Research paper Development of potential novel cushioning agents for the compaction of coated multi-particulates by co-processing micronized lactose with polymers Xiao Lin a,c , Chin Wun Chyi b , Ke-feng Ruan a , Yi Feng a,⇑ , Paul Wan Sia Heng b,⇑ a Engineering Research Center of Modern Preparation Technology of TCM, Ministry of Education, Shanghai University of TCM, Shanghai, China b GEA-NUS Pharmaceutical Processing Research Laboratory, Department of Pharmacy, National University of Singapore, Singapore c College of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China article info Article history: Received 19 September 2010 Accepted in revised form 25 March 2011 Available online 31 March 2011 Keywords: Micronized lactose Cushioning effect Spray drying Hydroxypropylcellulose Hydroxypropylmethylcellulose Polyvinylpyrrolidone abstract This work aimed to explore the potential of lactose as novel cushioning agents with suitable physicome- chanical properties by micronization and co-spray drying with polymers for protecting coated multi-par- ticulates from rupture when they are compressed into tablets. Several commercially available lactose grades, micronized lactose (ML) produced by jet milling, spray-dried ML (SML), and polymer-co-pro- cessed SMLs, were evaluated for their material characteristics and tableting properties. Hydroxypropyl- cellulose (HPC), hydroxypropylmethylcellulose (HPMC), and polyvinylpyrrolidone (PVP) at three different levels were evaluated as co-processed polymers for spray drying. Sugar multi-particulates layered with chlorpheniramine maleate followed by an ethylcellulose coat were tableted using various lactose types as fillers. Drug release from compacted multi-particulate tablets was used to evaluate the cushioning effect of the fillers. The results showed that the cushioning effect of lactose principally depended on its particle size. Micronization can effectively enhance the protective action of lactose. Although spray drying led to a small reduction in the cushioning effect of ML, it significantly improved the physicome- chanical properties of ML. Co-spray drying with suitable polymers improved both the cushioning effect and the physicomechanical properties of SML to a certain degree. Among the three polymers studied, HPC was the most effective in terms of enhancing the cushioning effect of SML. This was achieved by reducing yield pressure, and enhancing compressibility and compactibility. The combination of micron- ization and co-spray drying with polymers is a promising method with which new applications for lac- tose can be developed. Ó 2011 Elsevier B.V. All rights reserved. 1. Introduction Multi-particulate dosage forms generally consist of coated or/ and uncoated multi-particulates that are conventionally filled into hard gelatin capsules. There is increasing interest to prepare multi- particulates in compressed tablets as tableting confers several advantages such as reduced risk of product tampering, lower cost by higher throughput production, flexibility in dosing regimen by allowing scoring tablets without loss of sustained release property, easier swallow ability compared with capsules [1], and avoidance of animal-derived gelatin. Following oral administration, tablets containing compacted multi-particulates need to disintegrate quickly and release the individual multi-particulates. This will enable the multi-particulates to spread uniformly throughout the gastrointestinal tract and maintain their advantages as a multi- ple-unit dosage form, which include the reduced risk of local irri- tation and dose dumping, good bioavailability, and long retention times within the gastrointestinal tract. However, compacting multi-particulates poses considerable challenges during formulation and process development, espe- cially if they are polymer coated. The polymeric coating must possess sufficient elasticity to withstand the compaction force without rupturing while the core should have some degree of plasticity to accommodate stresses associated with deformation during tableting. It has been reported that the ability of films to withstand pressure followed the order: films cast from acrylic polymers  films cast from organic ethylcellulose solution > films cast from aqueous ethylcellulose dispersion [1]. Excipients with a variety of particle sizes, rheological properties, and bulk densities have been investigated, either alone or in combination, as cushioning agents to minimize the deleterious effects of compac- tion force and hence, to protect the coated multi-particulates 0939-6411/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.ejpb.2011.03.024 ⇑ Corresponding authors. Engineering Research Center of Modern Preparation Technology of TCM, Ministry of Education, Shanghai University of TCM, 1200 Cailun Road, Shanghai 201203, China, Tel./fax: +86 21 58950297 (Y. Feng). Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore, Tel.: +65 65162930; fax: +65 67752265 (P.W.S. Heng). E-mail addresses: yy090503@163.com (Y. Feng), phapaulh@nus.edu.sg (P.W.S. Heng). European Journal of Pharmaceutics and Biopharmaceutics 79 (2011) 406–415 Contents lists available at ScienceDirect European Journal of Pharmaceutics and Biopharmaceutics journal homepage: www.elsevier.com/locate/ejpb