Successfully preventing crystallization of parenteral formulations using solubility measurements.

  • Article
  • July 5, 2023

Successful parenteral formulations by preventing crystallization


Many drug substances are formulated as parenteral formulations and administrated directly into the systemic circulation in animals and humans. In order to improve the stability and solubility of the drug, many parenteral formulations are formulated using a co-solvent. Ampule or vial dosage forms are often co-solvent concentrated formulations. These concentrates are finally diluted before being administered to the patient. Nevertheless, there are many cases known where dilution of drug formulations has the potential to generate conditions where drug concentrations are supersaturated.

Under these circumstances, drug precipitation/crystallization 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 main challenge is that the solubility of an active ingredient in a mixture of solvents may not be linear during dilution. The sooner the temperature-dependent solubility of the active ingredient is determined, the better.

Simple Crystal16 solubility measurements help avoid vulnerable formulations and foresee mechanical and chemical irritation at the injection site. Additionally, the particle visualization module of the Crystalline instrument can provide in situ information about the crystallization behavior of a compound and the stability of a final formulation.

Figure 1 Solubility curves for stable (left) and unstable (right) formulations.

Lorazapam cases study

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.

Figure 2 Lorazepam crystallization during dilution in a syringe

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 al1 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.

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 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 the generation of solubility curves in a short time. The solubility diagram was constructed as a function of the volume fraction of the glucose solution added when preparing the solution. 

The phase diagram showed that high lorazepam concentrations (low glucose solution volume fractions) lead to a stable solution in which no lorazepam crystallization will occur. This conīŦrmed that the glucose solution acts as an anti-solvent, greatly reducing the lorazepam solubility in the infusion solution.


A common way of administering drugs is through liquid formulations such as parental formulations, as they provide a way to improve the stability and solubility of a drug molecule. However, in order to take advantage of the properties the active molecule needs to remain in solution during storage, transport, and administration. These formulations are stabilized by using a co-solvent to prevent crystallization. The Crystal16 combines automation, temperature, and agitation control with integrated turbidity measurement to determine clear and cloud points resulting in generating solubility curves in a short time. Using the Crystal16 a solubility diagram of lorazepam was constructed varying the volume fraction of the glucose solution. It was found that glucose solution acts as an antisolvent gently reducing the solubility in the formulation.


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, Volume 44, Issue 5, 2011,

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