Spray Drying for Pharmaceutical Raw Materials: A Systematic Review on Enhancing Bioavailability and Stability

Introduction

The pharmaceutical and cosmetic industries acknowledge the significance of pharmaceutical raw materials and natural goods owing to their robust market demand, resource accessibility, and proven safety profiles. Pharmaceutical compounds frequently exhibit inadequate solubility and restricted bioavailability, whereas natural goods are susceptible to chemical and physical deterioration.^1,2 Improving solubility, bioavailability, and stability is crucial to avert degradation induced by pH, humidity, and light. Spray-drying encapsulation provides an efficient method that enhances solubility and bioavailability, while ensuring prolonged stability and product quality.^3,4

Spray drying is an economical method that generates homogeneous spherical powders while minimizing moisture content without sacrificing product quality. It provides adaptable, scalable, and entirely automated continuous processing, appropriate for both heat-stable and heat-sensitive chemicals.^3,5–9 Spray drying remains a pivotal technique for solid product development, processing solutions, suspensions, dispersions, or emulsions to produce powders or granules with generally low moisture content (<5%), hence improving storage stability.⁶ The qualities of a product, including moisture content, particle density, and size, are significantly influenced by the drying temperature and the choice of carrier.^10,11 Employing polymer-based encapsulation, spray drying generates micro-sized particles between 5 and 5000 µm by the interaction of the active core, polymeric wall material, and solvent, culminating in a cohesive film that stabilizes and safeguards the active chemical.⁶

Spray drying offers continuous operation, high throughput, narrow particle-size distributions,^12–14 spherical morphology, and tunability of the solid state (amorphization, porosity). Freeze and vacuum drying excel for labile biologics but face higher capital expenditure/operational expenditure, longer cycles, lower yields, and limited control over particle engineering for oral solids. Freeze drying poses difficulties in large-scale production owing to elevated equipment expenses, increased energy usage, and comparatively diminished yield.¹⁵ Despite its numerous benefits, spray-dried products encounter various challenges, such as potential thermal and oxidative stress, carrier incompatibility, and recrystallization risks, necessitating judicious solvent selection, precise control of inlet and outlet temperatures, adherence to feed solids and viscosity targets, and the use of stabilizing polymers and surfactants.¹⁵

The selection of carriers is essential, as polymers, surfactants, proteins, and polysaccharides influence the stability, solubility enhancement, and overall efficacy of spray-dried formulations.¹⁶ Maltodextrin, a biodegradable starch derivative with low viscosity, is extensively utilized in spray-drying microencapsulation due to its cost-effectiveness, neutral sensory characteristics, and robust oxidative protection.^17,18 Eudragit L100 offers pH-dependent dissolution and is recognized as a polymer for intestinal-targeted delivery and nanoparticulate systems.¹⁹ Soluplus, an amphiphilic graft copolymer, improves aqueous solubility by stabilizing poorly soluble pharmaceuticals inside molecularly distributed amorphous matrices.²⁰ CMC, an anionic cellulose derivative, enhances colloidal stability via hydrogen bonding and electrostatic interactions,²¹ serving as a thickening and film-forming agent.²² PVP K30 stabilizes amorphous pharmaceuticals by inhibiting aggregation and recrystallization, thus enhancing solubility and storage stability.²²

Regulatory frameworks additionally influence the advancement of spray-dried systems. Regulatory agencies generally accept spray-dried solid dispersion (SD), solid self-nanoemulsifying drug delivery systems (S-SNEDDS), and microencapsulation when manufacturers demonstrate sufficient control over polymorphism and amorphous content, residual solvent levels, and excipient safety including PVP, HPMC/HPMCAS, soluplus, maltodextrin, and protein-based carriers and provide dissolution and supersaturation data substantiated by relevant stability and bioperformance justifications.²³

This review primarily examines pharmaceutical active ingredients, with a secondary discussion of natural products like oils, peptides, and antioxidant compounds to demonstrate how spray-drying-based microencapsulation can resolve stability and solubility issues in complex bioactive materials. This systematic review is essential for elucidating the long-term effects, stability, and potential interactions of diverse carriers and formulation strategies in the development of pharmaceutical products utilizing solid dispersion, microencapsulation, and solid-SNEDDS, while also identifying research gaps that necessitate further exploration.

Methods

This study employs a systematic literature review design following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The identification strategy was conducted by formulating research questions using the PICO (Population, Intervention, Comparison, and Outcome) framework, which was then adapted into keywords for database searches. The literature search was limited by predefined inclusion and exclusion criteria. Data sources were PubMed and Scopus, using the keywords (“spray” AND “drying”) AND (“solid”), supplemented with Medical Subject Headings (MeSH) to ensure greater specificity.

The PICO framework included four key elements: Population (P): active pharmaceutical ingredients (API) and natural products in the pharmaceutical field; Intervention (I): the use of spray drying methods; Comparison (C): formulations processed with spray drying versus those without treatment; Outcome (O): improvement in bioavailability and stability.

The inclusion criteria for this review were as follows: (1) original research articles, (2) published between 2021 and 2025, (3) full-text accessible, (4) use of a spray dryer as the experimental instrument, (5) studies investigating API and/or natural products as the research objects, and (6) availability of data on bioavailability and/or stability outcomes, with comparative results between treated and untreated groups. Articles not meeting these criteria, including non-original articles and duplicates, were excluded.

Result

A total of 27 articles fulfilled the inclusion criteria based on the search conducted across the two selected databases. The preliminary search, employing the required keywords, produced 1,534 main articles. Out of them, 928 publications were evaluated based on titles and abstracts, while 657 were subjected to full-text analysis. Subsequent to this evaluation, 27 articles were deemed eligible for inclusion, with no exclusions during the eligibility phase. Nevertheless, 630 articles were excluded for not satisfying the inclusion criteria.

The 27 research analyzed reported outcomes regarding bioavailability and stability, contrasting treated samples with untreated controls. The methodological attributes of these studies are encapsulated in Table 1, and the article selection procedure is depicted in the PRISMA flow diagram Figure 1.

Table 1 Evaluation of Bioavailability and Stability Improvements Achieved via Spray Drying

Figure 1 PRISMA flow diagram of study selection.

Discussion

Spray drying converts liquid formulations into solid forms through rapid solvent removal⁵⁰ and is widely used in pharmaceuticals due to its suitability for heat-sensitive API, continuous operation, and consistent powder quality.⁵¹ Among the studies examined, 6 assessed stability, while 23 indicated enhancements in bioavailability across various pharmaceutical source materials and natural products. Multiple individual and composite carriers were employed, with solid dispersions becoming the predominant method for improving solubility and bioavailability. This method can produce micron-sized particles in a short processing time.^52,53 Prior to spray drying, the active pharmaceutical ingredient (API) and carrier are first dissolved in a single solvent or a mixture of solvents. The subsequent removal of the solvent during spray drying produces a finely dispersed molecular mixture of the drug and the carrier⁵⁴ and it illustrates that spray drying safeguards encapsulated substances against oxidation and breakdown, hence prolonging shelf life.⁶ It also improves bioavailability by augmenting solubility via amorphization and expanding the surface area of the encapsulated medication.^7–9 The components of a laboratory-scale spray dryer are depicted in Figure 2.

Figure 2 Laboratory spray dryer.

Solid Dispersion

Solid dispersions (SD) represent a potent formulation approach employed to enhance the solubility and bioavailability of poorly water-soluble pharmaceuticals. Solid dispersions entail the incorporation of the active pharmaceutical ingredient (API) into a solid matrix, often comprising a polymeric carrier, to improve the dissolving rate and stability of the medicine.⁵⁵ SDs are primarily classified into crystalline solid dispersions (CSD) and amorphous solid dispersions (ASD) according to polymer characteristics.⁵⁵

Amorphous solid dispersions (ASD) are extensively employed to enhance the dissolution rate of poorly soluble pharmaceuticals, given that the amorphous state possesses elevated free energy and facilitates more rapid dissolution.⁵⁵ Crystalline solid dispersion (CSD) often employ semi-crystalline polymers to inhibit drug nucleation and crystal growth and reduce drug crystalline size, increasing the drug dissolution rate.⁵⁶ Enteric Solid Dispersion (ESD) is a solid dispersion formulated to safeguard the medicine from the stomach’s acidic environment. This formulation employs polymers that breakdown at elevated pH values, typically in the small intestine, to liberate the medicine. ESD is particularly advantageous for medications that are unstable or cause gastric irritation.²⁴ Surface-Attached Solid Dispersion (SASD) entails the adsorption of the medication onto the surface of a carrier, usually a porous substance. This method is advantageous for pharmaceuticals that are challenging to distribute uniformly within a matrix. SASD facilitates the stabilization of the active ingredient on a carrier’s surface, thereby improving the drug’s solubility and bioavailability without requiring an amorphous matrix.²⁶ Ternary Solid Dispersion (TSD) comprises three components: the medication, a polymeric carrier, and an extra excipient, such as a surfactant or co-polymer. The incorporation of the third component further augments solubility and dissolution rate, typically by enhancing the drug’s wettability or augmenting the carrier’s ability to solvate the drug. The formulation of ternary drug solid dispersions by the amalgamation of polymers and surfactants has been documented to efficiently address challenges associated with insufficient drug solubility and poor resistance to recrystallization, while simultaneously facilitating a decrease in polymer concentration.^57,58

Spray drying enables rapid vitrification and high apparent solubility, but stability hinges on polymer choice and drug loading. More hydrophilic polymers (eg, PVP/PVPVA) often boost dissolution yet increase moisture uptake and recrystallization risk; enteric or amphiphilic polymers (eg, HPMCAS, eudragit types, soluplus) improve physical stability and supersaturation maintenance but may slow release or require higher polymer fractions. pH-modifiers and surfactants can accelerate dissolution but may lower glass transition temperatures (Tg), narrowing stability margins in humid/tropical climates.^59–63 Schematic representation of solid dispersion system by spray drying is illustrated in Figure 3.

Figure 3 Simplified scheme of solid dispersion systems, amorphous solid dispersion (a), crystalline solid dispersion (b), enteric solid dispersion (c), ternary dispersion (d), surface-attached solid dispersion (e).

The various types of solid dispersion systems used to enhance bioavailability and stability have been discussed in this literature review, the following are the components that utilize the solid dispersion system are:

Terbinafine

Terbinafine (TER), a BCS Class II compound characterized by low solubility, 21, exhibited an 11.7-fold enhancement in AUC_{5–120 minutes} (mg/mL) (3500 vs 300) when synthesized as an amorphous solid dispersion with Soluplus.^64,65 The carrier boosted solubility by generating tiny, high-surface-area particles, and stabilizing terbinafine inside an amorphous, evenly dispersed polymer matrix, leading to significantly enhanced bioavailability relative to the untreated medication.⁶⁶ Simplified schematic amorphous solid dispersion is illustrated in Figure 3a.

Rifaximin

Rifaximin, a BCS Class IV medication characterized by inadequate solubility and permeability, shown significant bioavailability improvement when synthesized as an amorphous solid dispersion with β-lactoglobulin.⁶⁷ The ASD elevated Cmax (g/mL) by roughly 11-, 10.9-, and 16.3-fold at pH levels of 1.2 (13.7 vs 151.3), 4.5 (24.0 vs 260.6), and 6.5 (30.3 vs 492.7), respectively, in comparison to untreated rifaximin. The enhancement stemmed from the protein carrier transforming rifaximin into a stable amorphous form and diminishing particle size, therefore augmenting surface area, solubility, and overall bioavailability.^68,69

Oxyberberine

Oxyberberine (OBB), a highly hydrophobic compound with extremely poor water solubility,⁷⁰ showed markedly improved absorption when formulated as an amorphous solid dispersion.⁷¹ Using HPMCAS as the stabilizing polymer,^72,73 the ASD achieved 9-fold increase (1.26 ± 0.13 vs 11.34 ± 1.12) in AUC₀–₂₄ (μg/mL.h) compared with untreated OBB. HPMCAS enhanced solubility by forming strong hydrophilic interactions with OBB,⁷⁰ reducing molecular mobility,⁷⁴ inhibiting recrystallization,⁷⁵ and maintaining supersaturation during dissolution,⁷⁶ thereby preserving the amorphous state and significantly improving bioavailability.⁷⁷

Quercetin

Quercetin, a BCS Class II compound with poor water solubility, demonstrated markedly improved bioavailability when formulated as a solid dispersion.^78,79 Using PEG 8000 as the carrier, the SD system produced a 20.7-fold increase in AUC_0-∞ (μg·mL⁻¹·h) (304.820 ± 61.094 vs 14.753 ± 4.199), 16.8-fold in AUC_0-24 (μg·mL⁻¹·h) (182.981 ± 13.770 vs 10.860 ± 1.351), and 10.8-fold in Cmax (μg·mL⁻¹) (22.203 ± 2.147 vs 2.048 ± 0.334) compared with untreated quercetin. These improvements were attributed to PEG 8000 reducing quercetin crystallinity and enhancing solubility, resulting in a substantial increase in oral bioavailability.⁸⁰ Simplified schematic crystalline solid dispersion is illustrated in Figure 3b.

Olaparib

Olaparib (OLA), a BCS Class IV anticancer drug with extremely poor aqueous solubility (~0.1 mg/mL),⁸¹ exhibits low oral absorption and requires high dosing.⁸² Formulating olaparib as a solid dispersion effectively improves its solubility and bioavailability by molecularly dispersing the drug within a polymer matrix.⁸³ Amorphous OLA SDs produced a 4-fold increase in AUC₀–₂₄ (ng.h/mL) (1551.47 ± 484.09 vs 370.11 ± 63.75) and 10.7-fold in Cmax (ng/mL) (2001.25 ± 734.43 vs (187.31 ± 82.55) compared with crystalline OLA, supported by SEM⁸⁴ and PXRD data confirming amorphization without recrystallization.⁸⁵ Polymers such as HPMC,⁸⁶ particularly HPMC P645 with strong hydrogen-bonding capacity and a high glass transition temperature,⁸⁷ were shown to stabilize the amorphous state⁸⁸ and significantly enhance oral absorption.^89,90

Bavdegalutamide

Bavdegalutamide (ARV-110) is a PROTAC that specifically targets cereblon-containing E3 ubiquitin ligases, resulting in polyubiquitination and subsequent proteasomal destruction of target proteins.^91,92 The inadequate water solubility of ARV-110 necessitates strategies to improve its bioavailability, with spray-drying solid dispersion utilizing polyvinyl alcohol (PVA) as a carrier polymer recognized as an efficacious approach. This method markedly enhanced solubility in phosphate buffer (pH 6.8), leading to fast drug release within 5 minutes and sustained dissolution for 120 minutes.⁹³ The spray dried dispersion enhanced solubility by 3.5-fold relative to the untreated group (Cmax 34.0 μg/mL against 9.7 μg/mL). The spray dried dispersion preserved a stable temperature of 5°C for four weeks and inhibited recrystallization, maintaining elevated-free drug concentrations compared to the crystalline form for up to 6 hours.⁹⁴

Ezetimibe

Solid dispersion (SD) methodologies have been utilized for ezetimibe (EZT),⁹⁵ Notwithstanding the presence of ionizable groups, its solubility remains unaltered by conventional stomach pH levels.⁹⁶ EZT categorizes as a BCS Class II compound. The issue of low solubility was mitigated by employing poly(vinylpyrrolidone-co-vinyl acetate) (PVP/VA) as a carrier in a spray-dried solid dispersion, leading to a substantial enhancement in solubility (3.5-fold) from 27.2 ± 3.5% in crystalline form to 95% in the dispersion. PVP/VA stabilizes the amorphous form of EZT by diminishing molecular mobility, hence inhibiting crystal formation and preserving the amorphous state over time.^97,98 Even minimal quantities of polymeric crystallization inhibitors, such as PVP/VA, can efficiently stabilize amorphous active pharmaceutical ingredients like felodipine and carbamazepine due to robust intermolecular interactions.^99–101

Coenzyme Q10

Coenzyme Q10 (CoQ10), a lipophilic benzoquinone categorized as a BCS Class II compound, exhibits increased solubility through solid dispersion (SD) systems.¹⁰² Lamichhane et al demonstrated that amorphous CoQ10, utilizing Soluplus as a carrier, exhibited 6.1-fold increase in Cmax (μg/mL) (2.276 ± 0.014 vs 0.374 ± 0.094) and 7.4-fold in AUC₀–₂₄ (μg·h/mL) (19.763 ± 0.005 vs 2.656 ± 0.005), in contrast to crystalline CoQ10.^29,103 These findings underscore the substantial improvement in solubility attributed to soluplus, which inhibits recrystallization and preserves CoQ10 in its amorphous state. Elevated soluplus concentration enhances wettability and diminishes crystallinity, hence augmenting solubility.¹⁰⁴ Soluplus can also self-assemble into micelles, hence improving solubility beyond its critical micelle concentration.^29,103

Stiripentol

Stiripentol (STP) serves as an adjuvant therapy for Dravet syndrome, functioning as an antiepileptic by augmenting the action of the GABA neurotransmitter.^105,106 STP exhibits low water solubility (0.405 mg/mL) yet possesses strong permeability (log P = 3.01), with its absorption rate constrained by inadequate degradation in the intestines.¹⁰⁷ The amorphous variant of STP combined with eudragit L 100 improved drug release in SIF, exhibited delayedvrelease properties, and boosted bioavailability, as indicated 1.4-fold increase in AUC₀–_t (29.99 ± 3.35 vs 21.62 ± 4.32).²⁴ This illustrates that STP in amorphous or solid dispersion form augments resistance to acid hydrolysis and boosts chemical stability after 24 hour (83.06% vs 59.92%).¹⁰⁷ Simplified schematic enteric solid dispersion is illustrated in Figure 3c.

Resveratrol

Resveratrol (RES), a natural antioxidant present in fruits and nuts is classified as a BDDCS class II compound characterized by inadequate oral bioavailability (F < 2.6%)^108,109 and low solubility (20–30 μg/mL).¹¹⁰ To enhance its bioavailability, solid dispersion (SD) approaches utilize polymers such as PVPVA and Soluplus, which establish robust hydrogen bonds with RES. The amphiphilic characteristics of cremophor EL (EL) and labrasol (Lab) improve wettability and solubility.¹¹¹ RES formulations using soluplus-EL (3232.49 ± 680.88) increase 3.5-fold and PVPVA-Lab (3275.26 ± 923.46) increase 3.6-fold exhibited markedly superior dissolving profiles, with AUC_0–∞ (ng/mL.h) values exceeding thrice those of untreated RES (920.00 ± 229.24), signifying better solubility and bioavailability.⁶¹

Trans-Resveratrol

Trans-resveratrol (TRES) is biological form resveratrol often used in dietary supplements and classified as a BDDCS class II.^112,113 The limited water solubility of TRES (<60 μg/mL) restricts its oral absorption.¹¹⁰ Prior methods to augment absorption concentrated on the utilization of surfactants, hence enhancing bioavailability relative to pure TRES.^114,115 Solid dispersion systems, especially those employing neutralized eudragit E/HCl, have demonstrated enhanced TRES solubility and oral bioavailability.¹¹⁶ Eudragit E, which solubilizes under both acidic and gut pH conditions, stabilizes TRES in its amorphous state, inhibiting crystallization.¹¹⁷ Spray-dried amorphous TRES combined with Eudragit E markedly elevated AUC_{0–8 h} (ng.h/mL) values increase 4.2-fold (583.9 ± 92.1) compared for untreated TRES (138.9 ± 22.0), also in Cmax (ng/mL) increase 5.5-fold (204.4 ± 25.5 vs 37.0 ± 7.7) hence affirming improved solubility and bioavailability.¹¹⁸

Lacidipine

Lacidipine (LCDP) is a BCS Class II chemical characterized by restricted water solubility.¹¹⁹ Solid dispersion (SD) approaches have been employed to augment solubility, using Gelucire, a surfactant, facilitating solubility in aqueous conditions.¹²⁰ Gelucire enhanced solid-state medicine concentration when utilized in conjunction with spray drying.¹²¹ The amalgamation of diminished particle size, augmented surface area, and Gelucire’s hydrophilic characteristics improved hygroscopicity while concurrently diminishing drug-loading efficiency upon extended exposure to humidity. Following 10 days of exposure to extreme temperatures, LCDP amorphous properties and polymer linkages preserved robust dispersion, enhancing supersaturation stability and dissolution. The AUC_0-∞ (h.μg/mL) values for LCDP SD were markedly elevated 3.6-fold compared to untreated LCDP (5.41 ± 1.81 vs 1.51 ± 0.92), also in Cmax (μg/mL) increase 1.6-fold (0.85 ± 0.30 vs 0.52 ± 0.25).¹²¹ Simplified schematic ternary solid dispersion is illustrated in Figure 3d.

Methotrexate

Methotrexate (MTX) is a powerful chemotherapeutic agent characterized by low water solubility (0.01 mg/mL at 20°C) and restricted permeability, categorizing it as a BCS class IV medication.¹²² MTX also unstable degrading in the presence of light, elevated pH, and high temperatures. This complicates the formulation of efficient oral formulations.^123,124 The limited solubility of BCS class II and IV medications results in sluggish dissolution, inadequate gastrointestinal absorption, and diminished oral bioavailability, hence impacting therapeutic efficacy.⁶⁰ To mitigate MTX’s inadequate photostability, a surface-attached solid dispersion (SASD) approach that preserves crystallinity was employed to improve its solubility, bioavailability, and photostability.¹²⁵ Sodium carboxymethyl cellulose (Na-CMC) and sodium lauryl sulfate (SLS) enhanced solubility, yielding a 2.8-fold rise in AUC relative to untreated MTX (4890.45 ± 1447.53 vs 1738.71 ± 294.65). The improved solubility is ascribed to the hydrophilic carriers promoting accelerated water absorption and medication release. The MTX in the SASD formulation exhibited negligible degradation (about 5%) under UV radiation, whereas 65% of the pure medication degraded, demonstrating improved photostability. SASD enhances MTX’s solubility, dissolution, bioavailability, and photostability while preserving its crystallinity.¹²⁶ Simplified schematic surface-attached solid dispersion is illustrated in Figure 3e.

Apremilast

Apremilast (APST) is classified as a BCS class IV medication, characterized by low solubility, dissolution rate, and bioavailability (20–33%), which constrains its therapeutic effectiveness.^127,128 D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and poly(1-vinylpyrrolidone-co-vinyl acetate) (PVPVA) were employed to improve solubility and bioavailability. TPGS, a P-glycoprotein (P-gp) inhibitor, enhances intestinal absorption and intracellular accumulation, whereas PVPVA facilitates molecular dispersion.^129,130 TPGS additionally generates micelles that solubilize hydrophobic pharmaceuticals and lowers interfacial tension.¹³¹ The hydrogen connection between carriers and APST inhibits recrystallization.¹³² The AUC (h.ng/mL) for the solid dispersion is approximately 12.9-fold greater than that of crystalline APST (65.50 ± 5 vs 5.09 ± 5.2), also the Cmax (ng/mL) increase 22-fold (47.50 ± 29 vs 2.16 ± 1.5), signifying improved absorption and bioavailability attributable to the effects of TPGS and PVPVA on intestinal permeability.^126,133

Candesartan Cilexetil

Candesartan cilexetil (CC) is an effective antihypertensive prodrug with low solubility (BCS class II) and limited absorption.⁷⁶ To enhance its bioavailability, an amorphous solid dispersion (ASD) was formulated using a hydrophilic carrier, PVP K30, and a pH modulator, sodium carbonate, produced by spray drying.¹³⁴ The PVP K30 carrier improves water solubility and aids in water absorption, while spray drying reduces particle size and stabilizes the amorphous form of CC. This method enhances solubility and dissolution. Additionally, the incorporation of sodium caseinate further improves solubility and dissolution across physiological pH ranges. The AUC of the ASD formulation increased nearly 12-fold compared to untreated CC, demonstrating a significant improvement in bioavailability, increase 4.5-fold AUC (h.ng/mL) (65.50 ± 5 vs 5.09 ± 5.2).¹³⁵

Gefitinib

Gefitinib (ZD), a weak base with pKa values of 5.4 and 7.2, is insoluble in water and categorized as a BCS class II medication, signifying low solubility and high permeability. Polyvinylpyrrolidone (PVP) were employed as carriers in spray-dried solid dispersions to improve solubility.^136,137 PVP boost the solubility and dissolution rate of ZD, also Eudragit S100 serves as a pH-sensitive polymer for the colon-targeted delivery of Gefitinib (ZD).¹³⁸ At a low pH, untreated ZD exhibits high solubility, with 94% dissolving within 30 minutes at pH 1.2. Nonetheless, solid dispersions containing PVP exhibited merely 16% and 15.5% release at pH 1.2 after a duration of 3 hours.^139,140 At pH 7.2, the drug release from PVP dispersions was approximately 3.4-fold more than that of untreated ZD, respectively (96.7% vs 28.7%).¹⁴¹

Griseofulvin

Griseofulvin is an antifungal medication with poor water solubility (BCS class II) but good permeability.¹³⁷ To enhance its solubility, two main methods are employed: reducing particle size to increase surface area and amorphizing the drug to achieve supersaturation.^142,143 Particle size reduction accelerates dissolution but is less effective for achieving supersaturation, which is crucial for drugs with solubility below 50 mg/mL. Neusilin, a high-performance stabilizer and flow enhancer, was used as a carrier with high porosity and adsorption capacity,^144,145 prevents recrystallization of amorphous drugs,¹⁴⁶ such as acid–base interactions and hydrogen bonding.¹⁴⁷ In formulations with Neusilin, the concentration of griseofulvin increased by 3.7-fold after 30 minutes (36 vs 10 (mg/L)), demonstrating enhanced solubility, sustained supersaturation, and improved drug release.¹⁴⁸

Solid Self Nanoemulsifying Drug Delivery System

Solid self-nanoemulsifying drug delivery system (SNEDDS) is a system designed to enhance the solubility and bioavailability of poorly water-soluble pharmaceuticals. The process entails developing a robust formulation comprising lipophilic medicines, surfactants, and other excipients that, upon interaction with gastrointestinal fluids, generate a nanoemulsion. This nanoemulsion improves the solubility and bioavailability of the medicine in the body. Solid SNEDDS offer the advantages of a nanoemulsion technology while ensuring stability and facilitating handling typical of solid forms.¹⁴⁹

This technique is particularly advantageous for lipophilic pharmaceuticals, necessitating emulsification to improve absorption. Additionally, solid SNEDDS can be effortlessly produced through techniques such as spray drying or hot-melt extrusion, guaranteeing a stable formulation that enhances drug bioavailability. Spray drying converts liquid SNEDDS into free-flowing powders using carriers such as silica (eg, aerosil), PVP, or cyclodextrins. Advantages include rapid dispersion, high apparent solubility, and improved handling. Limitations include payload caps set by carrier porosity/affinity, susceptibility to lipid oxidation, and humidity-driven phase changes. Carrier selection mediates a trade-off between flowability, redispersibility, and long-term physical stability.^27,38,39 Schematic representation of solid nanoemulsifying drug delivery system by spray drying is illustrated in Figure 4.

Figure 4 Simplified scheme of solid self nanoemulsifying drug delivery system (S-SNEDDS).

The components utilizing the S-SNEDDS system are as follows are:

Aceclofenac

Aceclofenac, characterized by low water solubility, exhibits diminished oral bioavailability, hence constraining its therapeutic effectiveness.¹⁵⁰ Solid self nanoemulsifying drug delivery system (SNEDDS) utilizing appropriate carriers, such as sodium carboxymethylcellulose (Na-CMC), effectively enhance solubility and bioavailability.¹⁵¹ Na-CMC, a cellulose derivative characterized by its hydrophilic, nontoxic, biocompatible, and biodegradable attributes,¹⁵² has been utilized in numerous therapeutic applications.¹⁵³ This study utilized Na-CMC as a carrier to formulate a solid SNEDDS, leading to 2.9-fold augmentation in AUC (h·μg/mL) (12.92 ± 2.88 vs 4.46 ± 0.45), also leading to 3.9-fold in Cmax (μg/mL) (5.81 ± 0.82 vs 1.49 ± 0.49) relative to the untreated group,¹⁵⁴ hence improving the bioavailability of aceclofenac.¹⁵⁵

Olaparib

Olaparib (OLA) is classified as a BCS class IV medication, characterized by low water solubility, which leads to inadequate oral absorption and bioavailability.⁸⁶ To resolve this, solid self-nanoemulsifying drug delivery systems (S-SNEDDS) are employed, which generate nanoemulsions upon interaction with physiological fluids without requiring external energy.⁸⁷ Aerosil 200, characterized by its extensive surface area, functions as an adsorbent, whilst polyvinylpyrrolidone K30 (PVP K30) works as a precipitation inhibitor, improving solubility in gastrointestinal fluids.^156,157 Converting OLA from a crystalline to an amorphous state enhances its solubility and dissolution rates.¹⁵⁸ In the S-SNEDDS matrix, OLA is solubilized, enhancing the available surface area and dissolution rate.¹⁵⁹ This led to substantial dissolution profile until 120 minute increases 5.2-fold at pH 1.2 (89.9 ± 3.1% vs 17.2 ± 3.9%) and 3.7-fold at pH 6.8 (89.7 ± 0.4% vs 24.3 ± 3.7%) relative to untreated OLA, indicating improved bioavailability and consistent drug release despite variations in pH.²⁷

Sorafenib

Sorafenib, a medication with low solubility, rapid hepatic metabolism, and P-glycoprotein substrate action, exhibits reduced oral bioavailability.¹⁶⁰ Comparable to olaparib, its solubility can be markedly improved through the utilization of solid self-nanoemulsifying drug delivery systems (S-SNEDDS).¹⁶¹ Aerosil 200 functions as the solid carrier, whereas PVP K30 operates as a precipitation inhibitor in this formulation. Aerosil 200 offers an extensive surface area for adsorption, whereas PVP K30 enhances solubility in gastrointestinal fluids. Collectively, these elements inhibit recrystallization and markedly enhance the solubility of sorafenib. The AUC (h.µg/mL) value of sorafenib in S-SNEDDS was 4.6-fold greater than free sorafenib (136.1 ± 25.9 vs 29.8 ± 1.8), underscoring the enhancement in bioavailability attributed to improved dissolution and drug absorption.⁹

Enzalutamide

Enzalutamide (ENZ), an androgen receptor signaling inhibitor employed in prostate cancer therapy, exhibits low aqueous solubility (BCS class II) attributable to its lipophilic characteristics.¹⁶² Amorphous solid dispersions enhance solubility and mitigate recrystallization in supersaturated conditions.⁷² Kollidon VA64 served as a recrystallization inhibitor, and the drug release from S-SNEDDS was affected by its concentration. The improved oral bioavailability of ENZ in S-SNEDDS is due to the spontaneous generation of nanoemulsions in the gastrointestinal system and the polymer’s capacity to preserve ENZ in an amorphous, supersaturated condition. This dual process enhances solubility and prolongs supersaturation, leading increase 7.3-fold at AUC_0-72 (μg.h/mL) (274.4 ± 47.6 vs 37.5 ± 6.4) and 6.4-fold at Cmax (μg/mL) (8.9 ± 2.0 vs 1.4 ± 0.8) in bioavailability relative to untreated ENZ.⁹⁴

Niclosamide

Niclosamide, a crystalline compound with limited solubility in water, however, soluble in ethanol, chloroform, and ether, has garnered interest for its potential repurposing in the treatment of Parkinson’s disease, diabetes, and cancer.¹⁶³ Calcium silicate was employed as a porous polymeric carrier to enhance the solubility and stability of liquid SNEDDS by transforming it into a solid state.¹⁶⁴ Sodium alginate (Na-alginate) and poloxamer 407 were utilized to solubilize niclosamide.¹⁶⁵ Solid SNEDDS formulations markedly improved solubility by 158-fold relative to the pure medication (0.8 ± 0.3 vs 127.0 ± 18.4 μg/mL). These formulations enhanced solubility, dissolution rates, and plasma concentrations in rats, with AUC (h.μg/ mL) and Cmax (μg/mL) values increasing by 9.9-fold (7.37 ± 1.84 vs 0.75 ± 0.23) and 18.7-fold (1.68 ± 0.86 vs 0.09 ± 0.04), respectively, compared to untreated niclosamide, signifying a significant enhancement in bioavailability.¹⁶⁵

Dexibuprofen

Dexibuprofen, the S-isomer of ibuprofen, is categorized as a BCS class II medication, characterized by low water solubility and high permeability.¹⁶⁶ This attribute impacts absorption and may affect bioavailability.¹⁶⁷ Hydroxypropyl-β-cyclodextrin (HP-β-CD) is hydrophilic, biocompatible, and frequently employed to solubilize poorly water-soluble pharmaceuticals owing to its truncated cone-shaped architecture, characterized by a hydrophobic cavity and a hydrophilic exterior.¹⁶⁸ The integration of HP-β-CD into solid SNEDDS significantly improved the solubility, dissolving, and oral bioavailability of dexibuprofen, thereby hastening its therapeutic start. AUC (h.μg/mL) and Cmax (μg/mL) increase 1.9-fold (48.15 ± 7.42 vs 24.81 ± 5.06) and 5.8-fold (51.00 ± 8.82 vs 8.85 ± 1.36) respectively, in comparison to untreated dexibuprofen.^169,170

Microencapsulation

Microencapsulation entails encasing a medication or active chemical within a protective shell, typically composed of polymers or other materials. This method regulates medication release, safeguards it from environmental influences (including oxygen, light, and heat), and enhances the stability of the active component. The shell or matrix can facilitate sustained, delayed, or targeted drug release, contingent upon the microcapsule’s architecture.¹⁷¹

Microencapsulation extends beyond enhancing solubility; it also serves to safeguard delicate substances (eg, vitamins, probiotics, tastes) and to guarantee the targeted or sustained release of the active ingredient. In contrast to Solid SNEDDS, which generates a nanoemulsion within the gastrointestinal tract, microencapsulation facilitates regulated release without the requirement of an emulsion system. Spray drying provides oxidation and light protection with carbohydrate/gum walls (eg, maltodextrin, gum arabic, WPI). It is typically superior to bulk evaporation for controlling droplet size and drying history, but may be inferior to FD when maximal bioactivity retention is paramount or when wall materials are highly hygroscopic, reducing shelf-life under high RH.¹⁷² Schematic representation of microencapsulation system by spray drying is illustrated in Figure 5.

Figure 5 Simplified scheme of microencapsulation system.

The following are the components that utilize the microencapsulation system are:

Pepper Seed Oil

Pepper seed oil (PSO), abundant in unsaturated fatty acids, is susceptible to oxidative deterioration, compromising its nutritional value and sensory attributes.¹⁷³ It encounters difficulties in achieving uniform distribution within water-based food matrices and experiences oxidation during thermal processing. The microencapsulation of PSO safeguards it against oxidative degradation and enhances the delivery of bioactive components.⁶³ This procedure entails emulsifying the oil with coating agents such as polymers and subsequently drying the emulsion.¹⁷⁴ Oxidative stability assessments revealed that free PSO exhibited a substantial rise in peroxide value (18 meq/kg) after four days at 60°C, but encapsulated PSO with gum arabic (GA) and maltodextrin (MD) displayed a considerably lower peroxide value (6 meq/kg), indicating enhanced stability. MD, obtained from maize starch, and GA, a prevalent coating agent,¹⁷⁵ improved the oxidative stability and shelf life of PSO by creating robust microcapsules with superior emulsifying characteristics.¹⁷⁶

Pea Peptides

Pea peptides (PP), originating from peas, are water-soluble chains comprising 22 amino acids that possess antioxidant and anti-inflammatory effects; nevertheless,¹⁷⁷ they are susceptible to oxidation and hydrolysis.¹⁷⁸ Maltodextrin (MD) aids in stabilizing peptides and concealing bitterness, however it may independently induce microcapsule rupture.¹⁷⁹ Gum tragacanth (GT), a natural and biodegradable hydrocolloid, improves thermal stability and antioxidant activity, positioning it as a viable alternative to conventional carriers such as gum arabic (GA). The encapsulation of PP with MD and GT produced stable peptides that exhibited 25.2-fold enhancement in superoxide (25.2% vs 0%), 1.5-fold in hydroxyl (70.2% vs 47%) and ABTS (40.3% vs 24.46%) radical scavenging ability at 40°C on day 60, relative to untreated PP. This improvement is likely attributable to augmented surface area contact, rendering the peptides more vulnerable to breakdown under specific environmental circumstances. The stability of peptides is influenced by variables such as temperature, pH, and salinity, with certain amino acids, like threonine, serine, and cysteine, exhibiting notable instability in alkaline environments.¹⁸⁰

Prickly Ash Peel Oleoresin (PPO)

Prickly ash peel oleoresin (PPO) is a concentrated essential oil derived from Sichuan pepper, characterized by its potent aroma, yet exhibiting low water solubility and high volatility, hence complicating its transit, storage, and stability.¹⁸¹ PPO was encapsulated via spray-drying utilizing soy protein isolate (SPI) or gum arabic (GA) in conjunction with maltodextrin (MD) to resolve these difficulties.^182,183 Maltodextrin and GA serve as efficient encapsulating agents owing to their emulsifying and film-forming properties, enhancing PPO’s stability by mitigating exposure to light, heat, and oxygen.¹⁸⁴ Encapsulation improved PPO’s antioxidant efficacy by preserving flavor ingredients and safeguarding active oil constituents. The antioxidant activity, assessed through DPPH scavenging, hydroxyl radical scavenging, and lipid peroxidation inhibition, shown notable enhancements in encapsulated PPO, with increases of ± 20% (± 60% vs ± 40%) in DPPH scavenging, ± 20% (± 60% vs ± 40%) in hydroxyl radical scavenging, and ± 10% (± 60% vs ± 50%) in lipid peroxidation relative to free PPO.¹⁸⁵

Pomegranate Seed Oil (PGSO)

Pomegranate seed oil (PGSO), abundant in polyunsaturated fatty acids such as punicic acid (65–80%), and bioactive constituents including phenols, flavonoids, ellagitannins, and anthocyanidins, provides numerous health advantages, encompassing diminished diabetes risk, reduced blood pressure, obesity control, and skin improvement.^186,187 Nonetheless, PGSO is particularly vulnerable to oxidative deterioration caused by heat, light, oxygen, and humidity. To address this, carbohydrates such as maltodextrin (MD) and proteins like whey protein (WP) are employed as encapsulating agents.¹⁸⁸ Encapsulation using WP and MD markedly decreased peroxide concentrations, postponing oxidation. The maximum encapsulation efficiency (90%) was attained using 25% whey protein and 10% maltodextrin at a drying temperature of 150°C. This combination enhanced storage stability and safeguarded active components, but lipid oxidation was more evident in particles with diminished encapsulation efficiency, as indicated by the value of peroxide (meqO₂/kg) decrease 1.2-fold (12.5 vs 14.8), p-Anisidine (meqO₂/kg) decrease 1.1-fold (21.9 vs 24.6), and totox (meqO₂/kg) decrease 1.1-fold (34.4 vs 39.4) compare to free PSO during a 15-day period.¹⁸⁹

Scale-up of Spray Drying Processes

Scale up Consideration

When transitioning from pilot to industrial scale, it is essential to ensure consistency in fluid dynamics and processing parameters.¹⁹⁰ The subsequent measures can facilitate effective scale-up while regulating viscosity:

Maintaining Fluid Dynamics

Fluid dynamic parameters, including feed flow rate and retentate pressure, must be evaluated and optimized according to the operational scale. Sustaining uniform fluid dynamics across scales is crucial for reliable scale-up. The selection of geometry, including channel length and height, influences fluid dynamics and must be considered in the scaling process.¹⁹¹

Model-Based Methodologies

Employing model-based methodologies facilitates the incorporation of predictive analysis into the scaling procedure. Models may replicate the behavior of droplet formation and drying kinetics across different scales, offering insights into how variations in viscosity and other parameters may influence the final result. The approach delineates a methodology for the effective development of the spray drying process, including essential engineering models.^192,193

Use of Advanced Measurement Techniques

Utilizing inline process analytical technologies to monitor viscosity and other essential parameters in real time enables prompt modifications during the spray drying process, hence ensuring product quality and uniformity. Acoustic flowmeters have been employed to detect viscosity with precision, facilitating enhanced regulation of the spray drying environment.^194,195

Understanding and Managing Viscosity

Dilution of Feed Solutions

Decreasing the concentration of the feed solution can effectively reduce viscosity. This method requires careful calibration, as excessive dilution may result in inadequate solid content in the final product. For products where viscosity is a concern, it is essential to maintain an ideal solid content to achieve a high-quality spray-dried powder.^196,197

Use of Surfactants or Viscosity Modifiers

The inclusion of surfactants might diminish the effective viscosity of the feed solution, facilitating improved atomization during the spray drying process. The incorporation of hydroxypropyl cellulose (HPC) or polyvinyl alcohol (PVA) has demonstrated favorable outcomes in reducing viscosity problems while preserving the efficacy of the active ingredient.¹⁹⁸

Temperature Control

Elevating the feed temperature helps reduce viscosity, as temperature significantly influences the rheological characteristics of polymeric solutions. Modifying the temperature of the feed solution before atomization enhances flow properties, resulting in more uniform droplet production.¹⁹⁹

Practical Examples and Considerations

Air Temperature

The operating air temperature influences viscosity and evaporation rates. Modifications in air temperature can regulate the drying rate and influence particle shape. Elevated temperatures may decrease drying durations but could also result in the heat destruction of sensitive substances.²⁰⁰

Feed Flow Rate

The velocity of the feed entering the dryer affects droplet size and dispersion. An ideal flow rate guarantees consistent droplet generation while reducing viscosity-related issues.²⁰¹

Atomization Technique

Selecting the appropriate atomization technology such as rotary atomizers or nozzle atomizers can profoundly influence the management of feed viscosity. Rotary atomizers are more appropriate for high-viscosity feed solutions compared to nozzle atomizers.²⁰²

Comparative Analysis and Future^188,189

Comparative Analysis

Spray drying (SDG) is a versatile platform for engineering solid dispersion (ASD), solid SNEDDS (S-SNEDDS), and microencapsulation systems, with clear contexts where it is either advantageous or suboptimal. Versus hot melt extrusion (HME), SDG operates at lower thermal loads and accommodates thermolabile APIs and solvent-processable excipients, enables fine control of particle size/morphology, and readily scales from lab to commercial spray dryers. However, HME often achieves higher drug–polymer intimacy and robust amorphization without residual solvents; SDG can be inferior when feed solubility is limited, solvent handling is constrained, or long-term amorphous stability is marginal.^203–205

Compared with freeze-drying (FD), SDG offers far greater throughput and tighter particle engineering but may yield lower encapsulation efficiency for highly volatile oils and can be more sensitive to feed composition and atomization conditions; FD can outperform SDG for extremely labile bioconstituents where sublimation preserves structure. Relative to solvent evaporation/co-precipitation in bulk, SDG provides superior control over drying kinetics and particle attributes, yet may suffer from nozzle fouling, cyclone losses (lower yield), and the need for flammable-solvent controls.^203–205

Future Perspectives

Nano Spray Drying

Nanotechnology, specifically nano spray drying, has enhanced drug delivery methods by generating nanoparticles with superior attributes, including narrow size distributions, suitable for intricate drug compositions. A primary advantage of nano spray drying is its capacity to encapsulate active compounds within polymeric matrix, safeguarding delicate molecules and facilitating targeted distribution. This method transforms liquid feedstocks into dry powders, which is especially advantageous for safeguarding compositions from deterioration. Recent research have investigated nanoparticle synthesis for catalytic applications, highlighting the importance of precise control over particle morphology and dimensions.¹¹⁷

Nano spray drying has been utilized to produce sophisticated materials such as hierarchical zeolite microspheres to improve catalysis. Nano spray drying technology has potential for enhancing sophisticated medicine formulations and material production, hence improving therapy alternatives. Submicron particles with smaller size distributions improve solubility and absorption, especially for poorly soluble active pharmaceutical ingredients; yet, issues related to throughput, yield, and agglomeration control persist.^6,206

Greener Processes

The incorporation of green solvents in the development of solid dispersions, self-nanoemulsifying drug delivery systems (SNEDDS), and microencapsulation through spray drying markedly improves the sustainability and safety of pharmaceutical manufacturing. These environmentally sustainable solvents diminish ecological impact while enhancing the effectiveness of medicine delivery systems. The selection of solvent influences polymer conformation and drug interactions, hence affecting the dissolution rate and bioavailability of the active pharmaceutical ingredient (API). Ethanol mixed with water serves as a sustainable substitute for conventional organic solvents, enhancing the encapsulation efficiency and mechanical characteristics of solid dispersions. SNEDDS formulated with eco-friendly solvents exhibit comparable or superior drug content and release properties relative to liquid counterparts, hence improving the stability and bioavailability of lipophilic pharmaceuticals.^207,208

The incorporation of non-toxic carriers and environmentally friendly solvents enhances the efficacy and safety of SNEDDS, rendering them more appropriate for medicinal applications. Furthermore, in microencapsulation, eco-friendly solvents can safeguard sensitive active pharmaceutical ingredients (APIs) and enhance their release characteristics, thereby mitigating the health hazards linked to hazardous solvents. The integration of green solvents in pharmaceutical formulations signifies a shift towards enhanced sustainability, in accordance with advancing regulatory criteria. Investigations in this domain are crucial for the progression of sustainable drug delivery methods, augmenting bioavailability, and bolstering patient safety.^209–211

Process Analytical Technology (PAT) and Quality by Design (QbD)

Process Analytical Technology (PAT) offers real-time insights into production through the monitoring of critical quality attributes (CQAs) and critical process parameters (CPPs). Established by the FDA in 2004, PAT improves comprehension of production processes, facilitating continuous monitoring and control, which is essential in spray drying where factors like as temperature, pressure, and feed composition influence product quality.^23,212,213

Quality by Design (QbD) enhances Process Analytical Technology (PAT) by establishing processes with predetermined quality objectives, emphasizing the correlation between product characteristics and process factors to mitigate risks. In spray drying, Quality by Design (QbD) necessitates meticulous selection of excipients, comprehension of their interactions with active pharmaceutical ingredients (APIs), and optimization of process parameters for stability and efficacy. While PAT and QbD provide substantial advantages, like enhanced product uniformity and expedited regulatory approval, they also pose problems, notably the intricacy of real-time monitoring systems. Upon implementation, these technologies enhance manufacturing reliability and product quality, exemplified by the utilization of online mass spectrometry to forecast endpoint clarity, illustrating how real-time data may inform process decisions and optimize production workflows.^23,212–215

Current Controversies and Divergent Findings

The literature has a continuous discourse on many parameters influencing the generation and efficacy of amorphous solid dispersions (ASDs). These encompass: (i) the permissible degree of residual crystallinity prior to performance deterioration, (ii) the comparative efficacy of hydrophilic versus enteric polymers in sustaining supersaturation in biorelevant media, (iii) the influence of surfactants that enhance wetting yet may also plasticize the matrix, (iv) the stability implications of pH modifiers, and (v) the interplay between processing temperature and humidity with composition on stability outcomes. Discrepancies in findings frequently stem from variations in drug load, polymer ratio, media, and storage conditions; clearly addressing these variables may facilitate the reconciliation of divergent study conclusions. The selection of solvents for spray drying is a critical factor that influences the stability and bioavailability of ASDs. Some research indicates that organic solvents improve drug–polymer interactions and solubility, while other studies express concerns regarding the long-term stability of ASDs created using this method. Research indicates that spray drying with specific solvents can enhance immediate bioavailability, although it may jeopardize long-term stability due to the influence of evaporation kinetics on the physical stability of dispersions.^216–218

The comparative effectiveness of spray drying and hot-melt extrusion (HME) is also contested. Spray drying is esteemed for its simplicity and scalability, whereas hot melt extrusion (HME) provides superior control over process parameters and stability for specific formulations. This indicates that integrating these strategies may enhance performance optimization. The selection of excipients profoundly influences ASD formulation. Hydroxypropyl methylcellulose acetate succinate (HPMCAS) enhances solubility; yet, altering its concentrations and formulations poses difficulties. Research demonstrates that a comprehensive understanding of drug–excipient interactions is crucial for optimizing formulations, necessitating customized techniques for particular formulation requirements.^216–218

Safety, Toxicity, and Regulatory Considerations

Current regulatory frameworks from entities such as the FDA, EMA, and WHO underscore the necessity of diminishing dependence on conventional organic solvents due to their significant toxicity and environmental risks. Concerns about the safety and toxicological characteristics of solvents necessitate that producers adopt alternatives that adhere to changing regulatory standards. Regulatory trends in spray drying, especially with green solvents and safety considerations, indicate a notable transition towards enhancing sustainability and safety in pharmaceutical manufacture.^23,219

Research indicates that employing less hazardous solvents in spray drying enhances the safety profiles of the produced items. The implementation of green solvents in spray drying processes is motivated by regulatory requirements and public desire for safer industrial methods. The concepts of green chemistry promote the utilization of solvents that provide less risks to human health and the environment. Conventional solvents present health and safety hazards owing to their toxicity and flammability, particularly in spray drying processes. Green solvents, such as ethanol and bio-based alternatives, exhibit lower toxicity and mitigate workplace health risks. Traditional solvents such as methanol and acetone frequently provide toxicity and flammability hazards. Utilizing water as a solvent reduces energy consumption and adheres to the principles of green chemistry. Water and ethanol are becoming acknowledged as more suitable options for the processing of medicinal compounds. Incorporating a minor proportion of water in spray drying enhances the solubility and microstructural properties of solid dispersions, concurrently reducing dependence on toxic solvents. Regulatory agencies require that items comply with defined safety and efficacy requirements. The use of nanoparticles in combination with spray-dried formulations presents considerable safety and toxicity concerns. Recent literature underscores the necessity of comprehensive toxicokinetic and risk assessment evaluations of nanomaterials to comply with safety recommendations for their handling and processing. Comprehending the mechanisms of spray drying that generate particle matter interacting with biological systems through suitable toxicity evaluations is essential.^{211,220–223}

In addition to the solvent, another safety consideration is the carrier employed such as the safety profile of soluplus as an excipient in pediatric pharmaceutical formulations has been assessed. Preclinical research indicated that soluplus is non-toxic in animal models and shows little systemic exposure. Clinical findings from research involving adult populations further corroborate its safety in pediatric patients. Soluplus has been determined to be safe for oral formulations designed for pediatric populations and is regarded as a dependable carrier in the creation of pediatric pharmaceutical dosage forms.⁶⁶ PEG 8000 is a hydrophilic, biocompatible, and non-toxic homopolymer extensively utilized in pharmaceutical applications and also has received FDA approval for anti-inflammatory and antifungal purposes.²²⁴

Additionally, the safety of the formulation system must be evaluated, specifically regarding its potential hazardous effects or its safety in vivo such as oxyberberine amorphous solid dispersion (OBB-ASD) exhibited hepatoprotective effects in a mouse model of acute liver injury (ALI) induced by LPS/D-GalN. The findings indicated that the OBB-ASD formulation enhanced liver function by diminishing liver damage indicators, such as AST and ALT levels, in comparison to untreated controls. Histopathological analysis indicated that OBB-ASDs markedly mitigated liver damage, including bleeding, necrosis, and inflammatory cell infiltration, thereby restoring the liver’s state to nearly normal levels. The protective benefits against oxidative stress and inflammatory reactions were ascribed to the regulation of the TLR4/NF-κB pathway.⁴³

Conclusion

Spray drying has become a multifaceted method for improving the solubility, bioavailability, and stability of poorly water-soluble medicines and natural bioactive chemicals via systems like solid dispersions, solid SNEDDS, and microencapsulation. The efficacy of these formulations relies on the compatibility between the medicine and carrier, the physicochemical qualities of excipients, and the processing parameters that determine the final solid state. This review illustrates that spray-dried systems consistently enhance solubility and absorption of several APIs, while significantly improving the stability of natural oils and peptides. Future research must emphasize comparative carrier evaluations and mechanistic investigations that connect drying kinetics to drug-excipient interactions, facilitating more predictable, scalable, and logical design of spray-dried pharmaceutical formulations.