Improved Stability Drug Development
Background: Why there is a need for the Exalt™ application
Compounds that are crystalline in nature, often adopt a number of crystalline forms or polymorphs. Different polymorphs will have different physical characteristics which can impact on the manufacturing process, which canaffect the efficacy of the drug.
In the case of the anti-viral drug Ritonavir, not only was one polymorph virtually inactive compared to the alternative crystal form, but it was subsequently found to convert the active polymorph into the inactive form on contact due to its lower energy and greater stability, making spontaneous interconversion energetically favourable. Even a speck of the lower energy polymorph could convert large quantities of Ritonavir into the inactive polymorph, and this caused major production issues until the drug was finally reformulated.
It is also essential for all crystal forms to be listed on any drug patent. In the case of Prozac, an Eli Lilly drug, a generic drug manufacturer discovered another form not listed on the patent, and subsequently released a copy of the drug. A year prior to patent expiry, Eli Lilly lost several billion dollars in revenue as a result.
Regulatory authorities expect drug manufacturers to conduct thorough assessments of new drugs to form polymorphs. Pharmaceutical companies address the issues by carrying out a screen on the chosen compound to identify as many different polymorphic forms as possible. Ideally, this screen takes place at an early stage in the drug development cycle so that a manufacturing process can be defined to produce the correct form for clinical trials and the pharmaceutical market. A rational and extensive initial screen will be repeated as necessary throughout the project, for example, if the impurity profile of the material changes, the robustness of the crystallisation process will also be thoroughly investigated.
The screening process is time and resource consuming with no guarantee that all polymorphs will be discovered. It can also require a significant amount of active pharmaceutical ingredient (API). Polymorph studies are carried out manually, and each chemist usually employs slightly different approaches which can result in a lack of consistency.
Studies for polymorph screening can therefore take a long time and may be difficult to conduct. Working with researchers in the field, Genevac Ltd has developed Exalt™ (Figure 1.), a unique toolkit to help researchers conduct evaporative crystallisation studies in a number of ways, whether polymorph screening, or searching for metastable and stable forms. Many crystallisation tools are currently available, and researchers usually use all ofthem in an effort to reduce the risk of new forms appearing later in the project. Although these techniques cannot all be replaced by Exalt™, most, if not all of theevaporative methods can be, so the crystalline forms of a drug can now be delivered in a controlled andreproducible manner.
The development of Exalt™ by Genevac Ltd, began with a customer request to utilise evaporation in a controlled way to produce stable crystal forms, ie; very long evaporation times, (>72 hrs), evaporation of a wide range of solvents at the same time and at the same slow rate of evaporation for every solvent, volatile through to non-volatile. Analysis by X-ray diffraction (XRD) and Thermogravimetric differential thermal analysis, (TG-DTA) confirmed the presence of truepolymorphism rather than solvation.
How does Exalt work?The Exalt™ software allows the pressure reduction from atmospheric and the cycle time to be carefullycontrolled so that evaporation can take place from 6 hrs to 72 hours or more. The condenser must be able todefrost automatically every 6 hours, or a large plug of ice forms in the condenser inlet.
The combination of pressure cycling and baffles delivers slow, controlled evaporation of different solvents at the same time and at similar rates. Studies of solvents with BP’s in the range 40⁰C to 165⁰C, DCM toDMAc (including water) have been made possible.
Pressure cycling creates a serial dilution of the atmosphere surrounding the samples. Spinning the rotor induces a vortex in the tower, promoting vapour diffusion. This “chimney” effect helps the non-volatile solvents. Bafflesslow the flow of vapour from one chamber to the next.
Figure 2. Left to Right: Exalt baffles & tower assembly – Loading vials & towers – Complete holder assembly
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