Influence of manufacturing process on tabletting ability of powder: comparison between blending, grinding, and spray drying of two formulations made of theophylline and lactose/cellulose or Cellactose.

Three manufacturing processes were applied to two formulations composed of 20% anhydrous theophylline associated with either 20% microcrystalline cellulose and 60% lactose or 80% Cellactose. The processing method (dry blending, grinding, or spray drying) and the formulation were investigated through the comparison of the physical and flow characteristics and the compactibility of the end products. The results demonstrated that the formulation had a major effect on the mechanical properties, with binary blends exhibiting a higher resistance than ternary ones, whereas flow properties and densification depended on the process. Nevertheless, it was also observed that spray drying decreased the difference between the mechanical properties of the two formulations, probably by modifying the texture of the Cellactose in suspension.

The use of energy indices in estimating powder compaction functionality of mixtures in pharmaceutical tableting.

A series of binary powder blends comprising of microcrystalline cellulose (Avicel PH101), alpha-lactose monohydrate or theophylline anhydrous were prepared in order to investigate the densification of binary pharmaceutical powder mixes under compaction pressure. It is postulated that the use of derived energy parameters, as well as various evolved indices, calculated from the work expended during the fabrication and/or rupture of a compact can be employed to quantitatively predict the compaction properties of pharmaceutical powder mixes comprised of the same constituents. The relationship between the net work of compression normalized to powder volume and the resulting compact strength for mix constituents can be used to define a pharmaceutical formulation space in which compact mechanical properties can be estimated for other 'virtual mixes' of the same constituents in different proportions. The approach is successfully applied to the prediction of the mechanical properties of a ternary mix of these constituents.

The use of 13C solid state NMR to elucidate physico-chemical association in Eudragit RS100 microencapsulated acyl esters of salicylic acid.

A series of homogeneous Eudragit RS100 matrix microspheres containing molecularly dispersed acylated esterified homologues of salicylic acid, (acetylsalicylic acid, valerylsalicylic acid, or caprylsalicylic acid) were prepared in order to investigate the effect of encapsulation on solid-state orientation of the encapsulated molecule. Electrostatic association of the drug with the charged quaternary residues in the polymer may be responsible for the previously observed stability of acetylsalicylic acid (ASA) in aqueous swollen ASA-loaded Eudragit RS100 microspheres. Evaluation of the 13C nuclear magnetic resonance spectra for evidence of structural association of the incorporated probe molecules indicated that alteration of the microenvironment of the incorporated solutes had occurred. For instance, increasing the aliphatic character of the acyl side chain resulted in an increase in the upfield shift of the acyl bearing aromatic ring carbon, (C2), in the incorporated probe molecule as compared to the unincorporated probe molecule. Similarly, a downfield perturbation in the chemical shift of the free acid bearing aromatic ring carbon, (C1), was also observed. This microenvironment electrostatic shielding in the proximity of the ester carbonyl is attributed to an increase in the association of the probe molecule with the polymer subunits. Thereby, it is postulated that the matrix incorporated probe molecule is essentially shielded from hydrolytic attack until it is liberated into the external aqueous environment.

The use of particle characteristics to elucidate mix homogeneity in binary powder blends.

A series of binary powder blends comprising microcrystalline cellulose (Avicel PH101), alpha-lactose monohydrate, or anhydrous theophylline were prepared in order to investigate the ability of particle-characteristics measurements to express the homogeneity of the resulting mixture. It is postulated that fundamental physical characteristics, such as particle-specific surface area, true density, and size distribution, can be used to quantitatively ascertain mix homogeneity in routine pharmaceutical blending operations.

The influence of microencapsulation using Eudragit RS100 on the hydrolysis kinetics of acetylsalicylic acid.

Homogeneous Eudragit RS100 matrix microspheres containing molecularly dispersed acetylsalicylic acid (ASA) were prepared in order to investigate the effect of encapsulation on the decomposition rate of a hydrolytically susceptible drug. ASA-loaded microspheres of this non-eroding polymer matrix were analysed at predetermined time points following immersion of the microspheres in temperature controlled buffer systems at pH 1.2 or pH 12.1 at 30, 40 or 50 degrees C. The mass balance of the total amount of solutes (ASA and SA) initially located within the microsphere interior was equal to the sum of the amount of solutes remaining in the microsphere interior and the amount of solutes in the aqueous phase at any time during the course of the study. Each analysis involved the quantitation of four species; the drug and decomposition product, salicylic acid (SA), in both the microspheres phase and the external aqueous phase. A simple model system using first-order rate approximations for the concurrent Fickian diffusion and hydrolysis decomposition of the drug resulted in a multiexponential expression which adequately described the time-course profile of the drug. SA-loaded microspheres were used as a control under similar conditions to determine the magnitude of the contribution of microsphere phase hydrolysis of ASA to the overall rate of drug loss from the microspheres. Results indicated that microspheres phase hydrolysis of ASA was minimal. Even after 900 h of immersion in pH 12.1 buffer some ASA remained within the microsphere. It is postulated that the matrix incorporated drug is essentially shielded from hydrolytic attack until it is liberated into the external aqueous environment. Electrostatic association of the drug with the charged quaternary residues in the polymer along with the limiting availability of water within the microsphere may be responsible for the observed stability of ASA in aqueous swollen ASA-loaded Eudragit microspheres.

Physico-chemical evaluation of acetylsalicylic acid-Eudragit RS100 microspheres prepared using a solvent-partition method.

Controlled release homogeneous matrix microspheres containing acetylsalicylic acid (ASA) were prepared by a simple mechanical process using Eudragit RS100 as the matrix polymer. A drug-polymer solution in a binary solvent of methylene chloride/acetone (9:1) was prepared and infused at a rate of 15 microliters/min as small droplets into a flowing stream of mineral oil where partition of the solvent occurred. A series of experiments was conducted in which the polymer to drug ratio in the infusion solution was fixed at 5:1, 4:1, 3:1 or 2:1 while varying the infusion solution viscosity by altering the infusion solution total solids concentration. Results indicate that microsphere mean particle size was maintained at 200-300 microns once the infusion solution viscosity exceeded 2 cps. The physical state of the ASA incorporated into the microspheres, as confirmed by SEM and thermal analysis, was amorphous in nature until a drug loading of 24% was reached. Drug loading for each polymer to drug ratio increased in a proportional manner with respect to the initial drug concentration of the infusion solution. Dissolution release profiles were found to be biphasic and best analysed according to the semi-empirical equation of Ritger-Peppas, Mt/Mx = k2tn, for the initial phase and by the square-root model of Higuchi, Qt = k1t1/2 for the latter phase. This difference was attributed to the lack of a barrier effect to the drug diffusion process during the latter dissolution phase when the microspheres are fully hydrated.