Dilip M. Parikh
With the introduction of combinatorial chemistry and high-throughput screening, numerous new potential drug candidates are being investigated for their therapeutic usefulness. However, the molecular structure of new chemical entities is becoming more complex, leading to drugs with low aqueous solubility, a low dissolution rate, and limited absorption after oral administration. These issues result in decreased bioavailability.
Particle size reduction methods such as grinding, micronization, ball milling, precipitation, melt quenching, and freeze-drying have been used extensively to improve the solubility and dissolution rate of materials with poor water solubility. These processes generally change drug substances polymorphically by transforming their low-energy crystalline form into an amorphous form. Since the amorphous state represents the most energetic solid state, it provides the greatest advantage in terms of solubility. However, because amorphous particles have a tendency to be metastable, the amorphous state must be stabilized.
The solid dispersion approach to reducing particle size, increasing drugs’ dissolution rate and absorption, and thus stabilizing the amorphous state was first recognized in 1961. Solid dispersions consist of a carrier in which a compound is dispersed in the form of small particles. The development of solid dispersion using hydrophilic polymers is the preferred approach for improving the stability of the amorphous state. Commonly proposed mechanisms for achieving stabilization include increasing the glass transition temperature, immobilizing drug molecules, and performing hydrogen bonding with hydrophilic polymers.
Spray drying is a method for achieving a solid dispersion. The first significant spray drying application occurred in the dairy and detergent industries in the 1920s. It is one of the few technologies available for the conversion of a liquid, slurry, or low-viscosity paste to a free-flowing powder in one unit operation. The actual spray drying process is almost instantaneous, since most evaporation takes place in as little as a few milliseconds or a few seconds at most, depending on the design of the equipment and the process conditions. The method is applied in various industries. In the pharmaceutical industry, it is commonly used for antibiotics, vitamins, vaccines, enzymes, plasma substitutes, and excipients. It is also used in the preparation of microcapsules for inhalation or slow-release formulations.
Compounds that are sparingly soluble because of their crystalline morphology can be converted to an amorphous form using spray drying, enabling greater solubility and, hence, enhanced bioavailability. This result is possible because the hollow structure of spray-dried particles increases drugs’ solubility and subsequent dissolution rate severalfold. The rapidity of the spray drying process improves the stability of otherwise unstable amorphous forms. With a polymer as a carrier, a molecular dispersion is formed, or a so-called glass solution and crystallization are avoided as nucleation and growth slow down or even stop. Furthermore, in such materials, the total surface area of the particles is maximally increased.
The most commonly used hydrophilic carriers for solid dispersions include polyvinylpyrrolidone, polyethylene glycols, and polyvinyl alcohol. Surfactants can also be used to form a solid dispersion.
Spray drying is a continuous process. The physical properties of the resulting product, such as particle size and shape, moisture content, and flow properties, can be controlled by selecting the appropriate equipment and by manipulating the process variables. The solubility of compounds that are sparingly soluble in water can be enhanced by preparing solid dispersions using spray drying because the resulting amorphous-polymer complex dissolves at an accelerated rate. This acceleration is attributable to the large surface area, the amorphous state, and the improved wettability of the drug, causing carrier-controlled dissolution. Spray drying is the appropriate technology for producing scalable, commercially viable, and reproducible solid dispersions.
Dilip M. Parikh is president of DPharma Group Inc., a pharmaceutical technology development and consulting firm in Ellicott City, MD. He is an industrial pharmacist with more than 35 years of industrial experience in R&D, CGMP-compliant facility planning, construction, manufacturing, and operational management at pharmaceutical companies in Canada and the United States. The editor of the Handbook of Pharmaceutical Granulation Technology (second edition), Parikh has authored many scientific publications and has spoken worldwide at scientific conferences on solid dosage technology development and manufacturing. He is also a consultant to Anhydro Pharmaceutical Div. in Elkridge, MD.