Pre-formulation and Early-Formulation Studies to Drive Strategies to Enhance Drug Dissolution
Approximately 90% of new drug candidates are poorly water soluble which are related to various formulation-related performance challenges. Referring to this increasing number, Seqens experts have focused on the study of strategies to consider the enhancement of pharmaceutical drugs bioavailability.
Fueled by computational and scientific advances, such as combinatorial chemistry and high throughput
screening, the pipeline of Leads compounds in drug discovery is expanding remarkably. These strategies
have provided early-stage teams with improved tools to investigate previously undruggable targets, which consequently has oriented discovery toward increasingly complex, poorly soluble molecular targets.
In this white paper, a special focus is made on the need to understand, at early stage, the behaviour and the characteristics of these compounds, especially physical, chemical and biological properties. Pre-formulation studies are required to ensure the best drug performance prior to further process development for producing and delivering active ingredients.
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Introduction: The importance to solve the solubility concern
Fueled by computational and scientific advances, such as combinatorial chemistry and high throughput screening, the pipeline of Leads compounds in drug discovery is expanding remarkably. These strategies have provided early-stage teams with improved tools to investigate previously undruggable targets, which consequently has oriented discovery toward increasingly complex, poorly soluble molecular targets.
According to Biopharmaceutics Classification System (BCS), Class II drug substances (with low solubility & high permeability) are one of the most common examples, with these candidates often containing many chiral centers and larger molecular weights.
Approximately 75% of new drug candidates under development are poorly soluble in both water and organic solvents, which are related to various formulation-related performance issues[i].
Solubility impacts many key physicochemical properties in drug release and absorption, leading to poor bioavailability and, hence, efficacy. If the drug does not dissolve in the gastro-intestinal tract, then the patient might need a more frequent administration to achieve the desired therapeutic effect. Thus, for oral solid forms, low-solubility compounds cannot be orally absorbed and therefore cannot have a therapeutic effect.
The low gastro-intestinal solubility of these complex molecules can be driven by slow dissolution kinetics or can be truly solubility-limited due to either the lipophilicity of the molecule or high crystal forces that inhibit dissolution. These types of compounds are often referred to:
- as “grease ball” compounds: low melting points and low water solubility but have a relatively high solubility in lipophilic environments.
- or “brick dust” compounds: very stable crystals with high melting points (often over 200°C). These drugs are often not particularly lipophilic, therefore neither dissolve easily in oils nor water
Therefore, while poor drug solubility is a defined problem, depending on the properties of the molecule, these compounds require different formulation strategies to increase their dissolution rate, solubility, and ultimately bioavailability. In addition to improving solubility and dissolution, other aspects, such as the selection of drug delivery system need to be considered to ensure that the drug reaches its therapeutic target. Rather than increasing the bioavailability, the choice of an appropriate carrier system may be required.
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[i] J Han J, Wei Y, et al. Co-amorphous systems for the delivery of poorly water-soluble drugs: Recent
advances and an update, Expert Opinion on Drug Delivery (2020), DOI: 10.1080/17425247.2020.1796631
