Development of carbamazepine microparticulated solid dispersions by spray congealing.

Author(s)

Rodrigo Molina Martins

• Document type: Master's Dissertation
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC)
• Defense date: 2010-11-03

Examining board members

Luis Alexandre Pedro de Freitas; Juliana Maldonado Marchetti; Joao Claudio Thomeo

• Advisor: Luis Alexandre Pedro de Freitas

Abstract

Improvement of dissolution properties of pharmaceutical products is extremely important, especially because the percentage of poor water soluble drugs has increased in the pharmaceutical market lately. Several techniques have been used to improve the dissolution properties of drugs such as grinding, the use of surfactants and preparation of solid dispersions. The preparation of solid dispersions is a useful method for disperse the drug molecules in a hydrophilic solid matrix. The spray congealing technique is used for production of microparticles and do not require organic or aqueous solvents. This work aimed to produce microparticles of solid dispersion prepared by spray congealing and to study the influence of process parameters. Carbamazepine (CBZ) was used as model drug due to its poor solubility and because it is the first choice drug for the treatment of psychomotor epilepsy. Initially solid dispersions were prepared using as carriers polyoxylglyceride (Gelucire® 50/13), and polyethylene glycols (PEG 4000 and PEG 6000) in the proportions 1:9, 1:5 and 1:1 (drug: carrier), applying the hot melt method .Solid dispersion with Gelucire ® 50/13 (1:9) showed better solubility compared to pure CBZ, being selected for the further production of microparticles by spray congealing. The microparticles were obtained using a Box Behnken experimental design, studying the following parameters: flow rate of liquid dispersion, flow rate of cooling air and atomizing pressure for a total of 15 experiments. The microparticles were characterized by studies of particle size, bulk density, compacted density, Hausner factor, Carr index, angle of repose, encapsulation efficiency, water activity, solubility, moisture content and yield of the process. These effects were analyzed by response surface technique (ANOVA). Statistical analysis showed that the yield was influenced by all three variables while the moisture was only dependent on the flow dispersion. The other properties were not significantly influenced by the parameters. The solid dispersion, physical mixture and microparticles of CBZ in Gelucire® 50/13 had their physical and chemical characteristics evaluated by x-ray diffraction, infrared spectroscopy, hot stage microscopy and thermal analysis (DSC and TG). The analysis of the results showed that there were no physical-chemical interactions between the drug and carrier. However, the preparation process of dispersion has led to a change in the crystalline state of CBZ, partially converting the polymorphic form III to the polymorphic form I. The microparticles showed good to moderate flow and good yields (50-80%), low moisture content (<2%), water activity lowerless than 0.550 and good encapsulation efficiency (99.5 to 112%) The average size microparticles ranged from 53.09 to 78.75 m. The morphology was analyzed by scanning electron microscopy and showed spherical shape, smooth surface with minor irregularities and apparently non-porous. The solubility of CBZ in the microparticles showed an increase of 2.70 times the solubility CBZ alone. The characteristics of microparticulated solid dispersions were similar to that of the solid dispersion. The microparticles studied led to an increase in dissolution rate of CBZ in vitro compared to its corresponding solid dispersion and pure CBZ. Therefore, the spray congealing is a promising method to be developed and employed in the manufacture of microparticles of poorly soluble drugs. (AU)

• FAPESP's process: 08/07115-0 - Development of carbamazepine microparticulated solid dispersions by spray congealing
• Grantee: Rodrigo Molina Martins
• Support Opportunities: Scholarships in Brazil - Master