Fluidized Hot Melt Granulation Research Articles

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

Solid pharmaceutical formulations with class II active pharmaceutical ingredients (APIs) face dissolution challenges due to limited solubility, affecting in vivo behavior. Robust computational tools, via data mining, offer valuable insights into product performance, complementing traditional methods and aiding in scale-up decisions. This study utilizes the design of experiments (DoE) to understand fluidized hot-melt granulation manufacturing technology. Exploratory data analysis (MVDA) highlights similarities and differences in tablet manufacturability and dissolution profiles at both the lab and pilot scales. The study sought to gain insights into the application of multivariate data analysis by identifying variations among batches produced at different manufacturing scales for this technology. DoE and MVDA findings show that the granulation temperature, time, and Macrogol type significantly impact product performance. These factors, by influencing particle size distribution, become key predictors of product quality attributes such as resistance to crushing, disintegration time, and early-stage API dissolution in the profile. Software-aided data mining, with its multivariate and versatile nature, complements the empirical approach, which is reliant on trial and error during product scale-up.

Solubility Improvement and Dissolution Enhancement of Simvastatin using Fluidized Hot-melt Granulation Technique

A fluidized hot melt granulation (FHMG) technique was used to enhance the solubility and dissolution of simvastatin. Employing meltable hydrophilic binders and then converting the melt dispersion into flowable and compressible dispersion granules to yield a rapidly dissolving tablet formulation. Granules prepared by using hydrophilic polymer polyethylene glycol 4000 or 6000, Gelucire 50/13 or 44/14, and Poloxamer 188 or 407, spray-dried lactose as a fluidized substrate. The binder used for spray granulation in this technique was a mixture of molten Gelucire 50/13 and simvastatin. Phase Solubility studies showed an increase in solubility ratio of 1:4 for Simvastatin: Gelucire 50/13. The prepared granules were characterized using FTIR, and DSC spectra exhibited drug excipients compatibility. XRD data exhibited a partial loss of crystallinity as indicated by significantly less intensity of simvastatin peak in a sample than pure simvastatin. Tablets with the faster dissolution of simvastatin (98.99% of the drug release with 30 minutes). This was achieved with lactose/MCC as filler. A significant enhancement in-vitro dissolution profile of the melted granules was observed compared to the pure drug and marketed product. Therefore, the results confirmed the high potential of the FHMG technique to produce granules with enhanced drug solubility and release rate.

Gastroretentive extended-release floating granules prepared using a novel fluidized hot melt granulation (FHMG) technique.

The objective of this work was to investigate the feasibility of using a novel granulation technique, namely, fluidized hot melt granulation (FHMG), to prepare gastroretentive extended-release floating granules. In this study we have utilized FHMG, a solvent free process in which granulation is achieved with the aid of low melting point materials, using Compritol 888 ATO and Gelucire 50/13 as meltable binders, in place of conventional liquid binders. The physicochemical properties, morphology, floating properties, and drug release of the manufactured granules were investigated. Granules prepared by this method were spherical in shape and showed good flowability. The floating granules exhibited sustained release exceeding 10 h. Granule buoyancy (floating time and strength) and drug release properties were significantly influenced by formulation variables such as excipient type and concentration, and the physical characteristics (particle size, hydrophilicity) of the excipients. Drug release rate was increased by increasing the concentration of hydroxypropyl cellulose (HPC) and Gelucire 50/13, or by decreasing the particle size of HPC. Floating strength was improved through the incorporation of sodium bicarbonate and citric acid. Furthermore, floating strength was influenced by the concentration of HPC within the formulation. Granules prepared in this way show good physical characteristics, floating ability, and drug release properties when placed in simulated gastric fluid. Moreover, the drug release and floating properties can be controlled by modification of the ratio or physical characteristics of the excipients used in the formulation.

In situ fluidized hot melt granulation using a novel meltable binder: Effect of formulation variables on granule characteristics and controlled release tablets

In situ fluidized hot melt granulation (FHMG) for different (ternary) formulations based on glyceryl palmito-stearate as non-conventional meltable binder and ibuprofen as model drug was examined for controlled release applications. The process was robust, lasted only 15min, and enabled to attain high yields (95–98wt.%). The obtained granules presented a bimodal size distribution, having the major mode of 200μm and good flow properties, thus avoiding the necessity to add other lubricants for tablet compaction. The crystalline structure of ibuprofen and of the non meltable excipients was retained, and that of glyceryl palmito-stearate was recovered in the final granules. The resulting ibuprofen tablets had good pharmacotechnical properties. The granulation process did not modify release profiles from the tablets. The main factor influencing the release profiles was the content of glyceryl palmito-stearate in the formulations. A high drug load (50wt.%), which is particularly important in the case of high dose active pharmaceutical ingredients, was achieved. Glyceryl palmito-stearate performed a triple function in the tablet formulation: as a meltable binder, as a controlled release matrix and as a lubricant.

Nicotinamide pelletization by fluidized hot melt granulation: L18 Hunter design to screen high risk variables

L18 Hunter design was used to investigate the practicability of applying QbD approaches to fluidized hot melt granulation (FHMG) in preparing oral controlled release systems. Eight high-risk variables obtained from risk analysis were classified into chemical factors (type and percentage of meltable binder, matrix viscosity and percentage and filler type) and process variables (size fraction of meltable binder, inlet air volume and fluidization time). The variables were screened for their impacts on pellets characteristics. The obtained results showed that the meltable binder percentage was the significant variable affecting most responses. Flow properties, size distribution, bulk, and tapped densities were significantly (P<0.05) affected by the filler type, inlet air volume, and fluidization time. On the other hand, the matrix variables were non-significant to the dissolution parameters. Out of eight critical variables, it was found that the meltable binder percentage and size fraction, inlet air volume had the most significant effects and will be optimized in the second part of the study. In conclusion, QbD paradigm not only offered a robust FHMG technique to formulate controlled release formulations of hydrophilic drugs but also provided a time and cost saving advantage to pharmaceutical industry.

An investigation into the effect of formulation variables and process parameters on characteristics of granules obtained by in situ fluidized hot melt granulation

The aim of this study was to investigate the influence of binder content, binder particle size, granulation time and inlet air flow rate on granule size and size distribution, granule shape and flowability, as well as on drug release rate. Hydrophilic (polyethyleneglycol 2000) and hydrophobic meltable binder (glyceryl palmitostearate) were used for in situ fluidized hot melt granulation. Granule size was mainly influenced by binder particle size. Binder content was shown to be important for narrow size distribution and good flow properties. The results obtained indicate that conventional fluid bed granulator may be suitable for production of highly spherical agglomerates, particularly when immersion and layering is dominant agglomeration mechanism. Granule shape was affected by interplay of binder content, binder particle size and granulation time. Solid state analysis confirmed unaltered physical state of the granulate components and the absence of interactions between the active and excipients. Besides the nature and amount of binder, the mechanism of agglomerate formation seems to have an impact on drug dissolution rate. The results of the present study indicate that fluidized hot melt granulation is a promising powder agglomeration technique for spherical granules production.

Effect of Different Excipients on the Physical Characteristics of Granules and Tablets with Carbamazepine Prepared with Polyethylene Glycol 6000 by Fluidized Hot-Melt Granulation (FHMG)

The objective of this study was to investigate the properties of granules and tablets with carbamazepine which were prepared employing a fluidized hot-melt granulation (FHMG) technique. The FHMG process was carried out at 65°C. Macrogol 6000 (PEG 6000) was used as a binder at the content 10% (w/w) of the granulated mass. Granules containing up to 70% (w/w) of the drug and 20-90% (w/w) of a filler (lactose, mannitol, calcium hydrogen phosphate (Di-Cafos), pregelatinized starch, and microcrystalline cellulose (MCC)) were produced. When the drug content was 30% (w/w), the yield of the process was satisfying (>95%) and flowability of the granules was better than placebo granules or drug-loaded granules prepared by wet granulation. Type of a filler had strong impact on physical properties of granules, and size distribution of the particles was the most homogenous when lactose or Di-Cafos were used. The FHMG technique enabled preparation of granules with better compressability compared with the wet-granulated product or with non-granulated powders. Tablets with shorter disintegration time than 10 min were obtained with 2.0% crospovidone added as a disintegrant. In comparison to tablets prepared from the wet-granulated mass, employment of the FHMG method resulted in tablets with faster dissolution of carbamazepine (more than 80% of the drug released within 15 min). This was achieved with mannitol or lactose/MCC, as fillers.

Fluidized Hot Melt Granulation: Influence of Process and Formulation Parameters

Open AccessConference Report Fluidized Hot Melt Granulation: Influence of Process and Formulation Parameters by I. MAŠIĆ *, A. STOJKOVIĆ, J. PAROJČIĆ and Z. ĐURIĆ Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Belgrade, Serbia * Author to whom correspondence should be addressed. Sci. Pharm. 2010, 78(3), 638; https://doi.org/10.3797/scipharm.cespt.8.PMS11 Received: 12 July 2010 / Accepted: 12 July 2010 / Published: 12 July 2010 Download PDF Citation Export BibTeX EndNote RIS Cite This Paper

Pharmaceutically Engineering Powders Using FHMG: The Effects of Process Parameters and Formulation Variables

Fluidized hot melt granulation (FHMG) is an innovative granulation process that has distinct advantages over techniques that are typically used in the pharmaceutical industry for powder agglomeration and mixing. The aim of this research was to investigate process and formulation parameters that affect FHMG, in a pharmaceutical context, using Lutrol ® F68 (copolymer of polyoxyethylene-polyoxypropylene) as a meltable binder with inert glass ballotini acting as a model pharmaceutical powder. Granulation process parameters investigated were: binder/bulk powder ratio, binder viscosity and granulation time. The experimental data obtained from FHMG were correlated with current granulation theory. De-fluidization occurred at >10% w/w Lutrol ® F68 binder concentration and the resultant granules were highly irregular in shape. Furthermore, the dominant mechanism of granule growth altered from layering to coalescence with increasing binder content. Moreover, a modified growth regime map successfully described experimental data.

Effect of Crystallization Behavior of Polyethylene Glycol 6000 on the Properties of Granules Prepared by Fluidized Hot-Melt Granulation (FHMG)

The objective of this study was to investigate the effect of the crystallization behavior of Macrogol 6000 (polyethylene glycol 6000; PEG 6000), used as a binder, during the solidification process on the properties of mononucleic granules prepared by the fluidized hot-melt granulation (FHMG) technique. Crystallization of PEG 6000 from molten liquid was investigated using differential scanning calorimetry (DSC) and hot stage microscopy. The results obtained from the measurement of isothermal crystallization demonstrated that crystallization of PEG 6000 was either slow or rapid. Analysis based on solid-state decomposition showed that slow crystallization was due to the two-dimensional growth of nuclei mechanism, while rapid crystallization was due to the three-dimensional growth of nuclei mechanism. Observation of the crystallization of PEG 6000 by hot stage microscopy supported the existence of two different crystallization mechanisms. Granules containing PEG 6000 that underwent rapid crystallization during FHMG showed a significantly higher fraction powder under 150 microm in diameter. This was caused by the loss of powder particles from the surface of mononucleic granules during the solidification process, because many cracks were observed after crystallization of PEG 6000 with a short isothermal crystallization time (ICT) due to the reduced of sticking of particles. The results of this study suggested that the crystallization behavior of the binder during the solidification process of FHMG can influence the properties of the resultant granules, such as particle size distribution, content uniformity or taste masking. It was also indicated that measuring the ICT using DSC was a useful method to classify PEG 6000.

Application of Fluidized Hot-Melt Granulation (FHMG) for the Preparation of Granules for Tableting; Properties of Granules and Tablets Prepared by FHMG

ABSTRACTThe objective of this study was to investigate the properties of granules and tablets prepared by a novel Fluidized Hot-Melt Granulation (FHMG) technique. Macrogol 6000 (polyethylene glycol 6000, PEG 6000), macrogol 20000 (polyethylene glycol 20000, PEG 20000), and glyceryl monostearate (GMS) were used as binders with different levels of viscosity and water solubility. The properties of both granules and tablets were compared with those obtained using the Standard Tablet Formulation (STF, lactose/corn starch/hydroxypropylcellulose/magnesium stearate: 66/30/3.5/0.5) for fluidized-bed granulation, which is widely used for wet granulation. To obtain suitable flowability as granules for tabletting, the content of the melting material should be approximately 10 w/w%. The rate of increase in the mean diameter of the granules during FHMG was affected by both the melting temperature and the viscosity of the melting material used in the granules. The compression properties of granules prepared by FHMG were also investigated, demonstrating that these granules had a high pressure transmittance. The hardness and the disintegration time of tablets obtained from granules prepared by FHMG were influenced by the properties of the melting material, such as its compaction behavior, solubility, and wettability. No significant differences of hardness were observed when compared to STF tablets. Tablets prepared from FHMG granules disintegrated within 15 min, whereas the STF tablets showed faster disintegration. It was also demonstrated that the hardness and disintegration time of tablets prepared from FHMG granules were not affected by the tablet porosity. Therefore, tablets with a constant quality may be obtainable under a wide range of compression forces. The results of this study suggested that FHMG is a useful method of preparing granules for tableting without using any solvents or water.