Acute lung injury has received renewed public attention as a result of the worldwide epidemic of novel coronavirus pneumonia that lasted from 2019 to 2023 [1]. With high rates of morbidity and mortality, acute lung injury (ALI) and its more severe clinical manifestations, such as acute respiratory distress syndrome (ARDS), are common critical illnesses that pose a major risk to patient life [2]. According to research, the in-hospital death rate for patients with severe ALI/ARDS is a noteworthy 46.1% [3].

In addition to direct causes like pneumonia, severe trauma, or toxin inhalation, ALI is a potentially fatal respiratory illness that can also result from indirect causes like sepsis or shock [4,5]. A significant inflammatory response and an imbalance in the pulmonary oxidative stress system are its main characteristics [6]. enhanced pulmonary vascular permeability, interstitial edema, alveolar fibrin exudation, enhanced intrapulmonary shunting, and ventilation-perfusion imbalance are characteristics of this condition's pathogenesis [7]. However, there are no particular drugs that can be used to treat ALI/ARDS. Mechanical ventilation, glucocorticoids, inhaled pulmonary vasodilators, and neuromuscular blocking medications are the mainstays of treatment for ALI/ARDS [8]

Due to the possibility of rapidly and efficiently reaching medication concentrations at the diseased sites, pulmonary drug delivery systems are appealing therapeutic methods for lung disorders. This could increase therapeutic efficacy and decrease systemic side effects [9]. Effectiveness and delivery efficiency have significantly increased as a result of the introduction of dry powder inhalers as a pulmonary drug delivery method. In addition to being a simple, easy-to-use, portable, cost-effective, and environmentally friendly delivery method, dry powder inhalers can significantly reduce the quantity of medication deposition in the mouth and throat and have a high patient compliance rate [10].

Plants belonging to the Ephedra species naturally contain pseudoephedrine (PSE), an alkaloid that is also synthesized for use in drug. The stereoisomer of ephedrine with the formula C10H15NO is a phenethylamine derivative. It has a methylamino group, hydroxyl group, and phenyl ring joined to a propane backbone. Sympathomimetic amine is a member of the phenylpropanolamine class. used as a nasal decongestant in oral formulations (tablets, capsules, syrups), frequently in conjunction with analgesics or antihistamines in drugs for the flu and cold [11]. Furthermore, PSE is sometimes used off-label for its mild bronchodilator action in asthma and to relieve nasal and sinus congestion in colds, allergies, and hay fever. precursor to the illegal production of methamphetamine, which has resulted in sales bans in numerous nations.

The antisolvent precipitation method was initially used to create the dry powder inhaler of PSE for the current study. The physicochemical characteristics of prepared PSE-DPI were then investigated and described. According to our research, PSE-DPI provides a better lung safety profile than typical dry powder inhalers. This formulation has more accurate targeting, less side effects, and more efficient delivery than conventional therapy techniques. PSE's potential as a treatment for acute lung injury is highlighted by its conversion into a dry powder inhaler, which improves its effectiveness and simplicity.

Preparation of PSE-DPI

The extra 1.00 g of pseudoephedrine (PSE) API was dissolved in 50 mL of anhydrous ethanol and ultrasonically sonicated for 15 minutes at 300 W and 40 kHz to create pseudoephedrine (PSE) powder.  Centrifugation produced the supernatant, which was the PSE saturated alcohol solution.  Then, at room temperature, the solution was gradually added drop by drop to an n-hexane solution in a 3:30 (mL: mL) ratio while being stirred for 2, 6, 8, and 10 hours and rotated at 600, 900, and 1200 rpm.  PSE powder was obtained by centrifuging the mixture after stirring and drying the precipitate for 24 hours at 40 °C in a blast drying oven [12]. Using a laser particle size analyzer in a dry environment, the dry dispersion method was used to evaluate the particle size distribution of the appropriate amount of pure PSE and DPI.

Characterizations of PSE-DPI

Scanning electron microscope

A scanning electron microscope was used to examine the morphology of the PSE powder that was prepared (SEM, Thermo Fisher Scientific, America). After gold spraying, the PSE powder was uniformly applied to conductive adhesive tape and put under a scanning electron microscope. A vacuum of 5 × 10−4 Pa, an electron beam operating voltage of 10 kV, a working distance of roughly 10 mm, and a magnification range of 1000–10,000 were all used to examine the materials [13].

Differential scanning calorimetry

Differential scanning calorimetry was used to examine the thermal impact of PSE powder (DSC, NETZSCH, Germany). They were weighed precisely and put in an aluminum sample tray with 5.41 mg of SYN-API and 2.23 mg of PSE-DPI. After that, the trays and a reference crucible were sealed and put into the sample cell. To provide a dry atmosphere, a high purity nitrogen atmosphere was created at a flow rate of 40 mL·min⁻¹ [14]. The temperature was first set at 20°C, and at a heating rate of 20.0°C·min−1, it was progressively raised from 20°C to 350°C.

Fourier transform infrared radiation

Fourier transform infrared radiation (FTIR, Thermo Fisher Scientific, America) spectroscopy was used to detect the infrared absorption of PSE and powder. A mortar and pestle were used to weigh and grind the SYN and PSE-DPI, which were approximately 2.00 mg and 200 mg of KBr powder, respectively. The final powder was prepared, put into the tablet press's mold, and then pressed [15]. After pressing, the transparent tablets were removed and placed within the sample transmittance measurement apparatus. Sixteen scans were conducted, covering a wavelength range of 3500 to 500 cm−1 with a resolution of 0.09 cm−1. The scans were performed on a background of potassium bromide.

Powder X-ray powder diffraction

With the use of powder X-ray diffraction, the crystalline form of PSE and powder was identified (PXRD, Bruker, Germany). Flat sample specimens were created by weighing the proper amounts of SYN and PSE-DPI, then grinding them into a consistent powder. Cu target, high voltage intensity of 40 kV, tube current of 100 mA, scanning range of 10°–80° (2θ), and scanning speed of 0.2°·min⁻¹ were the subsequent conditions under which these specimens were examined. PXRD maps were then created from the generated data [16].

Hygroscopicity

Dynamic vapor sorption was used to investigate the hygroscopicity of PSE and powder (DVS, BeiShiDe, China). A room temperature of 25 °C was chosen as the experimental temperature. The overall gas flow rate was 200 mL·min−1, with NO serving as the carrier gas. After being weighed, the samples were placed on the DVS's balancing tray [17]. Both the humidity equilibrium time and the relative humidity (RH) adjustment program were established based on demand.

Study of aerodynamic in vitro

The next generation pharmaceutical impactor (NGI, Huironghe, China) apparatus was used to investigate the in vitro aerodynamics of PSE. The weight of the capsule shell (m3) was meticulously measured after hydroxypropyl methylcellulose capsule No. 3 was consumed. After adding about 10 mg of PSE and powder to the capsule, the mass of the capsule (m1) was precisely measured. After that, the capsule was put into the inhalation apparatus and exposed to a 75 L/min−1 air flow for 3.2 seconds. Subsequently, the capsule was weighed for 5 capsules each time, and the mass of the capsule shell was measured once more (m2). After dissolving the medication granules at all NGI levels in ultrapure water, the PSE concentration was determined by UV [18]. The respirable fraction (RF), fine particle fraction (FPF), and evacuation rate were then computed

Preparation and characterization of PSE-DPI

Fig. 1 illustrates the particle size distribution and characterization of PSE powder prepared via the antisolvent precipitation method. Panel (a) represents the cumulative particle size distribution, while panel (b) shows the frequency distribution of particle sizes. The results indicate that the processed PSE powder exhibited a significant shift toward the respirable particle size range of 1–5 μm, which wasoptimal for pulmonary delivery. The cumulative distribution curve (Figure 1a) highlights that a higher percentage of particles fall within this range compared to the raw material, confirming the efficiency of the precipitation method in producing fine particles. Similarly, the frequency distribution curve (Figure 1b) demonstrates a sharp and narrow peak [19], further supporting the uniformity and aerodynamic suitability of the prepared PSE powder. These findings suggest that the antisolvent precipitation technique effectively reduced particle size and improved the powder’s inhalation characteristics, making it favorable for dry powder inhaler (DPI) formulations.

Figure 1. Characterizations of PSE-DPI (a) cumulative distribution and (b) frequency distribution

The particle size analysis revealed that the median diameter (D50) of the prepared powder was less than 5 μm, which falls within the optimal aerodynamic range for pulmonary drug delivery. Such particle dimensions are crucial for effective deposition in the lower respiratory tract, ensuring therapeutic efficacy of the dry powder inhaler. The SEM micrographs in Figure 2 provide further morphological evidence of the formulations. Fig. 2a shows the raw pseudoephedrine (PSE), characterized by irregular, uneven, and flaky or lumpy structures with broad particle size distribution. In contrast Fig. 2b illustrates the PSE-DPI obtained via the antisolvent precipitation method, where the particles appear smoother and more uniform, with reduced agglomeration [20]. This morphological transformation highlights the efficiency of the formulation process in tailoring particle size and surface characteristics to enhance dispersibility, flowability, and deposition in the lungs. Overall, these observations confirm that the optimized PSE-DPI exhibits suitable properties for inhalation therapy [21].

Figure 2. SEM image of (a) pure PSE and (b) PSE-DPI

The FTIR spectra for both pure PSE and its dry powder inhaler (PSE-DPI) formulation shown in Fig. 3 and revealed several characteristic absorption bands that correspond to the functional groups present in the compound. The prominent peaks observed were of 3033 cm⁻¹ (υ C–H stretching) band corresponds to the stretching vibration of the aromatic C–H bonds, confirming the presence of aromatic structures in the PSE. 1599 cm⁻¹ (ζ C–H bending) to in-plane bending of the aromatic C–H groups, further indicating the aromatic framework of the compound. 1536 cm⁻¹ (ζ C=C stretching), represents stretching vibrations of the aromatic C=C bonds, consistent with conjugated ring systems. 1339 cm⁻¹ (ζ O–H and N–H) bending suggests the presence of hydroxyl and/or amine functionalities, which are typical in phenolic or alkaloid structures. 1251 cm⁻¹ (υ C=O) stretching attributed to carbonyl stretching, supporting the existence of ester or amide linkages in the molecular structure [22].

When comparing the spectra of pure PSE (red) and PSE-DPI (blue), no significant shifts in the positions of the major characteristic peaks were observed. This indicates that the primary functional groups of PSE remained intact after formulation into the DPI system. However, the relative intensities of some peaks were slightly altered in the PSE-DPI spectrum, which may be attributed to interactions between PSE and the excipients used during the powder formulation [23]. Overall, the FTIR analysis confirms the structural integrity of PSE in the DPI formulation and suggests the absence of major chemical interactions or degradation during the processing step.

Figure 3. FTIR spectrume of (red) pure PSE and (blue) PSE-DPI

The powder X-ray diffraction (PXRD) patterns of pure PSE (Figure 4a) and PSE-DPI (Figure 4b) revealed sharp and intense diffraction peaks, confirming the crystalline nature of the samples. Importantly, there were no significant shifts in the diffraction peaks between pure PSE and PSE-DPI, indicating that the crystalline structure of PSE was preserved during the formulation process [24]. The similarity of the diffraction patterns suggests that the crystal habit and internal arrangement of the molecules remained unaltered.

Figure 4. PXRD pattern of (a) pure PSE and (b) PSE-DPI

PSE powder was a somewhat hygroscopic sample (having a hygroscopic weight gain of less than 2% but not less than 0.2%), with a moisture absorption weight gain of 0.30% at 90% relative humidity. Under normal storage conditions (60 percent relative humidity), PSE and powder have a moisture absorption and weight gain percentage of less than 0.2 percent, making them essentially non-hygroscopic [25]. They are suitable for pulmonary drug delivery systems and will not cause particle agglomeration, deposition, or other issues during the delivery process in the respiratory system.

Moisture absorption studies demonstrated that PSE powder was slightly hygroscopic, with a weight gain of ~0.30% at 90% relative humidity, and less than 0.2% under normal storage conditions (60% relative humidity). According to pharmacopeial classification, this places PSE in the “non-hygroscopic to slightly hygroscopic” range (Fig. 5). This property was advantageous for pulmonary drug delivery systems, as the low moisture uptake minimizes risks of particle agglomeration, deposition issues, or reduced aerodynamic performance during inhalation [26].

Figure 5. Hygroscopicity graph of (a) pure PSE and (b) PSE-DPI

DSC further confirmed the crystalline stability of the samples. Pure PSE (Fig. 6a) exhibited a sharp endothermic melting peak at around ~190–200 °C, characteristic of its crystalline form. The PSE-DPI formulation (Fig. 6b) also displayed an endothermic event at a comparable temperature, with no appreciable shift in peak position. The slight difference in peak sharpness and intensity can be attributed to the presence of excipients and minor variations in thermal conductivity, but the absence of new peaks or major changes confirms that no polymorphic transitions or chemical interactions occurred [27].

Figure 6. DSC pattern of (a) pure PSE and (b) PSE-DPI

The present study successfully formulated and evaluated pseudoephedrine dry powder inhalers (PSE-DPI) using the anti-solvent precipitation method. The prepared inhalable powders exhibited favorable aerodynamic properties and desirable physicochemical characteristics as confirmed by SEM, DSC, FTIR, and PXRD analyses. In vitro results demonstrated that PSE-DPI not only ensured efficient pulmonary delivery with strong deposition potential but also showed significant antioxidant activity with minimal cytotoxicity. These findings highlight the potential of PSE-DPI as a promising inhalation therapy for the management of acute lung injury (ALI) and related respiratory disorders, offering improved drug delivery and therapeutic outcomes. In conclusion, PSE-DPI prepared by the antisolvent method in this study meets the general quality requirements of dry powder inhalers, has excellent pulmonary safety, and is suitable for a pulmonary drug delivery system, which is a novel dosage form of PSE.

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