Spray drying and hot-melt extrusion are among the most prevalent preparation techniques used in the pharmaceutical industry to produce amorphous solid dispersions (ASDs). This study advances previous research by integrating sample production, comprehensive analytical characterization, intrinsic dissolution rate measurements, and assessments of the behavior of ASDs under elevated temperature and humidity conditions. The study focuses on indomethacin, a widely used model for poorly soluble drugs, processed with PVP K30 or HPMC E5, both commonly used polymers. The findings demonstrate that hot-melt extruded samples exhibit superior stability against recrystallization, whereas spray dried samples achieve higher intrinsic dissolution rates. Furthermore, PVP K30 significantly outperforms HPMC E5 in the co-processing of indomethacin, enhancing both the intrinsic dissolution rate and the stability.
- MeSH
- deriváty hypromelózy chemie MeSH
- farmaceutická chemie metody MeSH
- indomethacin * chemie MeSH
- krystalizace * MeSH
- povidon chemie MeSH
- příprava léků metody MeSH
- rozpustnost * MeSH
- sprejové sušení * MeSH
- stabilita léku * MeSH
- technologie extruze tavenin * metody MeSH
- uvolňování léčiv MeSH
- vlhkost MeSH
- vysoká teplota MeSH
- vysoušení metody MeSH
- Publikační typ
- časopisecké články MeSH
The integration of 3D printing into the pharmaceutical sciences opens new possibilities for personalized medicine. Poly(lactide) (PLA), a biodegradable and biocompatible polymer, is highly suitable for biomedical applications, particularly in the context of 3D printing. However, its processability often requires the addition of plasticizers. This study investigates the use of phase diagram modeling as a tool to guide the rational selection of plasticizers and to assess their impact on the thermodynamic and kinetic stability of PLA-based amorphous solid dispersions (ASDs) containing active pharmaceutical ingredients (APIs). Thermodynamic stability against API recrystallization was predicted based on the API solubility in PLA and Plasticizer-PLA carriers using the Conductor-like Screening Model for Real Solvents (COSMO-RS), while the kinetic stability of the ASDs was evaluated by modeling the glass transition temperatures of the mixtures. Two APIs, indomethacin (IND) and naproxen (NAP), with differing glass-forming abilities (i.e., recrystallization tendencies), and three plasticizers, triacetin (TA), triethyl citrate (TEC), and poly(L-lactide-co-caprolactone) (PLCL), were selected for investigation. The physical stability of ASD formulations containing 9 wt% API and plasticizer to PLA in two ratios, 10:81 and 20:71 w/w %, was monitored over time using differential scanning calorimetry and X-ray powder diffraction and compared with phase diagram predictions. All formulations were predicted to be thermodynamically unstable; however, those containing no plasticizer or with TEC and TA at 10 wt% were predicted to exhibit some degree of kinetic stability. Long-term physical studies corroborated these predictions. The correlation between the predicted phase behavior and long-term physical stability highlights the potential of phase diagram modeling as a tool for the rational design of ASDs in pharmaceutical 3D printing.
- MeSH
- 3D tisk * MeSH
- citráty chemie MeSH
- diferenciální skenovací kalorimetrie metody MeSH
- farmaceutická chemie metody MeSH
- farmaceutická technologie metody MeSH
- indomethacin * chemie MeSH
- krystalizace MeSH
- naproxen chemie MeSH
- polyestery * chemie MeSH
- rozpouštědla chemie MeSH
- rozpustnost * MeSH
- stabilita léku MeSH
- termodynamika MeSH
- tranzitní teplota MeSH
- triacetin chemie MeSH
- změkčovadla * chemie MeSH
- Publikační typ
- časopisecké články MeSH
The purpose of the research consisted of assessing the modification produced by hydrogen peroxide (H2O2)-induced oxidative stress (OS) on the ketorolac therapeutic effects in the chickens which are the analgesic, antipyretic, and anti-inflammatory. A significant decrease in the total antioxidant capacity (T-AOC) and subsequent occurrence of OS was observed in the stressed (H2O2) group on days 7th, 10th, and 14th by 39, 29, and 41%, respectively in comparison to the control (non-stressed) group. The analgesic effect of ketorolac in the stressed group had more intense in comparison to the non-stressed group, the analgesic effectiveness of ketorolac raised by 16% in that group. In the non-stressed and stressed groups, ketorolac produces its antipyretic effect at 3 and 4 hours after fever induction by baker's yeast while it shows the effect significantly at 1, 2, and 4 hours. Furthermore, ketorolac has the superiority of antipyretic action in stressed group over the non-stressed group. Ketorolac carries out anti-inflammatory activity in the stressed and non-stressed groups by 61 and 75%, respectively. Ketorolac has a significant anti-inflammatory property in the stressed group through a significant decrease in the delta thickness compared to the non-stressed group. The stressed group was treated with ketorolac for five consecutive days signifi-cantly affect the kidney and liver function concerning the non-stressed group. The net findings proposed the ability of H2O2-induced OS to alter ketorolac's analgesic, antipyretic, and anti-inflammatory properties in the chickens thus, it is recommended to reduce the dose of ketorolac intended to be given to stressed animals involved.
- MeSH
- analgetika aplikace a dávkování farmakologie MeSH
- antiflogistika nesteroidní aplikace a dávkování farmakologie MeSH
- antipyretika aplikace a dávkování farmakologie MeSH
- ketorolak * aplikace a dávkování farmakologie MeSH
- kur domácí MeSH
- modely u zvířat MeSH
- oxidační stres * účinky léků MeSH
- statistika jako téma MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- klinická studie MeSH
- práce podpořená grantem 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.
- MeSH
- arginin * MeSH
- indomethacin * MeSH
- polymery MeSH
- rozpustnost MeSH
- vinylové sloučeniny MeSH
- Publikační typ
- časopisecké články MeSH
The transdermal application of actives offers numerous advantages over other conventional routes. Namely, a stable level of drugs in the bloodstream and reduced side effects are the argument for topical administration. Unfortunately, the exceptional skin barrier and unsuitable physico-chemical properties of drugs are the limiting factors for the transdermal passage. It is possible to overcome this by incorporating the drug into nano-carriers to enhance its permeation through the skin barrier. For this purpose, we prepared lipid nanocapsules (LNCs) to modulate skin passage of three pharmaceutically important drugs - indomethacin (IND), diclofenac sodium (DF) and caffeine (CF). We present a stable system prepared by the phase inversion temperature method with particle size under 100 nm and PDI < 0.1 with great encapsulation efficiency for indomethacin and diclofenac. By FTIR it was possible to confirm (for IND and DF) or disprove (in case of CF) the incorporation of a drug into the LNCs. By ex vivo permeation experiments on porcine skin, we confirmed the superior effect of the LNCs on the APIs skin passage. The drug permeated through the skin with higher intensity when delivered from LNCs compared to other standard formulations. We show that lipid nanocapsules play an important role in enhanced topical application of actives.
- MeSH
- aplikace kožní MeSH
- diklofenak MeSH
- indomethacin MeSH
- lipidy chemie MeSH
- nanokapsle * chemie MeSH
- nosiče léků chemie MeSH
- velikost částic MeSH
- Publikační typ
- časopisecké články MeSH
In drug development, preformulation is the key step, where compatibility between active pharmaceutical ingredient (API) and excipients is the crucial parameter. To simplify this process, reliable and suitable prediction models are needed. In this case, Hansen solubility parameters (HSPs) can be used. Moreover, HSPs can also describe and characterize the surface properties of the measured substances. Precisely, the surface properties of APIs and excipients affect the compatibility of the resulting dosage form. In this work, HSPs of six selected APIs of different chemical nature were determined (tadalafil, vardenafil-hydrochloride trihydrate, mefenamic acid, bisoprolol hemi-fumarate, meloxicam and indomethacin) using inverse gas chromatography (IGC) according to Snyder and Karger adsorption model. This study aimed to investigate the influence of APIs structure on HSPs and to prove the sensitivity of this method to different chemical nature of measured substances. Our results showed the influence of selected APIs chemical nature on HSPs. These results can provide a better understanding of API behaviour during the drug development process.
- MeSH
- chromatografie plynová MeSH
- indomethacin * MeSH
- pomocné látky * MeSH
- povrchové vlastnosti MeSH
- rozpustnost MeSH
- Publikační typ
- časopisecké články 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.
- MeSH
- indomethacin MeSH
- léčivé přípravky * MeSH
- povidon * MeSH
- příprava léků MeSH
- rozpustnost MeSH
- velikost částic MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- antirevmatika * aplikace a dávkování farmakologie MeSH
- bupivakain aplikace a dávkování terapeutické užití MeSH
- ketorolak aplikace a dávkování farmakologie MeSH
- kombinovaná farmakoterapie metody MeSH
- kyselina askorbová * aplikace a dávkování farmakologie terapeutické užití MeSH
- lidé MeSH
- poranění šlachy etiologie terapie MeSH
- revmatoidní artritida terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
A micellar electrokinetic chromatography method for the determination of indomethacin impurities (4-chlorobenzoic acid, 5-methoxy-2-methyl-3-indoleacetic acid, and 3,4-dichloroindomethacin) has been developed. A 64.5/56-cm fused silica 50 μm id capillary with extended light path (150 μm id) detection window was used. Internal standard was 1-naphthylacetic acid. The analytes were separated at 30 kV with DAD detection at 224 nm. A central composite face-centered design was applied for the optimization of the separation conditions. The effect of SDS concentration, content of methanol, concentration of phosphate buffer, and pH of the buffer were studied at three levels. The optimized background electrolyte was 20 mmol/L phosphate buffer (pH 7.57) containing 58 mmol/L SDS and 0% MeOH. Sufficient resolution of all compounds with Rs ≥ 3.5 was achieved within 10 min. The method was validated for a range of 1.25-80 μg/mL of each impurity corresponding to 0.05-3.2% relative to the concentration of indomethacin (2.5 mg/mL). The calibration curves were rectilinear with correlation coefficients r2 exceeding 0.9994. The lower limit of quantification was 0.05% or 1.25 μg/mL that complies with the reporting limits regarding the ICH Q3A guideline. The method was applied to purity assay of indomethacin in both bulk drug and gel.
Non-steroidal anti-inflammatory drugs (NSAIDs) belong to most used pharmaceuticals in the human and veterinary medicine. The widespread consumption of NSAIDs has led to their ubiquitous occurrence in water environment including large river systems. In the present study, concentrations of the five most frequently used NSAIDs (ibuprofen, diclofenac, naproxen, ketoprofen and indomethacin) were determined in the watercourses of the river Elbe basin in Czech Republic. The presence of the pharmaceuticals was measured at 29 sampling sites including urban and rural areas, small creeks and main tributaries of the Elbe monthly from April to December of 2011. For the NSAIDs quantitation, the comprehensive analytical method combing pentafluorobenzyl bromide (PFBBr) derivatization with highly sensitive two-dimensional gas chromatography time-of-flight mass spectrometry (GCxGC-TOFMS) was developed. Although the content of all NSAIDs varied at the particular sampling points significantly, total amount of particular compounds was relatively stable during all monitored periods with only non-significant increase in the spring and autumnal months. Ibuprofen was found to be the most abundant drug with maximum concentration of 3210 ng/L, followed by naproxen, diclofenac and ketoprofen (1423.8 ng/L, 1080 ng/L and 929.8 ng/L, respectively). Indomethacin was found only at several sampling sites (maximum concentration of 69.3 ng/L). Concentrations of all compounds except ibuprofen were significantly higher at sampling sites with low flow rates (creeks), followed by the biggest watercourses.
- MeSH
- antiflogistika nesteroidní analýza MeSH
- chemické látky znečišťující vodu analýza MeSH
- diklofenak analýza MeSH
- ibuprofen analýza MeSH
- indomethacin analýza MeSH
- ketoprofen analýza MeSH
- monitorování životního prostředí MeSH
- naproxen analýza MeSH
- plynová chromatografie s hmotnostně spektrometrickou detekcí metody MeSH
- řeky chemie MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
