J.P. Remon

Development and testing of bioadhesive, fluoride-containing slow-release tablets for oral use.

Abstract— The bioadhesive characteristics of tablets for oral use made from modified starch, polyacrylic acid (PAA), polyethylene glycol (PEG) and sodium carboxymethylcellulose (CMC) were investigated. Adhesion force and energy were determined in‐vitro and maximal adhesion time was evaluated in‐vivo in human subjects. In‐vitro, PAA showed the best bioadhesive properties, followed by modified maize starch and PEG with a mol. wt of 300 000–400 000 daltons. The presence of 0·1 mg of fluoride as NaF did not lead to significant differences in adhesion force and energy for the same formulation. The in‐vivo bioadhesion was not strongly correlated to the in‐vitro data. PAA, despite its excellent adhesion, proved to be irritating to the mucosa. PEG with a mol. wt of 200000 daltons was subject to erosion. CMC showed good bioadhesive properties but the mechanical strength of the tablets was low. Modified maize starch tablets containing 5% (w/w) PAA and PEG with a mol. wt of 300 000 daltons proved to be the most suitable formulations for a fluoride‐slow‐release tablet with bioadhesive properties. In‐vitro, the tablets released all of the fluoride within the 8 h period, with a high initial release. The release rate was related to the water absorption rate of the tablets. The PAA‐containing formulations and the CMC formulations had the fastest release. In‐vivo, fluoride levels with a minimum of 150 and a maximum of 1000 μg mL−1 were maintained for 8 h in the oral cavity. These fluoride levels were sustained significantly longer than those obtained with the administration of fourfold the amount of fluoride in the form of a fluoride‐containing toothpaste. The release characteristics in‐vivo exhibited a high variation. The use of bioadhesive polymers in oral pharmacotherapy seems promising.

In-Line and Real-Time Process Monitoring of a Freeze Drying Process Using Raman and NIR Spectroscopy as Complementary Process Analytical Technology (PAT) Tools

The aim of the present study was to examine the complementary properties of Raman and near infrared (NIR) spectroscopy as PAT tools for the fast, noninvasive, nondestructive and in-line process monitoring of a freeze drying process. Therefore, Raman and NIR probes were built in the freeze dryer chamber, allowing simultaneous process monitoring. A 5% (w/v) mannitol solution was used as model for freeze drying. Raman and NIR spectra were continuously collected during freeze drying (one Raman and NIR spectrum/min) and the spectra were analyzed using principal component analysis (PCA) and multivariate curve resolution (MCR). Raman spectroscopy was able to supply information about (i) the mannitol solid state throughout the entire process, (ii) the endpoint of freezing (endpoint of mannitol crystallization), and (iii) several physical and chemical phenomena occurring during the process (onset of ice nucleation, onset of mannitol crystallization). NIR spectroscopy proved to be a more sensitive tool to monitor the critical aspects during drying: (i) endpoint of ice sublimation and (ii) monitoring the release of hydrate water during storage. Furthermore, via NIR spectroscopy some Raman observations were confirmed: start of ice nucleation, end of mannitol crystallization and solid state characteristics of the end product. When Raman and NIR monitoring were performed on the same vial, the Raman signal was saturated during the freezing step caused by reflected NIR light reaching the Raman detector. Therefore, NIR and Raman measurements were done on a different vial. Also the importance of the position of the probes (Raman probe above the vial and NIR probe at the bottom of the sidewall of the vial) in order to obtain all required critical information is outlined. Combining Raman and NIR spectroscopy for the simultaneous monitoring of freeze drying allows monitoring almost all critical freeze drying process aspects. Both techniques do not only complement each other, they also provided mutual confirmation of specific conclusions.

Modified starches as hydrophilic matrices for controlled oral delivery. I. Production and characterisation of thermally modified starches

Abstract Thermal modified starches are introduced as hydrophilic matrices for controlled oral delivery systems. Three native starches, varying in their amylose/amylopectin content were pregelatinized by extrusion, drum-drying and a controlled pregelatinization-spray-drying technique in order to produce cold water-swellable starches. Partial pregelatinized starch could only be produced by the controlled pregelatinization-spray-drying technique. The influence of the amylose/amylopectin content and of the technique and degree of pregelatinization on the properties of the final products was evaluated. As regards the application as hydrogel matrices in controlled release tablets, promising results were seen for the extruded and drum-dried starches containing a medium to a high amount of amylopectin.

Modified starches as hydrophilic matrices for controlled oral delivery. II: In vitro drug release evaluation of thermally modified starches

Abstract Because of their cold water swellability, non-toxicity and low cost, thermally modified starches might be interesting excipients for sustained release tablets. The formation of an obstructive gel layer is required to ensure a sustained drug release. Only fully pregelatinized starches containing a low amount of amylose produced such gel layers in water. Tabletting additives as silicium dioxide did not influence the drug release rate while lubricants such as magnesium stearate and polyethyleneglycol 6000 increased the drug release rate dramatically. Only sodium benzoate seemed a useful lubricant which even prolonged the drug release. The gel strength of the hydrated tablets seemed proportional to the degree of amylose in the formulated starch. For starches containing 25% amylose, at a low compression force a splitting of the tablet was seen after a few hours of dissolution. This phenomenon, called “mussel effect”, caused a burst in the drug release which was increased by a large starch particle size. A compression force of at least 200 MPa could prevent this mussel effect. The drug release rate from tablets containing amylose-free starches was not influenced by the compression force, nor by the starch particle size. Thermally modified starches containing a low amount of amylose (25% and lower) revealed promising properties as directly compressible tabletting excipients for sustained release purposes.

Validation of a continuous granulation process using a twin-screw extruder

Using twin-screw granulation as particle size enlargement technique, the effect of modifying the screw configuration (number of mixing zones, configuration of kneading block) on granule quality, tablet properties and mixing efficiency was investigated. The amount of oversized agglomerates and yield was significantly influenced by the presence of an extra conveying element at the screw end. Changing the staggering angle of the kneading block significantly affected yield and granule friability. The 90 degrees configuration resulted in a lower yield and granule friability. Disintegration time was the only tablet property significantly influenced by the screw configuration as disintegration was significantly faster when an extra conveying element was placed at the screw end. The influence of tracer addition method (wet vs. dry) on mixing efficiency inside the extruder barrel was investigated by means of different tracers: riboflavin (0.05%) suspended in the granulation liquid and hydrochlorothiazide (2.5%) added separately as powder. Mixing efficiency in function of time and granule size (above and below 1400 microm) was tested using riboflavine sodium phosphate (0.05%) dissolved in the granulation liquid. Since a good mixing efficiency was obtained independent of tracer addition method, tracer solubility, granulation time and granule size, continuous granulation using a twin-screw extruder was identified as a robust process.

Matrix mini-tablets based on starch/microcrystalline wax mixtures.

Matrix mini-tablets based on a combination of microcrystalline waxes and starch derivatives were prepared using ibuprofen as a model drug. The production of mini-tablets was preferred over the production of pellets, as up-scaling of the pelletisation process seemed problematic. Prior to tabletting, melt granulation in a hot stage screw extruder and milling were required. The in vitro drug release was varied using microcrystalline waxes with a different melting range, the slowest drug release being obtained with a formulation containing a microcrystalline wax with a melting range between 68 and 72 degrees C. Generally speaking increasing the wax concentration resulted in a slower drug release. In vitro drug release profiles were also modified using different starches and mixtures of starches. Increasing the ibuprofen concentration to 70% resulted in a faster drug release rate.

Characterisation and disintegration properties of irradiated starch.

Irradiation treatment could provide a quick and simple way to modify the physical, chemical and pharmaceutical properties of biopolymers such as starch. Corn, potato and drum dried corn starch were exposed to X-ray and electron beam (e-beam) irradiation treatment at doses of 10, 50 and 100 kGy. The disintegration properties of these starches were compared using alpha-lactose monohydrate tablets containing 5% (w/w) starch as disintegrant. Starch solubility increased, while its swelling capacity decreased with increasing irradiation dose. The irradiation treatment caused fragmentation of the amylopectin fraction. Irradiation modified the different starches thoroughly, showing remarkable differences in disintegration properties after X-ray treatment and e-beam modification. The e-beam modification resulted in significantly higher disintegration times of the tablets.

Comparison of two twin-screw extruders for continuous granulation

A comparison was made between two twin-screw extruders (APV Baker and Leistritz Micro) used for continuous wet granulation. Both extruders had similar screw configurations, based on the length-to-diameter ratio of the screws, existing out of a conveying zone of 20 D, i.e. 20 times the screw diameter and a granulation zone of 4D. The kneading blocks in the granulation zone were 2.2 and 2.5D for the Leistritz and APV extruders, respectively. An experimental design was used to investigate the influence of process parameters (total input rate and screw speed) and extruder type on granule and tablet quality. Dicalcium phosphate and alpha-lactose monohydrate were used as water-insoluble and water-soluble excipients, respectively. For dicalcium phosphate, the amount of fines (<125 microm), median granule size and granule friability were significantly influenced by extruder type and total input rate. For lactose, the amount of oversized agglomerates and median granule size were significantly affected by extruder type and total input rate. The granule formulations were properly agglomerated on both the extruders, although the extruder type had an important influence on the granule properties, which was more pronounced for dicalcium phosphate. This study shows that a given formulation cannot simply be interchanged between the two extruders without further work on the geometrics of the extruders.

Instrumentation of a gravity feed extruder and the influence of the composition of binary and ternary mixtures on the extrusion forces.

Abstract— A gravity feed extruder was adapted to monitor the extrusion forces, the temperature during processing and the rotational speed of the extruding cylinders. The extruder was used to evaluate the influence of particle size of insoluble material and of product solubility on the extrusion forces. Microcrystalline cellulose, dicalcium phosphate dihydrate and different lactoses were used as model compounds. Difference in lactose and microcrystalline cellulose particle size did not influence extrusion forces. The amount of water in the mixtures to be processed and the initial difference in solubility for some of the lactose types investigated influenced the extrusion forces dramatically. Extrusion forces recorded during processing of a mixture previously granulated in a high shear granulator were higher than when processed in a planetary mixture. Loss of water during high shear granulation is probably the main cause of this phenomenon.

Formation of theophylline monohydrate during the pelletisation of microcrystalline cellulose-anhydrous theophylline blends

Abstract The influence of the degree of wetting, during the granulation step of the pelletisation process, on the drug release from several microcrystalline cellulose-anhydrous theophylline blends was examined. Blends containing 60% theophylline show a release rate inversely related to the amount of water used for granulation. The drug release rate from mixtures prepared with 25% theophylline is less influenced by the degree of wetting. Differences in release rate were correlated with the crystal transition from anhydrous theophylline to theophylline monohydrate.