Model Active Pharmaceutical Ingredient Research Articles

Insights into pharmaceutical co-crystallization using coherent Raman microscopy

Formulating active pharmaceutical ingredients (APIs) as co-crystals requires a thorough understanding of co-crystallization behavior under different process conditions. This study employs two forms of coherent Raman microscopy, narrowband coherent anti-Stokes Raman scattering (CARS) and stimulated Raman scattering (SRS) with spectral focusing, to study co-crystallization via liquid-assisted ball milling. Indomethacin and nicotinamide served as the model API and co-former, and the results were compared with established analytical methods. Narrowband CARS, with univariate peak position analysis, was useful to visualize co-crystal formation, but suffered some degree of signal mixing that affected component identification. Hyperspectral SRS imaging, combined with classical least squares multivariate analysis, separated the different components with high confidence and proved to be a robust and rapid tool to qualitatively and quantitatively image co-crystallization. The coherent Raman imaging results explained divergent co-crystallization endpoints obtained with the conventional solid-state analysis methods. CARS and SRS microscopies also revealed the presence of otherwise undetected trace forms. Finally, we also demonstrated the dramatic reversal of partial co-crystal formation during milling, depending on ethanol content. Overall, the study demonstrates the added value coherent Raman microscopy can provide for analysis of co-crystallization processes.

New Insights on the Burst Release Kinetics of Spray-Dried PLGA Microspheres.

Spray drying is one of the leading manufacturing methods for active pharmaceutical ingredients (APIs) owing to its rapid, single-step, and cost-effective nature. It also has the capacity to generate microspheres capable of controlled release of APIs including biomolecules and vaccines. However, one of the key challenges of spray-dried formulations especially with poly(lactic-co-glycolic acid) (PLGA)-based controlled-release injectables is burst release, where a significant fraction of the API is released prematurely within a short period of time following administration, leading to detrimental impact on the performance and quality of end products. This study uses a model API, bovine serum albumin (BSA) protein, to identify the sources of burst release that may affect the kinetics and performance of long-acting injectable microsphere formulations. Spray-dried microspheres with various formulations (i.e., variable BSA/PLGA ratios) were characterized in terms of their morphology, particle size, surface area, thermal properties, moisture content, as well as chemical compositions and their distributions to investigate the impact of spray drying on the burst release phenomenon. The results suggest that a relatively high initial release (85%) observed is mainly attributed to the protein distribution close to the particle surface. Morphology analysis provided evidence that the microspheres retained their spherical structure during the burst release phase. X-ray photoelectron spectroscopy, hard X-ray photoelectron spectroscopy, and argon cluster sputtering-assisted time-of-flight secondary ion mass spectrometry analysis suggest an enrichment of PLGA on particle surfaces with buried BSA protein. The statistically significant difference in particle size and surface area between three different formulations may be responsible for an initial variation in release but did not seem to alter the overall burst release profile. Considering the suggested source of burst release, the two-fluid spray-drying method, characterized by a single liquid feed delivering a preprepared emulsion, generated matrix-type microspheres with a surface layer of PLGA, as evidenced by surface analysis. The PLGA surface layer proved to be prone to degradation and pore formation, allowing for faster diffusion of BSA out of the microspheres, resulting in a burst release. Increasing the polymer concentration did not seem to halt this process.

Physicochemical characterization and evaluation of polarity influence in eutectic systems applied to drug solubility

In the process of discovery and development of APIs (Active Pharmaceutical Ingredients), the rate of solubility or aqueous dissolution plays a very important role from the first evaluations of the candidates to the development of final marketable products. Since only the solubilized form of an active ingredient is capable of being transported and exerting its therapeutic effect across biological membranes, it is of utmost importance to control its solubility. However, the number of APIs under development with low water solubility has notoriously grown in recent years. Their pharmaceutical use will face problems such as insufficient bioavailability, late onset of action, and the need for large dosages.The present study aims to evaluate the behavior of ciprofloxacin and norfloxacin (fluoroquinolones), as model APIs for their different solubilities, in aqueous and non-aqueous natural deep eutectic solvents (NADES). The main objective is to improve the solubility of both drugs in pharmaceutical studies and analytical applications. In order to do so, two sets of eutectic solvents were selected, each composed with a polar solvent, an intermediate one, and a nonpolar solvent, as well. Very promising results were obtained in NADES of polar and intermediate polarity, for both drugs. In addition, the physicochemical characterization of such solvents was carried out to better understand the aforementioned results.

Dandelion inspired microparticles with highly efficient drug delivery to deep lung

Active pharmaceutical ingredient (API) embedded dry powder for inhalation (AeDPI) shows higher drug loading and delivery dose for directly treating various lung infections. Inspired by the dandelion, we propose a novel kind of AeDPI microparticle structure fabricated by spray freeze drying technology, which would potentially enhance the alveoli deposition efficiency. When inhaling, such microparticles are expected to be easily broken-up into fragments containing API that acts as ‘seed’ and could be delivered to alveoli aided by the low density ‘pappus’ composed of excipient. Herein, itraconazole (ITZ), a first-line drug for treating pulmonary aspergillosis, was selected as model API. TPGS, an amphiphilic surfactant, was used to achieve stable primary ITZ nanocrystal (INc) suspensions for spray freeze drying. A series of microparticles were prepared, and the dandelion-like structure was successfully achieved. The effects of feed liquid compositions and freezing parameters on the microparticle size, morphology, surface energy, crystal properties and in vitro aerosol performance were systematically investigated. The optimal sample (SF(-50)D-INc7Leu3-2) in one-way experiment showed the highest fine particle fraction of ∼ 68.96 % and extra fine particle fraction of ∼ 36.87 %, equivalently ∼ 4.60 mg and ∼ 2.46 mg could reach the lung and alveoli, respectively, when inhaling 10 mg dry powders. The response surface methodology (RSM) analysis provided the optimized design space for fabricating microparticles with higher deep lung deposition performance. This study demonstrates the advantages of AeDPI microparticle with dandelion-like structure on promoting the delivery efficiency of high-dose drug to the deep lung.

Vapor/Vapor‐Solid Interfacial Growth of Covalent Organic Framework Membranes on Alumina Hollow Fiber for Advanced Molecular Separation

AbstractCovalent organic frameworks (COFs), known for their chemical stability and porous crystalline structure, hold promises as advanced separation membranes. However, fabricating high‐quality COF membranes, particularly on industrial‐preferred hollow fiber substrates, remains challenging. This study introduces a novel vapor/vapor‐solid (V/V−S) method for growing ultrathin crystalline TpPa‐1 COF membranes on the inner lumen surface of alumina hollow fibers (TpPa‐1/Alumina). Through vapor‐phase monomer introduction onto polydopamine‐modified alumina at 170 °C and 1 atm, efficient polymerization and crystallization occur at the confined V−S interface. This enables one‐step growth within 8 h, producing 100 nm thick COF membranes with strong substrate adhesion. TpPa‐1/Alumina exhibits exceptional stability and performance over 80 h in continuous cross‐flow organic solvent nanofiltration (OSN), with methanol permeance of about 200 L m−2 h−1 bar−1 and dye rejection with molecular weight cutoff (MWCO) of approximately 700 Da. Moreover, the versatile V/V−S method synthesizes two additional COF membranes (TpPa2Cl/Alumina and TpHz/Alumina) with different pore sizes and chemical environments. Adjusting the COF membrane thickness between 100–500 nm is achievable easily by varying the growth cycle numbers. Notably, TpPa2Cl/Alumina demonstrates excellent OSN performance in separating the model active pharmaceutical ingredient glycyrrhizic acid (GA) from dimethyl sulfoxide (DMSO), highlighting the method's potential for large‐scale industrial applications.

Vapor/Vapor-Solid Interfacial Growth of Covalent Organic Framework Membranes on Alumina Hollow Fiber for Advanced Molecular Separation.

Covalent organic frameworks (COFs), known for their chemical stability and porous crystalline structure, hold promises as advanced separation membranes. However, fabricating high-quality COF membranes, particularly on industrial-preferred hollow fiber substrates, remains challenging. This study introduces a novel vapor/vapor-solid (V/V-S) method for growing ultrathin crystalline TpPa-1 COF membranes on the inner lumen surface of alumina hollow fibers (TpPa-1/Alumina). Through vapor-phase monomer introduction onto polydopamine-modified alumina at 170 °C and 1 atm, efficient polymerization and crystallization occur at the confined V-S interface. This enables one-step growth within 8 h, producing 100 nm thick COF membranes with strong substrate adhesion. TpPa-1/Alumina exhibits exceptional stability and performance over 80 h in continuous cross-flow organic solvent nanofiltration (OSN), with methanol permeance of about 200 L m-2 h-1 bar-1 and dye rejection with molecular weight cutoff (MWCO) of approximately 700 Da. Moreover, the versatile V/V-S method synthesizes two additional COF membranes (TpPa2Cl/Alumina and TpHz/Alumina) with different pore sizes and chemical environments. Adjusting the COF membrane thickness between 100-500 nm is achievable easily by varying the growth cycle numbers. Notably, TpPa2Cl/Alumina demonstrates excellent OSN performance in separating the model active pharmaceutical ingredient glycyrrhizic acid (GA) from dimethyl sulfoxide (DMSO), highlighting the method's potential for large-scale industrial applications.

A robust self-regenerating graphene-based adsorbent for pharmaceutical removal in various water environments

The presence of active pharmaceutical ingredients (APIs) in wastewater effluents and natural aquatic systems threatens ecological and human health. While activated carbon-based adsorbents, such as GAC and PAC, are widely used for API removal, they exhibit certain deficiencies, including reduced performance due to the presence of natural organic macromolecules (NOMs) and high regeneration costs. There is growing demand for a robust, stable, and self-regenerative adsorbent designed for API removal in various environments. In this study, we synthesized a self-generating metal oxide nano-composite (S-MGC) containing titanium dioxide (TiO2) and silicon dioxide (SiO2) combined with 3D graphene oxide (GO) to adsorb APIs and undergo regeneration via light illumination. We determined optimal TiO2:SiO2:GO compositions for the S-MGCs through experiments using a model contaminant, methylene blue. The physical and chemical properties of S-MGCs were characterized, and their adsorption and photodegradation capabilities were studied using five model APIs, including sulfamethoxazole, carbamazepine, ketoprofen, valsartan, and diclofenac, both in single-component and multi-component mixtures. In the absence of TiO2/SiO2, 3D graphene oxide (CGB) displayed better adsorption performance compared to GAC, and S-MGCs further improve CGB's adsorption capacity. This performance remained consistent in two complex water environments: aqueous solutions at varying NOM levels and artificial urine. TiO2 supported on the GO surface exhibits similar photocatalytic activity to suspended TiO2. In a continuous fixed-bed column test, S-MGCs demonstrated robust API adsorption performance that is maintained in the presence of NOM or urine, and can be regenerated through multiple cycles of adsorption and light illumination.

Differentiation of solvatomorphs of active pharmaceutical ingredients (API) by solid-state vibrational circular dichroism (VCD)

Here, we present the new application of solid-state Vibrational Circular Dichroism (VCD) spectroscopy to differentiate several dutasteride (DS) solvatomorphs – the model active pharmaceutical ingredient (API). Several crystalline DS hydrochloride hydrates solvated with methanol, ethanol, acetonitrile, acetone, and acetic acid were prepared. In contrast to almost identical IR spectra, the VCD ones were very sensitive to changes in the sample composition. We marked significant differences in the shape of VCD spectra of studied DS solvatomorphs, DS hydrates, and DS polymorphic forms. Our findings, supported by DFT calculations, show that VCD spectroscopy has the pronounced ability to distinguish their crystal arrangements. We believe that this contribution will extend the use of VCD in the pharmaceutical industry for developing and designing new chiral drug products for the identification, description, and in-depth probing of several pharmaceutical solvatomorphs in the future.

High-Degree Concentration Organic Solvent Forward Osmosis for Pharmaceutical Pre-Concentration.

Over half of the pharmaceutical industry's capital investments are related to the purification of active pharmaceutical ingredients (APIs). Thus, a cost-effective purification process with a highly concentrated solution is urgently required. In addition, the purification process should be nonthermal because most APIs and their intermediates are temperature-sensitive. This study investigated a high-degree concentration organic solvent forward osmosis (OSFO) membrane process. A polyketone-based thin-film composite hollow fiber membrane with a polyamide selective layer on the bore surface was used as the OSFO membrane to achieve a high tolerance for organic solvents and an effective concentration. MeOH, sucrose octaacetate (SoA), and 2M polyethylene glycol 400 (PEG-400)/MeOH solution were used as the solvent, model API, and a draw solution (DS), respectively. OSFO was performed at room temperature (23 ± 3 °C). Consequently, the 11 wt% SoA/MeOH solution was concentrated to 52 wt% without any SoA leakage into the DS. To our knowledge, there are no studies in which up to a 5 wt% concentration by OSFO has been demonstrated. However, the final feed solution contained 17 wt% PEG-400. This study demonstrates the promising potential of OSFO for pharmaceutical pre-concentration and the technical problems that need to be solved for social implementation.

Towards rational design of API-poly(D, L-lactide-co-glycolide) based micro- and nanoparticles: The role of API-polymer compatibility prediction

Due to their unique properties, such as controlled drug release and improved bioavailability, polymeric microparticles and nanoparticles (MPs and NPs) have gained considerable interest in the pharmaceutical industry. Nevertheless, the high costs associated with biodegradable polymers and the active pharmaceutical ingredients (APIs) used for treating serious diseases, coupled with the vast number of API-polymer combinations, make the search for effective API-polymer MPs and NPs a costly and time-consuming process. In this work, the correlation between the compatibility of selected model APIs (i.e., ibuprofen, naproxen, paracetamol, and indomethacin) with poly(lactide-co-glycolide) (PLGA) derived from respective binary phase diagrams and characteristics of prepared MPs and NPs, such as the drug loading and solid-state properties, was investigated to probe the possibility of implementing the modeling of API-polymer thermodynamic and kinetic phase behavior as part of rational design of drug delivery systems based on MPs and NPs. API–PLGA-based MPs and NPs were formulated using an emulsion-solvent evaporation technique and were characterized for morphology, mean size, zeta potential, drug loading, and encapsulation efficiency. The solid-state properties of the encapsulated APIs were assessed using differential scanning calorimetry and X-ray powder diffraction. The evaluated compatibility was poor for all considered API–PLGA pairs, which is in alignment with the experimental results showing low drug loading in terms of amorphous API content. At the same time, drug loading of the studied APIs in terms of amorphous content was found to follow the same trend as their solubility in PLGA, indicating a clear correlation between API solubility in PLGA and achievable drug loading. These findings suggest that API-polymer phase behavior modeling and compatibility screening can be employed as an effective preformulation tool to estimate optimum initial API concentration for MP and NP preparation or, from a broader perspective, to tune or select polymeric carriers offering desired drug loading.

Effect of tableting temperature on tablet properties and dissolution behavior of heat sensitive formulations

The tableting process involves the conversion of mechanical to thermal energy. This study evaluated the influence of temperature on the tableting behavior of formulations with different compositions. The tableting machine was equipped with a thermally controlled die to mimic the heat evolution from tableting on an industrial scale. Six formulations containing binders with a comparably low glass transition temperature were examined. Besides the polymer type and concentration, the filler was varied. Paracetamol was chosen as the model active pharmaceutical ingredient. The investigation included alterations in tabletability, disintegration and dissolution. Elevated temperatures led to an enhanced tabletability. The polymer type and concentration were decisive for the extent of alterations. The variation of the filler composition played a minor role due to the high melting points of its components. The results were confirmed in disintegration and dissolution studies. A high binding capacity and a low glass transition temperature resulted in a stronger delay of disintegration. The dissolution was sustained. Increased concentrations of the binding polymer enhanced the effect. If the tableting behavior of a formulation is changed by elevated temperatures during formulation development and production, a change of the binder type or concentration should be considered to ensure a reproducible tablet quality.

Supercritical antisolvent-fluidized bed for the preparation of dry powder inhaler for pulmonary delivery of nanomedicine

The supercritical antisolvent-fluidized bed coating process (SAS-FB) shows great potential as a technique to manufacture dry powder inhaler (DPI) that incorporate nanodrugs onto micronized matrix particles, capitalizing on the merits of both nanoparticle and pulmonary delivery. In this study, naringin (NAR), a pharmacologically active flavonoid with low solubility and in vivo degradation issues, was utilized as a model active pharmaceutical ingredient to construct nanomedicine-based DPI through SAS-FB. It is showed that processed NAR exhibited a near-spherical shape and an amorphous structure with an average size of around 130 nm. Notably, SAS-FB products prepared with different fluidized matrices resulted in varying deposition patterns, particularly when mixed with a coarse lactose to enhance the fine particle fraction (FPF) of the formulations. The FPF was positively associated with specific surface area of the SAS-FB products, while the specific surface area was directly related to surface roughness and particle size. In vitro dissolution studies using simulated lung fluid revealed that the NAR nanoparticles coated on the products were released immediately upon contact with solution, with a cumulative dissolution exceeding 90% within the first minute. Importantly, compared to oral raw NAR, the optimized DPI formulation demonstrated superior in vivo plasmatic and pulmonary AUC0→∞ by 51.33-fold and 104.07-fold respectively in a Sprague-Dawley rat model. Overall, SAS- FB technology provides a practical approach to produce nanomedicine DPI product that combine the benefits of nanoparticles with the aerodynamics properties of inhaled microparticles.

Possibilities and advantages of additive manufacturing in dry powder formulations for inhalation

In dry powder formulations for inhalation, coarse carrier particles are often used to improve handling, dosing and dispersion of the active pharmaceutical ingredient (API). Carrier particles, mostly alpha-lactose monohydrate crystals, always show a certain size distribution and are never exactly uniform in their geometry. This might be one factor of the rather high invivo variability in fine particle dose from dry powder inhalers. To address the inhomogeneity of carrier particles, additive manufacturing has come to mind. The parametric design of the perfect carrier geometry could further improve the efficiency of dry powder formulations. In this study, a numerical simulation setup using the discrete element method as well as an experimental approach with 3D printed particles were used to determine the loading capacity of a model API onto two different carrier geometries. The difference between the two geometries was reduced solely to their surface's topology to assess the impact of that. The results indicate differences in the loading capacity for the two geometries, depending on the loading process. This study highlights the importance of the carrier geometry for the efficiency of dry powder formulations and thus, strengthens the idea of artificially designed and printed carrier particles.

Personalizing oral delivery of nanoformed piroxicam by semi-solid extrusion 3D printing

Semi-solid extrusion (SSE) 3D printing enables flexible designs and dose sizes to be printed on demand and is a suitable tool for fabricating personalized dosage forms. Controlled Expansion of Supercritical Solution (CESS®) is a particle size reduction technology, and it produces particles of a pure active pharmaceutical ingredient (API) in a dry state, suspendable in the printing ink. In the current study, as a model API of poorly water-soluble drug, nanoformed piroxicam (nanoPRX) prepared by CESS® was accommodated in hydroxypropyl methylcellulose- or hydroxypropyl cellulose-based ink formulations to warrant the printability in SSE 3D printing. Importantly, care must be taken when developing nanoPRX formulations to avoid changes in their polymorphic form or particle size. Printing inks suitable for SSE 3D printing that successfully stabilized the nanoPRX were developed. The inks were printed into films with escalating doses with exceptional accuracy. The original polymorphic form of nanoPRX in the prepared dosage forms was not affected by the manufacturing process. In addition, the conducted stability study showed that the nanoPRX in the prepared dosage form remained stable for at least three months from printing. Overall, the study rationalizes that with nanoparticle-based printing inks, superior dose control for the production of personalized dosage forms of poorly water-soluble drugs at the point-of-care can be achieved.

Evaluation of a compact composite sensor array for concentration monitoring of solutions and suspensions via multivariate analysis

Compact composite probes were identified as a priority to alleviate space constraints in miniaturized unit operations and pharmaceutical manufacturing platforms. Therefore, in this proof of principle study, a compact composite sensor array (CCSA) combining ultraviolet and near infrared features at four different wavelengths (280, 340, 600, 860 nm) in a 380 × 30 mm housing (length x diameter, 7 mm diameter at the probe head), was evaluated for its capabilities to monitor in situ concentration of solutions and suspensions via multivariate analysis using partial least squares (PLS) regression models. Four model active pharmaceutical ingredients (APIs): warfarin sodium isopropanol solvate (WS), lidocaine hydrochloride monohydrate (LID), 6-mercaptopurine monohydrate (6-MP), and acetaminophen (ACM) in their aqueous solution and suspension formulation were used for the assessment. The results demonstrate that PLS models can be applied for the CCSA prototype to measure the API concentrations with similar accuracy (validation samples within the United States Pharmacopeia (USP) limits), compared to univariate CCSA models and multivariate models for an established Raman spectrometer. Specifically, the multivariate CCSA models applied to the suspensions of 6-MP and ACM demonstrate improved accuracy of 63% and 31%, respectively, compared to the univariate CCSA models [1]. On the other hand, the PLS models for the solutions WS and LID showed a reduced accuracy compared to the univariate models [1].

Understanding the role of magnesium stearate in lowering punch sticking propensity of drugs during compression

The sticking of active pharmaceutical ingredient (API) to the surfaces of compaction tooling, frequently referred to as punch sticking, causes costly downtime or product failures in commercial tablet manufacturing. Magnesium stearate (MgSt) is a common tablet lubricant known to ameliorate the sticking problem, even though there exist exceptions. The mechanism by which MgSt lowers punch sticking propensity (PSP) by covering API surface is sensible but not yet experimentally proven. This work was aimed at elucidating the link between PSP and surface area coverage (SAC) of tablets by MgSt, in relation to some key formulation properties and process parameters, namely MgSt concentration, API loading, API particle size, and mixing conditions. The study was conducted using two model APIs with known high PSPs, tafamidis (TAF) and ertugliflozin-pyroglutamic acid (ERT). Results showed that PSP decreases exponentially with increasing SAC by MgSt. The composition of material stuck to punch face was also explored to better understand the onset of punch sticking and the impact of possible MgSt-effected punch conditioning event.

Analysis of Cimetidine Crystal Polymorphs by X-ray Absorption Near-Edge Spectroscopy.

Sulfur K-edge X-ray absorption near-edge spectroscopy (XANES) measurements were performed to characterize the crystal polymorphs of the active pharmaceutical ingredients (APIs) containing sulfur atoms. Cimetidine (CIM) was used as a model API. Each crystal form of CIM has its own XANES spectrum, so we can discriminate the crystal form by its spectrum. The analysis of the crystal structure of CIM revealed that the difference in the shape of XANES spectra was ascribable to the difference in the C-S-C bond angle of CIM molecules and the intermolecular hydrogen bonds, such as C-H···S and N-H···S, and S-S interaction. It was found that the peak shape of the XANES spectrum is gentle when the C-S-C bond angle is large, while the peak shape can be steep when the C-S-C bond angle is small. Furthermore, it was found that the peak energy values varied depending on the hydrogen bonds and S-S interaction. By linear combination fitting using XANES spectra, it was possible to quantify the ratio of CIM form A crystal in mixed powders of form A and monohydrate crystals. These results indicate that XANES measurements can be a useful technique to evaluate the crystal polymorphism of APIs containing S atom in pharmaceutical formulation.

High-throughput kinetic turbidity analysis for determination of amorphous solubility and excipient screening for amorphous solid dispersions

Many poorly water-soluble active pharmaceutical ingredients (APIs) rely on supersaturating formulations, such as amorphous solid dispersions (ASDs), to enhance oral bioavailability. ASDs kinetically trap amorphous solid drugs within polymer excipient matrices to maintain the amorphous drug states. The maximum solution concentration of the API in these formulations is known as the amorphous solubility. In early drug development with scarce material and time, high-throughput approaches to measuring amorphous solubility and screening excipient effects on crystallization risk offer significant benefits to preclinical formulation scientists. Here, we developed a high-throughput screening (HTS) workflow to quantify amorphous solubility and screen ASD excipients by automated kinetic turbidity analysis. Testing 20 model APIs with a wide range of biorelevant solubility, we demonstrated their apparent amorphous solubility determined by the HTS approach strongly correlated with quantification results using conventional liquid chromatography; while the real-time analysis significantly saved analytical time and experimental efforts. Furthermore, kinetic turbidity profiles elucidated distinct excipient effects on the precipitation process of APIs. These results were successfully translated to dissolution and precipitation behaviors of ASD formulations composed of the tested polymers. The high-throughput kinetic turbidity workflow presents a facile and information-rich approach for amorphous solubility screenings against excipients, and helps guide enabling formulation development.

Selecting the most appropriate formulation excipient for manufacture of amorphous solid dispersions: a case study of lumefantrine

This work demonstrated the importance of pre-formulation studies and proposed a generalised scheme for excipient screening in the early stage of amorphous solid dispersion(ASD) system development by profiling the excipients’ capability to solubilise, amorphisise, and stabilise the chosen active pharmaceutical ingredient (API) in an effort to rank their suitability. Lumefantrine, an antimalarial active compound with both poor solubility and permeability, was used as a model API and solvent evaporation film casting was used to prepare the candidate ASD matrices in this work. 

Elucidation of the effect of added fines on the performance of dry powder inhalation formulations

Dry powder inhalers (DPIs) are regularly used to treat respiratory diseases. Adding extrinsic fine excipient particles to the blend of active pharmaceutical ingredient (API) and carrier is an established strategy to improve aerosolization efficiency during pulmonary drug delivery. Different amounts and grades of lactose fines may, however, compromise the flowability and downstream processing of the material. Further, given the particle size of the inhaled fine particles (<5.5 µm), also deposition of lactose fines to different lung regions following inhalation cannot be excluded. This study aimed to investigate the impact of commercially available extrinsic lactose fine materials produced using different milling parameters, on physicochemical properties and aerosolization performance of ternary blends, as a factor of time and storage conditions. Further, for the first time, it was attempted to elucidate the effect that the amount of present fines has on the dissolution of the model API from the ternary blends exposed to different storage conditions. We showed that rheological behavior was impacted when a higher amount of fines was present, and this effect was further enhanced by storage at high relative humidity. The aerosolization efficiency was vastly improved with increasing content of fines. Still, initial data indicated that the dissolution of the poorly soluble API was retarded when more fines were present in blends.