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Ibuprofen Development using HME

Hot-melt extrusion (HME) has been used in a wide range of manufacturing processes. Aside from its use in the plastics, rubber and food manufacturing sectors, HME has been used in the manufacture of pharmaceutical dosage forms e.g. tablets or films. In general terms, HME involves pumping a mixture of raw materials at controlled (often elevated) temperature and/or pressure through a barrel to produce a composition that is forced out of the barrel through a die. The raw materials are typically fed into the extruder (the extruder barrel) via a hopper. Flow through the barrel is usually associated with mixing, grinding, compressing, kneading and/or venting. Within the barrel are typically one or two rotating screws (corotating or counter rotating).

Initial extruded compositions (extrudates) usually require further processing before final use, for example into powders for tabletisation in the field of pharmaceuticals. However, many prior art extrusion methods (especially where Ibuprofen is extruded) result in sticky extrudates that require cryo-milling for powder formation. Cryo-milling is a time consuming and costly processing step that inhibits the scale-up of such processes to an industrial operation. Other resource-consuming, post-extrusion processing steps can include cooling, cutting, pelletising and micronisation.

It is amongst the objects of the present invention to attempt a solution to this problem (i.e. to improve the speed and efficiency with which a powdered extrudate can be formed), and to improve various characteristics of extrudates (and pharmaceutical forms derived therefrom) for pharmaceutical use, such as improved drug-loading, stability and taste-masking and, in the case of tablet forms in particular, increased disintegration rate, increased hardness and decreased friability.




HDEG (Platform Technology)

Hot-melt extrusion (HME) has been used in a wide range of manufacturing processes. Aside from its use in the plastics, rubber and food manufacturing sectors, HME has been used in the manufacture of pharmaceutical dosage forms e.g. tablets or films. In general terms, HME involves pumping a mixture of raw materials at controlled (often elevated) temperature and/or pressure through a barrel to produce a composition that is forced out of the barrel through a die. The raw materials are typically fed into the extruder (the extruder barrel) via a hopper. Flow through the barrel is usually associated with mixing, grinding, compressing, kneading and/or venting. Within the barrel are typically one or two rotating screws (corotating or counter rotating).

Initial extruded compositions (extrudates) usually require further processing before final use, for example into powders for tabletisation in the field of pharmaceuticals. However, many prior art extrusion methods (especially where Ibuprofen is extruded) result in sticky extrudates that require cryo-milling for powder formation. Cryo-milling is a time consuming and costly processing step that inhibits the scale-up of such processes to an industrial operation. Other resource-consuming, post-extrusion processing steps can include cooling, cutting, pelletizing and micronisation.

It is amongst the objects of the present invention to attempt a solution to this problem (i.e. to improve the speed and efficiency with which a powdered extrudate can be formed), and to improve various characteristics of extrudes (and pharmaceutical forms derived therefrom) for pharmaceutical use, such as improved drug-loading, stability and taste-masking and, in the case of tablet forms in particular, increased disintegration rate, increased hardness and decreased friability.




SiSTME

Over the last decade, there has been an increased interest in crystal engineering (e.g. salts) research to enhance drug solubility and mechanical properties. About 40% of the drugs in the discovery pipeline are failing out due to poor solubility with massive inherent costs (over £20 billion a year) and lengthy time. Thus, there is a clear market need to develop methods to make drugs more soluble. We propose a multi-disciplinary study involving continuous manufacturing (CM) of pharmaceutical salts (SiSTME) to tackle this growing need. Batch processes are highly costs and time intensive with low plant productivity. Thus, a CM process eliminating intermediate steps will improve product quality assurance. SiSTME (a process to manufacture salts of poorly water soluble weak acidic drugs in presence of neutral components such as a base with/without any addition of solvents) is an easy to scale up, economically practical and solvent free (with an option to use liquid if required) process with fewer processing steps. Apart from saving time and costs, CM via SiSTME can dramatically reduce building, energy and carbon footprints. The optimization and consequent development of this study is very crucial to the economic impact as it relates the global pharmaceutical needs to its implementations. This project entirely fits within the regulatory priority remit by providing state-of-the-art experimental techniques tuned to the current problems of pharmaceutical salts manufacturing and scale up.

SiSTME aims to disclose, for the first time, the study of feasibility of CM of salts of various water insoluble drugs (e.g. ibuprofen, phenytoin, diclofenac, and indomethacin).

The proposed development of SiSTME will indeed accelerate industrial interest in this field, providing direct benefits to the European pharmaceutical sector and wider long-term benefits to public health through the feasibility of otherwise unusable drugs.

Pharmaceutical salts are crystals that contain two or more neutral components (both solid at ambient temperatures), present in stoichiometric amounts. To date, salts are an emerging interest in pharmaceutical drug development to improve the solubility, dissolution and thus bioavailability of various poorly water soluble drugs. Salts enable the modification of key physicochemical properties of pharmaceuticals (e.g. stability) that impact on processing, pharmacokinetics, efficacy, toxicity, stability and design of the final dosage forms. As a result there is growing interest in the development of salts of active pharmaceutical ingredients (APIs).

Up to date, the ‘solvent growth method’ and ‘mechanical method’ are two most common techniques that have been used to make pharmaceutical salts. But in reality none of the techniques except the solvent growth method is scalable and all of them are time consuming. Excessive use of solvent can be harmful and costly as well and small residues of solvent can be toxic which can again raise regulatory issues. Another disadvantage of using the solvent growth method is the dispersion of two molecules in same solvent, which is not always possible as it creates equilibrium solubility difficulties.