methylcellulose and dibutyl-sebacate

The aim of this study was to develop sustained-release matrix tablets by means of injection moulding and to evaluate the influence of process temperature, matrix composition (EC and HPMC concentration) and viscosity grade of ethylcellulose (EC) and hydroxypropylmethylcellulose (HPMC) on processability and drug release. The drug release data were analyzed to get insight in the release kinetics and mechanism. Formulations containing metoprolol tartrate (30%, model drug), EC with dibutyl sebacate (matrix former and plasticizer) and hydrophilic polymer HPMC were extruded and subsequently injection moulded into tablets (375 mg, 10 mm diameter, convex-shaped) at temperatures ranging from 110 to 140 degrees C. Tablets containing 30% metoprolol and 70% ethylcellulose (EC 4mPa s) showed an incomplete drug release within 24 h (<50%). Increasing production temperatures resulted in a lower drug release rate. Substituting part of the EC fraction by HPMC (HPMC/EC-ratio: 20/50 and 35/35) resulted in faster and constant drug release rates. Formulations containing 50% HPMC had a complete and first-order drug release profile with drug release controlled via the combination of diffusion and swelling/erosion. Faster drug release rates were observed for higher viscosity grades of EC (Mw>20 mPa s) and HPMC (4000 and 10,000 mPa s). Tablet porosity was low (<4%). Differential scanning calorimetry (DSC) and X-ray powder diffraction studies (X-RD) showed that solid dispersions were formed during processing. Using thermogravimetrical analysis (TGA) and gel-permeation chromatography no degradation of drug and matrix polymer was observed. The surface morphology was investigated with the aid of scanning electron microscopy (SEM) showing an influence of the process temperature. Raman spectroscopy demonstrated that the drug is distributed in the entire matrix, however, some drug clusters were identified.

Topics: Calorimetry, Differential Scanning; Cellulose; Delayed-Action Preparations; Dicarboxylic Acids; Excipients; Hypromellose Derivatives; Methylcellulose; Metoprolol; Plasticizers; Porosity; Spectrum Analysis, Raman; Tablets; Technology, Pharmaceutical; Temperature; Viscosity; X-Ray Diffraction

The compression and compaction properties of plasticised high molecular weight USP2208 HPMC were investigated with the aim of improving tablet formation in HPMC matrices. Experiments were conducted on binary polymer-plasticiser mixtures containing 17 wt.% plasticiser, and on a model hydrophilic matrix formulation. A selection of common plasticisers, propylene glycol (PG) glycerol (GLY), dibutyl sebacate (DBS) and triacetin (TRI), were chosen to provide a range of plasticisation efficiencies. T(g) values of binary mixtures determined by Dynamic Mechanical Thermal Analysis (DMTA) were in rank order PG>GLY>DBS>TRI>unplasticised HPMC. Mean yield pressure, strain rate sensitivity (SRS) and plastic compaction energy were measured during the compression process, and matrix properties were monitored by tensile strength and axial expansion post-compression. Compression of HPMC:PG binary mixtures resulted in a marked reduction in mean yield pressure and a significant increase in SRS, suggesting a classical plasticisation of HPMC analogous to that produced by water. The effect of PG was also reflected in matrix properties. At compression pressures below 70 MPa, compacts had greater tensile strength than those from native polymer, and over the range 35 and 70 MPa, lower plastic compaction values showed that less energy was required to produce the compacts. Axial expansion was also reduced. Above 70 MPa tensile strength was limited to 3 MPa. These results suggest a useful improvement of HPMC compaction and matrix properties by PG plasticisation, with lowering of T(g) resulting in improved deformation and internal bonding. These effects were also detectable in the model formulation containing a minimal polymer content for an HPMC matrix. Other plasticisers were largely ineffective, matrix strength was poor and axial expansion high. The hydrophobic plasticisers (DBS, TRI) reduced yield pressure substantially, but were poor plasticisers and showed compaction mechanisms that could be attributed to phase separation. The effect of different plasticisers suggests that the deformation characteristics of this HPMC in the solid state is dominated by hydroxyl mediated bonding, rather than by hydrophobic interactions between methoxyl-rich regions.

Topics: Chemistry, Pharmaceutical; Dicarboxylic Acids; Drug Carriers; Elasticity; Hypromellose Derivatives; Methylcellulose; Models, Chemical; Molecular Weight; Plasticizers; Polymers; Pressure; Propylene Glycols; Tablets; Technology, Pharmaceutical; Tensile Strength; Triacetin

The mechanical properties of polymer films used in pharmaceutical coatings of pulsatile drug delivery systems were evaluated in the dry and the wet state by a newly developed puncture test, which allowed the time-dependent measurement of the mechanical properties on the same film specimen. Force, puncture strength, energy at break, modulus, and strain were investigated as a function of water exposure time with respect to the type of polymer and the type and concentration of plasticizer and pore former (hydroxypropyl methylcellulose, HPMC). Eudragit RS films were very flexible, had a high strain, and broke upon puncture with only small cracks. In contrast, ethylcellulose films were more brittle with a lower strain and showed complete film rupture. Increased amounts of the hydrophilic pore former, HPMC, resulted in a reduced puncture strength and in an increase in water uptake and weight loss of the films. The puncture strength decreased with increasing plasticizer concentration and was lower with the lipophilic dibutyl sebacate than with the hydrophilic triethyl citrate.

Topics: Acrylic Resins; Cellulose; Citrates; Dicarboxylic Acids; Drug Delivery Systems; Hypromellose Derivatives; Mechanics; Methylcellulose; Pulsatile Flow; Time Factors; Water