The Developability Classification System (DCS): Enabling an Optimized Approach for Formulation of Poorly Soluble Molecules

Ensuring sufficient solubility for orally delivered solid dosage forms is a critical step in their development. Most, if not all, of the absorption of these dosage forms takes place in the small intestine, where the drug must be sufficiently dissolved in the gastrointestinal fluids to pass through the membrane and into the systemic circulation. If the drug is not soluble in gastrointestinal fluids, this process cannot occur and the intended physiological effect will not be realized. The importance of solubility is highlighted in the biopharmaceutics classification system (BCS).

The BCS framework originated in the 1990s and sought to correlate in-vitro solubility and permeability with the potential in-vivo performance of drug molecules. In the system, molecules are categorized based on the combination of solubility and permeability. BCS Class I, for example, includes molecules that have both high solubility and permeability, and as such are expected to have good absorption in the gastrointestinal tract. BCS Class II compounds, on the other hand, have low solubility and high permeability, while BCS Class III molecules have high solubility and low permeability. The most challenging class of molecules are those categorized as BCS Class IV; these molecules have both low solubility and permeability.

The BCS was originally used by the US Food and Drug Administration (FDA) as the basis for biowaiver applications for immediate release formulations in order to reduce the need for additional in-vivo studies for bioavailability and bioequivalence.2 Still today, this framework is important for regulatory considerations, as referenced by the recent publication from the FDA regarding BCS-based biowavers.3 Since the introduction of the BCS, the solubility landscape of marketed drugs continues to evolve.4 It is conservatively estimated that approximately 40 to 60% of approved drugs suffer with poor solubility (BCS Class II or BCS Class IV).

The same assessment applied to drug candidates in development reveals that 60 to 90% of drugs are classified as poorly soluble and risk failure due to poor performance and poor absorption in the gastrointestinal tract.5 This white paper explores the developability classification system (DCS), a recent advancement based on the BCS system but, instead of focusing on regulatory aspects, this framework assists formulators in the development of poorly soluble drug formulations.6 This is achieved by identifying the root cause for low solubility and providing strategies for molecules that are either dissolution limited or solubility limited.

The Developability Classification System

Expanding upon the BCS, the DCS introduced key modifications to improve applicability to formulation development. For example, biorelevant media was introduced to provide a more reliable assessment of in-vivo solubility, and the BCS Class II was further divided into two sub-categories: DCS Class IIa and DCS Class IIb. Another modification was the shift in dose solubility ratio, resulting in a lower threshold for a molecule to be considered “soluble”. As a result, the appearance of the DCS is different than the BCS, with the cut-off between DCS I and III and DCS IIa/b and IV appearing at a dosesolubility ratio of 500, as opposed to 250 in the BCS. Furthermore, the BCS II portion of the graph is split into two sections in the DCS to represent DCS IIa and IIb.

This line, which separates the two sub-categories, is the solubility-limited absorbable dose (SLAD) line. The line uses a ratio of solubility and permeability to determine if an increase in dissolution rate will have a measurable impact on overall absorption. Based on this ratio, a drug molecule is placed either above or below the SLAD line. Molecules above the line are dissolution rate-limited (DCS Class IIa). Theoretically, if the maximum solubility is reached faster, absorption of the molecule can be enhanced; development should therefore focus on the dissolution rate. Molecules below the SLAD line (DCS Class IIb) have such a low solubility that no matter how quickly the drug gets into solution, there will not be a measurable impact on absorption. The fundamental challenge with DCS IIb molecules is therefore solubility.

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Article information: Daniel Joseph Price, Merck – Millipore Sigma, Darmstadt.