About
In this article, we discuss about a solubility-based method for screening co-crystals, which is gaining increasing attention in the pharmaceutical industry for improving the solubility, stability, and bioavailability of APIs.
The experiments presented in this article, involving carbamazepine (CBZ) and various co-formers, successfully demonstrated co-crystal formation. The experiments were carried with the Crystal16, highlighting the instrument's effectiveness in pharmaceutical development.
Experiment Procedure
The experiments [1] were conducted using the Crystal16 instrument to identify co-crystals of carbamazepine (CBZ) with various co-formers such as isonicotinamide (INA), nicotinamide (NA), benzamide (BA), 3-nitrobenazamide (NBA), picolinamide (PA) and 2-ethoxybenzamide (EBA). The following steps were used to determine co-crystals (as illustrated in Figure 1):
- Solubility Measurement: The solubility of compounds A (API) and B (co-former) in the chosen solvent was measured using the Crystal16 instrument.
- Temperature Selection: At a set temperature (T), the solubility of both compounds was determined in mole fractions (xA* and xB*).
- Mixture Preparation: A mixture of compounds A and B with their respective mole fractions (xA* and xB*) was prepared, and the saturation temperature (Ts) was determined using the Crystal16. If Ts was greater than T°C, this indicated the formation of a stable co-crysta.
- Varying composition and Phase Diagram Construction: Phase diagrams were constructed by systematically varying the mole fractions of compounds A and B, keeping xA* and xB* constant (Figure 2). A phase diagram was plotted by graphing the solvent-free mole fraction (yA) against the saturation temperature (Ts), allowing for the analysis of co-crystal formation.
Figure 1: The subsequent steps in the co-crystal screening method.
Figure 2. Co-crystal phase diagram.
Results
The systematic approach facilitated by the Crystal16 allowed for the successful identification of several co-crystals, including CBZ-INA, CBZ-NA, CBZ-BA, and CBZ-NBA, as presented in Figure 3. The solubility curves and phase diagrams indicated the regions where co-crystals were most stable. Additionally, the experiments demonstrated that the solubility temperature of the co-crystals was typically 10°C higher than that of the individual components, confirming their formation.
Figure 3. Phase diagrams from co-crystal screen.
Conclusion
The solubility-based approach with the Crystal16 efficiently screens co-crystals, increasing the chances of identifying stable forms. It requires minimal samples, delivers rapid results, and is valuable for improving API properties. Carbamazepine experiments highlight its effectiveness and broader potential in drug development.
References
[1] The experiments highlighted above are part of the application note on "Screening for co-crystals with a solubility-based approach". Technobis is deeply grateful to Prof. Joop ter Horst for his help with this application note.
The original publication is authored by J. H. ter Horst, M. A. Deij, P. W. Cains in ‘Crystal Growth & Design’, Vol. 9, No. 3, 2009, and can be found here: https://pubs.acs.org/doi/abs/10.1021/cg801200h
Want to learn more about co-crystallization?
To dive into the topic, we recommend the two case studies below: