Influence of excipients on spray-dried powders for inhalation

Two areas attracting considerable attention when developing effective pulmonary drug delivery systems include the improvement of aerosolisation efficiency of the inhaled formulation and the controlled release of drug from the formulation following deposition within the lung. In this study, four saccharides were employed as excipients in the preparation of spray-dried powder formulations for the pulmonary drug delivery. Beta-cyclodextrin-, starch-, and sodium carboxymethylcellulose (NaCMC)-based spray-dried powders showed a significant (one-way ANOVA, Duncan's test, p < 0.05) increase in lower stage drug deposition in the Next Generation Impactor (NGI) when compared to lactose-based spray-dried powders. Furthermore, NaCMC-based spray-dried powder formulations exhibited a sustained drug release profile in dissolution testing; approximately 80% of salbutamol sulphate was released after an hour, whereas drug from the lactose-based spray-dried powder formulation was released within 5 min. Our results clearly demonstrate that the inclusion of NaCMC in spray-dried powder formulations increases the aerosolisation efficiency of the powder and also offers the potential for sustained drug release, which may be of benefit in the treatment of local and systemic conditions

Evolutionary algorithms in modeling aerodynamic properties of spray-dried microparticulate systems

Spray drying is a single step process in which solutions or dispersions are converted into dry particles. It is widely used in pharmaceutical technology to produce inhalable particles. Dry particle behavior during inhalation, described as the emitted dose (ED) and fine particle fraction (FPF), is determined in vitro by standardized procedures. A large number of factors influencing the spray drying process and particle interaction makes it difficult to predict the final product properties in advance. This work presents the development of predictive models based on experimental data obtained by aerodynamic assessment of respirable dry powders. Developed models were tested according to the 10-fold cross-validation procedure and yielded good predictive ability. Both models were characterized by normalized root-mean-square error (NRMSE) below 8.50% and coefficient of determination (R2) above 0.90. Moreover, models were analyzed to establish a relationship between spray drying process parameters and the final product quality measures. Presented work describes the strategy of implementing the evolutionary algorithms in empirical model&rsquo;s development. Obtained models can be applied as an expert system during pharmaceutical formulation development. The models have the potential for product optimization and a knowledge extraction to improve final quality of the drug

Modeling, optimization, and sensitivity analysis of a continuous multi-segment crystallizer for production of active pharmaceutical ingredients

We have investigated the simulation-based, steady-state optimization of a new type of crystallizer for the production of pharmaceuticals. The multi-segment, multi-addition plug-flow crystallizer (MSMA-PFC) offers better control over supersaturation in one dimension compared to a batch or stirred-tank crystallizer. Through use of a population balance framework, we have written the governing model equations of population balance and mass balance on the crystallizer segments. The solution of these equations was accomplished through either the method of moments or the finite volume method. The goal was to optimize the performance of the crystallizer with respect to certain quantities, such as maximizing the mean crystal size, minimizing the coefficient of variation, or minimizing the sum of the squared errors when attempting to hit a target distribution. Such optimizations are all highly nonconvex, necessitating the use of the genetic algorithm. Our results for the optimization of a process for crystallizing flufenamic acid showed improvement in crystal size over prior literature results. Through the use of a novel simultaneous design and control (SDC) methodology, we have further optimized the flowrates and crystallizer geometry in tandem.^ We have further investigated the robustness of this process and observe significant sensitivity to error in antisolvent flowrate, as well as the kinetic parameters of crystallization. We have lastly performed a parametric study on the use of the MSMA-PFC for in-situ dissolution of fine crystals back into solution. Fine crystals are a known processing difficulty in drug manufacture, thus motivating the development of a process that can eliminate them efficiently. Prior results for cooling crystallization indicated this to be possible. However, our results show little to no dissolution is used after optimizing the crystallizer, indicating the negative impact of adding pure solvent to the process (reduced concentration via dilution, and decreased residence time) outweighs the positive benefits of dissolving fines. The prior results for cooling crystallization did not possess this coupling between flowrate, residence time, and concentration, thus making fines dissolution significantly more beneficial for that process. We conclude that the success observed in hitting the target distribution has more to do with using multiple segments and having finer control over supersaturation than with the ability to go below solubility. Our results showed that excessive nucleation still overwhelms the MSMA-PFC for in-situ fines dissolution when nucleation is too high

Effect of curing conditions and harvesting stage of maturity on Ethiopian onion bulb drying properties

The study was conducted to investigate the impact of curing conditions and harvesting stageson the drying quality of onion bulbs. The onion bulbs (Bombay Red cultivar) were harvested at three harvesting stages (early, optimum, and late maturity) and cured at three different temperatures (30, 40 and 50 oC) and relative humidity (30, 50 and 70%). The results revealed that curing temperature, RH, and maturity stage had significant effects on all measuredattributesexcept total soluble solids

Inside the Phenomenological Aspects of Wet Granulation: Role of Process Parameters

Granulation is a size-enlargement process by which small particles are bonded, by means of various techniques, in coherent and stable masses (granules), in which the original particles are still identifiable. In wet granulation processes, the powder particles are aggregated through the use of a liquid phase called binder. The main purposes of size-enlargement process of a powder or mixture of powders are to improve technological properties and/or to realize suitable forms of commercial products. A modern and rational approach in the production of granular structures with tailored features (in terms of size and size distribution, flowability, mechanical and release properties, etc.) requires a deep understanding of phenomena involved during granules formation. By this knowledge, suitable predictive tools can be developed with the aim to choose right process conditions to be used in developing new formulations by avoiding or reducing costs for new tests. In this chapter, after introductive notes on granulation process, the phenomenological aspects involved in the formation of the granules with respect to the main process parameters are presented by experimental demonstration. Possible mathematical approaches in the granulation process description are also presented and the one involving the population mass balances equations is detailed

Design of inhaled insulin dry powder formulations to bypass deposition in the human extrathoracic region and enhance lung targeting

The effectiveness of aerosol drug delivery to the lungs depends on both the drug formulation and device. Currently marketed inhalation drug products often deliver no more than 15 – 30% of the packaged dose to the lung, either due to losses in the inhaler device, or deposition in the patient’s mouth-throat. This poses a significant challenge in the development of inhalation drugs, as it can dictate higher nominal doses in order to compensate for losses, and can result in increased systemic exposure for drugs that are orally bioavailable and, in some instances, increases in local and systemic side effects (e.g., for inhaled corticosteroids). In addition, large extrathoracic region losses can lead to increased variance in dose delivery to the lung. The goal of this research was to demonstrate that for dry powder inhalers, improved targeting to the lungs may be achieved by tailoring the micromeritic properties of the particles (e.g., size, density, and rugosity) to reduce deposition in the mouth and throat to negligible levels, thereby maximizing the total dose delivered to the lung. This can be achieved by co-solvent spray drying approach to modulate particle morphology and dose delivery characteristics of engineered powder formulations