Use of к-carrageenan, chitosan and Carbopol 974P in extruded and spheronized pellets that are devoid of MCC.

The search for excipients to replace microcrystalline cellulose (MCC) in the production of pellets by extrusion-spheronization in cases of drug incompatibility or the lack of pellet matrix disintegration forms the basis of this study. A combination of к-carrageenan as a spheronization aid, chitosan as a diluent and Carbopol(®) 974P as a binder in the production of pellets containing no MCC has been investigated using acetaminophen as a model drug. Design of experiments allowed assessment of formulation and processing effects on pellet responses that included size, shape, fines, yield and friability. Statistical analysis revealed that the main factors and some of the two-factor interactions had a significant effect on pellet characteristics. Formulations containing high levels of к-carrageenan required more water to produce a wetted mass with good extrudability and extrudate capable of being spheronized. Although only a low level of Carbopol was used in the formulation, it imparted cohesiveness to the wetted mass as well as the extrudate. Furthermore, it was discovered that Carbopol could act as an extrusion aid, enabling the wetted mass to flow easily through the extruder screen holes without building up heat. Spherical and rugged pellets were produced that met the immediate release criterion.

Interplay of formulation and process methodology on the extent of nifedipine molecular dispersion in polymers.

The aim of this study is to evaluate effects of formulation and process technology on drug molecular dispersibility in solid dispersions (SDs). Nifedipine solid dispersions with ethylcellulose (EC) and/or Eudragit RL (RL) prepared by co-precipitation, co-evaporation, and fusion methods were characterized with FTIR, DSC, and XRPD for the content of nifedipine as molecular dispersion, amorphous and/or crystalline suspensions. A method was developed based on regular solution and Flory-Huggins theories to calculate drug-polymer interaction parameter in solid dispersion systems. A synergic effect of RL and EC on nifedipine molecular dispersibility in solid dispersions was observed. Increasing RL/EC ratio resulted in a higher degree of drug-polymer interaction that thermodynamically favored molecular dispersion, which, however, was counteracted by a corresponding decrease in the matrix glass transition point that kinetically favored phase-separation. Process methodology was found to play an important role in the formation of amorphous SD. The ranking of technologies with respect to the extent of molecular dispersion from high to low is fusion>co-evaporation>co-precipitation, wherein the solidification rate of polymeric solution and non-solvent effects were linked to kinetic entrapment of drug molecules in polymeric networks. Since nifedipine molecular dispersibility in EC/RL polymer(s) is a result of interplay between thermodynamic and kinetic factors, nifedipine molecular dispersions prepared for this study are thermodynamically metastable systems. To explore those supersaturation systems for use in drug delivery of poorly water soluble drugs, it is critical to balance drug-polymer interactions and matrix glass transition point and to consider a process technology with a fast solidification rate during formulation and process development of amorphous SD.

Drug-polymer interaction and its significance on the physical stability of nifedipine amorphous dispersion in microparticles of an ammonio methacrylate copolymer and ethylcellulose binary blend.

Using spectroscopic and thermal analysis, this study investigated drug-polymer interaction and its significance on the physical stability of drug amorphous dispersion in microparticles of an ammonio polymethacrylate copolymer (Eudragit RL) (RL) and ethylcellulose (EC) binary blend (RL/EC = 2:1 w/w) prepared for use in controlled release of poorly water-soluble drugs. Solid dispersion of the model drug, nifedipine in the microparticles could be described as an ideal amorphous mixture for drug loadings up to 11% w/w. The antiplasticizing effect of the polymer blend was indicated by a significant increase in the glass transition point from approximately 50 degrees C for the amorphous nifedipine to approximately 115 degrees C for its solid solution. Moreover, shifts in infrared vibration wavenumber of nifedipine carbonyl and amine groups suggested that the hydrogen bonds (H-bonds) originally formed among nifedipine molecules were broken and replaced by those formed between nifedipine and polymers in the microparticles. Further infrared analysis on nifedipine amorphous dispersions with a single polymer, namely RL or EC, confirmed the proposed hydrogen-bonding interactions; and their stability study results suggested that both antiplasticizing effects and hydrogen bonding of EC and RL with nifedipine might be responsible for the physical stability of the microparticles of nifedipine amorphous dispersion with a RL/EC binary blend.

Nifedipine molecular dispersion in microparticles of ammonio methacrylate copolymer and ethylcellulose binary blends for controlled drug delivery: effect of matrix composition.

The objective of this study is to explore matrix-type microparticles, comprising a solid dispersion of drug with an ammonio methacrylate copolymer and ethylcellulose binary blend, for use in the controlled release of a poorly water-soluble drug, nifedipine. Microparticles consisting of an ethylcellulose N7 (N7) and Eudragit RL (RL) binary blend at different ratios were prepared using phase-separation methodology. The effects of matrix composition on microparticle properties were evaluated by polarized light microscopy, differential scanning calorimetry (DSC), FT-infrared and UV-visible spectroscopy, stability, and drug release studies. Study results indicate that the particle size distribution, particle morphology, and drug release rate from the microparticles were influenced by the ratio of RL to N7. Discrete spherical microparticles with a narrow size distribution and a controlled release profile were obtained when the ratio of RL to N7 was in the range from 1:1 to 2:1 w/w. Solid-state characterization and release kinetic studies on these microparticles confirmed that the nifedipine release from the microparticles followed the Baker and Lonsdale's matrix diffusion model (1974) for microspheres containing dissolved drug, and the nifedipine diffusion in the microparticle matrix was the rate-limiting step. As the ratio of RL to N7 was changed from 0:1 to 4:1 w/w, the effective drug diffusion coefficient in the micro-matrix increased from 5.8 x 10-10 to 8.6 x 10-9 (cm2/h). In addition, probably due to formation of a stable molecular dispersion promoted by hydrogen bonding between nifedipine and the polymers, no significant changes in the nifedipine physical form or release kinetics were observed after 1-year storage at ambient room temperature followed by 3-month accelerated stability at 40 degrees C/75% RH in a closed container.

Thermogravimetric analysis for the determination of water release rate from microcrystalline cellulose dry powder and wet bead systems.

The purpose of this work was to determine the total amount of water contained in dry powder and wet bead samples of microcrystalline cellulose, MCC, (Avicel PH-101), taken from various stages of the extrusion/marumerization process used to make beads and to determine the kinetic rates of water release from each sample. These samples were allowed to equilibrate in controlled humidity chambers at 25 degrees C. The total amount of water in each sample, after equilibration, was determined by thermogravimetric analysis (TGA) as a function of temperature. The rates of water release from these samples were determined by using isothermal gravimetric analysis (ITGA) as a function of time. Analysis of the results for these studies suggest that water was released from these systems by several different kinetic mechanisms. The water release mechanisms for these systems include: zero order, second order, and diffusion controlled kinetics. It is believed that all three kinetic mechanisms will occur at the same time, however; only one mechanism will be prominent. The prominent mechanism was based on the amount of water present in the sample.

Nifedipine solid dispersion in microparticles of ammonio methacrylate copolymer and ethylcellulose binary blend for controlled drug delivery. Effect of drug loading on release kinetics.

In order to elucidate the controlled-release mechanism of a poorly water-soluble drug from microparticles of ammonio methacrylate copolymer and ethylcellulose binary blend prepared by a phase-separation method, nifedipine-loaded microparticles with different levels of drug loading were evaluated by micromeritic properties, drug physical state, matrix internal structure, drug dissolution, and release modeling. Drug release study indicated that nifedipine release from the microparticles followed the Fickian diffusion mechanism, which supported the study hypothesis that as a result of formation of a nifedipine molecular dispersion, nifedipine dissolution inside the matrix was no longer the rate-limiting step for drug release, and the drug diffusion in matrix became the slowest step instead. Moreover, study results indicated that even though drug loading did not significantly affect the microparticle size distribution and morphology, nifedipine release rate from those microparticles was more or less influenced by the level of drug loading, depending on matrix formulation. At lower levels of drug loading, nifedipine release was well described by the Baker and Lonsdale's matrix diffusion model for microspheres containing dissolved drug and nifedipine had a plasticizing effect on the polymers that caused an increase in drug effective diffusion coefficient with increasing drug loading. However, at higher levels of drug loading, probably due to formation of solid nifedipine domains in microparticles, a change in the release kinetics was observed.