Mechanical Properties and Tableting Behavior of Amorphous Solid Dispersions

Amorphous solid dispersions (ASDs) consisting of acetaminophen (APAP) and copovidone were systematically studied to identify effects of drug loading and moisture content on mechanical properties, thermal properties, and tableting behavior. ASDs containing APAP at different levels were prepared by film casting and characterized by differential scanning calorimetry and nanoindentation. The glass transition temperature (T_g) continuously decreased with increasing amount of APAP, but the hardness of ASDs was increased at a low APAP content and reduced at high APAP content. This in turn significantly influenced tablet quality. Water reduced both the hardness and T_g of ASDs, and the APAP loading level corresponding to the transition to the softening mechanism was lower at a higher relative humidity. Overall, the mechanical properties, rather than the thermal properties, better represent the plasticization/antiplasticization effect of small molecule to ASDs.     

Phase Behavior of Ritonavir Amorphous Solid Dispersions during Hydration and Dissolution

Pharmaceutical Research - The aim of this research was to study the interplay of solid and solution state phase transformations during the dissolution of ritonavir (RTV) amorphous solid dispersions...     

Correlating the Behavior of Polymers in Solution as Precipitation Inhibitor to its Amorphous Stabilization Ability in Solid Dispersions

Our major goals were to understand the mechanism of dipyridamole (DPD) precipitation inhibition in the presence of polymers and to correlate the polymers-mediated precipitation inhibition in solution to the amorphous stabilization in the solid state. A continuous UV spectrophotometer was used to monitor the DPD concentration with time in the absence and presence of different polymers. Six polymers: PVP K90, hydroxypropylmethylcellulose (HPMC), Eudragit E100, Eudragit S100, Eudragit L100, and PEG 8000 were screened at different drug-to-monomer ratios. Solid dispersions were characterized by X-ray powder diffraction and modulated differential scanning calorimetry, whereas infrared (IR) and Raman were used to investigate the possible drug-polymer interactions. Eudragit E100 and HPMC were found to delay both DPD precipitation initiation time and precipitation rates. Eudragit S100 delayed only the precipitation initiation time and PVP K90 decreased only the precipitation rates. In solid state, Eudragit S100, PVP K90, HPMC, and Eudragit L100 were effective stabilizers of the DPD solid dispersion. Eudragit S100 was found to be most effective DPD-stabilizing polymer. The IR and Raman spectra of the solid dispersion of Eudragit S100 and HPMC showed peak shift, indicating drug-polymer molecular interactions. It is concluded that the drug-polymer interaction plays a significant role in precipitation inhibition and amorphous stabilization.     

Molecular Dynamics Simulations of Selected Amorphous Stilbenoids and Their Amorphous Solid Dispersions with Poly(Vinylpyrrolidone)

Amorphous solid dispersions (ASDs) are one of the promising strategies to improve the solubility and dissolution rate of poorly soluble compounds. In this study, Molecular Dynamics simulations were used to investigate the interactions between three selected stilbenoids with important biological activity (resveratrol, pinostilbene and pterostilbene) and poly(vinylpyrrolidone). The analysis of the pair distribution functions and hydrogen bond distributions reveals a significant weakening of the hydrogen bond network of the stilbenoids in ASDs compared to the pure (no polymer) amorphous systems. This is accompanied by an increase in the mobility of the stilbenoid molecules in the ASDs, both in the translational dynamics determined from the molecular mean square displacements, and in the molecular reorientations followed by analysing several torsional distributions.     

Influence of Low-Molecular-Weight Excipients on the Phase Behavior of PVPVA64 Amorphous Solid Dispersions

Purpose

The oral bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs) can be improved by the preparation of amorphous solid dispersions (ASDs) where the API is dissolved in polymeric excipients. Desired properties of such ASDs like storage stability, dissolution behavior, and processability can be optimized by additional excipients. In this work, the influence of so-called low-molecular-weight excipients (LMWEs) on the phase behavior of ASDs was investigated.

Method

Binary ASDs of an amorphous API, naproxen (NAP) or acetaminophen (APAP), embedded in poly-(vinylpyrrolidone-co-vinyl acetate) (PVPVA64) were chosen as reference systems. Polyethylene glycol 1500 (PEG1500), D-α-tocopherol polyethylene glycol 1000 succinate (TPGS1000), propylene glycol monocaprylate type II (Capryol? 90), and propylene glycol monolaurate type I (Lauroglycol? FCC) were used as LMWEs. The API solubility in the excipients and the glass-transition temperature of the ASDs were modeled using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) and the Kwei equation, respectively, and compared to corresponding experimental data.

Results

The API solubility curves in ternary systems with 90/10 wt%/wt% PVPVA64/LMWE ratios were very close to those in pure PVPVA64. However, the glass-transition temperatures of API/PVPVA64/LMWE ASDs were much lower than those of API/PVPVA64 ASDs. These effects were determined experimentally and agreed with the predictions using the PC-SAFT and Kwei models.

Conclusion

The impact of the LMWEs on the thermodynamic stability of the ASDs is quite small while the kinetic stability is significantly decreased even by small LMWE amounts. PC-SAFT and the Kwei equation are suitable tools for predicting the influence of LMWEs on the ASD phase behavior.

     

Correlationship of Drug-Polymer Miscibility,Molecular Relaxation and Phase Behavior of Dipyridamole Amorphous Solid Dispersions

In present work, a correlationship among quantitative drug-polymer miscibility, molecular relaxation and phase behavior of the dipyridamole (DPD) amorphous solid dispersions (ASDs), prepared with co-povidone (CP), hydroxypropyl methylcellulose phthalate (HPMC P) and hydroxypropyl methylcellulose acetate succinate (HPMC AS) has been investigated. Miscibility predicted using melting point depression approach for DPD with CP, HPMC P and HPMC AS at 25 °C was 0.93% w/w, 0.55% w/w and 0.40% w/w, respectively. Stretched relaxation time (τ^β) for DPD ASDs, measured using modulated differential scanning calorimetry (MDSC) at common degree of undercooling, was in the order of DPD- CP > DPD-HPMC P > DPD-HPMC AS ASDs. Phase behavior of 12 months aged (25 ± 5 °C and 0% RH) spray dried 60% w/w ASDs was tracked using MDSC. Initial ASD samples had homogeneous phase revealed by single glass transition temperature (T_g) in the MDSC. MDSC study of aged ASDs revealed single-phase DPD-CP ASD, amorphous-amorphous and amorphous-crystalline phase separated DPD-HPMC P and DPD-HPMC AS ASDs, respectively. The results were supported by X-ray micro computed tomography and confocal laser scanning microscopy studies. This study demonstrated a profound influence of drug-polymer miscibility on molecular mobility and phase behavior of ASDs. This knowledge can help in designing “physical stable” ASDs.     

Polymer/Amorphous Salt Solid Dispersions of Ciprofloxacin

Purpose

To improve the pharmaceutical properties of amorphous ciprofloxacin (CIP) succinate salts via formulation as polymer/amorphous salt solid dispersions (ASSDs).

Methods

ASSDs consisting of an amorphous CIP/succinic acid 1:1 or 2:1 salt dispersed in PVP or Soluplus were produced by spray drying and ball milling. The solid state characteristics, miscibility, stability, solubility and passive transmembrane permeability of the ASSDs were then examined.

Results

The ASSDs had higher glass transition and crystallization temperatures than the corresponding amorphous succinate salts, and were also more stable during long-term stability studies. The results of inverse gas chromatography and thermal analysis indicated that the salts and polymers form a miscible mixture. The solubility of the pure drug in water and biorelevant media was significantly increased by all of the formulations. The permeability of the ASSDs did not differ significantly from that of the amorphous CIP succinate salts, however all samples were less permeable than the pure crystalline drug.

Conclusions

The formulation of amorphous CIP succinate salts as ASSDs with polymer improved their long-term stability, but did not significantly affect their solubility or permeability.

     

Solid-State NMR Investigation of Drug-Excipient Interactions and Phase Behavior in Indomethacin-Eudragit E Amorphous Solid Dispersions

Purpose

To investigate the nature of drug-excipient interactions between indomethacin (IMC) and methacrylate copolymer Eudragit® E (EE) in the amorphous state, and evaluate the effects on formulation and stability of these amorphous systems.

Methods

Amorphous solid dispersions containing IMC and EE were spray dried with drug loadings from 20% to 90%. PXRD was used to confirm the amorphous nature of the dispersions, and DSC was used to measure glass transition temperatures (T_g). ¹³C and ¹⁵N solid-state NMR was utilized to investigate changes in local structure and protonation state, while ¹H T₁ and T_1ρ relaxation measurements were used to probe miscibility and phase behavior of the dispersions.

Results

T_g values for IMC-EE solid dispersions showed significant positive deviations from predicted values in the drug loading range of 40–90%, indicating a relatively strong drug-excipient interaction. ¹⁵N solid-state NMR exhibited a change in protonation state of the EE basic amine, with two distinct populations for the EE amine at ?360.7 ppm (unprotonated) and ?344.4 ppm (protonated). Additionally, ¹H relaxation measurements showed phase separation at high drug load, indicating an amorphous ionic complex and free IMC-rich phase. PXRD data showed all ASDs up to 90% drug load remained physically stable after 2 years.

Conclusions

¹⁵N solid-state NMR experiments show a change in protonation state of EE, indicating that an ionic complex indeed forms between IMC and EE in amorphous solid dispersions. Phase behavior was determined to exhibit nanoscale phase separation at high drug load between the amorphous ionic complex and excess free IMC.

     

Physical Stability Studies of Miscible Amorphous Solid Dispersions

Physical stability of 12 amorphous solid dispersions was evaluated over 9–22 months under ambient conditions using X-ray powder diffraction. The nine dispersions initially characterized as miscible drug-polymer systems all remained X-ray amorphous for the duration of their respective studies. In contrast, the three phase-separated systems all crystallized in 1–2 months, while the pure amorphous active pharmaceutical ingredients used in this study all crystallized within a few days, under the conditions of this study. Changes in the local order of dispersions that included polyvinylpyrrolidone were observed and appeared to correlate to periods of higher relative humidity (RH), reverting back to the original local order as the RH decreased. Phase-separation in the miscible dispersions as a result of ambient RH conditions did not appear to take place. Finally, formation of pores (voids) was observed through small-angle X-ray powder diffraction during crystallization of one model drug (felodipine). © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:4005–4012, 2010     

Leaching of Lopinavir Amorphous Solid Dispersions in Acidic Media

Purpose

Amorphous solid dispersions (ASDs) formulated with acid-insoluble (enteric) polymers form suspensions in acidic media where the polymer is largely insoluble. However, a small amount of drug can dissolve and a supersaturated solution may be generated. The goal of this study was to gain insight into the leaching mechanisms of both drug and polymer from the suspended particles, studying the impact of solution additives such as surfactants.

Methods

ASDs were prepared by spray drying lopinavir (LPV) with an enteric polymer, either hydroxypropylmethylcellulose acetate succinate (HPMCAS) or hydroxypropylmethylcellulose phthalate (HPMCP). Four surfactants and a suspending agent were added to the liquid media to evaluate the effect of these excipients on leaching. pH 3 and pH 5 buffers were used to investigate the effect of pH.

Results

The extent of drug leaching from the amorphous formulation was proportional to the crystalline solubility of the drug in the same medium. All surfactants promoted solubilization of LPV with the exception of poloxamer and sodium dodecyl sulfate-HPMCP combinations. A small amount of polymer ionization significantly enhanced LPV leaching in solutions containing an ionic surfactant.

Conclusions

The mechanism of enhanced leaching appeared to be solubilization, with the apparent supersaturation remaining the same for systems containing the same polymer.

     

Phase Behavior of Amorphous Molecular Dispersions I: Determination of the Degree and Mechanism of Solid Solubility

PURPOSE: To understand the phase behavior and the degree and mechanism of the solid solubility in amorphous molecular dispersions by the use of thermal analysis. METHODS: Amorphous molecular dispersions of trehalose-dextran and trehalose-PVP were prepared by co-lyophilization. The mixtures were exposed to 23 degrees C, 40 degrees C, and 50 degrees C [75% relative humidity (RH)] and 23 degrees C (69% RH) storage conditions, respectively. Thermal analysis was conducted by modulated differential scanning calorimeter (MDSC). RESULTS: Upon exposure to moisture, two glass transition temperatures (TgS), one for phase-separated amorphous trehalose (Tg1) and the other for polymer-trehalose mixture (Tg2), were observed. With time, Tg2 increased and reached to a plateau (Tg(eq)), whereas Tg1 disappeared. The disappearance of Tg1 was attributed to crystallization of the phase-separated amorphous trehalose. It was observed that Tg(eq) was always less than Tg of pure polymer. The lower Tg(eq) when compared to Tg of pure polymer may be the result of solubility of a fraction of trehalose in the polymers chosen. The miscible fraction of trehalose was estimated to be 12% and 18% wt/wt in dextran at 50 degrees C/75% RH and 23 degrees C/75% RH, respectively, and 10% wt/wt in PVP at 23 degrees C/69% RH. CONCLUSIONS: Mixing behavior of trehalose-dextran and trehalose-PVP dispersions were examined both experimentally and theoretically. A method determining the "extent of molecular miscibility," referred to as "solid solubility," was developed and mechanistically and thermodynamically analyzed. Solid dispersions prepared at trehalose concentrations below the "solid solubility limit" were physically stable even under accelerated stability conditions.     

Screening Methodologies for the Development of Spray-Dried Amorphous Solid Dispersions

Pharmaceutical Research - To present a new screening methodology intended to be used in the early development of spray-dried amorphous solid dispersions. A model that combines thermodynamic,...     

Synergistic Effect of Polyvinyl Alcohol and Copovidone in Itraconazole Amorphous Solid Dispersions

Purpose

The first objective is to evaluate the feasibility of melt-extruding polyvinyl alcohol-based amorphous solid dispersions for oral drug delivery. The second objective is to investigate the miscibility between polyvinyl alcohol 4-88 and copovidone, and to characterize the properties of ternary itraconazole amorphous solid dispersions comprising both polymers.

Methods

Samples were prepared using a co-rotating, twin-screw extruder. A solution precipitation study was conducted to compare the precipitation inhibition of polyvinyl alcohol against other commonly used polymers for amorphous solid dispersions. Miscibility between polyvinyl alcohol 4-88 and copovidone was determined using DSC and XRD analyses. All extrudates were characterized using DSC, XRD, and non-sink dissolution.

Results

Polyvinyl alcohol demonstrated the highest capacity for inhibiting the precipitation of itraconazole. Itraconazole was found to be more soluble in copovidone (>30%) than in polyvinyl alcohol 4-88 (<5%) in binary extrudates. Polyvinyl alcohol and copovidone are miscible when the proportion of polyvinyl alcohol 4-88 does not exceed 30% (w/w). Compared to binary extrudates, the ternary extrudate demonstrated a higher degree of supersaturation and more sustained supersaturation of itraconazole in purified water and phosphate buffer pH 6.8 solution.

Conclusion

As a surface-active material, polyvinyl alcohol was effective in inhibiting precipitation of itraconazole in aqueous media. Solubility of itraconazole in polyvinyl alcohol in solid state was limited because of the high polarity of the polymer. Ternary systems comprising a mixture of polyvinyl alcohol and copovidone demonstrated better supersaturation in aqueous media than binary systems. Ternary systems benefited from both the high solubilizing capacity of copovidone and high precipitation inhibition capacity of polyvinyl alcohol.

     

A Practical Method to Predict Physical Stability of Amorphous Solid Dispersions

Purpose

To predict the crystallization time of amorphous solid dispersions by controlling the combined effect of temperature and moisture content.

Methods

The authors exposed amorphous samples of spray-dried API and Hydroxypropylmethylcellulose Phtalate to various temperature and humidity conditions below and above the glass transition temperature (Tg) until crystallization of the API was observed. The crystallization of API was detected by XRPD, while the T _g and the water absorption by the amorphous dispersion are quantified by mDSC and water sorption analysis.

Results

Extrapolation of the data obtained at a temperature above T _g to conditions below T _g gives only a qualitative trend. By contrast, in conditions below T _g the logarithm of onset of crystallization time was shown to vary linearly with the T _g /T ratio. A statistical analysis shows that the data obtained in the highest temperature/humidity conditions, for which the onset of crystallization is below 3?months, can be extrapolated over 15?months.

Conclusions

The proposed methodology can be used as a stress program to predict long-term stability from a relatively short observation period and to design appropriate temperature and humidity conditions for long-term storage to prevent crystallization.     

A Rheological Approach for Predicting Physical Stability of Amorphous Solid Dispersions

Miscibility is an important indicator of physical stability against crystallization of amorphous solid dispersions (ASDs). Currently available methods for miscibility determination have both theoretical and practical limitations. Here we report a method of miscibility determination based on the overlap concentration, c*, which can be conveniently determined from the viscosity-composition diagram. The determined c* values for ASDs of two model drugs, celecoxib and loratadine, with four different grades of polyvinylpyrrolidone (PVP), were correlated strongly with the physical stability of ASDs. This result suggests potential application of the c* concept in guiding the design of stable high drug loaded ASD formulations. A procedure is provided to facilitate broader adoption of this methodology. The procedure is easy to apply and widely applicable for thermally stable binary drug/polymer combinations.     

Phase Behavior of Amorphous Molecular Dispersions II: Role of Hydrogen Bonding in Solid Solubility and Phase Separation Kinetics

No HeadingPurpose. To determine the factors influencing solid solubility and phase separation kinetics of drugs from amorphous solid dispersions.Methods. Solid dispersions of griseofulvin-poly(vinyl pyrrolidone) (PVP) and indoprofen-PVP were prepared using solvent evaporation technique. Dispersions demonstrating single T_g were exposed to 40°C/69% RH for 90 days. Drug solid solubility in the polymer and phase separation rates were determined from changes in T_g of solid dispersions. FTIR spectroscopy and XRD were used to characterize drug-polymer interactions and drug crystallinity, respectively.Results. Freshly prepared solid dispersion of up to 30% w/w griseofulvin and indoprofen were molecularly miscible with PVP. Hydrogen bonding was evident in indoprofen-PVP, but not in griseofulvin-PVP dispersions. When exposed to 40°C/69% RH, griseofulvin phase separated completely, whereas the solid solubility of indoprofen was determined as 13% w/w. The first-order rate constants of phase separation for 10%. 20%, and 30% w/w griseofulvin dispersions were estimated as 4.66, 5.19, and 12.50 (×10²) [day^–1], and those of 20% and 30% w/w indoprofen were 0.62 and 1.25 (×10²) [day^–1], respectively.Conclusions. Solid solubility of griseofulvin and indoprofen in PVP is 0% w/w and 13% w/w, respectively. Drug-polymer hydrogen bonding in indoprofen-PVP dispersions favors solid solubility. Phase separation rate of drug from the solid dispersions depends on the initial drug content and the nature of drug-polymer interactions.     

Impact of Drug-Polymer Miscibility on Enthalpy Relaxation of Irbesartan Amorphous Solid Dispersions

Purpose

Drug-polymer miscibility has been proposed to play a critical role in physical stability of amorphous solid dispersions (ASDs). The purpose of the current work was to investigate the role of drug-polymer miscibility on molecular mobility, measured as enthalpy relaxation (ER) of amorphous irbesartan (IBS) in ASDs.

Methods

Two polymers, i.e. polyvinylpyrrolidone K30 (PVP K30) and hydroxypropyl methylcellulose acetate succinate (HPMCAS), were used to generate ASDs with 10% w/w of the polymer. Drug-polymer miscibility was determined using melting point depression (MPD) method. Molecular mobility was assessed from ER studies at a common degree of undercooling (DOU) (T_g???13.0°C?±?0.5°C).

Results

IBS exhibited higher miscibility in PVP K30 as compared to HPMCAS at temperature?>?140°C. However, extrapolation of miscibility data to storage temperature (62°C) using Flory-Huggins (F-H) theory revealed a reversal of the trend. Miscibility of IBS was found to be higher in HPMCAS (2.6%) than PVP K30 (1.3%) at 62°C. Stretched relaxation time (τ^β) of 17.4365 h and 7.0886 h was obtained for IBS-HPMCAS and IBS-PVP K30 ASDs, respectively.

Conclusion

Miscibility of drug-polymer at storage temperature explained the behavior of the molecular mobility, while miscibility near the melting point provided a reverse trend. Results suggest that drug-polymer miscibility determined at temperatures higher than the storage temperature should be viewed cautiously.

     

A Mechanistic Model for Predicting the Physical Stability of Amorphous Solid Dispersions

In this paper, we establish a mechanistic model for the prediction of amorphous solid dispersion (ASD) stability. The novel approach incorporates fundamental physical parameters, principally supersaturation, diffusivity, and interfacial energy, to model crystallization in ASDs accounting for both kinetic and thermodynamic drivers. API dependent decoupling coefficients were also considered which allowed dynamic mechanical analysis to probe molecular mobility, with viscosity measurements, across an exceptionally broad range of temperatures to support ASD stability simulations. ASDs are multicomponent systems in which the amorphous form of active pharmaceutical ingredients (APIs) are molecularly dispersed within a carrier. This gives rise to a transiently supersaturated API solution upon dissolution which increases the driving force for oral absorption and results in increased bioavailability as compared to that of the crystalline API. A major shortcoming of ASDs, however, is that there is the potential for amorphous APIs to revert to their more stable crystalline form during storage, despite the use of polymer carriers to stabilize formulations and limit recrystallization. Hot melt extrusion (HME) has been employed as the preparation method for ASDs used in this study as it is well-suited for the formation of uniform dispersions. The ASDs were stored under controlled temperature conditions, in the absence of humidity, to determine recrystallization kinetics. Our mechanistic model, considering both crystal nucleation and growth processes, describes temporal ASD stability through a system of coupled differential equations that connect the physiochemical properties of the ASD system to drug recrystallization. The model and prolonged time scale of crystallization observed highlight the importance of considering both thermodynamic and kinetic factors in the preparation of stable ASDs. Experimental observations were found to be in good agreement with predictions of the model confirming its utility in predicting the temporal physical stability of amorphous solid dispersions through a mechanistic lens.     

Release Mechanisms of Amorphous Solid Dispersions: Role of Drug-Polymer Phase Separation and Morphology

Formulating poorly soluble molecules as amorphous solid dispersions (ASDs) is an effective strategy to improve drug release. However, drug release rate and extent tend to rapidly diminish with increasing drug loading (DL). The poor release at high DLs has been postulated to be linked to the process of amorphous-amorphous phase separation (AAPS), although the exact connection between phase separation and release properties remains somewhat unclear. Herein, release profiles of ASDs formulated with ritonavir (RTV) and polyvinylpyrrolidone/vinyl acetate (PVPVA) at different DLs were determined using surface normalized dissolution. Surface morphologies of partially dissolved ASD compacts were evaluated with confocal fluorescence microscopy, using Nile red and Alexa Fluor 488 as fluorescence markers to track the hydrophobic and hydrophilic phases respectively. ASD phase behavior during hydration and release of components were also visualized in real time using a newly developed in situ confocal fluorescence microscopy method. RTV-PVPVA ASDs showed complete and rapid drug release below 30% DL, partial drug release at 30% DL and no drug release above 30% DL. It was observed that formation of discrete drug-rich droplets at lower DLs led to rapid and congruent release of both drug and polymer, whereas formation of continuous drug-rich phase at the ASD matrix-solution interface was the cause of poor release above certain DLs. Thus, the domain size and interconnectivity of phase separated drug-rich domains appear to be critical factors impacting drug release from RTV-PVPVPA ASDs.     

Physical Stability and Dissolution of Lumefantrine Amorphous Solid Dispersions Produced by Spray Anti-Solvent Precipitation

This study aims to develop amorphous solid dispersion (ASD) of lumefantrine with a cost-effective approach of spray anti-solvent precipitation. Four acidic polymers, hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), poly(methacrylic acid–ethyl acrylate) (EL100) and cellulose acetate phthalate (CAP) were studied as excipients at various drug-polymer ratios. Of the studied polymers, satisfactory physical stability was demonstrated for HPMCP- and HPMCAS-based ASDs with no observed powder X-ray diffraction peaks for up to 3 months of storage at 40 °C/75% RH. HPMCP and HPMCAS ASDs also achieved greater drug release levels in the dissolution study than other polymers. The HPMCP-based ASDs with a drug:polymer ratio of 2:8 exhibited a maximum drug release of 140 μg/mL for up to 2 h, which is significantly higher than the currently marketed formulation of Coartem® (<80 ng/mL). Relatively, the CAP and EL100 ASDs indicated a higher water content and crystallized within a day when stored at 40 °C/75% RH. The choice of polymer, and the drug-polymer ratio played a crucial role in the solubility enhancement of lumefantrine. Our study indicates that the developed spray anti-solvent precipitation method could be an affordable approach for producing ASDs.