March 2012
N. Passerini, B. Albertini, L.Rodriguez
Department of Pharmaceutical Sciences, University of Bologna C. Funaro, G. Mondelli
IMA s.p.a. Solid Dose Division
Directly compressed mini-tablets coated in a solid-wall pan
for sustained drug release
Sustained-release mini-tablets can be produced either as a matrix or by coating the mini-tablets in a fluid bed apparatus.
Thus far, the pan-coating of mini-tablets has not been extensively imple- mented; however, this pro- cess produces the following advantages over the fluid bed method: increased pro- duction capabilities, redu- ced waste of coating mate- rials and shorter equipment clean-ing time.
The results showed that di- rect compression yielded mini-tablets with a high amount of TH, a low friability and a high crushing strength.
A solid-wall pan proved a suitable technique for mini-tablet coating and the ready-to-mix piment dispersion proved a suitable method for short- ening coating suspension preparation time.
Thus, a sustained-release multiple-dosage form was successfully manufac- tured using a tablet press and a solid wall pan.
Introduction Aim of the
study Conclusion
The aim of this study was to investigate the possibility of manufacturing a sustain- ed-release multiple dosage form by coating direct- compression mini-tablets in a solid wall pan.
Theophylline was used as a model drug and WAS – an innovative ready-to-use pig- ment dispersion – was test- ed to evaluate the possibility of reducing production time.
The production of mini-tab- lets for sustained drug re- lease is a new and promis- ing area of pharmaceutical research.
Mini-tablets are a multiple- unit dosage form, with the following advantages over single-unit dosage forms:
low risk of dose dumping, high degree of dispersion in the GI tract and reproducible bioavailability.
Moreover, when manufac- tured by direct compres- sion instead of granulation or extrusion and spheroniza- tion, production is comple- ted in one step, with lower costs and higher produc- tion yields.
Methods
Preparation of mini-tablets
TH, Avicel PH 102, spray-dried lactose and magnesium stearate (total 4 kg per batch) were blended using an IMA Cyclops blender. Direct compression was performed using IMA Pressima, a tablet press machine for R&D and small batches, equipped with 2 EU-D punches fitting 24 mini-punches, each 2 mm in diameter. The compression force used to obtain 9 mg mini-tablets was 20 kN for all batches, with a 25-rpm fill shoe speed.
2 EU-D punch fitting several mini-punches
Materials
Theophylline (TH, particle lower than 100 microns) was purcha- sed from BASF, Ludwigshafen, Germany. Avicel PH 102 was kindly supplied by FMC Bio- polymer Brussels, Belgium.
Spray-dried lactose, magnesium stearate, talc, titanium dioxide, trietilcitrate and Yellow Quinoline (all FU-grade) were purchased from Polichimica, in Bologna, Italy, and used as received.
Eudragit RL, Eudragit RS (polymer conforming to ‘Am- monio Methacrylate Copolymer, Type A’ USP/NF 31) and WAS (containing talc, Titanium dioxi- de, Yellow Quinoline and Trietil- citrate) were kindly supplied by Rofarma Italia, in Milano, Italy.
Experiment part
Methods
Coating of mini-tablets
Each batch of 10 kg mini-tablets was coated in an IMA GS 25 L solid-wall pan.
Two different coating formulae were used: a traditional formula containing single components to be dissolved in water before use (A) and the WAS ready-to-use pigment dispersion (B).
Process parameters for formu- lae A and B are described in the table.
The mini-tablets (mT) were test- ed for uniformity of mass, fria- bility (using the Roche friabilator) and crushing strength (TBH 200, Erweka, Germany) and the sur- face characteristics were obser- ved using Scanning Electron Mi-
croscopy (SEM ESEM-FEI Quanta 200). The actual drug content and in-vitro drug release profiles of the coated mini-tablets (CmT) were characterized (USP paddle method, 50 rpm, 900 ml pH 7.4 phosphate buffer at 37 °C). The analysis was performed spectro- photometrically (UV2, Unicam) at 271.8 nm
Methods
Coating of mini-tablets
Both formulae were tested at dif- ferent polymer amounts expres- sed in total solids weight gain percentage.
Result and discussion
Characterization
In the first part of the study, four batches of mini-tablets
containing different amounts of the drug were produced in order to determine the formu- lation which had mechanical properties suitable for pan- coating, minimal weight varia- tion and maximum drug content.
* The mixture of excipients contains: spray-dried lactose 60%, Avicel PH 102 39%, magnesium stearate 1%.
All the mTs produced had technological properties suit- able for coating (high crushing strength and very low friability) and complied with the test for uniformity of mass, according to European Pharmacopoeia.
Batch mT4 was then selected for coating due to its high drug content.
The second part of the study was aimed at demonstrating the feasibility of coating mTs in a solid wall pan and to test the possibility of replacing the stan- dard coating preparation with a ready-to-use system.
When comparing the opera- tive parameters used in coating, it is evident that the coating conditions for formula A and B were very similar.
This demonstrates the inter- changeability of the traditional formula containing single com- ponents with the ready-to-use pigment dispersion.
The SEM photographs of un- coated mT4 and coated mTs at different levels show that a complete, uniform layer was achieved using both formulae, even at a low coating level.
As shown in the figure, the un- coated mT released 100% of the active ingredients in less than 90 minutes.
Sustained release was ensur- ed by both formulae and all polymer amounts, proportionate
to the coating level. At the same coating level, the dissolution pro- files of both formulae were not significantly different, suggesting that the ready-to-use system is equivalent to the traditional one.
Dissolution of uncoated and coated mT (formula A and B) at different total solids weight gain.
