Solubilizing the Insoluble

An analysis of the approaches and tools used to tackle the problem of poorly soluble drugs.
Nov 02, 2010

Improving the solubility of poorly water-soluble drugs is of crucial importance. As the number and diversity of molecules resulting from drug-discovery activities increases through methods such as combinatorial chemistry and high-throughput screening, scientists are faced with the task of developing formulations that may contain poorly soluble active pharmaceutical ingredients (APIs). The need for technical solutions to solubility problems has commercial implications for both pharmaceutical companies and their suppliers.

The solubility of an API plays a crucial role in drug disposition because the main pathway for drug absorption is a function of permeability and solubility. Poor aqueous solubility is caused by two main factors: high hydrophobicity and highly crystalline structures. The aqueous solubility of a compound plays a role in its success or failure as a drug candidate. Better solubility results in better absorption in the gastrointestinal tract, reduced dosage-level requirements, and better bioavailability. In the development phase, poor solubility can lead to inadequate exposure in efficacy and toxicity studies. Higher dosages required to compensate for poor solubility can lead to side effects, food effects, and intersubject variability. It may drive up overall costs for drug development and production and lead to poor patient compliance because of the higher doses required to achieve a therapeutic effect. As pharmaceutical companies attempt to resolve these issues, contract-service providers and suppliers also are seeking to meet these challenges through targeted offerings.

Defining the challenge

The Biopharmaceutics Classification System (BCS), as forwarded by Amdion et al., categorizes compounds based on solubility and permeability (1). The BCS is a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability. When combined with the dissolution of the drug product, the BCS takes into account three major factors that govern the rate and extent of drug absorption: dissolution, solubility, and intestinal permeability. According to the BCS, drug substances are classified into four major classes:
  • Class I: high permeability, high solubility
  • Class II: high permeability, low solubility
  • Class III: low permeability, high solubility
  • Class IV: low permeability, low solubility (2).

According to a recent analysis, most new chemical entities (NCEs) are poorly water-soluble. Approximately 30% of marketed APIs are classified as BCS Class II compounds (i.e., high permeability and low solubility), and 10% of marketed APIs are classified as BCS Class IV compounds (low permeability, low solubility). For NCEs under development, the level of drugs that may be classified as poorly water-soluble increases. Approximately 70% of NCEs under development may be classified as BCS Class II compounds (i.e., high permeability and low solubility), and 20% of NCEs are classified as BCS Class IV compounds (low permeability, low solubility) (3).

Solubilization strategies

Both physical and chemical methods can be used to improve drug solubility, explains Firouz Asgarzadeh, principal scientist at Evonik Degussa (Piscataway, NJ). Asgarzadeh was a panelist on an educational webcast on pharmaceutical melt extrusion held by Pharmaceutical Technology in September 2010. Chemical methods to improve solubility include developing more soluble prodrugs or improving solubility through salt formation. Physical methods include micronization or nanosizing, producing a polymorph, changing the crystal habit, complexation, solubilization through self-microemulsifying drug-delivery systems, and solid dispersions.