Strategies for Improving Bioavailability Through Drug Solubility Enhancement

Since drugs must be soluble to achieve GI tract absorption, the majority of drug modification and formulation strategies focus on improving solubility. The higher the concentration of drug in solution, and the longer the drug stays in solution as it travels through the GIT, the higher the absorption and bioavailability.

A drug’s solubility/rate-of-dissolution is often related to its in vivo performance (bioavailability). Therefore, prediction and measurement of these properties becomes critical in characterizing new drug candidates and the formulations in which they are developed. The establishment and understanding of IVIVC’s (in-vitro-in-vivo correlations) of drug candidates formulated into dosage forms begins with measurement of the drug’s solubility and dissolution rate.

Today, a variety of techniques support the understanding of solubility and other factors involved in bioavailability. These include:

  • 1. Determining solubility and intrinsic or apparent dissolution rates.
  • 2. Characterizing particle properties, such as size and crystalline form, which influence dissolution rate.
  • 3. Computational approaches for predicting pharmacokinetics based on physical-chemical properties that provide an approximate understanding of bioavailability. In principle, this is a more mechanistic approach to developing IVIVC (in-vitro-in-vivo correlation).

Many drug candidates exhibit high lipophilicity (cLogP) and low solubility in simulated biological media (<10 µg/mL). This combination often translates into poor and variable exposure. Clearly, the solid-state form of the API and its lipophilicity are related to a drug’s solubility, as expressed in the general solubility equation:

Log S = log P – 0.01 (MP – 25) + 0.05 [Equation 1]

Where S is the solubility, P is lipophilicity as measured by octanol/water partitioning, and MP is the melting point. Based on this relationship, drug substance modifications such as salt formation, co-crystallization, form transformation, and amorphicity (lack of crystallinity) have all been used to improve solubility of an API.

Hill and Young modeled the interrelationship between kinetic solubility and lipophilicity for more than 100,000 compounds.2 Building on the relationships described in the general solubility equation led the authors to derive the solubility forecast index (SFI) as defined below:

SFI = cLogD7.4 + Number_of_Aromatic_Rings [Equation 2]

where cLogD is the calculated distribution coefficient at a pH value of 7.4 (intestinal pH). The authors proposed using SFI as a simple and effective means of predicting the aqueous solubility of a drug.

Another helpful tool for the formulation scientist is the developability classification system (DCS). Proposed by Butler and Dressman, DSC allows the modeling of candidate molecules based on solubilities measured under bio-relevant conditions (e.g., fed state/fasted state simulated intestinal solubility), permeability, and clinical dose. The DCS system also splits BCS class II into two sub-divisions (DCS IIa and IIb). The former encompasses molecules that typically show dissolution rate-limited absorption. In contrast, the latter show solubility rate-limited absorption. Importantly, the DCS model allows for an assessment of the formulation strategies for optimizing oral bioavailability, particularly by comparison with formulations utilized by marketed reference compounds in the same DCS-space. For dissolution rate-limited absorption (DCS IIa), the formulation strategy involves increasing dissolution rate enhancements. Dissolution rate is often accelerated by increasing surface area of the API through particle size reduction technologies such as milling, micronization, or nano-milling. The formulation strategy appropriate for compounds exhibiting intrinsic solubility-limited absorption involves increasing the aqueous solubility through complexation (e.g. with cyclodextrins), delivery of API pre-solubilized API (hydrophilic or lipophilic solvents, especially in softgel dosage forms) or by using amorphous stabilized approaches.

Thus, determiningwhether absorption is limited by the API’s dissolution rate or its intrinsic solubility provides valuable insight into the potential for developing an NCE as an orally administered drug.

The Strategies for Oral Delivery and Bioavailability Enhancement of Poorly Soluble Drugs may be broadly classified as:

2Hill, A.P. and Young, R.J. Drug Discovery Today, Nos. 15/16 (2010), 15: 648-655.

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