Biomimetic Dissolution: A Tool to Predict Amorphous Solid Dispersion Performance.

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.

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

Introduction. Ebastine is a second-generation antihistamine drug available in the form of orally disintegrating tablets and film-coated tablets. Ebastine substance exhibits high bioavailability, but low solubility in water and gastrointestinal tract media. The technology of solid dispersions based on polymer carriers by hot melt extrusion is proposed to solve the problem of ebastine low solubility.Aim. Composition development of extrudate and its production technology to create an amorphous solid dispersion of ebastine in oder to increase the recovery rate and bioavailability.Materials and methods. Ebastin micronized (JSC "Active Component", Russia); ebastin crystalline (Arevipharma GmbH, Germany); VIVAPHARM® PVP/VA 64 (JRS Pharma GMbH & Co. KG, Germany). Extrudates were obtained on a HAAKE™ miniCTW co-rotating twin-screw laboratory extruder (Thermo Fisher Scientific, Germany). Extrudates were studied by differential scanning calorimetry, synchronous thermal analysis, powder X-ray diffraction and FTIR-spectroscopy. The quantitative content of the active ingredient was determined by spectrophotometry. The content of related impurities in the amorphous solid dispersion of ebastine was determined by HPLC.Results and discussion. The technology of amorphous solid dispersion of ebastine by hot melt extrusion was developed. The pharmacokinetic properties of ebastine were significantly improved. The process of obtaining solid dispersion with 20 % of ebastine was optimized in order to reduce the content of impurities in the extrudate.Conclusion. The maximum concentration of ebastine for proper quality amorphous solid dispersion based on PVP/VA64 amounted to 20 %. Obtaining a solid dispersion by hot melt extrusion with ebastine content in PVP/VA64 higher than 30 % is impossible because the melt does not possess the glass transition property.

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

In vitro-in silico evaluation of Apremilast solid dispersions prepared via Corotating Twin Screw Extruder

Effect of temperature and moisture on the miscibility of amorphous dispersions of felodipine and poly(vinyl pyrrolidone)

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.

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

Development of novel darunavir amorphous solid dispersions with mesoporous carriers

Investigation of a suitable in vitro dissolution test for itraconazole-based solid dispersions

Impact of surfactant selection and incorporation on in situ nanoparticle formation from amorphous solid dispersions

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

In this study, we investigated the effects of ingested water volume on the oral absorption of fenofibrate (FEN) with several formulations to confirm the applicability of rats for oral formulation screening. Oral absorption of suspended crystalline FEN was significantly improved by increasing ingested water volume (from 0.5 to 2 mL). FEN absorption improvement by particle size reduction and the linearity in oral absorption by dose escalation suggested that the rate-limiting step of FEN absorption in rats was the dissolution rate, consistent with that in humans. When FEN, as an amorphous solid dispersion (ASD) formulation, was suspended in water followed by immediate administration, oral FEN absorption was significantly higher than when administered in crystalline form and was not influenced by the differences in ingested water volume. Oral absorption of FEN from encapsulated ASD formulation in 1 or 2 mL of water was comparable with that of the suspension form. However, 0.5 mL of water significantly reduced the oral absorption of the solid ASD FEN formulation. These results indicate that to improve the oral absorption of poorly water-soluble drugs when performing a preclinical study with rats, 1 mL of water is the minimum preferable ingested volume to evaluate in vivo formulation performance.

The underestimated contribution of the solvent to the phase behavior of highly drug loaded amorphous solid dispersions

Weakly acid polymerswith pH-responsive solubility arebeing usedwith increasing frequency in amorphous solid dispersion (ASD) formulationsof drugs with low aqueous solubility. However, drug release and crystallizationin a pH environment where the polymer is insoluble are not well understood.The aim of the current study was to develop ASD formulations optimizedfor release and supersaturation longevity of a rapidly crystallizingdrug, pretomanid (PTM), and to evaluate a subset of these formulationsin vivo. Following screening of several polymers for their abilityto inhibit crystallization, hypromellose acetate succinate HF grade(HPMCAS-HF; HF) was selected to prepare PTM ASDs. In vitro releasestudies were conducted in simulated fasted- and fed-state media. Drugcrystallization in ASDs following exposure to dissolution media wasevaluated by powder X-ray diffraction, scanning electron microscopy,and polarized light microscopy. In vivo oral pharmacokinetic evaluationwas conducted in male cynomolgus monkeys (n = 4)given 30 mg PTM under both fasted and fed conditions in a crossoverdesign. Three HPMCAS-based ASDs of PTM were selected for fasted-stateanimal studies based on their in vitro release performance. Enhancedbioavailability was observed for each of these formulations relativeto the reference product that contained crystalline drug. The 20%drug loading PTM-HF ASD gave the best performance in the fasted state,with subsequent dosing in the fed state. Interestingly, while foodimproved drug absorption of the crystalline reference product, theexposure of the ASD formulation was negatively impacted. The failureof the HPMCAS-HF ASD to enhance absorption in the fed state was hypothesizedto result from poor release in the reduced pH intestinal environmentresulting from the fed state. In vitro experiments confirmed a reducedrelease rate under lower pH conditions, which was attributed to reducedpolymer solubility and an enhanced crystallization tendency of thedrug. These findings emphasize the limitations of in vitro assessmentof ASD performance using standardized media conditions. Future studiesare needed for improved understanding of food effects on ASD releaseand how this variability can be captured by in vitro testing methodologiesfor better prediction of in vivo outcomes, in particular for ASDsformulated with enteric polymers.