European Journal of Pharmaceutics and Biopharmaceutics
Research paperMechanism of drug release from polymethacrylate-based extrudates and milled strands prepared by hot-melt extrusion
Introduction
Hot-melt extrusion has attracted a considerable interest in describing an efficient production process for pharmaceutical drug delivery systems [1]. With regard to this technique, a wide scope of different dosage forms covering oral, parenteral, and topical applications have been investigated. More specifically, Breitenbach [2] describes the development of melt extrusion in pharmaceutical manufacturing operations and discusses the advantages and drawbacks of the application of melt extrusion technology in the production of solid dispersions. Disadvantages of this technology are often related to high energy input, which can be a strain on thermally sensitive drugs or systems.
Six et al. [3] investigated the influence of the extrusion temperature on the physical state of solid dispersions with itraconazole and Eudragit® E. They performed experiments at two temperature settings, whereby one was adjusted above (heating zones: 50, 79, 170, 175, and 179 °C) and one below (heating zones: 49, 103, 131, 133, and 140 °C) the melting point of itraconazole (168 °C for stable crystalline form). Depending on the drug concentration, they obtained single molecular dispersions or a molecular dispersion in combination with a second phase of pure amorphous itraconazole at 179 °C. Below the melting point of the drug, the second phase consisted of pure crystalline itraconazole.
The efficacy of a drug is mainly defined by the formulation and its solid state. The physical state of the drug in the melt-extruded formulations reaches from simple crystalline embeddings to amorphous or molecularly dissolved stages [4], [5]. Therefore, the study of the nature of the solid state is indispensable for the understanding of the mechanism of dissolution enhancement.
The mechanism by which drugs may be released from hot-melt extruded solid dispersions and the processing of the strands to solid dosage forms are issues that are not completely clarified yet. Corrigan and Craig [6], [7] highlighted the theories of dissolution with regard to the solid-state structure and dissolution properties of solid dispersions.
Overall, there appears to be two sets of observations that describe the mechanism of drug release from solid dispersions: carrier- or drug-controlled dissolution [7]. In the first instance, the rate of release is controlled by that of the carrier and is independent of the drug properties. In the second instance, mostly observed in conjunction with high drug loads, the dissolution is dominated by the properties of the drug itself [6].
Additional problems of solid dispersions are caused by their thermodynamic instability under storage and especially under drug release. One strategy to solve this problem is to increase the solubility of the drug in a polymeric carrier and then to control drug release by incorporation of a second excipient as described by Zhu et al. [8].
The objective of this study was to elucidate the mechanism of dissolution enhancement and to establish a connection between the nature of solid state, the dissolution proceedings and the stability of the system. Therefore, the transformation of the crystalline state of the drug to the amorphous form was examined with regard to the physical characteristics, the dissolution rate and the recrystallization tendency. As there is insufficient knowledge on the processing to oral dosage forms, additionally the influence of mechanical stress on the solid dispersions was investigated.
Section snippets
Materials
Celecoxib, CEL (Aarti Drugs, Mumbai, India) a selective cyclooxygenase-2 inhibitor, was used as model drug. The BCS Class II drug [9] with a melting point of 162 °C has a pKa of 9.68 and a low aqueous solubility of about 3 mg/L. CEL was applied in micronized form with a median particle size of 27.8 μm. The cationic basic butylated methacrylate copolymer Eudragit® E PO (aPMMA) with a median particle size of 9.3 μm was kindly donated by Evonik (Darmstadt, Germany). Cetrimide, a mixture mainly
Extrudate characteristics and dissolution behaviour
Transparent extrudates with a drug load of 50% can be produced with the temperature profile described in Fig. 1. Decreasing the temperature in the central part of the extruder barrel leads to opaque strands of CEL and aPMMA, which are the result of insufficient dissolution of the drug in the molten carrier.
Extrudates were characterized regarding their dissolution behaviour in 0.1 N HCl under non-sink conditions employing the paddle method according to Ph.Eur. for 30 min. Crystalline CEL has a
Conclusion
This study has elucidated the mechanisms by which drug is released from solid dispersions. Depending on the solid-state properties, the glassy solid solutions follow a carrier-controlled mechanism, crystalline glass suspensions follow a drug-controlled mechanism. Whether a glassy solid solution or a crystalline glass suspension is produced in the hot-melt extrusion process, this is mainly dependent on the temperature settings of the barrel segments. If the system is undergoing
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