Comparative Evaluation of Pellet Cushioning Agents by Various Imaging Techniques and Dissolution Studies.

Most of the commercially available pharmaceutical products for oral administration route are marketed in the tablet dosage forms. However, compression of multiparticulate systems is a challenge for the pharmaceutical research and industry, especially if the individual unit is a coated particle, as the release of the active ingredient depends on the integrity of the coating. In the present study, polymer-coated pellets tableted with different types of excipients (powder, granules, pellets) then were investigated by various tablet-destructive (microscopic) and tablet non-destructive (microfocus X-ray; microCT) imaging methods. The information obtained from the independent evaluation of the in vitro drug release profiles model is confirmed by the results obtained by image analysis, regardless of whether X-ray or stereomicroscopic images of the coated, tableted pellets were used for image analysis. The results of this study show that the novel easy-to-use, fast, and non-destructive MFX method is a good alternative to the already used microscopic image analysis methods regarding the characterization of particulates, compressed into tablets.

Comparison of directly compressed vitamin B12 tablets prepared from micronized rotary-spun microfibers and cast films.

Fiber-based dosage forms are potential alternatives of conventional dosage forms from the point of the improved extent and rate of drug dissolution. Rotary-spun polymer fibers and cast films were prepared and micronized in order to direct compress after homogenization with tabletting excipients. Particle size distribution of powder mixtures of micronized fibers and films homogenized with tabletting excipients were determined by laser scattering particle size distribution analyzer. Powder rheological behavior of the mixtures containing micronized fibers and cast films was also compared. Positron annihilation lifetime spectroscopy was applied for the microstructural characterization of micronized fibers and films. The water-soluble vitamin B12 release from the compressed tablets was determined. It was confirmed that the rotary spinning method resulted in homogeneous supramolecularly ordered powder mixture, which was successfully compressed after homogenization with conventional tabletting excipients. The obtained directly compressed tablets showed uniform drug release of low variations. The results highlight the novel application of micronized rotary-spun fibers as intermediate for further processing reserving the original favorable powder characteristics of fibrous systems.

Micro- and macrostructural characterization of polyvinylpirrolidone rotary-spun fibers.

The application of high-speed rotary spinning can offer a useful mean for either preparation of fibrous intermediate for conventional dosage forms or drug delivery systems. Polyvinylpyrrolidone (PVP) and poly(vinylpyrrolidone-vinylacetate) (PVP VA) micro- and nanofibers of different polymer concentrations and solvent ratios were prepared with a high-speed rotary spinning technique. In order to study the influence of parameters that enable successful fiber production from polymeric viscous solutions, a complex micro- and macrostructural screening method was implemented. The obtained fiber mats were subjected to detailed morphological analysis using scanning electron microscope (SEM), and rheological measurements while the microstructural changes of fiber samples, based on the free volume changes, was analyzed by positron annihilation lifetime spectroscopy (PALS) and compared with their mechanical characteristics. The plasticizing effect of water tracked by ortho-positronium lifetime changes in relation to the mechanical properties of fibers. A concentration range of polyvinylpyrrolidone solutions was defined for the preparation of fibers of optimum fiber morphology and mechanical properties. The method enabled fiber formulation of advantageous functionality-related properties for further formulation of solid dosage forms.

EFFECT OF STORAGE TEMPERATURE ON THE STABILITY OF TOTAL PARENTERAL NUTRITION ADMIXTURES PREPARED FOR INFANTS.

Physical, chemical and microbiological stability of total parenteral nutrient (TPN) admixtures was studied as a function of storage time and temperature. Particle size analysis and zeta potential measurements were carried out to evaluate the possible changes in the kinetic stability of the emulsions as a function of storage time and temperature. The concentration changes of the applied additives, those of the ascorbic acid and L-alanyl-L-glutamine, were also determined under different storage conditions. Our results indicate that there were no significant differences in the particle size and zeta potential values of admixtures stored at the three examined temperatures. The best results were obtained in the case of admixtures stored at 30°C temperature. Rapid decomposition of vitamin C was found while the glutamine showed adequate stability as a function of storage time and temperature. According to the results of the physicochemical examinations 10-day storage period of this type of TPN admixtures can be accepted at room temperature. Their storage does not require refrigeration (2-8°C) thus they can be administered without special preheating ensuring better physiological tolerance. Ascorbic acid can be added to the system preceding the administration to the patient because of its rapid decomposition.

Development and Dissolution Study of a ß-Galactosidase Containing Drinking Straw.

Today, in addition to many different physicochemical and pharmacological properties of the active ingredients and excipients, the developer of a pharmaceutical formulation must take into account several factors during the formulation process in order for the patient to cooperate to use the formulation accurately. One of the innovative solutions in paediatrics may be the use of medicated drinking straws. For our studies, we successfully prepared lactase-containing, rapid disintegration particles by two techniques commonly used in the pharmaceutical industry. The simulation of the usage of the filled straws was presented from a new perspective for the patient by an in vitro method. The effect of the temperature of the liquid used during the administration of the straw and the effect of the frequency during the application on the dissolution rate were investigated. According to our results, in the case of a straw containing rapidly dissolving particles, the temperature of the used liquid and the mode of administration (frequency) play a significant role in the release rate from the composition.

Development of laboratory-scale high-speed rotary devices for a potential pharmaceutical microfibre drug delivery platform.

The production of polymer microfibres and nanofibres using rotary jet spinning as platforms for drug delivery and tissue engineering applications has been explored. The aligned orientation of fibres and consequent improvement in the mechanical properties of the scaffold are essential in several pharmaceutical and biomedical applications, where elastic materials with high tensile resistance are required. This study aimed to develop high-speed rotary jet devices to fabricate polyvinylpyrrolidone-based homopolymer and copolymer rotary-spun fibres and establish a correlation between the operational parameters of the devices and the morphology and microstructure of the fabricated fibres. Preconstruction modelling was carried out using computer-aided design through parametric 3D body modelling of the rotary device components by assigning appropriate dimensions and tolerances, as well as material parameters. Finite-element modelling was used to analyse the mechanical stress of the designed spinnerets. The obtained fibre mats were subjected to a detailed morphological analysis using optical and scanning electron microscopy, while the microstructural changes in the fibre samples, based on the free volume changes, were analysed by positron annihilation lifetime spectroscopy. The results indicate that the compact design and the controllability of the operational parameters enabled the formation of continuous aligned-oriented homogeneous fibres of variable diameters depending on the type of forming fibre polymer for further processing to formulate pharmaceutical drug delivery systems.

Physicochemical analysis in the evaluation of reconstituted dry emulsion tablets.

The aim of this study was to characterize the formation of emulsions by droplet size analysis and turbidimetry during reconstitution from a solid dosage form, namely from dry emulsion systems, which carry an oil phase for poorly soluble active ingredients. For the dry emulsion systems tablets were prepared either from oil-in-water systems using a freeze-drying process or through direct compression containing the same oil and excipients. The ratios of oil to emulgents and oil to xanthan gum were equal in both methods. In the preparation methods applied, mannitol, erythritol and lactose were used as excipients and mannitol was found to be the most effective excipient based on droplet size reconstitution, turbidimetry and physical properties. Quality control involved testing the physical properties of tablets and characterizing the reconstituted emulsions.

Lubricant-Induced Crystallization of Itraconazole From Tablets Made of Electrospun Amorphous Solid Dispersion.

Investigation of downstream processing of nanofibrous amorphous solid dispersions to generate tablet formulation is in a quite early phase. Development of high speed electrospinning opened up the possibility to study tableting of electrospun solid dispersions (containing polyvinylpyrrolidone-vinyl acetate and itraconazole [ITR] in this case). This work was conducted to investigate the influence of excipients on dissolution properties and the feasibility of scaled-up rotary press tableting. The dissolution rates from tablets proved to be mainly composition dependent. Magnesium stearate acted as a nucleation promoting agent (providing an active hydrophobic environment for crystallization of ITR) hindering the total dissolution of ITR. This crystallization process proved to be temperature dependent as well. However, the extent of dissolution of more than 95% was realizable when a less hydrophobic lubricant, sodium stearyl fumarate (soluble in the medium), was applied. Magnesium stearate induced crystallization even if it was put in the dissolution medium next to proper tablets. After optimization of the composition, scaled-up tableting on a rotary press was carried out. Appropriate dissolution of ITR from tablets was maintained for 3 months at 25°C/60% relative humidity. HPLC measurements confirmed that ITR was chemically stable both in the course of downstream processing and storage.

Incorporating small molecules or biologics into nanofibers for optimized drug release: A review.

Over the past several decades, the formulation of novel nanofiber-based drug delivery systems focusing on specific delivery purposes has been investigated worldwide with a continuous level of interest. The unique structure and properties of nanoscale fibrous systems, such as their high specific-area-to-volume ratio and high porosity and the possibility of controlling their crystalline-amorphous phase transitions, make them a desirable formulation pathway to satisfy the needs of recent pharmaceutical development. Fibrous delivery systems can facilitate the accelerated dissolution and increased solubility of small molecules and can also be useful in controlling drug delivery over time (for local or systemic drug administration). In the latter case, the release periods can be tuned over a wide range (from hours to weeks), e.g., by adjusting the fiber diameter and selecting the appropriate polymers. The solubility of the polymer, the fiber diameter and the fiber structure are the primary parameters affecting drug release. In addition to immediate and sustained release, other release profiles, such as biphasic release, can also be achieved. Chemical conjugation and surface functionalization offer further possibilities for the control of drug release. In the case of small molecules, developments focus mostly on overcoming the unfavorable physicochemical nature of the active agents. By contrast, in the preparation of macromolecule-loaded nanofibers, maximizing the biological activity of the macromolecules presents the greatest challenge. The authors' intent is to provide a comprehensive overview of the key parameters of advanced drug delivery systems of this type.

Tracking of crystalline-amorphous transition of carvedilol in rotary spun microfibers and their formulation to orodispersible tablets for in vitro dissolution enhancement.

Physicochemical characterization of microfibers including powder X-ray diffraction, differential scanning calorimetry, attenuated total reflectance Fourier transform infrared spectroscopy, and positron annihilation spectroscopy were used to track the crystalline-amorphous transition of carvedilol during formulation and stability testing. The applied methods unanimously indicated the amorphous transition of carvedilol in the course of rotary spinning, furthermore a supramolecular ordering of chains of polymer matrix was revealed out by positron annihilation spectroscopy. The accelerated stability study (40±2°C/75±5% RH, for 4 weeks) indicated a large stress tolerance capacity of fibers, since only a partial crystallization of the active compound was observable at the last sampling point. To demonstrate possible utilization of microfibers, orodispersible tablets containing 10mg of carvedilol were successfully prepared by direct compression applying common tableting excipients. All of the investigated tablet parameters (hardness, friability, in vitro disintegration time) complied with the pharmacopoeial requirements. The performed dissolution (pH 1.0 and 6.8) study indicated that the drug dissolution from the microfiber based formula was rapid, complete and independent from the pH of the applied media, while the dissolution from the control tablets, containing crystalline carvedilol was incomplete and was strongly influenced by the pH of the applied media.

Improvement of mechanical properties of pellet containing tablets by thermal treatment.

Batches of partially spray-dried lactose tablets with three different initial tensile strength (∼20N, ∼35N, ∼50N) were made. Changes along a 24h long thermal treatment at 100°C in tensile strength, friability, individual mass, water content, disintegration time, average free volume and wetting properties were evaluated. Caffeine containing gastroresistant pellets were gained by drug layering and filmcoating of inert microcrystalline cellulose pellet cores in fluid bed equipment. Shape, size, mechanical properties, drug content and dissolution profile of the coated pellets were determined. Batches of pellet containing tablets with three different pellet-filler ratios were compressed where partially spray-dried lactose was used as a filler-binder material.Characteristics of pellet containing tablets were evaluated before and after a 24h long thermal treatment at 100°C. Results shown that the poor initial mechanical properties (friability, tensile strength) were improved by thermal exposure while there were no remarkable alterations in drug release profiles.

Preformulation study of fiber formation and formulation of drug-loaded microfiber based orodispersible tablets for in vitro dissolution enhancement.

Preformulation study of rotary spun hydroxypropyl cellulose fibers was carried out using the combination of textural characterization of gels in the concentration range of 42-60% w/w and optical microscopic evaluation of formed fibers. High adhesiveness values resulted in bead formation at lower polymer concentration, meanwhile fiber formation was hindered when high adhesiveness values were associated with high polymer content. The optimum gel concentration for fiber formation was given to 50% w/w. Drug loaded microfibers were prepared using a model drug of biopharmaceutical drug classification system class II. Fibers were milled, sieved and mixed with tableting excipients in order to directly compress orodispersible tablets. Hardness, friability, in vitro disintegration time values complied with the pharmacopoeial requirements. In vitro dissolution profiles obtained from three distinct dissolution media (pH 1.0; 4.5; 6.8) were quite differentiated compared to the compressed physical mixture of the same composition. Difference and similarity factors confirmed that the drug dissolution from microfiber based formula was almost independent from the pH value of the media. X-ray diffraction patterns indicated that the drug embedded in microfibers was in amorphous state, and the decrease of o-Ps lifetime values suggested that fiber formation enabled the development of a more ordered fibrous system.

Comparative dissolution study of drug and inert isomalt based core material from layered pellets.

Layered and coated pellets were formulated to control the release of the diclofenac sodium selected as model drug. A highly water soluble isomalt inert pellet core material was used to osmotically modulate the drug release through the swellable polyvinyl acetate coating layer. Image analysis was applied to determine the shape parameters and the swelling behavior of the pellets. UV-spectroscopy and liquid chromatography with refractive index detection were applied to measure the concentration of the model drug and the core materials. Simultaneous dissolution of both the diclofenac sodium and isomalt was observed. Relationship was found between the dissolution profile of the drug and the core material which linear correlation was independent on the coating level. The latter enables the modulation of drug release beside the permeability control of the swelled coating polymer.