Rok Dreu

The compressibility and compactibility of different types of lactose

Objective: The purpose of this study was to investigate and quantify flow properties, compressibility, and compactibility of various pharmaceutical lactose powders found on the market today (DCL-11, DCL-21, M‐200, Flowlac-100, and Tablettose 70, 80, and 100). Methods: Flow properties were estimated by measuring flow time, angle of repose, and the Hausner ratio. Particle rearrangement was studied using Kawakitas linear model. Compressibility was studied using two ‘out-of-die’ methods: (i) the Heckel model and (ii) a modified Walker model. Compactibility was quantified using two methods: (i) the tensile strength profile (Cp) and (ii) the compactibility factor (Pr). Statistical approach was used to analyze the results. Results: Flow properties of all materials were passable or better, except for M-200, which has very poor flowability. Compressibility results demonstrated that the most compressible lactose is spray-dried grade of lactose (Flowlac-100) and the least compressible is milled lactose (M-200). Compactibility studies showed that β‐lactose (DCL-21) forms tablets with superior tensile strength in comparison with α-lactose. Conclusion: Results of the compressibility study showed that the discriminative power of modified Walker model is greater in comparison with Heckel model. Compactibility methods yield similar and comparable results.

Mini-tablets: a contemporary system for oral drug delivery in targeted patient groups

Introduction: Mini-tablets represent a new trend in solid dosage form design, with the main goal of overcoming some therapeutic obstacles such as impaired swallowing and polypharmacy therapy, and also offering some therapeutic benefits such as dose flexibility and combined release patterns. Mini-tablets are a promising patient-friendly drug delivery system. Areas covered: Mini-tablets are tablets with a diameter ≤ 3 mm produced on conventional tablet presses equipped with multiple tooling. Mini-tablet production is similar to the production of standard tablets but requires excellent powder flow due to the small dies, exact control of process parameters and special caution during tablet press assembly in order to avoid tool damage. Mini-tablets (coated or uncoated and single- or multiple-unit systems) are mainly developed as patient-friendly systems for pediatric and geriatric patients and also for personalized medicine because they offer improved swallowing and flexible dosing, combining various release kinetics, doses and active compounds in only one system. Mini-tablets may also be successfully used as multiple-unit modified release systems (extended release, delayed-colon release, pulsatile and bi-modal release and gastroretentive systems) providing improved drug bioavailability compared with single-unit systems. Expert opinion: Mini-tablets used as single- or multiple-unit oral dosage forms have enormous potential as a patient-friendly drug delivery system for targeted populations, providing improved swallowing, flexible dosing and a combination of different release patterns and/or different active compounds (decreasing dosing frequency and/or polypharmacy therapy problems). In terms of complete expression of the benefits of mini-tablets over other oral dosage forms on the market, further investigation in formulation possibilities and development of suitable dosing devices is of essential importance.

Influence of dry granulation on compactibility and capping tendency of macrolide antibiotic formulation.

The effect of dry granulation (roller compaction and slugging) on compactibility and tablet capping tendency in a formulation with macrolide antibiotic and microcrystalline cellulose (MCC) was investigated. Direct tableting of this formulation revealed a pronounced capping tendency. Both dry granulated systems exhibit better compactibility and significant reductions in capping tendency compared to direct tableting. The capping tendency was also reduced through the use of precompression during direct tableting. The main volume reduction mechanism for macrolide antibiotic is fragmentation; this was confirmed by Heckel analysis, the lubricant sensitivity test, and SEM images. The yield pressure (Py) of the direct tableting system is lower than the Py of dry granulated systems, which indicates the lower plasticity of dry granulated systems. These findings do not explain the lower capping tendency of dry granulated systems compared to direct tableting. The main differentiating bonding mechanism is attributed to long distance intermolecular bonds due to the intense amorphization of macrolide antibiotic that occurs during dry granulation. Amorphization leads to a significant increase in surface free energy and consequently stronger long distance bonding between particles, which can withstand elastic relaxation and therefore reduce the capping problem. Solid bridges probably do not make a notable contribution to the mechanical strength of tablets, due to the brittle nature of the particles and the complex molecular structure of macrolide antibiotic.

Deformation properties of pharmaceutical excipients determined using an in-die and out-die method

This study investigated deformation mechanisms of some commonly used pharmaceutical fillers, such as microcrystalline cellulose, lactose, dicalcium phosphate, isomalt and cornstarch, using a combination of the in-die and out-die method with the Heckel and Walker models. The tableting mixtures contained of 98.5% (w/w) filler, the rest consisted of dry binder and an antiadhesive agent. Our results showed that plasticity and elasticity may be considered independent deformation properties as highly plastic materials (microcrystalline cellulose, cornstarch) also exhibited high elasticity. Particular emphasis was placed on explaining the differences observed between the in-die and out-die method-comparison revealed that the differences are a consequence of the materials elastic properties. Larger error of in-die results can be expected for more elastic materials, and thus in-die Heckel should be used with some considerations. In contrast, the Walker model was found to be more robust and smaller differences were observed between the two methods. We consider the most correct results to have been obtained by the out-die approach, which excludes the elastic properties of the material evaluated. An excellent correlation between elastic determination at the single-particle level and multiple-particle scale was demonstrated, suggesting a great potential of nanoscale determination of a materials mechanical properties for better elucidation of deformation mechanisms.

Influence of inverse gas chromatography measurement conditions on surface energy parameters of lactose monohydrate.

Surface energy of any powder determined by inverse gas chromatography (IGC) should be independent of the measurement conditions or type of column used. In this study stainless steel and glass columns were filled with lactose powder. Dispersive and polar components of surface free energy were determined at different flow rates of carrier gas using lactose alone or diluted with calcinated diatomite (Chromosorb W). It was found that measurement conditions did not influence the value of the dispersive parameter of surface energy. On the contrary, K(a) and K(d) values were found to be dependent on dilution of lactose with Chromosorb W. The influence of other parameters on the results was found to be much smaller.

Comparative study of the uniformity of coating thickness of pellets coated with a conventional Wurster chamber and a swirl generator-equipped Wurster chamber.

This study evaluated the performance of two bottom-spray coaters and the effect of pellet-size variability on coating uniformity. A conventional Wurster chamber was used for the first group of trials, and a Wurster chamber with a novel swirl-flow generator design was used for the second. The results confirmed that when using a conventional Wurster coating chamber, pellets with a smaller diameter receive significantly less coating material compared to those with larger diameters. The swirl generator-equipped Wurster chamber achieved close to uniform coating thickness regardless of pellet size. The ratio (MS) of the mass of dye deposited in the coating layer to pellet surface area indicates that coating was much more evenly distributed using the swirl-flow coater. Coating thickness was also analyzed using SEM micrographs and the results were in close agreement with the MS factor values. Inter-particle coating mass variation was also lower in case of swirl-flow coater. The results of this study show that a swirl-flow coater is suitable for coating particles of variable size. They also showed an improvement in coating process yield when using the swirl-flow coater.

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.

Fluid-bed coater modifications and study of their influence on the coating process of pellets

Objective: In this study, different modifications of bottom spray fluid-bed coater with draft tube inserted were characterized and evaluated. Materials and methods: After coating the neutral pellets with polymeric solution comprising coloring agent pellet batches were characterized for coating variation, yield and degree of agglomeration. Results: Funnel-shaped distribution plate was found to improve process yield and decrease the degree of agglomeration at selected values of process parameters, whereas coating uniformity was worse in all cases when compared to conventional Wurster chamber. Results of the coating chamber with the swirl airflow generator indicate more uniform deposition of the coating material and in some cases an improved process yield and decreased formation of agglomerates when compared to conventional Wurster chamber. In series of experiments using Wurster chamber, having tangentially oriented air intake slots, which enabled introduction of air above the distribution plate, coating layer was more uniformly deposited on the pellet cores and formation of agglomerates was lower compared to the results obtained in a conventional Wurster coating chamber. Conclusion: Modifications of Wurster coating process by introducing swirling air motion within the draft tube or by introduction of air above the distribution plate have at selected values of process parameters resulted in reduced per-particle coating variation, degree of agglomeration and improved process yield.

Characterization of agglomerated carvedilol by hot-melt processes in a fluid bed and high shear granulator

The purpose of this study was to prepare and characterize granulated carvedilol by melt-in and spray-on melt granulation in a fluid bed and a high shear granulator. Granulates having comparable particle size distribution and good flow properties were obtained with proper adjustment of process parameters for each binder (poloxamer 188, polyethylene glycol 4000, and gliceryl monosterate), procedure (spray-on and melt-in) and equipment (fluid bed and high shear granulator). In-line probes for particle size measurements proved to be a useful tool for determining the end point of melt granulation. The product temperature during melt granulation was found to be the critical process parameter for achieving appropriate granulate particle size distribution. The results showed that melt granulation using hydrophilic binders is an effective method to improve the dissolution rate of carvedilol. The method of binder addition to the powders (melt-in or spray-on procedure) was found to strongly influence the dissolution rate of carvedilol. The highest dissolution rates were obtained when the spray-on procedure is used, independently from the type of granulator used. The results also suggest that the most probable explanation for the increase in the dissolution rate of granulated carvedilol is improvement of the wettability through intimate contact between hydrophilic binder and hydrophobic drug.

Nanosized particles of orlistat with enhanced in vitro dissolution rate and lipase inhibition

Orlistat is locally acting inhibitor of gastrointestinal lipases which has been developed for the treatment of obesity. The present study was designed with the intent to formulate orlistat in a different way compared to the current practice and investigate its inhibition of gastrointestinal lipases. Orlistat is considered as a technologically problematic and unmanageable substance because of waxy nature, low melting point and low chemical stability. The manuscript presents the critical issues regarding engineering of its nanosuspension with controlled particle size by melt emulsification and high pressure homogenization. In order to formulate dry product, lactose was dissolved in nanosuspension as filler and spray drying has been performed for obtaining the final powder product. Laser diffraction, scanning electron microscopy and atomic force microscopy have been used for orlistat nanosuspension characterization, dissolution studies and lipase inhibition studies were performed to characterize the in vitro efficacy of formulated orlistat. The advantage of selected technological procedures is nanosized orlistat with elevated in vitro dissolution rate in comparison to raw drug, physical mixture and marketed product. Furthermore, nanosuspension demonstrated significantly higher in vitro lipase inhibition in comparison to references. To conclude, the results show new technological solution and remarkable increase of pharmacological effect which could potentially lead to decreasing the dose and consequently dose dependent side effects.