How to avoid solvate formation: a practical case study using buprenorphine
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By the virtue of the fact that an Active Pharmaceutical Ingredient (API) must be able to interact with its biological target the compound has the ability to form inter and intra molecular hydrogen bonds.  This ability not only opens the potential for the formation of co-crystals but also hydrates and solvates of which the latter can be a real issue for development.  Even if your API is not rich in hydrogen bond donors and acceptors, solvates may still be formed.  To demonstrate the issues with solvates this newsletter focuses on isomorphous solvates.  Isomorphous crystalline compounds will, when investigated by X-Ray Powder Diffraction (XRPD), result in very similar powder patterns.

Buprenorphine (Figure 1) is a well known semi-synthetic opiod drug and prescribed as a strong pain killer.  The molecule possesses a well defined hydrophobic, as well as, hydrophilic part.  From the locations of the hydrogen donors and acceptors of this molecule it can be predicted that co-crystallization of buprenorphine will be difficult due to the lack of a clear synthon1.  On the other hand, salt formation along the row of alicyclic amine should be possible with a diversity of acids.

Figure 1. 2D structure of buprenorphine


The crystal structure of buprenorphine freebase (Mazurek et al 20142) shows the presence of relative large voids that theoretically can be filled with hydrophobic solvent molecules (Figure 2).  Hence, we predict that crystallization from hydrophobic solvents will result in so called isomorphous crystalline powders.  To confirm this we performed a buprenorphine crystallization study using a variety of solvents.  The study demonstrated that non-solvated buprenorphine was obtained from the experiments with polar hydrophilic, non polar aliphatic and small hydrophobic solvents.  However, using non polar medium size solvents consistently resulted in a solvated crystalline form of buprenorphine (Figure 3).  As expected, single crystal analysis confirmed that the solvent molecules were occupying the voids without interacting with the API.  Single crystal analysis of the solvated form in comparison to the solvent free crystal form clearly demonstrates the isomorphous nature of these crystal structures.  The unit cell increases significantly with the size of the solvent molecule.  The volume of the unit cell increases from 1303.37 Å3 (solvent free) to 1628.1 Å3 (for p-Xylene).  But all the crystals, whether solvated or not, have similar density, as well as, package index independently of the solvent incorporated.

Figure 2. Solvents used for the buprenorphine solvate study.  From left to right with increasing volume: Chloroform, 1,4-Dioxane, Toluene, p-Xylene and Anisole


Figure 3. Overlay of XRPD patterns of solvent free buprenorphine and solvated forms of buprenorphine with various hydrophobic solvent molecules.


Figure 4 shows a superposition of the crystal structures of the solvated forms of buprenorphine.  The small difference of the position of buprenorphine and the lack of interactions between the solvent molecules and buprenorphine becomes very apparent in this illustration.  The position of the solvent molecules also suggests that these can easily be replaced or removed from the structure.  This is an important hypothesis to be tested because it would give guidance towards the production of solvent-free crystalline buprenorphine.  Figure 5 shows the conversion of the Anisole solvate (poorly volatile solvent) to a 1,4-Dioxane solvate (more volatile) by solvent slurry conversion and after drying under ambient conditions solvent free buprenorphine is obtained.

Figure 4. Superposition of the crystal structure of various buprenorphine solvates


Figure 5. Overlay of XRPD patterns of the solvent exchange and drying experiment.  Starting with the least volatile solvent Anisole the buprenorphine Anisole solvate was slurried for 1 hr in 1,4-Dioxane to achieve full conversion to the Dioxane solvate.  After drying under ambient conditions almost all Dioxane had evaporated illustrated by an XRPD diffractogram almost identical to that of the solvent free buprenorphine.


Analysis of the crystal structure of solvated forms of an API can provide good insights into the nature of the interaction between the solvent molecules and the API functional groups.  Not only does this knowledge provide guidance in the desolvation of such crystalline forms, but also, desolvation solvent-free crystalline forms may become accessible which otherwise remain would remain undiscovered.  Hence such information aids in the selection of proper solvents avoiding solvate formation in the first place.

1 Arenas-Garcia, J.I. et al., Co-crystals of active pharmaceutical ingredients – Acetazolamide.  Crystal Growth & Design, (2010), 10 pp3732-3742

2 Mazurek, J., Hoffmann, M., Fernandez Casares, A., Cox, P.D. & Minardi, M. D., Acta Cryst. (2014).E70, o635