Search Results (39)

Amorphous solid dispersion (ASD) technology is popularly used for enhancing the solubility of poorly water-soluble drugs. Drug molecules in ASDs can be dispersed in the form of either amorphous (AASD) or molecular (MASD) forms. The boundary between AASDs and MASDs (A–M boundary) is defined as the drug concentration at which the existence of MASDs obviously influences the physicochemical properties of ASDs. In this work, fluorescence spectroscopy based on the aggregation-caused quenching (ACQ) phenomenon was used to determine the A–M boundary of curcumin (CUR) ASDs prepared via neat ball milling. The relationship between the fluorescence intensity and the loading of CUR in the sample is consistent with the Stern–Volmer equation. For the CUR ASDs with PVP, the samples with CUR loading below 10% show significantly increased fluorescence and have a higher solubility (~178 μg·mL⁻¹), suggesting the A–M boundary is around 10%. Similar A–M boundaries around 10% were also observed for CUR ASDs with PVPVA, Soluplus, HPMC, and HPMCAS. It is of great significance to define the A–M boundary of ASDs for guiding pharmaceutical ASD formulas by balancing drug loading, stability, and solubility. Full article

Background/Objectives: Triamcinolone acetonide (TA), a poorly water-soluble corticosteroid, presents formulation challenges due to limited membrane permeability. This study aimed to identify suitable drug–polymer–plasticizer systems for TA using combined theoretical and experimental methods. Methods: Using Hansen solubility parameters, seven hot-melt extrusion (HME)-grade polymers and four plasticizers were initially screened for miscibility with TA. Based on Δδt values, four polymers—Eudragit^® L100 (EUD), Parteck^® MXP (PVA), Plasdone^® S-630 (PVPVA), and Aquasolve™ AS-MG (HPMCAS)—along with triethyl citrate (TEC), were selected for experimental evaluation. Differential scanning calorimetry, thermogravimetric analysis, and Fourier transform infrared spectroscopy assessed thermal behavior, miscibility, and chemical compatibility. Results: Amorphous TA content was highest with EUD (81.1%), followed by PVA (67.5%), PVPVA (45.6%), and HPMCAS (8.5%). Thermal incompatibility and TEC evaporation were observed in PVA, PVPVA, and HPMCAS systems. FTIR suggested TEC should be avoided in melt-based formulations with PVA and PVPVA due to PVA degradation and partial TA oxidation. No significant interactions were detected in HPMCAS samples heated to 220 °C, aligning with theoretical predictions. In contrast, the EUD–TEC system showed limited chemical reactivity and maintained TA’s structural integrity. Infrared bands at 1758 and 1802 cm⁻¹ indicated minor anhydride formation above 160 °C with partial TEC evaporation. Conclusions: EUD/TEC were identified as a promising combination for the HME processing of TA. This work supports the rational formulation of stable amorphous systems for thermolabile drugs with poor solubility. Full article

Multi-drug delivery systems have gained increasing interest from the pharmaceutical industry. Alongside this is the interest in amorphous solid dispersions as an approach to achieve effective oral delivery of compounds with solubility-limited bioavailability. Despite this, there is limited information regarding predicting the behavior of two or more drugs (in amorphous forms) in a polymeric carrier and whether molecular interactions between the compounds, between each compound, and if the polymer have any effect on the physical properties of the system. This work studies the interaction between model drug combinations (two of ibuprofen, malonic acid, flurbiprofen, or naproxen) dispersed in a polymeric matrix of hypromellose acetate succinate (HPMCAS) using a solvent evaporation technique. Hildebrand and Hansen calculations were used to predict the miscibility of compounds as long as the difference in their solubility parameter values was not greater than 7 MPa^1/2. It was observed that the selected APIs (malonic acid, ibuprofen, naproxen, and flurbiprofen) were miscible within the formed polymeric matrix. Adding the API caused depression in the Tg of the polymer to certain concentrations (17%, 23%, 13%) for polymeric matrices loaded with malonic acid, ibuprofen, and naproxen, respectively. Above this, large crystals started to form, and phase separation was seen. Adding two APIs to the same matrix resulted in reducing the saturation concentration of one of the APIs. A trend was observed and linked to Hildebrand and Hansen solubility parameters (HSP). Full article

Phase separation is quite common in formulations for hydrophobic active pharmaceutical ingredients (APIs) due to their thermodynamic instability in a supersaturated state during in vitro dissolution or in vivo absorption. Phase separation possibly accompanies the formation of a disordered drug-rich phase, but this is still not thoroughly understood. In this study, the phase separation of supersaturated axitinib (Axi) in media with or without polymers was evaluated via multiple analytical methods, including UV–vis and fluorescence spectroscopy, dynamic light scattering, and microscopy. The phase separation of Axi occurred at an Axi concentration of 25–30 µg/mL in the media, while the addition of quantitative hypromellose acetate succinate (HPMCAS) MG and povidone (PVP) K30 did not alter its phase separation concentration. The second scattering dispersion phase of the system exhibited superior stability and reversibility as the formative filamentous crystalline condensates could disintegrate upon dilution. These disparate analyses consistently detected the phase separation of Axi. This manuscript could provide a better understanding of the supersaturation state of hydrophobic APIs upon pharmaceutical application. Full article

Background/Objectives: Drug–polymer interactions and miscibility promote the formation and performance of amorphous solid dispersions (ASDs) of poorly soluble drugs for improved oral bioavailability. The objective of this study was to employ drug–polymer interaction calculations and small-scale experimental characterization to screen polymers for potential ASDs of ritonavir. Methods: Seven polymers across four polymer types were screened as follows: an enteric one (EudragitS100), amphiphilic ones (HPMCAS-L, HPMCAS-H, and their 1:1 combination), hydrophilic ones (PEG-6000, PVP-VA), and a surfactant (Soluplus), including PVP-VA as a positive control, as the commercial ASD employs PVP-VA. Drug–polymer interaction calculations were performed for Hansen solubility parameter, Flory–Huggins parameter, and glass transition temperature. ASDs were prepared via film casting. Experimental characterizations included drug solubility in polymer solutions, polymer inhibition of drug precipitation, polarized light microscopy, differential scanning calorimetry, solubilization capacity, and dissolution studies. Results: HPMCAS-L, HPMCAS L:H, and Soluplus, along with the positive control PVP-VA, were identified as polymers for potential ASDs of ritonavir, with HPMCAS-L and PVP-VA being preferable. HPMCAS-L and the positive control PVP-VA were always viable for both 20% and 40% drug loads across all tests. Films with each of these four polymers showed improved dissolution compared to amorphous ritonavir without polymer. Drug–polymer interaction calculations anticipated the unfavorable small-scale experimental results for PEG-6000 and EudragitS100. Conclusion: Overall, the results contribute towards a resource-sparing approach to identify polymers for ASDs. Full article

Today, therapeutic candidates with low solubility have become increasingly common in pharmaceutical research pipelines. Several techniques such as hot melt extrusion, spray drying, supercritical fluid technology, electrospinning, KinetiSol, etc., have been devised to improve either or both the solubility and dissolution to enhance the bioavailability of these active substances belonging to BCS Class II and IV. The principle involved in all these preparation techniques is similar, where the crystal lattice of the drug is disrupted by either the application of heat or dissolving it in a solvent and the movement of the fine drug particles is arrested with the help of a polymer by either cooling or drying to remove the solvent. The dispersed drug particles in the polymer matrix have higher entropy and enthalpy and, thereby, higher free energy in comparison to the crystalline drug. Povidone, polymethaacrylate derivatives, hydroxypropyl methyl cellulose (HPMC) and hydroxypropyl methylcellulose acetate succinate derivatives are commonly used as polymers in the preparation of ASDs. Specifically, hydroxypropylmethylcellulose acetate succinate (HPMCAS)-based ASDs have become well established in commercially available products and are widely explored to improve the solubility of poorly soluble drugs. This article provides an analysis of two widely used manufacturing techniques for HPMCAS ASDs, namely, hot melt extrusion and spray drying. Additionally, details of HPMCAS-based ASD marketed products and patents have been discussed to emphasize the commercial aspect. Full article

Dual-nozzle fused deposition modeling (FDM) is a 3D printing technique that allows for the simultaneous printing of two polymeric filaments and the design of complex geometries. Hence, hybrid formulations and structurally different sections can be combined into the same dosage form to achieve customized drug release kinetics. The objective of this study was to develop a novel bicompartmental device by dual-nozzle FDM for colon-specific drug delivery. Hydroxypropylmethylcellulose acetate succinate (HPMCAS) and polyvinyl alcohol (PVA) were selected as matrix-forming polymers of the outer pH-dependent and the inner water-soluble compartments, respectively. 5-Aminosalicylic acid (5-ASA) was selected as the model drug. Drug-free HPMCAS and drug-loaded PVA filaments suitable for FDM were extruded, and their properties were assessed by thermal, X-ray diffraction, microscopy, and texture analysis techniques. 5-ASA (20% w/w) remained mostly crystalline in the PVA matrix. Filaments were successfully printed into bicompartmental devices combining an outer cylindrical compartment and an inner spiral-shaped compartment that communicates with the external media through an opening. Scanning electron microscopy and X-ray tomography analysis were performed to guarantee the quality of the 3D-printed devices. In vitro drug release tests demonstrated a pH-responsive biphasic release pattern: a slow and sustained release period (pH values of 1.2 and 6.8) controlled by drug diffusion followed by a faster drug release phase (pH 7.4) governed by polymer relaxation/erosion. Overall, this research demonstrates the feasibility of the dual-nozzle FDM technique to obtain an innovative 3D-printed bicompartmental device for targeting 5-ASA to the colon. Full article

Spray-dried amorphous solid dispersions of new chemical entities and pH-dependent soluble polymer hydroxypropyl methylcellulose acetate succinate (HPMC-AS) were found to form solid agglomerates in the gastrointestinal tract of rodents after oral administration. These agglomerates, referring to descriptions of intra-gastrointestinal aggregated oral dosage forms termed pharmacobezoars, represent a potential risk for animal welfare. Previously, we introduced an in vitro model to assess the agglomeration potential of amorphous solid dispersions from suspensions and how it can be reduced. In this work, we investigated if the in vitro effective approach of viscosity enhancement of the vehicle used to prepare suspensions of amorphous solid dispersions could reduce the pharmacobezoar formation potential following repeated daily oral dosing to rats as well. The dose level of 2400 mg/kg/day used in the main study was determined in a dose finding study carried out in advance. In the dose finding study, MRI investigations were carried out at short time intervals to gain insights into the process of pharmacobezoar formation. Whereas MRI investigations underlined the importance of the forestomach for the formation of pharmacobezoars, viscosity enhancement of the vehicle reduced the incidence of pharmacobezoars, delayed the onset of pharmacobezoar formation and reduced the overall mass of pharmacobezoars found at necropsy. Full article

This study aimed to develop a cyclosporine A (CsA)-loaded ternary solid dispersion (tSD/CsA) to improve the storage stability of a solid dispersion (SD) system and the oral absorbability of CsA. Hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose acetate succinate (HPMCAS) were selected as carrier materials of tSD, and tSD/CsA was prepared with a fine droplet drying process, a powderization technology that employs an inkjet head. The physicochemical properties of tSD/CsA were evaluated in terms of morphology, storage stability, dissolution behavior, and mucoadhesive property. After the oral administration of CsA samples (10 mg-CsA/kg) to rats, the plasma concentration of CsA was monitored to estimate oral absorbability. tSD/CsA comprised uniform shriveled particles with a diameter of 3.4 mm and span factor of 0.4, which is a parameter to estimate the particle size distribution. Although HPC-based binary SD showed marked aggregation of the particles after storage under 40 °C/75% relative humidity, there were no significant aggregations of tSD/CsA, due to the relatively low hygroscopic property of HPMCAS. The pH-dependent release of CsA with improved dissolution was observed in tSD/CsA. In the in vitro mucoadhesive evaluation using a mucin disk, tSD/CsA exhibited a better mucoadhesive property than HPC-based SD, possibly leading to prolonged retention of tSD particles in the gastrointestinal tract after oral administration. Orally-dosed tSD/CsA in rats resulted in significantly improved oral absorption of CsA, as evidenced by a 27-fold higher bioavailability than amorphous CsA. tSD/CsA may be a promising dosage option to improve the storage stability of a SD system and the biopharmaceutical properties of CsA. Full article

The aim of this study was to improve the solubility, bioavailability, and stability of resveratrol (RES-SD) Solid Dispersion in Polygonum cuspidatum extract (PCE) by hot melt extrusion (HME). In addition, the role of the auxiliary substances in PCE was also studied. The solid dispersion of Polygonum cuspidatum extract was prepared by hot-melt extrusion. The optimum formula was selected by single factor design and orthogonal test. The optimum formula was barrel temperature 140 °C, screw rotation speed 40 rpm/min, and the ratio of Polygonum cuspidatum extract to HPMCAS was 1:2. The dissolution test showed that PCE-SD increased the dissolution of RES from 46.75 ± 0.47% to 130.06 ± 0.12%. The pharmacokinetics curve of rats showed that PCE-SD increased AUC0-t of RES from 111,471.22 ± 11.4% to 160,458.968 ± 15.7%, indicating an approximately 1.44-fold increase in absorption. In addition, the rotation speed of PCE-SD screw is less than that of RES-SD screw. The bioavailability of PCE-SD was slightly better than that of RES-SD. PCE-SD is more hygroscopic than RES-SD. PCE-SD increased the solubility and oral bioavailability of RES. The auxiliary substances in Polygonum cuspidatum extract have influence on its preparation technology, stability, and bioavailability. Full article

PROteolysis TArgeting Chimaeras (PROTACs) offer new opportunities in modern medicine by targeting proteins that are undruggable to classic inhibitors. However, due to their hydrophobic structure, PROTACs typically suffer from low solubility, and oral bioavailability remains challenging. At the same time, due to their investigative state, the drug supply is meager, leading to limited possibilities in terms of formulation development. Therefore, we investigated the solubility enhancement employing mini-scale formulations of amorphous solid dispersions (ASDs) and liquisolid formulations of the prototypic PROTAC ARCC-4. Based on preliminary supersaturation testing, HPMCAS (L Grade) and Eudragit^® L 100-55 (EL 100-55) were demonstrated to be suitable polymers for supersaturation stabilization of ARCC-4. These two polymers were selected for preparing ASDs via vacuum compression molding (VCM), using drug loads of 10 and 20%, respectively. The ASDs were subsequently characterized with respect to their solid state via differential scanning calorimetry (DSC). Non-sink dissolution testing revealed that the physical mixtures (PMs) did not improve dissolution. At the same time, all ASDs enabled pronounced supersaturation of ARCC-4 without precipitation for the entire dissolution period. In contrast, liquisolid formulations failed in increasing ARCC-4 solubility. Hence, we demonstrated that ASD formation is a promising principle to overcome the low solubility of PROTACs. Full article

Luteolin (LUT), a bioactive flavonoid, possesses various pharmacological properties, including antioxidant, antimicrobial, anti-allergic, cardio-protective, and anti-cancer activity. Among them, LUT’s administration for the treatment of periodontal disease is very promising. However, its low water solubility magnifies the challenge of formulating LUT into an effective dosage form. In this vein, the aim of the present study examines the preparation of amorphous solid dispersions (ASD) for the solubility improvement of LUT in saliva. At first, the physicochemical properties of the active pharmaceutical ingredient (API) were studied before the selection of the most suitable ASD matrix/carrier. For this reason, six commonly used polymeric ASD matrix/carriers (namely, povidone, PVP; copovidone, coPVP; hydroxypropyl cellulose, HPC-SL; hydroxypropyl methyl cellulose acetate succinate, HPMC-AS; Eudragit^® RS, Eud-RS; and Soluplus^®, SOL) were screened via the film casting method, as to whether they could suspend the drug’s recrystallization. The most promising matrix/carriers were then evaluated, based on their ability to inhibit LUT’s precipitation after its solubilization, via the solvent shift method. Based on both screening methods, it was determined that PVP was the most promising matrix/carrier for the preparation of LUT’s ASDs. Hence, in a further step, after the successful testing of components’ miscibility, LUT-PVP ASDs were prepared via the solvent evaporation method. These systems (examined via powder X-ray diffractometry, pXRD) showed full API amorphization immediately after preparation and excellent physical stability (since they were stable after 3 months of storage). The study of LUT-PVP ASD’s ATR-FTIR (Attenuated Total Reflectance-Fourier Transform Infrared) spectra demonstrated strong H-bonds between the molecules of the drug and the matrix/carrier, while molecular dynamics (MD) simulations were able to shed light on these drug–matrix/carrier interactions, at a molecular level. Finally, in vitro dissolution studies in simulated saliva proved that the prepared ASDs were able to significantly enhance LUT’s dissolution profile. Hence, according to findings of the present work, the preparation of LUT-ASDs utilizing PVP as the polymeric matrix/carrier is regarded as a highly promising technique for the improvement of API’s solubility in the oral cavity. Full article

Amorphous solid dispersion (ASD) is one of the most promising technologies for improving the oral absorption of poorly soluble compounds. In this study, naftopidil (NFT) ASDs were prepared using vinylpyrrolidone-vinyl acetate copolymer (PVPVA), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and poly(methacrylic acid-co-methyl methacrylate) L100-55 (Eudragit) to improve the dissolution and oral absorption behaviors of NFT. During the dissolution process of ASD, liquid–liquid phase separation (LLPS) may occur when certain requirements are met for providing a maximum quasi-stable concentration achievable by amorphization. The occurrence of LLPS was confirmed in the presence of PVPVA and HPMCAS; however, Eudragit inhibited LLPS owing to its molecular interaction with NFT. Although the dissolution behavior of the Eudragit ASD was found to be markedly poorer than that of other ASDs, it offered the best oral absorption in rats. The findings of the current study highlight the possibility for improving the oral absorption of poorly soluble drugs by this ASD, which should be eliminated from candidate formulations based on the conventional in vitro tests. Full article

The formation of pharmacobezoars from suspensions of spray-dried amorphous solid dispersions (SD-ASDs) of new chemical entities (NCEs) and hydroxypropyl methylcellulose acetate succinate (HPMC-AS) represents a non-compound related adverse effect in preclinical oral toxicity studies in rodents. Whereas the contribution of the insolubility of the carrier polymer to this process taking place in the acidic environment of the rodent stomach is conclusive, unawareness of the extent of in vivo pharmacobezoar formation is adverse. In order to evaluate the risk of pharmacobezoar formation before in vivo administration, we subsequently introduce an in vitro model to assess the agglomeration potential of solid dispersions. To verify that the pharmacobezoar formation potential can be assessed based on the observed agglomeration potential, we conducted a sequence of experiments with two HPMC-AS-based SD-ASD formulations. In vitro, we found their different in vivo pharmacobezoar formation potential reflected by a significantly increased agglomerated mass of formulation 1 per day compared to formulation 2. In order to find an approach to reduce the agglomeration potential of solid dispersion from suspensions, we further applied the model to investigate the impact of the viscosity of the vehicle used to prepare suspensions on agglomerate formation. Full article

The pH–induced crystallization of weakly basic drugs in the small intestine limits oral bioavailability. In this study, we investigated the solubilization and inhibitory effects on nintedanib in the presence of enteric polymers (HPMCAS LG, HPMCAS MG, Eudragit L100 55, and Eudragit L100). These polymers provided maintenance of supersaturation by increasing the solubility of nintedanib in PBS 6.8 in a concentration-dependent manner, and the improved ranking was as follows: Eudragit L100 > Eudragit L100 55 > HPMCAS MG > HPMCAS LG. After being formulated into amorphous solid dispersions (ASDs) by a solvent evaporation method, the drug exhibited an amorphous state. The pH shift dissolution results of polymer-ASDs demonstrated that four polymers could effectively maintain the drug supersaturation even at the lowest ratio of nintedanib and polymer (1:1, w/w). Eudragit L100–ASD could provide both acid resistance and the favorable mitigation of crystallization in GIF. In comparison to the coarse drug, the relative bioavailability of Eudragit L100–ASD was 245% after oral administration in rats, and T_max was markedly delayed from 2.8 ± 0.4 h to 5.3 ± 2.7 h. Our findings indicate that enteric ASDs are an effective strategy to increase the intestinal absorption of nintedanib by improving physiologically generated supersaturation and subsequent crystallization. Full article