Directly compressed mini-tablets coated in a solid-wall pan for sustained drug release 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
Introduction The production of mini-tablets for sustained drug release is a new and promising area of pharmaceutical research. 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 Aim of the study The aim of this study was to investigate the possibility of manufacturing a sustained-release multiple dosage Conclusion The results showed that direct compression yielded mini-tablets with a high amount of TH, a low friability and a high crushing strength. Mini-tablets are a multipleunit 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. been extensively implemented; however, this process produces the following advantages over the fluid bed method: increased production capabilities, reduced waste of coating materials and shorter equipment clean-ing time. form by coating directcompression mini-tablets in a solid wall pan. Theophylline was used as a model drug and WAS an innovative ready-to-use pigment dispersion was tested to evaluate the possibility A solid-wall pan proved a suitable technique for mini-tablet coating and the ready-to-mix piment dispersion proved a suitable method for shortening coating suspension preparation time. Moreover, when manufactured by direct compres- of reducing production time. Thus, a sustained-release multiple-dosage form was sion instead of granulation successfully manufac- or extrusion and spheroniza- tured using a tablet press tion, production is comple- and a solid wall pan. ted in one step, with lower costs and higher production yields. p. 1
Experiment part Materials 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 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). Theophylline (TH, particle lower than 100 microns) was purchased from BASF, Ludwigshafen, Germany. Avicel PH 102 was kindly supplied by FMC Biopolymer Brussels, Belgium. Spray-dried lactose, magnesium stearate, talc, titanium dioxide, trietilcitrate and Yellow Quinoline (all FU-grade) were purchased 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. from Polichimica, in Bologna, Italy, and used as received. Eudragit RL, Eudragit RS (polymer conforming to Ammonio Methacrylate Copolymer, Type A USP/NF 31) and WAS (containing talc, Titanium dioxide, Yellow Quinoline and Trietilcitrate) were kindly supplied by Rofarma Italia, in Milano, Italy. 2 EU-D punch fitting several mini-punches p. 2
Methods Coating of mini-tablets Characterization croscopy (SEM ESEM-FEI Quanta 200). The actual drug content and in-vitro drug release profiles Both formulae were tested at different polymer amounts expressed in total solids weight gain percentage. Process parameters for formulae A and B are described in the table. The mini-tablets (mt) were tested for uniformity of mass, friability (using the Roche friabilator) and crushing strength (TBH 200, Erweka, Germany) and the sur- 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- face characteristics were obser- photometrically (UV2, Unicam) ved using Scanning Electron Mi- at 271.8 nm Result and discussion containing different amounts of the drug were produced in order to determine the formulation which had mechanical properties suitable for pan- In the first part of the study, four batches of mini-tablets coating, minimal weight variation and maximum drug content. * The mixture of excipients contains: spray-dried lactose 60%, Avicel PH 102 39%, magnesium stearate 1%. p. 3
All the mts produced had When comparing the opera- As shown in the figure, the un- to the coating level. At the same technological properties suit- tive parameters used in coating, coated mt released 100% of coating level, the dissolution pro- able for coating (high crushing it is evident that the coating the active ingredients in less files of both formulae were not strength and very low friability) conditions for formula A and B than 90 minutes. significantly different, suggesting and complied with the test for were very similar. Sustained release was ensur- that the ready-to-use system is uniformity of mass, according ed by both formulae and all equivalent to the traditional one. to European Pharmacopoeia. This demonstrates the inter- polymer amounts, proportionate Batch mt4 was then selected changeability of the traditional for coating due to its high drug formula containing single com- content. ponents with the ready-to-use pigment dispersion. The second part of the study was aimed at demonstrating The SEM photographs of un- the feasibility of coating mts in coated mt4 and coated mts a solid wall pan and to test the at different levels show that a possibility of replacing the stan- complete, uniform layer was dard coating preparation with a achieved using both formulae, ready-to-use system. even at a low coating level. Dissolution of uncoated and coated mt (formula A and B) at different total solids weight gain. p. 4