title: Evaluation of in vitro-in vivo correlation and anticonvulsive effect of carbamazepine after cogrinding with microcrystalline cellulose.
abstract: OBJECTIVE
  Carbamazepine is a poor water soluble drug and its bioavailability is limited by dissolution rate. Dissolution, serum concentration and anticonvulsive effect of the drug have been evaluated after cogrinding with microcrystalline cellulose. A cogrinding technique was used to increase the dissolution, serum concentrations and anticonvulsive effect of the drug. A novel deconvolution technique of in vitro in vivo correlation was evaluated.
  
  
  METHODS
  The drug coground with microcrystalline cellulose, the corresponding physical mixture, unground and ground drug powder were subjected to dissolution measurement. Coground and unground drug serum concentrations were investigated in rabbits. Also the anticonvulsive effects of the latter preparations were assessed in mice. For elucidation of observed in vitro and in vivo differences FT-IR spectroscopy, X-ray diffraction patterns and DSC thermograms of the preparations were studied.
  
  
  RESULTS
  The dissolution of the coground was the highest (percent dissolved in the first 20 minutes, %D20', was 97.5). The unground drug powder exhibited the lowest dissolution (%D20'=40). The difference was reflected in their corresponding area under the mean serum concentration curves between 0-16 hr (118.96 vs 54.17 microg x hr/ml) as well as protection abilities against strychnine and electrically induced seizures. The onset of tonic seizures induced by strychnine was increased between 40-140% in the case of the coground system depending on dose and time of carbamazepine administration.
  
  
  CONCLUSIONS
  Cogrinding was an effective technique in increasing carbamazepine dissolution due to reduced crystallinity as seen in X-ray pattern, enhanced wettability and decreased particle size, which in turn resulted in increased serum concentrations and its anticonvulsive effect. A novel simple deconvolusion technique not requiring intravenous data denoted as the double reciprocal area method was used to establish correlation between in vitro and in vivo parameters.
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy and Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. barzegar_jalali@yahoo.com
authors.forename: Mohammad
authors.initials: M
authors.lastname: Barzegar-Jalali
authors.forename: Alireza Mohajjel
authors.initials: AM
authors.lastname: Nayebi
authors.forename: Hadi
authors.initials: H
authors.lastname: Valizadeh
authors.forename: Jalal
authors.initials: J
authors.lastname: Hanaee
authors.forename: Azim
authors.initials: A
authors.lastname: Barzegar-Jalali
authors.forename: Khosro
authors.initials: K
authors.lastname: Adibkia
authors.forename: Mahdieh
authors.initials: M
authors.lastname: Anoush
authors.forename: Mohammad
authors.initials: M
authors.lastname: Sistanizad
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000737:chemistry* / Q000627:therapeutic use; D002220:Carbamazepine / Q000097:blood / Q000737:chemistry* / Q000627:therapeutic use; D002482:Cellulose / Q000737:chemistry* / Q000627:therapeutic use; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D008297:Male; D051379:Mice; D011817:Rabbits; D012640:Seizures / Q000517:prevention & control; D012995:Solubility
chemical_list: D000927:Anticonvulsants; D002220:Carbamazepine; D002482:Cellulose; C109691:microcrystalline cellulose