title: Clozapine-carboxylic acid plasticized co-amorphous dispersions: Preparation, characterization and solution stability evaluation.
abstract: This study addressed the possibility of forming of co-amorphous systems between clozapine (CZ) and various carboxylic acid plasticizers (CAPs). The aim was to improve the solubility and oral bioavailability of clozapine. Co-amorphous dispersions were prepared using modified solvent evaporation methodology at drug/plasticizer stoichiometric ratios of 1:1, 1:1.5 and 1:2. Solid state characterization was performed using differential scanning calorimetry, X-ray diffraction and infra red spectroscopy. Highly soluble homogeneous co-amorphous dispersions were formed between clozapine and CAPs via hydrogen bonding. The co-amorphous dispersions formed with tartaric acid (1:2) showed the highest dissolution percentage (>95% in 20 minutes) compared to pure crystalline CZ (56%). Highly stable solutions were obtained from co-amorphous CZ-citric and CZ-tartaric acid at 1:1.5 molar ratio. The prepared dispersions suggest the possibility of peroral or sublingual administration of highly soluble clozapine at a reduced dose with the great chance to bypass the first pass metabolism.
authors.forename: Ahmed Mahmoud Abdelhaleem
authors.initials: AM
authors.lastname: Ali
authors.forename: Adel Ahmed
authors.initials: AA
authors.lastname: Ali
authors.forename: Ibrahim Abdullah
authors.initials: IA
authors.lastname: Maghrabi
mesh_terms: D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D002152:Calorimetry, Differential Scanning; D002264:Carboxylic Acids / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003024:Clozapine / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D003460:Crystallization; D004339:Drug Compounding / Q000379:methods; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry*; D019999:Pharmaceutical Solutions; D010968:Plasticizers / Q000737:chemistry*; D012995:Solubility; D012997:Solvents / Q000737:chemistry; D017550:Spectroscopy, Fourier Transform Infrared; D014961:X-Ray Diffraction
chemical_list: D014150:Antipsychotic Agents; D002264:Carboxylic Acids; D005079:Excipients; D019999:Pharmaceutical Solutions; D010968:Plasticizers; D012997:Solvents; D003024:Clozapine