TPLS as predictive platform for twin-screw wet granulation process and formulation development.

In recent years, the interest in continuous manufacturing techniques, such as twin-screw wet granulation, has increased. However, the understanding of the influence of the combination of raw material properties and process settings upon the granule quality attributes is still limited. In this study, a T-shaped partial least squares (TPLS) model was developed to link raw material properties, the ratios in which these raw materials were combined and the applied process parameters for the twin-screw wet granulation process with the granule quality attributes. In addition, the predictive ability of the TPLS model was used to find a suitable combination of formulation composition and twin-screw granulation process settings for a new API leading to desired granule quality attributes. Overall, this study helped to better understand the link between raw material properties, formulation composition and process settings on granule quality attributes. Moreover, as TPLS can provide a reasonable starting point for formulation and process development for new APIs, it can reduce the experimental development efforts and consequently the consumption of expensive (and often limited available) new API.

Evaluation of torque as an in-process control for granule size during twin-screw wet granulation.

The potential of torque as in-process control (IPC) to monitor granule size in twin-screw wet granulation (TSG) was investigated. An experimental set-up allowing the collection of granules at four different locations (i.e., in the wetting zone, after the first and second kneading zone and at the end of the granulator) of the granulator screws was used to determine the change in granule size, granule temperature and the contribution of each compartment to the overall torque for varying screw speed, mass feed rate and liquid-to-solid ratio. The only observed correlation was between the granule size and torque increase after the first kneading zone because the torque increase was an indication of the degree in granule growth which was consistently observed with all applied granulation process parameters. No correlation was observed in the other locations as changes of torque were accompanied to either granule breakage and/or growth. Moreover, torque increase was correlated to higher granule temperature, suggesting that energy put into the granulator was partly used to heat up the material being processed and explains additionally the lack of correlation between granule size and torque. Therefore, this study showed that torque could not be used as IPC to monitor granule size during TSG.

In-line temperature measurement to improve the understanding of the wetting phase in twin-screw wet granulation and its use in process development.

Wetting is the initial stage of wet granulation processes during which the first contact between the powder and the liquid occurs. Wetting is a critical step to allow granule growth and consolidation, but also to ensure uniform active pharmaceutical ingredient (API) distribution over all granule size fractions. A physical understanding of the wetting stage is therefore crucial to design a robust granulation process. In twin-screw granulation, wetting is physically separated from granule consolidation, growth, breakage and attrition. The present study used this particularity to investigate the wetting step in such a way that the fundamental mechanisms governing the wetting can be linked and understood. A modified granulator barrel was used allowing the collection of granules immediately after the wetting. A low drug-loaded pharmaceutical formulation containing a poorly soluble and poorly wettable API was used for this investigation. Granules obtained after the wetting zone were analysed for granule size distribution, API distribution over the different size fractions and granule temperature. It was found that "wetting efficiency" (i.e., fraction of powder being nucleated during the wetting stage) could be predicted using an energy balance based on in-line measurement of the granule temperature. Wetting efficiency could moreover be linked to final granule quality attributes (i.e., granule size distribution) at the outlet of the granulator. It was further demonstrated that granule growth and consolidation could only be achieved when complete wetting was achieved in the wetting zone of the granulator. This study suggested a methodology based on in-line temperature measurements to quickly determine wetting efficiency. The described methodology could therefore be used as a tool to gain more fundamental understanding of the wetting stage during twin-screw granulation as well as to define suitable formulation and process ranges for further granulation process development.

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.

Use of thermogram in detection of meningitis.

Thermography of the lumbar area was performed on 169 patients under two years of age. Twenty-four percent (21/87) of afebrile patients and nine percent (6/66) of febrile patients without meningitis had increased lumbar heat (false-positive). Sixteen patients with a cerebrospinal fluid pleocytosis and/or pathogens present demonstrated increased heat in the lumbar area. Clinical evaluation at a level of greater than 2 (0-10) had a sensitivity of 100% and a specificity of 80%. Thermographic evaluation at a grade of 6 or higher (0-10) for the presence of midline heat had a sensitivity of 100% and a specificity of 92%. Thermography of the lumbar area may be a useful clinical adjunct to screen for meningitis.