Surface responses and desirability functions to determine optimal granulation domains.

BACKGROUND: Single pot mixer-granulator-dryer (high-shear granulator with in situ double jacket vacuum drying) and multiphase equipment (high-shear granulator associated with fluid bed dryer) are classically used for wet granulation. At present time, industrial production imperatives may require to switch one formulation from one equipment to another. METHOD: To compare the two processes and to define, for each of them, the optimal formulation domain, experiments were organized according to Doehlert experimental designs. Response surfaces were used to identify the levels of each factor (binder and filler ratios) inducing the more satisfying responses. The contribution of binder and filler ratios to granule properties was highlighted according to the process. Then the desirability function was used to determine and compare the optimal formulation domain for each process. RESULTS AND CONCLUSION: In the studied formulation domain and for the considered equipment, the transposition from a single pot to a multiphase high-shear granulation process did not seem to raise difficulties; the same formulations were out of specification for both processes and other trials, the technological properties were maintained or improved in the Fielder/Niro equipment.

Comparison of single pot and multiphase granulation. Part 1: Effect of the high shear granulator on granule properties according to the drug substance and its concentration.

Pharmaceutical granulations are usually developed with regard to a specific manufacturing process but switching from one piece of equipment to another can be necessary to comply with the available industrial equipment. Investigations were undertaken on formulations differing in the drug substance and in its concentration. Our aim was to highlight the effect of the granulation process on granules manufactured in a pilot scale Moritz Turbosphere TS50 or in Fielder PMA 65 and dried in a Glatt GPCG1 fluid bed dryer. The granulation process and formulation parameters showed a significant impact on granule size distribution, behaviour under pressure, and on tablet mechanical properties and dissolution kinetics.

Comparison of single pot and multiphase granulation. Part 2: Effect of the drying process on granules manufactured in a single pot granulator and dried either in situ or in a fluid bed dryer.

The aim of this study was to highlight the effect of the drying process on granules manufactured in a pilot scale single pot granulator and dried either in situ or in a fluid bed dryer, for formulations differing in drug substance and its concentration (1%; 25%). Although most of raw data were within specifications, single pot drying tended to improve granule comprimability and seemed less sensitive to formulation. Moreover, it was demonstrated that the formulation impacted on granule median diameter, packing ability, comprimability, residual lower punch pressure and tablet dissolution kinetics. Interactions between process and formulation were highlighted concerning tablet tensile strength and uniformity of mass.

Comparison of single pot and multiphase high shear wet granulation processes related to excipient composition.

At present time, industrial production imperatives can require the transposition of a formulation from one equipment to another. In order to evaluate the impact of such a switch on the properties of granules and tablets, investigations were undertaken on formulations manufactured both in a single pot mixer-granulator-dryer (high shear granulator with in situ double jacket vacuum drying) and in a multiphase equipment (high shear granulator/fluid bed dryer). Principal component analysis highlighted the major contribution of the binder ratio on granule size distribution, flow and packing ability whereas the relative ratio of mannitol and lactose, used as fillers, mainly impacted on compressibility and tablet cohesion. In the studied domain, the lubricant ratio did not explain the considered responses. Statistical analysis (comparison of means, analysis of variance and PCA) showed that both processes led to products with similar characteristics which demonstrated the ability of the processes to produce granules with close quality. However, Fielder/Niro granule characteristic data were found to be more dispersed, thus demonstrating a higher sensitivity of the multiphase process to formulation changes. Technological properties of granules and tablets were found to be maintained or improved therefore securing the switch from single pot to multiphase equipments.

Drug/lactose co-micronization by jet milling to improve aerosolization properties of a powder for inhalation.

The aim of this work was to formulate a powder for inhalation with fusafungine, a drug substance initially highly cohesive. The classical approach based on micronization by jet milling to prepare respirable drug particles and then blending with a carrier was first applied. A fractional factorial experimental design was implemented to screen six formulation parameters. The effect of drug/lactose co-micronization on aerosolization was then evaluated. In vitro deposition studies were performed with the twin stage glass impinger and the inhaler Spinhaler. Micronization did not induce DSC-detectable amorphization and gave a highly cohesive, poor flowable powder with a theoretical aerodynamic diameter of 5 microm. The powder was then blended with coarse lactose and optionally fine lactose. Unfortunately, the respirable fraction could not be optimized and remained below 10%. On the other hand, a co-micronized powder drug/fine lactose 50:50 gave a respirable fraction of 16%. Following blending with a carrier, the respirable fraction and the emitted dose fraction reached 23% and 69%, respectively. The use of a fine lactose grade for co-micronization was essential. In conclusion, this study demonstrated that co-micronization with a fine lactose is an efficient and simple strategy to formulate a powder for inhalation with enhanced aerosolization properties, especially for highly cohesive drug substance.

Multiphase versus single pot granulation process: influence of process and granulation parameters on granules properties.

High-shear wet granulation is widely used for the production of pharmaceutical dosage forms. Different equipment is available for high-shear granulation and drying. This review focuses on two main processes for granules production: multiphase consisting of high-shear granulation followed by drying in a separate apparatus, and single pot granulation/drying. At present, formulas are specifically developed with regard to the production equipment, which raises many problems when different industrial manufacturing equipment is used. Indeed, final granules properties are likely to depend on equipment design, process, and formulation parameters. Therefore, a good understanding of these parameters is essential to facilitate equipment changes. The aim of this review is to present the influence of equipment, process, and formulation parameters on granules properties, considering both the granulation and the drying steps of multiphase and single pot processes.