Granule size distributions after twin-screw granulation - Do not forget the feeding systems.

The aim of this study was to investigate the influence of qualitatively different powder feeder performances on resulting granule size distributions after twin-screw granulation of a highly drug loaded, hydrophobic mixture and a mannitol powder. It was shown that powder feeder related problems usually cannot be identified by trusting in the values given by the feeder. Therefore, a newly developed model for the evaluation of the performance of powder feeders was introduced and it was tried to connect this model to residence time distributions in twin-screw granulation processes. The influence of feeder performances on resulting granule size distributions varied, depending on the applied screw configuration and the used powder. Regarding the hydrophobic and highly drug loaded formulation, which was granulated at an L/S-ratio of 0.5, a pure conveying screw and a medium kneading configuration, consisting of 60° kneading blocks were negatively influenced by poor feeder settings. For optimal settings more narrow distributions could be obtained. For an extensive kneading configuration good and poor settings resulted in mono-modal granule size distributions but were differing in the overall size. Mannitol, a model substance for a liquid sensitive formulation was granulated at an L/S-ratio of 0.075. It was even more important to maintain optimal feeding as mannitol was highly affected by poor feeder performances. Even an extensive kneading configuration could not level the errors in powder feeder performance, resulting in qualitatively different granule size distributions. The results of this study demonstrate the importance of detailed knowledge about applied feeding systems to gain optimal performance in twin-screw granulation.

Simplified formulations with high drug loads for continuous twin-screw granulation.

As different batches of the same excipients will be intermixed during continuous processes, the traceability of batches is complicated. Simplified formulations may help to reduce problems related to batch intermixing and traceability. Twin-screw granulation with subsequent tableting was used to produce granules and tablets, containing drug, disintegrant and binder (binary and ternary mixtures), only. Drug loads up to 90% were achieved and five different disintegrants were screened for keeping their disintegration suitability after wetting. Granule size distributions were consistently mono-modal and narrow. Granule strength reached higher values, using ternary mixtures. Tablets containing croscarmellose-Na as disintegrant displayed tensile strengths up to 3.1MPa and disintegration times from 400 to 466s, resulting in the most robust disintegrant. Dissolution was overall complete and above 96% within 30 min. Na-starch glycolate offers tensile strengths up to 2.8MPa at disintegration times from 25s to 1031s, providing the broadest application window, as it corresponds in some parts to different definitions of orodispersible tablets. Tablets containing micronized crospovidone are not suitable for immediate release, but showed possibilities to produce highly drug loaded, prolonged release tablets. Tablets and granules from simplified formulations offer great opportunities to improve continuous processes, present performances comparable to more complicated formulations and are able to correspond to requirements of the authorities.

Effect of carbomer concentration and degree of neutralization on the mucoadhesive properties of polymer films.

Mucoadhesive drug delivery systems may enable a prolonged and localized drug release at various sites of the gastrointestinal tract. In the present study, the mucoadhesive properties of flexible polymeric films based on PVP or PVA as film-forming polymers were assessed by measuring the detachment force from excised porcine duodenal mucosa using a tensile strength tester. The mucoadhesive films were comprised of an impermeable backing layer of cellulose acetate butyrate. Carbopol 934P, Carbopol 974NF, and Noveon AA1 were incorporated as mucoadhesive excipients in concentrations of 0-22 wt% relative to the dry mass of the mucoadhesive layer and with various degrees of neutralization corresponding to pH 4.8, 5.5, 6.8, or 7.5. Films based on PVP were generally more mucoadhesive than corresponding formulations based on PVA. Maximum adhesion of PVP-films was observed at pH 5.5 and 6.8 depending on the type of the mucoadhesive polymer and its concentration. An optimal mucoadhesive polymer concentration range was found to be between 2 and 10 wt%. Higher polymer concentrations did not further enhance the mucoadhesive properties, and in some cases even decreased mucoadhesion. Film formulations based on PVA demonstrated no satisfactory mucoadhesive strength.

Development of disintegrating multiple-unit tablets on a high-speed rotary tablet press.

Enteric coated bisacodyl pellets were compressed into divisible disintegrating tablets on a high speed rotary tablet press and investigated for pellet damages. The degree of pellet damages was examined via the bisacodyl dissolution during the acid treatment of' the drug release test for enteric coated articles according to USP 23. The damages depended on the type of filler-binder used and settings of the tablet press. Avicel PH 101 proved to be the most suitable filler-binder, effecting homogeneous distribution of the pellets within the tablets, as could be shown by image analysis of coloured pellets. The speed of the tablet press had noo influence on the pellet damages using Avicel PH 101 as a filler-binder, however, tablets containing 70% (w/w) of coated pellets did not fulfil the requirements of USP 23, despite optimum elasticity and coating thickness of a new Eudragit FS 30 D coating. Reducing the proportion of pellets to 60% per tablet, less than 10% of bisacodyl were released within 2 h during acid treatment thus fulfilling the requirements of the USP 23.

Development of computerised procedures for the characterisation of the tableting properties with eccentric machines: extended Heckel analysis.

Heckel plots are a suitable and valuable method for analysis of powder compaction with very small amounts of powder. The determination is based upon a non-linear transformation of compression data and thus the signal errors that might be introduced into the analysis might be enlarged and become critical. The method of determination of true density affects the results dramatically as does the accuracy of the powder height determination. The porosity should be corrected for compression of the solid fraction. The accuracy of the powder height detection is the most demanding parameter. The statements are proven by simulations based on real data and analytic calculation. According to these highly corrected Heckel plots, the shape of the plots during the compression phase gives the information about fragmentation and plasticity and additionally about the time dependency of the compression behaviour within one compression on an eccentric press.

A novel method for the detection of sticking of tablets.

The purpose of this work was to develop an instrumented upper punch to measure the adhesion force which occurs when the punch detaches itself from the upper surface of the tablet after compression. A specially designed adhesion force sensor instrumented with semiconductor strain gauges was inserted into an upper punch with a 25-mm punch face diameter suitable for a Korsch EK II eccentric press. Sorbitol, microencapsulated acetylsalicylic acid (ASA), and a formulation of a new active ingredient resulted in characteristic pull-off signals, providing a quantitative measure of the adhesion force. With "sticking-free" substances such as microcrystalline cellulose, tension signals could not be obtained; only Starch 1500 showed small adhesion force signals that indicated a sticking tendency. The compression force had a specific influence on the extent of the adhesion force; increasing the compression force caused an increase (sorbitol) or a decrease (ASA) of the adhesion force signals due to the plastic and elastic behavior of the substances. Depending on running time, ASA showed an increase in the adhesion force, reaching a plateau after 150 tablets. The addition of lubricants such as magnesium stearate resulted in smaller adhesion forces. The instrumented upper punch is a new helpful tool for the quantification of sticking and a valuable instrument in the development of formulations.

The influence of engravings on the sticking of tablets. Investigations with an instrumented upper punch.

The purpose of this study was to investigate the influence of engravings on the sticking of tablets. Therefore, an instrumented upper punch capable of measuring the pull-off force, which occurs when the punch detaches itself from the upper surface of a tablet, was equipped with small cones of different angles between the punch face and the cones' lateral face. The cones could be screwed into a threaded hole at the center of the punch face. The adhesion forces of two formulations known to stick to engravings during production increased with a greater steepness of the cones' lateral face. With microencapsulated acetylsalicylic acid, no quantitative differences could be found between the adhesion forces obtained with plain and modified punch faces, indicating that the sticking behavior of the substance was not affected by shear forces. Starch 1500 showed higher adhesion force signals in comparison to those obtained with a plain punch face. Microcrystalline cellulose, which gave no adhesion force signals with a plain punch face and did not stick to the cones, showed distinct pull-off signals. The instrumented upper punch equipped with shear cones is a valuable instrument for detecting the adhesion caused by engravings and is therefore a helpful tool for tablet formulation development and the design optimization of tablet identification.

Investigation of the pellet-distribution in single tablets via image analysis.

The influence of five different microcrystalline cellulose filler-binders on the pellet-distribution in tablets was investigated under production-scale conditions. Coloured coated pellets were tableted on an instrumented high speed rotary tablet press at four machine speed levels. The pellet-distribution on the upper and the lower tablet surfaces was detected via image analysis and correlated with the disintegration time and the crushing strength of the tablets. Filler-binders with a large surface area and a fibrous texture, like Avicel PH 101, enable the production of disintegrating tablets with an approximately homogeneous pellet-distribution within a large range of machine speeds, while pellet-containing tablets prepared with coarse microcrystalline cellulose granules showed an inhomogeneous pellet-distribution, depending on machine speed.

Development of computerised procedures for the characterization of the tableting properties with eccentric machines. High precision displacement instrumentation for eccentric tablet machines.

The paper deals with the instrumentation of displacement on an eccentric machine. Two instrumentation variants are evaluated. A displacement instrumentation consisting of two transducers attached to the frame was corrected for a slight non-linear calibration curve and corrected for machine deformation. A powder height signal was calculated from both signals. Upon dynamic punch to punch compression the powder height signal showed an oscillation of +/- 17 microns in amplitude due to tilting of the upper punch holder. A newly developed direct powder height instrumentation consisting of a set of special punches and a special die was also corrected for nonlinearities and punch deformation. The signal was free from any tilting effects and its accuracy is in the order of magnitude of the surface roughness of the punches. The machine deformation is discussed in detail. The instrumentation of the frame of the eccentric press in terms of force is possible but less sensitive by a factor of 5.4 than the use of the force sensors. The total machine deformation reaches nearly 0.5 mm under maximum load which is more than is often expected. The deformation was found to be non-linear for about 2% of the total deformation, the remaining 98% are linear deformation.

Force-time curves of a rotary tablet press. Interpretation of the compressibility of a modified starch containing various amounts of moisture.

On a rotary tablet press, the force-time curves are segmented into three phases: the compression phase, the dwell phase during which both stress and strain are variable for plastically deforming materials and the decompression phase. The following seven parameters were investigated: the compression area (A1) and the compression slope (Slc) describing the initial phase, the area ratio (AR) and the peak offset time (t(off)) characterizing the dwell time, the decompression area (A4) and the decompression slope (Sld) describing the terminal phase and the total area under the force-time curve (Atot). AR, t(off), Slc and A1 (the last with limitations) are used for phase-specific allocation of the occurrence of plastic flow, which is found to be a function of compression force and moisture content. Tablet strength, tablet porosity and in-die bulk porosity provide additional information for comprehensive interpretation. The values of A4 for the four starch batches are not significantly different. Sld provides somewhat better information about the elastic compact recovery. In general, however, the short decompression phase seems to be inappropriate for characterization by force-time curve parameters, because it is difficult to separate machine recovery from that of the tablet. Porosity above the porosity limit of the material was found to be a prerequisite for plastic flow within the compact. When the porosity limit is reached, further densification remains elastic and leads to a reduced compact strength during expansion. The area ratio, as a robust in-process control parameter for plastically flowing formulations, is suggested as a means of preventing this effect.

Use of molecular techniques to evaluate the survival of a microorganism injected into an aquifer.

A PCR primer set and an internal probe that are specific for Pseudomonas sp. strain B13, a 3-chlorobenzoate-metabolizing strain, were developed. Using this primer set and probe, we were able to detect Pseudomonas sp. strain B13 DNA sequences in DNA extracted from aquifer samples 14.5 months after Pseudomonas sp. strain B13 had been injected into a sand and gravel aquifer. This primer set and probe were also used to analyze isolates from 3-chlorobenzoate enrichments of the aquifer samples by Southern blot analysis. Hybridization of Southern blots with the Pseudomonas sp. strain B13-specific probe and a catabolic probe in conjunction with restriction fragment length polymorphism (RFLP) analysis of ribosome genes was used to determine that viable Pseudomonas sp. strain B13 persisted in this environment. We isolated a new 3-chlorobenzoate-degrading strain from one of these enrichment cultures. The B13-specific probe does not hybridize to DNA from this isolate. The new strain could be the result of gene exchange between Pseudomonas sp. strain B13 and an indigenous bacterium. This speculation is based on an RFLP pattern of ribosome genes that differs from that of Pseudomonas sp. strain B13, the fact that identically sized restriction fragments hybridized to the catabolic gene probe, and the absence of any enrichable 3-chlorobenzoate-degrading strains in the aquifer prior to inoculation.

Degradation of trichloroethylene by Pseudomonas cepacia G4 and the constitutive mutant strain G4 5223 PR1 in aquifer microcosms.

Pseudomonas cepacia G4 degrades trichloroethylene (TCE) via a degradation pathway for aromatic compounds which is induced by substrates such as phenol and tryptophan. P. cepacia G4 5223 PR1 (PR1) is a Tn5 insertion mutant which constitutively expresses the toluene ortho-monooxygenase responsible for TCE degradation. In groundwater microcosms, phenol-induced strain G4 and noninduced strain PR1 degraded TCE (20 and 50 microM) to nondetectable levels (< 0.1 microM) within 24 h at densities of 10(8) cells per ml; at lower densities, degradation of TCE was not observed after 48 h. In aquifer sediment microcosms, TCE was reduced from 60 to < 0.1 microM within 24 h at 5 x 10(8) PR1 organisms per g (wet weight) of sediment and from 60 to 26 microM over a period of 10 weeks at 5 x 10(7) PR1 organisms per g. Viable G4 and PR1 cells decreased from approximately 10(7) to 10(4) per g over the 10-week period.

Kinetics of phenol biodegradation by an immobilized methanogenic consortium.

A phenol-degrading methanogenic enrichment was successfully immobilized in agar as shown by the stoichiometric conversion of phenol to CH(4) and CO(2). The enrichment contained members of three physiological groups necessary for the syntrophic mineralization of phenol: a phenol-oxidizing bacterium, a Methanothrix-like bacterium, and an H(2)-utilizing methanogen. The immobilization technique resulted in the cells being embedded in a long, thin agar strand (1 mm in diameter by 2 to 50 cm in length) that resembled spaghetti. Immobilization had three effects as shown by a comparative kinetic analysis of phenol degradation by free versus immobilized cells. (i) The maximum rate of degradation was reduced from 14.8 to 10.0 mug of phenol per h; (ii) the apparent K(m) for the overall reaction was reduced from 90 to 46 mug of phenol per ml, probably because of the retention of acetate, H(2) and CO(2) in the proximity of immobilized methanogens; and (iii) the cells were protected from substrate inhibition caused by high concentrations of phenol, which increased the apparent K(i) value from 900 to 1,725 mug of phenol per ml. Estimates for the kinetic parameters K(m), K(i), and V(max) were used in a modified substrate inhibition model that simulated rates of phenol degradation for given phenol concentrations. The simulated rates were in close agreement with experimentally derived rates for both stimulatory and inhibitory concentrations of phenol.