Chemicals & raw materials
clinical trials and are an early-stage discovery and development problem. A lot of the solubility and formulation challenges are solved at the pre-clinical stage, and there are now fewer challenges with small-molecule API synthesis. A molecule won’t make it through to the later development stages unless it can be run at the higher exposure levels required in the animal studies – which is anywhere from 10 to 100 times higher dose and exposure that a human would ever receive. The industry has developed alternative formulation approaches to solve the bioavailability issue for many small- molecule APIs that have a poor solubility.
Solving the solubility problem for small molecules
Addressing the solubility problem has involved pharmaceutical companies developing different formulation approaches. While some involve chemical changes, the most successful have involved making physical changes to the formulations – such as making the formulation amorphous and nanosizing the formulation – as well as loading the APIs into more soluble carriers, such as lipids. The decision of which one will be chosen for a specific API is determined at the discovery phase.
While not all drugs being developed today will need these advanced formulations, those classified in the biopharmaceutical classification system (BCS) class II (low solubility and high permeability) and class IV (low solubility and low permeability) are typically targeted for these advanced formulation techniques.
Amorphous solid dispersions Among the formulation approaches that solve the solubility and bioavailability problem of insoluble APIs, ASDs have become the most common option within the industry. According to academic literature, around 30% of commercial products that require solubility enhancement used this approach between 2000 and 2020.
ASDs are amorphous formulations where the drug has been dispersed inside a polymer matrix – such as cellulose derivatives, polyvinylpyrrolidones and vinyl acetate balanced co-polymers, and methacrylic acid and methacrylate esters – as they all have chemical functional groups that promote dissolution in water. Because the drug is loaded inside the polymer and the amorphous form has a high surface area, the solubility and bioavailability of the drug is significantly increased. For example, an ASD increases the human bioavailability of vemurafenib five-fold compared with its crystalline form. ASDs are synthesised by several methods, such as hot melt extraction, spray-drying and co-precipitation methods, which create a homogeneous dispersion of the API throughout the polymer matrix. Deciding whether a crystalline drug is suitable for being converted into an
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amorphous form is done at the discovery stage. Micro- scale screening and high throughput screening (HTS) combine the API with different polymer materials under different heating and cooling conditions to find the most stable ASD and optimal drug-polymer ratio. The different ASDs with different drug loading levels (μg to mg) are tested in very small amounts to ensure that they remain stable and don’t recrystallise.
Nanosizing – a key approach Another key approach is nanosizing APIs in formulations, because the solubility of a drug is directly related to its particle size. As the API particles become smaller, the surface area to volume ratio increases. A larger surface area interacts more with a solvent and improves the wettability of the drug. This leads to an increased drug solubility.
In nanosizing methods, the API particle size is reduced to 100-200nm using top-down milling and homogenisation methods and bottom-up precipitations and supercritical fluid methods. The nanoparticles are then stabilised using either polymers or surfactants and processed into dosage forms.
The nanosized APIs have a higher dissolution rate and a reduced variability, leading to a higher oral bioavailability. Nanosizing does offer a way to get a higher drug loading than other methods, but it’s not an approach that is suitable for all APIs, so can only be chosen in certain circumstances. Nanosizing is also being enhanced by advanced data analysis approaches, such as machine learning, which are better at predicting the particle size and polymer dispersity index of these nanoforms when created by top-down methods.
Lipid carriers
Outside of physical modifications to the drug, carrying them in lipids is another key approach. Hydrophobic drugs are dissolved in lipids or encapsulated in a phospholipid bilayer, so the drug is delivered to the body without needing to change its physical form. Lipids have a high biocompatibility, solubilisation, degradability and low immunogenicity, so can deliver drugs to the body.
Some lipid carriers improve the uptake of poorly bioavailable drugs as they can penetrate through the membranes of the gastrointestinal tract, and selectively into the lymphatic system, allowing the drugs to get into the body and enhance cellular uptake. However, many of them tend to have a lower loading capacity than other approaches. There are currently many different lipid carriers in use today, including liposomes, solid lipid nanoparticles, transferosomes, nanostructured lipid carriers, lipid nanocapsules and self-microemulsifying drug delivery system (SMEDDS) – so there are lots of choices depending on the drug and the target.
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