title: Performance comparison of a co-crystal of carbamazepine with marketed product.
abstract: The carbamazepine: saccharin co-crystal (1) was studied in terms of a series of attributes, including suitability for multi-gram scale-up, propensity for crystal polymorphism, physical stability, in vitro dissolution and oral bioavailability, with the goal of comparing 1 with the marketed form of carbamazepine (Tegretol). Preparation of 1 was achieved on a 30g scale with a conventional cooling crystallization process from alcohol solution without seeding. The compound is not overtly polymorphic. This finding is in contrast to the form diversity of pure carbamazepine, which has four known polymorphs and a host of solvates, including a dihydrate, which is the stable form in the presence of water. Physical and chemical stability of the co-crystal is also shown to be quantitatively similar to the pure drug in the marketed product (Tegretol). Finally, comparison of oral bioavailability of 1 with Tegretol tablets in dogs shows the co-crystal to be a viable alternative to the anhydrous polymorph in formulated solid oral products. The balance of properties and performance of 1 as a model co-crystal is discussed.
authors.affiliation: TransForm Pharmaceuticals, Inc., Lexington, MA 02421, USA. Mhickey1@tpius.jnj.com
authors.forename: Magali B
authors.initials: MB
authors.lastname: Hickey
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Peterson
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Scoppettuolo
authors.forename: Sherry L
authors.initials: SL
authors.lastname: Morrisette
authors.forename: Anna
authors.initials: A
authors.lastname: Vetter
authors.forename: Hector
authors.initials: H
authors.lastname: Guzmán
authors.forename: Julius F
authors.initials: JF
authors.lastname: Remenar
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zhang
authors.forename: Mark D
authors.initials: MD
authors.lastname: Tawa
authors.forename: Sean
authors.initials: S
authors.lastname: Haley
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Zaworotko
authors.forename: Orn
authors.initials: O
authors.lastname: Almarsson
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry* / Q000493:pharmacokinetics; D001682:Biological Availability; D002220:Carbamazepine / Q000737:chemistry* / Q000493:pharmacokinetics; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003460:Crystallization; D004285:Dogs; D007536:Isomerism; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D014961:X-Ray Diffraction
chemical_list: D000927:Anticonvulsants; D002220:Carbamazepine