Hydrophobic deep eutectic solvent (HDES) as oil phase in lipid-based drug formulations.

There is increasing pharmaceutical interest in deep eutectic solvents not only as a green alternative to organic solvents in drug manufacturing, but also as liquid formulation for drug delivery. The present work introduces a hydrophobic deep eutectic solvent (HDES) to the field of lipid-based formulations (LBF). Phase behavior of a mixture with 2:1 M ratio of decanoic- to dodecanoic acid was studied experimentally and described by thermodynamic modelling. Venetoclax was selected as a hydrophobic model drug and studied by atomistic molecular dynamics simulations of the mixtures. As a result, valuable molecular insights were gained into the interaction networks between the different components. Moreover, experimentally the HDES showed greatly enhanced drug solubilization compared to conventional glyceride-based vehicles, but aqueous dispersion behavior was limited. Hence surfactants were studied for their ability to improve aqueous dispersion and addition of Tween 80 resulted in lowest droplet sizes and high in vitro drug release. In conclusion, the combination of HDES with surfactant(s) provides a novel LBF with high pharmaceutical potential. However, the components must be finely balanced to keep the integrity of the solubilizing HDES, while enabling sufficient dispersion and drug release.

Oral Absorption from Surfactant-Based Drug Formulations: The Impact of Molecularly Dissolved Drug on Bioavailability.

Enabling drug formulations are often required to ensure sufficient absorption after oral administration of poorly soluble drugs. While these formulations typically increase the apparent solubility of the drug, it is widely acknowledged that only molecularly dissolved, i.e., free fraction of the drug, is prone for direct absorption, while colloid-associated drug does not permeate to the same extent. In the present study, we aimed at comparing the effect of molecularly and apparently (i.e., the sum of molecularly and colloid-associated drug) dissolved drug concentrations on the oral absorption of a poorly water-soluble drug compound, Alectinib. Mixtures of Alectinib and respectively 50 %, 25 %, 12.5 %, and 3 % sodium lauryl sulfate (SLS) relative to the dose were prepared and small-scale dissolution tests were performed under simulated fed and fasted state conditions. Both the molecularly and apparently dissolved drug concentrations were assessed in parallel using microdialysis and centrifugation/filtration sampling, respectively. The data served as the basis for an in vitro-in vivo correlation (IVIVC) and as input for a GastroPlusTM physiologically-based biopharmaceutics model (PBBM). It was shown that with increasing the content of SLS the apparently dissolved drug in FeSSIF and FaSSIF increased to a linear extent and thus, the predicted in vivo performance of the 50 % SLS formulation, based on apparently dissolved drug, would outperform all other formulations. Against common expectation, however, the free (molecularly dissolved) drug concentrations were found to vary with SLS concentrations as well, yet to a minor extent. A systematic comparison of solubilized and free drug dissolution patterns at different SLS contents of the formulations and prandial states allowed for interesting insights into the complex dissolution-/supersaturation-, micellization-, and precipitation-behavior of the formulations. When comparing the in vitro datasets with human pharmacokinetic data from a bioequivalence study, it was shown that the use of molecularly dissolved drug resulted in an improved IVIVC. By incorporating the in vitro dissolution datasets into the GastroPlusTM PBBM, the apparently dissolved drug concentrations resulted in both, a remarkable overprediction of plasma concentrations as well as a misprediction of the influence of SLS on systemic exposure. In contrast, by using the molecularly dissolved drug (i.e., free fraction) as the model input, the predicted plasma concentration-time profiles were in excellent agreement with observed data for all formulations under both fed and fasted conditions. By combining an advanced in vitro assessment with PBBM, the present study confirmed that only the molecularly dissolved drug, and not the colloid-associated drug, is available for direct absorption.

Bosentan monohydrate and sildenafil base as two companions in enabling formulations.

HYPOTHESIS: Sildenafil base and bosentan monohydrate are co-administered in a chronic therapy of pulmonary arterial hypertension (PAH). Both drugs are poorly soluble in water, and their bioavailability is limited to ca. 50 %. Since bosentan is a weak acid, whereas sildenafil is a weak base, we assumed that their co-amorphization could: (i) improve their solubility in the gastrointestinal fluids, (ii) enable to reach supersaturation and (iii) ensure stabilization of supersaturated solutions. If successful, this could accelerate the development of new fixed-dose combination drugs. EXPERIMENTS: The co-amorphous formulations were prepared using high energy ball milling. Their solid state properties were assessed using XRD, DSC, FT-MIR, and dielectric spectroscopy. Particle size distribution and surface wetting were also analyzed. Polarizing optical microscopy and scanning electron microscopy were applied to assess the microstructure of these powders. A new HPLC-DAD method was developed for a simultaneous quantification of both drugs. FINDINGS: It was shown that binary formulations in which bosentan was molecularly dispersed in sildenafil base (Tg = 64-78 °C) could be manufactured in the high energy ball milling process. When the sildenafil load was below 50 wt. %, the formulations showed the greatest thermal stability and formed long-lasting bosentan supersaturation in PBS.

Advances in Nanotechnology for Enhancing the Solubility and Bioavailability of Poorly Soluble Drugs.

This manuscript offers a comprehensive overview of nanotechnology's impact on the solubility and bioavailability of poorly soluble drugs, with a focus on BCS Class II and IV drugs. We explore various nanoscale drug delivery systems (NDDSs), including lipid-based, polymer-based, nanoemulsions, nanogels, and inorganic carriers. These systems offer improved drug efficacy, targeting, and reduced side effects. Emphasizing the crucial role of nanoparticle size and surface modifications, the review discusses the advancements in NDDSs for enhanced therapeutic outcomes. Challenges such as production cost and safety are acknowledged, yet the potential of NDDSs in transforming drug delivery methods is highlighted. This contribution underscores the importance of nanotechnology in pharmaceutical engineering, suggesting it as a significant advancement for medical applications and patient care.

In Vitro Lipolysis Model to Predict Food Effect of Poorly Water-Soluble Drugs Itraconazole, Rivaroxaban, and Ritonavir.

It is desirable to predict positive food effect of oral formulations due to food mediated dissolution enhancement of lipophilic drugs. The objective was to assess the ability of in vitro lipolysis to anticipate a positive food effect. Tested formulations included rivaroxaban and itraconazole, where some formulations, but not all, exhibit a positive food effect in vivo in humans. Amorphous solid dispersion formulations of ritonavir, which exhibit a negative food effect in vivo in humans, were also studied. Fe-lipolysis and Fa-lipolysis media representing fed and fasted intestinal conditions were used. Results show frequent agreement between in vitro lipolysis predictions and in vivo human outcomes. For rivaroxaban, food effect of unformulated active pharmaceutical ingredient (API) and products were correctly predicted where 2.5 mg and 10 mg strengths did not show any food effect; however, 20 mg did show a positive food effect. For itraconazole, all four products were correctly predicted, with Sporanox, Sempera, and generic capsules having a food effect, but Tolsura not having a positive food effect. For ritonavir, lipolysis predicted a positive food effect for API and Norvir tablet and powder, but Norvir products have negative food effect in vivo in humans. Overall, the lipolysis model showed favorable predictability and merits additional evaluation.

Design of Etched- and Functionalized-Halloysite/Meloxicam Hybrids: A Tool for Enhancing Drug Solubility and Dissolution Rate.

The study focuses on the synthesis and characterization of Meloxicam-halloysite nanotube (HNT) composites as a viable approach to enhance the solubility and dissolution rate of meloxicam, a poorly water-soluble drug (BCS class II). Meloxicam is loaded on commercial and modified halloysite (acidic and alkaline etching, or APTES and chitosan functionalization) via a solution method. Several techniques (XRPD, FT-IR, 13C solid-state NMR, SEM, EDS, TEM, DSC, TGA) are applied to characterize both HNTs and meloxicam-HNT systems. In all the investigated drug-clay hybrids, a high meloxicam loading of about 40 wt% is detected. The halloysite modification processes and the drug loading do not alter the structure and morphology of both meloxicam and halloysite nanotubes, which are in intimate contact in the composites. Weak drug-clay and drug-functionalizing agent interactions occur, involving the meloxicam amidic functional group. All the meloxicam-halloysite composites exhibit enhanced dissolution rates, as compared to meloxicam. The meloxicam-halloysite composite, functionalized with chitosan, showed the best performance both in water and in buffer at pH 7.5. The drug is completely released in 4-5 h in water and in less than 1 h in phosphate buffer. Notably, an equilibrium solubility of 13.7 ± 4.2 mg/L in distilled water at 21 °C is detected, and wettability dramatically increases, compared to the raw meloxicam. These promising results can be explained by the chitosan grafting on the outer surface of halloysite nanotubes, which provides increased specific surface area (100 m2/g) disposable for drug adsorption/desorption.

Mesoporous Silica as an Alternative Vehicle to Overcome Solubility Limitations.

Toxicological studies are a part of the drug development process and the preclinical stages, for which suitable vehicles ensuring easy and safe administration are crucial. However, poor aqueous solubility of drugs complicates vehicle screening for oral administration since non-aqueous solvents are often not tolerable. In the case of the anti-infective corallopyronin A, currently undergoing preclinical investigation for filarial nematode and bacterial infections, commonly used vehicles such as polyethylene glycol 200, aqueous solutions combined with cosolvents or solubilizers, or aqueous suspension have failed due to insufficient tolerability, solubility, or the generation of a non-homogeneous suspension. To this end, the aim of the study was to establish an alternative approach which offers suitable tolerability, dissolution, and ease of handling. Thus, a corallopyronin A-mesoporous silica formulation was successfully processed and tested in a seven-day toxicology study focused on Beagle dogs, including a toxicokinetic investigation on day one. Sufficient tolerability was confirmed by the vehicle control group. The vehicle enabled high-dose levels resulting in a low-, middle-, and high-dose of 150, 450, and 750 mg/kg. Overall, it was possible to achieve high plasma concentrations and exposures, leading to a valuable outcome of the toxicology study and establishing mesoporous silica as a valuable contender for challenging drug candidates.

Nanocrystals and nanosuspensions: an exploration from classic formulations to advanced drug delivery systems.

Nanocrystals and nanosuspensions have become realistic approaches to overcome the formulation challenges of poorly water-soluble drugs. They also represent a less-known but versatile platform for multiple therapeutic applications. They can be integrated into a broad spectrum of drug delivery systems including tablets, hydrogels, microneedles, microparticles, or even functionalized liposomes. The recent progresses, challenges, and opportunities in this field are gathered originally together with an informative case study concerning an itraconazole nanosuspension-in-hydrogel formulation. The translational aspects, historical and current clinical perspectives are also critically reviewed here to shed light on the incoming generation of nanocrystal formulations.

Effect of Drug Loading in Mesoporous Silica on Amorphous Stability and Performance.

The encapsulation of drugs within mesoporous silica (MS) has for several years been a subject of research. Previous studies proposed that drug loadings up to the monomolecular loading capacity (MLC) are the optimal choice for maintaining the drug in an amorphous form, whereas filling the pores above the monolayer and up to the pore filling capacity (PFC) may introduce some physical instabilities. The aim of this study was to assess the effect of drug loading in MS-based amorphous formulations on the stability of the amorphous form of the drug as well as the dissolution. In particular, the following drug loadings were investigated: below MLC, at MLC, between MLC and PFC and at PFC. The drug-loaded MS formulations were analyzed directly after preparation and after 18 months of storage under accelerated conditions (40 °C in both dry and humid conditions). The MLC and PFC for the drug celecoxib (CEL) on the MS ParteckSLC500 (SLC) were determined at 33.5 wt.% and 48.4 wt.%, respectively. This study found that SLC can effectively preserve the amorphous form of the drug for 18 months, provided that the loading is below the PFC (<48.4 wt.%) and no humidity is present. On the other hand, drug loading at the PFC showed recrystallization even when stored under dry conditions. Under humid conditions, however, all samples, regardless of drug loading, showed recrystallization upon storage. In terms of dissolution, all freshly prepared formulations showed supersaturation. For drug loadings below PFC, a degree of supersaturation (DS) around 15 was measured before precipitation was observed. For drug loadings at PFC, the DS was found to be lower and only 6-times compared to the crystalline solubility. Lastly, for those samples that remained amorphous during storage for 18 months, the release profiles were found to be the same as the freshly loaded samples, with similar Cmax, Tmax and dissolution rate.

Using molecularly dissolved drug concentrations in PBBMs improves the prediction of oral absorption from supersaturating formulations.

Predicting the absorption of drugs from enabling formulations is still challenging due to the limited capabilities of standard physiologically based biopharmaceutics models (PBBMs) to capture complex absorption processes. Amongst others, it is often assumed that both, molecularly and apparently dissolved drug in the gastrointestinal lumen are prone to absorption. A recently introduced method for measuring concentrations of molecularly dissolved drug in a dynamic in vitro dissolution setup using microdialysis has opened new opportunities to test this hypothesis and refine mechanistic PBBM approaches. In the present study, we compared results of PBBMs that used either molecularly or apparently dissolved concentrations in the simulated gastrointestinal lumen as input parameters. The in vitro dissolution data from three supersaturating formulations of Posaconazole (PCZ) were used as model input. The modeling outcome was verified using PCZ concentration vs. time profiles measured in human intestinal aspirates and in the blood plasma. When using apparently dissolved drug concentrations (i.e., the sum of colloid-associated and molecularly dissolved drug) the simulated systemic plasma exposures were overpredicted, most pronouncedly with the ASD-based tablet. However, if the concentrations of molecularly dissolved drug were used as input values, the PBBM resulted in accurate prediction of systemic exposures for all three PCZ formulations. The present study impressively demonstrated the value of considering molecularly dissolved drug concentrations as input value for PBBMs of supersaturating drug formulations.

Rubusoside As a Multifunctional Stabilizer for Novel Nanocrystal-Based Solid Dispersions with a High Drug Loading: A Case Study.

The oral bioavailability of poorly soluble drugs has always been the focus of pharmaceutical researchers. We innovatively combined nanocrystal technology and solid dispersion technology to prepare novel nanocrystalline solid dispersions (NCSDs), which enable both the solidification and redispersion of nanocrystals, offering a promising new pathway for oral delivery of insoluble Chinese medicine ingredients. The rubusoside (Rub) was first used as the multifunctional stabilizer of novel apigenin nanocrystal-based solid dispersions (AP-NSD), improving the in vitro solubilization rate of the insoluble drug apigenin(AP). AP-NSD has been produced using a combination of homogenisation and spray-drying technology. The effects of stabilizer type and concentration on AP nanosuspensions (AP-NS) particles, span, and zeta potential were studied. And the effects of different types of protective agents on the yield and redispersibility of AP-NSD were also studied. Furthermore, AP-NSD was characterized by infrared spectroscopy (IR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD). Solubility was used to assess the in vitro dissolution of AP-NSD relative to APIs and amorphous solid dispersions (AP-ASD), and AP-ASD was prepared by the solvent method. The results showed that 20% Rub stabilized AP-NSD exhibited high drug-loading and good redispersibility and stability, and higher in vitro dissolution rate, which may be related to the presence of Rub on surface of drug. Therefore provides a natural and safe option for the development of formulations for insoluble drugs.

A Review of Hydrotropic Solubilization Techniques for Enhancing the Bioavailability of Poorly Soluble Drugs.

Hydrotropic solubilization is a technique that can be used to improve the solubility of drugs that are poorly soluble. This technique involves adding a large amount of a second solute, known as a hydrotrope, which increases the aqueous solubility of the poorly soluble drug. Hydrotropes such as sodium citrate, sodium benzoate, and urea have been shown to be effective in enhancing the solubility of poorly soluble drugs. This technique has several advantages over other solubility enhancement techniques, including its cost-effectiveness, eco-friendliness, and the fact that it does not require chemical modification of hydrophobic drugs or the use of organic solvents. Hydrotropic agents are now being used to develop various dosage forms, including solid dispersions, mouth-dissolving tablets, and injections, to improve poorly water-soluble drugs' therapeutic effectiveness and bioavailability. This review paper will provide an overview of hydrotropic solubilization techniques.

Preparation and Characterization of Spray-Dried Hybrid Nanocrystal-Amorphous Solid Dispersions (HyNASDs) for Supersaturation Enhancement of a Slowly Crystallizing Drug.

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.

Effect of Deep Eutectic System (DES) on Oral Bioavailability of Celecoxib: In Silico, In Vitro, and In Vivo Study.

Different deep eutectic systems (DES) of choline chloride (CC)-urea (UA) (1:2), CC-glycerol (GLY) (1:2), CC-malonic acid (MA) (1:1), and CC-ascorbic acid (AA) (2:1) were generated and characterized by polarized light microscope (PLM) and Fourier transform infrared spectroscope (FTIR). The equilibrium solubility of celecoxib (CLX) in DES was compared to that in deionized water. The CC-MA (1:1) system provided ~10,000 times improvement in the solubility of CLX (13,114.75 µg/g) and was used for the generation of the CLX-DES system. The latter was characterized by PLM and FTIR to study the microstructure and intermolecular interaction between the CLX and CC-MA (1:1) DES. FTIR demonstrated the retention of the chemical structure of CLX. In vitro drug release studies in FaSSIF initially demonstrated high supersaturation, which decreased by ~2 fold after 2 h. Density functional theory (DFT)-based calculations provided a molecular-level understanding of enhanced solubility. Gibbs free energy calculations established the role of the strongest binding of CLX with CC and MA. A phase solubility study highlighted the role of hydrotropy-induced solubilization of the CLX-DES system. Animal pharmacokinetic studies established 2.76 times improvement in Cmax, 1.52 times reduction in tmax, and 1.81 times improvement in AUC0-∞. The overall results demonstrated the potential of developing a DES-based supersaturating drug-delivery system for pharmaceutical loading of drugs having solubility and dissolution rate-limited oral bioavailability.

Solvent electrospinning amorphous solid dispersions with high itraconazole, celecoxib, mebendazole and fenofibrate drug loading and release potential.

In this work, the feasibility of ultra-high drug loaded amorphous solid dispersions (ASDs) for the poorly soluble itraconazole, mebendazole and celecoxib via solvent electrospinning in combination with poly(2-ethyl-2-oxazoline) and fenofibrate in combination with polyvinylpyrrolidone is demonstrated. By lowering the polymer concentration in the electrospinning solution below its individual spinnable limit, ASDs with a drug content of up to 80 wt% are obtained. This is attributed to drug-polymer interactions not being limited by default to hydrogen bonds, as also Van der Waals interactions can result in high drug loadings. The theoretically predicted miscibility by the Flory-Huggins theory is corroborated by the experimental findings based on (modulated) differential scanning calorimetry and x-ray diffraction. Globally, the maximally obtained amorphous drug loadings are higher compared to the loadings found in literature. Additionally, non-sink dissolution tests demonstrate an increase in solubility of up to 50 times compared to their crystalline counterparts. Moreover, due to the lack of precipitation biocompatible PEtOx succeeds in stabilizing the dissolved drug and inhibiting its instant precipitation. The current work thus demonstrates the broader applicability of the electrospinning technique for the production of physically stable ASDs with ultra-high drug loadings, a result which has been validated for several Biopharmaceutics Classification System class II drugs.

Combining in vitro dissolution/permeation with microdialysis sampling: Capabilities and limitations for biopharmaceutical assessments of supersaturating drug formulations.

Many novel small drug molecules are poorly water-soluble and thus, enabling drug formulations may be required to ensure sufficient absorption upon oral administration. Biopharmaceutical assessment and absorption prediction of enabling formulations, however, remains challenging. Combined in vitro dissolution/permeation (D/P) assays have gained increasing interest since they may provide a more realistic formulation ranking based on the drug permeation profiles from different formulations as compared to conventional dissolution, which captures both readily permeable and not readily permeable fractions of "dissolved" drug. Moreover, the combined in vitro D/P assays allow to better predict intestinal supersaturation and precipitation processes as compared to simple dissolution setups due to the effect of an absorptive sink. Microdialysis on the other hand has proven useful to determine molecularly dissolved drug in colloidal dispersions, thus allowing for a deeper mechanistic insight into the mechanism of drug release from supersaturating formulations. Here, microdialysis sampling from the donor compartment was used in combination with the dissolution/permeation (D/P) tool PermeaLoop™ to study commercial supersaturating drug formulations of the poorly soluble and weakly basic drug Posaconazole (PCZ). An amorphous solid dispersion (ASD)-based tablet, as well as a crystalline suspension in acidified and neutral dilution medium, respectively, were tested. Microdialysis sampling allowed for differentiation between molecularly dissolved and micellar drug concentration, as expected, but, surprisingly, it was found that the presence of the microdialysis probe affected the precipitation behavior of a crystalline suspension within the two-stage D/P setup, simulating the oral administration of the acidified PCZ (Noxafil®) suspension: the extent and duration of supersaturation in the donor decreased significantly, which also affected permeation. Similarly, for the ASD-based tablet, a less pronounced supersaturation was observed during the first 120 min of the experiment. Hence, in this case, the formulation ranking and the prediction of intestinal supersaturation in the in vitro D/P assay became less predictive as compared to a conventional PermeaLoop™ study without microdialysis sampling. It was concluded that valuable mechanistic insights into the molecularly dissolved drug profiles over time can be obtained by microdialysis. However, since the presence of the probe may affect the degree of supersaturation and precipitation, a conventional D/P assay (without microdialysis sampling) is preferred for formulation ranking of supersaturating drug formulations.

Review of industrially recognized polymers and manufacturing processes for amorphous solid dispersion based formulations.

Evolving therapeutic landscape through combinatorial chemistry and high throughput screening have resulted in an increased number of poorly soluble drugs. Drug delivery strategies quickly adapted to convert these drugs into successful therapies. Amorphous solid dispersion (ASD) technology is widely employed as a drug delivery strategy by pharmaceutical industries to overcome the challenges associated with these poorly soluble drugs. The development of ASD formulation requires an understanding of polymers and manufacturing techniques. A review of US FDA-approved ASD-based products revealed that only a limited number of polymers and manufacturing technologies are employed by pharmaceutical industries. This review provides a comprehensive guide for the selection and overview of polymers and manufacturing technologies adopted by pharmaceutical industries for ASD formulation. The various employed polymers with their underlying mechanisms for solution-state and solid-state stability are discussed. ASD manufacturing techniques, primarily implemented by pharmaceutical industries for commercialization, are presented in Quality by Design (QbD) format. An overview of novel excipients and progress in manufacturing technologies are also discussed. This review provides insights to the researchers on the industrially accepted polymers and manufacturing technology for ASD formulation that has translated these challenging drugs into successful therapies.

Advanced In Vivo Prediction by Introducing Biphasic Dissolution Data into PBPK Models.

Coupling biorelevant in vitro dissolution with in silico physiological-based pharmacokinetic (PBPK) tools represents a promising method to describe and predict the in vivo performance of drug candidates in formulation development including non-passive transport, prodrug activation, and first-pass metabolism. The objective of the present study was to assess the predictability of human pharmacokinetics by using biphasic dissolution results obtained with the previously established BiPHa+ assay and PBPK tools. For six commercial drug products, formulated by different enabling technologies, the respective organic partitioning profiles were processed with two PBPK in silico modeling tools, namely PK-Sim and GastroPlus®, similar to extended-release dissolution profiles. Thus, a mechanistic dissolution/precipitation model of the assessed drug products was not required. The developed elimination/distribution models were used to simulate the pharmacokinetics of the evaluated drug products and compared with available human data. In essence, an in vitro to in vivo extrapolation (IVIVE) was successfully developed. Organic partitioning profiles obtained from the BiPHa+ dissolution analysis enabled highly accurate predictions of the pharmacokinetic behavior of the investigated drug products. In addition, PBPK models of (pro-)drugs with pronounced first-pass metabolism enabled adjustment of the solely passive diffusion predicting organic partitioning profiles, and increased prediction accuracy further.

Protein Based Amorphous Solid Dispersion: a Case Study Investigating Different Whey Proteins at High Drug Loading.

PURPOSE: Whey protein isolate (WPI) has previously been shown to be a promising new excipient for the development of amorphous solid dispersions (ASD) at a high drug loading of 50% (w/w). Whilst WPI is a protein mixture, comprising mainly the three proteins ß-lactoglobulin (BLG), α-lactalbumin (ALA), casein glycomacropeptides (CGMP), the individual contributions of these three proteins to the overall performance of whey protein based ASDs has still not been investigated. In addition, the limitations of the technology at even higher drug loadings (i.e., more than 50%) have not yet been explored. In this study, BLG, ALA, CGMP and WPI were each prepared as ASDs with the two poorly water-soluble drugs (Compound A and Compound B) at 50%, 60% and 70% drug loadings. METHODS: Solid state characterization, dissolution rate and physical stability of the obtained samples were analyzed. RESULTS: All the obtained samples were amorphous and showed faster dissolution rates compared to the respective pure crystalline drugs. However, the BLG based formulations-at least for Compound A-were outperforming the other ASDs in terms of stability, dissolution enhancement and solubility increase. CONCLUSION: Overall, the study confirmed that the investigated whey proteins showed their potential in developing ASDs even at high drug loadings of up to 70%.

High energy ball milling vs. nano spray drying in the development of supersaturated systems loaded with bosentan.

In this study, high energy ball milling and nano spray drying were used to prepare amorphous solid dispersions of bosentan in copovidone for the first time. In particular, the impact of this polymer on the bosentan amorphization kinetics was investigated. Copovidone was shown to facilitate the amorphization of bosentan upon ball milling. As a result, bosentan was dispersed in copovidone at the molecular level, forming amorphous solid dispersions, regardless of the ratio of the compounds. The similarity between the values of the adjustment parameter that describes the goodness of fit of the Gordon-Taylor equation to the experimental data (K = 1.16) and that theoretically calculated for an ideal mixture (K = 1.13) supported these findings. The kind of coprocessing method determined the powder microstructure and the release rate. The opportunity to prepare submicrometer-sized spherical particles using nano spray drying was an important advantage of this technology. Both coprocessing methods allowed the formation of long-lasting supersaturated bosentan solutions in the gastric environment with maximum concentrations reached ranging from four (11.20 µg/mL) to more than ten times higher (31.17 µg/mL) than those recorded when the drug was vitrified alone (2.76 µg/mL). Moreover, this supersaturation lasted for a period of time at least twice as long as that of the amorphous bosentan processed without copovidone (15 min vs. 30-60 min). Finally, these binary amorphous solid dispersions were XRD-amorphous for a year of storage under ambient conditions.