The aim of the work was to analyze the influence of process parameters of high shear granulation on the process yield and on the morphology of granules on the basis of dynamic image analysis. The amount of added granulation liquid had a significant effect on all monitored granulometric parameters and caused significant changes in the yield of the process. In regard of the shape, the most spherical granules with the smoothest surface were formed at a liquid to solid ratio of ≈1. The smallest granules were formed at an impeller speed of 700 rpm, but the granules formed at 500 rpm showed both the most desirable shape and the highest process yield. Variation in the shape factors relied not only on the process parameters, but also on the area equivalent diameter of the individual granules in the batch. A linear relationship was found between the amount of granulation liquid and the compressibility of the granules. Using response surface methodology, models for predicting the size of granules and process yield related to the amount of added liquid and the impeller speed were generated, on the basis of which the size of granules and yield can be determined with great accuracy.

• Klíčová slova
• dynamic image analysis, granules, high shear granulation, liquid to solid ratio,
• Publikační typ
• časopisecké články MeSH

In this study, the origins of granule content non-uniformity in the high-shear wet granulation of a model two-component pharmaceutical blend were investigated. Using acetaminophen as the active pharmaceutical ingredient (API) and microcrystalline cellulose as the excipient, the distribution of the API across the granule size classes was measured for a range of conditions that differed in the duration of the initial dry mixing stage, the overall composition of the blend and the wet massing time. The coarse granule fractions were found to be systematically sub-potent, while the fines were enriched in the API. The extent of content non-uniformity was found to be dependent on two factors - powder segregation during dry mixing and redistribution of the API between the granule size fractions during the wet massing phase. The latter was demonstrated in an experiment where the excipient was pre-granulated, the API was added later and wet massed. The content non-uniformity in this case was comparable to that obtained when both components were present in the granulator from the beginning. With increasing wet massing time, the extent of content non-uniformity decreased, indicating that longer wet massing times might be a solution for systems with a natural tendency for component segregation.

• Klíčová slova
• Content uniformity, Granulation, Powder mixing, Segregation, Wet massing,
• MeSH
• celulosa chemie   MeSH
• molekulová hmotnost MeSH
• paracetamol chemie   MeSH
• pomocné látky chemie   MeSH
• prášky, zásypy, pudry MeSH
• příprava léků * MeSH
• velikost částic MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• celulosa MeSH
• paracetamol MeSH
• pomocné látky MeSH
• prášky, zásypy, pudry MeSH

In this study, the torque profiles of heterogeneous granulation formulations with varying powder properties in terms of particle size, solubility, deformability, and wettability, were studied, and the feasibility of identifying the end-point of the granulation process for each formulation based on the torque profiles was evaluated. Dynamic median particle size (d50) and porosity were correlated to the torque measurements to understand the relationship between torque and granule properties, and to validate distinction between different granulation stages based on the torque profiles made in previous studies. Generally, the torque curves obtained from the different granulation runs in this experimental design could be categorized into two different types of torque profiles. The primary factor influencing the likelihood of producing each profile was the binder type used in the formulation. A lower viscosity, higher solubility binder resulted in a type 1 profile. Other contributing factors that affected the torque profiles include API type and impeller speed. Material properties such as the deformability and solubility of the blend formulation and the binder were identified as important factors affecting both granule growth and the type of torque profiles observed. By correlating dynamic granule properties with torque values, it was possible to determine the granulation end-point based on a pre-determined target median particle size (d50) range which corresponded to specific markers identified in the torque profiles. In type 1 torque profiles, the end-point markers corresponded to the plateau phase, whereas in type 2 torque profiles the markers were indicated by the inflection point where the slope gradient changes. Additionally, we proposed an alternative method of identification by using the first derivative of the torque values, which facilitates an easier identification of the system approaching the end-point. Overall, this study identified the effects of different variations in formulation parameters on torque profiles and granule properties and implemented an improved method of identification of granulation end-point that is not dependent on the different types of torque profiles observed.

• Klíčová slova
• End-point determination, Growth regimes, Over-granulation, Porosity, Torque, Wet granulation,
• Publikační typ
• časopisecké články MeSH

A fuzzy model has been developed for the optimization of high-shear wet granulation wetting on a plant scale depending on the characteristics of pharmaceutical active substance particles. The model optimized on the basis of experimental data involves a set of rules obtained from expert knowledge and full-scale process data. The skewness coefficient of particle size distribution and the tapped density of the granulated mixture were chosen as the model input variables. The output of the fuzzy ruled system is the optimal quantity of wetting liquid. In comparison to manufacturing practice, a very strong sensitivity of the optimal quantity of the added wetting liquid to the size and shape of the active substance particles has been identified by fuzzy modeling.

• MeSH
• farmaceutická chemie MeSH
• farmaceutická technologie metody   MeSH
• fuzzy logika * MeSH
• léčivé přípravky chemie   MeSH
• pomocné látky chemie   MeSH
• rozpustnost MeSH
• smáčivost MeSH
• velikost částic MeSH
• voda chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• léčivé přípravky MeSH
• pomocné látky MeSH
• voda MeSH

The effect of process scale-up from 4 to 400-L high-shear granulator on the release kinetics of the active ingredient from pharmaceutical granules has been investigated. The dissolution and disintegration rates of the granules were measured simultaneously by the combination of UV/vis spectroscopy and static light scattering. The granule batches were found to consist of sub-populations with qualitatively different dissolution behavior: "weaker" granules that disintegrated during dissolution, and "stronger" granules that retained their size and from which the active ingredient was gradually leached. The existence of these sub-populations was attributed to non-uniform distribution of normal and shear forces that prevail in granulators of different size. This hypothesis was confirmed by preparing granules at increasing values of the Froude number at the 4-L scale, and observing a transition from the break-up dissolution mode to the leaching dissolution mode with increasing granule densification. The simultaneous observation of solute concentration and particle size distribution during granules dissolution proved to be a useful tool for the understanding of dissolution mechanisms and for identifying non-uniformities of process conditions that can occur during scale-up.

• Klíčová slova
• High-shear granulation, Laser diffraction, Particle size distribution, Release curve, Scale-up,
• MeSH
• farmaceutická chemie * MeSH
• kinetika MeSH
• mikroskopie elektronová rastrovací MeSH
• rentgenová mikrotomografie MeSH
• rozpustnost * MeSH
• velikost částic MeSH
• Publikační typ
• časopisecké články MeSH

The aim of this systematic study was to analyze the granulometric and rheological behavior of tableting mixtures in relation to tabletability by single tablet and lab-scale batch compression with an eccentric tablet machine. Three mixtures containing 33, 50, and 66% of the cohesive drug paracetamol were prepared. The high compressibility of the powder mixtures caused problems with overcompaction or lamination in the single tablet compression method; due to jamming of the material during the filling of the die, the lab-scale batch compression was impossible. Using high shear granulation, the flow properties and tabletability were adjusted. A linear relationship between the span of granules and the specific energy measured by FT4 powder rheometer was detected. In parallel, a linear relationship between conditioned bulk density and the tensile strength of the tablets at lab-scale batch tableting was noted. The combination of dynamic image analysis and powder rheometry was useful for predicting the tabletability of pharmaceutical mixtures during the single tablet (design) compression and the lab-scale batch compression.

• Klíčová slova
• Dynamic image analysis, Heckel analysis, High shear granulation, Paracetamol, Powder rheology, Tabletability,
• MeSH
• paracetamol * MeSH
• pevnost v tahu MeSH
• prášky, zásypy, pudry MeSH
• příprava léků MeSH
• reologie MeSH
• tablety MeSH
• velikost částic MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• paracetamol * MeSH
• prášky, zásypy, pudry MeSH
• tablety MeSH

The aim of the present study was to investigate the suitability of insoluble Eudragit® water dispersions (NE, NM, RL, and RS) for direct high-shear granulation of very soluble levetiracetam in order to decrease its burst effect from HPMC K100M matrices. The process characteristics, ss-NMR analysis, in vitro dissolution behavior, drug release mechanism and kinetics, texture profile analysis of the gel layer, and PCA analysis were explored. An application of water dispersions directly on levetiracetam was feasible only in a multistep process. All prepared formulations exhibited a 12-hour sustained release profile characterized by a reduced burst effect in a concentration-dependent manner. No effect on swelling extent of HPMC K100M was observed in the presence of Eudragit®. Contrary, higher rigidity of formed gel layer was observed using combination of HPMC and Eudragit®. Not only the type and concentration of Eudragit®, but also the presence of the surfactant in water dispersions played a key role in the dissolution characteristics. The dissolution profile close to zero-order kinetic was achieved from the sample containing levetiracetam directly granulated by the water dispersion of Eudragit® NE (5% of solid polymer per tablet) with a relatively high amount of surfactant nonoxynol 100 (1.5%). The initial burst release of drug was reduced to 8.04% in 30 min (a 64.2% decrease) while the total amount of the released drug was retained (97.02%).

• MeSH
• deriváty hypromelózy * chemie   farmakokinetika   farmakologie   MeSH
• kyseliny polymethakrylové * chemie   farmakokinetika   farmakologie   MeSH
• laktosa analogy a deriváty   chemie   farmakokinetika   farmakologie   MeSH
• léky s prodlouženým účinkem farmakokinetika   farmakologie   MeSH
• methylcelulosa analogy a deriváty   chemie   farmakokinetika   farmakologie   MeSH
• nonoxynol * chemie   farmakokinetika   farmakologie   MeSH
• uvolňování léčiv MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• deriváty hypromelózy * MeSH
• hydroxypropylmethylcellulose-lactose matrix MeSH Prohlížeč
• kyseliny polymethakrylové * MeSH
• laktosa MeSH
• léky s prodlouženým účinkem MeSH
• methylcelulosa MeSH
• methylmethacrylate-methacrylic acid copolymer MeSH Prohlížeč
• nonoxynol * MeSH

Hypromellose matrices exhibit extended burst effect immediately after contact with aqueous medium, especially when a water-soluble drug is incorporated. The objective of this study was to reduce burst effect and maintain complete dissolution of a very soluble levetiracetam over 12 h period from hypromellose K4M matrices to obtain zero-order kinetics. Desired changes were achieved by applying water dispersions of insoluble Eudragits® (NE, NM, RL, RS) as a granulation liquid to the drug/microcrystalline cellulose mixture during high-shear granulation (non-thermal treated set) and consequently by thermally treating granules or final tablets (TT), respectively. Applying Eudragit® water dispersions to the drug/microcrystalline cellulose mixture was recognized as an effective method of significantly reducing the burst release (25.4-33.7%) of levetiracetam in comparison with a reference sample without Eudragit®. Multivariate data analysis showed that the addition of Eudragit® reduced burst effect, increased fitting with zero-order kinetics, and supported matrix erosion as the supplementary mechanism to predominant diffusion. Moreover, resulting PCA sub-model revealed the addition of Eudragit® RL and thermal treatment of tablets to be the most suitable method of all. For a 12 h dissolution profile, characterized by low burst effect and drug release close to 100% at the 12th hour, sample RL_TT was the most suitable.

• Klíčová slova
• Eudragit® NE, HPMC, NM, Prolonged drug release, RL, RS, burst effect, levetiracetam, matrix tablets, multivariate data analysis, thermal treatment,
• MeSH
• antikonvulziva aplikace a dávkování   chemie   MeSH
• celulosa chemie   MeSH
• deriváty hypromelózy chemie   MeSH
• kyseliny polymethakrylové chemie   MeSH
• léky s prodlouženým účinkem chemie   MeSH
• levetiracetam MeSH
• multivariační analýza MeSH
• piracetam aplikace a dávkování   analogy a deriváty   chemie   MeSH
• příprava léků metody   MeSH
• rozpustnost MeSH
• tablety MeSH
• teplota MeSH
• uvolňování léčiv MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antikonvulziva MeSH
• celulosa MeSH
• deriváty hypromelózy MeSH
• kyseliny polymethakrylové MeSH
• léky s prodlouženým účinkem MeSH
• levetiracetam MeSH
• methylmethacrylate-methacrylic acid copolymer MeSH Prohlížeč
• microcrystalline cellulose MeSH Prohlížeč
• piracetam MeSH
• tablety MeSH

Burst drug release is often considered a negative phenomenon resulting in unexpected toxicity or tissue irritation. Optimal release of a highly soluble active pharmaceutical ingredient (API) from hypromellose (HPMC) matrices is technologically impossible; therefore, a combination of polymers is required for burst effect reduction. Promising variant could be seen in combination of HPMC and insoluble Eudragits® as water dispersions. These can be applied only on API/insoluble filler mixture as over-wetting prevention. The main hurdle is a limited water absorption capacity (WAC) of filler. Therefore, the object of this study was to investigate the dissolution behavior of levetiracetam from HPMC/Eudragit®NE matrices using magnesium aluminometasilicate (Neusilin® US2) as filler with excellent WAC. Part of this study was also to assess influence of thermal treatment on quality parameters of matrices. The use of Neusilin® allowed the application of Eudragit® dispersion to API/Neusilin® mixture in one step during high-shear wet granulation. HPMC was added extragranularly. Obtained matrices were investigated for qualitative characteristics, NMR solid-state spectroscopy (ssNMR), gel layer dynamic parameters, SEM, and principal component analysis (PCA). Decrease in burst effect (max. of 33.6%) and dissolution rate, increase in fitting to zero-order kinetics, and paradoxical reduction in gel layer thickness were observed with rising Eudragit® NE concentration. The explanation was done by ssNMR, which clearly showed a significant reduction of the API particle size (150-500 nm) in granules as effect of surfactant present in dispersion in dependence on Eudragit®NE amount. This change in API particle size resulted in a significantly larger interface between these two entities. Based on ANOVA and PCA, thermal treatment was not revealed as a useful procedure for this system.

• Klíčová slova
• Burst effect, Eudragit® NE30D, HPMC, Levetiracetam, Neusilin® US2, gel layer, matrix tablets, multivariate data analysis, thermal treatment,
• MeSH
• aplikace orální MeSH
• gely MeSH
• kyseliny polymethakrylové aplikace a dávkování   chemie   metabolismus   MeSH
• léky s prodlouženým účinkem aplikace a dávkování   chemie   metabolismus   MeSH
• magnetická rezonanční spektroskopie metody   MeSH
• pomocné látky chemie   MeSH
• rozpustnost MeSH
• silikáty aplikace a dávkování   chemie   metabolismus   MeSH
• sloučeniny hliníku aplikace a dávkování   chemie   metabolismus   MeSH
• sloučeniny hořčíku aplikace a dávkování   chemie   metabolismus   MeSH
• uvolňování léčiv MeSH
• velikost částic MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aluminum magnesium silicate MeSH Prohlížeč
• gely MeSH
• kyseliny polymethakrylové MeSH
• léky s prodlouženým účinkem MeSH
• methylmethacrylate-methacrylic acid copolymer MeSH Prohlížeč
• pomocné látky MeSH
• silikáty MeSH
• sloučeniny hliníku MeSH
• sloučeniny hořčíku MeSH