Use of Gastrointestinal Simulator, Mass Transport Analysis, and Absorption Simulation to Investigate the Impact of pH Modifiers in Mitigating Weakly Basic Drugs' Performance Issues Related to Gastric pH: Palbociclib Case Study.

It is well known that reduced gastric acidity, for example with concomitant administration of acid reducing agents, can result in variable pharmacokinetics and decreased absorption of weakly basic drugs. It is important to identify the risk of reduced and variable absorption early in development, so that product design options to address the risk can be considered. This article describes the utilization of and tools to predict the effect of gastric pH, as well as the impact of adding pH modifiers, in mitigating the effect of acid reducing agents on weak base drugs' dissolution and absorption.

Improving Dissolution Behavior and Oral Absorption of Drugs with pH-Dependent Solubility Using pH Modifiers: A Physiologically Realistic Mass Transport Analysis.

Orally dosed drugs must dissolve in the gastrointestinal (GI) tract before being absorbed through the epithelial cell membrane. drug dissolution depends on the GI tract's physiological conditions such as pH, residence time, luminal buffers, intestinal motility, and transit and drug properties under fed and fasting conditions (Paixão, P. and Bermejo, M.

Cocrystal Solubility Advantage and Dose/Solubility Ratio Diagrams: A Mechanistic Approach To Selecting Additives and Controlling Dissolution-Supersaturation-Precipitation Behavior.

Two of the main questions regarding cocrystal selection and formulation development are whether the will be stable and how fast can it dissolve the drug dose. Dissolving the drug dose may require cocrystals with a high solubility advantage over drug (SA = /), but these may have limited potential to sustain drug supersaturation. Thus, we propose a twofold approach to mitigate the risk of drug precipitation by optimizing thermodynamic (SA) and kinetic factors (nucleation inhibitors).

The role of pH and dose/solubility ratio on cocrystal dissolution, drug supersaturation and precipitation.

Cocrystals that are more soluble than the constituent drug, generate supersaturation levels during dissolution and are predisposed to conversion to the less soluble drug. Drug release studies during cocrystal dissolution generally compare several cocrystals and their crystal structures. However, the influence of drug dose and solubility in different dissolution media has been scarcely reported.

Cocrystal Solubility Advantage Diagrams as a Means to Control Dissolution, Supersaturation, and Precipitation.

Cocrystals are often more soluble than needed and pose unnecessary risks for precipitation of less soluble forms of the drug during processing and dissolution. Such conversions lead to erratic cocrystal behavior and nullify the cocrystal solubility advantage over parent drug (SA = /). This work demonstrates a quantitative method for additive selection to control cocrystal disproportionation based on cocrystal solubility advantage (SA) diagrams.

Exploring Bioequivalence of Dexketoprofen Trometamol Drug Products with the Gastrointestinal Simulator (GIS) and Precipitation Pathways Analyses.

The present work aimed to explain the differences in oral performance in fasted humans who were categorized into groups based on the three different drug product formulations of dexketoprofen trometamol (DKT) salt-Using a combination of in vitro techniques and pharmacokinetic analysis. The non-bioequivalence (non-BE) tablet group achieved higher plasma C and area under the curve (AUC) than the reference and BE tablets groups, with only one difference in tablet composition, which was the presence of calcium monohydrogen phosphate, an alkalinizing excipient, in the tablet core of the non-BE formulation. Concentration profiles determined using a gastrointestinal simulator (GIS) apparatus designed with 0.

Linking the Gastrointestinal Behavior of Ibuprofen with the Systemic Exposure between and within Humans-Part 1: Fasted State Conditions.

The goal of this project was to explore and to statistically evaluate the responsible gastrointestinal (GI) factors that are significant factors in explaining the systemic exposure of ibuprofen, between and within human subjects. In a previous study, we determined the solution and total concentrations of ibuprofen as a function of time in aspirated GI fluids, after oral administration of an 800 mg IR tablet (reference standard) of ibuprofen to 20 healthy volunteers in fasted state conditions. In addition, we determined luminal pH and motility pressure recordings that were simultaneously monitored along the GI tract.

Evaluation and optimized selection of supersaturating drug delivery systems of posaconazole (BCS class 2b) in the gastrointestinal simulator (GIS): An in vitro-in silico-in vivo approach.

Supersaturating drug delivery systems (SDDS) have been put forward in the recent decades in order to circumvent the issue of low aqueous solubility. Prior to the start of clinical trials, these enabling formulations should be adequately explored in in vitro/in silico studies in order to understand their in vivo performance and to select the most appropriate and effective formulation in terms of oral bioavailability and therapeutic outcome. The purpose of this work was to evaluate the in vivo performance of four different oral formulations of posaconazole (categorized as a biopharmaceutics classification system (BCS) class 2b compound) based on the in vitro concentrations in the gastrointestinal simulator (GIS), coupled with an in silico pharmacokinetic model to predict their systemic profiles.

Cocrystals to facilitate delivery of poorly soluble compounds beyond-rule-of-5.

Besides enhancing aqueous solubilities, cocrystals have the ability to fine-tune solubility advantage over drug, supersaturation index, and bioavailability. This review presents important facts about cocrystals that set them apart from other solid-state forms of drugs, and a quantitative set of rules for the selection of additives and solution/formulation conditions that predict cocrystal solubility, supersaturation index, and transition points. Cocrystal eutectic constants are shown to be the most important cocrystal property that can be measured once a cocrystal is discovered, and simple relationships are presented that allow for prediction of cocrystal behavior as a function of pH and drug solubilizing agents.

Pharmacokinetics of Saquinavir Mesylate from Oral Self-Emulsifying Lipid-Based Delivery Systems.

Background And Objectives: Although lipid-based drug delivery systems have gained much importance in recent years due to their ability to improve the solubility and bioavailability of poorly soluble drugs, compartmental pharmacokinetic analyses have not been extensively explored. The oral pharmacokinetics of commercial liquid formulation and a developed semisolid system containing saquinavir mesylate (SQVM) were compared in Beagle dogs. A compartmental analysis after intravenous bolus administration of this drug (1 mg/kg) was also performed.

Ilex paraguariensis hydroalcoholic extract exerts antidepressant-like and neuroprotective effects: involvement of the NMDA receptor and the L-arginine-NO pathway.

Ilex paraguariensis St. Hilaire (Aquifoliaceae) is a typical plant from South America. Preclinical studies have reported the effect of I.

Atorvastatin evokes a serotonergic system-dependent antidepressant-like effect in mice.

Atorvastatin is a statin largely used in the treatment of hypercholesterolemia and recently revealed as a neuroprotective agent. The antidepressant-like effect of acute atorvastatin treatment in mice has been previously demonstrated by our laboratory. The purpose of this study was to explore the contribution of the serotonergic system in the antidepressant-like effect of atorvastatin in mice.

HPMC as a potential enhancer of nimodipine biopharmaceutical properties via ball-milled solid dispersions.

The poor solubility of drugs remains one of the most challenging aspects of formulation development. Aiming at improving the biopharmaceutical limitations of the calcium channel blocker nimodipine, the development of solid dispersions is proposed herein. Three different proportions of nimodipine:HPMC were tested and all of them generated amorphous solid dispersions.

Solid-state evaluation and polymorphic quantification of venlafaxine hydrochloride raw materials using the Rietveld method.

Venlafaxine hydrochloride (VEN) is an antidepressant drug widely used for the treatment of depression. The purpose of this study was to carry out the preparation and solid state characterization of the pure polymorphs (Forms 1 and 2) and the polymorphic identification and quantification of four commercially-available VEN raw materials. These two polymorphic forms were obtained from different crystallization methods and characterized by X-ray Powder Diffraction (XRPD), Diffuse Reflectance Infrared Fourier Transform (DRIFT), Raman Spectroscopy (RS), liquid and solid state Nuclear Magnetic Resonance (NMR and ssNMR) spectroscopies, Differential Scanning Calorimetry (DSC), and Scanning Electron Microscopy (SEM) techniques.

Single crystal structure, solid state characterization and dissolution rate of terbinafine hydrochloride.

Terbinafine hydrochloride (TH), a poorly water soluble antifungal agent, was characterized by solid state techniques including differential scanning calorimetry, thermogravimetry, X-ray powder diffraction, optical and electron microscopies, Fourier transform infrared, Raman and solid-state nuclear magnetic resonance spectroscopies and intrinsic dissolution rate (IDR). A colorless single crystal of TH was grown from an ethanol:water solution and its crystalline structure was determined through X-ray single crystal diffraction. Also, a new crystal habit of TH was obtained through the slow solvent evaporation technique revealing a needle-like shape.

Determination of nimodipine in the presence of its degradation products and overall kinetics through a stability-indicating LC method.

The determination of nimodipine in the presence of its degradation products, formed through photolysis, acidic and alkaline hydrolysis, and the drug degradation kinetics under these conditions, was investigated through a validated liquid chromatography method. Separation was achieved using a Phenomenex Luna C18 column (250 × 4.6 mm i.

High-performance column liquid chromatographic method for the simultaneous determination of buclizine, tryptophan, pyridoxine, and cyanocobalamin in tablets and oral suspension.

An HPLC method was developed and validated for the simultaneous determination of buclizine, tryptophan, pyridoxine, and cyanocobalamin in pharmaceutical formulations. The chromatographic separation was carried out on an RP-C18 column using a mobile phase gradient of methanol, 0.015 M phosphate buffer (pH 3.

Pharmacokinetic study of a carbamazepine nanoemulsion in beagle dogs.

This work describes the pharmacokinetics of a novel carbamazepine nanoemulsion. The plasma concentration profiles were determined in beagle dogs after i.v.

Preliminary study on the development of nanoemulsions for carbamazepine intravenous delivery: an investigation of drug polymorphic transition.

Carbamazepine (CBZ) is available on the pharmaceutical market as tablets, capsules, and oral suspensions, but not as a parenteral formulation for clinical use. Parenteral emulsions are a good alternative to poorly water-soluble drugs such as CBZ. In this way, four different emulsions containing 3 mg/mL of CBZ were developed, but during a period of storage, drug crystal precipitates appeared.

Carbamazepine parenteral nanoemulsions prepared by spontaneous emulsification process.

Carbamazepine (CBZ), a widely used anticonvulsant drug, is a poorly soluble drug with no parenteral treatment available for patients. This study was aimed at developing a nanoemulsion for CBZ intravenous delivery. The spontaneous emulsification method was used to prepare different formulations containing 2mg/mL CBZ.