Avoid Vulnerable Formulations with Simple Solubility and Crystallization Measurements on the Crystal16 and Crystalline

Lorazepam is a strong sedative for intensive care patients and a commonly used method of administering it to the patient is by infusion of a freshly prepared lorazepam solution. During lorazepam infusion, unwanted lorazepam crystallization occurs, resulting in line obstruction and reduced lorazepam concentrations. There are many cases know where dilution of drug formulations has the potential to generate conditions where drug concentrations are supersaturated. Under these circumstances, drug precipitation is likely to take place. Drug precipitation after parenteral administration may cause mechanical or chemical irritation at the injection site, and potentially even more serious systemic effects.

The commercial lorazepam solution is quite viscous and therefore dilutions with aqueous NaCl solution or 5% glucose are always prepared before injection. Nevertheless, upon administering lorazepam, obstruction of the infusion lines or syringe occurs frequently. Experiments to visualize the crystallization process of lorazepam were carried out in the Crystalline multiple reactor setup. Known volumes of the commercially available lorazepam solution and the aqueous glucose solution were added to prepare lorazepam solutions with known overall composition. The crystallization process of lorazepam could be followed in situ with the help of the Crystalline particle visualization module. 

ter Horst et al observed that lorazepam crystals exhibit an extremely needle-like morphology when formed at or below a concentration of 0.5 mg/ml. Interestingly, at higher concentrations the needles were deformed and strongly curled. 




Needle-like lorazepam crystals in a suspension at an overall concentration of 0.5 mg/ml (left) and 1mg/ml (right)


These differences indicated that for a 1 mg/ml solution, the supersaturation for crystallization is much larger than for a 0.5 mg/ml solution. All these results led ter Horst et al to investigate the phase behavior of lorazepam in mixed solutions.

The authors determined the solid–liquid phase diagram for commercially available lorazepam in mixtures with aqueous glucose solution by performing simple solubility measurements on the Crystal16 instrument. Known volumes of a commercially available lorazepam solution and a glucose solution in water were added to prepare 1 ml of a lorazepam crystal suspensions with known overall compositions. The Crystal16 combines automation with integrated turbidity measurement to determine clear and cloud points resulting in solubility data and simply generate solubility curves in short time. The solubility diagram was constructed as a function of the volume fraction of glucose solution added when preparing the solution. The phase diagram showed that high lorazepam concentrations (low glucose solution volume fractions) leads to a stable solution in which no lorazepam crystallization will occur. This confirmed that the glucose solution acts as an anti-solvent, greatly reducing the lorazepam solubility in the infusion solution.

This study shows that simple Crystal16 solubility measurements help avoid vulnerable formulations and foresee mechanical and chemical irritation at injection site. Additionally the PV module of the Crystalline instrument can in situ provide information about the crystallization behavior of a compound and implicitly about the stability of a final formulation.


J. Vellema, N.G.M. Hunfeld, H.E.A. Van den Akker, J.H. ter Horst, Avoiding crystallization of lorazepam during infusion, European Journal of Pharmaceutical Sciences, 44, 2011, 621–626.