Biorelevant Dissolution Media Research Articles

Serum and lymph pharmacokinetics of nilotinib delivered by yeast glucan particles per os

Nilotinib is a selective tyrosine-kinase inhibitor approved for the treatment of chronic myeloid leukemia. It is poorly soluble in aqueous media and has a low oral bioavailability. Nilotinib encapsulation into yeast glucan particles (GPs) was investigated in this work as a means of increasing bioavailability. The amorphization of nilotinib in GPs resulted in an increased dissolution rate, which was confirmed by in vitro experiments using biorelevant dissolution media. Simultaneously, GPs containing nilotinib were effectively taken up by macrophages, which was quantified in vitro on cell cultures. The overall oral bioavailability in a rat model was approximately 39 % for nilotinib delivered in a reference formulation (Tasigna) and was almost doubled when delivered in GPs. The contribution of glucan particles to the lymphatic transport of nilotinib was quantified. When delivered by GPs, cumulative nilotinib absorption via the lymphatic system increased by a factor of 10.8 compared to the reference, but still represented arelative bioavailability of only 1.12 %. The cumulative uptake of GPs in the lymph was found to be 0.54 mg after a single dose of 50 mg. Yeast glucan particles can therefore serve as a drug delivery vehicle with a dual function: dissolution rate enhancement by amorphization, and, to asmaller extent, lymphatic delivery due to macrophage uptake.

Inhibition of Crystal Nucleation and Growth in Aqueous Drug Solutions: Impact of Different Polymers on the Supersaturation Profiles of Amorphous Drugs-The Case of Alpha-Mangostin.

The polymer used in supersaturated solutions plays a critical role in maintaining supersaturation levels of amorphous drugs. The prevention of drug crystallization in the supersaturated solutions by adding polymers depends on their ability to inhibit nucleation and crystal growth of drugs. This showed that understanding the mechanism of nucleation inhibition by polymers is necessary to develop the drug formulation in supersaturated solutions. Therefore, this study aims to evaluate the impact of water-soluble polymers on the supersaturation behavior of drugs and elucidate the mechanism of maintaining the supersaturation levels in an aqueous solution. It was carried out using alpha-mangostin (AM) as a model of the poorly water-soluble drug, while hypromellose (HPMC), polyvinylpyrrolidone (PVP), and eudragit were used as polymers. Their ability to inhibit the nucleation and crystal growth of AM was also evaluated. The supersaturation profiles of AM were measured in biorelevant dissolution media, while the crystal growth rate of AM was evaluated from the decrease in dissolved drug concentration by determining the induction time for AM nucleation. The interaction of AM with each polymer was evaluated and predicted by FT-IR, NMR measurement, and an in silico study, respectively. Based on observation, the PVP effectively maintained AM in a supersaturated state for the long term while eudragit conserved for 15 min. Meanwhile, an inhibitory effect of HPMC on the AM crystal nucleation was not observed. It was also \]-+discovered that the effectiveness of the various polymers depends on the interaction between the polymer and the drug. FT-IR and in silico studies demonstrated that the interaction of PVP-AM had the best polymer compared to eudragit and HPMC. NMR analysis suggested that the interaction between the methyl group from PVP with the carbonyl group of AM occurred in the PVP solution. The viscosity measurement revealed that the inhibition of nucleation and crystal growth of AM was not caused by increasing the viscosity. These results indicated that polymer-AM interactions could contribute to the crystallization inhibition and maintenance of AM in a supersaturated state. Therefore, an investigation of the mechanism of drug nucleation inhibition by polymers is recommended in the selection of crystallization inhibitors and a planned strategy to develop supersaturated formulations of drugs.

Targeted colonic release formulations of mesalazine – A clinical pharmaco-scintigraphic proof-of-concept study in healthy subjects and patients with mildly active ulcerative colitis

Colonic targeting of orally applied therapeutic drugs remains a challenge. Tablet coatings relying on gastrointestinal pH and colonic bacterial enzymes as triggers in association with an inner alkaline layer are expected to improve targeting efficiency. Mesalazine release from three differently coated tablets labelled with 1 MBq 153Sm was characterised in a single centre, open-label, parallel group study in nineteen healthy subjects and seven patients with mildly active ulcerative colitis. Two semi-organic and one aqueous-based outer coating with different ratios of enteric polymer and resistant starch were tested. All coatings showed comparable release lagtimes in biorelevant dissolution media and were not affected by neutron-activation of the samarium tracer. Mesalazine pharmacokinetics and gamma scintigraphy were used to characterise drug release, anatomical site of tablet disintegration and gastrointestinal transit. Initial tablet disintegration occurred at the ileo-caecal junction or beyond in 92 % of the subjects. Time to initial tablet disintegration was inversely correlated with maximal plasma concentrations and systemic mesalazine exposure. Although high inter-subject variability precluded detection of differences between solvent types and different enteric polymer to polysaccharide ratios, the dual pH and enzymatic triggered release system in combination with an inner alkaline layer promoted mesalazine release at the target site with high accuracy.

Sources of dissolution variability into biorelevant media

Identifying sources of dissolution variation is often challenging. Biorelevant dissolution media are compositionally complex, can require multiple steps to fabricate, and are utilized across differing laboratories. The objective was to determine the contributions of location, operator, media fabrication method, day, and tablet to total dissolution variability into biorelevant media. Thirty min dissolution data from a prior report were subjected to analysis-of-variable (ANOVA). Results showed that total dissolution variance was highest for medium dissolution (versus high or low dissolution). Overall, across both ibuprofen and ketoconazole, the rank-order importance of sources of variation were location > operator (nested in sequence) > day > fabrication method > tablet. Location and day were the factors that most frequently were significant sources of variability. However, location was generally much more impactful than day, and location frequently contributed to the majority of total variance. Day never contributed as the majority factor and was generally minor. Fabrication method was occasionally significant, although never a majority contributor. Overall, of all factors, location contributed most to dissolution variance here, using biorelevant media, as observed in other studies not using biorelevant media. This impact of location with and without biorelevant media supports our prior findings that biorelevant media generally showed favorable repeatability and reproducibility.

Pharmacokinetics of a new fixed-dose combination of candesartan cilexetil, hydrochlorothiazide, and rosuvastatin in healthy adult subjects.

A fixed-dose combination (FDC) of candesartan cilexetil, hydrochlorothiazide and rosuvastatin (CC/HCTZ/RSV) has been developed to enhance patient compliance in the primary prevention of cardiovascular diseases. To evaluate if the combination of the product components in the new FDC capsule formulation affects their respective pharmacokinetic and in vitro dissolution patterns. In vitro dissolution profiles were compared in USP-43 and in biorelevant dissolution media. In vivo comparisons were obtained in a randomized, open-label, single-dose, two-treatment, two-way crossover study in 24 healthy subjects. During each treatment period, subjects received the test formulation (FDC hard capsule containing CC/HCTZ/RSV) or the reference formulation (co-administration of a FDC CC/HCTZ tablet and a RSV tablet). Plasma samples were collected periodically over 48 hours post-dose. Safety and tolerability were assessed. Dissolution profiles of all active drugs in the Test (capsule) and Reference Products (as tablets) were within the tolerance dissolution criteria of USP-43 conditions. HCTZ dissolution profiles were closely similar whereas those for RSV and CC did not match at specific pHs. In the pharmacokinetic study, the 90% confidence intervals (CIs) for the geometric least-square mean ratios of Cmax, AUC0-last, and AUC0-inf were 0.95-1.18, 0.95-1.15 and 0.95-1.13 (CC); 0.91-1.10, 0.96-1.08, and 0.96-1.09 (HCTZ) and 0.82-1.23, 0.81-1.13, and 0.82-1.12 (RSV), respectively. All adverse events were mild. The new FDC product (Sinlip Prevent), a stable FDC hard capsule, was bioequivalent (similar pharmacokinetics) when compared to the co-administration of the components and may be considered as a suitable and simplified medication for cardiovascular disease management.

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.

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.

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-situ Intestinal Absorption and Pharmacokinetic Investigations of Carvedilol Loaded Supersaturated Self-emulsifying Drug System.

Carvedilol (CD), a non-selective beta-blocker, is indicated for the management of mild to moderate congestive heart failure. After oral administration, CD is rapidly absorbed with an absolute bioavailability of 18-25% because of low solubility and extensive first-pass metabolism. The present investigation focused on enhanced oral delivery of CD using supersaturated self-emulsifying drug delivery (SEDDS) system. Optimized SEDDS consisted of a blend of Oleic acid and Labrafil-M2125 as an oil-phase, Cremophor-RH40, polyethylene glycol-400 and HPMC-E5 as a surfactant, co-surfactant and supersaturation promoter respectively. Formulations were characterized for physical characteristics, invitro release in simulated and biorelevant dissolution media, intestinal permeability and bioavailability studies in Wistar rats. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analysis, scanning electron microscopy (SEM) studies were used to confirm the crystalline nature and shape of the optimized formulation. DSC and XRD, SEM studies showed that the drug was in amorphous form, and droplets were spherical in shape. Dissolution studies clearly showed distinct CD release in compendial and biorelevant dissolution media. The results from permeability and in-vivo studies depicted 2.2-folds and 3.2-folds increase in permeability and bioavailability, respectively from supersaturated SEDDS in comparison with control. The results conclusively confirmed that the SEDDS formulation could be considered as a new alternative delivery vehicle for the oral supply of CD. Lay Summary: Carvedilol (CD) is a non-selective antihypertensive drug with poor oral bioavailability. Previously, various lipid delivery systems were reported with enhanced oral delivery. We developed suprsaturable SEDDS formulation with immediate onset of action. SEDDS formulation was developed and optimized as per the established protocols. The optimized SEDDS formulation was stable over three months and converted to solid and supersaturated SEDDS. The results from permeability and in-vivo studies demonstrated an enhancement in permeability and bioavailability from supersaturated SEDDS in comparison with control. The results conclusively confirmed that the SEDDS formulation could be considered as a new alternative delivery vehicle for the oral administration of CD.

Polymeric Precipitation Inhibitor Assisted Supersaturable SMEDDS of Efavirenz Based on Experimental Observations and Molecular Mechanics.

Supersaturable SMEDDS, a versatile dosage form, was investigated for improving the biopharmaceutical attributes and eradicating the food effect of poorly water soluble drug efavirenz. The present research pursues the development of efavirenz loaded Supersaturable Self- Microemulsifying Drug Delivery System (SS SMEDDS) for improving biopharmaceutical performance. Preformulation studies were carried out to determine the optimized range of lipid excipients to develop stable supersaturated SMEDDS (ST SMEDDS). The SS SMEDD formulation was prepared by adding hydroxypropyl methylcellulose as a polymeric precipitation inhibitor. The developed SS SMEDDS were evaluated for supersaturation behavior by performing in vitro supersaturation studies and molecular simulations by in silico docking. Dissolution was performed in biorelevant media to simulate fed/fasted conditions in gastrointestinal regions. Absorption behavior was determined through in vivo pharmacokinetics approach. The optimized ST SMEDDS formulation containing Maisine® CC, Tween 80 and Transcutol-P exhibited thermodynamic stability with quick rate of emulsification. The optimized SS SMEDDS containing suitable polymeric precipitation inhibitor exhibited enhanced efavirenz concentration in in vitro supersaturation test. The theoretical simulations by molecular docking revealed strong intermolecular interactions with a docking score of -3.004 KJ/mol. The dissolution performance of marketed product in biorelevant dissolution media inferred the existence of food effect in the dissolution of efavirenz. However, in SS SMEDDS, no significant differences in drug release behavior under different fasted/fed conditions signify that the food effect was neutralized. In vivo pharmacokinetics revealed a significant increase in the absorption profile of efavirenz from SS SMEDDS than that of ST SMEDDS and marketed product. The designed delivery system indicated promising results in developing an effectual EFV formulation for HIV treatment.

Prediction of In-vivo Performance of Naproxen and Esomeprazole Magnesium Delayed-Release Tablets using Biorelevant Dissolution Tests

Main objective of this research work was to develop a biorelevant dissolution method by correlating the in-vivo behavior of Naproxen and Esomeprazole magnesium delayed release tablets 500/20mg, when administered orally under pre-prandial condition. The target dissolution profile for bio-relevant dissolution media was derived, by deconvoluting mean blood plasma concentration time profile of Naproxen and Esomeprazole, achieved after oral administration under pre-prandial condition. The dissolution media volume and RPM were optimized using full factorial design of experiment. The dissolution profile observed with office of generic drugs recommended dissolution media was faster in release for Naproxen part and slower in release for Esomeprazole part in comparison to target release of bio-relevant dissolution method, with the F 2 value of 31 for Naproxen and 29 for Esomeprazole. USP Apparatus-I with fasted state simulated gastro intestinal change over dissolution media were used for method development. Based on ANOVA results, for Naproxen part, 250ml of fasting change over dissolution medium, and 50RPM, with the desirability factor of 0.508 was concluded as bio relevant dissolution medium. For esomeprazole part, the 900ml of fasting change over dissolution medium, and 100RPM, with the desirability factor of 0.479 was concluded as bio-relevant dissolution medium. The F 2 value observed between in-vitro and in-vivo dissolution profile is 64 and 63, the regression co-efficient (R 2 ) value of 0.987 and 0.997 for Naproxen and Esomeprazole respectively demonstrates a very good in-vitro/in-vivo correlation under pre-prandial condition. The developed method shall be used as a predictive in-vitro tool for evaluation Naproxen from Naproxen and Esomeprazole magnesium delayed release tablets, and also gives the advantage for claiming bio-waiver for remaining strengths.

Fatty acid chain length impacts nanonizing capacity of albumin-fatty acid nanomicelles: Enhanced physicochemical property and cellular delivery of poorly water-soluble drug

This study aimed to design the ideal nanonizing vehicle for poorly water-soluble model curcumin (CCM) using fattigation-platform nanotechnology, and to investigate the effects of fatty acid salts chain length on nanonizing CCM and its efficient delivery to different cancer cells. HSA-fatty acid conjugates were synthesized by EDC/NHS coupling. Fattigation-platform nanomicelles (NMs), prepared by film hydration, exhibited uniform and spherical morphology, although, each NM varied in particle size, zeta potential, and critical micelle concentration according to the types of fatty acid. Preliminary solubility studies of albumin conjugates with 5 types of fatty acid salts of different chain lengths revealed that C14 exhibited the highest solubilization of CCM. CCM-loaded HSA-C14 NMs demonstrated the highest drug content (5.35 ± 0.48%) and loading efficiency (95.93 ± 1.87%) compared to other NMs. It exhibited enhanced drug release rate and reduced micelle size in biorelevant dissolution medium. Interestingly, this solubilization approach was well applied in poorly water-soluble docetaxel trihydrate (DTX). Preliminary solubility results of DTX was also corresponded to the stable nanonization phenomenon in biorelevant dissolution medium. Compared to the CCM EtOH solution, HSA-C14 NMs showed higher internalization in cancer cell lines A549 and MCF-7, and consequently, exhibited significantly increased cytotoxicity against both cell lines. Therefore, this study provides a new solubilization approach for poorly water-soluble drugs using fatty acid salts of different chain lengths and their micellar formations via nanonization, which could be a promising tool for targeted cancer therapy using poorly water-soluble drugs.

Selection of In Vivo Predictive Dissolution Media Using Drug Substance and Physiological Properties

ABSTRACTThe rate and extent of drug dissolution in the gastrointestinal (GI) tract are highly dependent upon drug physicochemical properties and GI fluid properties. Biorelevant dissolution media (BDM), which aim to facilitate in vitro prediction of in vivo dissolution performance, have evolved with our understanding of GI physiology. However, BDM with a variety of properties and compositions are available, making the choice of dissolution medium challenging. In this tutorial, we describe a simple and quantitative methodology for selecting practical, yet physiologically relevant BDM representative of fasted humans for evaluating dissolution of immediate release formulations. Specifically, this methodology describes selection of pH, buffer species, and concentration and evaluates the importance of including bile salts and phospholipids in the BDM based upon drug substance log D, pKa, and intrinsic solubility. The methodology is based upon a mechanistic understanding of how three main factors affect dissolution, including (1) drug ionization at gastrointestinal pH, (2) alteration of surface pH by charged drug species, and (3) drug solubilization in mixed lipidic aggregates comprising bile salts and phospholipids. Assessment of this methodology through testing and comparison with literature reports showed that the recommendations correctly identified when a biorelevant buffer capacity or the addition of bile salts and phospholipids to the medium would appreciably change the drug dissolution profile. This methodology can enable informed decisions about when a time, complexity, and/or cost-saving buffer is expected to lead to physiologically meaningful in vitro dissolution testing, versus when a more complex buffer would be required.

Erlotinib-Valproic Acid Liquisolid Formulation: Evaluating Oral Bioavailability and Cytotoxicity in Erlotinib-Resistant Non-small Cell Lung Cancer Cells.

Lung cancer patients develop acquired resistance to tyrosine kinase inhibitors including erlotinib (ERL) after few months of primary treatment. Evidently, new chemotherapy strategies to delay or overcome the resistance are urgently needed to improve the clinical outcome in non-small cell lung cancer (NSCLC) patients. In this paper, we have investigated the cytotoxic interaction of ERL and valproic acid (VA) in ERL-resistant NSCLC cells and developed a liquisolid formulation of ERL-VA for improving oral bioavailability of ERL. ERL is weakly basic, biopharmaceutical classification system (BCS) class II drug with extremely poor aqueous solubility while VA is a branched chain fatty acid. Ionic interaction between ERL and VA (1:2M ratio) resulted in significant enhancement in saturation solubility of ERL at different pH range. Liquisolid formulation of ERL-VA (EVLF) developed using PEG 400 and mesoporous calcium silicate was characterized for solid state and in vitro dissolution in biorelevant dissolution medium (FaSSIF and FeSSIF). Cytotoxicity of ERL was enhanced by 2-5 folds on co-incubation with VA in HCC827/ERL cell line. Flow cytometry analysis using AnnexinV-FITC assay demonstrated that VA and ERL alone have poor apoptotic effect on HCC827/ERL cells while combination showed around 69% apoptotic cells. Western blot analysis confirmed the role of survivin in overcoming resistance. In vivo pharmacokinetic studies of EVLF in rats demonstrated a 199% relative bioavailability compared to ERL suspension. Thus, EVLF could be a promising alternative to current ERL formulations in the treatment of NSCLC.

Hot-melt extrusion process impact on polymer choice of glyburide solid dispersions: The effect of wettability and dissolution

The aim of this study was to evaluate the choice of polymer and polymer level on the performance of the microstructure and wettability of hot-melt extruded solid dispersion of Glyburide (Gly) as a model drug. The produced solid dispersion were characterised using scanning electron microscopy (SEM), image analysis using a focus variation instrument (FVI), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), X-ray microtomography (XµT), dynamic contact angle measurement and dissolution analysis using biorelevant dissolution media (FASSIF). SEM and focus variation analysis showed that the microstructure and surface morphology was significantly different between samples produced. This was confirmed by further analysis using XµT which showed that an increase in polymer content brought about a decrease in the porosity of the hot-melt extruded dispersions. DSC suggested complete amorphorisation of Gly whereas XRPD suggested incomplete amorphorisation. The static and dynamic contact angle measurement correlated with the dissolution studies using FASSIF media indicating that the initial liquid imbibition process as captured by the dynamic contact angle directly affects the dissolution performance.

METHOD DEVELOPMENT AND VALIDATION FOR THE SIMULTANEOUS DETERMINATION OF METOPROLOL AND ATORVASTATIN BY REVERSED-PHASE HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY IN ITS BULK AND PHARMACEUTICAL TABLET DOSAGE FORM USING BIORELEVANT DISSOLUTION MEDIA (FASTED STATE SMALL INTESTINAL FLUID)

Objective: A present investigation is based on method development and validation for the simultaneous determination of metoprolol and atorvastatin by reversed-phase high-performance liquid chromatography in its bulk and pharmaceutical dosage form using a biorelevant dissolution media (fasted state small intestinal fluid). Methods: The chromatographic separation technique performed by an isocratic method for this column used Inertsil ODS-3 (4.6×150 mm, 5 μm). The ratio of mobile phase used is phosphate buffer 4.8 pH: acetonitrile (35:65v/v), flow rate 1 ml/min, and analysis time 15.0 min, UV detection was at 244 nm. Results: According to the International Conference on Harmonisation Q2 (R1) guidelines, the method validation was done. Peaks were observed at 2.227 min and 5.819 min, concentration range of linearity was obtained at 50–250 μg/ml and 10–50 μg/ml, linearity correlation coefficients were 0.9997 and 0.9995, limit of detection was 0.33 mg/ml and 0.21 mg/ml, and limit of quantification was 1.08 mg/ml and 0.69 mg/ml for metoprolol and atorvastatin, respectively. Conclusion: The obtained results for this method validation are within acceptance criteria. This method was more economical and stable for routine analysis.

Effect of Surfactant-Bile Interactions on the Solubility of Hydrophobic Drugs in Biorelevant Dissolution Media.

Biorelevant dissolution media (BDM) methods are commonly employed to investigate the oral absorption of poorly water-soluble drugs. Despite the significant progress in this area, the effect of commonly employed pharmaceutical excipients, such as surfactants, on the solubility of drugs in BDM has not been characterized in detail. The aim of this study is to clarify the impact of surfactant-bile interactions on drug solubility by using a set of 12 surfactants, 3 model hydrophobic drugs (fenofibrate, danazol, and progesterone) and two types of BDM (porcine bile extract and sodium taurodeoxycholate). Drug precipitation and sharp nonlinear decrease in the solubility of all studied drugs is observed when drug-loaded ionic surfactant micelles are introduced in solutions of both BDM, whereas the drugs remain solubilized in the mixtures of nonionic polysorbate surfactants + BDM. One-dimensional and diffusion-ordered 1H NMR spectroscopy show that mixed bile salt + surfactant micelles with low drug solubilization capacity are formed for the ionic surfactants. On the other hand, separate surfactant-rich and bile salt-rich micelles coexist in the nonionic polysorbate surfactant + bile salt mixtures, explaining the better drug solubility in these systems. The nonionic alcohol ethoxylate surfactants show intermediate behavior. The large dependence of the drug solubility on surfactant-bile interactions (in which the drug molecules do not play a major role per se) highlights how the complex interplay between excipients and bile salts can significantly change one of the key parameters which governs the oral absorption of poorly water-soluble drugs, viz. the drug solubility in the intestinal fluids.

Физико-химическое и технологическое исследование интерполимерного комплекса полиметакриловой кислоты и полиэтиленгликоля как основы для создания матричных систем

Проведено изучение физико-химических и технологических свойств интерполимерного комплекса полиметакриловой кислоты и полиэтиленгликоля, известного под торговым названием «Композиционный полимерный носитель» (ФГУП НИИ Полимеров, Россия). Данный полимер является вспомогательным веществом, использующемся в технологии твердых лекарственных форм как матрицеобразователь и как пленкообразователь для достижения пролонгированного и замедленного высвобождения. С целью расширения возможностей применения композиционного полимерного носителя изучены растворимость полимера в водных растворах и органических растворителях, технологические и поверхностно-активные свойства полимера, определена критическая концентрация гелеобразования. Получены экспериментальные образцы таблеток и пероральных гелей модельных веществ, близких по физико-химическим свойствам, на основе композиционного полимерного носителя в различных концентрациях, для которых изучали технологические, реологические и биофармацевтические свойства. Показана перспективность использования полимера в составе как твердых, так и мягких лекарственных форм для обеспечения пролонгированного высвобождения лекарственных веществ.

Lipid based delivery of Efavirenz: An answer to its erratic absorption and food effect

The current investigation entails systematic development of EFV (Efavirenz) loaded isotropic mixture prepared with long chain triglycerides for obliterating food associated variability and minimizing the erratic absorption behavior. For this purpose, the optimized isotropic mixture (EF1) consists of Maisine 35-1 (20%), Transcutol HP (17.7% w/w) and Cremophor RH 40:Labrasol (1:1) (62.3% w/w) was formulated by employing D-optimal mixture design that after numerical optimization showed highest desirability of 0.995. Further, the dissolution behavior of EFV suspension in biorelevant dissolution media's simulate the fed and fasted small intestine conditions, clearly anticipated that there is an influence of food effect for EFV. However, when EFV loaded into isotropic mixture, the food effect was abolished and no significant difference was seen in biorelevant dissolution media's. The tissue distribution of EFV from EF1 follows order: blood plasma > heart > brain > lymph nodes > liver. Interestingly, the in-vivo animal pharmacokinetic performance showed positive food effect after administration of EFV suspension and marketed formulation. However, the developed formulation (EF1) nullifies this food effect. In nutshell, these studies suggested significant enhancement in the biopharmaceutical attributes of a stable and robust EFV loaded isotropic mixture.

Variation in Supersaturation and Phase Behavior of Ezetimibe Amorphous Solid Dispersions upon Dissolution in Different Biorelevant Media.

The delivery of poorly water-soluble drugs using amorphous solid dispersions (ASDs) has been widely acknowledged as a promising strategy for enhancing oral bioavailability. Upon dissolution, ASDs have accelerated dissolution rates and yield supersaturated solutions leading to higher apparent solubilities. Understanding the complex phase behavior of ASDs during dissolution is crucial for developing an effective formulation. Since the absorption of a lipophilic, high permeability drug is determined primarily by the intraluminal dissolution process and the final concentration achieved, there is a need for evaluation in biorelevant dissolution media that simulate both fasting and fed gastrointestinal states. In this study, using ezetimibe as a model drug, three different ASDs were prepared using poly(acrylic acid) (PAA), polyvinylpyrrolidone (PVP), and hydroxypropyl methylcellulose acetyl succinate (HPMC-AS). Dissolution of ASDs was carried out in sodium phosphate buffer, fed-state simulated intestinal fluid (FeSSIF), and Ensure Plus to evaluate the impact of different dissolution media on release profile, supersaturation, and phase behavior. The supersaturation level and crystallization kinetics varied among the dispersions and were found to be highly dependent on the medium employed. The presence of solubilizing additives in biorelevant media greatly affected the generation and stabilization of supersaturated solutions. Second harmonic generation microscopy was found to enable the detection of crystals in all media including the highly turbid Ensure Plus system. In conclusion, it is important to evaluate the impact of complex biorelevant media on the dissolution performance of ASDs to better design supersaturating formulations for oral delivery.