Novel formulations of a poorly soluble drug using the extrusion process.

Hot melt extrusion has attracted recent interest from the pharmaceutical industry and academia as an innovative drug delivery technology. This novel technique has been shown to be a viable and robust method for preparing different drug delivery systems including pellets, implants, tablets, capsules and granules. The aim of this research was to understand hot melt extrusion processing and explore its pharmaceutical applications. Two applications of hot melt extrusion (HME) have been investigated to improve the properties of poorly soluble thermolabile drugs; polymeric solid dispersions and solid state polymorphic transformation. HME is a solvent free, continuous and readily scalable technique which is increasingly being considered as a viable alternative to conventionally used batch techniques. However, the high temperature and shear forces imparted by the extrusion process can limit its applications with heat sensitive active pharmaceutical ingredients (APIs). Artemisinin was selected as a model drug which being thermolabile in nature and possesses processing challenges to processing HME. A low Tg amphiphillic copolymer, Soluplus® was selected as a matrix material. Drug-polymer compatibility was studied using rotational rheometry and thermal characterisation. The drug was found to be completely dissolved within the polymer, although some discolouration of the mixture was observed, indicating degradation of the API. The addition of a small percentage of citric acid to the formulation was found to prevent this degradation by increasing the pH. The dissolution profile of the formulation was approximately five times higher compared to that of the pure drug. The pharmacokinetic study was carried out using Albino rats to calculate bioavailability. The area under plasma concentration time curve (AUC0-24hr) and peak plasma concentration (Cmax) were four times higher for the prepared solid dispersion compared to that of pure artemisinin. Extruded solid dispersions were found to be amorphous in nature and maintained stability for 2 years. A second route to improving the solubility of poorly soluble APIs was also investigated. It was found that under carefully controlled conditions, high temperature extrusion (HTE) could be used to achieve polymorphic transformation with a number of APIs. This solvent-free continuous process was demonstrated with artemisinin, piracetam, carbamazepine and chlorpropamide. Artemisinin was used as a detailed case study of stability, solvent mediated transformation and mechanism of polymrophic transformation during extrusion, using computational modelling and model shear flows. At high temperature, phase transformation from orthorhombic to triclinic crystals was found to occur via the vapour phase. Under mechanical stress the crystalline structure was disrupted, leading to new surfaces being continuously formed and exposed to high temperatures; thus accelerating the transformation process. Polymorphic transformation during HTE was found to comprise three stages; i) preheating and conveying; ii) vapour phase transformation and size reduction and iii) continuous transformation and agglomeration. The triclinic form showed four times greater dissolution rate as compared to the orthorhombic form. The triclinic form showed two fold increase in bioavailability in Albino rats

Stoichiometric control of co-crystal formation by solvent free continuous co-crystallization (SFCC).

yesReproducible control of stoichiometry and difficulties in large scale production have been identified as two of the major challenges to commercial uptake of pharmaceutical co-crystals. The aim of this research was to extend the application of SFCC to control stoichiometry in caffeine: maleic acid co-crystals. Both 1:1 and 2:1 caffeine: maleic acid co-crystals were produced by control of the feedstock composition and process conditions. It was also observed that formation of 2:1 stoichiometry co-crystals involved formation of a 1:1 co-crystal which was subsequently transformed to 2:1 co-crystals. The investigation of stoichiometric transformation revealed that although 1:1 co-crystals could be converted into 2:1 form with addition of excess caffeine, the reverse was not possible in the presence of excess maleic acid. However, conversion from 2:1 into 1:1 was only achieved by melt seeding with the phase pure 1:1 co-crystals. This investigation demonstrates that stoichiometric control can be achieved by SFCC by control of parameters such as extrusion temperature

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Mechanism for Polymorphic Transformation of Artemisinin during High Temperature Extrusion

A novel, green, and continuous method for solid-state polymorphic transformation of artemisinin by high temperature extrusion has recently been demonstrated. This communication describes attempts to understand the mechanisms causing phase transformation during the extrusion process. Polymorphic transformation was investigated using hot stage microscopy and a model shear cell. At high temperature, phase transformation from orthorhombic to the triclinic crystals was observed through a vapor phase. Under mechanical stress, the crystalline structure was disrupted continuously, exposing new surfaces and accelerating the transformation process

Polymorphic transformation of artemisinin by high temperature extrusion

NoThis communication reports a novel solvent free method to generate and stabilise the triclinic form of artemisinin. We show that the stability of the triclinic form obtained by high temperature extrusion is greater than that of material made using a solvent based technique

Mechanism for Polymorphic Transformation of Artemisinin during High Temperature Extrusion

NoA novel, green, and continuous method for solid-state polymorphic transformation of artemisinin by high temperature extrusion has recently been demonstrated. This communication describes attempts to understand the mechanisms causing phase transformation during the extrusion process. Polymorphic transformation was investigated using hot stage microscopy and a model shear cell. At high temperature, phase transformation from orthorhombic to the triclinic crystals was observed through a vapor phase. Under mechanical stress, the crystalline structure was disrupted continuously, exposing new surfaces and accelerating the transformation process