European Journal of Pharmaceutics and Biopharmaceutics (v.75, #1)

APV Diary (S1).

Lubrication in tablet formulations by Jennifer Wang; Hong Wen; Divyakant Desai (1-15).
Theoretical aspects and practical considerations of lubrication in tablet compression are reviewed in this paper. Properties of the materials that are often used as lubricants, such as magnesium stearate, in tablet dosage form are summarized. The manufacturing process factors that may affect tablet lubrication are discussed. As important as the lubricants in tablet formulations are, their presence can cause some changes to the tablet physical and chemical properties. Furthermore, a detailed review is provided on the methodologies used to characterize lubrication process during tablet compression with relevant process analytical technologies. Finally, the Quality-by-Design considerations for tablet formulation and process development in terms of lubrication are discussed.
Keywords: Lubrication; Lubricants; Tablet formulation; Tablet compression; Magnesium stearate; Quality-by-Design; Process analytical technology;

The aim of this study was to establish and evaluate a screening method for the physical characterization of protein–protein interactions of therapeutic proteins based on the determination of the osmotic second virial coefficient (B22). B22 of an IgG1 was measured by self-interaction chromatography (SIC) and was compared to data obtained from static light scattering (SLS). As assessed by Fourier transform infrared spectroscopy (FTIR), the protein coupling to chromatography particles had no relevant influence on the three-dimensional native structure of the IgG1.B22 variations could be measured for physiological relevant excipient concentrations. Significant positive B22 values were observed for the following solution conditions of the investigated antibody: (i) acidic pH conditions, (ii) low buffer concentrations, (iii) low salt concentrations and (iv) high amino acid concentrations. B22 was compared to IgG1 stability data derived from a study conducted for 12 weeks at 40 °C. A concentration of 5 mM histidine, which was the most promising buffer candidate according to B22, showed a slightly better physical stability (as assessed by turbidity and size exclusion chromatography) compared to the other tested formulations. This is confirmed in a stress study investigating the colloidal stability.Thus, measuring protein–protein interactions with SIC appeared as a promising screening tool for physical characterization of protein formulations for cases in which the protein stability is governed by interparticle interactions.
Keywords: Immunoglobulin; Antibody; Self-interaction chromatography; Osmotic second virial coefficient; B22; Colloidal stability; Protein interactions;

A comparative study of chitosan and chitosan/cyclodextrin nanoparticles as potential carriers for the oral delivery of small peptides by Adriana Trapani; Angela Lopedota; Massimo Franco; Nicola Cioffi; Eliana Ieva; Marcos Garcia-Fuentes; Maria José Alonso (26-32).
The aim of this study was to characterize new nanoparticles (NPs) containing chitosan (CS), or CS/cyclodextrin (CDs), and evaluate their potential for the oral delivery of the peptide glutathione (GSH). More precisely, NP formulations composed of CS, CS/α-CD and CS/sulphobutyl ether-β-cyclodextrin (SBE7m-β-CD) were investigated for this application. CS/CD NPs showed particle sizes ranging from 200 to 500 nm. GSH was loaded more efficiently in CS/SBE7m-β-CD NPs by forming a complex between the tripeptide and the CD. X-ray Photoelectron Spectroscopy (XPS) analysis suggested that GSH is located in the core of CS/SBE7m-β-CD NPs and that it is almost absent from the NP surface. Release studies performed in vitro at pH 1.2 and pH 6.8 showed that NP release properties can be modulated by selecting an appropriate CD. Transport studies performed in the frog intestine model confirmed that both CS and CS/CD nanoparticles could induce permeabilization of the intestinal epithelia. However, CS/SBE7m-β-CD NPs provided absorption-enhancing properties in all segments of the duodenum, whereas CS NPs effect was restricted to the first segment of the duodenum. From the data obtained, we believe that CS/CD nanoparticles might represent an interesting technological platform for the oral administration of small peptides.
Keywords: Glutathione; Chitosan; Cyclodextrins; Nanoparticles; Oral administration;

The effect of supersaturation on bioavailability of inhaled nebulized aerosols is compared for amorphous versus crystalline nanoparticulate dispersions. The nanocrystalline formulations of itraconazole (ITZ) were made by wet milling (i.e. Wet-milled ITZ), whereas amorphous nanostructured aggregates (ITZ/mannitol/lecithin = 1:0.5:0.2, weight ratio) were made by an ultra-rapid freezing process (i.e. URF–ITZ). Dissolution tests revealed the extent of supersaturation was 4.7-times higher for URF–ITZ versus Wet-milled ITZ, though their dissolution rates were similar. The aerodynamic performances of both aqueous colloidal dispersions were comparable and suitable for deep lung delivery. Single-dose 24-h pharmacokinetic studies were conducted in Sprague–Dawley rats following inhalation of the nebulized colloidal dispersions (equivalent to 20 mg ITZ/mL dispersion in 5 mL) in a nose-only dosing apparatus. Lung depositions following inhalation were similar for both compositions. In systemic circulation, Wet-milled ITZ and URF–ITZ achieved C max of 50 and 180 ng/mL at 2.7 and 4.0 h, and AUC0–24 of 662 and 2543 ng h/mL, respectively, based on a one-compartmental analysis. Pulmonary delivery of the nanoparticulate amorphous ITZ composition resulted in significantly higher systemic bioavailability than for the nanocrystalline ITZ composition, as a result of the higher supersaturation that increased the permeation.
Keywords: Poorly water-soluble drug; Aerosol; Supersaturation; Nebulization; Inhalation; Lung; Pharmacokinetics; In vivo;

Tapioca starch graft copolymers and Dome Matrix® modules assembling technology. I. Effect of module shape on drug release by Marta Casas; Orazio Luca Strusi; Ma Rosa Jiménez-Castellanos; Paolo Colombo (42-47).
This paper studies the Riboflavin release from compressed disc modules of Dome Matrix® technology using tapioca starch–ethylmethacrylate (TSEMA) and tapioca hydroxypropylstarch–ethylmethacrylate (THSEMA), graft copolymers produced by two different drying methods. The comparison with the release behaviour of similar HPMC modules was performed. Two different shape modules have been made, identified as female and male modules, in order to obtain their assemblage by interlocking the disc bases. HPMC matrices showed quasi-linear Riboflavin release in case of both female and male modules, with faster drug release than TSEMA modules. In the case of THSEMA modules, a faster release was observed compared to HPMC modules. Furthermore, matrices obtained with TSEMA copolymers remained nearly intact after dissolution process, while matrices containing HPMC experimented a complete dissolution of the modules. Combining these results with the release curve analysis using the Korsmeyer and Peppas exponential equation, HPMC modules controlled the drug release by polymer relaxation or erosion. For TSEMA and THSEMA, the drug release mechanism was controlled mainly by drug diffusion. The pronounced faster releases for the matrices containing THSEMA copolymers compared with the ones with TSEMA were due to a more important erosive support; however, the main structure of the matrix remains coherent. Porosity and tortuosity values and the shape of the modules explained the drug release observed.
Keywords: Dome Matrix®; Release modules; Tapioca starch; Graft copolymers; Hydroxypropylmethylcellulose; Riboflavin;

Development of microemulsions to topically deliver 5-aminolevulinic acid in photodynamic therapy by Luciana Mattoso Pires de Campos Araújo; José Antônio Thomazine; Renata Fonseca Vianna Lopez (48-55).
The aim of this study was to obtain and to characterize microemulsions containing 5-aminolevulinic acid (5-ALA) and to investigate the influence of these systems in drug skin permeation for further topical photodynamic therapy (PDT). 5-ALA was incorporated in water-in-oil (W/O), bicontinuous (Bc), and oil-in-water (O/W) microemulsions obtained by the titration of ethyl oleate and PEG-8 caprylic/capric glycerides:polyglyceryl-6 dioleate (3:1) mixtures with water. Selected systems were characterized by conductivity, viscosity, size of the droplets, and drug release. The stability of the drug in the microemulsions was also assessed. Moreover, the in vitro and in vivo skin permeation of 5-ALA was investigated using diffusion cells and confocal scanning laser microscopy (CSLM), respectively. Despite the fact that the O/W microemulsion decreased the 5-ALA diffusion coefficient and retarded the drug release, it also significantly increased the in vitro drug skin permeation when compared to other 5-ALA carriers. It was observed by CSLM that the red fluorescence of the skin increased homogeneously in the deeper skin layers when the 5-ALA microemulsion was applied in vivo, probably due to the formation of the photoactive protoporphyrin IX. The microemulsion developed carried 5-ALA to the deeper skin layers, increasing the red fluorescence of the skin and indicating the potentiality of the system for topical 5-ALA-PDT.
Keywords: Microemulsion; Skin penetration; 5-Aminolevulinic acid; Photodynamic therapy; Protoporphyrin;

Development of lipophilic calcium stearate pellets using ibuprofen as model drug by Eva Roblegg; Stephanie Ulbing; Sabine Zeissmann; Andreas Zimmer (56-62).
The aim of the study was the development of lipophilic pellets containing calcium stearate and ibuprofen as model drug. The pellets were produced by a standard wet extrusion and spheronisation technology. As a main target, the pellets should exhibit sufficient mechanical stability, should not disintegrate in an aqueous vehicle and should show a retarded release kinetic. Furthermore, the drug release should be adjusted only by the ratio between drug and excipient without any additional coating procedure.Different lipids (Precirol®, Compritol®, glyceryl monostearate, magnesium stearate and vegetable calcium stearate) were used as lipophilic pelletisation excipients in extrusion/spheronisation using ethanol/water as granulation liquid. The lipids were combined with ibuprofen as a model drug with pH-dependent solubility in several concentrations (15%, 20% and 25% drug content).Calcium stearate (CS) was found to be a suitable carrier substance for the preparation of spherical pellets (AR ⩽ 1.2). As pellet properties, the mean particle random diameter, surface area, porosity, tensile strength and dissolution profile were determined. By variation of the die plate (1 mm, 0.8 mm and 0.5 mm) and variation of the ethanol/water composition (96% and 50%) of the granulation liquid, pellets in the size range from 800 to 1250 μm with a sufficient drug loading capacity up to 20%, a zero-order drug release and high mechanical stability could be produced.The results demonstrated that calcium stearate can be used as pelletisation excipient for slow release formulations by a wet extrusion/spheronisation technique. With this technology, a continuous production of slow release multiple unit preparations will be possible without further coating steps.
Keywords: Pellets; Extrusion/spheronisation; Calcium stearate; Ibuprofen; Zero-order release;

The objective of this study was to improve the film formation and permeability characteristics of extended release ethylcellulose coatings prepared by dry polymer powder coating for the release of drugs of varying solubility. Ethylcellulose (7 and 10 cp viscosity grades) and Eudragit® RS were used for dry powder coating of pellets in a fluidised bed ball coater. Pre-plasticised ethylcellulose powder was prepared by spray-drying aqueous ethylcellulose dispersions (Surelease® and Aquacoat®) or by hot melt extrusion/cryogenic grinding of plasticised ethylcellulose. Chlorpheniramine maleate and theophylline were used as model drugs of different solubilities. The film formation process, polymeric films and coated pellets were characterised by differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), scanning electron microscopy (SEM) and dissolution testing. Film formation and extended drug release was achieved with ethylcellulose, a polymer with a high glass transition temperature (T g) without the use of water, which is usually required in dry powder coating. DMA-measurements revealed that plasticised ethylcellulose had a modulus of elasticity (E′) similar to the low T g Eudragit® RS. With increasing plasticiser concentration, the T g of ethylcellulose was reduced and the mechanical properties improved, thus facilitating coalescence of the polymer particles. SEM-pictures revealed the formation of a dense, homogeneous film. The lower viscosity grade ethylcellulose (7 cp) resulted in better film formation than the higher viscosity grade (10 cp) and required less stringent curing conditions. Successful extended release ethylcellulose coatings were also obtained by coating with pre-plasticised spray-dried ethylcellulose powders as an alternative to the separate application of pure ethylcellulose powder and plasticiser. The permeability of the extended release coating could be controlled by using powder blends of ethylcellulose with the hydrophilic polymer HPMC. In conclusion, dry polymer powder coating is an interesting technique to achieve extended release of drugs with varying solubility as an alternative to classical coatings obtained from organic polymer solution or aqueous polymer dispersions.
Keywords: Dry powder coating; Ethylcellulose; Extended drug release; Film formation; Curing;

The objective of this study was to investigate the influence of talc and humidity conditions during storage on the crystal growth of guaifenesin on the surface of melt-extruded matrix tablets. Tablets consisted of the model drug guaifenesin in a matrix of either Acryl-EZE® or Eudragit® L10055 and either no talc, 25% or 50% talc. After processing, the hot-melt-extruded matrix tablets were supersaturated with amorphous guaifenesin, which resulted in the development of guaifenesin drug crystals on exposed surfaces of the tablet during storage (all tablets were stored at 24 °C). A previously developed, quantitative test was used to assay for surface guaifenesin. In tablets with a drug-to-polymer ratio of 19:81, talc-containing tablets exhibited an earlier onset of crystal growth (storage at 17% relative humidity). The presence of talc also increased the amount of surface crystallization and was independent of the talc concentration, since the talc levels used in this study exceeded the critical nucleant concentration. Additional non-melting components did not have an additive effect on surface crystal growth. High humidity during storage (78%) increased guaifenesin crystallization, but moisture uptake of tablets did not correlate with increased drug recrystallization. When storage at 17% relative humidity was interrupted for 3 days by storage at 78% relative humidity before the tablets were returned to their previous low RH storage conditions, crystal growth quickly increased during the high RH interval and remained at an elevated level throughout the remaining storage period. A similar intermediate period of low, 17% relative humidity in tablets stored before and after that time at 78% RH did not affect surface crystallization levels. The effects of humidity and talc on the crystallization of guaifenesin from melt-extruded dosage forms supersaturated with amorphous drug were ascribed to heterogeneous nucleation.
Keywords: Hot-melt extrusion; Eudragit® L10055; Acryl-EZE®; Guaifenesin; Recrystallization; Matrix tablets; Physical stability; Talc; Storage; Relative humidity;