Continuous direct compression as manufacturing platform for sustained release tablets

This study presents a framework for process and product development on a continuous direct compression manufacturing platform. A challenging sustained release formulation with high content of a poorly flowing low density drug was selected. Two HPMC grades were evaluated as matrix former: standard Methocel CR and directly compressible Methocel DC2. The feeding behavior of each formulation component was investigated by deriving feed factor profiles. The maximum feed factor was used to estimate the drive command and depended strongly upon the density of the material. Furthermore, the shape of the feed factor profile allowed definition of a customized refill regime for each material. Inline NIRs was used to estimate the residence time distribution (RTD) in the mixer and monitor blend uniformity. Tablet content and weight variability were determined as additional measures of mixing performance. For Methocel CR, the best axial mixing (i.e. feeder fluctuation dampening) was achieved when an impeller with high number of radial mixing blades operated at low speed. However, the variability in tablet weight and content uniformity deteriorated under this condition. One can therefore conclude that balancing axial mixing with tablet quality is critical for Methocel CR. However, reformulating with the direct compressible Methocel DC2 as matrix former improved tablet quality vastly. Furthermore, both process and product were significantly more robust to changes in process and design variables. This observation underpins the importance of flowability during continuous blending and die-filling. At the compaction stage, blends with Methocel CR showed better tabletability driven by a higher compressibility as the smaller CR particles have a higher bonding area. However, tablets of similar strength were achieved using Methocel DC2 by targeting equal porosity. Compaction pressure impacted tablet properties and dissolution. Hence controlling thickness during continuous manufacturing of sustained release tablets was crucial to ensure reproducible dissolution. (C) 2017 Elsevier B.V. All rights reserved

Impact of blend properties on die filling during tableting

Based on characterization of a wide range of fillers and APIs, thirty divergent blends were composed and subsequently compressed on a rotary tablet press, varying paddle speed and turret speed. The tablet weight variability was determined of 20 grab samples consisting of each 20 tablets. Additionally, the bulk residence time, ejection force, pre-compression displacement, main compression force, die fill fraction and feed frame fill fraction were determined during each run. Multivariate data analysis was applied to investigate the relation between the process parameters, blend characteristics, product and process responses. Blends with metoprolol tartrate as API showed high ejection forces. This behavior could be linked to the high wall friction value of metoprolol tartrate. The main responses related to the die filling could be predicted via a PLS model based on blend characteristics. Tablet weight variability was highly correlated with the variability on pre-compression displacement and main compression force. A good predictive model for tablet weight variability was obtained taking the porosity, wall friction angle, flowability, density, compressibility and permeability into account. Additionally, turret speed and paddle speed were included in the calibration of the model. The applied approach can save resources (material, time) during early drug product development

Effects of unilateral and bilateral squatting on rotational speed in male and female collegiate golfers

Resistance training in combination with plyometrics and medicine ball routines has been shown to improve rotational speed and power. One area that has not been observed has been the difference between bilateral squatting and unilateral squatting on rotational speed. The purpose of the study was to observe the effects of unilateral and bilateral squatting on club head speed in collegiate golfers. Eight male and nine female collegiate golfers were randomly assigned to a unilateral squat group which was the experimental and a bilateral squat group which was the control group and participated in twelve training sessions over the course of four weeks. Club head speed measurements were taken prior to the first training session and after the twelfth training session on a Trackman 4 indoor unit. After the intervention, there were no statistically significant improvements in either group and no statistically significant differences between the unilateral group (pre-training = 100.8 mph ± 12.2 mph, post-training = 100.9 mph ± 12.5 mph) and the control group (pre-training = 102.8 mph ± 11.7 mph, post-training = 103.3 mph ± 12.3 mph). Short duration squat training does not appear to positively impact club head speed in collegiate golfers

Selective pathogenicity of murine rheumatoid factors of the cryoprecipitable IgG3 subclass

To analyze the involvement of rheumatoid factors (RF) in the generation of cryoglobulins and the development of related tissue injuries, we have established a panel of anti-IgG2a RF mAbs derived from MRL/MpJ-lpr/lpr (MRL-lpr), C3H/HeJ-lpr/lpr, and 129/Sv mice. After injection of hybridoma cells to normal mice, all four IgG3 RF mAbs induced cryoglobullnemia, and various degrees of glomerulonephritis and skin leukocytoclastic vasculitis. In contrast, none of the RF mAbs of the other isotypes generated cryoglobulins or tissue lesions. Since the same observation was obtained with another panel of five clonally related anti-IgG2a RF mAbs of MRL-lpr origin with almost Identical heavy and light chain variable (V) regions but five different Isotypes, it seems unlikely that the absence of pathogenicity of non-IgG3 RF mAbs was due to differences in fine specificity or V framework regions. In addition, the analysis of serum RF In MRL-lpr mice has demonstrated that a majority of 4 month old MRL-lpr mice produced substantial amounts of IgG3 RF with cryoglobulin activity. Because the cryoglobulin activity is associated with the murine IgG3 heavy chain constant region, RF of this subclass may play a significant role in the development of autoimmune-related tissue injuries, especially In MRL-lpr mic

Age-dependent production of IgA and IgM autoantibodies against IgG2a in a colony of 129/Sv mice

Although much of the basic immunological work has been done with mice, little is known about anti-IgG autoantibodies in this species. Dresser (1, 2) has reported the occurrence, in CBA mice, of anti-IgG antibody (Ab)(1) detected by a hemolytic-plaque assay after stimulation with endotoxin or immunization against sheep erythrocytes. IgM rheumatoid factor has also been described in various strains of mice with a systemic lupus erythematosus-like disease (3). Recently, we have tried to induce anti-IgG in mice of the 129/Sv strain by inoculating autologous IgG. To our surprise, we found that the sera of all the animals had, before any inoculation, anti-IgG detectable by agglutination of particles coated with autologous IgG. The possibilities to investigate the mechanism of production and the biological role of this kind of Ab prompted us to undertake a study of the nature and specificity of the mouse anti-IgG

Monoclonal anti-IgG autoantibodies derived from lipopolysaccharide-activated spleen cells of 129/Sv mice

In some colonies, 129/Sv mice produce, upon aging, a rheumatoid factor (RF) that is specific for mouse IgG2a but fails to react with IgG2a of the b allotype. It is not known whether this narrow specificity is due to the absence of other RF specificities in the repertoire of these mice or to the selective activation of the production of anti-IgG2a autoantibodies by a specific stimulus. To analyze the RF repertoire of 129/Sv mice, we have derived hybridomas from their spleen cells 3 d after an intraperitoneal injection of lipopolysaccharide. We have obtained 68 hybridomas secreting a monoclonal IgM with RF activity. This represents approximately 3 percent of the total number of hybridomas generated in four hybridizations. In addition, one monoclonal IgA RF was derived from unstimulated 129/Sv spleen cells. The specificities of these monoclonal RF were examined by testing their ability to bind to a panel of homologous and heterologous IgG preparations. The majority of the IgM RF reacted exclusively with a single mouse IgG subclass: 58 with IgG1, and 1 with IgG2a. Eight bound preferentially to IgG1 but cross-reacted to some extent with IgG2a and one was specific for a determinant shared by IgG1, IgG2a, and IgG3. The IgA RF derived from unstimulated spleen cells was primarily directed against IgG2a but cross- reacted somewhat with IgG2b. Identical results were obtained with two different monoclonal IgG1 and IgG2a proteins of the a allotype. No allotypic specificity was found for the anti-IgG1 RF, which all reacted well with IgG1 of the b allotype. In contrast, the IgM anti-IgG2a antibody exhibited such allotypic specificity because it failed to react with IgG2a of the b allotype. When tested on heterologous IgG preparations, all anti-IgG1 RF reacted better with rat IgG1, rat IgG2c, bovine IgG2, goat IgG2, and rabbit IgG than with mouse IgG1, demonstrating a particular homology between these Ig. On the basis of additional cross-reactions with other IgG, including rat IgG2a, rat IgG2b, bovine IgG1, goat IgG1, human IgG, and chicken IgG, seven different anti-IgG1 clonotypes could be identified. However, despite their heterogeneity, nearly all antigenic determinants recognized by anti-IgG 1 RF appeared to be located in the hinge region of the molecule. Total lack of binding to IgG1 Fab fragments was indeed observed, and only one antibody reacted with IgG1 Fc fragments. Unlike the anti-IgG1 RF, the IgM and the IgA anti-IgG2a antibodies did not cross-react with any heterologous IgG of the same panel. Altogether, t 1 different RF clonotypes could be distinguished on the basis of their fine specificity. The anti-IgG2a specificity of the RF spontaneously produced by 129/ Sv mice is thus not due to the absence of other RF specificities in the repertoire of these mice

A multivariate approach to predict the volumetric and gravimetric feeding behavior of a low feed rate feeder based on raw material properties

In this study, the volumetric and gravimetric feeding behavior of 15 pharmaceutical powders on a low feed rate feeder was correlated with their material properties through a multivariate approach. The powders under investigation differ substantially in terms of material properties, making the selected powders representative for powders typically used in pharmaceutical manufacturing. The material properties were described by 25 material property descriptors, obtained from a rational selection of critical characterization techniques that provided maximal information with minimal characterization effort. From volumetric feeding experiments (i.e., powder feed rate not controlled), the maximum feeding capacity (maximum feed factor (FFmax)) and optimal hopper fill level at which the feeder should be refilled during gravimetric feeding (feed factor decay (FFdecay)) were obtained. During gravimetric feeding experiments (i.e., powder feed rate controlled), the variability on the feed rate (relative standard deviation (RSD)) and the difference between the setpoint and mean feed rate (relative error (RE)) were determined. Partial least squares (PLS) regression was applied to correlate the volumetric and gravimetric feeding responses (Y) with the material property descriptors (X). The predictive ability of the developed PLS models was assessed by predicting the feeding responses of two new powders (i.e., validation set). Overall, the volumetric feeding responses (FFmax, and FFdecay) were predicted better than the gravimetric feeding responses (RSD and RE), since in gravimetric mode the impact of material properties on the feeding behavior is reduced due to the control system of the feeder. Especially RE was weakly correlated with material properties as RE of most powders varied around zero with only a small numerical variation. Interestingly, this confirms that the control system is working properly and that the feeder is capable of feeding different powders accurately at low feed rates. The developed models allowed to predict the feeding behavior of new powders based on their material properties. Consequently the number of feeding experiments during process development can be greatly reduced, thereby leading to a more efficient and faster development of new drug products

FK 506 pre-treatment is associated with reduced levels of tumor necrosis factor and interleukin 6 following hepatic ischemia/reperfusion

Using a rat model, the effect of pre-treatment with FK 506 on hepatic ischemia/reperfusion injury was investigated. All control animals died within 72 h of the ischemia/reperfusion injury. Pre-treatment of the animals with FK 506 (0.3 mg/kg in 0.5 ml saline) administered intravenously improved survival. The most striking protection against fatal ischemia/reperfusion injury was achieved in rats that were given FK 506 6 and 24 h prior to the induction of the hepatic ischemic insult (70% and 80% 10-day survival rates, respectively). The hepatoprotective effect of FK 506 was assessed further in a second experiment in which the serum levels of tumor necrosis factor (TNF) and interleukin 6 (IL-6) were measured. These results suggest that a 60-min period of hepatic ischemia and subsequent reperfusion triggers the release of both TNF and IL-6, and that FK 506 pre-treatment (6 h before the ischemic episode) significantly inhibits the production and/or release of these two cytokines compared to untreated controls. These data provide additional information concerning the immunosuppressive and hepatoprotective activities of FK 506. Based upon these data, it is probable that FK 506 attenuates hepatic ischemia/reperfusion injury, at least in part, by reducing TNF and IL-6 levels. © 1993 Elsevier Scientific Publishers Ireland Ltd. All rights reserved