Drug release from MCC- and carrageenan-based pellets: experiment and theory.
Microcrystalline cellulose (MCC) is a well-established pelletisation aid. However, MCC pellets generally do not disintegrate, resulting in prolonged drug release, especially in the case of drugs with poor/low aqueous solubility. The major objectives of this study were (i) to modify the prolonged matrix-type drug release from MCC pellets by addition of a disintegrant (croscarmellose Na) or pore former (PEG 6000), (ii) to evaluate carrageenan as potential alternative pelletisation aid for manufacturing high-dose immediate release pellets, and (iii) to better understand the underlying drug release mechanisms. Pellets containing 77-90% drug with poor/low aqueous solubility (vatalanib succinate, SAG/ZK, or theophylline) were prepared by extrusion-spheronisation. All batches showed acceptable yields, aspect ratios, tensile strengths, and porosities. Drug release from MCC pellets was predominantly controlled by pure diffusion and limited drug solubility and could be quantitatively described using Fick's law. Importantly, the apparent drug diffusivity could effectively be adjusted by adding small amounts of a disintegrant or pore former, allowing for release periods ranging from a few minutes to several hours. The drug diffusion coefficients varied between 0.36 and 29 x 10(-6)cm(2)/s. In contrast, carrageenan-based pellets very rapidly disintegrated upon contact with aqueous media and released high doses of drugs with poor/low aqueous solubility within a few minutes.
Kranz
H
H
Pharmaceutical Technology, Bayer Schering Pharma AG, Berlin D-13342, Germany. Heiko.Kranz@bayerhealthcare.com
Jürgens
K
K
Pinier
M
M
Siepmann
J
J
D002266:Carboxymethylcellulose Sodium / Q000737:chemistry; D002351:Carrageenan / Q000737:chemistry*; D002482:Cellulose / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004058:Diffusion; D004337:Drug Carriers; D004339:Drug Compounding; D007700:Kinetics; D008956:Models, Chemical; D010793:Phthalazines / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D016062:Porosity; D011725:Pyridines / Q000737:chemistry*; D012995:Solubility; D013806:Theophylline / Q000737:chemistry*
D003692:Delayed-Action Preparations; D004337:Drug Carriers; D010793:Phthalazines; D011725:Pyridines; D011092:Polyethylene Glycols; C404768:vatalanib; D002351:Carrageenan; D002482:Cellulose; D013806:Theophylline; D002266:Carboxymethylcellulose Sodium; C109691:microcrystalline cellulose