A study of in situ fluid bed melt granulation using response surface methodology / Uporaba metodologije odgovornih površin za študij in situ granulacije s talinami v zvrtinčenih plasteh

Abstract

Melt granulation belongs to the group of hot-melt technologies, which represent an alternative to the classical solvent-mediated technological processes of agglomeration. The main advantage of hot-melt processes, including melt granulation, is the absence of solvents, which can be efficiently utilized in enhancing chemical stability of moisture sensitive drugs and also improving their physical properties. Moreover, a drying phase is eliminated, which results in a more economical and environmentally friendly process. There are also some limitations in using melt granulation processes. The major drawback is the required high temperature during the process, which can cause degradation and/or oxidative instability of the ingredients, especially of thermolabile drugs (1, 2).Equipment used for melt granulation technologies must be modified to promote melting and prevent unwanted solidification of the product on exposed equipment sur- The objective of this work was to investigate the influence of selected individual variables (binder content, inlet air temperature, and product endpoint temperature) of in situ fluid bed melt granulation on the granule particle size distribution and percentage of dissolved carvedilol using a three-factor, five-level circumscribed central composite design. Increased binder content had the effect of increasing the granule particle size and drug dissolution rate. The effect of inlet air temperature and product endpoint temperature was found to be more pronounced in case of granule particle size parameters. Within the studied intervals, the optimal quantity of binder as well as optimal process parameters were identified and validated using response surface methodology. Utilizing these optimal process and formulation parameters, successful scaling up of the fluid bed melt granulation process was carried out. Granule characteristics obtained at pilot scale are comparable to those obtained at laboratory scale.

Solvent-Free Melting Techniques for the Preparation of Lipid-Based Solid Oral Formulations

“…Moreover, the fluid bed offers a more efficient cooling process without additional densification, which is an advantage for up-scaling and enables the addition of higher binder contents ( 343 ). Further, Kukec et al were able to successfully scale an in-situ laboratory method up to pilot scale by the aid of a three-factor, five-level circumscribed central composite design, whereby the resulting dissolution rate was affected mainly by the binder content ( 261 ). Hence, in-situ melt fluid bed granulation is a viable and fast method to obtain granules from moisture sensitive drugs.…”

The Effect of Formulation Variables on the Manufacturability of Clopidogrel Tablets via Fluidized Hot-Melt Granulation—From the Lab Scale to the Pilot Scale

“…A successful scale-up requires a holistic approach, integrating process optimization, equipment design considerations, and a thorough understanding of material behavior. The most relevant input variables for FHMG are binder content and binder particle size, inlet air temperature and/or flow rate, granulation time, and product endpoint temperature [ 19 , 23 , 24 , 25 ]. Monitored output variables include granule size, size distribution, and growth kinetics, as well as physical and technological properties of granules (shape, porosity, flowability, and compressibility) and tablets (resistance to crushing and dissolution) [ 19 , 20 , 23 , 26 ].…”

Fluidized Bed Co-Melt Granulation: New Insights in the Influence of Process Variables and Validation of Regime Map Theory

“…In this sense, fluidized bed melt granulation (FBMG) has received wide interest in the pharmaceutical research field, being the most common application the preparation of pharmaceutical granules for tableting [6]. Although granulation processes involving the incorporation of the binder as droplets have received significantly more attention from a scientific point of view, both for wet and melt granulation, it is notable that co-melt processes are much more practical from an industrial point of view, since they avoid the spraying stage with hot-melt flows, leading to a simpler production process [7]. To our knowledge, for co-melt granulation, the Walker et al have been the first to extensively study this process.…”

“…From the experimental results of a response surface design, a polynomial model, describing the relation between a response and considered factors, is built. Afterwards, graphical and/or statistical analysis is carried out to determine the optimal operating conditions in order to obtain the desired formulation properties [7]. In this sense, a reduced group of authors used DoE for elucidating FBMG under a more systematic approach.…”

“…Mangwandi et al [13] also performed studies with a DoE approach (a two-level factorial design). Kukec et al [7] granulated Carvediol and lactose with a poloxamer to study the binder/seed mass ratio, fluidization air temperature, and endpoint temperature on granules' PSD, morphology, flow properties, and drug release through a Circumscribed Central Composite Design. More recently, Korteby et al [6] related granules' PSD, aspect ratio, porosity, and granulation yield with the binder/seed mass ratio, viscosity and size of the binder, and outlet temperature through another empirical technique as Artificial Neural Networks (ANNs).…”