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The fundamental idea underlying the use of amorphous solid dispersions (ASDs) is to make the most of the solubility advantage of the amorphous form of a drug. However, the drug stability becomes compromised due to the higher free energy and disorder of molecular packing in the amorphous phase, leading to crystallization. Polymers are used as a matrix to form a stable homogeneous amorphous system to overcome the stability concern. The present work aims to design ASD-based formulations under the umbrella of quality by design principles for improving oral drug bioavailability, using celecoxib (CXB) as a model drug. ASDs were prepared from selected polymers and tested both individually and in combinations, using various manufacturing techniques: high-shear homogenization, high-pressure homogenization, microfluidics-on-a-chip, and spray drying. The resulting dispersions were further optimized, resorting to a 32 full-factorial design, considering the drug:polymers ratio and the total solid content as variables. The formulated products were evaluated regarding analytical centrifugation and the influence of the different polymers on the intrinsic dissolution rate of the CXB-ASDs. Microfluidics-on-a-chip led to the amorphous status of the formulation. The in vitro evaluation demonstrated a remarkable 26-fold enhancement in the intrinsic dissolution rate, and the translation of this formulation into tablets as the final dosage form is consistent with the observed performance enhancement. These findings are supported by ex vivo assays, which exhibited a two-fold increase in permeability compared to pure CXB. This study tackles the bioavailability hurdles encountered with diverse active compounds, offering insights into the development of more effective drug delivery platforms. [ABSTRACT FROM AUTHOR]

Background: Atomization plays a key role in spray drying, a process widely used in the pharmaceutical, chemical, biological, and food and beverage industries. In the pharmaceutical industry, spray drying is particularly important in the preparation of amorphous solid dispersions, which enhance the bioavailability of active pharmaceutical ingredients when mixed with a polymer. Methods: In this study, a 3D-printed adaptation of a commercial spray dryer nozzle (PHARMA-SD® PSD-1, GEA Group AG) was used to investigate the atomization of PVP-VA 64 polymer solutions under varying flow conditions using high-speed diffuse back-illumination. Results: Unlike pure water, the atomization process of the polymer solution was governed by viscous effects rather than surface tension, as indicated by stringing effects in the liquid core and the formation of larger droplets. In addition, the classical Ohnesorge diagram accurately predicted the atomization regime with increasing Reynolds numbers and could be modified to reasonably predict the breakup regime by considering the transitions between regime boundaries. Conclusions: The use of such a modified diagram facilitates the efficient selection of viscous fluid solutions and process parameters to achieve complete spray formation. [ABSTRACT FROM AUTHOR]

Background: Melt-based 3D printing technologies are currently extensively evaluated for research purposes as well as for industrial applications. Classical approaches often require intermediates, which can pose a risk to stability and add additional complexity to the process. The Advanced Melt Drop Deposition (AMDD) technology, is a 3D printing process that combines the principles of melt extrusion with pressure-driven ejection, similar to injection molding. This method offers several advantages over traditional melt-based 3D printing techniques, making it particularly suitable for pharmaceutical applications. Objectives: This study evaluates the AMDD printing system for producing solid oral dosage forms, with a primary focus on the thermo-stable polymer polyvinyl alcohol (PVA). The suitability of AMDD technology for creating amorphous solid dispersions (ASDs) is also examined. Finally, the study aims to define the material requirements and limitations of the raw materials used in the process. Methods: The active pharmaceutical ingredients (APIs) indometacin and ketoconazole were used, with PVA 4-88 serving as the carrier polymer. Powders, wet granulates, and pellets were investigated as raw materials and characterized. Dissolution testing and content analyses were performed on the printed dosage forms. Solid-state characterization was conducted using differential scanning calorimetry (DSC) and X-ray diffraction (XRD). Degradation due to thermal and mechanical stress was analyzed using nuclear magnetic resonance spectroscopy (NMR). Results/Conclusions: The results demonstrate that the AMDD 3D printing process is well-suited for producing solid dosage forms. Tablets were successfully printed, meeting mass uniformity standards. Adjusting the infill volume from 30% to 100% effectively controlled the drug release rate of the tablets. Solid-state analysis revealed that the AMDD process can produce amorphous solid dispersions with enhanced solubility compared to their crystalline form. The experiments also demonstrated that powders with a particle size of approximately 200 µm can be directly processed using AMDD technology. [ABSTRACT FROM AUTHOR]

Background/Objectives: This project aims to provide valuable insights into the formulation of orodispersible films (ODFs) for the delivery of PROTAC ARV-110. The primary objective of this drug delivery formulation is to enhance the solubility of PROTAC ARV-110, which faces significant challenges due to the low solubility of this active pharmaceutical ingredient, as it belongs to a molecular class that is considered to exceed the "Rule of Five". Methods: We employed the concept of developing a rapidly disintegrating ODF to enhance the solubility of PROTAC ARV-110, utilizing polyvinyl alcohol as the polymer of choice. Given the high thermal stability of ARV-110, the PROTAC was subjected to two primary ODF manufacturing techniques: Hot melt extrusion (HME) and solvent casting. To establish the HME method, pre-screening through vacuum compression molding was performed. The films were characterized based on their disintegration in artificial saliva, drug release in a physiological environment, and mechanical strength. Results: All formulations demonstrated enhanced solubility of ARV-110, achieving exceptional results in terms of disintegration times and resistance to applied stress. Conclusions: The findings from the experiments outlined herein establish a solid foundation for the successful production of orodispersible films for the delivery of PROTACs. [ABSTRACT FROM AUTHOR]

Amorphous solid dispersions are good candidates for improving solubility in water and the oral bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). Amorphous solids become supercooled liquids when the temperature reaches the glass transition temperature (Tg). For APIs with low melting points, Tg can be below room temperature, which makes it difficult to prepare long-term stable amorphous solids. Studies on the physicochemical properties of supercooled liquids shed light on the design of ASDs for APIs with low melting points. Racemic ibuprofen (IBU) supercooled liquid has been detected using differential scanning calorimetry and powder X-ray diffraction during the melt-quenching of IBU at a low temperature (0 °C). In this work, gram-scaled IBU supercooled liquid was prepared using the melt-quenching method, maintaining a liquid state for minutes at room temperature and for hours at 10 °C, as confirmed by visual observation. The Raman spectra, IR spectra, and UV-vis spectra results indicate that the structure of the IBU supercooled liquid is similar to that of an IBU solution instead of IBU Form I. The rate of recrystallization into Form I can be adjusted by controlling the temperature and additives, as confirmed by visual observation. Moreover, long-term stable IBU dispersions, with improved aqueous solubility, were inspired by the IBU supercooled liquid. The IBU supercooled liquid model can guide the preparation of ASDs for low melting point drugs. [ABSTRACT FROM AUTHOR]

3D electron diffraction (3DED) is increasingly employed to determine molecular and crystal structures from micro-crystals. Indomethacin is a well known, marketed, small-molecule non-steroidal anti-inflammatory drug with eight known polymorphic forms, of which four structures have been elucidated to date. Using 3DED, we determined the structure of a new ninth polymorph, σ, found within an amorphous solid dispersion, a product formulation sometimes used for active pharmaceutical ingredients with poor aqueous solubility. Subsequently, we found that σ indomethacin can be produced from direct solvent evaporation using dichloromethane. These results demonstrate the relevance of 3DED within drug development to directly probe product formulations.

Abstract Oxyberberine (OBB) is a significant natural compound, with excellent hepatoprotective properties. However, the poor water solubility of OBB hinders its release and absorption thus resulting in low bioavailability. To overcome these drawbacks of OBB, amorphous spray-dried powders (ASDs) of OBB were formulated. The dissolution, characterizations, and pharmacokinetics of OBB-ASDs formulation were investigated, and its hepatoprotective action was disquisitive in the D-GalN/LPS-induced acute liver injury (ALI) mouse model. The characterizations of OBB-ASDs indicated that the crystalline form of OBB active pharmaceutical ingredients (API) was changed into an amorphous form in OBB-ASDs. More importantly, OBB-ASDs showed a higher bioavailability than OBB API. In addition, OBB-ASDs treatment restored abnormal histopathological changes, improved liver functions, and relieved hepatic inflammatory mediators and oxidative stress in ALI mice. The spray drying techniques produced an amorphous form of OBB, which could significantly enhance the bioavailability and exhibit excellent hepatoprotective effects, indicating that the OBB-ASDs can exhibit further potential in hepatoprotective drug delivery systems. Our results provide guidance for improving the bioavailability and pharmacological activities of other compounds, especially insoluble natural compounds. Meanwhile, the successful development of OBB-ASDs could shed new light on the research process of poorly soluble medicine.

The present study investigated the effect of different polymers and manufacturing methods (hot melt extrusion, HME, and spray drying, SD) on the solid state, stability and pharmaceutical performance of amorphous solid dispersions. In the present manuscript, a combination of different binary amorphous solid dispersions containing 20% and 30% of drug loadings were prepared using SD and HME. The developed solid-state properties of the dispersions were evaluated using small- and wide-angle X-ray scattering (WAXS) and modulated differential scanning calorimetry (mDSC). The molecular interaction between the active pharmaceutical ingredients (APIs) and polymers were investigated via infrared (IR) and Raman spectroscopy. The in vitro release profile of the solid dispersions was also evaluated to compare the rate and extend of drug dissolution as a function of method of preparation. Thereafter, the effect of accelerated stability conditions on the physicochemical properties of the solid dispersions were also evaluated. The results demonstrated higher stability of Soluplus® (SOL) polymer-based solid dispersions as compared to hydroxypropyl methylcellulose (HPMC)-based solid dispersions. Moreover, the stability of the solid dispersions was found to be higher in the case of API having high glass transition temperature (Tg) and demonstrated higher interaction with the polymeric groups. Interestingly, the stability of the melt-extruded dispersions was found to be slightly higher as compared to the SD formulations. However, the down-processing of melt-extruded strands plays critical role in inducing the API crystal nuclei formation. In summary, the findings strongly indicate that the particulate properties significantly influence the performance of the product. [ABSTRACT FROM AUTHOR]

In response to the growing ethical and environmental concerns associated with animal testing, numerous in vitro tools of varying complexity and biorelevance have been developed and adopted in pharmaceutical research and development. In this work, we present one of these tools, i.e. , the Meso-fluidic Chip for Permeability Assessment (MCPA), for the first time. The MCPA combines an artificial barrier (PermeaPad®) with an organ-on-chip device (MIVO®) and real-time automated concentration measurements, to yield a sustainable, yet effortless method for permeation testing. The system offers three major physiological aspects, i.e., a biomimetic membrane, an optimal membrane interfacial area-to-donor-volume-ratio (A/V) and a physiological flow on the acceptor/basolateral side, which makes the MPCA an ideal candidate for mechanistic studies and excellent in vivo bioavailability predictions. We validated the method with a handful of assorted drug compounds in unstirred and stirred donor conditions, before exploring its applicability as a tool for dissolution/permeation testing on a BCS class III/I drug (pyrazinamide) crystalline adducts and BCS class II/IV (hydrocortisone) amorphous solid dispersions. The results were highly reproducible and clearly displayed the method's potential for evaluating the performance of enabling formulations, and possibly even predicting in vivo performance. We believe that, upon further development, the MCPA will serve as a useful in vitro tool that could push sustainability into pharmaceutics by refining, reducing and replacing animal testing in early-stage drug development. [ABSTRACT FROM AUTHOR]

The co-administration of curcumin and hesperetin might be beneficial in terms of neuroprotective activity; therefore, in this study, we attempted to develop a fixed-dose formulation comprising these two compounds in an amorphous state. The aim of obtaining an amorphous state was to overcome the limitations of the low solubility of the active compounds. First, we assessed the possibility of using popular sweeteners (erythritol, xylitol, and sorbitol) as plasticizers to reduce the glass transition temperature of PVP K30 to prepare the polymer–excipient blends, which allowed the preparation of amorphous solid dispersions via hot-melt extrusion at a temperature below the original glass transition of PVP K30. Erythritol proved to be the superior plasticizer. Then, we focused on the development of fixed-dose amorphous solid dispersions of curcumin and hesperetin. Powder X-ray diffraction and thermal analysis confirmed the amorphous character of dispersions, whereas infrared spectroscopy helped to assess the presence of intermolecular interactions. The amorphous state of the produced dispersions was maintained for 6 months, as shown in a stability study. Pharmaceutical parameters such as dissolution rate, solubility, and in vitro permeability through artificial membranes were evaluated. The best improvement in these features was noted for the dispersion, which contained 15% of the total content of the active compounds with erythritol used as the plasticizer. [ABSTRACT FROM AUTHOR]

The application of mesoporous carriers in formulations of amorphous solid dispersions (ASDs) has been suggested to enhance the stability of amorphous drugs. However, mesoporous carriers do not demonstrate satisfactory inhibitory effects on the precipitation of active pharmaceutical ingredients (APIs), and the inclusion of an appropriate polymer within ASDs becomes imperative to maintaining drug supersaturation. The aim of this study was to evaluate ternary olanzapine (OLN) ASDs with Syloid 244FP and to find an appropriate polymeric carrier. The polymer's selection criteria were based on the physical stability of the ASDs and the release rate of the drug from the systems. The polymers investigated were hydroxypropylmethyl cellulose (HPMC) and copovidone (coPVP). The formation of ASDs was achievable in all investigated cases, as demonstrated by the complete lack of crystallinity confirmed through both powder X-ray diffraction (pXRD) analysis and differential scanning calorimetry (DSC) for all developed formulations. The solvent shift method was employed to evaluate the ability of the studied carriers to inhibit the precipitation of supersaturated OLN. coPVP emerged as a more suitable precipitation inhibitor compared with HPMC and Syloid 244 FP. Subsequently, in vitro dissolution studies under non-sink conditions revealed a higher degree of supersaturation in ternary systems where coPVP was used as a polymeric carrier, as these systems exhibited, under the examined conditions, up to a 2-fold increase in the released OLN compared with the pure crystalline drug. Moreover, stability studies conducted utilizing pXRD demonstrated that ternary formulations incorporating coPVP and Syloid 244 FP maintained stability for an extended period of 8 months. In contrast, binary systems exhibited a comparatively shorter stability duration, indicating the synergistic effect of coPVP and Syloid 244 FP on the physical stability of the amorphous API. Attenuated total reflectance–Fourier transform infrared (ATR-FTIR) studies showed that the development of stronger molecular interactions can be provided as an explanation for this synergistic effect, as the formation of robust H-bonds may be considered responsible for inhibiting the precipitation of the supersaturated API. Therefore, the incorporation of coPVP into OLN ASDs with Syloid 244 FP is considered a highly promising technique for increasing the degree of OLN supersaturation in in vitro dissolution studies and improving the stability of systems. [ABSTRACT FROM AUTHOR]

Melt viscosity is an essential property in pharmaceutical processes such as mixing, extrusion, fused deposition modeling, and melt coating. Measuring and modeling of the melt viscosity for drug/polymer mixtures is essential for optimization of the manufacturing process. In this work, the melt viscosity of nine formulations containing the drug substances acetaminophen, itraconazole, and griseofulvin, as well as the pharmaceutical polymers Eudragit EPO, Soluplus, and Plasdone S-630, were analyzed with a rotational and oscillatory rheometer. The shear rate, temperature, and drug fraction were varied systematically to investigate their influence on viscosity. The results for the pure polymers showed typical shear-thinning behavior and are fundamental for modeling with the Carreau and Arrhenius approaches. The investigations of the viscosity of the drug/polymer mixtures resulted in a plasticizing or a filler effect, depending on the type of drug and the phase behavior. A drug shift factor was proposed to model the change in viscosity as a function of the drug fraction. On this basis, a universal model to describe the melt viscosity of drug/polymer mixtures was developed, considering shear rate, temperature, and drug fraction. [ABSTRACT FROM AUTHOR]

Determining solubility of drugs is laborious and time-consuming process that may not yield meaningful results. Amorphous solid dispersion (ASD) is a widely used solubility enhancement technique. Predictive models could streamline this process and accelerate the development of oral drugs with improved aqueous solubilities. This study aimed to develop a predictive model to estimate the solubility of a compound from the ASDs in polymer matrices. ASDs of model drugs (acetazolamide, chlorothiazide, furosemide, hydrochlorothiazide, sulfamethoxazole) with model polymers (PVP, PVPVA, HPMC E5, Soluplus) and a surfactant (TPGS) were prepared using hotmelt process. The prepared ASDs were characterized using DSC, FTIR, and XRD. The aqueous solubility of the model drugs was determined using shake-flask method. Multiple linear regression was used to develop a predictive model to determine aqueous solubility using the molecular descriptors of the drug and polymer as predictor variables. The model was validated using Leave-One-Out Cross-Validation. The ASDs' drug components were identified as amorphous via DSC and XRD Studies. There were no significant chemical interactions between the model drugs and the polymers based on FTIR studies. The ASDs showed a significant (p < 0.05) improvement in solubility, ranging from a 3-fold to 118-fold, compared with the pure drug. The developed empirical model predicted the solubility of the model drugs from the ASDs containing model polymer matrices with an accuracy greater than 80%. The developed empirical model demonstrated robustness and predicted the aqueous solubility of model drugs from the ASDs of model polymer matrices with an accuracy greater than 80%. [ABSTRACT FROM AUTHOR]

Amorphous solid dispersions are good candidates for improving solubility in water and the oral bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). Amorphous solids become supercooled liquids when the temperature reaches the glass transition temperature (Tg). For APIs with low melting points, Tg can be below room temperature, which makes it difficult to prepare long-term stable amorphous solids. Studies on the physicochemical properties of supercooled liquids shed light on the design of ASDs for APIs with low melting points. Racemic ibuprofen (IBU) supercooled liquid has been detected using differential scanning calorimetry and powder X-ray diffraction during the melt-quenching of IBU at a low temperature (0 °C). In this work, gram-scaled IBU supercooled liquid was prepared using the melt-quenching method, maintaining a liquid state for minutes at room temperature and for hours at 10 °C, as confirmed by visual observation. The Raman spectra, IR spectra, and UV-vis spectra results indicate that the structure of the IBU supercooled liquid is similar to that of an IBU solution instead of IBU Form I. The rate of recrystallization into Form I can be adjusted by controlling the temperature and additives, as confirmed by visual observation. Moreover, long-term stable IBU dispersions, with improved aqueous solubility, were inspired by the IBU supercooled liquid. The IBU supercooled liquid model can guide the preparation of ASDs for low melting point drugs.

Amorphous solid dispersions (ASDs) are a formulation and development strategy that can be used to increase the apparent aqueous solubility of poorly water-soluble drugs. Their implementation, however, can be hindered by destabilization of the amorphous form, as the drug recrystallizes from its metastable state. Factors such as the drug-polymer solubility, miscibility, mobility, and nucleation/crystal growth rates are all known to impact the physical stability of an ASD. Non-covalent interactions (NCI) between the drug and polymer have also been widely reported to influence product shelf-life. In this review, the relationship between thermodynamic/kinetic factors and adhesive NCI is assessed. Various types of NCIs reported to stabilize ASDs are described, and their role in affecting physical stability is examined. Finally, NCIs that have not yet been widely explored in ASD formulations, but may potentially impact their physical stability are also briefly described. This review aims to stimulate further theoretical and practical exploration of various NCIs and their applications in ASD formulations in the future. [ABSTRACT FROM AUTHOR]

Dronedarone (DRN), an antiarrhythmic drug, exhibits potent pharmacological effects in the management of cardiac arrhythmias. Despite its therapeutic potential, DRN faces formulation challenges due to its low aqueous solubility. Hence, the present study is dedicated to the examination of amorphous solid dispersions (ASDs) as a strategic approach for enhancing the solubility of DRN. Initially, the glass forming ability (GFA) of API was assessed alongside its thermal degradation profile, and it was revealed that DRN is a stable glass former (GFA III compound) that remains thermally stable up to approximately 200 °C. Subsequently, five commonly used ASD matrix/carriers, i.e., hydroxypropyl methylcellulose (HPMC), povidone (PVP), copovidone (PVP/VA), Soluplus® (SOL), and Eudragit® E PO (EPO), were screened for the formation of a DRN-based ASD using film casting and solvent shift methods, along with miscibility evaluation measurements. SOL proved to be the most promising matrix/carrier among the others, and, hence, was used to prepare DRN ASDs via the melt-quench method. The physicochemical characterization of the prepared systems (via pXRD) revealed the complete amorphization of the API within the matrix/carrier, while the system was physically stable for at least three months after its preparation. In vitro release studies for the ASDs, conducted under non-sink conditions, revealed the sustained supersaturation of the drug for at least 8 h. Finally, the use of attenuated total reflectance (ATR) FTIR spectroscopy showed the formation of a strong molecular interaction between the drug molecules and SOL. [ABSTRACT FROM AUTHOR]

We prepared hybrid nanocrystal–amorphous solid dispersions (HyNASDs) to examine their supersaturation capability in the release of a poorly soluble drug, itraconazole (ITZ), a slow crystallizer during dissolution. The HyNASD formulations included a polymer (HPC: hydroxypropyl cellulose, Sol: Soluplus, or VA64: Kollidon-VA64) and a surfactant (SDS: sodium dodecyl sulfate). Additionally, the dissolution performance of the HyNASDs and ASDs was compared. To this end, wet-milled aqueous nanosuspensions containing a 1:5 ITZ:polymer mass ratio with/without SDS as well as solutions of the same ratio without SDS in dichloromethane were spray-dried. XRPD–DSC confirmed that ASDs were formed upon spray drying the solution-based feeds, whereas HyNASDs (~5–30% amorphous) were formed with the nanosuspension-based feeds. SDS aided to stabilize the ITZ nanosuspensions and increase the amorphous content in the spray-dried powders. During dissolution, up to 850% and 790% relative supersaturation values were attained by HyNASDs with and without SDS, respectively. Due to the stronger molecular interaction between ITZ–Sol than ITZ–HPC/VA64 and micellar solubilization by Sol, Sol-based HyNASDs outperformed HPC/VA64-based HyNASDs. While the ASD formulations generated greater supersaturation values (≤1670%) than HyNASDs (≤790%), this extent of supersaturation from a largely nanocrystalline formulation (HyNASD) has not been achieved before. Overall, HyNASDs could boost drug release from nanoparticle-based formulations and may render them competitive to ASDs. [ABSTRACT FROM AUTHOR]

Objectives: Amorphous solid dispersions (ASDs), wherein a drug is molecularly dispersed in a polymer, can improve physical stability and oral bioavailability of poorly soluble drugs. Risk of drug crystallization is usually averted using high polymer concentrations. However, we demonstrated recently that the overlap concentration, C*, of polymer in drug melt is the minimum polymer concentration required to maintain drug in the amorphous state following rapid quench. This conclusion was confirmed for several drugs mixed with poly(vinylpyrrolidone) (PVP). Here we assess the solid-state stability of ASDs formulated with a variety of polymers and drugs and at various polymer concentrations (C) and molecular weights (MWs). We further test the hypothesis that degree of drug crystallization decreases with increasing C/C* and vanishes when C>C*, where C* depends on polymer MW and strength of drug-polymer interaction. Methods: We test our hypothesis with ASDs consisting of ketoconazole admixed with polyacrylic acid, polymethacrylic acid and poly (methacrylic acid-co-ethyl acrylate); and felodipine admixed with PVP and poly (vinylpyrrolidone-co-vinyl acetate). Values of C* for polymers in molten drug are rheologically determined. Crystallization behavior is assessed by measuring enthalpy of fusion, ΔHf and by X-ray diffraction. Results: We confirm that ΔHf/ΔHf, C = 0 = f(C/C∗), and essentially no crystallization occurs when C>C*. Conclusions: Our findings will aid researchers in designing or selecting appropriate polymers to inhibit crystallization of poorly soluble drugs. This research also suggests that C* as determined by rheology can be used to compare drug-polymer interactions for similar molecular weight polymers. [ABSTRACT FROM AUTHOR]

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. [Display omitted] [ABSTRACT FROM AUTHOR]

Etoposide is a well-known anti-tumor agent used to treat a variety of cancers. Although it is a BCS class IV drug, applications are restricted due to poor solubility and bioavailability. Hence, the current research was designed to overcome these pitfalls. A total of 16 formulation batches were developed using the physical mixture and kneading method and optimized by Design-Expert® software. A selected batch was evaluated using solubility, differential scanning calorimetry, X-ray diffraction, motic microscopy, scanning electron microscopy, Fourier transform infrared (FTIR), gastrointestinal distribution, pharmacokinetic and cytotoxicity study. The results showed that the saturated solubility of formulation was 19.76 mg mL-1. FTIR showed C-O=1646 cm-1, and C-H=2956 cm-1. The distribution study indicated 9.11, 5.39 and 4.23 µg mL-1 colon concentrations at 8h, 16h, and 24h, respectively. The Cmax and AUC were found at 741.17±12.29 ng mL-1 and 3089.23 ±34.69 ng mL-1 with less viability on HeLa cells. Therefore, the study investigates the developed solid dispersions enhanced solubility and bioavailability with an antiproliferative effect. [ABSTRACT FROM AUTHOR]

In this work, the manufacture of amorphous solid dispersions of poorly water-soluble carbamazepine using a laboratory spray drying setup with a three-fluid nozzle and two separate liquid feed solutions of (a) the active and (b) the polymeric excipient (copovidone or basic butylated methacrylate copolymer) was investigated and compared to a traditional two-fluid nozzle setup. Results show that particles with the desired drug content were manufactured using the three-fluid nozzle setup. Amorphous solid dispersion could be obtained up to a drug load of 50% (w/w) processing solutions with miscible solvents and copovidone as polymer. Higher active concentrations, the use of immiscible solvents or switching of the capillaries led to a substantial crystallization of carbamazepine as seen in XRD and DSC analysis. The polymorphic form IV of carbamazepine was formed in the presence of copovidone at high solid concentrations of the liquid feed. [ABSTRACT FROM AUTHOR]

The prevalence of active pharmaceutical ingredients (APIs) with low water solubility has experienced a significant increase in recent years. These APIs present challenges in formulation, particularly for oral dosage forms, despite their considerable therapeutic potential. Therefore, the improvement of solubility has become a major concern for pharmaceutical enterprises to increase the bioavailability of APIs. A promising formulation approach that can effectively improve the dissolution profile and the bioavailability of poorly water-soluble drugs is the utilization of amorphous systems. Numerous formulation methods have been developed to enhance poorly water-soluble drugs through amorphization systems, including co-amorphous formulations, amorphous solid dispersions (ASDs), and the use of mesoporous silica as a carrier. Furthermore, the successful enhancement of certain drugs with poor aqueous solubility through amorphization has led to their incorporation into various commercially available preparations, such as ASDs, where the crystalline structure of APIs is transformed into an amorphous state within a hydrophilic matrix. A novel approach, known as ternary solid dispersions (TSDs), has emerged to address the solubility and bioavailability challenges associated with amorphous drugs. Meanwhile, the introduction of a third component in the ASD and co-amorphous systems has demonstrated the potential to improve performance in terms of solubility, physical stability, and processability. This comprehensive review discusses the preparation and characterization of poorly water-soluble drugs in ternary solid dispersions and their mechanisms of drug release and physical stability. [ABSTRACT FROM AUTHOR]

This work aimed to develop and characterize a water-soluble, high-release active pharmaceutical ingredient (API) composite based on the practically water-insoluble API N-butyl-N-methyl-1-phenylpyrrolo[1,2-a]pyrazine-3-carboxamide (GML-3), a substance with antidepressant and anxiolytic action. This allows to ensure the bioavailability of the medicinal product of combined action. Composites obtained by the method of creating amorphous solid dispersions, where polyvinylpyrrolidone (PVP) or Soluplus® was used as a polymer, were studied for crystallinity, stability and the release of API from the composite into purified water. The resulting differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD), and dissolution test data indicate that the resulting composites are amorphous at 1:15 API: polymer ratios for PVP and 1:5 for Soluplus®, which ensures the solubility of GML-3 in purified water and maintaining the supercritical state in solution. [ABSTRACT FROM AUTHOR]

Amorphous solid dispersion (ASD) is one of the most effective approaches for delivering poorly soluble drugs. In ASDs, polymeric materials serve as the carriers in which the drugs are dispersed at the molecular level. To prepare the solid dispersions, there are many polymers with various physicochemical and thermochemical characteristics available for use in ASD formulations. Polymer selection is of great importance because it influences the stability, solubility and dissolution rates, manufacturing process, and bioavailability of the ASD. This review article provides a comprehensive overview of ASDs from the perspectives of physicochemical characteristics of polymers, formulation designs and preparation methods. Furthermore, considerations of safety and regulatory requirements along with the studies recommended for characterizing and evaluating polymeric carriers are briefly discussed. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this work was to study the effectiveness of various methods for improving the solubility and bioavailability of darunavir by mesoporous carriers and water-soluble polymers in the form of amorphous solid dispersions. Methods: Preliminarily, using the solvent wetting method, solid dispersions with various water-soluble polymers were obtained, which were tested for the presence of amorphism by X-ray diffraction and scanning electron microscopy methods and to determine the leader in increasing the solubility of darunavir. The selected polymer became the basis for the formulations, which were separately obtained by industrially available hot-melt extrusion and spray-drying methods, mixed with needful excipients and compressed to form dispersible tablets. The resulting tablets were tested in vitro using a dissolution test and in vivo for bioavailability in minipigs. Results: Of all tested polymer dispersions, the best solubility results have been shown with Eudragit EPO systems for solvent wetting, hot melt extrusion, and fluidized bed methods. These compositions became the basis of polymer formulations that showed better dissolution compared to physical mixture on a mesoporous carrier without polymer. The bioavailability test revealed the highest efficacy of the polymer dispersion on the mannitol particles. Conclusion: All formulations obtained, containing various solid dispersions, performed better than the original Prezista. This observation allows us to take further steps to reduce the drug load. [ABSTRACT FROM AUTHOR]

The current study aimed to see the effects of poloxamer P407 on the dissolution performance of hydroxypropyl methylcellulose acetate succinate (AquaSolve™ HPMC-AS HG)-based amorphous solid dispersions (ASD). A weakly acidic, poorly water-soluble active pharmaceutical ingredient (API), mefenamic acid (MA), was selected as a model drug. Thermal investigations, including thermogravimetry (TG) and differential scanning calorimetry (DSC), were conducted for raw materials and physical mixtures as a part of the pre-formulation studies and later to characterize the extruded filaments. The API was blended with the polymers using a twin shell V-blender for 10 min and then extruded using an 11-mm twin-screw co-rotating extruder. Scanning electron microscopy (SEM) was used to study the morphology of the extruded filaments. Furthermore, Fourier-transform infrared spectroscopy (FT-IR) was performed to check the intermolecular interactions of the components. Finally, to assess the in vitro drug release of the ASDs, dissolution testing was conducted in phosphate buffer (0.1 M, pH 7.4) and hydrochloric acid–potassium chloride (HCl-KCl) buffer (0.1 M, pH 1.2). The DSC studies confirmed the formation of the ASDs, and the drug content of the extruded filaments was observed to be within an acceptable range. Furthermore, the study concluded that the formulations containing poloxamer P407 exhibited a significant increase in dissolution performance compared to the filaments with only HPMC-AS HG (at pH 7.4). In addition, the optimized formulation, F3, was stable for over 3 months when exposed to accelerated stability studies. [ABSTRACT FROM AUTHOR]

Particulate amorphous solid dispersions (ASDs) have been recognised for their potential to enhance the performance of various solid dose forms, especially oral bioavailability and macromolecule stability. However, the inherent nature of spray-dried ASDs leads to their surface cohesion/adhesion, including hygroscopicity, which hinders their bulk flow and affects their utility and viability in terms of powder production, processing, and function. This study explores the effectiveness of L-leucine (L-leu) coprocessing in modifying the particle surface of ASD-forming materials. Various contrasting prototype coprocessed ASD excipients from both the food and pharmaceutical industries were examined for their effective coformulation with L-leu. The model/prototype materials included maltodextrin, polyvinylpyrrolidone (PVP K10 and K90), trehalose, gum arabic, and hydroxypropyl methylcellulose (HPMC E5LV and K100M). The spray-drying conditions were set such that the particle size difference was minimised, so that it did not play a substantial role in influencing powder cohesion. Scanning electron microscopy was used to evaluate the morphology of each formulation. A combination of previously reported morphological progression typical of L-leu surface modification and previously unreported physical characteristics was observed. The bulk characteristics of these powders were assessed using a powder rheometer to evaluate their flowability under confined and unconfined stresses, flow rate sensitivities, and compactability. The data showed a general improvement in maltodextrin, PVP K10, trehalose and gum arabic flowability measures as L-leu concentrations increased. In contrast, PVP K90 and HPMC formulations experienced unique challenges that provided insight into the mechanistic behaviour of L-leu. Therefore, this study recommends further investigations into the interplay between L-leu and the physico-chemical properties of coformulated excipients in future amorphous powder design. This also revealed the need to enhance bulk characterisation tools to unpack the multifactorial impact of L-leu surface modification. [ABSTRACT FROM AUTHOR]

Drug amorphization is one of the major approaches in pharmaceutical sciences to improve the solubility and dissolution rate of poorly water-soluble drugs. Amorphous solid dispersions are widely discussed approach to convert the drug into an amorphous state but due to its high energy state, the system tends to recrystallize upon storage. Co-amorphous system is a single-phase low energy system that falls under the glass solution, a type of solid dispersion. Being low-energy state and single-phase, co-amorphous dispersions are more stable than amorphous solid dispersions. In co-amorphous dispersions, the homogeneous single phase is formed only with low molecular weight co-formers, so the amount of co-former required is relatively low and this reduces the bulk of the system. This aspect of co-amorphous dispersions makes it popular over the amorphous solid dispersions in the area of solid dispersion researchers. This review provides an overview of co-amorphous dispersions and their recent advances. Particularly, this review will discuss various factors (physical and chemical) that affect and provide the stability of the co-amorphous dispersions formulation. [ABSTRACT FROM AUTHOR]

Spray drying is one of the most frequently used solvent-based processes for manufacturing amorphous solid dispersions (ASDs). However, the resulting fine powders usually require further downstream processing when intended for solid oral dosage forms. In this study, we compare properties and performance of spray-dried ASDs with ASDs coated onto neutral starter pellets in mini-scale. We successfully prepared binary ASDs with a drug load of 20% Ketoconazole (KCZ) or Loratadine (LRD) as weakly basic model drugs and hydroxypropyl-methyl-cellulose acetate succinate or methacrylic acid ethacrylate copolymer as pH-dependent soluble polymers. All KCZ/ and LRD/polymer mixtures formed single-phased ASDs, as indicated by differential scanning calorimetry, X-ray powder diffraction and infrared spectroscopy. All ASDs showed physical stability for 6 months at 25 °C/65% rH and 40 °C/0% rH. Normalized to their initial surface area available to the dissolution medium, all ASDs showed a linear relationship of surface area and solubility enhancement, both in terms of supersaturation of solubility and initial dissolution rate, regardless of the manufacturing process. With similar performance and stability, processing of ASD pellets showed the advantages of a superior yield (>98%), ready to use for subsequent processing into multiple unit pellet systems. Therefore, ASD-layered pellets are an attractive alternative in ASD-formulation, especially in early formulation development at limited availability of drug substance. [ABSTRACT FROM AUTHOR]

Based on a working fluid consisting of a poorly water-soluble drug and a pharmaceutical polymer in an organic solvent, electrospinning has been widely exploited to create a variety of amorphous solid dispersions However, there have been very few reports about how to prepare the working fluid in a reasonable manner. In this study, an investigation was conducted to determine the influences of ultrasonic fluid pretreatment on the quality of resultant ASDs fabricated from the working fluids. SEM results demonstrated that nanofiber-based amorphous solid dispersions from the treated fluids treated amorphous solid dispersions exhibited better quality than the traditional nanofibers from untreated fluids in the following aspects: 1) a straighter linear morphology; 2) a smooth surface; and 3) a more evener diameter distribution. The fabrication mechanism associated with the influences of ultrasonic treatments of working fluids on the resultant nanofibers’ quality is suggested. Although XRD and ATR–FTIR experiments clearly verified that the drug ketoprofen was homogeneously distributed all over the TASDs and the traditional nanofibers in an amorphous state regardless of the ultrasonic treatments, the in vitro dissolution tests clearly demonstrated that the TASDs had a better sustained drug release performance than the traditional nanofibers in terms of the initial release rate and the sustained release time periods.

The impact of residual drug crystals that are formed during the production and storage of amorphous solid dispersions (ASDs) has been studied using micron-sized seed crystals in solvent-shift (desupersaturation) and dissolution tests. This study examines the impacts of the seed size loading on the solution-mediated precipitation from griseofulvin ASDs. Nanoparticle crystals (nanoseeds) were used as a more realistic surrogate for residual crystals compared with conventional micron-sized seeds. ASDs of griseofulvin with Soluplus (Sol), Kollidon VA64 (VA64), and hydroxypropyl methyl cellulose (HPMC) were prepared by spray-drying. Nanoseeds produced by wet media milling were used in the dissolution and desupersaturation experiments. DLS, SEM, XRPD, and DSC were used for characterization. The results from the solvent-shift tests suggest that the drug nanoseeds led to a faster and higher extent of desupersaturation than the as-received micron-sized crystals and that the higher seed loading facilitated desupersaturation. Sol was the only effective nucleation inhibitor; the overall precipitation inhibition capability was ranked: Sol > HPMC > VA64. In the dissolution tests, only the Sol-based ASDs generated significant supersaturation, which decreased upon an increase in the nanoseed loading. This study has demonstrated the importance of using drug nanocrystals in lieu of conventional coarse crystals in desupersaturation and dissolution tests in ASD development. [ABSTRACT FROM AUTHOR]