Publicação
From synthesis to formulation of gliclazide and glibenclamide cocrystal pharmaceutical solid dosage forms
| Resumo: | Low solubility of pharmaceutical drugs is very often a limiting factor in the development of drug products. Cocrystals are known for a long time but still little explored as an alternative for drug solubility increase. Cocrystals are crystalline homogenous structures composed by two or more molecules in the same crystal lattice, all solid at room temperature. They are different from the precursors held together by noncovalent interactions (normally hydrogen bonds) with a well-defined stoichiometry. In this work, two sulfonylureas used in the treatment of non-insulin-dependent diabetes mellitus – glibenclamide (GBL) and gliclazide (GCZ) – were chosen as cocrystallization targets due to their categorization as class II drugs (low solubility, high permeability) by the Biopharmaceutical Classification System. The development of GBL and GCZ cocrystals was developed in two stages: screening and production experiments. Screening experiments performed by solvent evaporation, were designed to evaluate the most promising cocrystal forms produced with three different coformers – tromethamine (TRIS), nicotinamide (NICO) and p-aminobenzoic acid (PABA). Differential scanning calorimetry, near- and mid-infrared spectroscopy and powder x-ray diffraction comprehended the selected crystal characterization methods. Products of the cocrystallization process were characterized and compared with the respective drug, coformer and binary physical mixture. Screening experiments showed that cocrystals of GLB and GCZ were preferentially formed with TRIS. Production experiments (still lab scale) were performed for the GBL:TRIS 1:1 and GCZ:TRIS 3:2 systems, aiming at obtaining a sufficient amount of product for incorporation in pharmaceutical solid oral dosage forms. For this, two different cocrystallization methods were tested – solvent evaporation and slurry. Contrarily to the slurry method, solvent evaporation operated at a 20-fold scale increase resulted in the production of impure cocrystals. To better understand this result, a D-optimal experimental design was proposed to understand the impact of temperature, volume of solvent and molar ratio on products purity. The slurry cocrystallization method was selected as preferential method for the production of higher cocrystals’ quantities ensuring a suitable level of purity. The solubility increase was assessed for the cocrystals produced with the slurry method (GBL:TRIS and GCZ:TRIS) using three different dissolution media. Results revealed a maximum solubility enhancement in water, with a 54.7-fold and 82.5-fold increase for GBL and GCZ, respectively. |
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| Autores principais: | Baptista, Bárbara Violinha |
| Assunto: | pharmaceutical cocrystals glibenclamide gliclazide solvent evaporation cocrystallization slurry cocrystallization cocrystals characterization Teses de mestrado - 2017 |
| Ano: | 2017 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Low solubility of pharmaceutical drugs is very often a limiting factor in the development of drug products. Cocrystals are known for a long time but still little explored as an alternative for drug solubility increase. Cocrystals are crystalline homogenous structures composed by two or more molecules in the same crystal lattice, all solid at room temperature. They are different from the precursors held together by noncovalent interactions (normally hydrogen bonds) with a well-defined stoichiometry. In this work, two sulfonylureas used in the treatment of non-insulin-dependent diabetes mellitus – glibenclamide (GBL) and gliclazide (GCZ) – were chosen as cocrystallization targets due to their categorization as class II drugs (low solubility, high permeability) by the Biopharmaceutical Classification System. The development of GBL and GCZ cocrystals was developed in two stages: screening and production experiments. Screening experiments performed by solvent evaporation, were designed to evaluate the most promising cocrystal forms produced with three different coformers – tromethamine (TRIS), nicotinamide (NICO) and p-aminobenzoic acid (PABA). Differential scanning calorimetry, near- and mid-infrared spectroscopy and powder x-ray diffraction comprehended the selected crystal characterization methods. Products of the cocrystallization process were characterized and compared with the respective drug, coformer and binary physical mixture. Screening experiments showed that cocrystals of GLB and GCZ were preferentially formed with TRIS. Production experiments (still lab scale) were performed for the GBL:TRIS 1:1 and GCZ:TRIS 3:2 systems, aiming at obtaining a sufficient amount of product for incorporation in pharmaceutical solid oral dosage forms. For this, two different cocrystallization methods were tested – solvent evaporation and slurry. Contrarily to the slurry method, solvent evaporation operated at a 20-fold scale increase resulted in the production of impure cocrystals. To better understand this result, a D-optimal experimental design was proposed to understand the impact of temperature, volume of solvent and molar ratio on products purity. The slurry cocrystallization method was selected as preferential method for the production of higher cocrystals’ quantities ensuring a suitable level of purity. The solubility increase was assessed for the cocrystals produced with the slurry method (GBL:TRIS and GCZ:TRIS) using three different dissolution media. Results revealed a maximum solubility enhancement in water, with a 54.7-fold and 82.5-fold increase for GBL and GCZ, respectively. |
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