Development of drug substances with poor aqueous solubility has become more common, presenting formulators and manufacturing experts with significant new challenges. One technology that has gained momentum and a reputation for providing a relatively simple solution to these solubility challenges is solid dispersion technology. Solid dispersions are molecular (thermodynamically stable) or colloidal (kinetically stable) dispersions of amorphous compounds dispersed in a polymeric matrix. It is a well known scientific principle that the amorphous form of a molecule is easier to dissolve than the crystalline form.

Until recently, pharmaceutical scientists had been reluctant to utilize this principle because of stability concerns and the threat of limited shelf-life. However, there is enough evidence reported in the literature and the marketplace demonstrating the long-term stability of properly formulated solid dispersions, thus eliminating a major barrier for evaluating the technology. Solid dispersions can be prepared by melt extrusion or spray-drying from lab through commercial scale. Both processes have advantages and limitations; this article will focus on spray-drying. The advantages of spray-drying allow the formulator to choose from a wide variety of polymers, solvents and adjuvants. Because spray-drying is performed at relatively low temperatures and has short contact times with the hot processing gas, it is an excellent manufacturing option when working with temperature sensitive compounds.

Proof of Concept

Before the spray drying process development begins, a stable, amorphous formulation with increased solubility needs to be developed and selected for clinical testing. The first step in developing a successful solid dispersion is to screen a variety of polymers systems. Such systems include polyvinyl pyrrolidone homopolymers and polyvinyl pyrrolidone-vinyl acetate co-polymers, HPMC and HPMC derivatives and acrylate copolymers. Formulators will typically prepare model formulations using polymers from each class and then test the formulations in in-vitro dissolution models and in accelerated stabilitystudies. Evaluating the different polymer systems requires expertise in formulation development and analytical sciences. Once the polymer system is chosen, further process and formulation development work can be performed to enhance the solid dispersion.

Process Steps

On the surface, the use of spray-drying to manufacture solid dispersions appears to be a relatively simple process. The poorly soluble drug substance or compound is dissolved in a solvent system along with a polymer dispersant system and any other desired adjuvants to form the spray-drying feed solution. The feed solution is then pumped into the top of the spray-dryer concurrently with a heated drying gas, typically nitrogen, and atomized into fine droplets using various types of nozzles or other atomizing techniques. As the liquid droplets fall through the drying chamber, the solvent is rapidly removed, forming a dry powder with distinct characteristics. The powder is usually collected in a cyclone and then secondarily dried in a vacuum oven or fluid bed dryer to remove residual solvents to meet ICH guidelines.

One of the advantages of spray-drying is its ability to control powder characteristics which can have a tremendous impact on secondary formulation and manufacturing of tablets or capsules. This is where expertise and a strong understanding of the fundamentals of spray-drying can define success or failure of a solid dispersion. Powder characteristics such as particle size and distribution, bulk density, residual moisture and solvent level, wettability, dispersability and flow properties can all be controlled through proper selection of spray-drying equipment and process parameters, such as nozzle selection, inlet and outlet temperatures and feed solution characteristics.

Feed Solution Development

Feed solution development is critical for determining powder characteristics, throughput and capacity for any given spray-dryer. Factors such as solvent selection, solids concentration, and physical properties of the solutions greatly influence powder characteristics. For example, lower solids concentration typically results in smaller particle size while higher solids concentration or viscosity will produce a larger particle. These factors also influence throughput which dictates capacity. Spray-dryers are sized based on their evaporative capacity for a given solvent under a specific set of conditions. Lower boiling solvents are easier to evaporate and result in higher throughputs and production capacity. Similar results are achieved with higher solids concentration in the feed solution which results in less solvent to evaporate. Another factor to consider when selecting solvents is the ICH residual solvent limits.

Once feed solution development is complete, it is important to determine feed solution stability. A feed solution can be a reactive system and must be evaluated for chemical stability over several days due to potential chemical interactions with the solvent, drug substance, polymeric dispersant and other adjuvants.

Atomization

The most common atomizers in pharmaceutical use are rotary atomizers (spinning wheel), two-fluid (pneumatic) and pressure (hydraulic) nozzles. Atomization through a two-fluid nozzle typically produces small particles in the range of 2-75μm while atomization through pressure nozzles produces a larger particle in the range of 50-200μm. Rotary atomizers span both ranges (2-200μm).

Process Temperatures

Evaluating inlet, outlet and condenser temperatures allows the engineer to design a highly efficient and reproducible spray-drying manufacturing process for solid dispersions. Bulk density, flowability and residual solvent levels are highly impacted by the process temperatures. For example, spray-drying at lower outlet temperatures will produce a powder with greater bulk density but a higher residual solvent level. Although most spray-dried solid dispersions will require some level of secondary drying, residual solvent levels of the powder must be evaluated as they can have a significant impact on the short term, and thereby long-term physical stability. Different rates of evaporation and secondary drying can plasticize the solid dispersion, leading to the formation of small levels of crystallinity that can serve as nucleation sites for crystal growth during storage. Careful evaluation must be conducted to determine the impact of the process outlet temperatures on the physical stability of the amorphous powder and other characteristics that may influence secondary dosage development.

Summary

Solid dispersion technology has become an accepted and proven technology for increasing the solubility and bioavailability of poorly soluble compounds. These dispersions can be manufactured by spray-drying, which is one of the most efficient processes for removing solvent to form a dry powder in a single step. It is a well known industrial process that is scalable and easily adapted to meet expected QbD manufacturing conditions. A host of factors influence the design and quality of the process and product including feed solution, atomization and process temperatures. Careful evaluation of each of these factors will result in the successful development of a manufacturing process to produce a stable solid dispersion with increased solubility and bioavailability.

Dean Ross is business development manager for ISP’s technology development and contract services business located in Columbia, MD. He can be reached at dross@ispcorp.com