Jyrki Heinämäki

Extrusion-spheronization of pH-sensitive polymeric matrix pellets for possible colonic drug delivery.

The aim of this study was to investigate extrusion-spheronization pelletization for preparing pH-sensitive matrix pellets for colon-specific drug delivery. The effects of three independent variables (amounts of Eudragit S, citric acid and spheronizing time) on pellet size, shape (roundness and aspect ratio), and drug release were studied with central composite design. The pellets contained ibuprofen as a model drug, citric acid as a pH-adjusting agent, Eudragit S as a pH-sensitive binder and microcrystalline cellulose (MCC). The pellets were prepared with Nica extrusion-spheronizing equipment and subsequently enteric-coated using an air-suspension technique. Eudragit S as a pH-sensitive matrix former in pellets increased the pellet size and influenced pellet roundness. In small amounts Eudragit S increased pellet roundness but in larger amounts pellet roundness was reduced. Citric acid promoted the pelletization process resulting in a narrower area distribution. The pH-sensitive matrix pellet failed to delay the drug release. The combination of citric acid and enteric coating, however, delayed the drug release for 15 min in a pH 7.4 phosphate buffer.

Solid-State and Mechanical Properties of Aqueous Chitosan-Amylose Starch Films Plasticized With Polyols

The film-forming ability of chitosan and binary mixtures of chitosan and native amylose corn starch (Hylon VII) was evaluated with free films prepared by a casting/solvent evaporation method. Unplasticized and plasticized free chitosan films in aqueous acetic acid and respective films containing a mixture of chitosan and native amylose starch in acetic acid were prepared. Glycerol, sorbitol, and i-erythritol were used as plasticizers. Solid-state and mechanical properties of the films were studied by powder x-ray diffractometry (XPRD), differential scanning calorimetry (DSC), and a materials testing machine. The films composed of a mixture of chitosan and native amylose starch in acetic acid were clear and colorless. A plasticizer concentration of 20% wt/wt (of the polymer weight) ws sufficient to obtain flexible films with all samples tested. X-ray diffraction patterns and DSC thermograms indicated an amorphous state of the films independent of the type of plasticizer used. In conclusion, incorporation of native amylose com starch into chitosan films improves the consistency and the mechanical properties of the films.

A novel technique for imaging film coating defects in the film-core interface and surface of coated tablets

Confocal laser scanning microscopy (CLSM) was introduced and examined as a novel technique for imaging film-core interface and surface defects of film-coated tablets. Tablets of acetylsalicylic acid, microcrystalline cellulose (MCC) and lactose monohydrate were film-coated with aqueous hydroxypropyl methylcellulose using an instrumented side-vented pan coater. The film coatings were applied using 100- and 500-kPa spraying air pressures. The CLSM images of the coating surface were compared with surface roughness measurements using a laser profilometer and an optical roughness analyzer. The spraying air pressure affected the film-core interface and the occurrence of coating defects. With the lower spraying pressure the aqueous coating solution penetrated into the tablet core, the core components migrated to the coating layer, and the film coating surface was clearly rougher compared to the higher spraying pressure. Storage at 25 degrees C/60% RH or 40 degrees C/75% RH for 3 months expanded the MCC-containing tablet core impaired the film structure and increased the film roughness. Based on the present results, CLSM is an effective tool for imaging film-core interface and surface defects of film-coated tablets. The CLSM images are supported by the results obtained with the other surface roughness measuring techniques.

Monitoring tablet surface roughness during the film coating process

The purpose of this study was to evaluate the change of surface roughness and the development of the film during the film coating process using laser profilometer roughness measurements, SEM imaging, and energy dispersive X-ray (EDX) analysis. Surface roughness and texture changes developing during the process of film coating tablets were studied by noncontact laser profilometry and scanning electron microscopy (SEM). An EDX analysis was used to monitor the magnesium stearate and titanium dioxide of the tablets. The tablet cores were film coated with aqueous hydroxypropyl methylcellulose, and the film coating was performed using an instrumented pilot-scale side-vented drum coater. The SEM images of the film-coated tablets showed that within the first 30 minutes, the surface of the tablet cores was completely covered with a thin film. The magnesium signal that was monitored by SEM-EDX disappeared after ∼15 to 30 minutes, indicating that the tablet surface was homogeneously covered with film coating. The surface roughness started to increase from the beginning of the coating process, and the increase in the roughness broke off after 30 minutes of spraying. The results clearly showed that the surface roughness of the tablets increased until the film coating covered the whole surface area of the tablets, corresponding to a coating time period of 15 to 30 minutes (from the beginning of the spraying phase). Thereafter, the film only became thicker. The methods used in this study were applicable in the visualization of the changes caused by the film coating on the tablet surfaces.

Corn starches as film formers in aqueous-based film coating.

The purpose of this study was to evaluate the film formation ability and mechanical stress–strain properties of aqueous native corn starches, using free films and film coatings applied to tablets. Free films were prepared from high-amylose corn (Hylon VII), corn and waxy corn starches, using sorbitol and glycerol as plasticizers. The tablets and pellets were film-coated using an air-suspension coater, and characterized with respect to the film coating surface topography, cross-sectional structure and thickness (SEM), and dissolution in vitro. The amylose content of the starch film formers affected both the tensile strength and the elongation. The elongations were under 5% for even the plasticized starches, and in most cases, no plasticization effect was seen by either of the plasticizers. Dissolution of native corn starch film-coated tablets (weight gain 1%) did not differ from uncoated ones. A notable delay in dissolution of the drug was found by increasing Hylon VII film coating thickness, suggesting controlled-release characteristics.

Enhanced stability of rubbery amylose-rich maize starch films plasticized with a combination of sorbitol and glycerol

Well known aging problems with rubbery starch films are the migration of plasticizer and increased crystallinity leading to embrittlement. The effects of a combination of sorbitol and glycerol used as plasticizers on mechanical, moisture permeability and solid-state properties of rubbery amylose maize starch (Hylon VII) films were studied. The films were prepared by casting and were exposed to conditions of 25 degrees C/60% relative humidity (RH) and 40 degrees C/75% RH for 9 months. The starch films plasticized with a combination of sorbitol and glycerol (1:1) at equal amount to the polymer weight, were shown to be the most stable alternative of the studied films during the 9 months storage period. The water vapor transmission (WVTR) of the films did not change during the period of storage and neither did the elongation at break, but the tensile strength increased. X-ray diffraction (XRD) results showed that during storage no crystallization had occurred. The combination of sorbitol and glycerol prevented the migration of the plasticizer molecules out of the film.

Tablet film-coating with amylose-rich maize starch.

The purpose of the present study was to investigate an aqueous-based amylose-rich maize starch (Hylon VII) film-coating process of tablets performed by a side-vented pan coating system. Three formulation or process parameters of potential importance, including the plasticizer concentration (X(1)), the temperature of coating pan (X(2)) and the spray rate of the coating solution (X(3)), were evaluated using a central composite face-centred experimental design. Only a few process-related limitations associated with the aqueous film coating of Hylon VII were observed, and, in general, the coated tablets were of fairly good quality. At low spray rates, the temperature of the coating pan did not affect the roughness of the coated tablets. At higher spray rates, higher temperature gave smoother films. As regards surface quality and smoothness, a plasticizer concentration (i.e., a 1:1 mixture of sorbitol and glycerol) of approximately 65% of the polymer weight, seems to be suitable for the present formulations. The dissolution of all Hylon VII-coated tablets in an acidic medium was rapid, more than 75% of the drug (theophylline) dissolved within 15 min. On the basis of the present results, it can be concluded that amylose-rich maize starch (Hylon VII) may be considered as an aqueous film-coating agent to be used for pharmaceutical purposes and in established film-coating processes.

Establishing quantitative in-line analysis of multiple solid-state transformations during dehydration

The aim of the study was to conduct quantitative solid phase analysis of piroxicam (PRX) and carbamazepine (CBZ) during isothermal dehydration in situ, and additionally exploit the constructed quantitative models to analyze the solid-state forms in-line during fluidized bed drying. Vibrational spectroscopy (near-infrared (NIR), Raman) was employed for monitoring the dehydration and the quantitative model was based on partial least squares (PLS) regression. PLS quantification was confirmed experimentally using isothermal thermogravimetric analysis (TGA) and X-ray powder diffractometry (XRPD). To appraise the quality of quantitative models several model parameters were evaluated. The hot-stage spectroscopy quantification results were found to be in reasonable agreement with TGA and XRPD results. Quantification of PRX forms showed complementary results with both spectroscopic techniques. The solid-state forms observed during CBZ dihydrate dehydration were quantified with Raman spectroscopy, but NIR spectroscopy failed to differentiate between the anhydrous solid-state forms of CBZ. In addition to in situ dehydration quantification, Raman spectroscopy in combination with PLS regression enabled in-line analysis of the solid-state transformations of CBZ during dehydration in a fluidized bed dryer.

The mechanical and moisture permeability properties of aqueous-based hydroxypropyl methylcellulose coating systems plasticized with polyethylene glycol

Abstract The effects of polyethylene glycols (PEG 400, 1500 and 4000) used as plasticizer on the moisture permeability and mechanical properties of aqueous hydroxypropyl methylcellulose (HPMC) films were evaluated with free films. The free films were prepared by using a pneumatic spraying technique similar to that used in fluidized-bed coaters. There was a clear relationship between some physical film properties and the molecular weights and concentrations of the PEGs used as plasticizer. Over the range of concentrations tested, the moisture permeability of the films decreased slightly as compared to unplasticized control films with increasing molecular weight of the plasticizer. The mechanical strength of the films was shown to be more dependent on the concentration than on the molecular weight of the PEGs, while the ductility of the films was mainly dependent on the molecular weight of the PEG. The addition of PEG at a concentration of 10% resulted in relatively hard and strong films with a moderate elongation (ductility), especially when lower molecular weight plasticizers (PEG 400 or 1500) were used. As regards permeability to moisture and mechanical properties, the addition of PEG at a concentration in the range of 10–20% of the polymer weight seems to be beneficial for aqueous-based HPMC film coats.

Electrospun nanofibers as a potential controlled-release solid dispersion system for poorly water-soluble drugs.

Electrospinning was introduced as a novel technique for preparing controlled-release (CR) amorphous solid dispersions (SD) and polymeric nanofibers of a poorly water-soluble drug. Piroxicam (PRX) was used as a low-dose poorly-soluble drug and hydroxypropyl methylcellulose (HPMC) as an amorphous-state stabilising carrier polymer in nanofibers. Raman spectroscopy, X-ray powder diffraction (XPRD), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM) were used in the physical characterisation of the CR-SD nanofibers. Special attention was paid on the effects of a polymer and solvent system on the solid-state properties and physical stability of nanofibers. The average dry diameter of the electrospun CR-SD nanofibers ranged from 400 to 600 nm (SEM). PRX existed in amorphous form in the nanofibers immediately after fabrication and after a short-term (3-month) aging at low temperature (6-8 °C/0% RH) and ambient room temperature (22 °C/0% RH). At higher temperature and humidity (30 °C/85% RH), however, amorphous PRX in the nanofibers tended to slowly recrystallise to PRX form III. The electrospun CR-SD nanofibers exhibited a short lag-time, the absence of initial burst release and zero-order linear CR dissolution kinetics. In conclusion, electrospinning can be used to fabricate supersaturating CR-SD nanofibers of PRX and HPMC, and to stabilise the amorphous state of PRX.