A novel method for preparing stabilized amorphous solid dispersion drug formulations using acoustic fusion.

The present study was designed to determine the applicability of a newly derived dimensionless number precipitation parameter, "supersaturation holding capacity (SHC)" in development of amorphous solid dispersion (ASD) of a rapidly crystallizing drug, nisoldipine. Also, ASD preparation from lab scale formulation technique to scalable spray drying technique followed by oral bioavailability study was demonstrated. Solution state screening of polymers was performed by determining nucleation induction time (tin) and SHC. With screened polymers, lab scale ASDs of nisoldipine were prepared using rotary evaporation (solvent evaporation) method, and the optimized stable ASDs were scaled up by spray drying. The ASDs were characterized by DSC, PXRD, and FTIR for amorphous nature and evaluated for apparent solubility, dissolution, and solid-state stability improvement. The spray dried ASDs were additionally evaluated for micrometric properties and oral bioavailability study.PVP grades demonstrated superior crystal growth inhibition properties (with 2-4-fold enhancements in SHC). ASDs prepared by both lab scale and scale-up technique using PVP stabilized the amorphous nisoldipine via antiplasticization effect that maintained the stability under accelerated stability conditions (40°C/75% RH) for 6months. Additionally, FTIR study confirmed the role of intermolecular interactions in amorphous state stabilization of PVP-based solid dispersions. PVP-based spray dried ASDs improved the apparent solubility 4-fold for PVP K17 and more than 3-fold for remaining spray dried ASDs. The enhanced solubility was translated to improved dissolution of the drug when compared with crystalline and amorphous form complementing the outcome of the solution state study. The spray dried ASD showed 2.3 and > 3-fold the improvement in Cmax and AUC (0-24h) respectively when compared with crystalline nisoldipine during oral bioavailability study which highlights the significance of SHC parameter of polymers. The spray dried ASD has shown improved micromeritics properties then crystalline nisoldipine in terms of flow behavior.This unique study provides a rational strategy for selection of appropriate polymer in development of ASDs that can tackle both precipitation during dissolution and amorphous state stabilization in solid state and also considers the SHC in scale-up study. Graphical abstract.

Simvastatin(SMV) is poorly soluble drug classified as belonging to Class II of BiopharmaceuticsClassification System. Common approach to improve apparent solubility of drugsis production of amorphous solid dispersions (ASD) by means of spray drying(SD) or hot-melt extrusion. Spray drying of low-glass transition temperature(Tg) ASDs is challenging due to the risk of material being exposed to SD outlettemperatures close to its Tg which may result in melting of ASD and subsequentcrystallisation of amorphous drug. It was hypothesised that addition ofeasily-crystallising material to ASD will improve its SD processability. Inaddition, it was hypothesised that produced ternary solid dispersions (TSD)composed of amorphous composite of drug and the polymer (PVP K17, 55 and 150) andcrystalline, soluble nanoparticles (NaCl) will improve dissolution of TSDtablets. The dissolution of SMV fromTSDs was faster compared with that of binary solid dispersion in case of SMV-TSDsproduced with PVP K55 and 150. The tabletabilityassessment showed increase in compression led to increase in tensile strengthand decrease in porosities of SDs tablets.

Comparative study of Hot-Melt Extrusion, spray drying, and KinetiSol® processing to formulate a poorly water-soluble and thermolabile drug.

The presented study describes the development of a membrane permeation non-sink dissolution method that can provide analysis of complete drug speciation and emulate the in vivo performance of poorly water-soluble Biopharmaceutical Classification System class II compounds. The designed membrane permeation methodology permits evaluation of free/dissolved/unbound drug from amorphous solid dispersion formulations with the use of a two-cell apparatus, biorelevant dissolution media, and a biomimetic polymer membrane. It offers insight into oral drug dissolution, permeation, and absorption. Amorphous solid dispersions of felodipine were prepared by hot melt extrusion and spray drying techniques and evaluated for in vitro performance. Prior to ranking performance of extruded and spray-dried felodipine solid dispersions, optimization of the dissolution methodology was performed for parameters such as agitation rate, membrane type, and membrane pore size. The particle size and zeta potential were analyzed during dissolution experiments to understand drug/polymer speciation and supersaturation sustainment of felodipine solid dispersions. Bland-Altman analysis was performed to measure the agreement or equivalence between dissolution profiles acquired using polymer membranes and porcine intestines and to establish the biomimetic nature of the treated polymer membranes. The utility of the membrane permeation dissolution methodology is seen during the evaluation of felodipine solid dispersions produced by spray drying and hot melt extrusion. The membrane permeation dissolution methodology can suggest formulation performance and be employed as a screening tool for selection of candidates to move forward to pharmacokinetic studies. Furthermore, the presented model is a cost-effective technique.

The influence of hydrogen bonding between different crystallization tendency drugs and PVPVA on the stability of amorphous solid dispersions

Continuous production of itraconazole-based solid dispersions by hot melt extrusion: Preformulation, optimization and design space determination

Corroborating various material-sparing techniques with hot melt extrusion for the preparation of triclabendazole amorphous solid dispersions

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.

Oral delivery of poorly water-soluble, weakly basic drugs may be problematic based on the drugs' intrinsic properties. Many drugs in this subset have overcome barriers to delivery following successful formulation as amorphous solid dispersions (ASDs). To process drugs as ASDs, multiple commercially relevant technologies have been developed and become well understood. However, ASD-producing technologies like spray drying and KinetiSol produce ASDs with vastly differing particle characteristics. Ultimately, the objective of this study was to assess whether processing an ASD of identical composition utilizing two different ASD-producing technologies (KinetiSol and spray drying) may impact the oral bioavailability of a weakly basic drug. For this study, we selected a weakly basic drug (Boehringer Ingelheim research compound 639667, BI 667) and processed it with an anionic polymer (hypromellose acetate succinate MMP grade (HPMCAS-MMP)) to evaluate whether the processing technology could modulate drug release in acidic and neutral media. Multiple characterization techniques (specific surface area (SSA), particle size distribution (PSD), scanning electron microscopy (SEM)) were utilized to evaluate the surface characteristics and differences in particles produced by KinetiSol and spray drying. Molecular interactions and drug-polymer miscibility of the processed particles were assessed using Fourier transform infrared spectroscopy and solid-state nuclear magnetic resonance, respectively. In vitro nonsink, pH-shift dissolution in biorelevant media and dissolution/permeation studies were conducted to better understand the release of BI 667 based on processing technology and particle size distribution. Finally, an in vivo male Beagle dog study was conducted to assess the impact of processing technology on oral bioavailability. In this study, we demonstrate that particles produced by KinetiSol have enhanced oral bioavailability compared with spray-dried particles when delivering a weakly basic drug processed with an anionic polymer. The findings of this study demonstrate that by utilizing KinetiSol, drug release may be controlled such that supersaturation in acidic media is inhibited and supersaturation of the drug is designed to occur in neutral media, ultimately enhancing oral bioavailability.

Bottom-Up and Top-Down Approaches to Explore Sodium Dodecyl Sulfate and Soluplus on the Crystallization Inhibition and Dissolution of Felodipine Extrudates

Development of stability-enhanced ternary solid dispersions via combinations of HPMCP and Soluplus® processed by hot melt extrusion

Spray drying is one of the most commonly used manufacturing techniques for amorphous solid dispersions (ASDs). During spray drying, very fast solvent evaporation is enabled by the generation of small droplets and exposure of these droplets to a heated drying gas. This fast solvent evaporation leads to an increased viscosity that enables kinetic trapping of an active pharmaceutical ingredient (API) in a polymer matrix, which is favorable for the formulation of supersaturated, kinetically stabilized ASDs. In this work, the relation between the solvent evaporation rate and the kinetic stabilization of highly drug-loaded ASDs was investigated. Accordingly, thermal gravimetric analysis (TGA) was employed to study the evaporation kinetics of seven organic solvents and the influence of solutes, i.e., poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA), fenofibrate (FNB), and naproxen (NAP), on the evaporation behavior. At 10 °C below the boiling point of the respective solvent, methanol (MeOH) had the lowest evaporation rate and dichloromethane (DCM) had the highest. PVPVA decreased the evaporation rate for all solvents, yet this effect was more pronounced for the relatively faster evaporating solvents. The APIs had opposite effects on the evaporation process: FNB increased the evaporation rate, while NAP decreased it. The latter might indicate the presence of interactions between NAP and the solvent or NAP and PVPVA, which was further investigated using Fourier transform-InfraRed (FT-IR) spectroscopy. Based on these findings, spray drying process parameters were adapted to alter the evaporation rate. Increasing the evaporation rate of MeOH and DCM enabled the kinetic stabilization of higher drug loadings of FNB, while the opposite trend was observed for ASDs of NAP. Even when higher drug loadings could be kinetically stabilized by adapting the process parameters, the improvement was limited, demonstrating that the phase behavior of these ASDs of FNB and NAP immediately after preparation was predominantly determined by the API-polymer-solvent combination rather than the process parameters applied.

Solid-state analysis of amorphous solid dispersions: Why DSC and XRPD may not be regarded as stand-alone techniques

One of the biggest challenges for the application of materials extrusion (ME) technology in the pharmaceutical sector is the lack of ready-to-use polymeric materials (filaments) of pharmaceutical quality. To overcome this challenge materials extrusion can be combined with the Hot Melt Extrusion (HME) process enabling the production of filaments using pharmaceutically approved polymers with incorporated drugs. This manuscript presents a step by step approach for the formulation of additively manufactured tablets containing a high melting point API (hydrochlorothiazide, HCT, T m = 266-268 °C) with two pharmaceutically approved polymers (polyvinyl alcohol, PVA and hydroxypropyl methylcellulose acetate succinate, HPMCAS) of different technological and pharmaceutical properties via combined HME and ME processing. The thermal properties of a model drug were adapted to the processing window of both HME and ME by obtaining a hydrochlorothiazide: nicotinamide cocrystal (HCT:NIC) with a lower melting point (T m = 173.3 °C) than the starting material. Two plasticizers were used - triethyl citrate (TEC) for HPMCAS and sorbitol (SOR) for PVA. Blends containing 10-50 wt. % of plasticizer were prepared using the fusion method and thoroughly analysed using PXRD, DSC, and FTIR enabling the selection of formulations for further HME processing. Placebo filaments with 10-30 wt. % of plasticizer were obtained and their mechanical properties and ME processability were assessed to select a polymer blend with desirable process parameters. Finally, the filaments containing 20 wt. % of plasticizer with HCT or the HCT:NIC cocrystal were produced and processed using ME to form tablets. The phase of the drug (crystalline or amorphous), mechanical properties of filaments and tablets as well as the drug content in the obtained materials were assessed using PXRD, DSC, and FTIR followed by materials imaging with polarising microscopy and SEM. The cocrystal formation not only enabled to modify the melting point of the drug to match the temperature of both processes but also improved the mechanical properties of the filaments which is important for ME processing. In the case of PVA based formulations the cocrystal turned amorphous upon HME processing forming flexible and printable filaments. In contrast, the drug embedded in HPMCAS based filaments formed crystals that affected the mechanical properties of the extrudates. The mechanical properties of the obtained tablets and the release profile of the drug from the AM tablets were enhanced as compared to the materials obtained using conventional methods, i.e. tableting and encapsulation. • High melting drugs can be incorporated into pharmaceutically approved polymers in the form of cocrystals via combined HME and ME processing, • Modification of physicochemical properties of the API via cocrystal formation enables successful processing of high melting point APIs into elastic filaments, • Low miscibility of the drug with polymers and the presence of crystalline drug in the filaments may result in brittle materials difficult to process via ME, • Openwork 3D tablet structure and cocrystal formation substantially improve drug dissolution.

Ritonavir (RTN) is frequently administered as a drug metabolism inhibitor to “boost” other drugs, such as nirmatrelvir to treat COVID-19. However, like many orally administered drugs, RTN has low water solubility. Hence, RTN is formulated as an amorphous solid dispersion (ASD). The objective was to prepare an optimal RTN- spray dried dispersion (SDD) via spray drying. Using the polymer HPMCAS-L, an optimal spray drying condition was identified, where aspirator rate, spray gas flow, and solution feed rate were varied in a 23 (3 repeated) full factorial design. Yield %, moisture %, and Carr index were assessed. Optimal spray drying conditions were aspirator rate of 38 m3/h, spray gas flow rate of 742 L/h, and solution feed rate of 6mL/min, resulting in highest yield %, lowest moisture %, and lower Carr index. Next, optimal spray drying conditions were applied to fabricate RTN SDDs using HPMCAS-L, at each 70 °C and 140 °C inlet temperatures. Particle size, drug content %, DSC, yield %, moisture %, bulk density, tapped density, Hausner ratio, and Carr index of each SDD was assessed or conducted. Solubility, stability, and dissolution studies were also carried out. Both SDD were stable for three months and exhibited improved solubility, compared to unprocessed RTN and physical mixtures. SDD using HPMCAS-L polymer provided rapid RTN release. Overall, an optimal RTN SDD was achieved, and employed HPMCAS-L rather than PVP-VA, which is used in several commercial forms of RTN, albeit using hot melt extrusion.