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Paul Kippax is a product manager, Laser Diffraction, Malvern Instruments Ltd., Enigma Business Park, Grovewood Road, Malvern Worcestershire, UK WR14 1XZ, Paul.Kippax@malvern.co.uk.
Julie Suman is President at NextBreath LLC, USA.
Gerallt Williams is Director, R&D Laboratory Services at AptarGroup SAS, France.
One particularly crucial parameter for nasal sprays is the size of the droplets produced during actuation, which can potentially impact bioavailability.
Nasal sprays are widely used for locally acting preparations, such as decongestants and allergy treatments, as well as for the rapid delivery of systemic therapies, hormones and migraine treatments. In each case, the effectiveness of drug delivery depends on both the delivered dose and the size of the droplets produced by the spray pump during actuation. The latter influences both deposition and, potentially, bioavailability. In turn, droplet size derives from the characteristics of both the device and formulation, in combination, as recognised in the testing protocols.1–3 To achieve the desired performance of a product, developers may choose to manipulate the properties of the formulation or the design of the device, or both; however, developers require clear and relevant data on which to base their decisions.
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Laser diffraction-based particle size analysis is a powerful tool for nasal spray characterisation primarily because it is fast enough to capture droplet size evolution in real time. This article examines its value, and describes studies that explore the effect of formulation viscosity on droplet size, as well as device characteristics, such as orifice diameter of the nasal actuator and spray pump mechanism. Such studies support the faster and more efficient development of nasal spray products.
Regulatory guidance recommends that nasal sprays are tested as combined products (device and formulation together) to determine reproducible delivery.1–3 Achieving clinical efficacy and good product consistency relies on understanding and controlling the interactions between device and formulation, which together dictate performance. Invitro testing is specified for a range of variables, with droplet size being one of the most important parameters. Droplet size measurements are used to assess:
Quality — the consistency of performance; for example, over the lifetime of the product, from batch-to-batch, or after storage.
Safety — droplets of 10 µm and below may pass through the nasal passages and penetrate into the lungs.3 Consequently, APIs in this fraction will enter the body by pulmonary absorption, rather than by the intended route. Quantifying the extent of this risk and assessing the associated clinical effect is essential.
Efficacy — droplet size influences the site of deposition within the nasal passages, which may affect bioavailability.
The FDA recommends droplet size measurement at several stages of the product life cycle, including: development/optimisation and preclinical/IND trials; stability, robustness and in vitro bioequivalence testing; and batch release.1,2 The European Medicines Evaluation Agency (EMA) sets out similar guidance for droplet sizing as part of product applications,3 although the extension to in vitro bioequivalence testing is not as clearly stated. Such testing allows developers to successfully optimise controllable parameters to meet performance targets and provides quality control for the manufactured product.
The two droplet sizing techniques for nasal spray testing highlighted by the regulators are cascade impaction and laser diffraction. Cascade impaction is a relatively time and labour-intensive technique that allows measurement of the amount of API in the sub -µm aerodynamic fraction, which is important for assessing the potential for pulmonary absorption (as noted above). Laser diffraction, in contrast, is sufficiently rapid to provide real-time size measurement of the whole droplet rather than just the API. Because of this, laser diffraction is an excellent tool to use during the development cycle when the aim is to target a defined droplet size and obtain an early assessment of the percentage of droplets less than 10 µm in size.
Developers of nasal spray products tune an array of variables, some relating to the formulation others to the device, to achieve a target droplet size profile. Nasal spray devices usually incorporate a manually driven spray pump, which when actuated by the patient, pushes the liquid formulation through an orifice, thereby applying energy for atomisation (Figure 1). Aspects of spray pump design, such as the precompression ratio, and the geometry, length and orifice size of the actuator determine the shear force applied during use, which, in turn, influences the size of the droplets produced. The number and size of doses for which the product is intended will also be taken into account when determining the design of the device.
Figure 1: Schematic of a nasal spray device.
In terms of the formulation, modifying properties by changing the composition alters the response to conditions imposed by the device. A product may be solution- or suspension-based, with excipients levels controlled to meet atomisation and stability requirements. Viscosity modifiers such as glycerin, polyvinylpyrrolidone (PVP) and various cellulose-derivatives are especially common because the viscosity of the formulation has a marked impact on behaviour, with more viscous liquids requiring greater energy for dispersion to the same droplet size. Surface tension is also an important physical property and may affect droplet size.
Developing an optimal product relies on the effective manipulation of these influential variables, but this is only possible with reference to relevant droplet size data. Laser diffraction meets this need by providing real-time particle size analysis through a spray event.
With laser diffraction, the size of droplets in a spray is determined from the scattering pattern produced as particles pass through a collimated beam of light. Smaller particles scatter light weakly at wider angles, while larger particles produce a stronger signal at narrower angles. The technique is non-destructive, requires no calibration and is suitable for even concentrated sprays, providing that appropriate mathematical algorithms are used to analyse the scattered light pattern.
To be effective for spray measurement, laser diffraction systems must meet some essential criteria, including the ability to rapidly acquire data to track the droplet size of a spray as it evolves during a single actuation of the device. For nasal sprays, a wide dynamic range is needed so that the very large droplets (up to 600 µm in size) delivered at the beginning and end of a spray pump actuation can be detected, along with any fines. This enables researchers to understand each phase of atomisation during actuation, aiding the process of product optimisation.
An example of the data that can be obtained using laser diffraction is shown in Figure 2. Here, the output of a typical nasal pump spray has been measured during actuation for solutions containing increasing concentrations of PVP (PVP K90) up to and beyond the normal concentrations found in commercial products. PVP is commonly used to provide relatively high viscosity to improve product stability for suspension formulations. In this case, actuation of the spray pump has been controlled using a velocitycontrolled actuator (SprayVIEW NSx; Proveris Scientific, MA, USA), set to achieve a maximum velocity of 40 mm/s. Measurements were made 30 mm from the nozzle, at the centre of the spray plume, directly above the nozzle. This is within the range mentioned in the FDA guidance.2
The lower three profiles on Figure 2 are typical for a nasal spray event. During the initial formation phase, droplet size falls rapidly as flow rate through the spray pump increases. There is then a prolonged period of steady atomisation behaviour — the fully developed phase — during which droplet size remains relatively consistent; the FDA recommends that data from this period is used for statistically valid comparisons between different products. Towards the end of the spray event, flow rate through the spray pump decreases again to produce a corresponding increase in droplet size. This latter phase is referred to as the dissipation phase. The entire spray event is complete in less than 200 ms, underlining the importance of a rapid measurement technique.
Figure 2: Using the technique of laser diffraction to investigate the impact of solution viscosity on atomisation behaviour and droplet size.
The upper profiles (Figure 2) for 1.0 and 1.5% PVP concentrations, respectively, show the impact of increasing solution viscosity; there is an approximate doubling of viscosity as additive level is increased from 0.5 to 1.5%. These profiles indicate less than ideal behaviour and suggest that at higher viscosities the spray pump is unable to adequately atomise the formulation. With this particular nasal spray pump, flow rate through the device varies during actuation and reaches a peak towards the end of the profile. For the 1.0% solution, flow rate becomes high enough at around 100 ms after the start of actuation to achieve effective atomisation and a short-lived fully developed phase is observed. With the 1.5% solution, however, this point is never reached because the device is unable to supply sufficient energy to properly disperse the most viscous formulation.
The authors say...
In the case studies below, which follow the principles of quality by design, the limits of pump performance are sought to fully understand the nasal spray performance. In the example above, just one parameter (formulation viscosity) is changing. More frequently, developers need to assess the impact of changes to both device and formulation to find a combination that delivers the required performance. One option may be to modify the way energy is released into the liquid during atomisation by selecting an alternative spray pump mechanism.
Modifying nozzle spray mechanism to control atomisation
Figure 3 shows data for the same formulations as those in Figure 2, but this time using a spray pump mechanism that incorporates an energy storage mechanism (Equadel; Aptar Pharma Prescription Division, IL, USA). As the user depresses the spray pump, energy is stored within a spring and is released when the spray pump reaches a pre-determined hydraulic pressure. This has a pronounced impact on atomisation behaviour, with an obvious stable phase being observed even at high viscosities. In addition, the length of the stable phase is much longer, which may help to improve the efficiency of droplet deposition within the nasal passages.
Figure 3: Droplet size profiles obtained using the Equadel pump mechanism for the formulations shown in figure 2.
Modifying actuator orifice diameter to improve nasal spray performance
Although changing the spray pump mechanism offers some advantages, Figure 3 shows that the droplet size delivered for high viscosity solutions, although more controlled, is still large. While the FDA provides no upper size limit for nasal sprays, a Dv90 of up to 150 µm is typical. Droplets sized towards the upper end of this range and beyond increase the risk of product dripping out of the nasal cavity and an associated reduction in drug delivery efficiency to the posterior nasal cavity. Since switching to the Equadel spray pump leaves droplet size largely unchanged, it is useful to identify additional levers to tune droplet size. Dv50, one of the defined parameters of interest in the FDA guidance,2 provides a simple representative measure for comparative studies of spray pump output. The experimental measurements of Dv10 and Dv90 indicate similar trends, although the data are not shown.
If atomisation to a finer droplet size is considered important then changes to the geometry of the nasal spray pump actuator may deliver desirable performance. Important parameters include the geometry of the swirl chamber within the actuator and the diameter of the actuator orifice. This case study involves investigating the impact of actuator orifice diameter and actuation velocity on droplet size for different solutions.
Figure 4A shows the data reported using a smaller actuator orifice diameter than that used in Figure 3. These data indicate that with the smaller orifice, effective atomisation to a finer droplet size is achieved with all three solutions — a rapidly established fully developed phase is observed in each case. Droplet size increases with increasing viscosity, as expected, and is unaffected by actuation velocity.4 For this system then, moving to a small diameter may provide one means of ensuring a more effective spray deposition pattern in the nose.
Figure 4: Size profiles obtained using the Equadel pump mechanism with a small and large actuator orifice diameter.
It is also possible to determine the effect of increasing the actuator orifice size. In this case, a very large orifice size (approximately 0.2 mm larger than the small orifice tested above) was used. Although the diameter of this orifice was considered unrealistic in terms of standard product design, these measurements allowed the robustness of the pump to actuator design changes to be understood. Figure 4B shows the data recorded for actuation velocities of 40, 70 and 100 mm/s with water only. The results suggest that a stable phase is achieved at each actuation velocity when using the larger actuator orifice. At the lowest actuation speed (40 mm/s), however, the pump is seen to produce larger droplets. This trend holds for the 0.5% PVP and 1.0% PVP solutions.4
Analysis of the atomisation mechanism at work in the device provides a rationalisation of the observations made. As actuator orifice diameter decreases, the pressure drop across it (at any given flow rate) increases, thereby improving the atomisation characteristic. This explains the improvement in atomisation performance observed when using the smaller orifice diameter. However, the Equadel spray pump energy storage mechanism of actuation, which is triggered by the back pressure developed during the initial stages, is also affected. Because a smaller nozzle diameter induces a greater back pressure, the trigger mechanism works more effectively. When the actuator orifice diameter is increased, the back pressure is reduced causing the spray pump to actuate differently at low velocities. This is why the results obtained at 40 mm/s are not the same as those obtained at high actuation velocities.
The conclusion from this study is that reducing actuator orifice diameter makes it easier to access the optimal performance of the spray pump and actuation independent drug delivery. With a smaller diameter, solution viscosity is not as critical for effective drug delivery, which gives the formulator greater flexibility — although there is clearly a link between viscosity and droplet size.
To achieve optimal product performance, nasal spray developers need to manipulate device and formulation parameters on the basis of detailed understanding. Laser diffraction is a valuable technique for accessing relevant information because it captures droplet size data in real time, enabling researchers to evaluate the impact of any change. The influence of formulation properties such as viscosity and device parameters, including actuation profile, spray pump mechanism and actuator orifice size, can be systematically studied to facilitate a knowledge-based approach, as the presented data show. The recommendation by the regulators of laser diffraction as a measurement technique, relevant across the complete product lifecycle, from development through to quality control, underlines its value.
Paul Kippax is Product Manager — Diffraction Products at Malvern Instruments Ltd., UK. Tel. +44 (0)1684 892 456 firstname.lastname@example.org.
Julie Suman is President at NextBreath LLC, USA.
Gerallt Williams is Director, R&D Laboratory Services at AptarGroup SAS, France.
1. Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products — Chemistry, Manufacturing, and Controls Documentation (FDA, USA, July 2002). www.fda.gov
2. Bioavailability and Bioequivalence Studies for Nasal Aerosols and Nasal Sprays for Local Action (FDA, USA, April 2003). www.fda.gov
3. Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products (European Medicines Agency, London, UK, June 2006). www.ema.europa.eu
4. Data on file at Malvern Instruments.