José Luis Gómez-Amoza

Powdered cellulose as excipient for extrusion-spheronization pellets of a cohesive hydrophobic drug.

This study compared a powdered cellulose (PC) and a microcrystalline cellulose (MCC) as sole excipients in the preparation of furosemide pellets by extrusion-spheronization. Pellets prepared with PC and 25 or 50% furosemide showed smaller mean size, a broader particle size distribution, similar sphericity, greater surface roughness and higher friability than equivalent pellets prepared with MCC. Furosemide release rate was markedly higher from PC pellets, which may be attributable to their higher micropore volume.

Mechanical and drug-release properties of atenolol-Carbomer hydrophilic matrix tablets

Abstract The potential of three varieties of Carbomer (934,940 and 941) as excipients for hydrophilic matrix tablets containing the hydrosoluble drug atenolol was assessed. The technological variables, type and proportion of polymer and maximum force applied over the compression cycle, were varied according to a 2 × 2 factorial experimental design to investigate their influence on the mechanical and drug release properties of the tablets, identifying those that were significant with the corresponding ANOVA. The influence of each significant variable was quantified by way of multiple stepwise sequential linear regression, which gave, on the whole, acceptable fits. Similar mechanical and release properties were observed for all the varieties of Carbomer. In all cases, drug release profiles fitted Higuchis square root kinetics and showed strong dependence on the proportion of polymer; the compression force and the microporous structure were not important in this respect.

The adsorption of cellulose ethers in aqueous suspensions of pyrantel pamoate: effects on zeta potential and stability

This work examined the physico-chemical phenomena induced in aqueous suspensions of pyrantel pamoate by two varieties of hydroxypropylmethylcellulose (HPMC) and sodium carboxymethylcellulose (NaCMC) of different molecular weights, and the effects of these phenomena on the physical stability of the suspension. The mechanism of the interfacial adsorption of the polymer was investigated by constructing adsorption isotherms: for the two HPMC varieties, the isotherms were of type L and were fitted with the Langmuir model; of the NaCMCs, only the variety with higher molecular weight was adsorbed, its adsorption isotherm being of type S (sigmoidal). The resulting monolayer films were characterized viscosimetrically, determining their thickness and the number of polymer molecules adsorbed per unit area. The nonionic polymers formed thinner, more continuous monolayers than the NaCMC. Only the nonionic polymers significantly altered the zeta potential of the systems. In the range of conditions studied, all the polymers stabilized the initially flocculated systems, decreasing sedimentation volume and increasing the time necessary to redisperse them (the redispersability value). This stabilization occurred either by the steric mechanism (HPMCs and the high-molecular-weight NaCMC) or by depletion mechanisms (low-molecular-weight NaCMC). Owing to the complexity of these mechanisms, sedimentation volume was not found to be a useful index of the consistency of the sediments obtained from the suspensions.

Hydration and N-acetyl-l-cysteine alter the microstructure of human nail and bovine hoof: Implications for drug delivery

This work aimed to (a) characterize the microstructure and porosity of human nail and bovine hoof by mercury intrusion porosimetry and SEM image analysis, (b) study the effects of hydration and of N-acetyl-l-cysteine treatment on the microstructure of both membranes, and (c) determine whether the microstructural modifications were associated with changes in drug penetration measured by standard diffusion studies. Bovine hoof surface is more porous than nail surface although there were no differences between the mean surface pore sizes. Hydration and N-acetyl-l-cysteine increased the roughness and apparent surface porosity, and the porosity determined by mercury intrusion porosimetry of both membranes. Pore-Cor™ was used to generate tridimensional structures having percolation characteristics comparable to nail and hooves. The modeled structures were horizontally banded having an inner less-porous area which disappeared upon treatment. Treatment increased the predicted permeability of the simulated structures. Triamcinolone permeation increased significantly for hooves treated N-acetyl-l-cysteine, i.e., the membranes for which microstructural and permeability changes were the largest. Thus, microstructural changes determined via mercury intrusion porosimetry and subsequently modeled by Pore-Cor™ were related to drug diffusion. Further refinement of the technique will allow fast screening of penetration enhancers to be used in ungual drug delivery.

Interactions between hydroxypropylcelluloses and vapour/liquid water

Understanding of the uptake of water vapour or liquid water by cellulose-based polymers is important because of the influence of these processes on many of the biologically or technologically relevant properties of these polymers. In this work we studied these processes in the cases of twelve hydroxypropylcelluloses with low or medium-high degrees of substitution (L-HPCs and HPCs, respectively), characterization of which showed significant differences in structural and physical parameters (substitution pattern, crystallinity, particle size, specific surface area, and intraparticular porosity). Water vapour sorption-desorption isotherms determined to characterize the uptake of water vapour were fitted well by the Young-Nelson model, the optimized parameters of which indicated that at all relative humidities the capacity to bind water vapour as a surface monolayer is greater for HPCs than L-HPCs, but the capacity to absorb water vapour internally is greater for L-HPCs than HPCs. Guggenheim-Anderson-deBoer (GAB) models fitted the sorption-desorption isotherms less well. Differential scanning calorimetry (DSC) experiments showed all sorbed water vapour to be held as non-freezing water. Isoperibol microcalorimetry experiments carried out to investigate interactions with liquid water showed enthalpies of hydration/dissolution of between -62.86 and -71.35 J g(-1) for L-HPCs and between -82.95 and -99.80 J g(-1) for HPCs, and DSC showed average numbers of non-freezing water molecules per polymer repeat unit of 2.65-4.19 for L-HPCs and 18.10-22.42 for HPCs. DSC characterization of the kinetics of the water uptake by 10 mg compacts obtained by direct compression of hydroxypropylcelluloses showed faster uptake by L-HPC compacts than by HPC compacts, among which there were significant differences in capacity for diffusive uptake. The explanations of the above differences in terms of the different substituent contents, particle sizes and porosities of the HPCs is supported by multiple linear regression analyses.

Competitive displacement of drugs from cyclodextrin inclusion complex by polypseudorotaxane formation with poloxamer: Implications in drug solubilization and delivery

The competitive interactions between the poly-[propylene oxide] (POO)-poly-[ethylene oxide] (PEO) block copolymer poloxamer 407 (Pluronic F127) and two drugs, triamcinolone acetonide and ciclopirox olamine, by the formation of inclusion complexes with two cyclodextrin hydrophilic derivatives, hydroxypropyl-β-cyclodextrin (HPβCD; molar substitution (MS) 0.65) and partially methylated-β-cyclodextrin (MβCD; MS 0.57), were studied by means of one-dimensional (1)H NMR, 2D ROESY experiments, solubility studies and drug release studies. 1D and 2D NMR and solubility studies indicate that both triamcinolone acetonide and ciclopirox olamine form stable inclusion complexes with the cyclodextrin derivatives. In the case of ciclopirox olamine the complex was more stable at pH 1. Effective complexation of poloxamer with the two cyclodextrins (CDs) was also evidenced by NMR analysis, and competitive displacement of the drugs from the CD cavity by the polymer was observed. Drug solubility in CD solutions was not modified by the addition of polymers, indicating that a decrease in solubility due to the competitive displacement is probably compensated by the solubilizing effect of polymer micellization. Finally, polypseudorotaxanes formation has a significant influence on the release of the drugs studied. Changes in the release rate depend on the stability of drug-CD inclusion complex and on cyclodextrin concentration in the bulk solution; so polypseudorotaxane formation can be employed to modulate drug controlled release from thermosensitive hydrogels.

Incidence of drying on microstructure and drug release profiles from tablets of MCC–lactose–Carbopol® and MCC–dicalcium phosphate–Carbopol® pellets

The influence of intragranular excipients (lactose or dicalcium phosphate) and the drying procedure and conditions (oven-drying and freeze-drying after freezing at -30 or -196 degrees C) on the properties of tablets of MCC-Carbopol pellets was evaluated. The drying procedure caused remarkable differences in pellet size and porosity (freeze-dried pellets were 3-fold more porous than those oven dried). Theophylline release from pellets was completed in less than 30 min and followed first-order kinetics, with a rate closely related to the intragranular porosity. The total porosity of the tablets (5-10%) was conditioned by the compression force (10-20 N), the drying procedure applied to the pellets and the coexcipient nature. Their intergranular porosity ranged inversely to the initial porosity of pellets due to the greater deformability of the most porous ones. A wide range of theophylline release rates were achieved depending on the drying procedure; tablets prepared from freeze-dried pellets sustained the release for 3h. Most profiles showed a bimodal kinetics with an initial zero-order release (while the tablets did not completely disintegrate) that changed, after a certain time, to a first-order kinetics. The intergranular porosity determined drug release rate up to disintegration. Then, the release kinetics became first-order and the rate constant, which was conditioned by the intragranular porosity, showed a complex dependence on the drying procedure, the compression force, and the nature of coexcipient. In sum, the modulation of drug release profiles from tablets of MCC-Carbopol pellets through an adequate control of the effects of the coexcipient nature, the drying procedure of pellets, and the compression force on the inter- and intragranular porosity opens interesting possibilities to control the release of hydrosoluble drugs.

Intersupplier and interlot variability in hydroxypropyl celluloses: implications for theophylline release from matrix tablets

The physical and physicochemical properties of three lots of high-viscosity hydroxypropylcellulose (HPC) (two lots from a Japanese supplier and one lot from a US supplier) were compared. The drug-release properties of theophylline matrix tablets prepared with the different polymers were also investigated. HPCs from the two suppliers showed clear differences in molecular weight, molecular structure, particle size distribution, particle shape, and water affinity. Furthermore, clear differences were observed in the time-course of drug release from tablets made with the different polymers. The differences in basic physical and physicochemical properties of the HPCs affect compression behaviour, the capacity for and time-course of water uptake, and the rheological properties of aqueous dispersions, which explains the observed differences in time-course of drug release. Molecular weight and particle size distribution are particularly important determinants of drug release properties. Abnormally rapid drug release was observed from tablets prepared with relatively small amounts of the highest-molecular-weight highest-particle-size HPC. This result, together with the fact that the time-course of drug release differs markedly between matrix tablets prepared with HPCs that come from different suppliers but that are nominally interchangeable (at least according to the criteria given in the US Pharmacopoeia), suggests that these two properties (mean molecular weight and particle size distribution) are of value for quality control of HPCs destined for use in the manufacture of matrix tablets.

Modelling of porosity and waterfronts in cellulosic pellets for understanding drug release behavior

The microstructure of cellulose microcrystalline-Carbopol pellets, prepared under different drying conditions (oven-dried or freeze-dried), was experimentally characterized using mercury intrusion porosimetry and then computationally modelled using Pore-Cor software. Connectivity (mean number of throats per pore), pore skew (sigma), throat skew (q) and correlation level were estimated and simultaneously optimized from the mercury intrusion porosimetry cumulative curves using the Boltzmann-annealed simplex algorithm. Unit cells with percolation properties close to the real ones were generated. Water penetration rate in the simulated structures was also modelled using Pore-Cor and the waterfront position was calculated using the Bosanquet equation. A close correlation was found between the simulated water flow rate in the unit cell and the experimental theophylline first-order release rate constant. Thus, modelling of network microstructure and waterfronts appears as an useful tool for predicting drug release rate from matrix pellets.

Utility of the hyperbranched polymer Hybrane S1200 for production of instant-release particles by hot melt extrusion

Particles composed of 90:10 or 80:20 mixtures of the hyperbranched poly(esteramide) Hybrane S1200 and the poorly water-soluble drug hydrochlorothiazide were produced by hot melt extrusion at maximum temperatures of 90°C without any need for addition of a plasticizer. In dissolution rate assays in USP 29 apparatus II, particles of the smallest size category (<250 µm) containing 10% of hydrochlorothiazide released 95% of their load within 5 min. This fast release is attributed to the combination of the high solubility of Hybrane S1200, the dispersion of the drug in non-crystalline form in the polymer matrix (attested to by the results of powder X-ray diffractometry, and scanning electron microscopy), and to the fact that the main interaction between drug and polymer is through hydrogen bonds (attested to by ATR-IR difference spectra).