Results and discussion
The target of this study was to investigate from the industrial point of view the possibility of manufacturing a final solid-dosage
form containing a multiparticulate system providing a controlled release of the drug. The work was divided into three steps:
first the feasibility of producing minitablets by direct compression was evaluated, secondly the coating of the produced minitablets
in a solid wall pan was studied, and finally the process of filling the minitablets into hard gelatine capsules was checked.
Four batches of minitablets containing an increased amount of TH from 50% to 80% (w/w) were produced and characterized in
terms of weight variations, friability, and crushing strength. These four batches were labelled mT1, which contained 50% (w/w)
TH; mT2, which contained 60% (w/w) TH; mT3, which contained 70% (w/w) TH; and mT4, which contained 80% (w/w) TH. Because the
second step of the production was a film coating in a pan, particular attention had to be paid to friability and crushing
strength to assess that the cores had enough mechanical resistance to tolerate the stress involved in pan coating, especially
in production size.
The results showed that all the formulations considered were successfully compressed into minitablets having small weight
variations, high crushing strength, and very low friability (see Table IV). Among the produced batches, formulation mT4 was
selected for the subsequent steps due to its high TH content, which enables the production of a 300-mg dosage unit.
Figure 4: Scanning electron microscopy images of the uncoated batch labeled "mT4" that was prepared by the authors. The images
show formula A at different coating levels and formula B at different coating levels. (FIGURE COURTESY OF THE AUTHOR)
The second part of the study was aimed at demonstrating the feasibility of coating minitablets in a solid-wall pan. The first
challenge was to avoid coating defects. In fact all coating processes, if not properly controlled, could lead to defects such
as sticking or twinning of two or more cores together, nonuniform distribution of the coating, peeling of the coating surface,
weakness of the coating, especially cracking on the tablet edges, and coating roughness/orange-peel effect. For this reason,
preliminary tests (not reported) were performed to find the best coating conditions. Different combinations of pan speed (range
15–24 rpm), atomization pressure (range 0.8–1.5 bar), inlet air temperature (range 55–65 °C), inlet air quantity (range 200–250
m3/h); cores' temperature (range 30–35 °C) and spray rate (range 30–45 ml/min.) were investigated to create process harmony.
The optimal combination of parameters found for the traditional coating formulation A are reported in Table II. Subsequently,
the possibility of replacing the standard coating preparation with a ready-to-use system (formulation B) was tested with the
aim to reduce both total process time (starting from the coating preparation) and the need for ancillary equipment.
Comparing Tables II and III, it is evident that for both formulation A and B the coating conditions were identical, which
demonstrates the interchangeability of the traditional formula containing the single components with the ready-to-use pigment
dispersion at least regarding the process parameters. Two different coating levels were tested for both coating formulas to
check the influence of the amount of polymers on drug release.
To assess the coating quality, the surface characteristics and the cross-section slides of the coated minitablets were observed
using scanning electron microscopy at different coating levels for either minitablets coated with the standard formula A and
the innovative formula B (7). The results in Figure 4 show that a complete and uniform layer was achieved using both formulas
even at low coating levels.
Figure 5: Dissolution of uncoated and coated minitablets A and B at different total solid-weight gain. TH is theophylline,
Awg is weight gain for formula A, and Bwg is weight gain for formula B. (FIGURE COURTESY OF THE AUTHOR)