Performance comparison of a co-crystal of carbamazepine with marketed product.
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.
Hickey
Magali B
MB
TransForm Pharmaceuticals, Inc., Lexington, MA 02421, USA. Mhickey1@tpius.jnj.com
Peterson
Matthew L
ML
Scoppettuolo
Lisa A
LA
Morrisette
Sherry L
SL
Vetter
Anna
A
Guzmán
Hector
H
Remenar
Julius F
JF
Zhang
Zhong
Z
Tawa
Mark D
MD
Haley
Sean
S
Zaworotko
Michael J
MJ
Almarsson
Orn
O
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
D000927:Anticonvulsants; D002220:Carbamazepine