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Developing Dissolution Testing Methods for Poorly Soluble Compounds

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Since the therapeutic effectiveness of a drug depends upon the bioavailability and ultimately upon the solubility of the molecule, the proper dissolution testing method plays crucial role in the new drug development process and quality control.

Currently only about 10% of new drug candidates have both high solubility and permeability.  Therefore, one of the current challenges in pharmaceutical product development is dealing with low solubility and/or low permeability.  A common strategy here is to go to smaller particle sizes, thereby increasing the specific surface area (SSA) and solubility of the product.  For very small particles with a nano or submicron size, either a bottom up or a top down approach can be applied. Other considerable factors that will affect drug solubility are polarity and polymorphism.  Generally non-polar drug molecules will dissolve in non-polar solvents and polar molecules will dissolve in polar solvents.  The different types of intermolecular forces such as Dipole-Dipole, London Dispersion or Vander-Waals have to be taken in consideration at early stage of drug development during the solubility studies.

Polymorphism is the ability of a compound to crystallize in different forms.  The two polymorphs cannot be converted from one another without undergoing a phase transition.  Polymorphs can vary in melting point.  Since the melting point of the solid is related to solubility, so polymorphs will have different solubility.

The medium, temperature and stirring are the factors that control a dissolution process.  In some cases, the method used in the early phase of product/formulation development could be different from the final test procedure used for control of the product quality. Indeed, methods used for formulation screening or understanding of the release mechanism may simply not be viable for quality control or drug stability studies.

During pharmaceutical product development, dissolution testing is primarily used in measuring the rate of drug release and solubilization, assessing the stability of the formulations, monitoring product consistency, assessing formulation changes, and establishing in-vitro in-vivo correlation (IVIVC).  For a commercial product, dissolution testing is primarily used to confirm product consistency, to evaluate the quality of the product during its shelf life, and to assess post approval changes and the need for bioequivalency studies.  It is essential that with the accumulation of experience, the early method be critically re-evaluated and potentially simplified, giving preference to compendial apparatus.

A novel in-vitro dissolution model based on the principle of flow-through technique has been recently designed in order to evaluate the in-vitro release rate of poorly water-soluble compounds.  The flow through apparatus (USP 4) has been coupled with the compendial dissolution apparatus (USP 2).  The main objective of this study was to develop a novel in vitro dissolution method that can be applicable to identify changes in formulation, thus avoiding expensive in vitro studies.

The existing compendial methods for poorly soluble drugs usually require huge volumes of dissolution media for complete release of a drug from its formulations. For example, a drug with a solubility of 1μg/mL and dosage strength of 25-mg will need 25 liters of dissolution medium for complete solubilization.  This makes the dissolution testing physiologically irrelevant and practically difficult.  The in vitro release profiles obtained from this dissolution model were able to distinguish the formulation changes of several poorly water-soluble drugs from their dosage forms.

The model has successfully demonstrated bioequivalency and/or non-bioequivalency for commercial formulations.  In the future, an established IVIVC model can be used to characterize the biopharmaceutical quality of products at different stages of formulation development.

When the opposite is true, where dissolution is "too rapid", conventional dissolution approaches won't work here and either way, a customized in vitro dissolution method needs to be developed where a stable and reproducible method can be validated.  This requires more research to be conducted.  So, solubilization of poorly soluble drugs is a common problem.  Rapid dissolution should be fine for immediate release formulations unless one is attempting to reduce solubility on purpose to have more control over the dissolution rates that could eventually alter drug absorption in pre-determined ways.