Hot-melt co-extrusion for the production of fixed-dose combination products with a controlled release ethylcellulose matrix core.

In this study, hot-melt co-extrusion was evaluated as a technique for the production of fixed-dose combination products, using ethylcellulose as a core matrix former to control the release of metoprolol tartrate and a polyethylene oxide-based coat formulation to obtain immediate release of hydrochlorothiazide. By lowering the concentration of the hydrophilic additive polyethylene oxide in the plasticized ethylcellulose matrix or by lowering the drug load, the in vitro metoprolol tartrate release from the core was substantially sustained. The in vitro release of hydrochlorothiazide from the polyethylene oxide/polyethylene glycol coat was completed within 45 min for all formulations. Tensile testing of the core/coat mini-matrices revealed an adequate adhesion between the two layers. Raman mapping showed no migration of active substances. Solid state characterization indicated that the crystalline state of metoprolol tartrate was not affected by thermal processing via hot-melt extrusion, while hydrochlorothiazide was amorphous in the coat. These solid state characteristics were confirmed during the stability study. Considering the bioavailability of metoprolol tartrate after oral administration to dogs, the different co-extruded formulations offered a range of sustained release characteristics. Moreover, high metoprolol tartrate plasma concentrations were reached in dogs allowing the administered dose to be halved.

Coprocessing via spray drying as a formulation platform to improve the compactability of various drugs.

It was evaluated if coprocessing via spray drying can be used as a formulation platform to improve the compactability of formulations containing drug substance (acetaminophen, ibuprofen, cimetidine) and excipients (carbohydrates, disintegrant, glidant, surfactant). Experimental design was applied to optimise the drug concentration and solid content of the feed suspension. In addition, scaling-up of acetaminophen- and ibuprofen-containing formulations was performed on a production-scale spray dryer. Optimised acetaminophen (drug concentration: 70% w/w), ibuprofen (drug concentration: 75% w/w) and cimetidine (drug concentration: 70% w/w) powders were obtained via co-spray drying of aqueous suspensions with a high solid content of the feed (35% w/w) and the resulting powders were directly compressed. Scaling-up of optimised acetaminophen and ibuprofen formulations was performed successfully, resulting in a robust and reproducible manufacturing process. It can be concluded that a combination of mannitol, erythritol, Glucidex 9, Kollidon CL, colloidal silicon dioxide and polyoxyethylene 20 sorbitan monooleate allowed the spray drying of highly dosed drug substances (acetaminophen, ibuprofen, cimetidine) in order to obtain 'ready-to-compress' powder mixtures on lab-scale and production-scale equipment.

Effect of maltodextrin and superdisintegrant in directly compressible powder mixtures prepared via co-spray drying.

The effect of maltodextrins and superdisintegrants on the tablet properties was evaluated in directly compressible powders coprocessed via spray drying. Powder mixtures containing acetaminophen, mannitol, erythritol and different maltodextrin types were prepared via co-spray drying and physically mixed with crospovidone (6% w/w, Kollidon CL) in order to evaluate the influence of maltodextrin grade (amylose/amylopectin ratio) on powder hygroscopicity, flowability, density and compactability. In addition, different superdisintegrant types and grades (6% w/w) were co-spray dried to evaluate their effect on tablet disintegration time. Tablet disintegration was affected by the amylose/amylopectin ratio of the maltodextrins. Tablets containing Glucidex 2 (1-5% amylose) had a longer disintegration time compared to Glucidex 9 (20% amylose) (11.8min versus 5.7min) and Unipure DC (50-70% amylose) (1min). The disintegration time of tablets containing a coprocessed superdisintegrant was long due to loss of superdisintegrant during processing (preferential depositing on the spray dryer wall) and was in the following order: Kollidon CL

Process design applied to optimise a directly compressible powder produced via a continuous manufacturing process.

Manufacturing of 'ready-to-compress' powder mixtures for direct compression was performed by spray drying, without granulation, milling and/or blending steps in between spray drying and compaction. Powder mixtures containing acetaminophen, mannitol, erythritol, maltodextrin, crospovidone, colloidal silicon dioxide and polyoxyethylene 20 sorbitan monooleate were prepared via co-spray drying. A feed suspension having a solid content of 27.2% w/w was selected for further process optimisation because of its high process yield, excellent flowability and short tablet disintegration time. Experimental design was applied to evaluate processibility, physico-chemical properties and compactability of the spray dried powder mixtures. Significant and adequate regression models were developed for powder flowability, median particle size, bulk density, residual moisture content and process yield. An increasing inlet and outlet drying air temperature improved process yield. However, a higher inlet drying air temperature had a negative influence on density and moisture content, while the latter decreased at higher outlet drying air temperatures. Median particle size increased with a higher inlet temperature, while the outlet temperature had the opposite affect. Numerical optimisation determined the optimal spray drying process (inlet temperature: 221 degrees C, outlet temperature: 81 degrees C and atomisation pressure: 6 bar) in order to produce 'ready-to-compress' powder mixtures.

Development of directly compressible powders via co-spray drying.

Continuous production of directly compressible powders was achieved by coprocessing acetaminophen and carbohydrates via spray drying. Binary and ternary powder mixtures containing drug substance and carbohydrates were prepared by co-spray drying and evaluated on spray drying processibility, powder hygroscopicity, flowability, and compactability. The influence of process parameters during spray drying on the compaction behaviour of drug/excipient mixtures was investigated via Heckel analysis. Erythritol, lactose, maltodextrin, and mannitol were efficient in co-spray drying with acetaminophen. However, lactose mixtures showed poor flowability. Spray dried mixtures containing mannitol and erythritol were characterised as non-hygroscopic, highly dense, and good flowing powders. Mannitol increased tablet tensile strength in contrast with the poor compactability of erythritol. Maltodextrin was selected for further experiments because it provided excellent tablet tensile strength. The use of erythritol, maltodextrin and mannitol in binary drug/excipient mixtures resulted in high process yields. Compacts of erythritol, mannitol, and maltodextrin were characterised by higher tablet tensile strength at higher spray drying temperatures due to the increased particle fragmentation of erythritol and mannitol mixtures and to the increased plastic deformation of maltodextrin formulations. A combination of erythritol, maltodextrin, and mannitol was selected for further formulation and process optimisation of co-spray dried powders for direct compression.