RESUMEN
Limited research has been performed on the downstream processing of nano-co-crystal suspensions into solid oral dosage forms. The objectives of this study were to evaluate the impact of three downstream processes (wet granulation, spray granulation and bead layering) on the performance of itraconazole-succinic acid (ITZ-SUC) nano-co-crystal suspension. An optimized ITZ-SUC nano-co-crystal suspension mixed with HPMC E5 was utilized for the downstream processing. The suspension was converted in the solid state either by wet or spray granulation (with microcrystalline cellulose or lactose as substrates) or by layering onto microcrystalline cellulose and sugar beads. The multiparticulate solid dosage forms were characterized by optical microscopy, differential scanning calorimeter (DSC), X-ray powder diffraction (XRPD) and in situ dissolution studies. Spray granulation and bead layering resulted in less particle aggregation, a faster dissolution rate, and higher kinetic solubility when compared to wet granulation. ITZ-SUC nano-co-crystals spray granulated with lactose resulted in higher kinetic solubility profiles compared to microcrystalline cellulose granules. The type of bead core had no impact on the dissolution behavior. A slower dissolution and decreased kinetic solubility were observed with increasing drug loading for sprayed granules when microcrystalline cellulose was used as substrate. All dosage forms were stable under accelerated storage conditions (40 °C/75% RH) when blistered. Nano-co-crystals incorporated in granules were less stable than layered beads under non-blistered condition. Nano-co-crystals layered sugar beads are an interesting alternative to amorphous solid dispersion; a comparable kinetic solubility but a faster drug release were achieved. This study identified bead layering as a superior downstream process approach for incorporating ITZ-SUC nano-co-crystals into an oral solid dosage form without compromising drug dissolution.
Asunto(s)
Itraconazol , Nanopartículas , Composición de Medicamentos/métodos , Itraconazol/química , Lactosa , Nanopartículas/química , Tamaño de la Partícula , Solubilidad , SuspensionesRESUMEN
The objectives of this study were to evaluate the impact of formulation variables on the drying of nanocrystalline suspensions either via bead layering or spray granulation and develop mini-tablets from the dried nanocrystalline powders. Irbesartan (crystalline Form B), a poorly soluble drug substance was chosen as a model compound. An optimized irbesartan nanocrystalline suspension with a mean particle size of 300â¯nm was utilized for the downstream processing. Irbesartan nanocrystalline suspension was dried either by layering onto the microcrystalline cellulose beads (i.e. 200 or 500⯵m) or by granulation (mannitol or microcrystalline cellulose as substrates) at two different drug loadings (i.e. 10% or 30% w/w). Smaller size beads layered with nanocrystals resulted in faster dissolution profiles compared to larger size beads at both the studied drug loadings (i.e. 10 and 30% w/w). Mannitol granules containing irbesartan nanocrystals resulted in faster dissolution profiles compared to microcrystalline cellulose granules. Microcrystalline cellulose beads and mannitol granules containing irbesartan nanocrystals (i.e. 30% w/w drug loading) were further compressed into mini-tablets. Mini-tablets retained fast drug dissolution characteristics of the dried powders. The results from this study indicated that the spray granulation is a superior drying approach compared to bead layering for drying of irbesartan nanocrystalline suspension and mini-tablet development.
Asunto(s)
Antihipertensivos/química , Composición de Medicamentos/métodos , Irbesartán/química , Nanopartículas/química , Celulosa/química , Desecación , Liberación de Fármacos , Estabilidad de Medicamentos , Manitol/química , Suspensiones , ComprimidosRESUMEN
Nanocrystalline suspensions offer a promising approach to improve the dissolution rate of BCS Class II/IV drugs and hence oral bioavailability. Irbesartan (crystalline Form B), a poorly soluble drug substance was chosen as a model compound for the study. The objectives of the study were to formulate Irbesartan nanocrystalline suspension via media milling, study the effects of process and formulation variables on particle size reduction, and evaluate bead layering or spray granulation as drying processes. A Design of Experiment approach was utilized to understand the impact of formulation variables on particle size reduction via media milling. Drug concentration and type of stabilizer were found to be significant in particle size reduction. Optimized Irbesartan nanocrystalline suspension (i.e. at 10% w/w with 1% w/w poloxamer 407) showed superior in vitro dissolution profile compared to unmilled suspension. Optimized Irbesartan nanocrystalline suspension was converted into dried powders either by bead layering (with microcrystalline cellulose) or by spray granulation (either with mannitol or microcrystalline cellulose). DSC and PXRD studies revealed that Irbesartan remained crystalline post drying. Microcrystalline cellulose beads layered with Irbesartan nanocrystals showed about 65% drug dissolution within the first 10â¯min of dissolution study. Mannitol granules containing Irbesartan nanocrystals were fast dissolving (i.e. >90% drug dissolution within 10â¯min) compared to microcrystalline cellulose granules (i.e. approx. 46% drug dissolution within 10â¯min). Irbesartan nanocrystalline suspension had the fastest dissolution rates (i.e. >90% drug dissolution in two minutes) followed by mannitol-based granules containing dried Irbesartan nanocrystals (i.e. >90% drug dissolution in ten minutes).
Asunto(s)
Antihipertensivos/química , Composición de Medicamentos/métodos , Irbesartán/química , Nanopartículas/química , Celulosa/química , Desecación/métodos , Liberación de Fármacos , Estabilidad de Medicamentos , Manitol/química , Tamaño de la Partícula , PolvosRESUMEN
In order to increase the dissolution rate and oral bioavailability of bifendate, coated beads with core-shell structure were prepared via a combination use of wet media milling method and bead layering process. Hydroxypropyl cellulose (HPC-SL) and sodium lauryl sulfate (SLS) were found to be the best pair to stabilize the nanosuspension during milling process. A 10:1 ratio of mixture of mannitol and SLS was chosen as most suitable coating matrix to maintain the redispersability of dried nanoparticles in the shell of beads. The mean particle size of the nanosuspension was 139 nm and the zeta potential was -20.2 mV. Nanoscale bifendate particles with a mean diameter of 360 nm could be generated when redispersing the prepared beads in water. The differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) analysis indicated that the crystalline state of the drug was not changed. The stability test confirmed that coated beads showed no distinct difference in particle size and dissolution velocity during 6 month storage while liquid nanosuspension was stable no more than 3 weeks. Dissolution rate of coated beads was increased significantly compared with commercially available pills. Likewise, the Cmax and AUC (0â24) of nanosuspension based beads in beagle dogs were 2.40-fold and 1.66-fold greater than that of commercially available pills, respectively. The present work is a reliable approach to stabilize nanosuspension based product, and improve dissolution velocity and bioavailability of poor soluble drugs.