Solid‐state stereochemistry of (−)‐scopolamine hydrobromide sesquihydrate, a new polymorph of the anticholinergic drug

Andre Michel, Marc Drouin, Robert Glaser

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


The solid‐state structure of (−)‐scopolamine hydrobromide sesquihydrate was determined by single‐crystal X‐ray diffraction analysis at low temperature. (Nr, Cα‐S)‐(−)‐Scopolamine hydrobromide sesquihydrate gives crystals belonging to the tetragonal space group P43212, and at 180 K: a = 11.870(4), c = 26.193(3) Å, V = 3691(1) Å3, Z = 8, R(F) = 0.062, and Rw(F) = 0.059. Thermogravimetric analysis afforded a total weight loss of ∼6%, consistent with a loss of 1.5 molecules of water and in accord with the sesquihydrate stoichiometry found by single‐crystal X‐ray crystallography. The unit cell dimensions, molecular structure, basic packing arrangement [minus the full water molecule], and the crystal system are all the same as that of the P41212 hemihydrate from [R(F) = 0.09] reported earlier by Pauling and Petcher. This suggests that the previously reported “hemihydrate” description of the structure should be reconsidered. In addition to partial dehydration of the sesquihydrate crystal, non‐observance of the eight water molecules might have arisen from their relatively large thermal motions at ambient temperature coupled with a lack of sufficient data versus the number of variable parameters. The phenyl ring syn‐to‐oxirane arrangement in the sesquihydrate form is the same as that in the corresponding crystalline methyliodide quaternary ammonium salt and in (−)‐(Ns, Cα‐S)‐hyoscyamine [atropine] hydrobromide, but differs from the elongated anti‐to‐oxirane arrangement in anhydrous (Nr, Cα‐S)‐(−)‐scopolamine hydrobromide. The United States Pharmacopoeia XXII Official Monographs list the trihydrate form for scopolamine hydrobromide, and states a maximum permissible 13% weight loss after drying at 105 °C for 3 h, although no lower limits for weight loss are given. Because the melting point range, specific rotation, and IR spectrum are all performed on predried anhydrous samples, the theoretical weight loss from anhydrous, hemihydrate, sesquihydrate, and trihydrate polymorphs all fall within the permissible limit.

Original languageEnglish
Pages (from-to)508-513
Number of pages6
JournalJournal of Pharmaceutical Sciences
Issue number4
StatePublished - 1 Jan 1994


Dive into the research topics of 'Solid‐state stereochemistry of (−)‐scopolamine hydrobromide sesquihydrate, a new polymorph of the anticholinergic drug'. Together they form a unique fingerprint.

Cite this