Minitablets Coated in a Solid-Wall Pan for Theophylline Sustained-Release Capsules

November 1, 2010
Pharmaceutical Technology

Volume 2010 Supplement, Issue 6

The authors describe an alternative approach to compressing and coating minitablets for use in a sustained-release, solid oral-dosage form. This article is part of a special Drug Delivery issue.

This article is part of a special issue on Drug Delivery

The production of minitablets for the sustained release of a drug is a new and promising area in pharmaceutical research. Minitablets (also known as microtablets) have a diameter equal to or smaller than 2–3 mm and can be filled into hard gelatine capsules (1).

Minitablets are multiple-unit dosage forms, therefore, they present all the advantages of these systems over the single-unit dosage forms. These advantages include a low risk of dose dumping, less inter- and intra-subject variability, and a high degree of dispersion in the digestive tract, thus minimizing the risks of high local drug concentrations and reproducible bioavailability.


Minitablets are good substitutes for other multiparticulate dosage forms (e.g., granules and pellets) because they can be manufactured by direct compression. As a consequence, the use of solvents is avoided and high production yields are obtained compared to extrusion and spheronization processes. Furthermore, due to the manufacturing process, defined size and strengths can easily be produced, with small variability within and between batches (1, 2).

Sustained-release minitablets can be produced either by matrix or by coating them in a fluid bed or coating pan (3–6). Unfortunately, little published information is available on both minitablet-coating technologies and the coating of minitablets in a pan (5, 6). However, from an industrial point of view, the coating of minitablets in a pan should be extremely convenient because it provides higher production capabilities, lower waste of coating materials, and faster equipment cleaning time with respect to the fluid bed.

The aim of this research was to investigate the possibility of manufacturing a sustained-release, multiple-dosage form by coating minitablets, produced by direct compression, in a solid wall pan. Theophylline (TH) was used as the model drug, and an innovative ready-to-use pigment dispersion was tested to evaluate the possibility of reducing production time when compared with a traditional coating formulation. Finally, coated minitablets were filled into hard gelatine capsules.

Experimental methods

Materials. TH (particles lower than 100 µm) was purchased from BASF (Ludwigshafen, Germany). Avicel PH 102 was supplied by FMC Biopolymer (Brussels). Spray-dried lactose, magnesium stearate, talc, titanium dioxide, trietilcitrate and yellow quinoline (all European Pharmacopoeia-grade) were purchased from Polichimica (Bologna, Italy) and used as received. Eudragit RL, Eudragit RS (Evonik, Darmstadt, Germany, polymer conforms to Ammonio Methacrylate Copolymer, Type A USP/NF 31) and WAS (a product containing talc, titanium dioxide, yellow quinoline and trietilcitrate) were supplied by Rofarma Italia (Milano, Italy). Hard gelatine capsules size 0 were purchased from Capsugel (Colmar, France).


Preparation of the minitablets. TH, Avicel PH 102, spray-dried lactose, and magnesium stearate in four different ratios (total 4 kg per batch) were blended using an IMA Cyclops blender (IMA, Ozzano, Italy).

Direct compression was performed using a tablet press machine for research and development and small batches (IMA Pressima equipped with 2 EU-D punches fitting 24 minipunches, 2 mm diameter each, (see Figure 1). Compression force used to obtain 9 mg minitablets was maintained at 20 kN for all batches with fill-shoe speed adjusted to 25 rpm.

Figure 1: Special tooling for minitablets (IMA, Ozzano, Italy). (FIGURE COURTESY OF THE AUTHOR)

Coating of minitablets. The coating process of 10 kg of minitablets for each batch was carried out in an IMA GS 25-L solid wall pan (see Figure 2). Two different coating formulas were used (see Table I): a traditional one containing single components to be previously dispersed in water (A) and the ready-to-use pigment dispersion WAS (B).

Table I: Comparison of the two coating formulas.

Coating dispersion A was prepared by homogenizing, in a separate vessel, pigments, plasticizer, and part of the solvent for 10 min. The dispersion obtained was then added to a main vessel containing Eudragit RL/RS and the remaining water and stirred continuously. Coating dispersion B was prepared by simply adding WAS to the main vessel containing Eudragit RL/RS and solvent without the need of predispersion. The coating suspension was than stirred continuously. Both formulas were tested at different polymer amounts expressed in total solids' weight-gain percentage.

Figure 2: Schematic of the solid-wall coating pan. (FIGURE COURTESY OF THE AUTHOR)

The coating process was started by loading the minitablets in the pan manually and without any drum rotation. A preheating phase was carried out at the minimum drum speed to ensure the proper temperature of the cores prior to the spray phase. When the minitablets reached the proper temperature, all the coating dispersion was sprayed by a dedicated compressed-air-fed gun. At the same time, the pan speed was adjusted to the ideal value to avoid the cores sticking or being damaged; mixing was ensured by six shark-fin-type mixing baffles placed in the center of the drum.

During the process, drying was ensured by a special paddle system blowing the correct amount of inlet air at the desired temperature and humidity. Cores were dried from the surface and from the bottom, improving the uniformity of evaporation.

Table II: Optimized process parameters for formula A.

When all the coating dispersion was sprayed, a drying step was performed to reduce the humidity of the cores, then the minitablets were unloaded manually after a short cooling phase. Optimized process parameters for formula A and B are described in Table II and III, respectively.

Table III: Optimized process parameters for formula B.

Filling of hard gelatine capsules. The coated minitablets were then filled (n = 42) into size 0 hard gelatine capsules using a Zanasi Lab capsule filler (IMA Ozzano, Italy), which has a maximum speed of 12000 capsules/h, equipped with a minitablets dosing group (Figure 3). The dosing group is composed of a minitablets hopper, a special wheel with a predefined number of holes (the dimensions of which are dictated by the size of the minitablets) and a drum with pushers for the discharge of the minitablets in the capsule body.

Figure 3: Capsule filler for the minitablets dosing group (IMA, Ozzano, Italy). (FIGURE COURTESY OF THE AUTHOR)

The minitablets enter into the wheel's holes by means of vacuum. The wheel rotates, the vacuum is cut off and the minitablets are dosed into the capsules by gravity fall.

The minitablets dosing unit is equipped with a camera to check that all the holes are filled with minitablets. If one or more minitablets are missing, the corresponding capsule is rejected.

Characterization. The minitablets were characterized as follows:

Weight variation. The weight variation was determined weighing 20 minitablets.

Friability. The friability of minitablets was determined by introducing 6.5 g of them in a Roche friabilator (Erweka, Düsseldorf, Germany) at a rotational speed of 25 rpm. After 100 rotations, the minitablets were sieved over a 250 µm sieve. The friability value was calculated as the percentage of the final weight after sieving to the initial weight of the minitablets.

Crushing strength. The crushing strength was tested (n=20) using a TBH 200 (Erweka).

Scanning electron microscopy (SEM). The coating surface and the cross-section slice of minitablets were examined using scanning electron microscopy (ESEM-FEI QUANTA 200, FEI, Eindhoven, The Netherlands); the samples were previously sputter-coated with gold.

Determination of actual drug content. The analysis of the drug content was carried out by dissolving 30 mg of minitablets in 100 mL of pH 7.4 buffer. The amount of drug was then spectrophotometrically determined after 24 h (UV2 Spectrometer, Unicam, Cambridge, UK) at 271.8 nm. Each sample was analyzed at least in triplicate.

In vitro drug release profiles. In vitro dissolution tests were performed using the USP Apparatus 2 (paddle) (Pharmatest, Steinheim, Germany) rotating at 50 rpm. As a dissolution media, 900 ml of pH 7.4 phosphate buffer was used at a temperature of 37 ± 0.5 °C. Samples of uncoated and coated minitablets containing an amount of drug chosen to assure sink conditions (C < 0.2 Cs) were added to the dissolution medium. The solution was filtered and continuously pumped to a flow cell in a spectrometer (UV2 Spectrometer, Unicam, Cambridge, UK) The amount of drug dissolved was analyzed at 271.8 nm. The dissolution tests were performed at least in triplicate.

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)

Dissolution tests were then performed on mT4 uncoated and mT4 coated with formula A and formula B at two different coating amounts. These tests aimed to confirm the absence of coating defects such as cracking and to evaluate the effect of the amount of polymer on drug release. In addition, the equivalence of both coating formulations was checked. As expected, Figure 5 shows that the uncoated mT4 released 100% of the active ingredient in less than 90 minutes, clearly demonstrating the need for film coating to achieve a sustained release. The good coating quality was demonstrated by obtaining a sustained release behavior using both formulas even at the lowest polymer amount. Furthermore, the release data showed the influence of the coating level on TH release. The dissolution profiles of both formulas at the same coating levels were not significantly different, which is evidence that the ready-to-use system is equivalent to the traditional one.

Table IV: Characteristics of the four formulations used in minitablet compression.

Finally, coated minitablets were filled into hard gelatine capsules size 0. The maximum speed achieved for the production was 12000 capsules/hour, representing 80% of the highest speed of the capsule filler when dosing standard volumetric pellets. Production was successfully carried out for 2 h without any rejected capsules, thereby confirming the system reliability.


Minitablets containing a high amount of TH, low friability, and high crushing strength were obtained by direct compression and then coated in a solid-wall pan. The use of a ready-to-mix pigment dispersion represents an interesting alternative to shorten coating-suspension-preparation time when compared with traditional formulations. The coated minitablets were then successfully filled into hard gelatine capsules. In conclusion, the results demonstrated that the innovative approach used in this study could be potentially useful for the industrial-scale manufacture of a sustained-release, oral-solid-dosage form.


The authors would like to thank Rosamund Cervo for her kind support in checking the English.

Caterina Funaro* is a process laboratory manager, and Giusi Mondelli is a process specialist at IMA Active Division, Via 1° Maggio, 14 40064 Ozzano dell' Emilia, Bologna, Italy, tel. 0039 0516 5141 11, fax 0039 0516 514287, Nadia Passerini and Beatrice Albertini are both assistant professors in the Department of Pharmaceutical Sciences, University of Bologna, Italy.

*To whom all correspondence should be addressed.


1. C. M. Lopes et al., Int. J. Pharm. 323 (1–2), 93–100 (2006).

2. T. Riis et al., Eur. J. Pharm. Biopharm. 65 (1) 78–84 (2007).

3. C. M. Lopes et al., Drug. Dev. Ind. Pharm. 32 (1) 95–106. (2006).

4. I. Tomuta and S.E. Leucuta. Drug. Dev. Ind. Pharm. 33 (1) 1070–1077 (2007).

5. A. Spadoni, Pharm. Proc. published online (Jan. 2001),, accessed Oct. 22, 2010.

6. M. Ishida et al., Int. J. Pharm, 359 (1–2), 46–52 (2008).

7. L. Ho et al., J. Control. Rel. 127 (1), 79–87 (2008).