Joel A. Sequeira

Assessment of Value and Applications of In Vitro Testing of Topical Dermatological Drug Products

The FDA recently issued a guidance covering practices of scaleup and post approval changes with semisolids (SUPAC-SS). This guidance outlines the steps that must be taken by a company to maintain certification of its semisolid dermatological products after quantitative changes have been made in their compositions and/or after changes have been made in the sourcing of their key ingredients, in their processing, in their batch sizes, and/or after their site of manufacture has been relocated. A key element within the guidance is a release test to be used to determine if the diffusional release of a drug found in a formulation is the same after changes have been made to the formulation as it was prior to implementing the changes. The AAPS-FDA sponsored workshop was set up to explore this qualifying test. The stated aims of the workshop were: a) to illustrate the methodology and techniques of in vitro release testing, b) to show the sensitivity of in vitro release with respect to manufacturing variables and to variations in components and composition (of specific formulations), c) to recognize in vitro release testing as a useful procedure for SUPAC documentation, d) to highlight and evaluate other applications of in vitro release testing, e) to explore the degree to which in vitro release testing and bioavailability may be related, and f) to evaluate the role of in vitro release testing of topical dosage forms as a tool to improve product quality.

Influence of the Metering Chamber Volume and Actuator Design on the Aerodynamic Particle Size of a Metered Dose Inhaler

Abstract Presented in this work are the results of a study designed to investigate the impact of the valve metering chamber volume and actuator design on the aerodynamic particle size distribution (PSD) of a suspension metered dose inhaler (MDI) containing propellant HFA-227. It was hypothesized that the valve metering volume and the actuator design in the MDI could influence the PSD of the emitted dose since it would affect the aerosol spray dynamics. The PSD results from this study, measured using cascade impaction, revealed that samples containing an actuator intended for oral delivery (rectangular mouthpiece and orifice diameter of ≈0.5 mm) produced a higher fine particle dose (FPD) than those containing an actuator intended for nasal delivery (circular nosetip and orifice diameter of ≈1 mm). In addition, the drug PSD profile was shown to be more sensitive to differences in the particle size of the suspended material when the oral actuator was used compared to when the nasal actuator was used. The valve metering chamber (25 vs. 63 μL volume) did not appear to have a major effect on the product aerodynamic PSD or the droplet size. These results demonstrate the importance of actuator design and orifice size in determining the aerodynamic PSD of an MDI.

Relationship among physicochemical properties, skin permeability, and topical activity of the racemic compound and pure enantiomers of a new antifungal

The topical antifungal Sch-39304 is a racemic compound comprised of two enantiomers, Sch-42427 and Sch-42426, only one of which (Sch-42427) is pharmacologically active. The pure enantiomers have a lower melting point and, therefore, a higher solubility than the racemic compound. Because of these differences in physicochemical properties, the concentration of the pure enantiomers in vehicles and in the skin was predicted to be an order of magnitude higher than the racemic compound. It was hoped that the pharmacological activity would also be higher. By measuring the flux of the chiral forms through human cadaver skin, the expected differences in skin solubility were confirmed. However, only a minimal difference between racemate and active enantiomer was observed in the lesion scores using a guinea pig dermatophyte model. By fitting the data to the Emax pharmacodynamic model, it is demonstrated that the maximum effect occurs at a concentration lower than the saturated concentration of the less soluble racemic compound. The data illustrate that the efficacy of topically active compounds may not be linearly related to drug concentration in either the vehicle or the skin.

Influence of the Storage Orientation on the Aerodynamic Particle Size of a Suspension Metered Dose Inhaler Containing Propellant HFA-227

Abstract Presented in this work are the results of a study designed to investigate the impact of the storage position on the particle size distribution (PSD) of a steroid suspension metered dose inhaler (MDI) containing propellant HFA-227. It was hypothesized that the orientation of MDI samples upon storage could influence the PSD of the emitted dose, since it determines the amount of contact the liquid formulation has with the valve and therefore the quantity of nonvolatile leachable materials from the valve components that may enter the product and potentially impact the aerosol spray dynamics. Samples stored in the valve down orientation (i.e., complete contact of the liquid formulation with the valve) showed a higher level of leachables compared to those samples stored valve up (i.e., minimal contact of the formulation with the valve). The valve down samples were found to produce larger particles in the emitted aerosol spray using both cascade impaction, the preferred method of regulatory submission, as well as laser diffraction. It was postulated that the larger particle size of the inverted samples was attributed to its higher levels of leachables. Based on our findings, it is recommended that in order to set appropriate controls on the product PSD, the storage orientation of the product will need to be considered.

Influence of the valve lubricant on the aerodynamic particle size of a metered dose inhaler.

Presented in this work are the results of a study designed to investigate the impact of valve lubricant (i.e., silicone oil) on the aerodynamic particle size distribution (PSD) of a steroid suspension metered dose inhaler (MDI) containing propellant HFA‐227. The objective of this study was to explore whether the valve lubricant, which is often used in MDI products to prevent valve sticking, can enter an MDI product and potentially impact the aerosol spray dynamics. The results of this work have shown that samples containing valves with high silicone levels produced a larger aerodynamic particle size (by cascade impaction) than samples with low‐silicone or silicone‐free valves. It is postulated that the presence of silicone in the product may increase the propensity for drug aggregation, thereby leading to an increase in the aerodynamic particle size of the emitted aerosol. These findings stress the importance of evaluating the effects of valve lubricant on the aerodynamic PSD in the early formulation development stage of an MDI.

Influence of the Size of Micronized Active Pharmaceutical Ingredient on the Aerodynamic Particle Size and Stability of a Metered Dose Inhaler

Pharmaceutical inhalers are often used to treat pulmonary diseases. Only active pharmaceutical ingredient (API) particles from these inhalers that are less than approximately 5 µm are likely to reach the lung and be efficacious. This study was designed to investigate the impact of micronized API particle size on the aerodynamic particle size distribution (PSD) profile and the particle size stability of a suspension metered dose inhaler (MDI) containing propellant HFA‐227 (1,1,1,2,3,3,3 heptafluoropropane) and a corticosteroid. The median API particle size ranged from 1.1 µm to 1.8 µm (97% to 70% of particles < 3 µm, respectively). This study showed that increasing the particle size of the API used to manufacture a suspension MDI product increased the aerodynamic PSD of the MDI product. Furthermore, upon storage of the MDI product under temperature cycling conditions, samples containing larger‐size API particles were less stable with respect to their aerodynamic PSD than those with smaller‐size API particles. It was found that size‐dependent particle growth and/or aggregation of the suspended API may be occurring as a result of temperature cycling. In conclusion, this study has shown that the particle size of the raw API impacts the properties and stability of the emitted aerosol spray. Based on the findings from this study, it is recommended that the API particle size be carefully controlled in order to meet specifications set for the finished MDI product.

Entry port selection for detecting particle size differences in metered dose inhaler formulations using cascade impaction

Different sized glass entry ports were evaluated for their drug collection efficiency during aerodynamic particle sizing of metered dose inhalers (MDIs) using cascade impaction. A comparison was made between collection efficiency in the entry port, impactor plates, and filter using the 1 L, 2 L, and 20 L glass entry ports and the USP and twin impinger entry ports. Entry port losses were dependent on the size of entry port selected, with 1–2 L ports showing optimal recovery on impactor plates, compared to the USP entry port. The 1 L entry port was further compared with the USP entry port in its ability to discriminate between subtle changes in particle size distribution (PSD) in an investigational hydrofluoroalkane (HFA)‐based MDI formulation. Deliberately induced differences during product manufacture were easily detected using the 1 L entry port with the Andersen cascade impactor. The USP port was unable to distinguish among products with small particle size differences. An alternative entry port such as the 1 L glass entry port used in this study may provide better means of characterizing the PSD during formulation development and stability testing of MDIs.

Comparison of the Flow Properties of Aqueous Suspension Corticosteroid Nasal Sprays Under Differing Sampling Conditions

Abstract Many aqueous suspension corticosteroid nasal sprays become less viscous when shaken and sprayed, then return to a more viscous state after application. This time-dependent, reversible loss of viscosity under shear (e.g., shaking or spraying) can be quantified in the rheological property of thixotropy. The flow properties of 5 corticosteroid nasal sprays were measured over a range of shear rates. The formulations tested included Nasonex®, Vancenase® AQ, Nasacort® AQ, Rhinocort Aqua®, and Flonase®. The yield stress values, as well as an estimate of thixotropy, were compared by using three different sampling techniques, including one that simulated patient use (shaking for 30 sec, spraying, and immediately transferring the sample to the rheometer). The rheological properties of all products indicated that when initially shaken and dispensed, they flowed more freely, followed by recovery of viscosity that would likely inhibit the suspensions from flowing out of the nasal cavity. Under all three tested conditions, Nasonex exhibited the highest yield stress, the largest apparent initial and final viscosities, and the highest apparent thixotropy. The study protocol that simulated patient-use conditions produced the following rank order of measured thixotropy: Nasonex>Flonase>Vancenase AQ>Rhinocort Aqua>Nasacort AQ. The thixotropy of Nasonex was 3.4 to 21.4 times greater and the final viscosity was 3.2 to 17.4 times greater than the values of the other tested products.

Particle size coarsening induced by valve silicone in a metered dose inhaler.

ABSTRACT The objective of this study was to evaluate the effect of valve silicone on the delivered particle size distribution of a suspension metered dose inhaler (MDI). Valves were manufactured with distinct levels of silicone, which could be differentiated with Fourier transform infrared spectroscopy (FT-IR). The amount of silicone in the valve was proportional to the amount of silicone that entered the formulation and the subsequent decrease in fine particle fraction (FPF) of the active pharmaceutical ingredient (API) measured by Andersen cascade impaction. The effect of silicone content was not linear as even small amounts of silicone made a significant contribution to particle size coarsening. This coarsening was also a function of storage time and temperature. Accelerated stability conditions greatly increased coarsening kinetics as 1 month at 40°C and 75% RH induced significantly more coarsening than 12 months at room temperature. Field emission scanning electron micrograph images suggest that the primary mechanism of particle size change may be aggregation as particle clusters were seen. This study indicates that silicone can be a critical process parameter for particle size distribution of a suspension MDI product. Thus, the amount of silicone in the valves needs to be minimized and controlled.

Comparison of in Vitro Release Rates of Nitroglycerin by Diffusion Through a Teflon Membrane to the USP Method

The in vitro release profile of nitroglycerin (GTN) from different transdermal patches through synthetic membranes has been determined and compared to the USP adapted release rate method. Five different nitroglycerin transdermal test formulations were compared to commercially available Nitro-Dur®. All formulations display similar release rate profiles when tested by the USP adapted release rate method. In contrast, significant differences among the tested formulations were observed by using a synthetic Teflon membrane. In these studied an attempt was made to develop a simple, reliable, and reproducible method for testing the release of GTN from different transdermal patches in vitro.