Ramón Martínez-Pacheco

3D printing of medicines: Engineering novel oral devices with unique design and drug release characteristics

Three dimensional printing (3D printing) was used to fabricate novel oral drug delivery devices with specialized design configurations. Each device was loaded with multiple actives, with the intent of applying this process to the production of personalized medicines tailored at the point of dispensing or use. A filament extruder was used to obtain drug-loaded--paracetamol (acetaminophen) or caffeine--filaments of poly(vinyl alcohol) with characteristics suitable for use in fused-deposition modeling 3D printing. A multinozzle 3D printer enabled fabrication of capsule-shaped solid devices containing the drug with different internal structures. The design configurations included a multilayer device, with each layer containing drug, whose identity was different to the drug in the adjacent layers, and a two-compartment device comprising a caplet embedded within a larger caplet (DuoCaplet), with each compartment containing a different drug. Raman spectroscopy was used to collect 2-dimensional hyper spectral arrays across the entire surface of the devices. Processing of the arrays using direct classical least-squares component matching to produce false color representations of distribution of the drugs was used. This clearly showed a definitive separation between the drug layers of paracetamol and caffeine. Drug release tests in biorelevant bicarbonate media showed unique drug release profiles dependent on the macrostructure of the devices. In the case of the multilayer devices, release of both paracetamol and caffeine was simultaneous and independent of drug solubility. With the DuoCaplet design, it was possible to engineer either rapid drug release or delayed release by selecting the site of incorporation of the drug in the device; the lag-time for release from the internal compartment was dependent on the characteristics of the external layer. The study confirms the potential of 3D printing to fabricate multiple-drug containing devices with specialized design configurations and unique drug release characteristics, which would not otherwise be possible using conventional manufacturing methods.

Effect of country of origin on the properties of microcrystalline cellulose

Abstract The characteristics of four brands of microcrystalline cellulose manufactured in Finland, India, Ireland and Japan have been determined; all four were nominally similar to Avicel PH 101. There were significant differences in lignin content, hemicellulose sugars content and composition, presence or absence of cellulose II, enthalpy of immersion, particle size and flow properties. Crystallinity correlated with water-cellulose interaction, and particle size with flow properties.

Effect of batch variation and source of pulp on the properties of microcrystalline cellulose

Abstract We have investigated the characteristics of three batches of microcrystalline cellulose supplied by the same manufacturer but differing in the manufacturing process employed and/or the type of wood pulp used as raw material. Significant differences were found as regards lignin and hemicellulose contents, percentage crystallinity (calculated from IR spectra and X-ray diffraction data), enthalpies of immersion and capacity for moisture absorption. There were close correlations between crystallinity and the parameters reflecting interaction between microcrystalline cellulose and water. All three varieties had very similar particle size distributions, but the variety obtained from non standard pulp had a significantly greater specific surface due to greater intraparticle porosity. These differences did not significantly affect parameters such as compressibility and mean yield pressure, but are nevertheless potential causes of differences in behaviour in pharmaceutical products.

Interfacial Adsorption of Polymers and Surfactants: Implications for the Properties of Disperse Systems of Pharmaceutical Interest

This review considers basic aspects of the interfacial adsorption of polymers and surfactants, with particular reference to the relevance of these processes for the formulation of pharmaceutical disperse systems. First, we discuss different approaches to the interpretation of adsorption isotherms, paying particular attention to systems containing more than one adsorbate. Second, we consider the implications of adsorption for the properties of suspensions, emulsions, and colloidal systems, particularly as regards the use of polymers and surfactants for stabilizing disperse systems, for controlling flocculation, and for modifying the biopharmaceutical behavior of colloidal drug carriers. Finally, we present a number of representative examples of the importance of adsorption of macromolecules in pharmaceutical systems.

Microviscosity of hydroxypropylcellulose gels as a basis for prediction of drug diffusion rates

This study investigated the influence of the rheological properties of hydroxypropylcellulose (HPC) gels on the in vitro release of theophylline included in the gel at 0.2 g/l. Experiments were performed with six HPC varieties (mean molecular weight between 5x105 and 1.2x106, nominal viscosity between 100 and 4000 mPa.s) at concentrations of 0-2% (w/w). Theophylline diffusion coefficients at 37 degrees C ranged from 3.5x10-7 to 1.1x10-3 cm2/min, and were in all cases markedly higher than those predicted on the basis of gel macroviscosity as determined by capillary viscometry. In general, the theophylline diffusion coefficient declined exponentially with HPC concentration; in the case of the lowest-molecular-weight HPC, however, the diffusion coefficient remained constant to HPC concentrations of up to 0.8%, probably because of the high entanglement concentration of the HPC. Gel microviscosities as determined by dynamic light scattering (DLS) with latex microspheres (162 nm diameter) were considerably lower than the macroviscosities determined by capillary viscometry, and similar to microviscosities estimated on the basis of theophylline diffusion. Nevertheless, macroviscosity was correlated with microviscosity, suggesting that it is of value for approximate estimates of rates of diffusion of theophylline from HPC gels.

Usefulness of certain varieties of Carbomer in the formulation of hydrophilic furosemide matrices

Abstract This paper deals with the evaluation of the possible use of three types of Carbomer, with different molecular weights, in the formulation of hydrophilic furosemide matrices. To this purpose the effects of the most outstanding elaboration variables; type and proportion of polymer and maximum compression force on the mechanical and release characteristics of tablets are studied. The factorial designs that were used as the basis for the development of this study have made it possible, through the respective ANOVA, to identify the factors having a significant effect on the properties of the tablets. Among the effects observed, which were quantified by sequential multiple linear regression, with acceptable adjustment levels, one of the most noteworthy is the effect that the maximum compression force has on the dissolution efficiency of furosemide from the formulations, regardless that variety of Carbomer employed. In all cases, the furosemide dissolution profiles, whose dependency on the microporous structure has been discussed, were fit to a zero order releasing kinetics, pointing to an erosion mechanism.

Konjac glucomannan/xanthan gum enzyme sensitive binary mixtures for colonic drug delivery

The polysaccharide konjac glucomannan (KGM) is degraded in the colon but not the small intestine, which makes it potentially useful as an excipient for colonic drug delivery. With xanthan gum (XG) KGM forms thermoreversible gels with hitherto unexplored biodegradation properties. In this work, rheological measurements of KGM and KGM/XG systems incubated with and without Aspergillus niger beta-mannanase (used to mimic colonic enzymes) showed that KGM was degraded by the enzyme even when interacting with XG. Tablets with KGM/XG/sucrose matrices that varied in accordance with a simplex design and bore diltiazem as a typical highly soluble drug load were prepared by wet granulation, and in most cases were found to possess satisfactory mechanical strength and exhibit slow, nearly zero-order drug release. Drug release from these tablets remained zero-order, but was accelerated (presumably due to degradation of KGM), in the presence of A. niger beta-mannanase at concentrations equivalent to human colonic conditions. However, marked differences between Japanese and American varieties of KGM as regards degree of acetylation and particle size led to significant differences in swelling rate and drug release between formulations prepared with one and the other KGM: whereas a formulation with Japanese KGM released its entire drug load within 24h in the presence of beta-mannanase, only 60% release was achieved under the same conditions by the corresponding formulation with American KGM, suggesting that with this KGM it will be necessary to optimize technological variables such as compression pressure in order to achieve suitable porosity, swelling rate, and drug release. To sum up, the results of this study suggest that sustained release of water-soluble drugs in the colon from orally administered tablets may be achieved using simple, inexpensive formulations based on combinations of KGM and XG that take the variability of KGM characteristics into account.

Atenolol release from hydrophilic matrix tablets with hydroxypropylmethylcellulose (HPMC) mixtures as gelling agent: effects of the viscosity of the HPMC mixture

Abstract The aims of this study were to assess the potential value of hydroxypropylmethylcellulose (HPMC) mixtures as gelling agents in matrix tablets for hydrosoluble drugs, and to investigate relationships between gelling agent viscosity and the kinetics of drug release from such tablets. Experiments were carried out with MethocelR K100LV (an HPMC with nominal viscosity of 100 cP) and MethocelR K100M (an HPMC with nominal viscosity of 100000 cP). Rheological characterization of 2% dispersions of the polymers, and of 30:70, 50:50 and 70:30 mixtures, indicated that it is possible to obtain a wide range of rheological behaviours by mixing K100LV and K100M, and that the two polymers display rheological antagonism. Trials were carried out with atenolol tablets made with 40% or 80% gelling agent (i.e. K100LV, K100M or one of the K100LV:K100M mixtures). Analysis of drug dissolution profiles in 0.1 N HCI, on the basis of Higuchis model and the equation of Korsmeyer and coworkers, indicated that drug release was in all cases diffusion-limited. A negative relationship was observed between the Higuchi constant for each tablet type and the apparent viscosity of the corresponding gelling agent in aqucous dispersion. In addition, apparent viscosity was negatively related to rate of attrition, suggesting that the observed relationship between the Higuchi constant and apparent viscosity is a reflection of differences in attrition resistance.

Fused-filament 3D printing of drug products: Microstructure analysis and drug release characteristics of PVA-based caplets.

Fused deposition modeling (FDM) 3-Dimensional (3D) printing is becoming an increasingly important technology in the pharmaceutical sciences, since it allows the manufacture of personalized oral dosage forms by deposition of thin layers of material. Here, a filament extruder was used to obtain filaments of polyvinyl alcohol (PVA) containing paracetamol or caffeine appropriate for 3D printing. The filaments were used to manufacture caplets for oral administration by FDM 3D printing, with the aim of evaluating the effect of the internal structure (micropore volume), drug loading and composition on drug dissolution behaviour. Micropore volume of the caplets was primarily determined by the presence of large pores due to gaps in the printed layers/net while printing, and the porosity of the caplets was 10 fold higher than the porosity of the extruded filament. Dynamic dissolution drug release tests on the caplets in biorelevant bicarbonate media revealed distinctive release profiles, which were dependent on drug solubility and drug loading. Porosity of the caplets did not help to predict the different drug release profiles. This study confirms the potential of 3D printing to fabricate caplets and helps to elucidate which factors influence drug release from this type of new dosage form.

Dicalcium phosphate dihydrate and anhydrous dicalcium phosphate for direct compression: A comparative study

Abstract Dicalcium phosphate dihydrate (Emcompress) and anhydrous dicalcium phosphate (Anhydrous Emcompress) for direct compression were compared as regards particle size distribution and flow properties, which were found to be similar for the two products, and microporous structure and compression properties, which differed markedly. Specifically, intraparticular porosity and mean yield pressure of the anhydrous product were greater than for the dihydrate. Several properties of compacts of both products were also compared: compacts of the anhydrous phosphate disintegrated much more rapidly in distilled water than those of the dihydrate, which was attributed to the greater porosity of the former compacts.