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Formation of high viscous inverse lyotropic liquid crystalline phases in situ upon exposure of low viscous drug-loaded lipid preformulations to synovial fluid provides a promising approach for design of depot formulations for intra-articular drug delivery. Rational formulation design relies on a fundamental understanding of the synovial fluid-mediated dynamic structural transitions occurring at the administration site. At conditions mimicking the in vivo situation, we investigated in real-time such transitions at multiple positions by synchrotron small-angle X-ray scattering (SAXS) combined with an injection-cell. An injectable diclofenac-loaded quaternary preformulation consisting of 72/8/10/10% (w/w) glycerol monooleate/1,2-dioleoyl-glycero-3-phospho-rac-(1-glycerol)/ethanol/water was injected into hyaluronic acid solution or synovial fluid. A fast generation of a coherent drug depot of inverse bicontinuous Im3m and Pn3m cubic phases was observed. Through construction of 2D spatial maps from measurements performed 60 min after injection of the preformulation, it was possible to differentiate liquid crystalline rich- and excess hyaluronic acid solution- or synovial fluid-rich regimes. Synchrotron SAXS findings confirmed that the exposure of the preformulation to the media leads to alterations in structural features in position- and time-dependent manners. Effects of biologically relevant medium composition on the structural features, and implications for development of formulations with sustained drug release properties are highlighted.

Nanoparticles (NPs) are increasingly applied in research and development of new therapies. Characterization of NP systems most often include size, shape, size distribution, and charge but information on the chemical stability of NPs and investigation of the presence of dissolved species is most often missing in efficacy studies due to lack of appropriate methods. In this study, a method based on capillary electrophoresis coupled to inductively coupled plasma mass spectrometry (CE-ICP-MS) was established for analysis of selenium (Se) NPs and dissolved Se species in aqueous media. Peak area and migration time precisions (RSD) of 1.4-3.0% and 1.0-2.6%, respectively, were obtained. CE-ICP-MS analysis of a commercially available SeNP suspension (Q-SeNP) revealed large amounts of selenite corresponding to 32% of the total Se content in the suspension, indicating considerable NP degradation upon storage. The CE-ICP-MS method was modified using a coated fused silica capillary in order to analyze SeNPs in human plasma. Peak area and migration time precisions (RSD) in the range of 3.3-10.7% and 0.8-2.8%, respectively, were achieved. Degradation of polyvinyl alcohol (PVA)-coated SeNPs to selenite in human plasma was demonstrated using the modified method. The amounts of SeNP and selenite were estimated based on a correction factor for the ICP-MS signals of PVA-SeNP and dissolved Se. To the best of our knowledge, this is the first study of SeNPs by CE-ICP-MS and highlights the potential of CE-ICP-MS for quantitative characterization of the behavior of SeNPs in biological media.

Purpose: To evaluate clinical practice in the diagnosis and treatment of progressive keratoconus with corneal crosslinking (CXL) in four Nordic countries. Methods: A questionnaire was sent to all centres at which keratoconus patients are evaluated and CXL is performed in Sweden, Denmark, Norway and Iceland. Nineteen of 20 centres participated. Results: CXL is performed approximately 1300 times per year in these four Nordic countries with a population of around 21.7 million (2019). In most cases, progression is evaluated using the Pentacam HR, and the maximum keratometry reading (Kmax) is considered the most important parameter. The most frequently used treatment protocol in Scandinavia is the 9 mW/cm2 epi-off protocol, using hydroxylpropyl methylcellulose riboflavin (HPMC-riboflavin). The participants deemed the following areas to be in most need of improvement: adaptation of the CXL protocol to individual patients (5/19), the development of effective epi-on treatment protocols (4/19), optimal performance of CXL in thin corneas (4/19), improvement of the definition of progression (2/19), and diagnosis of the need for re-treatment (2/19). Conclusions: We concluded that the diagnosis of progressive keratoconus and the diagnostic equipment used are similar. Treatment strategies are also similar but are suitably different to provide an interesting basis for the comparison of treatment outcomes. The high degree of participation in this survey indicates the possibility of future scientific collaboration on CXL focusing on the areas deemed to need improvement. It would also be of interest to evaluate the possibility of creating a Nordic CXL Registry. The high number of CXL treatments performed ensures sufficient statistical power to solve many questions. Such a registry could be an important contribution to evidence-based care and would allow for longitudinal evaluation.

The initial drug release from in situ forming implants is affected by factors such as the physicochemical properties of the active pharmaceutical ingredient, the type of the excipients utilized, and the surrounding environment. The feasibility of UV-vis imaging for characterization of the initial behavior of poly(d,l-lactide-co-glycolide) (PLGA)/1-methyl-2-pyrrolidinone (NMP) in situ forming implants was investigated. The in vitro release of leuprolide acetate (LA) and implant formation in real time were monitored using dual-wavelength imaging at 280 and 525 nm, respectively, in matrices based on agarose gel and hyaluronic acid (HA) solution emulating the subcutaneous matrix. Three hours upon injection of the pre-formulation, approximately 15% of the total amount of LA administered was found in the agarose gel, while 5% was released from the implant into the HA solution. Concurrently, more extensive swelling of the implants in the HA solution as compared to implants in the agarose gel was observed. Transport of both LA and the solvent NMP was investigated using UV-vis imaging in a small-scale cell where the geometry of the formulation was controlled, showing a linear correlation between drug release and solvent escape. Light microscopy showed that the microstructures of the resulting implants in agarose gel and HA solution were different, which may be attributed to the different solvent exchange rates. UV imaging was also used to examine the interaction of LA with the release medium by characterizing the diffusion of LA in agarose gel, HA solution, and phosphate buffered saline. The reduced LA diffusivity in HA solution as compared to agarose gel and the LA distribution coefficient in the agarose gel-HA system indicated the presence of interactions between LA and HA. Our findings show that the external environment affects the solvent exchange kinetics for in situ forming implants in vitro, resulting in different types of initial release behavior. UV-vis imaging in combination with biorelevant matrices may offer an interesting approach in the development of in situ forming implant delivery systems.

Intra-articular depot injectables based on in situ suspension formation of ester prodrugs of nonsteroidal anti-inflammatory drugs are promising for management of joint pain. As candidates for this delivery approach, 5 diclofenac ester prodrugs comprising different imidazole-containing promoieties were synthesized and their physicochemical properties characterized. In vitro hydrolysis rates were investigated in buffer solutions, in 40% (v/v) human, equine, canine, and rat plasma, and in 80% (v/v) human and equine synovial fluid. Bioconversion of the prodrugs to diclofenac was found to be enzyme-mediated and follow pseudo-first-order kinetics. Large variations in hydrolysis rates were observed between species and between prodrugs, with prodrug half-lives in plasma from canine, rat, horse, and human of 3.44-141 min, 2.51-14 min, 0.58-1.31 min, and 0.23-1.70 min, respectively. Half-lives in human and equine synovial fluid were 1.6- to 28-fold larger than in plasma. The results highlight the significance of species and tissue variation in prodrug design and suggest that the horse may constitute a suitable model for testing the intra-articular depot approach. Two prodrug candidates appeared promising for future in vivo studies based on their rapid in vitro enzyme-mediated bioconversion to diclofenac and physiochemical characteristics.

A UV imaging release-testing setup comprising an agarose gel as a model for tumorous tissue was developed. The setup was optimized with respect to agarose concentration (0.5% (w/v)), injection procedure, and temperature control. A repeatable injection protocol was established allowing injection into cavities with well-defined geometries. The effective resolution of the SDi2 UV imaging system is 30–80 µm. The linear range of the imaging system is less than that of typical spectrophotometers. Consequently, non-linear cAMP calibration curves were applied for quantification at 280 nm. The degree of deviation from Beer’s law was affected by the background absorbance of the gel matrix. MATLAB scripts provided hitherto missing flexibility with respect to definition and utilization of quantification zones, contour lines facilitating visualization, and automated, continuous data analysis. Various release patterns were observed for an aqueous solution and in situ forming Pluronic F127 hydrogel and PLGA implants containing cAMP as a model for STING ligands. The UV imaging and MATLAB data analysis setup constituted a significant technical development in terms of visualizing behavior for injectable formulations intended for intra-tumoral delivery, and, thereby, a step toward establishment of a bio-predictive in vitro release-testing method. A UV imaging release-testing setup comprising an agarose gel as a model for tumorous tissue was developed. The setup was optimized with respect to agarose concentration (0.5% (w/v)), injection procedure, and temperature control. A repeatable injection protocol was established allowing injection into cavities with well-defined geometries. The effective resolution of the SDi2 UV imaging system is 30–80 µm. The linear range of the imaging system is less than that of typical spectrophotometers. Consequently, non-linear cAMP calibration curves were applied for quantification at 280 nm. The degree of deviation from Beer’s law was affected by the background absorbance of the gel matrix. MATLAB scripts provided hitherto missing flexibility with respect to definition and utilization of quantification zones, contour lines facilitating visualization, and automated, continuous data analysis. Various release patterns were observed for an aqueous solution and in situ forming Pluronic F127 hydrogel and PLGA implants containing cAMP as a model for STING ligands. The UV imaging and MATLAB data analysis setup constituted a significant technical development in terms of visualizing behavior for injectable formulations intended for intra-tumoral delivery, and, thereby, a step toward establishment of a bio-predictive in vitro release-testing method.

In situ formation of high viscous inverse lyotropic non-lamellar liquid crystalline phases is a promising approach for sustained drug delivery in the joint. The in situ forming process on exposure of two diclofenac-loaded preformulations to aqueous media was characterized with respect to depot size and shape, initial release and structural transitions using UV–Vis imaging and spatially and time-resolved synchrotron small-angle X-ray scattering (SAXS). The preformulations consisted of 10 % (w/w) ethanol, 10 % (w/w) water and a binary lipid mixture of glycerol monooleate (GMO):1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) (DOPG) or GMO:medium chain triglycerides (MCT). Upon injection of preformulations into an employed injection-cell containing excess of bio-relevant medium, rapid generation of liquid crystalline depots was observed. UV–Vis images and constructed 2D SAXS maps of the injection-cell showed depots with different shapes and sizes, and features with high nanostructural heterogeneity. More extensive swelling of the GMO:DOPG-based preformulation was observed compared to the GMO:MCT-based preformulation. The UV image analysis found that a higher amount of diclofenac was released in the image area after 20 h from the GMO:MCT depot compared to the GMO:DOPG depot. The injection-cell setup employing UV–Vis imaging and synchrotron SAXS constitutes an attractive approach for evaluating the in situ forming processes of liquid crystalline depots.

Assessment of protein stability and function is key to the understanding of biological systems and plays an important role in the development of protein-based drugs. In this work, we introduce an integrated approach based on Taylor dispersion analysis (TDA), flow induced dispersion analysis (FIDA), and in-line intrinsic fluorescence which enables rapid and detailed assessment of protein stability and unfolding. We demonstrate that the new platform is able to efficiently characterize chemically induced protein unfolding of human serum albumin (HSA) in great detail. The combined platform enables local structural changes to be probed by monitoring changes in intrinsic fluorescence and loss of binding of a low-molecular weight ligand. Simultaneously, the size of the unfolding HSA is obtained by TDA on the same samples. The integration of the methodologies enables a fully automated characterization of HSA using only a few hundred nanoliters of sample. We envision that the presented methodology will find applications in fundamental biophysics and biology as well as in stability screens of protein-based drug candidates.

The study concerns development of simulated synovial fluid for in vitro release testing of drug and prodrug-based depot delivery systems for joint injection. The importance of drug protein binding and esterase-catalyzed prodrug hydrolysis was investigated using a membrane-based in vitro release testing system, the rotating dialysis cell. Protein binding was investigated in synovial fluid from arthritic patients, human plasma and phosphate buffer, pH 7.4, containing serum albumin. Compounds with low (sodium diatrizoate) and high (naproxen and diclofenac) degrees of protein binding were investigated. The cleavage of two poorly soluble naproxen and diclofenac ester prodrugs was studied in esterase-containing media, diluted synovial fluid and plasma. Regarding protein binding, the in vitro release studies revealed that drug release profiles obtained using buffer comprising 2% (w/v) serum albumin, or 40% (v/v) plasma were comparable to profiles obtained employing 80% (v/v) synovial fluid. For prodrug-based depot injectables, application of 40% (v/v) plasma provided release profiles comparable to those using 80% (v/v) synovial fluid. Design of simulated synovial fluids for characterizing in vitro the interplay between drug/prodrug solubility, protein binding and susceptibility to enzymatic cleavage, and joint residence time is feasible. Synovial fluid may be replaced with readily accessible serum albumin solutions or diluted plasma.

In the present study, a method for quantitation of the pharmaceutical peptide oxytocin (OT) and its diselenide-containing analogue (SeOT) in human plasma was developed using gradient elution LC-ICP-MS/MS. Plasma samples were precipitated with acetonitrile containing 1.0% TFA in a volume ratio of 1+3 (sample+precipitation agent) before analysis. Post-column isotope dilution analysis (IDA) was applied for quantitation and was compared with external calibration. Both calibration methods appeared to be fit for purpose regarding figures of merit including linearity, precision, LOD, LOQ and recovery. Analysis of OT and SeOT showed that selenium-based analysis is considerably more sensitive and selective compared to the sulfur-based analysis. Despite the relatively simpler setup of external calibration, IDA can be advantageous because it compensates for instrument drift and changes in organic solvent concentration. The method was applied for a stability study showing the degradation of OT and SeOT in plasma. The degradation of SeOT was faster than the degradation of OT in plasma. Thus, possible stability effects should be considered before replacing a disulfide bridge with a diselenide bridge or introducing a diselenide label in a potential drug. Graphical abstract: [Figure not available: see fulltext.]

UV–vis spectrometry is widely used in the pharmaceutical sciences for compound quantification, alone or in conjunction with separation techniques, due to most drug entities possessing a chromophore absorbing light in the range 190–800 nm. UV dissolution imaging, the scope of this review, generates spatially and temporally resolved absorbance maps by exploiting the UV absorbance of the analyte. This review aims to give an introduction to UV dissolution imaging and its use in the determination of intrinsic dissolution rates and drug release from whole dosage forms. Applications of UV imaging to non-oral formulations have started to emerge and are reviewed together with the possibility of utilizing UV imaging for physical chemical characterisation of drug substances. The benefits of imaging drug diffusion and transport processes are also discussed.

Buccal films containing a pH modifying excipient may be able to increase bioavailability of drugs with pH-dependent solubility such as saquinavir. Access to suitable in vitro drug release testing methods may facilitate buccal formulation development. This study aimed to explore two release testing methods for characterising buccal films and to elucidate the relationship between microenvironmental pH (pHM, i.e. the pH around the swelling films) and saquinavir release. The Franz diffusion cell method was applicable to investigate the effect of hydroxypropyl methylcellulose (HPMC) grade on saquinavir release. Films containing HPMC K3 LV had a faster saquinavir release than films containing HPMC K100 LV. A UV/Vis imaging method was developed to visualise saquinavir release and pHM changes during the initial dissolution. Within 5 min, the pHM decreased from 6.8 to around 5.4 for HPMC K100 LV-based films containing 11.1 % or 16.6 % (w/w) malic acid. Subsequently, the pHM increased due to increasing concentrations of saquinavir. An increase in malic acid content led to a faster saquinavir release. The combination of methods may be broadly applicable for excipient screening in development of buccal formulations. The imaging approach holds promise for characterizing other pH modifying formulation principles.

In situ forming implants are exposed to an extracellular matrix resembling a gel rather than aqueous solution upon subcutaneous administration. The aim of study was to develop a gel-based release testing system for characterizing the long-term in vitro behavior of in situ forming implants. The gel-based system consisted of an agarose gel mimicking the subcutaneous injection site and a receiver layer comprising phosphate buffer. Poly(D,L-lactide-co-glycolide) in situ forming implants containing leuprolide acetate as the model peptide and N-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO) or triacetin as co-solvent were investigated. The gel-based release testing system discriminated between the formulations. Accelerated release data obtained at elevated temperatures were able to predict real-time release applying the Arrhenius equation. Monitoring of the microenvironmental pH of the implants was performed by UV–Vis imaging in the gel-based system at 50 °C. A pH drop (from pH 7.4 to 6.7 for the NMP and DMSO implants, to pH 5.5 for the triacetin implants) within the first day was observed, followed by an increase to pH ∼7.4. The gel-based system coupled with UV imaging offered opportunity for detailed evaluation and prediction of the in vitro performance of long-acting injectables, facilitating future development of in situ depot forming delivery systems.

The initial drug release from

The purpose of this study was to investigate whole-dosage form UV-vis imaging as a potential tool for functional characterization of excipients used in solid oral dosage forms. To this end, tablets (average mass 260.0 mg, 224.5 mg and 222.1 mg) containing theophylline anhydrate (20 % w/w), 1% (w/w) magnesium stearate, and 79 % (w/w) of either microcrystalline cellulose (MCC, Avicel PH 101) or hydroxypropyl methylcellulose (HPMC, Methocel K15 M or K100 M) were prepared as model systems. Drug liberation from tablets was studied in 0.01 M HCl at 37 degrees C using a Sirius SDi2 equipped with a USP IV type flow cell comprising a UV-vis imaging detector operating at 255 nm and 520 nm. The effluent from the flow cell was passed through a downstream spectrophotometer, and UV-vis spectra in the wavelength range 200-800 nm were recorded every 2 min. The erosion and swelling behavior of the MCC tablets and HPMC K15 M and K100 M tablets were visualized in real time. The swelling of HPMC K15 M and K100 M containing tablets was assessed quantitatively as changes in tablet diameter measured at 520 nm, and was clearly distinguished from the swelling of the MCC tablets. Namely, an increment of 2.5 mm in diameter was determined for the HPMC tablets while the MCC tablets increased by 0.5-1 mm in diameter. Gel layers of variable thickness were observed only for the HPMC K15 M and K100 M tablets. In addition, a relatively high initial liberation rate of theophylline was found for the MCC tablets as compared to the HPMC tablets. UV-vis imaging revealed features of liberation not revealed by simply measuring drug concentration in the dissolution media or by visual assessment. It may be sufficiently sensitive to be further developed for functional characterization of excipients and provide insights into drug-excipient interactions likely to be useful in formulation development. (C) 2020 Elsevier B.V. All rights reserved.

Elucidating the impact of excipient variability on oral product performance in a biopharmaceutical perspective would be beneficial and allow excipient implementation on Quality by Design (QbD) approaches. The current study investigated the impact of varying viscosity of binders (hypromellose (HPMC)) and superdisintegrants (sodium starch glycolate (SSG)) and particle size distribution of lubricants (magnesium stearate (MgSt)) on the in vitro dissolution of a highly and a poorly soluble drug from immediate release formulations. Compendial (pharmacopoeia buffers) and biorelevant (media simulating the gastrointestinal fluids) media and the USP 2 and USP 4 apparatuses were used to assess the exerted excipient effects on drug dissolution. Real-time dissolution UV imaging provided mechanistic insights into disintegration and dissolution of the immediate release formulations. Varying the viscosity type of HPMC or SSG did not significantly affect drug dissolution irrespective of the compound used. Faster drug dissolution was observed when decreasing the particle size of MgSt for the highly soluble drug. The use of real-time dissolution UV Imaging revealed the influential role of excipient variability on tablet disintegration, as for the highly soluble drug, tablets containing high viscosity HPMC or low particle size MgSt disintegrated faster as compared to the control tablets while for the poorly soluble drug, slower tablet disintegration was observed when increasing the viscosity of the HPMC as compared to the control tablets. Changes in drug dissolution when varying excipients may be anticipated if the excipient change has previously affected drug solubility. The use of multivariate data analysis revealed the influential biopharmaceutical factors such as critical excipient types/properties, drug aqueous solubility, medium/hydrodynamic characteristics affecting the impact of excipient variability on in vitro drug dissolution.

Co-amorphous systems comprising low-molecular weight drugs and co-formers constitute an interesting approach to optimize pharmaceutical performance of drugs with low aqueous solubility. Within the different types of co-amorphous systems, the combination of a drug with its own salt may be an attractive formulation option due the absence of any inactive co-formers. The aim of this study was to investigate the possibility of forming a co-amorphous system from naproxen (NAP) and its sodium salt (NAP(Na)). Ball milling of NAP and NAP(Na) at equal molar ratio resulted in the formation of a co-amorphous system whilst NAP and NAP(Na) alone were crystalline following both, ball milling and melt quenching. Infrared spectroscopy and physical stability testing revealed that intermolecular interactions were able to maintain the ball milled NAP-NAP(Na) system amorphous for 2 months at 40 °C. Surprisingly, the dissolution rate of co-amorphous NAP-NAP(Na) was only intermediate between those of crystalline NAP and crystalline NAP(Na). In situ Raman spectroscopic measurements indicated an initial phase separation of the co-amorphous form to NAP and NAP(Na) followed by dissociation of sodium from NAP(Na) and crystallization to NAP. These findings contribute to the design of co-amorphous formulations with the combination of a drug and its own salt.

For poly (lactide-co-glycolide acid) (PLGA)-based in situ forming implants, the rate of implant formation plays an important role in determining the overall drug release kinetics. Currently, in vitro techniques capable of characterizing the processes of drug release and implant formation at the same time are not available. A hydrogel-based in vitro experimental setup was recently developed requiring only microliter of formulation and forming a closed system potentially suitable for interfacing with various spectroscopic techniques. The aim of the present proof-of-concept study was to investigate the feasibility of concomitant UV imaging, Vis imaging and light microscopy for detailed characterization of the behavior of in situ forming PLGA implants in the hydrogel matrix mimicking the subcutis. The model compounds, piroxicam and α-lactalbumin were added to PLGA-1-methyl-2-pyrrolidinone and PLGA-triacetin solutions. Upon bringing the PLGA-solvent-compound pre-formulation in contact with the hydrogel, Vis imaging and light microscopy were applied to visualize the depot formation and UV imaging was used to quantify drug transport in the hydrogel. As compared to piroxicam, the α-lactalbumin invoked an acceleration of phase separation and an increase of implant size. α-Lactalbumin was released faster from the PLGA-1-methyl-2-pyrrolidinone system than the PLGA-triacetin system opposite to the piroxicam release pattern. A linear relationship between the rate of implant formation and initial compound release within the first 4h was established for the PLGA-NMP systems. This implies that phase separation may be one of the controlling factors in drug release. The rate of implant formation may be an important parameter for predicting and tailoring drug release. The approach combining UV imaging, Vis imaging and light microscopy may facilitate understanding of release processes and holds potential for becoming a useful tool in formulation development of in situ forming implants.

Taylor dispersion analysis (TDA) is an absolute method (no calibration needed) for the determination of the molecular diffusion coefficient (D) based on the band broadening of a solute in a laminar flow. TDA is virtually applicable to any solute with size ranging from angstrom to sub-micrometer. The higher sizing limit is restricted by the occurrence of possibly two regimes: convective and hydrodynamic chromatography (HDC) regimes, which have different physical origins that should not be confused. This work aims at clearly defining the experimental conditions for which these two regimes can play a role, alone or concomitantly. It also calculates the relative error on D due to the HDC regime according to the solute to capillary size ratio. It is demonstrated in this work that HDC does not significantly affect the TDA measurement as long as the hydrodynamic radius of the solute is lower than 0.0051 times the capillary radius. Experimental illustrations of the occurrence of the two regimes are given taking polystyrene nanoparticles as model solutes. Finally, application of TDA to the sizing of large real-life solutes is proposed, taking cubosomes as new drug nanocarriers of potential interest for drug delivery purposes.

Phase separation of in situ forming poly (lactide-co-glycolide acid) (PLGA) implants with agarose hydrogels as the provider of nonsolvent (water) mimicking subcutaneous tissue was investigated using a novel UV-vis imaging-based analytical platform. In situ forming implants of PLGA-1-methyl-2-pyrrolidinone and PLGA-triacetin representing fast and slow phase separating systems, respectively, were evaluated using this platform. Upon contact with the agarose hydrogel, the phase separation of the systems was followed by the study of changes in light transmission and absorbance as a function of time and position. For the PLGA-1-methyl-2-pyrrolidinone system, the rate of spatial phase separation was determined and found to decrease with increasing the PLGA concentration from 20% to 40% (w/w). Hydrogels with different agarose concentrations (1% and 10% (w/v)) were prepared for providing the nonsolvent, water, to the in situ forming PLGA implants simulating the injection site environment. The resulting implant morphology depended on the stiffness of hydrogel matrix, indicating that the matrix in which implants are formed is of importance. Overall, the work showed that the UV-vis imaging-based platform with an agarose hydrogel mimicking the subcutaneous tissue holds potential in providing bio-relevant and mechanistic information on the phase separation processes of in situ forming implants.

This work reports a novel approach to the assessment of the surface properties of compacts used in Surface Dissolution Imaging (SDI). SDI is useful for determining intrinsic dissolution rate (IDR), an important parameter in early stage drug development. Surface topography, post-compaction and post-SDI run, have been measured using a non-contact, optical, three-dimensional microscope based on focus variation, the Alicona Infinite Focus Microscope, with the aim of correlating the IDRs to the surface properties. Ibuprofen (IBU) was used as a model poorly-soluble drug. DSC and XRD were used to monitor possible polymorphic changes that may have occurred post-compaction and post-SDI run. IBUs IDR decreased from 0.033 mg/min/cm2 to 0.022 mg/min/cm2 from 10 to 20 min, respectively, during the experiment. XRD and DSC showed no form changes during the SDI run. The surface topography images showed that a distinct imprint was embossed on the surfaces of some compacts which could affect IDRs. Surface parameter values were associated with the SDI experiments which showed strong correlations with the IDR values. The variable-focus microscope can be used as a complimentary tool in the determination of IDR values from the SDI.

The pur­pose of this study was to con­duct an in­ter­lab­o­ra­tory ring-study, with six part­ners (aca­d­e­mic and in­dus­trial), in­ves­ti­gat­ing the mea­sure­ment of in­trin­sic dis­so­lu­tion rate (IDR) us­ing sur­face dis­so­lu­tion imag­ing (SDI) equip­ment. Mea­sure­ment of IDR is im­por­tant in phar­ma­ceu­ti­cal re­search as it pro­vides char­ac­ter­is­ing in­for­ma­tion on drugs and their for­mu­la­tions. This work al­lowed us to as­sess the SDI’s in­ter­lab­o­ra­tory per­for­mance for mea­sur­ing IDR us­ing a de­fined stan­dard op­er­at­ing pro­ce­dure (see sup­port­ing in­for­ma­tion) and six drugs as­signed as low (tadalafil, bromocrip­tine me­sy­late), medium (carvedilol, in­domethacin) and high (ibupro­fen, val­sar­tan) sol­u­bil­ity com­pounds. Fasted State Sim­u­lated In­testi­nal Fluid (FaS­SIF) and blank FaS­SIF (with­out sodium tau­ro­cholate and lecithin) (pH 6.5) were used as me­dia. Us­ing the stan­dard­ised pro­to­col an IDR value was ob­tained for all com­pounds and the re­sults show that the over­all IDR rank or­der matched the sol­u­bil­ity rank or­der. In­ter­lab­o­ra­tory vari­abil­ity was also ex­am­ined and it was ob­served that the vari­abil­ity for lower sol­u­bil­ity com­pounds was higher, co­ef­fi­cient of vari­a­tion >50%, than for in­ter­me­di­ate and high sol­u­bil­ity com­pounds, with the ex­cep­tion of in­domethacin in FaS­SIF medium. In­ter lab­o­ra­tory vari­abil­ity is a use­ful de­scrip­tor for un­der­stand­ing the ro­bust­ness of the pro­to­col and the sys­tem vari­abil­ity. On com­par­i­son to an­other pub­lished small-scale IDR study the rank or­der­ing with re­spect to dis­so­lu­tion rate is iden­ti­cal ex­cept for the high sol­u­bil­ity com­pounds. This re­sults in­di­cates that the SDI ro­bustly mea­sures IDR how­ever, no rec­om­men­da­tion on the use of one small scale method over the other is made.

Flow-Induced Dispersion Analysis (FIDA) enables characterization and quantification of proteins under native conditions. FIDA is based on measuring the change in size of a ligand as it selectively interacts with the target protein. The unbound ligand has a relatively small apparent hydrodynamic radius (size), which increase in the presence of the analyte due to binding to the analyte. The K

There is a need for bio-predictive and well-characterized in vitro release models in the development of intra-articular depot formulations. Here, the commercially-available Scissor system, a membrane-based two-compartment release testing instrument, was applied to characterize the transport and release of the drug diclofenac employing conditions intended to mimic transport in the synovial joint. The fate of hyaluronic acid and human serum albumin, the main bio-relevant components incorporated in the system, was investigated. A promising strategy for providing sustained drug release upon intra-articular administration are lipid-based preformulations forming non-lamellar liquid crystalline phases in situ. The usefulness of the Scissor system for investigating the initial drug release from these delivery systems was evaluated. The diclofenac release rate upon injection of an aqueous solution was influenced by the composition of the injection site matrix, i.e. the hyaluronic acid content. Hyaluronic acid and human serum albumin were found to escape from the donor compartment into the acceptor medium through the employed polycarbonate membrane. Sustained diclofenac release was obtained by formation of highly viscous liquid crystalline phases upon injection of the lipid-based preformulations. The study shows the feasibility and potential of the Scissor system for testing initial release of intra-articular depot formulations of low-molecular-weight drug compounds.

The purpose of this study was to characterize compact surfaces (surface roughness) and study its potential importance to the intrinsic dissolution rate (IDR) as determined by dissolution imaging. To this end, the effect of varying compaction pressures and the use of two stainless-steel surfaces with different textures/roughness on the intrinsic dissolution were investigated. Ketoprofen (KET), paracetamol (PAR) and ibuprofen (IBU) were compacted and a focus variation microscope used to determine the surface topology of the compacts. IDR determination was conducted using a surface dissolution imaging apparatus with the flow-through set up in phosphate buffer at pH 7.2 and at 37 °C. The results indicated a general decrease in the surface area of the drug compacts with an increase in compaction force (p values < 0.05 for IBU and PAR but not KET). This change in surface area was measured using the Sdr parameter, which can be defined as the developed interfacial area. The smoother stainless-steel plate insert produced significantly smoother compacts for KET (Sdr decreased from 0.30% to 0.07%). However, PAR and IBU compacts showed an increase in their Sdr values from 3.94% to 17.90% and from 0.60% to 0.83%, respectively, suggesting the changes in surface properties to be drug specific relating to poor compaction properties and elasticity. The dissolution studies suggested that low compaction forces were not suitable for PAR. Overall changes in the surface topology did not have a significant effect on the obtained IDR values.

Many bioanalytical methods rely on electrophoretic separation of structurally labile and surface active biomolecules such as proteins and peptides. Often poor separation efficiency is due to surfac ...