Comparison of Phosphate and Bicarbonate Buffer Solutions as Dissolution Test Media for Predicting Bioequivalence of Febuxostat Formulation.

The purpose of the present study was to compare phosphate buffer (PPB) and bicarbonate buffer (BCB) solutions as dissolution test media for predicting the bioequivalence (BE) of an immediate-release (IR) formulation. Febuxostat was used as a model of free acid drugs. One reference formulation (RF) and three test formulations (TF) were employed in this study.

Dissolution profiles of high-dose salt-form drugs in bicarbonate buffer and phosphate buffer.

The purpose of the present study was to compare the dissolution profiles of high-dose salt-form drugs in bicarbonate buffer (BCB) and phosphate buffer (PPB) focusing on the pH changes in the bulk phase. The pH titration curves of BCB and PPB (pH 6.5, buffer capacity (β) = 4.

Food and bile micelle binding of zwitterionic antihistamine drugs.

Background And Purpose: The food effects on oral drug absorption are challenging to predict from in vitro data. Food intake has been reported to reduce the oral absorption of several zwitterionic antihistamine drugs. However, the mechanism for this negative food effect has not been clear.

Triboelectrification of Active Pharmaceutical Ingredients: Amines and Their Hydrochloride Salts.

The triboelectric properties of active pharmaceutical ingredients (APIs) contribute to problems during the manufacturing of pharmaceuticals. However, the triboelectric properties of APIs have not been comprehensively characterized. In this study, the effect of salt formulation on the triboelectric properties of APIs was investigated.

A commentary on "Are all measures of liver Kpuu a function of F, as determined following oral dosing, or have we made a critical error in defining hepatic drug clearance?".

The clearance concept has been used in pharmacokinetics for over 50 years. However, there is still much debate regarding mathematical clearance models. A recent article discussed that there is a critical error in a basic assumption that leads to the mechanistic hepatic clearance models (Benet, L.

Drug Crystal Precipitation in Biorelevant Bicarbonate Buffer: A Well-Controlled Comparative Study with Phosphate Buffer.

The purpose of the present study was to clarify whether the precipitation profile of a drug in bicarbonate buffer (BCB) may differ from that in phosphate buffer (PPB) by a well-controlled comparative study. The precipitation profiles of structurally diverse poorly soluble drugs in BCB and PPB were evaluated by a pH-shift precipitation test or a solvent-shift precipitation test (seven weak acid drugs (p: 4.2 to 7.

Dissolution Profiles of Immediate Release Products of Various Drugs in Biorelevant Bicarbonate Buffer: Comparison with Compendial Phosphate Buffer.

Purpose: The purpose of this study was to clarify the extent to which the dissolution profiles of immediate release (IR) products of various drugs differ between biorelevant bicarbonate buffer (BCB) and compendial phosphate buffer (PPB).

Methods: The dissolution profiles of the IR products of fifteen poorly soluble ionizable drugs were measured in BCB and PPB. BCB was set to be relevant to the small intestine (pH 6.

Dissolution Profiles of Oral Disintegrating Tablet with Taste Masking Granule Polymer Coating in Biorelevant Bicarbonate Buffer.

The current study aimed to explore the impact of buffer species on the dissolution behavior of orally disintegrating tablets (ODT) containing a basic polymer and its influence on bioequivalence (BE) prediction. Fexofenadine hydrochloride ODT formulations were used as the model formulations, Allegra as the reference formulation, and generic formulations A and B as the test formulations. Allegra, generic A, and generic B are ODT formulations that contain aminoalkyl methacrylate copolymers E (Eudragit E, EUD-E), a basic polymer commonly used to mask the bitter taste of drugs.

Effect of Food Viscosity on Drug Dissolution.

Purpose: The purpose of the present study was to investigate the effect of food viscosity on the dissolution rate of a drug. There are two types of viscosity, macroviscosity and microviscosity. Macroviscosity affects the diffusion layer thickness, whereas microviscosity affects the molecular diffusion coefficient.

Bicarbonate buffer dissolution test with gentle mechanistic stress for bioequivalence prediction of enteric-coated pellet formulations.

This study aimed to develop a dissolution test that can predict the bioequivalence (BE) of enteric-coated pellet formulations. The original duloxetine hydrochloride capsule (reference formulation (RF); Cymbalta® 30 mg capsule) and four generic test formulations (two capsules (CP) and two orally disintegrating tablets (OD)) were used as model formulations. Clinical BE studies were conducted on 24-47 healthy male subjects under fasting conditions.

Food and bile micelle binding of quaternary ammonium compounds.

Background And Purpose: Physiologically-based biopharmaceutics modeling (PBBM) has been widely used to predict the oral absorption of drugs. However, the prediction of food effects on oral drug absorption is still challenging, especially for negative food effects. Marked negative food effects have been reported in most cases of quaternary ammonium compounds (QAC).

Phosphate buffer interferes dissolution of prazosin hydrochloride in compendial dissolution testing.

The purpose of this study was to elucidate the lack of supersaturation behavior in the dissolution profile of prazosin hydrochloride (PRZ-HCl) in the compendial dissolution test. The equilibrium solubility was measured by a shake-flask method. Dissolution tests were performed by a compendial paddle method with a phosphate buffer solution (pH 6.

Prediction of Liquid-Liquid Phase Separation at the Dissolving Drug Salt Particle Surface.

During the dissolution of drug salt particles, liquid-liquid phase separation (LLPS) of a free form can occur within the unstirred water layer (UWL) of the particles (UWL-LLPS). Theoretically, UWL-LLPS occurs when the free form concentration at the salt particle surface () exceeds the intrinsic LLPS concentration () of the free form. In the present study, we attempted to predict UWL-LLPS based on the intrinsic physicochemical properties of drugs.

Dissolution Profiles of Poorly Soluble Drug Salts in Bicarbonate Buffer.

Purpose: The purpose of the present study was to investigate the effect of buffer species on the dissolution profiles of poorly soluble drug salts, focusing on bicarbonate buffer (BCB).

Methods: Pioglitazone HCl (PIO HCl) and dantrolene sodium (DNT Na) were used as model drugs. Non-sink dissolution tests were performed using phosphate buffer (PB) and BCB (pH 6.

Application of Population Balance Model to Simulate Precipitation of Weak Base and Zwitterionic Drugs in Gastrointestinal pH Environment.

The purpose of the present study was to evaluate whether the population balance model (PBM) could be a suitable model for the precipitation of weak base and zwitterionic drugs in the gastrointestinal pH environment. Five poorly soluble drugs were used as model drugs (dipyridamole, haloperidol, papaverine, phenazopyridine, and tosufloxacin). PBM consists of the equations for primary nucleation, secondary nucleation, and particle growth.

Bioequivalence Dissolution Test Criteria for Formulation Development of High Solubility-Low Permeability Drugs.

The purpose of the present study was to provide the experimental and theoretical basis of bioequivalence (BE) dissolution test criteria for formulation development of high solubility-low permeability drugs. According to the biowaiver scheme based on the biopharmaceutics classification system (BCS), for BCS class III drugs, a test formulation and a reference formulation are predicted to be BE when 85% of the drug dissolves within 15 min (T < 15 min) in the compendial dissolution test. However, previous theoretical simulation studies have suggested that this criterion may possibly be relaxed for use in practical formulation development.

Effect of divalent and trivalent metal ions on artificial membrane permeation of fluoroquinolones.

The purpose of the present study was to evaluate the predictability of PAMPA for the effect of metal ions on the bioavailability of fluoroquinolones (FQ). Eleven FQs and seven metal ions were employed in this study. The PAMPA membrane consisted of a 10 % soybean lecithin (SL) - decane solution.

Thermodynamic Correlation between Liquid-Liquid Phase Separation and Crystalline Solubility of Drug-Like Molecules.

The purpose of the present study was to experimentally confirm the thermodynamic correlation between the intrinsic liquid−liquid phase separation (LLPS) concentration (S0LLPS) and crystalline solubility (S0c) of drug-like molecules. Based on the thermodynamic principles, the crystalline solubility LLPS concentration melting point (Tm) equation (CLME) was derived (log10S0C=log10S0LLPS−0.0095Tm−310 for 310 K).

Development of bicarbonate buffer flow-through cell dissolution test and its application in prediction of in vivo performance of colon targeting tablets.

The purpose of this study was to develop a bicarbonate buffer flow-through cell (FTC) dissolution test. Mesalazine colon targeting tablets of a generic development product (test formulation, TF; Mesalazine 400 mg tablet) and the original product (reference formulation, RF; Asacol® 400 mg tablet) were used as model formulations. A clinical bioequivalence (BE) study was conducted on 48 healthy male subjects under fasting conditions.

A Critical Overview of the Biological Effects of Excipients (Part II): Scientific Considerations and Tools for Oral Product Development.

It is now recognized that a number of excipients previously considered to be "inert" have the capacity to alter drug oral bioavailability through a range of in vivo effects. The various mechanisms through which an excipient can affect in vivo gastrointestinal physiology and drug absorption characteristics were explored in "A Critical Overview of The Biological Effects of Excipients (Part I): Impact on Gastrointestinal Absorption." The next critical issue that needs to be discussed is how these biological effects are evaluated.

Lost in modelling and simulation?

Over the past few decades, physiologically-based pharmacokinetic modelling (PBPK) has been anticipated to be a powerful tool to improve the productivity of drug discovery and development. However, recently, multiple systematic evaluation studies independently suggested that the predictive power of current oral absorption (OA) PBPK models needs significant improvement. There is some disagreement between the industry and regulators about the credibility of OA PBPK modelling.

Dissolution Profiles of Carbamazepine Cocrystals with Cis-Trans Isomeric Coformers.

Purpose: The purpose of the present study was to investigate the dissolution profiles of cocrystals with cis-trans isomeric coformers. Previously, the carbamazepine (CBZ) cocrystals with even-carbon dicarboxylic acids showed higher supersaturation than those with odd-carbon ones, attributed to particle surface solution-mediated phase transformation (PS-SMPT) to CBZ dihydrate (CBZ DH). However, it has been unknown whether this odd-even pattern holds for cis-trans isomeric coformers.

Prediction of Oral Drug Absorption in Rats from In Vitro Data.

Purpose: In drug discovery, rats are widely used for pharmacological and toxicological studies. We previously reported that a mechanism-based oral absorption model, the gastrointestinal unified theoretical framework (GUT framework), can appropriately predict the fraction of a dose absorbed (Fa) in humans and dogs. However, there are large species differences between humans and rats.

Dissolution Kinetics of Nifedipine-Ionizable Polymer Amorphous Solid Dispersion: Comparison Between Bicarbonate and Phosphate Buffers.

Purpose: The intestinal fluid pH is maintained by the bicarbonate buffer system that shows unique properties regarding drug dissolution. Nevertheless, current compendial dissolution tests use phosphate buffers. The purpose of the present study was to investigate the effect of bicarbonate and phosphate buffers on the dissolution profiles of amorphous solid dispersions (ASD) composed of ionizable polymers.

Salt Solubility and Disproportionation - Uses and Limitations of Equations for pH and the In-silico Prediction of pH.

A multiphasic mass action equilibrium model was used to study the phase properties near the critical pH ('pH') in an acid-base transformation of a solid drug salt into its corresponding solid free base form in pure water slurries. The goal of this study was to better define the characteristics of disproportionation of pharmaceutical salts, objectively (i) to classify salts as μ-type (microclimate stable) or δ-type (disproportionation prone) based on the relationship between the calculated pH and the calculated pH of the saturated salt solution, (ii) to compare the distribution of μ/δ-type salts to predictions from the disproportionation potential equation introduced by Merritt et al., (iii) to determine if the intrinsic solubility of the free base, S, can be predicted from the measured μ-type salt solubility as a means of estimating the value of pH, (iv) to determine S directly from the measured δ-type salt solubility, and (v) to address some of the limitations of the equations commonly used to calculate pH.