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This work details the in situ dynamical behaviour of local anaesthetic bupivacaine (BUP)-loaded L2 and H2 phase precursors (preformulations of BUP) upon rapid exposure to phosphate buffer under physiological conditions (pH 7.4, 37 °C). The hydration-induced structural transitions are characterized by time-resolved synchrotron SAXS.

Liposomes have attracted intensive attention as drug delivery systems in anti-cancer therapy. Since liposomes are constructed by self-assembling of phospholipids, ICP-MS is a suitable method for simultaneous determination of liposomes and encapsulated metallic drug substances such as platinum-based drugs. An efficient method for simultaneous determination of phosphorus and platinum in liposome samples has been established based on the use of xenon as a collision gas in DRC-ICP-MS. Under the optimum conditions with respect to signal to noise ratio, the interferences were suppressed and the detection limits of phosphorus and platinum were 0.3 and 0.05 ng mL−1, respectively. Quality control was performed by using a certified reference material BCR 273 and biological reference materials. For the purpose of investigation of liposome stability and metallo-drug release from liposomes, a hyphenated method based on size exclusion chromatography was developed for separation of free and encapsulated platinum in a model liposome formulation of oxaliplatin. Moreover, an accelerated drug release study was performed by sonication of liposomal samples and using the developed hyphenated method to determine the drug leakage. It has been demonstrated that the SEC-DRC-ICP MS method was an efficient tool in the development and characterization of liposome based formulations of metallic drugs.

Efficient drug delivery is dependent on the drug substance dissolving in the body fluids, being released from dosage forms and transported to the site of action. A fundamental understanding of the interplay between the physicochemical properties of the active compound and pharmaceutical excipients defining formulation behavior after exposure to the aqueous environments and pharmaceutical performance is critical in pharmaceutical development, manufacturing and quality control of drugs. UV imaging has been explored as a tool for qualitative and quantitative characterization of drug dissolution and release with the characteristic feature of providing real-time visualization of the solution phase drug transport in the vicinity of the formulation. Events occurring during drug dissolution and release, such as polymer swelling, drug precipitation/recrystallization, or solvent-mediated phase transitions related to the structural properties of the drug substance or formulation can be monitored. UV imaging is a non-intrusive and simple-to-operate analytical technique which holds potential for providing a mechanistic foundation for formulation development. This review aims to cover applications of UV imaging in the early and late phase pharmaceutical development with a special focus on the relation between structural properties and performance. Potential areas of future advancement and application are also discussed.

The purpose of study was to investigate the dissolution rate enhancement obtained when sodium dodecyl sulfate (SDS) is co-compressed with griseofulvin into discs using a UV imaging-based flow-through dissolution testing setup. Griseofulvin dissolution rates obtained from discs containing 5.92 and 10.6% (w/w) SDS in phosphate buffer (pH 6.5) were similar to dissolution rates from pure griseofulvin discs when applying 20 and 100 mM SDS as dissolution medium, respectively. Dynamic light scattering of effluent samples revealed nanosized particles (approximately 135 nm in diameter) escaping the discs during dissolution. Scanning electron microscopy of co-compressed griseofulvin-SDS discs prior to dissolution testing showed surfaces apparently consisting of granules (100 and 200 nm in diameter) as well as particles present on the disc surfaces possibly related to the high initial dissolution rates. Material swelling or precipitation was observed for discs containing 10.6 or 15.8% (w/w) SDS. UV imaging revealed increased griseofulvin concentrations near the solid-liquid interface of griseofulvin-SDS discs, e.g., a 45-fold increase in concentration was observed for discs containing 10.6% (w/w) SDS as compared to discs without SDS, which is the likely cause of the enhanced dissolution rates found for the co-compressed griseofulvin-SDS discs.

Concentrated solutions containing 6-aminocaproic acid and the excipients citric acid and sorbitol have been studied at temperatures of 50°C, 60°C, 70°C and 80°C as well as at 20°C. It has previously been reported that the commonly employed citric acid is a reactive excipient, and it is therefore important to thoroughly investigate a possible reaction between 6-aminocaproic acid and citric acid. The current study revealed the formation of 3-hydroxy-3,4-dicarboxy-butanamide-N-hexanoic acid between 6-aminocaproic acid and citric acid by high-resolution mass spectrometry (HRMS) and nuclear magnetic resonance spectroscopy (NMR). Less than 0.03% of 6-aminocaproic acid was converted to 3-hydroxy-3,4-dicarboxy-butanamide-N-hexanoic acid after 30 days of storage at 80°C. Degradation products of 6-aminocaproic acid were also observed after storage at the applied temperatures, e.g., dimer, trimer and cyclized 6-aminocaproic acid, i.e., caprolactam. No reaction products between D-sorbitol and 6-aminocaproic acid could be observed. 3-Hydroxy-3,4-dicarboxy-butanamide-N-hexanoic acid, dimer and caprolactam were also observed after storage at 20°C for 3 months. The findings imply that an oral solution of 6-aminocaproic acid is relatively stable at 20°C at the pH values 4.00 and 5.00 as suggested in the USP for oral formulations. Compliance with the ICH guideline Q3B is expected.

PURPOSE: To fabricate microcontainers in biodegradable polylactic acid (PLLA) polymer films using hot embossing, and investigate the application of fabricated microcontainers as an oral drug delivery system for a poorly soluble drug.METHODS: For fabrication of the PLLA microcontainers, a film of PLLA was produced by spin coating. The film was heated above the polymer glass transition temperature (Tg), and a stamp was forced into the film. Following cooling of the film the stamp was removed, exposing the formed microcontainers. Microcontainers were filled with amorphous furosemide sodium salt (produced by spray drying) using a simplified version of a screen printing technique. An enteric-resistant lid of Eudragit L-100 was subsequently spray coated onto the cavity of the microcontainers. Release of amorphous furosemide salt from the coated microcontainers was investigated using a μ-Diss profiler. Release experiments were carried out in biorelevant gastric medium (pH 1.6) for 2 h, followed by 3 h in a biorelevant intestinal medium (pH 6.5). Moreover, biorelevant flow through dissolution was also carried out in conjunction with UV imaging to visualize the release of amorphous furosemide salt from the coated microcontainers.RESULTS: Fabricated PLLA microcontainers had an inner diameter of 220 μm and a height of 100 μm. The screen printing technique was shown to be an optimized set-up to fill the microcontainers with drug. From the release experiments it was observed that the Eudragit layer prevented drug release in biorelevant gastric medium, while an immediate release of the amorphous furosemide salt was seen in the biorelevant intestinal medium. The same trend was observed in the UV imaging experiments –negligible drug release was observed in gastric medium, whereas following re-equilibration of the dissolution cell with the intestinal medium, a release of furosemide was observed after 1 min with an increased release after 5 min of dissolution.CONCLUSIONS: Biodegradable microcontainers were successfully fabricated and loaded with drug. Coating with Eudragit L-100 proved to be useful for protecting drug release from microcontainers in gastric medium, and facilitated an immediate release in the intestinal medium. The fabricated microcontainers therefore show considerable future potential as oral drug delivery systems.

for 25th European Congress of Psychiatry, European Psychiatry, Florence, Italy, April 1-4, 2017.

In drug discovery and early drug development, the amount of new chemical entity available is often limited preventing detailed physicochemical profiling and ADME characterization. Capillary-based techniques constitute an alternative to current methods requiring only microgram quantities for analysis. The use of capillary-based techniques for physicochemical profiling of drug development candidates is reviewed. Focus is on affinity methods based on capillary electrophoresis, such as mobility shift affinity capillary electrophoresis, electrokinetic chromatography, frontal analysis capillary electrophoresis and pre-equilibrium capillary zone electrophoresis, and on Taylor dispersion analysis. These approaches are efficient for quantifying ionization constants (pK a ), lipophilicity, distribution phenomena in relation to micelles, microemulsions and liposomes, protein binding, and interactions with pharmaceutical excipients. Taylor dispersion analysis can be used to quantify binding constants when both binding partners are neutral as well as to determine drug substance diffusivity and hydrodynamic radius.

The majority of drug candidates have molecular weights of about 200–500 Dalton. Bioreversible derivatives obtained by covalent attachment of a promoiety similar in size to drug candidates can be referred to as low molecular weight prodrugs. This approach has been used to improve drug performance by overcoming various barriers to drug delivery. When the barrier is target site access and the target site can only be reached after transport via the systemic circulation, the in vivo fate of the drug/prodrug is affected by distribution processes, protein binding, and excretion, not to mention the range of metabolic reactions that prodrugs may undergo. The latter processes are influenced by the physicochemical properties of the prodrug derivative. However, these are less predictable when using the low molecular weight prodrug approach to optimize systemic sitespecific drug delivery. The macromolecular prodrug approach, in which the small therapeutic agent is attached to a macromolecular promoiety, has been exploited to provide drug targeting. The basic rationale behind this approach is that the transport properties of the macromolecular prodrug should be dictated predominantly by those of the macromolecular transport vector. Thus, macromolecular conjugates derived from a wide array of macromolecules endowed with intrinsic target receptor affinities, especially of anticancer agents and other therapeutics have been evaluated.

A series of model phenol carbonate ester prodrugs encompassing derivatives with fatty acid-like structures were synthesized and their stability as a function of pH (range 0.4 - 12.5) at 37 degrees C in aqueous buffer solutions investigated. The hydrolysis rates in aqueous solutions differed widely, depending on the selected pro-moieties (alkyl and aryl substituents). The observed reactivity differences could be rationalized by the inductive and steric properties of the substituent groups when taking into account that the mechanism of hydrolysis may change when the type of pro-moiety is altered, e.g. n-alkyl vs. t-butyl. Hydrolysis of the phenolic carbonate ester 2-(phenoxycarbonyloxy)-acetic acid was increased due to intramolecular catalysis, as compared to the derivatives synthesized from omega-hydroxy carboxylic acids with longer alkyl chains. The carbonate esters appear to be less reactive towards specific acid and base catalyzed hydrolysis than phenyl acetate. The results underline that it is unrealistic to expect that phenolic carbonate ester prodrugs can be utilized in ready to use aqueous formulations. The stability of the carbonate ester derivatives with fatty acid-like structures, expected to interact with the plasma protein human serum albumin, proved sufficient for further in vitro and in vivo evaluation of the potential of utilizing HSA binding in combination with the prodrug approach for optimization of drug pharmacokinetics.