The importance of amorphous solid dispersions
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The interest in Amorphous Solid Dispersions (ASDs) as a means of improving solubility of Active Pharmaceutical Ingredients (APIs) is still strong as highlighted by several speakers at the recent Fourteenth International Workshop on Physical Characterization of Pharmaceutical Solids (IWPCPS14) held in Barcelona, Spain.  

Unlike crystalline APIs which solubilities and dissolution rates are reduced due to high lattice energy barriers, the amorphous phase has high apparent solubility and good dissolution rates.  Making use of the amorphous phase of your drug rather than cryastalline formscould shift your drug from a class 2 (or 4) into a class 1 (or 3) drug according to the biopharmaceutical classification system. 

“However, there is one major drawback” comments Marcel Hoffmann, Crystallics’ CSO “compounds in their amorphous state may, at one point in time, become crystalline”.  The crystalline form with its lower free energy level is, from a thermodynamically point of view, the preferred phase that a compound tries to attain. 

Demonstrating the physical stability of amorphous formulations is therefore one of the key regulatory demands.  Preventing the amorphous phase to crystallize has all to do with prevention of crystallization nuclei to be formed.  The most commonly used methodology is that of the solid dispersions. 

In an amorphous solid dispersion the API is at the molecular level dispersed in a polymer matrix.  The mobility of the API molecules must be low enough to ensure that it will be unlikely that crystallization nuclei are formed.  In a recent publication in the Journal of Pharmaceutical Sciences1 a review of 40 research papers on amorphous dispersions was made and found that the success rate of amorphous solid dispersions improving the bioavailability of an API is about 80%.  Marcel points out, “The success of an amorphous dispersion is highly dependent on factors such as choice of polymers, API to polymer ratio, addition of surfactants or other excipients and the method of preparation”.

Crystallics has developed a 96-well plate method for rapid screening and selection of potential stable amorphous dispersions.  Screening is done either by rapid solvent evaporation or dissolving the API in the molten polymer mimicking the melt process.  The 96-well plate screening platform enables rapid screening of multiple parameters such as solvent, API load and additional excipients like surfactants.  The so formed dispersions are all analyzed by Crystallics proprietary High Throughput X-ray powder diffraction platform.  Subsequently the dispersions are stressed at 40°C/75% rH for two weeks and re-analyzed by XRPD.  Samples that still show no hint of crystallinity are analyzed by TG-MS and DSC for detailed characterization.  The most promising dispersions can be scaled up with a Büchi bench top spray dryer for dissolution rate and solubility determinations. 

Marcel commented “Crystallics offers with this high throughput approach to amorphous solid dispersion screening a unique way to a successful dispersion.  Our screening combines a large variety in parameters with short timelines resulting in a cost effective comprehensive amorphous dispersion.”  For further information please contact Marcel Hoffmann on +31 20 820 2690 or This e-mail address is being protected from spambots. You need JavaScript enabled to view it

1 J. Pharm Sci, 101 (4), 2012, 1355-1377