It has been estimated that 40-60% of drugs in development have poor bioavailability due to low aqueous solubility. This percentage is likely to increase in the future with the increased use of combinatorial chemistry in drug discovery targeting lipophilic receptors. Poor bioavailability results in increased development times, decreased efficacy, increased inter- and intra-patient variability and side-effects, and higher dosages that reduce patient compliance and increase cost. Thus the ability to improve drug solubility and, hence, bioavailability through formulation and process technology is critical to improving a drug product's efficacy and safety and reducing its cost.
Solid dispersion technology, where the API is dispersed at the molecular or nanoparticle level as an amorphous material within a solid matrix, is a proven, effective technique for improving drug solubility. Solid dispersions can be produced practically at lab through to commercial scales, via spray drying or melt extrusion technology. Both processes have advantages and limitations but this article will focus on spray drying.
Solid dispersions are molecular (thermodynamically stable solid solutions) and/or colloidal (kinetically stable solid suspensions) dispersions of the amorphous active pharmaceutical ingredient (API) dispersed in a polymeric matrix. As a result of their morphology, thermodynamic and thermo-mechanical properties, solid dipersions increase drug surface area, reduce drug crystallinity and stabilise the system during storage and in vivo to inhibit drug recrystallisation.
When properly formulated and processed, the result is a system with excellent shelf-life stability and dramatically enhanced drug solubility and bioavailability that can often be orders of magnitude greater than that of the purely crystalline drug form.
While formulations of solid dispersions have been known to improve drug bioavailability since the 1960s, the technology began to receive greater attention in the late 1990s, primarily as a means to address the development challenges of the increasing number of poorly soluble APIs coming out of drug discovery research. In the past decade, solid dispersions have become more widely accepted because of successful adoptions of common process technologies utilised outside the pharmaceutical industry, mainly solvent spray drying and melt extrusion.
process steps
Solid dispersions are prepared through spray drying (see Fig.1) by: 1. Dissolving the API, the polymeric dispersant and any other desired adjuvants in a common organic solvent; 2. Atomising the liquid into fine droplets; 3. Rapidly removing the solvent from the liquid droplets as they fall through the drying chamber; 4. Collecting the resulting powder; and 5. Further drying the powder to remove residual solvents.
The advantages of this technology are tremendous formulation flexibility from the wide variety of solvents, polymers and adjuvants that can be employed, the ability to work with temperature sensitive APIs and the enhancement in performance that can be obtained by mixing the API and polymer at the molecular level in solution and then freezing this morphology in place through rapid solvent removal.
The disadvantages are added costs associated with the use and consumption of the organic solvents and the second unit operation required for residual solvent removal.
Spray drying is the most efficient process to convert a liquid solution directly into a dry powder in a single step. Other solvent evaporation methods such as bulk evaporation, rotary evaporation and lyophilisation or freeze-drying have numerous disadvantages. Primarily, these processes are neither scaleable nor economical for commercial production. In addition, the resulting powder characteristics from these processes are nowhere near as consistent and controllable as those of spray dried powders.
In pharmaceutical applications, spray drying is ideal for drying solutions, suspensions, dispersions and emulsions. Product powder characteristics such as particle size, distribution, and morphology, residual moisture/solvents, density, wettability/dispersability, flow properties and solubility can all be controlled through the proper selection of spray drying equipment and process parameters. These include feed preparation, feed atomisation type and rate, and spray rate/inlet and outlet temperature. Furthermore, the spray drying process and equipment are readily scalable from lab to pilot plant scale through to commercial production.
Screening studies: Powder characteristics and API dissolution rates can be greatly altered by API concentration in the feed solution, the choice of polymer and the ratio of polymer to API. Evaluating these parameters through appropriate screening studies is critical to the success of spray drying formulation projects. Furthermore, the impact of polymers and additives on feed solution stability needs to be considered. A feed solution can be a reactive system and must be evaluated for chemical stability over several days due to potential chemical reactions of APIs with solvents and additives and their respective impurities. ICH residual solvent limits should also be considered in proper solvent selection.
In spray dried solid dispersions, typical solvents include dichloromethane, acetone, methanol, tetrahydrofuran, ethanol, ethyl acetate, water and various combinations of these. Typical polymers include polyvinyl pyrrolidone homopolymers and polyvinyl pyrrolidone-vinyl acetate copolymers, HPMC and HPMC derivatives and acrylate copolymers. Addition of other solubilisers, such as surfactants and acids can be incorporated within limits.
Feed solution preparation: In solvent-based spray drying, to make solid dispersions the choice of solvent and the solids concentration in the feed solution determine the throughput and capacity for a given spray dryer. 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 solid production capacity. Similarly, higher solids concentration in the feed results in less solvent to evaporate and hence higher throughput and production capacity.
Just as important, powder product characteristics are greatly influenced by solvent selection, solid concentration in solution, feed solution viscosity, and less so by solution surface tension. Typically, dual solvent systems allow greater flexibility in operating conditions such as feed rates and inlet/outlet temperature parameters. Using solvent/non-solvent systems can greatly improve particle size, particle size distribution (Fig.2) and rates of dissolution. A low solid concentration in solution typically yields small particle sizes whereas a high solid concentration in solution spray dries into larger particles. Higher solution viscosity also yields larger particles.
Feed atomisation: The feed solution is pumped to an atomiser that is appropriately placed in the drying chamber to allow proper mixing with the heated drying gas - typically nitrogen with organic solutions. The most common atomisers in pharmaceutical use are two-fluid (pneumatic) nozzles, pressure (hydraulic) nozzles, and rotary (rotating wheel) atomisers. Atomisation through a two-fluid nozzle typically produces small particles in the range of 2-75µm. Atomisation through pressure nozzles typically produces larger particles in the range of 50-400µm and atomisation through a rotary atomiser typically produces particles that span both ranges (20-200µm).
The types of atomisers used in pharmaceutical applications are greatly influenced by process scale. Lab scale spray dryers with a nominal gas flow of 25kg/h can typically only handle two-fluid nozzles due to the short flight path and residence time of particles in the dryer. Pilot scale dryers with gas flows averaging 80kg/h can typically handle two-fluid nozzles and rotary atomisers. Nevertheless, the pilot scale dryer can be modified to handle pressure nozzles. This modification allows for the production of material with less feed supply - to ensure product powder characteristics similar to commercial scale equipment. Although commercial scale equipment can handle all three types of atomisers, the optimal nozzle for efficiency and reproducibility is the pressure nozzle. Each nozzle has unique intricacies that require careful evaluation to optimise processing conditions.
Spray dryer inlet/outlet temperatures: Several product powder characteristics can be altered by the outlet temperature, but the most impacted characteristics are density, flowability and residual solvent levels. Although most spray dried solid dispersions require some type of secondary drying, such as fluid bed drying, tray drying or conical drying, residual solvent levels in the powder exiting the spray dryer can greatly affect short term and, thereby, long term physical stability of amorphous solid dispersions. Different rates of evaporation and secondary removal of solvents can plasticise the solid dispersion particle, leading to the formation of small levels of crystallinity that can serve as nucleation sites for crystal growth during storage.
Spray drying at a lower outlet temperature (below the boiling point of the solvent) will yield high residual solvent levels, but a much higher product density. The higher residual solvent levels can also adversely affect the flowability of the product. Careful evaluation must be conducted to evaluate the outlet temperature on physical stability of the amorphous product and other powder characteristics required for further dosage form processing.
The inlet temperature governs the feed solution spray rate of the product. Once an outlet temperature has been optimised or determined, the inlet temperature should be ranged to determine the effect on powder properties and product yield. Spray drying too quickly could yield poor powder characteristics such as flowability, bulk density and low levels of crystallinity. Spray drying too slowly could yield an inefficient process wherein the residual solvent levels are very high that could also result in low levels of crystallinity.
In conclusion, solid dispersions have become an established formulation technology for improving solubility and hence bioavailability of poorly soluble APIs, which are effectively prepared and commercialised by solvent spray drying and melt extrusion.
A host of formulation, equipment and process factors influence the performance and production throughput of the resulting powders including solvent and polymer selection, polymer to API ratio, feed solution solids concentration, atomiser type, and spray dryer inlet/outlet temperatures.