Meeting Solubility Challenges

Pharmaceutical companies, equipment providers, contract-service providers, and excipient manufacturers apply various approaches for improving solubility. The article examines some recent developments. This article is part of a special issue on solid dosage and excipients.
Mar 01, 2012
Volume 2012 Supplement, Issue 2

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 (1). As pharmaceutical companies attempt to resolve these issues, contract-service providers and excipient suppliers are seeking to meet these challenges through targeted offerings.

Strategies for improving solubility

Both physical and chemical methods can be used to improve drug solubility, 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 (1).

The terms solid solution and solid dispersion define related compositions in which at least one active ingredient is dispersed in an inert matrix. In solid dispersions, separate regions of drug and polymer exist throughout the matrix, and the drug may be crystalline or be rendered in its amorphous state. A special subset of solid dispersions, solid solutions, refers to the case in which drug–polymer miscibility is attained at the molecular level, and the drug exists in its amorphous form. Pharmaceutical polymers are used to create this matrix. Polymer selection is based on many factors, including physicochemical (e.g., drug–polymer miscibility and stability) and pharmacokinetic (e.g., rate of absorption) constraints (1, 2).

Solid dispersions may be made through mechanical activation (i.e., cogrinding), coprecipitation, freeze drying, spray drying, melt extrusion, and KinetiSol technology (DisperSol Technologies), a fusion-processing technology. The solid-dispersion components consist of the API, the polymer, plasticizers, stabilizers, and other agents. Various polymers may be used in solid dispersions. These include methylacrylate polymers, polyvinyl acetate, polyvinylpyrrolidone, copovidone, poly-(ethylene-vinylacetate-vinylcaprolatam), and cellulose derivatives (e.g., hypromellose acetate succinate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, ethyl cellulose, and methyl cellulose) (1).

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