A new generation of drugs that target specific areas of the body has created new challenges for dissolution testing, as many recent active pharmaceutical ingredients (APIs) are poorly soluble in traditional media and need novel testing procedures.
Dissolution testing is a critical formulation tool, measuring the stability of the product, establishing its in vivo availability and ensuring uniformity between production lots.
But new less soluble compounds require 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.
Absorption of orally administered products, such as tablets and capsules, occurs as the product is dissolved within the digestive tract, so 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 was kept identical to body temperature.
However these traditional tests are inadequate for enteric coated tablets which are designed to pass through the acidic conditions of the stomach.
For these types of products more complex dissolution methods are needed, so the US Pharmacopoeia has developed various standards for apparatus use, and one of these, USP 4, covers the flow-through method, which is becoming more commonly used as it can handle a broad range of dosage forms, including not only tablets and capsules but also implants, stents, suppositories and powders or granules.
One of the analytical services providers that use USP 4 is Melbourn Scientific, which 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.
"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," Steve Westcott, managing director at Melbourn Scientific, said.
"However, where possible, we would recommend the development of methods using traditional apparatus with novel media that mimics the conditions in vivo more closely."
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, Westcott stressed.
Moreover, if a company is making a generic product, there may be differences in solubility of the product when compared to the original and dissolution tests are designed to discriminate between batches and reveal these problems.
Drug dissolution testing is likely to continue 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.