Solid Form Research Articles

Effect of Dual Curing Agent (TDI:DDI) on the Mechanical Properties and Burning Rate of HTPB-Based Solid Propellant

ABSTRACT In this study, the effect of dual curing agent (toluene diisocyanate:dimeryl diisocyanate (TDI:DDI)) on the properties of hydroxyl-terminated polybutadiene (HTPB)-based solid propellant (such as mechanical strength, elongation percentage, elastic modulus, hardness, burning rate and pressure exponent (n)) has been investigated. Thus, five solid propellant formulations with different proportional amounts of TDI and DDI, with same loading rate and constant R value, were prepared, and the mechanical properties and burning rate of the prepared samples were evaluated. Tensile test conducted on the solid propellant cured for 7 days showed that increasing the proportional amount of DDI compared to TDI in the solid propellant formulation increases the elongation percentage and decreases the tensile strength, modulus, burning rate and pressure exponent (n). Considering that DDI also plays the role of a softening agent in the solid propellant formulation, increasing its amount in the solid propellant formulation will decrease the viscosity, causing a higher pot life.

Design and Synthesis of Aggregation‐Caused Quenching Hydroxy‐Phenanthroimidazole Derivatives for Probing of Fe3+ Ions and as Potential Blue Light Emitters

AbstractFluorescence aggregated molecules tend to employ versatile opportunities in metal ion probe sensors and fluorescent lighting. To achieve this dual challenging task, currently synthesized three phenanthroimidazole‐naphthalene‐based compounds Pq‐tBu‐OH, Pq‐mF‐OH, and Pq‐pF‐OH are derived based on substitution at N1 position for better photophysical and electrochemical properties. Compared experimental and theoretical calculations define the highest bandgap to be 2.75 eV of Pq‐pF‐OH, and the same molecule expressed a higher (348 °C) thermal decomposition. The calculated singlet and triplet energies found in the range of 3.24–3.67 and 2.70–2.72 eV indicate well energy transfer from S1→S0 (quantum yield of 23.36 %, lifetime is 4.05 ns). Among the numerous morphologies, the solid form exhibited improved intensive deep blue emission (x=0.159, y=0.051), and its InGaN LED results demonstrated a strong deep blue emission at 418 nm. Moreover, the fluorophores were experimentally visualizing the aggregation‐caused quenching (ACQ) which enables the probing of Fe3+ ion. However, for the first time, the ACQ‐assisted concept is applied through synthesized molecules for Fe3+ ion probing via fluorescence spectra, Job's plot calculation, and 1H NMR results. In addition, the probe works excellently at a detection limit of 10 μM and it could also act as a potential competitor for lighting applications.

Spontaneous Formation of Polymeric Nanoribbons in Water Driven by π–π Interactions

AbstractA simple method was developed to produce polymeric nanoribbons and other nanostructures in water. This approach incorporates a perylene diimide (PDI) functionalized by triethylene glycol (TEG) as a hydrophobic supramolecular structure directing unit (SSDU) into the core of hydrophilic poly(N,N‐dimethylacrylamide) (PDMAc) chains using RAFT polymerization. All PDI‐functional polymers dissolved spontaneously in water, forming different nanostructures depending on the degree of polymerization (DPn): nanoribbons and nanocylinders for DPn=14 and 22, and spheres for DPn>50 as determined by cryo‐TEM and SAXS analyses. UV/Vis absorption spectroscopy was used to monitor the evolution of the PDI absorption signal upon dissolution. In solid form, all polymers show a H‐aggregate absorption signature, but upon dissolution in water, the shortest DPn forming nanoribbons evolved to show HJ‐aggregate absorption signals. Over time, the J‐aggregate band increased in intensity, while cryo‐TEM monitoring evidenced an increase in the nanoribbon's width. Heating the nanoribbons above 60 °C, triggered a morphological transition from nanoribbons to nanocylinders, due to the disappearance of J‐aggregates, while H‐aggregates were maintained. The study shows that the TEG‐PDI is a powerful SSDU to promote 2D or 1D self‐assembly of polymers depending on DPn through simple dissolution in water.

Spontaneous Formation of Polymeric Nanoribbons in Water Driven by π-π Interactions.

A simple method was developed to produce polymeric nanoribbons and other nanostructures in water. This approach incorporates a perylene diimide (PDI) functionalized by triethylene glycol (TEG) as a hydrophobic supramolecular structure directing unit (SSDU) into the core of hydrophilic poly(N,N-dimethylacrylamide) (PDMAc) chains using RAFT polymerization. All PDI-functional polymers dissolved spontaneously in water, forming different nanostructures depending on the degree of polymerization (DPn): nanoribbons and nanocylinders for DPn=14 and 22, and spheres for DPn>50 as determined by cryo-TEM and SAXS analyses. UV/Vis absorption spectroscopy was used to monitor the evolution of the PDI absorption signal upon dissolution. In solid form, all polymers show a H-aggregate absorption signature, but upon dissolution in water, the shortest DPn forming nanoribbons evolved to show HJ-aggregate absorption signals. Over time, the J-aggregate band increased in intensity, while cryo-TEM monitoring evidenced an increase in the nanoribbon's width. Heating the nanoribbons above 60 °C, triggered a morphological transition from nanoribbons to nanocylinders, due to the disappearance of J-aggregates, while H-aggregates were maintained. The study shows that the TEG-PDI is a powerful SSDU to promote 2D or 1D self-assembly of polymers depending on DPn through simple dissolution in water.

Large-Scale Parameter Estimation for Crystal Structure Prediction. Part 1: Dataset, Methodology, and Implementation.

Crystal structure prediction (CSP) seeks to identify all thermodynamically accessible solid forms of a given compound and, crucially, to establish the relative thermodynamic stability between different polymorphs. The conventional hierarchical CSP workflow suggests that no single energy model can fulfill the needs of all stages in the workflow, and energy models across a spectrum of fidelities and computational costs are required. Hybrid ab initio/empirical force-field (HAIEFF) models have demonstrated a good balance of these two factors, but the force-field component presents a major bottleneck for model accuracy. Existing parameter estimation tools for fitting this empirical component are inefficient and have severe limitations on the manageable problem size. This, combined with a lack of reliable reference data for parameter fitting, has resulted in development in the force-field component of HAIEFF models having mostly stagnated. In this work, we address these barriers to progress. First, we introduce a curated database of 755 organic crystal structures, obtained using high quality, solid-state DFT-D calculations, which provide a complete set of geometry and energy data. Comparisons to various theoretical and experimental data sources indicate that this database provides suitable diversity for parameter fitting. In tandem, we also put forward a new parameter estimation algorithm implemented as the CrystalEstimator program. Our tests demonstrate that CrystalEstimator is capable of efficiently handling large-scale parameter estimation problems, simultaneously fitting as many as 62 model parameters based on data from 445 structures. This problem size far exceeds any previously reported works related to CSP force-field parametrization. These developments form a strong foundation for all future work involving parameter estimation of transferable or tailor-made force-fields for HAIEFF models. This ultimately opens the way for significant improvements in the accuracy achieved by the HAIEFF models.

CTNI-22. DABRAFENIB (D) AND TRAMETINIB (T) EITHER IN COMBINATION OR AS MONOTHERAPY IN PEDIATRIC PATIENTS HARBORINGBRAF ALTERATIONS IN GLIOMAS OR OTHER RARE TUMORS: FINDINGS FROM AN EARLY ACCESS PROGRAM (EAP)

Abstract BACKGROUND In 2022, dabrafenib and trametinib (D+T) combination received an accelerated US FDA approval for use in adult and pediatric patients with BRAF V600E–mutated unresectable or metastatic solid tumors with no viable alternative therapy. However, to provide global access to therapy in countries where the suitable formulations and/or indications are not yet approved, EAPs are established. We report on patient data from an EAP for pediatric patients with BRAF V600-mutated gliomas or other rare tumors with BRAF alterations such as BRAF fusions, seeking clinical benefit from therapy with dabrafenib and/or trametinib. METHODS We analyzed data from the global EAP, where pediatric patients with BRAF alterations in solid tumors including gliomas or other rare tumors received D+T combination or monotherapy. Key eligibility criteria included: age <18 years, absence of approved indications, presence of BRAF V600E/K mutation or other BRAF alterations, and exhaustion of standard therapies. Requests were processed through a global system from November 2016 to December 12, 2022 (cutoff date). Key data on patient characteristics and median treatment duration (mDoT) were collected and will be presented. RESULTS Overall, 482 patients with solid or hematological malignancies were included, of which 35.1%, 31.7%, and 33.2% received combination therapy and dabrafenib and trametinib monotherapies, respectively. Across the treatment cohorts, median age was 4.2-6.6 years, and 49.4%-52.9% were males. Most patients had low-grade (72%) or high-grade (4.6%) gliomas, followed by Langerhans cell histiocytosis (17.8%) and other tumors (5.6%). The estimated mDoT for liquid and solid formulations were, respectively, 14.6 months and 10.1 months in combination therapy, 16.5 months and 12.8 months in dabrafenib monotherapy, and 8.8 months and 7.4 months in trametinib monotherapy. CONCLUSIONS EAP data represent a valuable real-world resource in understanding patient characteristics in rare tumors (pediatric gliomas). A significant number of treatment requests indicate substantial unmet need, and significant mDoT across age categories was suggestive of benefit to pediatric patients on therapy.

CO2-free production of hydrogen via pyrolysis of natural gas: influence of non-methane hydrocarbons on product composition, methane conversion, hydrogen yield, and carbon capture

Methane pyrolysis represents a CO2-free hydrogen production route that enables simultaneous carbon capture. While the majority of previous studies in the field focus on pure CH4 as feed gas stream, commercial processes will typically rely on natural gas as feedstock that contains also non-methane hydrocarbons such as ethane, propane, and n-butane. Therefore, the present study evaluates how CH4 conversion, H2 selectivity, product composition, and solid carbon yield evolve when using either pure CH4 or synthetic natural gas (SNG) as feed gas stream for a thermal pyrolysis process in a lab-scale high-temperature reactor. For this, industrially viable conditions are applied, namely temperatures between 1000 °C and 1600 °C, residence times between 1 s and 7 s, and molar H2 dilution ratios between 1:1 and 4:1. Although the use of SNG results in slightly lower hydrocarbon conversions because the additional components in SNG result in a higher effective H2 dilution ratio compared to a CH4-only feed, the non-methane hydrocarbons in the SNG have a positive effect on both H2 selectivity and solid carbon yield. Taking existing mechanistic understanding into account, these positive effects are attributed to radicals formed from the non-methane hydrocarbons, which facilitate dehydrogenation steps from ethane to ethylene and hereby increase the relative amount of H2 originating from CH4. The introduction of a carbonaceous fixed bed further benefits the performance of the pyrolysis process and ultimately enables to capture more than 98% of carbon in its solid form under industrially viable process conditions.

Carbon dioxide hydrate formation in porous media under dynamic conditions

AbstractInjecting carbon dioxide (CO2) into subsea water zones where the in situ temperatures are below the hydrate‐forming temperature of CO2 has been recently proposed to lock CO2 inside the water zones in solid hydrate form. It is a common concern that CO2 may form hydrates during the injection period that will reduce well injectivity. CO2 injection into sandstone cores under simulated subsea temperatures of 2°C and 3°C was investigated in this study. Experimental result shows that, at 2°C temperature, flowing CO2 at Darcy velocity 0.033 cm/s begins to form hydrate in the sandstone core at about 3.06 MPa (450 psi), which is much higher than the minimum required pressure of 1.5 MPa (220 psi) for CO2 to form hydrate in static condition. The pressure ratio is 450/220 = 2.05. At 3°C temperature, flowing CO2 at Darcy velocity 0.045 cm/s begins to form hydrate in sandstone core at about 3.67 MPa (540 psi), which is much higher than the minimum required pressure of 1.87 MPa (275 psi) for CO2 to form hydrate in static conditions. The pressure ratio is 540/275 = 1.96. The reason why the required minimum pressure for CO2 to form hydrates in dynamic conditions is about double the required hydrate‐forming pressure in static conditions is not fully understood. It is speculated that the shear rate effect of flowing fluids should slow down the growth of hydrate crystals or break down hydrate films, resulting in delayed formation of bulk CO2 hydrates. More investigations in this area are needed in the future.

Development of polymer-encapsulated microparticles of a lipophilic API-IL and its lipid based formulations for enhanced solubilisation

Active Pharmaceutical Ingredient-Ionic liquids (API-ILs) have the potential to improve the bioavailability of BCS Class IV Drugs. However, the problematic physical handling properties of room temperature API-ILs have impaired clinical and commercial exploitation to date. Lipid-based formulations (LBFs) are used to improve the absorption of drugs with limited bioavailability. Nonetheless, LBFs face limitations such as low drug loading capacity and sub-par physical stability. A platform for transforming API-ILs into solid forms at high loadings via spray encapsulation with polymers has been developed and previously demonstrated for hydrophilic API-ILs. The current work demonstrates that this platform technology can be applied to a lipophilic API-IL of the BCS Class IV API, chlorpromazine, and to multi-component solutions comprising API-IL and a LBF. Furthermore, solidification of a type IIIB, liquid LBF was achieved via spray encapsulation with cellulose- and methacrylate- based polymers for the first time. The spray-encapsulated formulations had excellent physical handling properties, and successfully eluted the API-IL in aqueous media. The chlorpromazine release profiles from the API-IL, the API-IL containing LBF, and the solidified formulations, were evaluated in vitro using phosphate buffer (pH 6.8) and fasted state simulated intestinal fluid (FaSSIF). Spray-encapsulated formulations exhibited improved release profiles compared to the liquid formulations. Overall, these findings indicate that phase-separated, polymeric, solid formulations of liquid API forms represent a promising platform technology for developing oral solid dosage forms of poorly bioavailable drugs.

A Survey of Solid Form Landscape: Trends in Occurrence and Distribution of Various Solid Forms and Challenges in Solid Form Selection

This survey provides a comprehensive analysis of solid form screens for 476 new chemical entities (NCEs) conducted at Pharmaron from 2016 to 2023. The findings from this survey reveal notable trends in polymorphism, salt formation, crystallization behavior and molecular weight (MW) distribution of the NCEs evaluated. Most solid form screens were conducted to select the preferred solid form for Investigational New Drug (IND) enabling projects, others were for candidate selection or late-stage development. Comparison to published historical data was made to show changes in occurrence of counterions/co-formers for salts/co-crystals, polymorphs, and the distribution of MWs over time. Increased complexity in the solid-form landscape and selection of the development form are discussed, including challenges in crystallization and selection of lead forms. The distribution of types of crystal forms and the observation of emerging and disappearing polymorphs are presented. These results highlight the evolving challenges and considerations in solid form screening and form selection and offer insights for future pharmaceutical development and crystallization strategies.

Production sustained release dosage forms from deliquescent substances by solid dispersion systems

Introduction. The production of solid dosage forms from hygroscopic substances is a complex technological task. The addition of hygroscopic substances into a polymer matrix allows to reduce their moisture absorption capacity.Aim. Reducing the hygroscopicity of deliquescent substances and obtaining sustained release solid dosage forms by using solid dispersion systems.Materials and methods. Substance: DEAE; excipients: Kollidon® VA 64, Soluplus®, PEG 1500, PEG 6000, PEG 8000, Poloxamer Kolliphor® P 188 and Kolliphor® P 407; reagents: hydrochloric acid, sodium dihydrogen phosphate, potassium hydrogen phosphate. The melt of the components was obtained on a twin-screw laboratory extruder and cast into silicone molds. The resulting solid dosage forms were studied for disintegration in three environments corresponding to the sections of the human gastrointestinal tract.Results and discussion. The active pharmaceutical substance DEAE is characterized as deliquescent substance. The introduction of DEAE into PEG-polymer matrices made it possible to reduce the hygroscopicity of solid dosage forms in the form of bars. The introduction of solubilizers into the melt made it possible to obtain bars with the appropriate organoleptic properties. The release of DEAE from bear- or toroid-shaped bars occurs on average 29–47 % faster than from heart-shaped bars.Conclusion. Compositions based on Soluplus® and Kolliphor® P 407 have proven promising for further development of tiles containing DEAE. In order to create tiles with a slow release, it is recommended to use heart-shaped forms, as they have a smaller surface area.

New Binary Adducts of Panobinostat with Different Carboxylic Acid Based NSAIDs: Structural Analysis and Physicochemical Properties Investigation

AbstractAdoption of multitarget, cost‐effective fixed‐dose medication combinations can help lower the pill load without increasing the risk of adverse events. In this study, three new 1:1 drug‐drug binary solid forms of panobinostat (PNB) and nonsteroidal anti‐inflammatory drugs (NSAIDs) were effectively synthesized by liquid‐assisted grinding and slow evaporation crystallization techniques. The obtained solid forms were extensively characterized by various analytical techniques. The structural investigation revealed that all molecular adducts formed salt with a comparable (10) graph set pattern created by heteromeric interactions formed between PNB and corresponding salt formers. To determine the dissolving behavior of the newly developed adducts, solubility tests were performed at various pH levels (pH 1.2 and pH 7), and the results indicated that the solubility of all forms is increased at pH 7.0, particularly PNB.NIF has a solubility of 0.195 mg/mL, which is seven times higher than the parent drug. Furthermore, PXRD was used to assess the stability of the synthesized adduct at varied temperature and humidity levels and it was found that all the adducts are stable. Based on the findings, we hope that the newly found PNB drug‐drug binary adducts have possible potential to broaden the use of drug combinations without changing the chemical structures.

Cyclodextrin-based iodophors with high iodine retention in solid state and in dilute solutions

Iodine is a broad-spectrum antiseptic with the advantage of not inducing bacterial resistance, but its use is limited by volatility. This issue can be overcome by using “iodophors”, which are molecular systems able to retain iodine and provide its sustained release. Cyclodextrins have proven effective in stabilizing iodine in solution through the formation of complexes, the preparation of which in solid form could offer additional benefits in terms of handling and storage. A series of cyclodextrins (CD) were tested for their ability to form solid complexes with iodine and it was found that the addition of potassium iodide in the solid-state preparation of the complexes significantly increases both iodine incorporation and long-term stability compared to the solids obtained without added potassium iodide. Dilute aqueous solutions of the obtained complexes were monitored for their iodine content in different conditions and excellent stability was observed in some cases. Furthermore, these cyclodextrin‑iodine complexes showed no cytotoxic effects on human corneal epithelial cells (HCE-2) while displayed very high antimicrobial (against Staphylococcus epidermis) and antiviral (against Human adenovirus 5) activities. These findings highlight the potential of cyclodextrins as a versatile platform for the development of solid iodophors as an alternative to the traditional povidone-iodide formulation.

Safety and efficacy of a feed additive consisting of ponceau 4R for its use in baits for freshwater fish (GIFAP)

Abstract Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety and efficacy of ponceau 4R as sensory additives (functional group: (a) colourants: (i) substances that add or restore colour in feedingstuffs). The additive is already authorised for use with cats and dogs and ornamental fish. The additive is intended to be incorporated in freshwater fishing baits up to a maximum of 15 mg/kg in complementary feed in order to colour them. The additive is intended to be incorporated into feed directly in solid form or via an aqueous solution. The additive is not intended for use in aquaculture. The FEEDAP Panel concluded that ponceau 4R is considered safe when used in fish baits for freshwater fish at the maximum proposed dose of 15 mg/kg complementary feed. The use of the feed additive ponceau 4R fish baits for freshwater fish under the conditions of use proposed is of no concern for consumer safety. Ponceau 4R is not skin irritant but should be considered a skin and respiratory sensitiser. Inhalation and dermal exposure are considered a risk. The FEEDAP Panel could not conclude on the eye irritation potential of the additive. In absence of data no conclusion can be reached on the efficacy of ponceau 4R in freshwater fish baits.

Development of 3D-Printed Two-Compartment Capsular Devices for Pulsatile Release of Peptide and Permeation Enhancer.

The oral absorption of a peptide is driven by a high local concentration of a permeation enhancer (PE) in the gastrointestinal tract. We hypothesized that a controlled release of both PE and peptide from a solid formulation, capable of maintaining an effective co-localized concentration of PE and peptide could enhance oral peptide absorption. In this study, we aimed to develop a 3D-printed two-compartment capsular device with controlled pulsatile release of peptide and sodium caprate (C10). 3D-printed two-compartment capsular device was fabricated using a fused deposition modeling method. This device was then filled with LY peptide and C10. The release profile was modulated by changing the thickness and polymer type of the capsular device. USP apparatus II dissolution test was used to evaluate the impacts of device thickness and polymer selection on release profile in vitro. An optimal device was then enteric coated with HPMCAS. A strong linear relationship between the thickness of capsular devices and the delay in the release onset time was observed. An increase in the device thickness or the use of PLA decreased the release rate. The capsular device with compartment 1, compartment 2 and fence thickness of 0.4; 0.95 and 0.5mm, respectively, and the use of PVA achieved desired pulsatile release profiles of both peptide and C10. Furthermore, enteric-coated capsular devices with HPMCAS had similar pulsatile release profiles compared to non-enteric coated devices. These findings suggest potential application of 3D-printing techniques in the formulation development for complex modified drug release products.

Mapping active pharmaceutical ingredients Distributions in tablets using Time-of-Flight secondary ion mass spectrometry with multivariate curve resolution

This study introduces an advanced approach to identifying signals associated with indapamide, amlodipine, and perindopril in solid dosage form using time-of-flight secondary ion mass spectrometry (ToF-SIMS) combined with multivariate curve resolution (MCR). The primary objective was to obtain and characterize these signals through MCR factors, which then led to identifying unique signals specific to each active pharmaceutical ingredient (API). These unique signals were crucial for constructing detailed 2D and 3D images of the API distribution within the tablet. The results demonstrated that indapamide and amlodipine exhibited multiple unique peaks, while perindopril had only one. Additionally, the study revealed non-homogeneous distribution patterns of APIs and excipients, such as SiO2 and Mg stearate. This work highlights the significance of applying advanced analytical techniques such as ToF-SIMS and MCR in the pharmaceutical field to ensure consistent therapeutic efficacy through a better understanding of API distribution.

Pemberdayaan Masyarakat di Bidang Pertanian melalui Pembuatan Pupuk Organik

Organic fertilizer is defined as fertilizer that is partly or wholly derived from plants and/or animals that has gone through an engineering process, can be in solid or liquid form which is used to supply organic material to improve the physical, chemical and biological properties of the soil. The aim of this activity is to empower the community through making organic fertilizer in the agricultural sector. The activity steps include: 1) Preparation stage. The preparation stage is very important as a form of more mature planning to achieve better things. This preparation stage includes observations and interviews with partners and the community, checking the implementation location, in this case I used Sumbek Hamlet, Wajageseng Village, Kopang District, Central Lombok Regency, establishing collaboration with youth and the entire community, preparing tools and materials for the main program which includes everything needed in this training; and 2) Program implementation stage. The program implementation stages are described as follows: the process of collecting cow dung which is processed into fertilizer, the process of mixing cow dung with straw, and the fermentation process for up to ± 30 days to make it into soil to be used as fertilizer. The results achieved in this training activity were the acquisition of knowledge by the community and youth about how to make organic fertilizer using existing materials. The community is able to minimize expenditure on purchasing fertilizer and reduce the use of chemical fertilizers. Through this activity, the public also understands more about the negative impacts caused by the use of chemical or inorganic fertilizers if used over a long period of time. This community empowerment can also support various village activities in organizing training in the agricultural sector, because the community is able to create their own fertilizer from materials that are easily obtained.

Various drugs used in oral disintegration tablet formulation

Oral drug administration is more widely accepted because it is used to provide between 50 and 60 percent of medications. The solid dosage forms are commonly utilized since they are simple to administer, precise in their dosage forms, beneficial for self-medication, and preventive of discomfort, and last but not least, the excellent level of patient adherence. The capsules and tablets are the most widely used solid dose form administered orally. Aside from ingesting it does not possess any noteworthy drawbacks. Water plays a crucial function in this swallowing process. Even following this, some people had difficulty swallowing. In order to prevent these issues, mouth dissolving tablets were developed. They have the benefit of not requiring water and don't require swallowing because they dissolve or disintegrate in saliva. In light of the design it began to behave in two ways: first, some tablets disintegrated quickly, taking just a few moments in saliva. Another kind of tablet is known as a "first disintegration tablet" since it contains some substances that slowed down the tablet's rate of breakdown. Review attention was drawn to the concise talk about mouth dissolving tablets and the most recent versions available.

Ultrasound-assisted extraction of itraconazole from pellets: an efficient approach for the recovery of active pharmaceutical compounds from solid dosage forms

IntroductionItraconazole is a widely used broad-spectrum antifungal drug on a global scale. However, its poor water solubility necessitates the development of advanced formulations for its effective use. Currently, itraconazole is available commercially in capsule form, with pellets containing the active drug. The extraction of itraconazole from these granules is often required when developing new formulations. Extracting active pharmaceutical ingredients (APIs) from pellets is crucial in ensuring precise and consistent dosing when producing pharmaceutical dosage forms. Surprisingly, no existing methods for extracting itraconazole from pellets have been reported thus far.ObjectiveTherefore, this study aimed to develop and evaluate an efficient method for extracting this API from pellets.MethodsTwo extraction methods were assessed: conventional Soxhlet extraction and ultrasound-assisted extraction.Results and DiscussionThe results demonstrated that ultrasound-assisted extraction significantly outperformed the conventional method, yielding higher amounts of itraconazole with a high purity level of 96.8%.

Assessing Drug Product Shelf Life Using the Accelerated Stability Assessment Program: A Case Study of a GLPG4399 Capsule Formulation

Objective: To evaluate and project the shelf life of GLPG4399, an early-phase clinical drug formulation by applying the Accelerated Stability Assessment Program (ASAP) approach. Methods: Forced degradation conditions were implemented to identify the stability-limiting degradation product. The drug and its degradation products were separated using a validated liquid chromatography method. Then, the selected clinical capsule formulation was placed in a glass vial and exposed to accelerated short-term conditions of combinations of high- and low-level heat and humidity in an open state for 5 weeks. The liquid chromatography results were evaluated using the ASAP, which is based on the moisture-modified Arrhenius principle. The resulting data were fitted using a suitable diffusion kinetics method. Results: The developed model was applied to predict the shelf life of the drug product when using clinically appropriate primary packaging (high-density polyethylene container). The derived stability parameters of the moisture-modified Arrhenius equation were the Arrhenius collision frequency, activation energy, and humidity sensitivity constant. The goodness of fit parameters R2 (>0.95) and goodness of prediction Q2 (>0.80) parameters for the selected model were acceptable. The results of the accelerated, short-term stability study were verified against real-time, long-term 12-month data. Conclusions: We demonstrated the application of the ASAP approach to evaluate the shelf life of a GLPG4399 solid capsule formulation. The studied ASAP approach can be extended to evaluate the stability and shelf-life estimations of other early-phase clinical formulations.