Application of in-line viscometer for in-process monitoring of microcrystalline cellulose-carboxymethylcellulose hydrogel formation during batch manufacturing.

Physical stability and consistent dose delivery of pharmaceutical suspension formulations comprised of microcrystalline cellulose (MCC) and sodium carboxymethylcellulose (NaCMC) hydrogels is dependent on their rheological properties. To obtain the desired rheological characteristics, good control of the hydrogel dispersion in water is required. The goal of this study was to evaluate whether the XL7-100 Process Viscometer could be employed as a process analytical technology (PAT) tool to monitor the dispersion process in real time during batch manufacturing. Using this instrument, viscosity profiles were measured during the hydrogel processing for a range of operating conditions. It was confirmed that viscosity obtained by the XL7-100 Process Viscometer in the off-line mode, could be linearly correlated to that of the conventional Brookfield viscometer. In addition, the XL7-100 Process Viscometer was able to detect variations in the hydrogel concentrations as well as process conditions in real time. Under fixed operating conditions, the dynamic viscosity profile showed low variability and good inter-batch reproducibility for a properly dispersed hydrogel. For a well-validated mixing process, an off-trend in-line viscosity reading may be indicative of batch failure or poor dispersion homogeneity. Therefore, the in-line viscometer can be used in manufacturing to monitor the batch to batch consistency. However, it is not proven to be able to characterize the real-time structure formation of the hydrogel. It is recommended that the in-line viscometer be used as a complimentary tool along with the off-line rheometer for both efficient and effective in-process quality control of the MCC & NaCMC hydrogel dispersion.

Comparison of optical particle sizing and cascade impaction for measuring the particle size of a suspension metered dose inhaler.

Optical techniques for the particle size characterization of metered dose inhaler (MDI) suspensions have been developed as an alternative to the labor-intensive and time-consuming impaction method. In this study, a laser diffraction (LD) apparatus with a liquid cell ("wet cell" method) and a "time-of-flight" apparatus named aerodynamic particle sizer (APS) were utilized to assess MDI suspensions with varied formulation compositions and storage conditions. The results were compared with the conventional Anderson cascade impaction (ACI) data. The two optical methods were able to detect the changes in particle size distributions between formulations, yet to a lesser extent than those observed using the cascade impaction methodology. The median aerodynamic particle size measured by the APS method and the median geometric particle size obtained from the LD method were linearly correlated with the corresponding ACI results in the range of 2-5 µm. It was also found that the APS measurement was biased towards the finer particle size region and resulted in overestimated fine particle fraction (FPF) values which were 2-3 times folds of the ACI results. In conclusion, the optical particle sizing techniques may, under some circumstances, be viable techniques for the rapid assessment of MDI suspensions. The "wet cell" LD method, in particular, is found to be a valuable means of detecting active pharmaceutical ingredient (API) particle size changes in an MDI suspension. Using both the LD and the APS methods in early formulation screening followed by a final assessment with cascade impaction analysis can improve the efficiency of MDI formulation development.

The in vitro and in vivo investigation of inhaled migraine therapies using a novel aerosol delivery system consisting of an air pressurized capsule device (APCD) in combination with a pMDI spacer for endotracheal dosing into beagle dogs.

CONTEXT: Aerosol delivery to animals in preclinical settings has historically been very challenging, requiring the use of techniques, such as intratracheal instillation and dry powder insufflation, that are somewhat invasive, inefficient and not representative of clinical inhalation. OBJECTIVE: The objective of this work is to develop a system to deliver dry powder to dogs in an efficient and effective manner for the study of new anti-migraine compounds in development. MATERIALS AND METHODS: The new device uses a metered aliquot of a dry gas to force dry powder drug from a pre-filled HPMC capsule into an AeroChamber® spacer for subsequent inhalation by the animal. RESULTS: The delivery of two invesigational migraine drugs via the new device was assessed in vitro using abbreviated Andersen cascade impaction and showed the device is capable of generating a reproducible delivered dose of up to ∼68% with more than 50% of the dose in the respirable range. In vivo studies have also been performed showing that this device effectively delivered the migraine drugs to spontaneously breathing dogs using a proprietary validated dog inhalation model. DISCUSSION: Results confirmed that the air pressurized capsule device (APCD) was effective in delivering the APIs to lungs of the animals. The in vivo data verified the advantages of inhaled delivery over oral delivery for this class of drugs and were used to establish the cardiopulmonary and respiratory side effect liability profile for these compounds. CONCLUSIONS: This work has demonstrated the utility of this device for quick and accurate screening of prospective drug candidates, representing a significant improvement in ease of use and reprodicibility over current delivery methods.

The application of "in-flight" laser diffraction to the particle size characterization of a model suspension metered dose inhaler.

Laser diffraction (LD) has been used to measure the particle size of pharmaceutical aerosols. In this study, the application of LD for measuring the particle size of a model suspension metered dose inhaler (MDI) containing a hydrofluorocarbon propellant was investigated using a Sympatec LD apparatus with an automatic spray device. In order to obtain meaningful results, test parameters such as spray distance and temperature needed to be optimized for this model formulation and then well-controlled during testing. Using a suitable LD test methodology, it was found that particle size variations as a function of nonvolatile excipient levels as well as changes to the suspended drug substance could be observed and, in some cases, correlated to cascade impaction results. Based on these studies, it is believed that the methodology is a valuable rapid screening tool for investigating variations in or permutations to suspension MDI formulations. Nonetheless, the trends in the LD droplet size are complicated by the presence of drug-free droplets. Consequently, the results are not always consistent with other particle sizing techniques such as cascade impaction in which the droplets associated with drug are evaluated. Therefore, for suspension MDIs, the "in-flight" LD method would probably best be utilized as a complementary sizing technique during formulation development.

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

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 degrees 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.

Influence of the metering chamber volume and actuator design 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 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 approximately 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 approximately 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 microL 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.

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.

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.

Influence of the storage orientation on the aerodynamic particle size of a suspension metered dose inhaler containing propellant HFA-227.

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 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 microm 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 microm to 1.8 microm (97% to 70% of particles <3 microm, 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.