Clozapine-carboxylic acid plasticized co-amorphous dispersions: Preparation, characterization and solution stability evaluation

Acta Pharm. 2015 Jun;65(2):133-46. doi: 10.1515/acph-2015-0014.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antipsychotic Agents / administration & dosage
  • Antipsychotic Agents / chemistry
  • Antipsychotic Agents / pharmacokinetics
  • Calorimetry, Differential Scanning
  • Carboxylic Acids / chemistry*
  • Chemistry, Pharmaceutical / methods
  • Clozapine / administration & dosage*
  • Clozapine / chemistry
  • Clozapine / pharmacokinetics
  • Crystallization
  • Drug Compounding / methods
  • Drug Stability
  • Excipients / chemistry*
  • Pharmaceutical Solutions
  • Plasticizers / chemistry*
  • Solubility
  • Solvents / chemistry
  • Spectroscopy, Fourier Transform Infrared
  • X-Ray Diffraction

Substances

  • Antipsychotic Agents
  • Carboxylic Acids
  • Excipients
  • Pharmaceutical Solutions
  • Plasticizers
  • Solvents
  • Clozapine