Biorelevant Dissolution Research Articles

DESIGN OF DISSOLUTION STUDY PROTOCOL FOR PULMONARY DOSAGE FORMS: CRITERIA FOR SELECTION OF BIO-RELEVANT DISSOLUTION MEDIUM

Pulmonary dosage forms constitute an important route of drug delivery for systemic absorption of drugs in management of respiratory diseases as well as diseases such as diabetes, migraine, osteoporosis, and cancer. Performance of different pulmonary dosage forms is greatly influenced by aerodynamic particle size distribution of inhalable particles, spray pattern, fraction of dose actually deposited on pulmonary epithelium, dissolution of active pharmaceutical ingredient and ultimately absorption across pulmonary barriers. In vitro dissolution study should be designed to predict in vivo performance precisely, providing key information on bioavailability and establishing in vitro-in vivo correlation. To obtain meaningful data from dissolution study, focus should be on composition of dissolution medium, dissolution conditions and dissolution test apparatus. For pulmonary dosage forms, selection of physiologically relevant dissolution medium, mimicking lung fluid (LF) is a challenging task. Attempts are being made to develop bio-relevant dissolution medium to overcome the limitations associated with use of conventional media lacking lung surfactant proteins, or several salts normally present in pleural fluid. Use of simulated LFs can give a better understanding of the release mechanisms and possible in vivo behavior of pulmonary dosage forms thereby enhancing the predictive capability of the dissolution testing. In the review, efforts have been taken to provide comprehensive information on composition, physicochemical characteristics and functions of physiological LF, challenges associated with the design and development of dissolution study protocol for pulmonary dosage forms, criteria for selection of an appropriate bio-relevant dissolution medium, comparative study on various reported bio-relevant dissolution media and dissolution apparatuses employed for in vitro characterization of performance of pulmonary dosage forms.

Exploration of Neusilin® US2 as an Acceptable Filler in HPMC Matrix Systems-Comparison of Pharmacopoeial and Dynamic Biorelevant Dissolution Study.

Modern pharmaceutical technology still seeks new excipients and investigates the further use in already known ones. An example is magnesium aluminometasilicate Neusilin® US2 (NEU), a commonly used inert filler with unique properties that are usable in various pharmaceutical fields of interest. We aimed to explore its application in hypromellose matrix systems (HPMC content 10–30%) compared to the traditionally used microcrystalline cellulose (MCC) PH 102. The properties of powder mixtures and directly compressed tablets containing individual fillers NEU or MCC, or their blend with ratios of 1.5:1, 1:1, and 0.5:1 were investigated. Besides the routine pharmaceutical testing, we have enriched the matrices’ evaluation with a biorelevant dynamic dissolution study and advanced statistical analysis. Under the USP apparatus 2 dissolution test, NEU, individually, did not provide advantages compared to MCC. The primary limitations were the burst effect increase followed by faster drug release at the 10–20% HPMC concentrations. However, the biorelevant dynamic dissolution study did not confirm these findings and showed similarities in dissolution profiles. It indicates the limitations of pharmacopoeial methods in matrix tablet development. Surprisingly, the NEU/MCC blend matrices at the same HPMC concentration showed technologically advantageous properties. Besides improved flowability, tablet hardness, and a positive impact on the in vitro drug dissolution profile toward zero-order kinetics, the USP 2 dissolution data of the samples N75M50 and N50M50 showed a similarity to those obtained from the dynamic biorelevant apparatus with multi-compartment structure. This finding demonstrates the more predictable in vivo behaviour of the developed matrix systems in human organisms.

Performance Evaluation of Montelukast Pediatric Formulations: Part I\u2014Age-Related In Vitro Conditions

This study aimed to explore the potential of biopharmaceutics in vitro tools to predict drug product performance in the pediatric population. Biorelevant dissolution set-ups were used to predict how age and medicine administration practices affect the in vitro dissolution of oral formulations of a poorly water-soluble compound, montelukast. Biorelevant age-appropriate dissolution studies of Singulair® (granules and chewable tablets) were conducted with the µDISS profiler™, USP 4 apparatus, USP 2 apparatus, and mini-paddle apparatus. Biorelevant simulating fluids representative of adult and pediatric conditions were used in the dissolution studies. The biorelevant dissolution conditions were appropriately selected (i.e. volumes, transit times, etc.) to mimic the gastrointestinal conditions of each of the subpopulations tested. Partial least squares regression (PLS-R) was performed to understand the impact of in vitro variables on the dissolution of montelukast. Montelukast dissolution was significantly affected by the in vitro hydrodynamics used to perform the dissolution tests (µDISS profiler™: positive effect); choice of simulation of gastric (negative effect) and/or intestinal conditions (positive effect) of the gastrointestinal tract; and simulation of prandial state (fasted state: negative effect, fed state: positive effect). Age-related biorelevant dissolution of Singulair® granules predicted the in vivo effect of the co-administration of the formulation with applesauce and formula in infants. This study demonstrates that age-appropriate biorelevant dissolution testing can be a valuable tool for the assessment of drug performance in the pediatric population.Graphical

Biorelevant dissolution studies of platelet aggregation inhibitor: Ticagrelor hydrochloride and its co-crystal with sodium salt of Aspirin

The comparative dissolution characteristics of poorly soluble platelet aggregation inhibitor Ticagrelor hydrochloride and its co-crystal with sodium salt of Aspirin in biorelevant media have been demonstrated. The API and co-crystal both are subjected to simulated gastric fluid (SGF) and fasted intestinal fluid without micelle forming components (blank FASSIF). The release of API is online monitored through reverse phase liquid chromatography. Prior to online monitoring, the chromatographic method is statistically validated in accordance with ICH guidelines. Chromatographic data reveals that the overall release of Ticagrelor after 3 h is about 6μg/mL higher in co-crystal (24.5μg/mL) compared to unaccompanied API (18.6μg/mL) in simulated gastric fluid (SGF). Whereas in fasted intestinal fluid without micelle forming components (blank FASSIF) more than threefold high release of API is observed in co-crystal (12.14μg/mL) compared to API (4.22μg/mL) in free form. Results clearly indicate the improved solubility in the lower regions of the gastrointestinal tract and better absorption of drug. This type of co-crystal would also allow the simultaneous dosing in suitable formulation.

Development and in vivo evaluation of lipid-based nanocarriers containing Jatropha isabellei dry extract from the dichloromethane fraction intended for oral treatment of arthritic diseases

In this study, a dichloromethane fraction dry extract from the underground parts of Jatropha isabellei (DFJi) was used to prepare lipid nanocarriers (LNCJi) aimed at providing the oral delivery of terpenic compounds in the treatment of arthritis. The lipid nanocarriers were prepared by the spontaneous emulsification method. The lipid nanocarriers displayed sizes ranging from 180 to 200 nm and zeta potential values of around -18 mV. A high value of entrapment efficiency (> 90%) was obtained for jatrophone, which was used as the chemical marker of DFJi. LNCJi stored at 4°C were demonstrated to be stable through measurements of transmitted light after analytical centrifugation of the samples. In vitro drug release studies conducted in biorelevant dissolution media demonstrated that jatrophone release was faster from LNCJi than from free DFJi. When tested in an acute arthritis model, the LNCJi exhibited antinociceptive properties after oral administration of a 50 mg/kg dose, unlike the free DFJi, although no reduction in articular diameter was observed. These results suggest that an increase in the oral absorption of DFJi constituents may have occurred through the carrying of this fraction in LNCJi, thus improving the antinociceptive activity of this compound.

Use of biorelevant dissolution media in dissolution tests as a predictive method of oral bioavailability

Use of biorelevant dissolution media in dissolution tests as a predictive method of oral bioavailability

Towards a Better Understanding of the Post-Gastric Behavior of Enteric-Coated Formulations

PurposeThe aim of our work was to develop a biorelevant dissolution method for a better understanding of the in vivo performance of delayed-release tablet formulations.MethodsThe typical pH profile and residence times in the stomach and small intestine were determined in fasted conditions based on the published results of swallowable monitoring devices. Then, a multi-stage pH shift dissolution method was developed by adding different amounts of phosphate-based buffer solutions to the initial hydrochloric acid solution. Because of the highly variable in vivo residence times in the stomach, two alternatives of the method were applied, modeling rapid and slow gastric emptying as well. This approach provided an opportunity to study the effect of the acidic treatment on post gastric release. Six enteric-coated low-dose acetylsalicylic acid (ASA) formulations including the reference Aspirin Protect were tested as a model compound. Moreover, the thickness of the coating of each formulation was investigated by scanning electron microscope.ResultsComparing the in vitro results to the known properties of the formulations, the new method was found to be more discriminative than the USP dissolution method. Ingredients affecting the in vitro dissolution, and thus probably the in vivo performance, were identified in both the tablet core and the coating of the tested formulations. The limited available in vivo data also indicated an increased predictivity.ConclusionOverall, the presented method may be an efficient tool to support the development of enteric coated generic formulations.Graphical abstract

Sustainable Stabilizer-Free Nanoparticle Formulations of Valsartan Using Eudragit® RLPO.

The bioavailability of the antihypertensive drug valsartan can be enhanced by various microencapsulation methods. In the present investigation, valsartan-loaded polymeric nanoparticles were manufactured from Eudragit® RLPO using an emulsion–solvent evaporation method. Polyvinyl alcohol (PVA) was found to be a suitable stabilizer for the nanoparticles, resulting in a monodisperse colloid system ranging in size between 148 nm and 162 nm. Additionally, a high encapsulation efficiency (96.4%) was observed. However, due to the quaternary ammonium groups of Eudragit® RLPO, the stabilization of the dispersion could be achieved in the absence of PVA as well. The nanoparticles were reduced in size (by 22%) and exhibited similar encapsulation efficiencies (96.4%). This more cost-effective and sustainable production method reduces the use of excipients and their expected emission into the environment. The drug release from valsartan-loaded nanoparticles was evaluated in a two-stage biorelevant dissolution set-up, leading to the rapid dissolution of valsartan in a simulated intestinal medium. In silico simulations using a model validated previously indicate a potential dose reduction of 60–70% compared to existing drug products. This further reduces the expected emission of the ecotoxic compound into the environment.

Developing a Biorelevant Dissolution Method for an Extrudable Core System (ECS) Osmotic Tablet.

The objective of this work is to develop a biorelevant dissolution method to support the clinical study for In Vitro In Vivo Correlation (IVIVC) of the first commercially approved single-layer extrudable core system (ECS) osmotic tablet - the 11mg tofacitinib modified-release tablet. The dissolution conditions were selected through analysis of experimental work including several designed experiments (DoE). The Apparatus 2 (paddles) was selected over the Apparatus 1 (baskets) to minimize the dissolution test variability. The paddle speed was kept at 50rpm to be conservative and because higher paddle speed did not offer statistically significant improvement in dissolution test variability. The buffer of 50mM potassium phosphate at pH 6.8 was selected over other buffers at lower or acid pH as the in vivo drug release is expected to occur in the small intestinal region, where the pH is approximately neutral. Finally, the statistically designed experiments proved that use of the Japanese basket sinkers was effective in reducing dissolution variability and eliminating the artificial shift in dissolution profile caused by final pink color-coated tablets sticking to the dissolution vessel. Discriminatory power of the method was verified and the method was validated per ICH and FDA guidelines. Since a Level A IVIVC is established from the analysis of the results of both in vivo clinical study and in vitro dissolution testing, the method is proven to be biorelevant. It also serves a suitable quality control dissolution method.

Enhancement of Drug Dissolution of Erlotinib Tablets by Micronization Technique Using Pharmaceutical Experimental Design

Lung cancer is the second most frequent cancer and among the top cause of death worldwide. Chemotherapy is the main therapeutic option for non-small-cell lung cancer (NSCLC), which accounts for the majority of all lung malignancies. The aim of the current work was to develop a tablet formulation having increased drug release profile to improve the bioavailability in order to reduce the dose of the drug. In this present study, Erlotinib tablet was prepared using micronization technique which showed increase drug release profile. Film-coated tablets containing Erlotinib hydrochloride (150 mg) were prepared by dry granulation technique and coated using Opadry ready-mix. Tablets were characterized for Hardness, Friability, Potency and Drug release profile. Drug release was checked in 0.1 N HCL containing 0.5 % SLS and biorelevant dissolution media up to 60 minutes. Tablets of the selected batch were subjected to dissolution in biorelevant media and compare with reference product. The improvement in the drug release was observed in the biorelevant media in comparison with reference product. The in-vitrodissolution data demonstrated the potential of micronization technology to prepare tablets with improved bioavailability of the drug.

The effect of buffer species on biorelevant dissolution and precipitation assays – Comparison of phosphate and bicarbonate buffer

Biorelevant solubility and dissolution testing is an important tool during pharmaceutical development, however, solubility experiments performed using biorelevant media often do not properly match the solubility data observed in human intestinal fluids. Even though the bicarbonate buffer is the predominant buffer system in the small intestine, in vitro assays are commonly performed using non-volatile buffer systems like phosphate and maleate. In the current study, bicarbonate- and phosphate-buffered biorelevant media were applied to solubility, dissolution, and precipitation testing for a broad range of model compounds. It was found that the medium affects primarily the dissolution kinetics. However, with the knowledge of the unique buffering properties of bicarbonate buffer in the diffusion layer, it was not always possible to predict the effect of buffer species on solubility and dissolution when changing from phosphate to bicarbonate buffer. This once again highlights the special role of bicarbonate buffer for simulating the conditions in the human intestinal fluids. Moreover, it is necessary to further investigate the factors which may cause the differences in solubility and dissolution behavior when using phosphate- vs. bicarbonate-buffered biorelevant media.

Dry powder inhaler formulation comparison: Study of the role of particle deposition pattern and dissolution

The composition, morphology and dissolution profile of particles and micro-sized agglomerates delivered upon inhalation may have a significant impact on the product clinical effect. However, although several efforts are ongoing, a methodology that considers deposition structures and dissolution performance evaluation in a biorelevant set-up is not yet standardized. The goal of this work is to apply a collection and dissolution methodology able to discriminate dry powder inhaler (DPI) formulations in terms of deposition structures and dissolution profile in vitro. Hence, Fluticasone Propionate (FP) engineered particles and formulated products (used as a case study) were collected employing a breath simulator and characterized regarding (i) aerodynamic particle size distribution; (ii) deposited microstructures; and (iii) dissolution/absorption profiles using the DissolvIt® bio-relevant dissolution equipment. The results indicated that the particle engineering technology had an impact on the generated and deposited microstructures, here associated to the differences on surface properties of jet milled and wet polished particles quantified by the specific surface area. Differences on surface properties modulate particle interactions, resulting in agglomerates of drug substance and excipient upon actuation with significant different morphologies, observed by microscope, as well as quantified by Marple cascade impactor. These observations allow for a further understanding of the DPI aerosolization and deposition mechanisms. The dissolution and absorption assessment indicates that the presence of lactose may accelerate the drug substance dissolution kinetics, and the FP dissolution can be significantly enhanced when formulated as a spray-dried dispersion particle. Ultimately, the results suggest dissolution testing can be an essential tool to both optimize an innovator DPI and de-risk generics development.

Towards Virtual Bioequivalence Studies for Oral Dosage Forms Containing Poorly Water-Soluble Drugs: A Physiologically Based Biopharmaceutics Modeling (PBBM) Approach

The objective of the present study was to develop a physiologically based biopharmaceutics (PBBM) approach to predict the bioequivalence of dosage forms containing poorly soluble drugs. Aripiprazole and enzalutamide were used as model drugs. Variations in the gastrointestinal (GI) physiological parameters of fasted humans were taken into consideration in in vitro biorelevant dissolution testing and in an in silico PBBM simulations. To estimate bioequivalence between dosage forms, the inter-individual variabilities in their performance in virtual human subjects were predicted from the in vitro studies and variability in e.g. gastric emptying and fluid volume in the stomach was also taken into account. Formulations with different in vitro dissolution performance, a solution and a tablet formulation, were used in order to evaluate the accuracy of bioequivalence prediction using the PBBM approach. The bioequivalence parameters, i.e. geometric mean ratio and 90% confidence interval, for both drugs were predicted well in the virtual studies. In order to achieve even more precise predictions, it will be important to continue characterizing GI physiological parameters, along with their variabilities, on both an inter-subject and inter-occasion basis.

In silico bioavailability for BCS class II efavirenz tablets using biorelevant dissolution media for IVIVR and simulation of formulation changes

Objective This work aims to evaluate the ability of biorelevant dissolution media to simulate the bioavailability of efavirenz tablets, establish an in vitro-in vivo relationship (IVIVR) based on in vivo data using GastroPlus® and simulate formulation changes using DDDPlus™. Methods Solubility and drug release profiles were conducted in SLS 0.5% and biorelevant media, such as FaSSIF, FeSSIF, FaSSIF-V2, and FeSSIF-V2. The efavirenz physicochemical properties were used to simulate the plasma concentration profile and compare the simulated pharmacokinetic parameters in fasted and fed states. An IVIVR was developed using Loo-Riegelman as the deconvolution method to estimate drug bioavailability. DDDPlus™ was used to perform virtual trials of formulations to evaluate whether formulations changes and the efavirenz particle size could influence the bioavailability. Results The drug dissolution displayed higher levels in the biorelevant media that simulated gut-fed state (FeSSIF and FeSSIF-V2). The absorption model successfully predicted the efavirenz pharmacokinetics, and FeSSIF-V2 was chosen as the predictive dissolution media, while an IVIVR was established using the Loo-Riegelman deconvolution method. Conclusions The present work provides valuable information about efavirenz solubility and kinetics in the gastrointestinal tract, allowing an IVIVR to support future formulation changes. This understanding is essential for rational science-driven formulation development. At least, this study also showed the validity and applicability of in vitro and in silico tools in the regulatory scenario helping on drug development.

Investigating In Vitro and Ex Vivo Properties of Artemether/Lumefantrine Double-Fixed Dose Combination Lipid Matrix Tablets Prepared by Hot Fusion.

Highly lipophilic antimalarial drugs, artemether and lumefantrine, whilst an effective fixed-dose combination treatment to lower the malarial disease burden, are therapeutically hindered by low aqueous solubility and varied bioavailability. This work investigates the plausibility of directly compressed lipid matrix tablets, their role as lipid-based formulations and their future standing as drug delivery systems. Lipid matrix tablets were manufactured from solid lipid dispersions in various lipid:drug ratios employing hot fusion—the melt mixing of highly lipophilic drugs with polymer(s). Sequential biorelevant dissolution media, multiple mathematical models and ex vivo analysis utilizing porcine tissue samples were employed to assess drug release kinetics and more accurately predict in vitro performance. Directly compressed stearic acid tablets in a 0.5:1 lipid:drug ratio were deemed optimal within investigated parameters. Biorelevant media was of immense value for artemether release analysis, with formulation SA0.5C1 (Stearic Acid:double fixed dose in a 0.5:1 ratio (i.e., Stearic acid 70 mg + Lumefantrine 120 mg + Artemether 20 mg); CombiLac® as filler (q.s.); and 1% w/w magnesium stearate) yielding a higher percentage of artemether release (97.21%) than the commercially available product, Coartem® (86.12%). However, dissolution media lacked the specificity to detect lumefantrine. Nonetheless, stearic acid lipid:drug ratios governed drug release mechanisms. This work demonstrates the successful utilization of lipids as pharmaceutical excipients, particularly in the formulation of lipid matrix tablets to augment the dissolution of highly lipophilic drugs, and could thus potentially improve current malarial treatment regimens.

Use of Physiologically Based Pharmacokinetic Modeling for Predicting Drug-Food Interactions: Recommendations for Improving Predictive Performance of Low Confidence Food Effect Models.

Food can alter drug absorption and impact safety and efficacy. Besides conducting clinical studies, in vitro approaches such as biorelevant solubility and dissolution testing and in vivo dog studies are typical approaches to estimate a drug's food effect. The use of physiologically based pharmacokinetic models has gained importance and is nowadays a standard tool for food effect predictions at preclinical and clinical stages in the pharmaceutical industry. This manuscript is part of a broader publication from the IQ Consortium's food effect physiologically based pharmacokinetic model (PBPK) modeling working group and complements previous publications by focusing on cases where the food effect was predicted with low confidence. Pazopanib-HCl, trospium-Cl, and ziprasidone-HCl served as model compounds to provide insights into why several food effect predictions failed in the first instance. Furthermore, the manuscript depicts approaches whereby PBPK-based food effect predictions may be improved. These improvements should focus on the PBPK model functionality, especially better reflecting fasted- and fed-state gastric solubility, gastric re-acidification, and complex mechanisms related to gastric emptying of drugs. For improvement of in vitro methodologies, the focus should be on the development of more predictive solubility, supersaturation, and precipitation assays. With regards to the general PBPK modeling methodology, modelers should account for the full solubility profile when modeling ionizable compounds, including common ion effects, and apply a straightforward strategy to account for drug precipitation.

Effect of gastrointestinal transit on micro-environmental pH inside HPMC matrix tablets – in vitro study

A commonly used approach to enhance the dissolution of drugs with pH-dependent solubility is the incorporation of pH modifiers. The aim of this study was to evaluate the duration and extent of pH modifying effect on the micro-environmental pH in HPMC matrix by applying two mechanistic approaches regarding hydrodynamic stress on the tested formulation (i.e. static dissolution apparatuses (USP2) and dynamic approaches including the Advanced gastric simulator (AGS) and the Intestinal model for simulation of peristaltic action (IMSPA)). Moreover, the aim of our research was also the preparation of sustained-release matrix systems with improved – enhanced drug dissolution. In our study, the occurrence of a pH gradient in the gel layer of the HPMC tablets was observed during simulation of their passage along different compartments of the GIT. The pH gradient was affected by the media composition and duration of tablet exposure to the surrounding media. Both dissolution methods were also used to evaluate the influence of the mechanical stress on the drug release kinetics. Micro-environmental pH (pHM) was evaluated, using two methods: the cryostatic method with a surface pH electrode, and with the incorporation of a pH sensitive dye (methyl orange) into the matrix tablets. Our study demonstrates a significantly higher dissolution rate due to mechanical stress during the bio-relevant simulation of GIT transit of the mechanically sensitive HPMC tablets with poorly soluble drugs. A considerably higher release rate was also observed from tablets with the weakly basic drugs dipyridamole and propranolol hydrochloride containing pH modifier in case of mechanically bio-relevant dissolution models compared to the USP2 apparatus. For the assessment of the pHM, the incorporation of a pH indicator dye in the HPMC tablet proved to be more suitable, while the cryostatic method was found to be useful only for a rough pHM estimation.

Precipitation from amorphous solid dispersions in biorelevant dissolution testing: The polymorphism of regorafenib

Amorphous Solid Dispersions (ASDs) are a major drug formulation technique to achieve higher bioavailability for poorly water-soluble active pharmaceutical ingredients. So far, dissolution tailoring and supersaturation enhancement have been studied in detail, whereas less is known about the importance of formed precipitates with amorphous or crystalline states at the site of drug absorption.Regorafenib monohydrate (RGF MH), a multikinase inhibitor drug categorized as Biopharmaceutics Classification System (BCS) class II compound, was formulated with povidone K25 and hypromellose acetate succinate (HPMCAS) as an ASD. Here, for the first time, the RGF precipitation process as well as the physicochemical properties of the arising precipitates are investigated. The formed precipitates from biorelevant dissolution showed varying drug content and were analyzed offline by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), confocal Raman microscopy (CRM), X-ray powder diffraction (XRPD), and small angle X-ray scattering (SAXS). In addition to different crystalline RGF precipitates, an amorphous co-precipitate of RGF and HPMCAS was identified, which was suppressed in the presence of PVP. Wide angle X-ray scattering (WAXS) and isothermal calorimetry (ITC) were used to track the precipitation process of RGF in-situ. From calorimetric data, the precipitation profile was calculated. RGF forms precipitates in multiple polymorphic states dependent on the environmental conditions, i.e., dissolution media composition and chosen excipients. The engineered formation of defined amorphous structures in-vivo may be a promising future drug formulation strategy.

Laser diffraction as a powerful tool for amorphous solid dispersion screening and dissolution understanding

Biopharmaceutics Classification System (BCS) class II and IV drugs may be formulated as supersaturating drug delivery systems (e.g., amorphous solid dispersions [ASDs]) that can generate a supersaturated drug solution during gastrointestinal (GI) transit. The mechanisms that contribute to increased bioavailability are generally attributed to the increased solubility of the amorphous form, but another mechanism with significant contributions to the improved bioavailability have been recently identified. This mechanism consists on the formation of colloidal species and may further improve the bioavailability several fold beyond that of the amorphous drug alone. These colloidal species occur when the concentration of drug generated in solution exceeds the amorphous solubility during dissolution, resulting in a liquid-liquid phase separation (LLPS). For the appearance of LLPS, the crystallization kinetics needs to be slow relatively to the dissolution process. This work intended to implement an analytical methodology to understand the ability of a drug to form colloidal species in a biorelevant dissolution media. This screening tool was therefore focused on following the colloidal formation and crystallization kinetics of itraconazole (ITZ; model drug from BSC class II) in the presence of hydroxypropyl methylcellulose (HPMC-AS L and HPMC-AS M, which are HPMC-AS with varying ratios of succinoyl:acetyl groups), using a laser diffraction-based methodology. The ability of ITZ to form colloids by a solvent-shift approach was compared with the actual colloidal formation of ITZ amorphous solid dispersions produced by spray-drying. Results indicate that regardless of the used methodology, colloids of ITZ can be detected and monitored. The extension of colloid generation showed to be correlated with the ASD disintegration/dissolution rate, i.e, polymers with faster wettability kinetics led to faster ASD disintegration and colloidal formation.As conclusion, this study showed that laser diffraction could give complementary information about colloidal formation and ASD dissolution profile, showing to be an excellent screening strategy to be applied in the early stage development of amorphous solid dispersions.

In Vitro Drug Release, Permeability, and Structural Test of Ciprofloxacin-Loaded Nanofibers.

Nanofibers of the poorly water-soluble antibiotic ciprofloxacin (CIP) were fabricated in the form of an amorphous solid dispersion by using poly(vinyl pyrrolidone) as a polymer matrix, by the low-cost electrospinning method. The solubility of the nanofibers as well as their in vitro diffusion were remarkably higher than those of the CIP powder or the physical mixture of the two components. The fiber size and morphology were optimized, and it was found that the addition of the CIP to the electrospinning solution decreased the nanofiber diameter, leading to an increased specific surface area. Structural characterization confirmed the interactions between the drug and the polymer and the amorphous state of CIP inside the nanofibers. Since the solubility of CIP is pH-dependent, the in vitro solubility and dissolution studies were executed at different pH levels. The nanofiber sample with the finest morphology demonstrated a significant increase in solubility both in water and pH 7.4 buffer. Single medium and two-stage biorelevant dissolution studies were performed, and the release mechanism was described by mathematical models. Besides, in vitro diffusion from pH 6.8 to pH 7.4 notably increased when compared with the pure drug and physical mixture. Ciprofloxacin-loaded poly(vinyl pyrrolidone) (PVP) nanofibers can be considered as fast-dissolving formulations with improved physicochemical properties.