Amorphous solid dispersions are a useful tool in overcoming solubility issues, but they have not yet reached full potential in commercial success.

Low aqueous solubility and poor bioavailability are common problems encountered in the formulation of new chemical entities. Poorly soluble drug candidates form a vast proportion of candidates in current development pipelines, and these challenging molecules tend to suffer from high attrition rates, which is costly for developers.

Oral dosage forms remain the most popular route of administration as a result of benefits offered, such as ease of administration, patient compliance, and cost-effectiveness. A poorly water-soluble drug being developed for oral ingestion will have low or variable bioavailability, which must be optimized to ensure the efficacy of the finished drug product.

Improving the solubility of a drug will improve the bioavailability, and so multiple techniques have been developed and employed by industry to achieve this task. One such technique employed by developers to improve solubility is through the use of amorphous solid dispersions (ASDs) as a drug delivery solution.

Advantages and disadvantages of ASDs

“An ASD contains the API in a high energy state, allowing supersaturation to be achieved in the gut and increasing the absorption rate as the apparent solubility is increased,” explains Alison Foster, head of technical—pre-clinical, Quay Pharma. However, in a high energy state, the API may be unstable and may have a tendency to revert to its more thermodynamically stable crystalline form over time or in contact with biological fluids, she continues.

“The formulation of ASDs can be achieved using well-characterized, off-the-shelf excipients, processes, and screening methods in order to differentiate and select formulations according to their in-vitro, and likely in-vivo behavior,” Foster notes.

Another advantage of using ASDs to improve solubility of a drug is that the processes typically used to produce ASDs, such as spray-drying and melt-extrusion, are well established and scalable to commercial quantities, Foster says. “This benefit is demonstrated by the number of ASD products that are now commercially available,” she adds.

Best practices

Despite the effectiveness of ASDs to overcome solubility and bioavailability challenges with poorly aqueous soluble compounds, the perceived risks associated with this drug delivery solution, such as system complexity or stability issues, have meant that ASDs are not yet being employed to their full potential in drug development (1). Hence, early development work in predicting the behavior of the drug product and its ability to mix with the chosen polymer is vital to ensure success (2).

The use of a film casting technique enables rapid screening of suitable matrices and drug loading for the ASD formulation, highlights Foster. “This method reduces the timescale to lead candidate identification whilst using minimal API .

Advancing strategies

Over the years, some strategies have advanced to help overcome some of the key challenges associated with ASDs. Using cellulose derivatives as stabilizers with specific pH solubility profiles, such as hydroxypropyl methylcellulose acetate succinate, has helped developers overcome some of the inherent drug release issues from monolithic products that are formulated with hydrophilic polymers, Foster explains.

“The hydrophilic polymers tend to gel on contact with aqueous solution at low pH, thus hindering release of the drug,” Foster states. “The cellulosic polymers enable the dissolution of discrete particles, providing rapid achievement of supersaturated conditions and reducing inter- and intra‑patient variability.”

“Co-amorphous systems are reported to combine the advantages of a co-crystal and solid dispersion system with fewer disadvantages,” Foster remarks. “The use of co-amorphous systems is a relatively new technique whereby the amorphous drug is stabilized through strong intermolecular interactions by low molecular weight co-formers (amino acids being a typical option).”

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