Meloxicam (MLX) is a poorly soluble drug exhibiting strong hydrophobicity. This combination of properties makes dissolution enhancement by particle size reduction ineffective; therefore, combined formulation approaches are required. Various approaches were investigated in this study, including milling, solid dispersions, and self-emulsified lipid formulations. Whereas milling studies of MLX and its co-milling with various polymers have been reported in recent literature, this study is focused on investigating the dissolution kinetics of particulate formulations obtained by co-milling MLX with sodium lauryl sulfate (SLS) in a planetary ball mill with 5-25 wt.% SLS content. The effects of milling time and milling ball size were also investigated. No significant reduction in drug crystallinity was observed under the investigated milling conditions according to XRD data. For the dissolution study, we used an open-loop USP4 dissolution apparatus, and recorded dissolution profiles were fitted according to the Weibull model. The Weibull parameters and a novel criterion-surface utilization factor-were used to evaluate and discuss the drug release from the perspective of drug particle surface changes throughout the dissolution process. The most effective co-milling results were achieved using smaller balls (2 mm), with a co-milling time of up to 15 min SLS content of up to 15 wt.% to increase the dissolution rate by approximately 100 times relative to the physical mixture reference. The results suggest that for hydrophobic drugs, particle performance during dissolution is very sensitive to surface properties and not only to particle size. Co-milling with SLS prepares the surface for faster drug release than that achieved with direct mixing.

• Klíčová slova
• co-milling, dissolution kinetics, dissolution rate, enhanced dissolution, meloxicam, sodium lauryl sulfate, surface modification,
• Publikační typ
• časopisecké články MeSH

Roller compaction is often utilized as the first step to improve flow properties and homogeneity of pharmaceutical mixtures. Since the dry granulation process is less complicated than its counterparts in the industry, it is possible to perform screening experiments readily to investigate granulate quality for further operations. In this study, the aim of the investigation focused on the effect of roller compaction on the dissolution of granules and tablets of two pharmaceutical formulations that contain APIs of different biopharmaceutical classification. This study underscores the benefits of granule dissolution testing as a crucial early-stage technique for optimizing granulate quality and facilitating progression through formulation manufacturing operations. For active pharmaceutical ingredients characterized by poor dissolution properties, this approach provides valuable insights during the initial development phases. By integrating granule dissolution testing into the development process, product manufacturability can be enhanced and optimal product performance can be ensured.

• Klíčová slova
• Disintegration kinetics, Dissolution behavior, Dissolution rate, Dry granulation, Flow-through cell, Granule dissolution, Granule properties, Paddle dissolution, Poller compaction, Porosity, Process engineering, Process parameters, Tablet dissolution, USP2 dissolution, USP4 dissolution,
• MeSH
• farmaceutická chemie metody   MeSH
• farmaceutická technologie metody   MeSH
• pomocné látky chemie   MeSH
• prášky, zásypy, pudry chemie   MeSH
• příprava léků * metody   MeSH
• rozpustnost MeSH
• tablety * chemie   MeSH
• uvolňování léčiv MeSH
• velikost částic MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• pomocné látky MeSH
• prášky, zásypy, pudry MeSH
• tablety * MeSH

To enhance dissolution rate of meloxicam (MX), a poorly soluble model drug, a natural polysaccharide excipient chitosan (CH) is employed in this work as a carrier to prepare binary interactive mixtures by either mixing or co-milling techniques. The MX-CH mixtures of three different drug loads were characterized for morphological, granulometric, and thermal properties as well as drug crystallinity. The relative dissolution rate of MX was determined in phosphate buffer of pH 6.8 using the USP-4 apparatus; a significant increase in MX dissolution rate was observed for both mixed and co-milled mixtures comparing to the raw drug. Higher dissolution rate of MX was evidently connected to surface activation by mixing or milling, which was pronounced by the higher specific surface energy as detected by inverse gas chromatography. In addition to the particle size reduction, the carrier effect of the CH was confirmed for co-milling by linear regression between the MX maximum relative dissolution rate and the total surface area of the mixture (R2 = 0.863). No MX amorphization or crystalline structure change were detected. The work of adhesion/cohesion ratio of 0.9 supports the existence of preferential adherence of MX to the coarse particles of CH to form stable interactive mixtures.

• Klíčová slova
• BCS class II, Chitosan, Co-milling, Dissolution rate, Interactive mixture, Meloxicam,
• MeSH
• chitosan * MeSH
• meloxikam MeSH
• pomocné látky MeSH
• rozpustnost MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chitosan * MeSH
• meloxikam MeSH
• pomocné látky MeSH

One of the conventional methods of alleviating the problem of poor drug solubility is the particle size reduction. The efficiency of this approach depends on successful formulation suppressing the drug agglomeration. The aim of this study was to circumvent the dissolution problems of model hydrophobic meloxicam drug (MLX) by using liquid media of different wetting capacity to comminute and formulate a rapidly dissolving carrier system without the use of surfactants. Micro-suspensions of MLX were prepared by ball milling, using water or n-Heptane as a liquid medium. The suspensions were used as granulation liquids to formulate granulate from microcrystalline cellulose and lactose mixture. The release kinetics from prepared granulates were studied using the USP-4 dissolution apparatus. Micro-suspensions prepared via wet milling in non-water liquid media exhibited a massive improvement of release rate compared with source meloxicam and they outperformed their water-milled counterparts. The release rates from those formulations, despite not comprising any surfactant, were comparable to those obtained by different authors using surfactant stabilized nanosuspension formulations. Thus, they can present an interesting formulation alternative for hydrophobic drugs that are dissolution limited.

• Klíčová slova
• carrier system, dissolution, enhanced dissolution rate, meloxicam, micro-particle,
• MeSH
• celulosa MeSH
• kinetika MeSH
• laktosa MeSH
• meloxikam aplikace a dávkování   chemie   MeSH
• nanostruktury MeSH
• nosiče léků chemie   MeSH
• povrchově aktivní látky MeSH
• rozpustnost MeSH
• suspenze MeSH
• uvolňování léčiv MeSH
• velikost částic MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• celulosa MeSH
• laktosa MeSH
• meloxikam MeSH
• microcrystalline cellulose MeSH Prohlížeč
• nosiče léků MeSH
• povrchově aktivní látky MeSH
• suspenze MeSH

CONTEXT: The preparation of liquisolid systems (LSS) represents a promising method for enhancing a dissolution rate and bioavailability of poorly soluble drugs. The release of the drug from LSS tablets is affected by many factors, including the disintegration time. OBJECTIVE: The evaluation of differences among LSS containing varying amounts and types of commercially used superdisintegrants (Kollidon® CL-F, Vivasol® and Explotab®). MATERIALS AND METHODS: LSS were prepared by spraying rosuvastatin solution onto Neusilin® US2 and further processing into tablets. Varying amounts of superdisintegrants were used and the differences among LSS were evaluated. The multiple scatter plot method was used to visualize the relationships within the obtained data. RESULTS AND DISCUSSION: All disintegrants do not showed negative effect on the flow properties of powder blends. The type and concentration of superdisintegrant had an impact on the disintegration time and dissolution profiles of tablets. Tablets with Explotab® showed the longest disintegration time and the smallest amount of released drug. Fastest disintegration and dissolution rate were observed in tablets containing Kollidon® CL-F (≥2.5% w/w). Also tablets with Vivasol® (2.5-4.0% w/w) showed fast disintegration and complete drug release. CONCLUSION: Kollidon® CL-F and Vivasol® in concentration ≥2.5% are suitable superdisintegrants for LSS with enhanced release of drug.

• Klíčová slova
• Data visualization, disintegration time, dissolution profile, liquisolid systems, superdisintegrant,
• MeSH
• anticholesteremika aplikace a dávkování   chemie   MeSH
• farmaceutické pomocné látky chemie   MeSH
• povidon chemie   MeSH
• příprava léků MeSH
• rosuvastatin kalcium aplikace a dávkování   chemie   MeSH
• rozpustnost MeSH
• silikáty chemie   MeSH
• škrob analogy a deriváty   chemie   MeSH
• sloučeniny hliníku chemie   MeSH
• sloučeniny hořčíku chemie   MeSH
• tablety chemie   MeSH
• uvolňování léčiv MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aluminum magnesium silicate MeSH Prohlížeč
• anticholesteremika MeSH
• farmaceutické pomocné látky MeSH
• povidon MeSH
• rosuvastatin kalcium MeSH
• silikáty MeSH
• škrob MeSH
• sloučeniny hliníku MeSH
• sloučeniny hořčíku MeSH
• sodium starch glycolate MeSH Prohlížeč
• tablety MeSH

Co-milling of a drug with a co-former is an efficient technique to improve the solubility of drugs. Besides the particle size reduction, the co-milling process induces a structural disorder and the creation of amorphous regions. The extent of drug solubility enhancement is dependent on the proper choice of co-milling co-former. The aim of this work was to compare the effects of different co-formers (meglumine and polyvinylpyrrolidone) on the dissolution rates of glass forming (indomethacin) and non-glass forming (mefenamic acid) model drugs. A positive impact of the co-milling on the dissolution behavior was observed in all co-milled mixtures, even if no substantial amorphization was observed. While meglumine exhibited pronounced effects on the dissolution rate of both drugs, the slightest enhancement was observed in mixtures with polyvinylpyrrolidone. The evaluation of specific release rate revealed the surface activation of drug particle is responsible for improving the dissolution rate of both drug types, but for the glass former, this surface activation could be persistent while maintaining a high dissolution rate even until a high fraction of drug is released. Our results, therefore, indicate that adequate co-former choice and consideration of drug glass forming ability are important for a successful co-milling approach to poorly water-soluble drugs.

• Klíčová slova
• Co-milling, Dissolution rate, Glass forming ability, Indomethacin, Mefenamic acid,
• MeSH
• indomethacin MeSH
• léčivé přípravky * MeSH
• povidon * MeSH
• příprava léků MeSH
• rozpustnost MeSH
• velikost částic MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• indomethacin MeSH
• léčivé přípravky * MeSH
• povidon * MeSH

Commonly applied approaches to enhance the dissolution properties of low water-soluble crystalline active pharmaceutical ingredients (APIs) include their amorphization by incorporation into a polymeric matrix and the formation of amorphous solid dispersions, or blending APIs with low-molecular-weight excipients and the formation of a co-amorphous system. This study focused on the preparation and characterization of binary (consisting of indomethacin (IND) and polymer - copovidone (PVP VA 64), as a carrier, or amino acid - L-arginine (ARG), as a co-former) and ternary (comprising the same API, polymer, and amino acid) formulations. Formulations were produced by ball milling (BM) and/or hot-melt extrusion (HME), and extensive physicochemical characterization was performed. Specifically, the physicochemical and solid-state properties of a model IND-ARG system incorporated into a polymeric matrix of PVP VA 64 by HME and BM as well as by combined BM/HME method together with the impact of the preparation strategy on the dissolution profiles and long-term physical stability were investigated. Ball-milled binary and ternary formulations were found to be amorphous. The residual crystals corresponding to IND-ARG salt were identified in the ternary formulations produced via HME. Despite the presence of a crystalline phase, dissolution tests showed that ternary systems prepared by HME exhibited improved IND solubility when compared to pure crystalline IND and their corresponding physical mixture. None of the binary and ternary formulations that were initially fully amorphous did undergo recrystallization during the entire period of preservation (minimum of 12 months) in dry conditions at 25 °C.

• Klíčová slova
• Amorphous solid dispersion, Co-amorphous, Dissolution performance, Physical stability, Solubility, Ternary formulation,
• MeSH
• arginin * MeSH
• indomethacin * MeSH
• polymery MeSH
• rozpustnost MeSH
• vinylové sloučeniny MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• arginin * MeSH
• indomethacin * MeSH
• polymery MeSH
• vinyl acetate MeSH Prohlížeč
• vinylové sloučeniny MeSH

Coccolith dissolution together with post-mortem morphological features are immensely important phenomena that can affect assemblage compositions, complicate taxonomic identification as well as provide valuable palaeoenvironmental insights. This study summarizes the effects of pH oscillations on post-mortem coccolith morphologies and the abundances and compositions of calcareous nannoplankton assemblages in three distinct types of material-(i) Cretaceous chalk, (ii) Miocene marls, and (iii) late Holocene calcareous ooze. Two independent experimental runs within a semi-enclosed system setting were realized to observe assemblage alterations. One experiment was realized with the presence of bacteria and, in contrast, the second one inhibited their potential effect on the studied system. The pH was gradually decreased within the range of 8.3-6.4 using a reaction of CO2 with H2 O forming weak carbonic acid (H2 CO3 ), thereby affecting [ CO 3 2 - ]. Further, a subsequent overgrowth study was carried out during spontaneous degassing accompanied by a gradual pH rise. The experiment revealed that the process and intensity of coccolith corrosion and subsequent overgrowth build-ups are influenced by a plethora of different factors such as (i) pH and associated seawater chemistry, (ii) mineral composition of the sediment, (iii) the presence of coccoliths within a protective substrate (faecal pellets, pores, pits), and (iv) the presence/absence of bacteria. Nannoplankton assemblages with corroded coccoliths or with coccoliths with overgrowth build-ups showed that the observed relative abundances of taxa experienced alteration from the original compositions. Additionally, extreme pH oscillations may result in enhanced morphological changes that make coccoliths unidentifiable structures, and might even evoke the absence of coccoliths in the fossil record.

• Klíčová slova
• coccolith abundance, coccolith corrosion, coccolith overgrowths, dissolution-resistant taxa, pH fluctuations,
• MeSH
• Haptophyta * MeSH
• mořská voda chemie   MeSH
• rozpustnost MeSH
• uhličitan vápenatý * chemie   MeSH
• zkameněliny MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• uhličitan vápenatý * MeSH

Cannabigerol is a bioactive compound derived from Cannabis sativa. It displays many promising pharmaceutical and nutraceutical properties. Its use and research are complicated by its thermally unstable solid form with low solubility and needle habit, preventing easy formulation into tablets or capsules. To overcome these problems, we conducted a crystallization screening with the aim to discover new crystal forms with enhanced properties. Though polymorph and solvate screenings did not yield new forms, the cocrystal screening was successful. Two cocrystals were discovered, one with piperazine and another with tetramethylpirazine, both in a 1:1 ratio. The latter can exist in three polymorphic forms. Both offer improvements in the melting point and crystal habit, and the cocrystal with tetramethylpirazine also shows a significant enhancement in dissolution rate. The new solid forms were analysed by a combination of methods, including X-ray powder diffraction, nuclear magnetic resonance spectroscopy, differential scanning calorimetry, thermogravimetric analysis and intrinsic dissolution rate. Single-crystal X-ray diffraction data were used to solve the crystal structures, which were then compared with that of pure CBG. The crystal morphologies and surfaces were comprehensively analysed using the CSD-Particle suite, with various properties correlated against dissolution rates. While surface attachment energy and roughness (rugosity) did not show significant effects, the concentration of unsatisfied hydrogen-bond donors displayed a positive correlation. There were two parameters with a very strong correlation to dissolution rate: the propensity for interactions with water molecules, determined by the maximum range in the full interaction maps on the surface calculated for the water probe, and also the difference in the positive and negative electrostatic charges. These parameters proved highly predictive of aqueous dissolution, offering immense utility in pharmaceutical development.

• Klíčová slova
• CSD-Particle, Cambridge Structural Database, cannabigerol, cocrystals, crystal design, crystal engineering, crystal structures, dissolution, particles, properties of solids, surfaces, topology,
• Publikační typ
• časopisecké články MeSH

Plant mucilages are commonly employed as excipients in pharmaceutical manufacturing. Ocimum basilicum (Lamiaceae family), a source of hydrophilic mucilage referred herein as Ocicum, was evaluated for the solubility enhancer of a model drug, aceclofenac, in solid dispersions prepared using different methods. Polymer was extracted from O. basilicum and solid dispersions of aceclofenac were fabricated with Ocicum or Poloxamer 407 using polymer-to-drug ratios of 1:1, 1:2 and 1:3 utilizing solvent evaporation, lyophilization and melt methods. Ocicum was evaluated for its safety via acute toxicity study including different biochemical and hematological parameters including liver and kidney profiles. Moreover, different characterization studies including melting-point, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and differential thermal analysis (TGA) were used for evaluation of polymer and solid dispersions. Furthermore, solubility and dissolution studies were performed to confirm solubility enhancement. Ocicum was found to be safer, and different characterization studies confirmed the purity of the compounds. In addition, Ocicum exhibited up to 6.27-fold enhanced solubility as compared to pure aceclofenac; similarly, 4.51-fold increased solubility by the synthetic polymer in their respective solid dispersions was shown. Furthermore, Ocicum-based solid dispersions showed substantial improvement in dissolution of aceclofenac. Therefore, it can be concluded from the above-mentioned results that Ocicum might be used as an economical natural oral delivery carrier alternative to the synthetic polymers.

• Klíčová slova
• Ocicum, Poloxamer 407, aqueous solubility, natural polymer, solid dispersion,
• Publikační typ
• časopisecké články MeSH