Interpharm Press Inc. Republished with permission.)
FIG 2. An OSCAR technique set-up.
TABLE I. Details of product development challenges resulting from the chlorofluorocarbon-to-hydrofluoroalkane transition Aspect
Surfactants Valve materials Filling equipment Seals in manufacturing equipment Regulatory requirements Patent situation
Challenges
Surfactants used in CFC products are not soluble in HFA propellants; therefore obtaining a stable suspension is difficult, and new stabilizers are required. Valve elastomers used in CFC products are not compatible with HFA propellants; new ones are required. Boiling points of HFAs are much lower than CFC propellant-11; no HFA exists as a substitute for P11. Seals are not compatible with HFA propellants; new ones are required. Requirements for the uniformity of dose had been tightened by the time the HFA products were being developed. Numerous patents started to be filed on HFA pMDI formulations, especially for generic drugs, thereby increasing competition and reducing the number of approaches available.
time when the patient releases the valve after actuating the pMDI. This could be 10 seconds or more depending on the individual patient’s inhaler technique and whether they use a spacer. If the suspension is not stable for that time, the volume sampled into the metering chamber may not be homogenous; therefore the next dose delivered to the patient may be either too low or too high, depending on the nature of the suspension instability.
Thus suspension stability is important for dose uniformity. Despite this, there have been few techniques available to monitor pMDI suspension stability, probably because the systems are pressurized, which makes assessment difficult. One method of measuring suspension stability is the visual method. Drug suspension is filled into transparent vials, shaken, and visually assessed over time; a determination is made on how
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A
B FIG 3. A, An example OSCAR profile for a stable creaming formulation. B, An example OSCAR profile for an unstable creaming formulation.
long it takes for flocculation and then either settling or creaming to occur. A variation on this is to determine how many lines of newsprint can be read through the suspension at various times. With the “newsprint” method, the less stable the suspension (ie, it has creamed or sedimented), the greater the number of lines of newsprint that can be read through the suspension. The obvious disadvantage with these methods is their subjective nature. More recently, a more objective test called OSCAR (optical suspension characterization) has been developed6 to assess HFA pMDI suspension stability. An alternative, more time-consuming method of determining suspension stability uses conventional analytic techniques. Dose delivery testing determines the dose of drug delivered from the pMDI by firing an actuation and assaying the drug released by techniques such as HPLC. A variation on this method is when, after shaking the pMDI, there is a pause time before firing off an actuation (this test is also known as “shake-pause-fire” testing). If the suspension is stable throughout the pause time, there will be no difference in the dose delivered compared with when there is no pause. However, if the suspension is unstable over the pause time (eg, it starts to settle out)
then the dose delivered will be affected and will no longer be the target dose required. The correlation of suspension stability measured by OSCAR with dose delivery testing using pause times has been attempted here for an unstable and a stable suspension formulation, and preliminary data are presented.
MATERIAL AND METHODS Preparation of pMDIs pMDIs were prepared for OSCAR evaluation by cooling down pMDIs manufactured by conventional pressure-filling techniques to below the boiling point of the propellant. The valve was then cut off the pMDI with a suitable cutting tool, and the contents were poured into a polyethylene terephthalate vial (Precise Plastics, London, UK). A new continuous valve was then rapidly crimped onto the vial to avoid excessive evaporation of propellant. pMDIs for conventional analytic testing were manufactured by pressure filling into aluminium cans fitted with metering valves on specially designed filling equipment. pMDIs were equilibrated before the testing to allow the valve seals to swell in the propellant.
OSCAR evaluation A schematic of the OSCAR set up is shown in Fig 2. Two matched pairs of infrared emitter/detector probes are directed at the transparent vial. The height of these photodetectors is adjustable; for these exper-
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FIG 4. An OSCAR profile for a stable suspension.
FIG 5. An OSCAR profile for an unstable suspension.
iments, the upper photodetectors were positioned 4 mm below the suspension surface, and the lower photodetectors were positioned 6 mm from the bottom of the vial. The infrared detector probes detect any changes in light transmission through the suspension. A personal computer then processes the voltage signal, and a profile of light transmission over time is attained. If the suspension is stable and occludes the infrared beam, the transmitted signal will be low. However, if the suspension is unstable and has either settled out or creamed (depending on the density of the drug relative to the propellant), the light transmission will be high. Before the test, the vial containing the suspension to be evaluated is shaken and placed in the OSCAR set up. Data were collected for up to 120 seconds.
OSCAR data analysis Fig 3 illustrates the types of profiles that can result from stable and unstable suspensions of creaming formulations. For an unstable suspension of a sedimenting drug, the light transmission at the upper pho-
todetector will be high; whereas for an unstable suspension of a creaming drug, the light transmission at the lower photodetector will be high. For a stable drug, the upper and lower sensors traces will be superimposable for some period of time. A simple judgement of the stability of the system can be determined by calculating the area under the profile (AUP), where: AUP α suspension stability-1
Conventional analytical testing For the stable and unstable suspensions, dose delivery testing was performed. For the stable suspension, doses at the start of can life were collected, and pause times of between 0 and 40 seconds were evaluated. For the unstable suspension, doses through the life of the inhaler were evaluated with pause times of 0 and 5 seconds. Dose delivery testing: stable suspension. The pMDI was shaken; then with a pause time of 0 seconds, 1 actuation was immediately fired to waste. A second actuation was collected after the inhaler had been shaken, by firing the pMDI into a specially designed dose
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FIG 6. Dose delivery data at different pause times between shaking and firing for stable suspension.
FIG 7. Dose delivery data at 0 pause time between shaking and firing for an unstable suspension.
FIG 8. Dose delivery data at 5 minutes of pause time between shaking and firing for an unstable suspension.
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collection apparatus (containing a filter on which the dose is collected). The second actuation (which is filled into the metering chamber of the valve as the first actuation is expelled) was the actuation of interest. Therefore to collect data at pause times greater than 0, there was a pause time of 10, 20, 30, or 40 seconds after the inhaler was shaken but before the first actuation was fired to waste. The second actuation was collected in the dose collection apparatus. This was performed for 3 separate pMDIs for pause times of 0, 10, 20, 30, and 40 seconds. Dose delivery testing: unstable suspension. Dose delivery testing for 10 actuations at the beginning, middle, and end of life of 5 inhalers were collected in the conventional way (shake then fire) with a pause time of 0 between every actuation. The experiment was then repeated for a pause time of 5 seconds between shaking and firing for every actuation.
RESULTS AND DISCUSSION OSCAR evaluation OSCAR profiles of the stable and unstable suspensions are shown in Figs 4 and 5, respectively. It is evident that there is a clear difference in the suspension stability of the two systems. For the unstable system (where the drug sediments when left standing for long periods), the upper photodetector signal is towards the top of the graph. For the stable system (where the drug creams when left standing for long periods), the upper and lower photodetector signals are superimposable.
Dose delivery testing A graph of the dose from the second actuation of the pMDI that contained the stable suspension at pause times of 0 through 40 seconds is shown in Fig 6. It is evident that there is little difference in the dose delivered between the different pause times, as expected. For the unstable suspension, Figs 7 and 8 show dose delivery profiles after pause times of 0 and 5 seconds, respectively. It is evident that the dose is generally increased after a pause time of 5 seconds. This would be
J ALLERGY CLIN IMMUNOL DECEMBER 1999
expected for a sedimenting suspension because the pMDI is operated in the valve down orientation and will be sedimenting during the 5-second pause. The suspension nearer the refill hole of the valve will start to concentrate with time; thus a superconcentrated suspension will be refilled into the metering chamber for the second actuation.
CONCLUSIONS Although slightly different methods of testing were used for the 2 suspension types, the preliminary data shown indicate that there is likely to be a correlation between the data obtained from the OSCAR technique and from conventional analytic testing for these stable and unstable suspension formulations. Further, more controlled studies are ongoing to better define the correlation between the two techniques. In the future, it is hoped that OSCAR evaluation can be used in early formulation screening studies in place of the more resourceintensive conventional dose delivery testing. The author thanks Peter Lambert, Adam Haigh, Cheryl Smith, and Nola Bowles for their assistance in performing this work. REFERENCES 1. UN 1989. Montreal protocol on substances that deplete the ozone layer. New York: Liaison Office of the United Nations Environment Program; 1989. 2. Smith IJ. The challenge of reformulation. J Aerosol Med 1995; 8(suppl):S19-27. 3. Purewal TS. Formulation of metered dose inhalers. In: Purewal TS, Grant DJW, editors. Metered dose inhaler technology. Buffalo Grove, Ill: Interpharm Press Inc, 1998. p. 9-68. 4. Hallworth GW. The formulation and evaluation of pressurised metereddose inhalers. In: Ganderton D, Jones T, editors. Drug delivery to the respiratory tract. Chichester, UK: Ellis Horwood; 1987. p. 87-118. 5. Purewal TS. Formulation of metered dose inhalers. In: Purewal TS, Grant DJW, editors. Metered dose inhaler technology. Buffalo Grove, Ill: Interpharm Press Inc, 1998. p. 9-68. 6. Jinks PA. A rapid technique for characterisation of the suspension dynamics of metered dose inhaler formulations. In: Proceedings of Drug Delivery to the Lungs VI. London: The Aerosol Society (Portishead, Bristol, UK); 1995. p. 10-13.
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The chlorofluorocarbon to hydrofluoroalkane transition: The effect on pressurized metered dose inhaler suspension stability Anne Brindley, BPharm, MRPharmS, PhD Leicestershire, United Kingdom The phase out of chlorofluorocarbon (CFC) propellants has necessitated the reformulation of pressurized metered dose inhalers (pMDIs) with hydrofluoroalkane (HFA) propellants. One of the main challenges has been that conventional surfactants used for CFC-based pMDIs were not soluble in HFAs. Since one of the main aims of a pMDI is to deliver a reproducible dose of medication to the patient, it is vital that, for suspension-type pMDI formulations, the suspension is stabilized sufficiently for a reproducible dose to be delivered. A new technique has been developed that measures suspension stability more objectively than before. This technique, optical suspension characterization, was used to compare the performance of different formulations of respiratory drugs in HFAs. The optical suspension characterization data were correlated with conventional analytic techniques for the determination of the stability of the suspension formulation. (J Allergy Clin Immunol 1999;104:S221-6.) Key words: Metered dose inhaler, formulation, suspension, stability hydrofluoroalkane
The Montreal Protocol1 came into force in 1989 and initiated the transition of the propellants essential for the operation of pressurized metered dose inhalers (pMDIs) from chlorofluorocarbons (CFCs) to hydrofluoroalkanes (HFAs). The HFA propellants, which have no chlorine atoms in their structure, have zero ozone depleting potential and also a reduced global-warming potential compared with CFC propellant 11.2 Two HFA propellants were soon selected by pharmaceutical companies to use for reformulation of their CFC-based products. These were HFA-134a (1,1,1,2-tetrafluoroethane) and HFA-227 (1,1,1,2,3,3,3heptafluoropropane). However, it soon became apparent that a direct switch of propellant was not straightforward; 10 years later, there are only 3 HFA-based pMDI products marketed in the United Kingdom (Airomir; 3M, marketed 1995; Qvar; 3M, marketed 1998; and Ventolin Evohaler; Glaxo Wellcome, marketed 1998) and one product in the United States (Proventil; Schering). There were significant hurdles to overcome before a suitable replacement product could be marketed. These hurdles spanned all aspects of product development. The major
From AstraZeneca R&D Charnwood, Leicestershire, United Kingdom. Reprint requests: Anne Brindley, AstraZeneca R&D Charnwood, Bakewell Rd, Loughborough, Leicestershire, LE11 5RH United Kingdom Copyright © 1999 by Mosby, Inc. 0091-6749/99 $8.00 + 0 1/0/102782
Abbreviations used OSCAR: Optical suspension characterization pMDI: Pressurized metered dose inhaler
formulation issues that arose as a result of the transition are detailed in Table I. This article will concentrate on how one of these issues (the fact that conventional CFC surfactants were not soluble in the HFA propellants) impacted on product performance particularly in light of the fifth issue listed in Table I: the tightening of regulatory requirements for dose uniformity from inhaled products.
SUSPENSION STABILITY AND PRODUCT PERFORMANCE Surfactants were used in CFC-based pMDI formulations to stabilize micronized drug particles (<10 µm) in a propellant mixture. The surfactants used to suspend the drug particles in CFCs (oleic acid, lecithin, and sorbitan trioleate) were soluble in the CFC propellants; and by adsorbing to the drug particles, the surfactants were therefore able to stabilize the drug particles to form relatively stable suspensions. However, these surfactants are virtually insoluble in the HFA propellants and therefore are not dispersed sufficiently to adsorb onto the drug particles.3 Solutions were sought by pharmaceutical companies, resulting in a variety of approaches to overcome the same problem. Most drug suspensions undergo destabilization over time (eg, flocculating, settling out, or creaming [movement to the surface]), even when surfactants are used to form the suspension.4 Metering valves used in pMDIs operate by sampling a volume of suspension from the bulk, which is retained in the metering chamber of the valve. Fig 1 shows a schematic diagram of the movement of suspension within the metering chamber when a pMDI is actuated.5 Briefly, when the patient actuates the pMDI, this volume of suspension in the metering chamber exits the inhaler through the valve stem and actuator into the patient’s mouth (or nose). At the same time as the dose is released, the metering chamber refills with the next dose. In suspension formulations of pMDIs, the suspension must remain stable between the time when the patient shakes the inhaler before taking a dose and the S221
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FIG 1. The operation of a pMDI valve. (Adapted from Purewal TS. Formulation of metered dose inhalers. In: Purewal TS, Grant DJW, editors. Metered dose inhaler technology. Buffalo Grove, Ill.: Interpharm Press Inc, 1998. p. 9-68. © Interpharm Press Inc. Republished with permission.)
FIG 2. An OSCAR technique set-up.
TABLE I. Details of product development challenges resulting from the chlorofluorocarbon-to-hydrofluoroalkane transition Aspect
Surfactants Valve materials Filling equipment Seals in manufacturing equipment Regulatory requirements Patent situation
Challenges
Surfactants used in CFC products are not soluble in HFA propellants; therefore obtaining a stable suspension is difficult, and new stabilizers are required. Valve elastomers used in CFC products are not compatible with HFA propellants; new ones are required. Boiling points of HFAs are much lower than CFC propellant-11; no HFA exists as a substitute for P11. Seals are not compatible with HFA propellants; new ones are required. Requirements for the uniformity of dose had been tightened by the time the HFA products were being developed. Numerous patents started to be filed on HFA pMDI formulations, especially for generic drugs, thereby increasing competition and reducing the number of approaches available.
time when the patient releases the valve after actuating the pMDI. This could be 10 seconds or more depending on the individual patient’s inhaler technique and whether they use a spacer. If the suspension is not stable for that time, the volume sampled into the metering chamber may not be homogenous; therefore the next dose delivered to the patient may be either too low or too high, depending on the nature of the suspension instability.
Thus suspension stability is important for dose uniformity. Despite this, there have been few techniques available to monitor pMDI suspension stability, probably because the systems are pressurized, which makes assessment difficult. One method of measuring suspension stability is the visual method. Drug suspension is filled into transparent vials, shaken, and visually assessed over time; a determination is made on how
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B FIG 3. A, An example OSCAR profile for a stable creaming formulation. B, An example OSCAR profile for an unstable creaming formulation.
long it takes for flocculation and then either settling or creaming to occur. A variation on this is to determine how many lines of newsprint can be read through the suspension at various times. With the “newsprint” method, the less stable the suspension (ie, it has creamed or sedimented), the greater the number of lines of newsprint that can be read through the suspension. The obvious disadvantage with these methods is their subjective nature. More recently, a more objective test called OSCAR (optical suspension characterization) has been developed6 to assess HFA pMDI suspension stability. An alternative, more time-consuming method of determining suspension stability uses conventional analytic techniques. Dose delivery testing determines the dose of drug delivered from the pMDI by firing an actuation and assaying the drug released by techniques such as HPLC. A variation on this method is when, after shaking the pMDI, there is a pause time before firing off an actuation (this test is also known as “shake-pause-fire” testing). If the suspension is stable throughout the pause time, there will be no difference in the dose delivered compared with when there is no pause. However, if the suspension is unstable over the pause time (eg, it starts to settle out)
then the dose delivered will be affected and will no longer be the target dose required. The correlation of suspension stability measured by OSCAR with dose delivery testing using pause times has been attempted here for an unstable and a stable suspension formulation, and preliminary data are presented.
MATERIAL AND METHODS Preparation of pMDIs pMDIs were prepared for OSCAR evaluation by cooling down pMDIs manufactured by conventional pressure-filling techniques to below the boiling point of the propellant. The valve was then cut off the pMDI with a suitable cutting tool, and the contents were poured into a polyethylene terephthalate vial (Precise Plastics, London, UK). A new continuous valve was then rapidly crimped onto the vial to avoid excessive evaporation of propellant. pMDIs for conventional analytic testing were manufactured by pressure filling into aluminium cans fitted with metering valves on specially designed filling equipment. pMDIs were equilibrated before the testing to allow the valve seals to swell in the propellant.
OSCAR evaluation A schematic of the OSCAR set up is shown in Fig 2. Two matched pairs of infrared emitter/detector probes are directed at the transparent vial. The height of these photodetectors is adjustable; for these exper-
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FIG 4. An OSCAR profile for a stable suspension.
FIG 5. An OSCAR profile for an unstable suspension.
iments, the upper photodetectors were positioned 4 mm below the suspension surface, and the lower photodetectors were positioned 6 mm from the bottom of the vial. The infrared detector probes detect any changes in light transmission through the suspension. A personal computer then processes the voltage signal, and a profile of light transmission over time is attained. If the suspension is stable and occludes the infrared beam, the transmitted signal will be low. However, if the suspension is unstable and has either settled out or creamed (depending on the density of the drug relative to the propellant), the light transmission will be high. Before the test, the vial containing the suspension to be evaluated is shaken and placed in the OSCAR set up. Data were collected for up to 120 seconds.
OSCAR data analysis Fig 3 illustrates the types of profiles that can result from stable and unstable suspensions of creaming formulations. For an unstable suspension of a sedimenting drug, the light transmission at the upper pho-
todetector will be high; whereas for an unstable suspension of a creaming drug, the light transmission at the lower photodetector will be high. For a stable drug, the upper and lower sensors traces will be superimposable for some period of time. A simple judgement of the stability of the system can be determined by calculating the area under the profile (AUP), where: AUP α suspension stability-1
Conventional analytical testing For the stable and unstable suspensions, dose delivery testing was performed. For the stable suspension, doses at the start of can life were collected, and pause times of between 0 and 40 seconds were evaluated. For the unstable suspension, doses through the life of the inhaler were evaluated with pause times of 0 and 5 seconds. Dose delivery testing: stable suspension. The pMDI was shaken; then with a pause time of 0 seconds, 1 actuation was immediately fired to waste. A second actuation was collected after the inhaler had been shaken, by firing the pMDI into a specially designed dose
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FIG 6. Dose delivery data at different pause times between shaking and firing for stable suspension.
FIG 7. Dose delivery data at 0 pause time between shaking and firing for an unstable suspension.
FIG 8. Dose delivery data at 5 minutes of pause time between shaking and firing for an unstable suspension.
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collection apparatus (containing a filter on which the dose is collected). The second actuation (which is filled into the metering chamber of the valve as the first actuation is expelled) was the actuation of interest. Therefore to collect data at pause times greater than 0, there was a pause time of 10, 20, 30, or 40 seconds after the inhaler was shaken but before the first actuation was fired to waste. The second actuation was collected in the dose collection apparatus. This was performed for 3 separate pMDIs for pause times of 0, 10, 20, 30, and 40 seconds. Dose delivery testing: unstable suspension. Dose delivery testing for 10 actuations at the beginning, middle, and end of life of 5 inhalers were collected in the conventional way (shake then fire) with a pause time of 0 between every actuation. The experiment was then repeated for a pause time of 5 seconds between shaking and firing for every actuation.
RESULTS AND DISCUSSION OSCAR evaluation OSCAR profiles of the stable and unstable suspensions are shown in Figs 4 and 5, respectively. It is evident that there is a clear difference in the suspension stability of the two systems. For the unstable system (where the drug sediments when left standing for long periods), the upper photodetector signal is towards the top of the graph. For the stable system (where the drug creams when left standing for long periods), the upper and lower photodetector signals are superimposable.
Dose delivery testing A graph of the dose from the second actuation of the pMDI that contained the stable suspension at pause times of 0 through 40 seconds is shown in Fig 6. It is evident that there is little difference in the dose delivered between the different pause times, as expected. For the unstable suspension, Figs 7 and 8 show dose delivery profiles after pause times of 0 and 5 seconds, respectively. It is evident that the dose is generally increased after a pause time of 5 seconds. This would be
J ALLERGY CLIN IMMUNOL DECEMBER 1999
expected for a sedimenting suspension because the pMDI is operated in the valve down orientation and will be sedimenting during the 5-second pause. The suspension nearer the refill hole of the valve will start to concentrate with time; thus a superconcentrated suspension will be refilled into the metering chamber for the second actuation.
CONCLUSIONS Although slightly different methods of testing were used for the 2 suspension types, the preliminary data shown indicate that there is likely to be a correlation between the data obtained from the OSCAR technique and from conventional analytic testing for these stable and unstable suspension formulations. Further, more controlled studies are ongoing to better define the correlation between the two techniques. In the future, it is hoped that OSCAR evaluation can be used in early formulation screening studies in place of the more resourceintensive conventional dose delivery testing. The author thanks Peter Lambert, Adam Haigh, Cheryl Smith, and Nola Bowles for their assistance in performing this work. REFERENCES 1. UN 1989. Montreal protocol on substances that deplete the ozone layer. New York: Liaison Office of the United Nations Environment Program; 1989. 2. Smith IJ. The challenge of reformulation. J Aerosol Med 1995; 8(suppl):S19-27. 3. Purewal TS. Formulation of metered dose inhalers. In: Purewal TS, Grant DJW, editors. Metered dose inhaler technology. Buffalo Grove, Ill: Interpharm Press Inc, 1998. p. 9-68. 4. Hallworth GW. The formulation and evaluation of pressurised metereddose inhalers. In: Ganderton D, Jones T, editors. Drug delivery to the respiratory tract. Chichester, UK: Ellis Horwood; 1987. p. 87-118. 5. Purewal TS. Formulation of metered dose inhalers. In: Purewal TS, Grant DJW, editors. Metered dose inhaler technology. Buffalo Grove, Ill: Interpharm Press Inc, 1998. p. 9-68. 6. Jinks PA. A rapid technique for characterisation of the suspension dynamics of metered dose inhaler formulations. In: Proceedings of Drug Delivery to the Lungs VI. London: The Aerosol Society (Portishead, Bristol, UK); 1995. p. 10-13.