New drugs challenge thinking on dissolution testing

The development of a new generation of pharmaceuticals that target specific areas of the body has created new challenges for dissolution testing. Mark Hammond, Business Development Manager of Melbourn Scientific explains that a large number of the more recent active ingredients are poorly soluble in traditional media and expose the limitations of some commonly used dissolution testing methods. The company has responded by increasing the diversity of its testing procedures.

Mark comments: "Less soluble compounds present demanding method development challenges for dissolution testing, and this requires a high degree of expertise when selecting the most appropriate analytical solution: this could be either traditional apparatus with novel media preparation or flow through apparatus depending on the type of product being tested."

Melbourn has doubled its capacity for traditional dissolution testing of tablets, capsules, suppositories and transdermal patches, and is incorporating Type IV flow through dissolution capability to enhance its offering for poorly soluble drugs.

Steve Westcott Managing Director at Melbourn Scientific explains the background to dissolution testing.

"Absorption of orally administered products, such as tablets and capsules, occurs as the product is dissolved within the digestive tract. Dissolution tests were originally used to emulate the release of drugs in the body: the in vitro conditions mimicking the conditions in vivo. The shape of the vessel and the rotational speed of the apparatus were designed to mimic stomach capacity and agitation rate, and the liquid temperature is kept to within 0.1ƒof body temperature. The concentration of active in the solution is then measured at regular time intervals."

"These traditional tests are inadequate for enteric coated tablets which are designed to pass through the acidic conditions of the stomach. Releasing drug compounds in the more neutral conditions of the small intestine where fat solublising bile acids act on them. For these types of products more complex dissolution methods are routinely developed at Melbourn to provide the discriminatory methods required."

Although devised to mimic release profiles, dissolution testing is also used for product development of pharmaceutical formulations which means more sophisticated tests are required.

Dr Westcott explains: "Formulations and the manufacturing process can have a great impact on the effectiveness of pharmaceutical products. If there are problems with a chemical process or with the compressional forces applied to the tablets during manufacture, release may be affected and the active compound may stay bound to the excipient. Alternatively, if a company is making a generic product, there may be differences in solubility of the product when compared to the original. Dissolution tests are designed to discriminate between batches and reveal these problems."

Besides the need for compliance testing for compendial products, dissolution is also used as a quality control test of a product's physical consistency.

"Although dissolution tests are used routinely for quality control testing, or as an indicator of product stability during ICH Stability studies, it is increasingly being used to evaluate at solubility of polymorphs of particular compounds and to optimise formulation parameters of new pharmaceuticals." He concludes.

Melbourn Scientific has invested significantly in additional capacity as well as new technologies to perform the tests and complement its other approaches to testing poorly soluble products, but Steve Westcott is aware of the need for skilled interpretation of the results.

"The USP type 4 dissolution apparatus uses large volumes of media for poorly soluble compounds and so does not correspond well to the conditions in vivo, but for some compounds this is the only suitable approach. However, where possible, we would recommend the development of methods using traditional apparatus with novel media that mimics the conditions in vivo more closely."

Drug dissolution testing continues to be one of the front line techniques during the drug development cycle, particularly with the increase in the development of poorly soluble and lipophilic drugs. Melbourn Scientific is well equipped to meet the demand for technical expertise in in vitro dissolution testing methods to provide meaningful release profiles for these exciting new pharmaceuticals.