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Homogeneous ultralow-dose (30 mg) tablets were prepared from perfectly free-flowing granules manufactured by continuous Twin-Screw Wet Granulation. The gravimetrically fed mixture of lactose and potato starch of low particle size was successfully agglomerated and the size enlargement technology proved to be very robust. Since the incorporated drug was dissolved in ethanolbased granulation liquid, the resulting homogeneity largely depended on the dosing of the applied liquid administering units. A peristaltic pump generated higher deviation of the drug content in tablets (Relative Standard Deviation (RSD): 7.7%) compared to a syringe pump (RSD: 2.3%) or a piston pump (RSD: 4.6%). This is due to the pulsation of the liquid flow generated by the peristaltic pump according to the real-time measured mass of the fed liquid. A good correlation was found between the RSD of the liquid mass flow (calculated from the recorded masses) and the RSD of the drug content. Based on the results, the goodness of Content Uniformity, as the most relevant critical quality attribute of low-dose products, was determined by the characteristics of the applied dosing units. The feeding characteristic of the different pumps could be easily measured by the introduced balance-based method and therefore, the applicability of the pumps could be evaluated. [ABSTRACT FROM AUTHOR]

[Display omitted] This paper presents new machine vision–based methods for indirect real-time quantification of ultralow drug content during continuous twin-screw wet granulation and tableting. Granulation was performed with a solution containing carvedilol (CAR) as API in the ultralow dose range (0.05 w/w% in the granule) and the addition of riboflavin (RI) as a coloured tracer. An in-line calibration in the range of 0.047–0.058 w/w% was prepared for the measurement of CAR concentration using colour analysis (CA) and particle size analysis (PSA), and the validation with HPLC resulted in respective relative errors of 2.62% and 2.30% showing great accuracy. To improve the technique, a second in-line calibration was conducted in a broader CAR concentration range of 0.039–0.063 w/w% utilizing only half the amount of RI (0.045 w/w%), while doubling the output of the granulation line to 2 kg/h, producing a relative error of 4.51% and 4.29%, respectively. Finally, it was shown that the CA technique can also be carried on to monitor the CAR content of tablets in the 42–62 μg dose range with a relative error of 5.20%. Machine vision was proven to be a potent indirect method for the in-line, determination and monitoring of ultralow API content during continuous manufacturing. [ABSTRACT FROM AUTHOR]