Atul Karanjkar

Traditional needle and syringe administration has several drawbacks. These include complexity of dose preparation, patient compliance, stability of the drug after reconstitution into its desired form and safety concerns - such as the handling and disposal of a used syringe. In response to safety considerations, several alternative drug delivery systems, such as powder injection, have been developed, together with techniques for the sustained release of drug formulations and the evaluation of new formulations for oral and injectable administration.		

It is possible to use animal experimentation to evaluate drug delivery systems; however, scientists are often uncertain how to apply the results to humans. For example, major differences between the respiratory tracts of humans and laboratory animals mean that inhaling the same amount of powder can result in dramatically different dosages. Given these issues, designers of drug delivery systems need a comprehensive design tool to enable them to evaluate different designs rapidly and economically. 	

Computational fluid dynamics (CFD) uses numerical methods to solve the equations that govern fluid flow. The basic premise of CFD is to divide the domain to be analysed into small volumes or elements (Figure 1). For each of these elements, a set of partial differential equations is solved; these approximate a solution for the flow to achieve the conservation of mass, momentum and energy for each volume or element. The three basic equations are solved simultaneously with any additional equations implemented in a particular model to obtain flow velocities, pressure and, hence, any derived quantities such as shear stress.				

The conservation of momentum, with F representing the convective flux and G representing the diffusive flux, is given in Equation 1. The conservation of mass is given in Equation 2.	

In addition to these model equations, the equations of turbulence are solved if they are applicable to the particular flow regime being analysed. From the flow domain, each cell is then analysed in relation to its neighbours in an iterative process until errors in the total conservation equation have been reduced to an acceptable level across the whole of the area being studied. 		

quick evaluation of various design and process parameters 

savings in work hours and other operating costs 

ideal conditions to be simulated and greater control of the physical process 

specific phenomena to be isolated for study.

Experiments only permit data to be extracted at a limited number of locations in the system by using measuring instruments, such as pressure and temperature probes, heat flux gauges and laser doppler velocity meters. CFD allows the analyst to examine a large number of locations in the region of interest and yields a comprehensive set of flow parameters for examination. The resulting design and parametric data, such as dose concentration and variation, particle dispersion process, as well as three-dimensional visualization of design performance, is invaluable. 

Cost savings can range from 10–30% depending on the type of device, its application, the complexity of the physical models and the target area (disease) for the medicine. Some of the current and possible applications of CFD in the development of drug delivery systems are reviewed below. 	

Inhalation technology is extensively used for treating lung diseases such as asthma, cystic fibrosis and emphysema. This method offers rapid and easy administration of drugs and the ability to administer low dosages. Most drug adsorption in the lung occurs across the alveolar epithelium.1 The rate of drug deposition depends on particle size and rate of inspiration.2 Dry powder inhalers and metered dose inhalers (MDIs) are two commonly available inhalers, with MDIs containing chlorofluorocarbon (CFC) gases being the most prescribed inhalation systems during the past few years. 	

Figure 1:  Fluid region of pipe flow discretized into a finite set of control volumes (mesh).				

However, MDIs have two main weaknesses: the actuation of the aerosol and the low dose concentration (typically 10% of the normal dose). Pharmaceutical companies started researching inhaler designs to improve ease of use and the efficiency of drug deposition (current efficiency is 30–35%3), and the reproducibility of the dosage. The research was accelerated because of the global drive towards reducing the level of CFC gas emissions. 	

Drug delivery systems normally involve the transportation of a secondary-phase material to the area being dosed. These secondary materials may be medicated particulates, liquid drops, a gaseous species or a mixture of all three. A variety of established multiphase modelling methodologies is available to the CFD practitioner to characterize a device for dose concentration, dose variation and the particle dispersion process. They can also be used to identify reasons for particle loss and review potential design improvements. 		

Figure 2:  Carrier particle trajectories and residence time in a dry powder inhaler.(4) 	

Figure 2 illustrates the residence time and trajectories for the medication particles in a transient simulation of an inhaler. Figure 3 illustrates the air flow in the inhaler.4 The simulation results were used to identify regions of high velocities, shear forces and circulation loops, particle residence times for larger and smaller diameter particles, and the separation of medication particles from carrier particles.	

CFD can also be used to evaluate other drug delivery systems such as needleless liquid and powder administration for the treatment of chronic problems and neurological diseases.5 A concentration profile of drug degradation rate can be evaluated using the values from diffusivity and reaction kinetics. In addition, these data are pertinent for regulatory authorities that seek information regarding bioavailability and bioequivalence for orally administered drug products.(6) 			

Figure 3:  Flow field across a dry powder inhaler.(4) 				

Complex oral cavity and oesophagus shapes can be discretized into a fine grid to model drug absorption and dissolution processes. Limitations of these approaches are the necessary simplification of the complex and varying geometry present in real life, the boundary conditions for the fluid and the porous nature of the oral cavity. 				

Drugs intended to be delivered via the respiratory tract are frequently micronized to create microparticles in the respirable range. These particles have a high surface area and high charges forming an unstable cohesive system. This means the particles could adhere to any surface on the way to the targeted region of the respiratory system. 			

Figure 4:  Mesh over nasal passages. Courtesy of TGS, Inc.	

CFD can be used to trace the trajectories of a medication particle through the nasal passage and lung. Figure 4 illustrates the nasal passage, to identify the region of high air velocity. CFD can also be used in model die design, extrusion, blow moulding, device filling and debubbling, and other elements of device manufacturing.	

CFD can be used for a range of applications, including the design of drug delivery systems and drug absorption. Accuracy of the CFD simulations will depend largely on the geometry, the physical models that are employed and the boundary conditions used in the simulation. Although CFD does not eliminate the necessity of experimental work, it provides quick and cost-effective evaluations of new designs, new molecules, the delivery process and the performance sensitivity of the drug delivery systems to changes in the parameters.	

Articles

Interest in more advanced drug delivery systems has increased, with an acceleration in the discovery and development of novel therapeutic macromolecules for targeted applications. Computational fluid dynamics is a design tool that allows producers of these and other products to evaluate different models rapidly and cost-effectively.