Long-term Physical Stability Research Articles

Microfluidic-Integrated Chip Resonators for Electron Spin Sensing in Submicromolar, Submicroliter Solutions.

Planar or chip microresonators decrease the sample volume required for magnetic resonance spectroscopies to the nanoliter scale. However, the interrogation of nanoliter-scale solution samples on planar sensors is hindered by the lack of microfluidic devices that can simultaneously provide a small total volume and long-term sample stability. Here, we report microfluidic devices that decrease the total required sample volume to the submicroliter scale and also provide long-term physical stability and storability. We also report a 3D-printed microfluidic with a self-contained actuation mechanism, which allows the sample to be retracted from the microresonator surface for storage. The microfluidic devices are fabricated easily by laser cutting or 3D printing and are integrable with a broad range of planar sensors. We use planar inverse anapole (PIA) microresonators to obtain continuous wave (CW) electron paramagnetic resonance (EPR) spectra of natural-isotopic-abundance nitroxide radicals, which are ubiquitously used as reporters of biomolecular dynamics. We provide experimental evidence for a concentration sensitivity of 330 ± 40 nmol L-1, a concentration sensitivity limit of 800 ± 100 nmol L-1/mT√Hz, and an active volume no greater than 30 nL. Together, these developments represent an advance not only in the sensitivity of EPR spectroscopy but also in the design of microfluidics for stable, dead-volume-free placement of nanoliter-scale volumes of solutions on planar sensors.

Long-Term Physical Stability of Amorphous Solid Dispersions: Comparison of Detection Powers of Common Evaluation Methods for Spray-Dried and Hot-Melt Extruded Formulations

Although physical stability can be a critical issue during the development of amorphous solid dispersions (ASDs), there are no established protocols to predict/detect their physical stability. In this study, we have prepared fenofibrate ASDs using two representative manufacturing methods, hot-melt extrusion and spray-drying, to investigate their physical stability for one year. Intentionally unstable ASDs were designed to compare the detection power of each evaluation method, including X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and dissolution study. Each method did not provide the same judgment results on physical stability in some cases because of their different evaluation principles and sensitivity, which has been well-comprehended only for one-component glass. This study revealed that the detection powers of each evaluation method significantly depended on the manufacturing methods. DSC was an effective method to detect a small amount of crystals for both types of ASDs in a quantitative manner. Although the sensitivity of XRPD was always lower compared to that of DSC, interpretation of the data was the easiest. SEM was very effective for observing the crystallization of the small amount of drug for hot-melt extruded products, as the drug crystal vividly appeared on the large grains. The dissolution performance of spray-dried products could change even without any indication of physical change including crystallization. The advantage/disadvantage and complemental roles of each evaluation method are discussed for deeper understanding on the physical stability data of ASDs.

Impact of drug compounds mechanical/deformation properties on the preparation of nano- and microsuspensions

The preparation of nano- and microsuspensions used for long-acting injectables include several advantages, where the ability to control the particle sizes of a drug compound, e.g., wet bead media milling, to obtain a desired release rate, has shown to be highly critical. Limiting factors, making the formulation screening process time-consuming, are both the grindability of a compound to obtain the desired particle size profile as well as the addition of a suitable stabilizer at a sufficient concentration to secure a long-term physical stability. Hence, the deformation properties of three different model compounds (i.e., cinnarizine, haloperidol, and indomethacin) were investigated in the present study by quantifying fragmentation after tableting followed by the preparation of nano- and microsuspensions with two different stabilizers (polysorbate 20 and poloxamer 188) and concentrations (1, 2, or 4%), as well as bead size (ø 0.5 or 1.0 mm), during processing. It was found that cinnarizine had brittle properties, haloperidol predominantly plastic properties, and indomethacin elastic properties. Distinct particle size profiles, after milling by the dual centrifugation approach, were achieved for the three model compounds, when prepared under the same manufacturing conditions. It was possible to obtain decreased sizes of cinnarizine particles, whereas the grindability for haloperidol was more restricted due to its plastic properties. The study further showed that higher concentrations of poloxamer 188 were needed to obtain smaller sizes of particles when compared to polysorbate 20. Short-term stability studies showed an increase in sizes of particles over 49 days stored at elevated temperatures, especially for indomethacin suspensions stabilized with the highest polysorbate 20 concentration, due to increased solubility from the stabilizer vehicle as confirmed by a solubility study. Sizes of haloperidol particles remained relatively stable when stabilized with the highest concentration of polysorbate 20, even with increased solubility, indicating a higher physical stability as compared to cinnarizine and indomethacin.

Electrochemical sensors based on molecularly imprinted polymers for the detection of chlorophenols as emergent distributing chemicals (EDCs): a review.

Environmental pollutants like chlorophenol chemicals and their derivatives are commonplace. These compounds serve as building blocks in the production of medicines, biocides, dyes, and agricultural chemicals. Chlorophenols enter the environment through several different pathways, including the breakdown of complex chlorinated hydrocarbons, industrial waste, herbicides, and insecticides. Chlorophenols are destroyed thermally and chemically, creating dangerous chemicals that pose a threat to public health. Water in particular is affected, and thorough monitoring is required to find this source of pollution because it can pose a major hazard to both human and environmental health. For the detection of chlorophenols, molecularly imprinted polymers (MIPs) have been incorporated into a variety of electrochemical sensing systems and assay formats. Due to their long-term chemical and physical stability as well as their simple and affordable synthesis process, MIPs have become intriguing synthetic alternatives over the past few decades. In this review, we concentrate on the commercial potential of the MIP technology. Additionally, we want to outline the most recent advancements in their incorporation into electrochemical sensors with a high commercial potential for detecting chlorophenols.

Polymer-inducing chemical degradation of amorphous solid dispersions driven by drug-polymer interactions for physical stabilization

Intermolecular interactions between active pharmaceutical ingredients (APIs) and carrier polymers are important for the long-term physical stability of amorphous solid dispersions (ASDs). However, the negative impact of intermolecular interactions on chemical stability has rarely been reported. In this study, the relationship between intermolecular interactions and physical and chemical stability was investigated using two ASDs composed of API and hydroxypropyl methylcellulose acetate succinate (HPMCAS) with different stabilities: ASD1 was physically stable but chemically unstable, whereas ASD2 was physically unstable but chemically stable. Ionic-bonding between the pyridine nitrogen in the API and succinyl group in HPMCAS was found in both ASDs. The additional interaction between the succinyl group in HPMCAS and the hydroxyl group in the API was suggested only in ASD1. It was concluded that the additional interaction contributed to the physical stability of ASD1; however, it accelerated the chemical reaction between the succinyl and hydroxyl groups to generate succinyl ester owing to its close proximity. This study shows that the intermolecular interaction between the API and carrier polymer is not always beneficial for chemical stability. Understanding the molecular states of APIs and polymers in ASDs is important for their successful development.

The shelf life of ASDs: 2. Predicting the shelf life at storage conditions

Amorphous solid dispersions (ASDs) are a widely used formulation technology for poorly water-soluble active pharmaceutical ingredients (API). Depending on the API-polymer combination and API load in the ASD, the amorphous API might be thermodynamically metastable and crystallize over time. The crystallization onset is one critical factor that can define the shelf life of the ASD. Thus, for ASD formulations, long-term stability against crystallization of the API is of particular interest. This work presents a method for predicting the long-term physical stability of ASDs (crystallization onset time). The new approach combines the Johnson-Mehl-Avrami-Kolmogorov (JMAK) equation with classical nucleation theory. The shelf life predicted using the new approach depends on supersaturation (determined with PC-SAFT), viscosity (determined with WLF equation or Arrhenius equation) and two specific model parameters k’ and B. The latter were fitted to a few fast crystallization-kinetics measurements above the glass transition of the ASD. An additional crystallization-kinetics measurement below the glass-transition temperature of the ASD was used to determine the Arrhenius parameters. Once all parameters are determined for a given API/polymer combination and manufacturing method, they are valid for any API load, temperature, and RH. The proposed approach allows predicting the shelf life (crystallization onset) of a potential ASD in early stage of development within a few days. It was successfully verified for ASDs stored at 25 °C and 10% RH or 60% RH.

One-Step Generation of O/W/O Double Pickering Emulsions Utilizing Biocompatible Gliadin/Ethyl Cellulose Complex Particles as the Exclusive Stabilizer.

Double emulsions hold great potential for various applications due to their compartmentalized internal structures. However, achieving their long-term physical stability remains a challenging task. Here, we present a simple one-step method for producing stable oil-in-water-in-oil (O/W/O) double emulsions using biocompatible gliadin/ethyl cellulose complex particles as the sole stabilizer. The resulting O/W/O systems serve as effective platforms for encapsulating enzymes and as templates for synthesizing porous microspheres. We investigated the impact of particle concentration and water fraction on the properties of Pickering O/W/O emulsions. Our results demonstrate that the number and volume of inner oil droplets increased proportionally with both the water fraction and particle concentration after a 60-day storage period. Moreover, the catalytic reaction rate of the encapsulated lipase within the double emulsion exhibited a significant acceleration, achieving a substrate conversion of 80.9% within 15 min. Remarkably, the encapsulated enzyme showed excellent recyclability, enabling up to 10 cycles of reuse. Additionally, by utilizing the O/W/O systems as templates, we successfully obtained porous microspheres whose size can be controlled by the outer water droplet. These findings have significant implications for the future design of Pickering complex emulsion-based systems, opening avenues for extensive applications in pharmaceuticals, food, cosmetics, material synthesis, and (bio)catalysis.

Stability-Enhanced Ternary Solid Dispersions of Glyburide: Effect of Preparation Method on Physicochemical Properties.

Limited aqueous solubility and subsequent poor absorption and low bioavailability are the main challenges in oral drug delivery. Solid dispersion is a widely used formulation strategy to overcome this problem. Despite their efficiency, drug crystallization tendency and poor physical stability limited their commercial use. To overcome this defect, ternary solid dispersions of glyburide: sodium lauryl sulfate (SLS) and polyethylene glycol 4000 (PEG), were developed using the fusion (F) and solvent evaporation (SE) techniques and subsequently evaluated and compared. Physicochemical and dissolution properties of the prepared ternary solid dispersions were evaluated using differential scanning calorimetry (DSC), infrared spectroscopy (FTIR), and dissolution test. Flow properties were also assessed using Carr's index and Hausner's ratio. The physical stability of the formulations was evaluated initially and after 12 months by comparing dissolution properties. Formulations prepared by both methods similarly showed significant improvements in dissolution efficiency and mean dissolution time compared to the pure drug. However, formulations that were prepared by SE showed a greater dissolution rate during the initial phase of dissolution. Also, after a 12-month follow-up, no significant change was observed in the mentioned parameters. The results of the infrared spectroscopy indicated that there was no chemical interaction between the drug and the polymer. The absence of endotherms related to the pure drug from thermograms of the prepared formulations could be indicative of reduced crystallinity or the gradual dissolving of the drug in the molten polymer. Moreover, formulations prepared by the SE technique revealed superior flowability and compressibility in comparison with the pure drug and physical mixture (ANOVA, P < 0.05). Efficient ternary solid dispersions of glyburide were successfully prepared by F and SE methods. Solid dispersions prepared by SE, in addition to increasing the dissolution properties and the possibility of improving the bioavailability of the drug, showed acceptable long-term physical stability with remarkably improved flowability and compressibility features.

Characterization of pickering emulsion stabilized by colloidal sodium caseinate nanoparticles prepared using complexation and antisolvent method

The aim of this study was to investigate the effect of different treatments on sodium caseinate (SC) colloidal suspension physicochemical properties and their ability to act as a Pickering stabilizer for reduced-fat formulations. Heat-treated SC (HSC) particles were prepared by adding glucose (HSC-Glc) and tannic acid (HSC-TA), followed by precipitation with ethanol (EtOH) and ethyl cellulose (EC) dissolved in ethanol (EC/EtOH). Stable colloidal suspensions were prepared by adjusting SC, Glc, TA, and EC to 10, 4, 2, and 5 mg/mL respectively, and using a 5: 3 solvent/antisolvent (mL/mL). The stable Pickering emulsions (PEs) in the volumetric ratio of 50: 50 (mL/mL) oil: water were prepared using HSC/EtOH, HSC-Glc/EtOH, and HSC-Glc-TA-EC/EtOH particles as the aqueous phases. They showed higher contact angles and lower interfacial tensions in comparison with native SC and long-term physical stability. Heating and the addition of anti-solvent played the main role in stabilizing PEs with SC and the addition of Glc, TA or EC has only an auxiliary role that could be added or removed depending on its application purpose in the food or pharmaceutical industry. They especially had a major role in the oxidative and thermal stability of the emulsion.

Effect of Copolymer Properties on the Phase Behavior of Ibuprofen–PLA/PLGA Mixtures

Prediction of compatibility of the active pharmaceutical ingredient (API) with the polymeric carrier plays an essential role in designing drug delivery systems and estimating their long-term physical stability. A key element in deducing API-polymer compatibility is knowledge of a complete phase diagram, i.e., the solubility of crystalline API in polymer and mutual miscibility of API and polymer. In this work, the phase behavior of ibuprofen (IBU) with different grades of poly(D,L-lactide-co-glycolide) (PLGA) and polylactide (PLA), varying in composition of PLGA and molecular weight of PLGA and PLA, was investigated experimentally using calorimetry and computationally by the perturbed-chain statistical associating fluid theory (PC-SAFT) equation of state (EOS). The phase diagrams constructed based on a PC-SAFT EOS modeling optimized using the solubility data demonstrated low solubility at typical storage temperature (25 °C) and limited miscibility (i.e., presence of the amorphous-amorphous phase separation region) of IBU with all polymers studied. The ability of PC-SAFT EOS to capture the experimentally observed trends in the phase behavior of IBU-PLA/PLGA systems with respect to copolymer composition and molecular weight was thoroughly investigated and evaluated.

The effects of surfactants on the performance of polymer-based microwave-induced in situ amorphization

Microwave-induced in situ amorphization is a novel technology for preparing amorphous solid dispersions (ASDs) to address the challenges of their long-term physical stability and downstream processing. To date, only few types of dielectric materials have been reported for microwave-induced in situ amorphization, which restricted the extensive research of this technology. This study aimed to investigate the feasibility and mechanisms of utilizing the non-ionic surfactants, i.e. Kollisolv P124, Kolliphor RH40, D-ɑ-tocopheryl polyethylene glycol succinate (TPGS), Tween (T) 60 (T60), T65, T80 and T85, as plasticizers to facilitate microwave-induced in situ amorphization. It was found that the successful application of surfactants could be related with their low Tm, low Mw and high HLB. Kolliphor RH40 was selected as a typical surfactant due to its excellent dielectric heating ability, plasticizing effect and solubilizing effect when facilitating amorphization. Then, the dissolution-mediated in situ amorphization mechanism was investigated and intuitively demonstrated. For the most promising formulation, i.e. microwaved systems with Korlliphor RH40 at 1.5 (w/w) plasticizer/polymer ratio, a complete and fast in vitro dissolution was observed relative to the untreated systems. In conclusion, non-ionic surfactants had the potential to facilitate microwave-induced in situ amorphization, which provided a new direction in the formulation designation for microwave-able systems.

Electrospinning as a method for preparation of redispersible dry product with high content of magnetic nanoparticles

One of the key technological challenges in the development of iron-oxide-based magnetic nanoparticles (MNPs) is their long-term physical stability in colloidal dispersions. This can be improved by their transformation into a dry form. Here, we introduce electrospinning as a drying method for ethanol-based and water-based MNP dispersions, which enables the preparation of high-loaded dry MNP products. The obtained easily dispersible electrospun product contained up to 50 % (w/w) of MNPs, homogeneously distributed in the fibrillar structure, which is much more compared to the products of currently available methods for drying MNP dispersions. The polymers used as building blocks of nanofibers, namely poloxamer 188 and polyethylene oxide, improved the tolerance of MNPs to high ionic strength dispersion medium and thus enhanced the short-term physical stability of MNP dispersions after reconstitution. The dry product was stable for up to 1 month at room temperature and relative humidity up to 70 %. It was in the form of a nanofiber mat, which prevented the aerosolization of MNPs and their unintentional ambient exposure. Therefore, the electrospun product with MNPs is expected to be a safer dry formulation of MNPs than the nanoparticulate powders, which are usually the final products of the conventional drying methods.

Formulation and Physical Characterization of a Polysaccharidic Gel for the Vehiculation of an Insoluble Phytoextract for Mucosal Application

Maintaining insoluble plant-based ingredients in suspension and ensuring long-term physical stability is particularly challenging for formulators of green cosmetics. This study aimed to evaluate the structure and applicative properties of gel and gel-cream topical formulations suitable for delivering an insoluble phytocomplex on the vaginal mucosa and maintaining its integrity. For this purpose, we studied the compatibility of Perilla frutescens (L.) Britton phytocomplex (PFP), derived from in vitro plant cell cultures and presented as a powder finely dispersed in glycerin, with different classes of natural rheological modifiers (such as xanthan gum, sclerotium gum, succinoglycan, xyloglucan, diutan gum, hydroxypropyl guar gum derivative) in gel and gel-cream formulations, to meet the needs of the cosmetic market for naturalness and biodegradability. Through rheological and texture analyses, we studied the physico–mechanical properties of the samples, comparing the performances of the chosen polysaccharides to those of acrylic polymeric rheological modifiers, evaluating their contribution in terms of stability and applicative properties. Since a weak-gel rheological pattern proved to be the optimal one to keep the actives in suspension, the associations of tamarind seed polysaccharides with succinoglycan or scleroglucan were the most suitable for the formulation of mucoadhesive gels.

Phycocyanin-rich water-in-oil-in-water (W1/O/W2) double emulsion with nanosized particles: Improved color stability against light exposure

Acidic environments and light exposure have been known to have detrimental effects on phycocyanin (PC), a spirulina-derived chromoprotein popular among food and pharmaceutical manufacturers. We developed a water-in-oil-in-water (W1/O/W2) double emulsion system for mitigating the discoloration and precipitation issues of PC at pH 3.0 and under light exposure. The nanostructured (∼170 nm) W1/O/W2 emulsion droplets were obtained under the combined efficacy of multiple stabilizing components. Glycerol (40 wt%) in the internal aqueous phase acted as both the protein stabilizer and thickener. Fine droplet size, optical clearness, and thermodynamic stability were obtained using polyglycerol polyricinoleate (PGPR, 4 wt%) as the lipophilic emulsifier and Tween 20 (8 wt%) as the hydrophilic emulsifier. The mechanical robustness of droplets withstood multiple emulsification steps by high pressure homogenization, an efficient, high energy technology amenable to industrial-scale productions. Lipid oxidation was suppressed by using medium-chain triglyceride coconut oil and multiple antioxidants, which offered photoprotection on the encapsulated PC against oxidative damage induced by UV irradiation. The optimized PC-rich W1/O/W2 emulsion exhibited high PC loading capacity and long-term physical stability without leakage, phase separation, and retained the vivid blue color with only slight turbidity. Overall, our PC-rich W1/O/W2 double emulsion system demonstrated good thermodynamical, mechanical, and photooxidative stabilities against the acidic and light storage conditions that are commonly used during food processing, making PC a widely applicable natural colorant and protein source in foods.

Influence of the crystallization tendencies of pharmaceutical glasses on the applicability of the Adam-Gibbs-Vogel and Vogel-Tammann-Fulcher equations in the prediction of their long-term physical stability

Amorphization is a powerful approach for improving the aqueous solubility and bioavailability of poorly water-soluble compounds. However, it can cause chemical and physical instability, the latter of which can lead to crystallization during storage, diminishing the solubility advantage of the amorphous state. As there is no standard method for predicting the physical stability of amorphous materials, a long-term stability study is needed in drug development. This study investigated the correlation between the physical stability of amorphous compounds and molecular mobility based on the assumption that physical stability is governed by the diffusional motion of a molecule. Model compounds were evaluated for crystallization onset time, structural relaxation time, fragility, and fictive temperature. The crystallization onset time of acetaminophen glass correlated with its relaxation time calculated from the Adam-Gibbs-Vogel equation; however, that of felodipine glass correlated with the relaxation time calculated from the Vogel-Tammann-Fulcher equation. The different crystallization tendencies of these compounds can be explained by the differences in the rate limiting steps in their crystallization processes, indicating the importance of distinguishing the critical process associated with crystallization. These findings will be useful for more accurate prediction of long-term physical stability of amorphous materials.

Spontaneously formed multiscale nano-domains in monophasic region of ternary solution

HypothesisTernary mixtures, containing one hydrotrope and two immiscible fluids, both being soluble in the hydrotrope at any proportion, exhibit unexpected solubilization power and unusual mesoscopic properties, which are a subject of long-standing controversies for decades. ExperimentsThis work investigates the entire monophasic region of ternary trans-anethol/ethanol/water system, where multiscale nanostructurings with correlation lengths exceeding dimensions of individual molecules are identified by dynamic light scattering. The physical properties of the ternary mixture are characterized, with revealing the compositional dependence of refractive index and dynamic viscosity. FindingsIn surfactant-free microemulsion (SFME) regime, the single phase consists of two distinct nanoscopic domains in equilibrium, one trans-anethol-rich aggregate at the molecular scale (∼1 nm) and one mesoscopic droplet at the mesoscale (∼100 nm). However, only a tiny fraction of the hydrophobic component trans-anethol (<∼0.025%) are initially incorporated in mesoscale structures, and the vast majority are molecularly dissolved or in the form of aggregates. The concentration of mesoscopic droplets increases sharply when shifting toward the miscibility gap, but their size exhibits a weak compositional dependence. The nanoscopic domains exhibit long-term physical stability, and the Ostwald ripening is still the primary mechanism governing such mesoscopic droplet aging, but with a rather low ripening rate.

The Designing of a Gel Formulation with Chitosan Polymer Using Liposomes as Nanocarriers of Amphotericin B for a Non-invasive Treatment Model of Cutaneous Leishmaniasis.

Leishmaniasis is a disease caused by different Leishmania spp., which are transmitted to humans by a bite of infected female sand flies. Cutaneous leishmaniasis (CL, oriental sore), visceral leishmaniasis (VL), and mucocutaneous leishmaniasis (MCL) are three main clinical forms, however, only CL and VL are seen in Turkey. Cutaneous leishmaniasis is characterized by skin lesion(s) and is one of the most important vector-borne diseases in Turkey with over 2000 cases reported annually in 40 out of 81 provinces. The treatment is usually made invasively and painfully by intralesional injection of pentavalent antimony compounds. Non-invasive and innovative treatment methods are needed as aimed in this study. In the present study, one of the classical antileishmanial drugs, amphotericin B (AmB), encapsulated in liposomes was evaluated using non-invasive design based on chitosan, which is a nontoxic, biocompatible and biodegradable polymer. To avoid the invasive effect of conventional intralesional needle application, the drug was encapsulated in liposomes and incorporated into a chitosan gel for applying topically on the skin lesion. The efficacy of encapsulation of amphotericin B into liposomes and the drug release from liposomes were studied. The chitosan gel was evaluated for viscosity, flowability, appearance and pH. The efficacy of the drug embedded into chitosan gel, liposomal AmB alone and chitosan gel alone in four different concentrations was also tested using Leishmania spp. promastigotes in vitro. The findings have shown that AmB was encapsulated into the liposomes with high efficiency (86.6%) and long-term physical and chemical stability. Therefore, designed liposomal formulation was suitable for sustained release. The appearance of the drug-embedded chitosan gel was transparent and appropriate. Chitosan gels showed non- Newtonian behavior and plastic flow. The liposomal AmB also showed higher efficacy with no parasites in all concentrations while drug embedded into chitosan gel and chitosan gel alone were effective in two higher concentrations. The lower efficacy of the drug-embedded chitosan gel in 24h in in-vitro study was probably due to slow release of the drug. The gel design created in this study will provide ease of use for the lesions of CL patients that do not have a specific number, size, and shape. Follow-up studies by the ex-vivo macrophage infection model with Leishmania intracellular amastigote forms and Leishmania-infected animal models are needed to understand the present design's efficacy better.

Inhalable Composite Microparticles Containing siRNA-Loaded Lipid-Polymer Hybrid Nanoparticles: Saccharides and Leucine Preserve Aerosol Performance and Long-Term Physical Stability

Thermostable dry powder formulations with high aerosol performance are attractive inhalable solid dosage forms for local treatment of lung diseases. However, preserved long-term physical stability of dry powder inhaler (DPI) formulations is critical to ensure efficient and reproducible delivery to the airways during the shelf life of the drug product. Here, we show that ternary excipient mixtures of the disaccharide trehalose (Tre), the polysaccharide dextran (Dex), and the shell-forming dispersion enhancer leucine (Leu) stabilize siRNA-loaded lipid-polymer hybrid nanoparticles (LPNs) during spray drying into nanocomposite microparticles, and result in inhalable solid dosage forms with high aerosol performance and long-term stability. The stabilizing roles of Tre and Dex were also studied separately by investigating DPI formulations containing binary mixtures of Leu/Tre and Leu/Dex, respectively. DPI formulations containing binary Leu/Dex mixtures were amorphous and displayed preserved long-term physical stability of LPNs and chemical stability of siRNA in accelerated stability studies under exaggerated storage conditions (ambient temperature and relative humidity). In contrast, powders containing binary Leu/Tre mixtures were amorphous, and hence metastable, and were recrystallized after six months of storage. Ternary mixtures of Tre, Leu, and Dex provided the most efficient protection of the LPNs during the spray drying process and prevented recrystallization of amorphous Tre. Hence, in ternary mixtures, Leu, Tre, and Dex have the following functions: the shell-forming Leu functions as a dispersion enhancer and is essential for high aerosol performance, the disaccharide Tre provides LPN protection during manufacturing and storage due to efficient coverage of the LPN surface, and the polysaccharide Dex promotes the formation of porous particles and prevents recrystallization of Tre during long-term storage. Therefore, the use of ternary excipient mixtures composed of Leu, Tre, and Dex, may prevent instability problems of DPI formulations and preserve the aerosol performance during long-term storage, which is essential for effective pulmonary drug delivery.

API solubility in semi-crystalline polymer: Kinetic and thermodynamic phase behavior of PVA-based solid dispersions

The formulation of amorphous solid dispersions (ASDs) represents a promising strategy for improving the poor bioavailability of many active pharmaceutical ingredients (APIs). The objective of this study was to investigate and compare the long-term physical stability (LTPS) of polyvinyl alcohol (PVA)-based solid dispersions formulated via hot-melt extrusion (HME) with their respective API–PVA temperature–composition (T–C) phase diagram. Furthermore, the impact of API glass-forming ability (GFA) on the LTPS was evaluated through the selection of two APIs with contrasting GFA (i.e., indomethacin (IND; good GFA) and naproxen (NAP; poor GFA)). Even though the predicted solubility of both APIs in PVA was less than 1 wt% at T = 25 °C, IND remained fully amorphous in HME-formulated IND–PVA extrudates with initial API loadings of 50, 40, and 30 wt% after a 24-month storage period. Meanwhile, NAP recrystallized to a considerable degree in each analogous sample with an amorphous NAP content of 22.5–23.5 wt% remaining after a 12-month storage period. While the constructed T–C phase diagrams were still in agreement with their respective LTPS study, they did not account for the impact of water uptake as well as potential HME-induced effects on the extrudate glass-transition temperature. This work may serve as a useful reference point for researchers who are interested in determining the solubility of an API in a semi-crystalline polymer and the challenges therein.

Ball milling and hot-melt extrusion of indomethacin–l-arginine–vinylpyrrolidone-vinyl acetate copolymer: Solid-state properties and dissolution performance

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.