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Query: UMLS:C0847097 (acidity)
 15,165 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

USP apparatus I and II are gold standard methodologies for determining the in vitro dissolution profiles of test drugs. However, it is difficult to use in vitro dissolution results to predict in vivo dissolution, particularly the pH-dependent solubility of weak acid and base drugs, because the USP apparatus contains one vessel with a fixed pH for the test drug, limiting insight into in vivo drug dissolution of weak acid and weak base drugs. This discrepancy underscores the need to develop new in vitro dissolution methodology that better predicts in vivo response to assure the therapeutic efficacy and safety of oral drug products. Thus, the development of the in vivo predictive dissolution (IPD) methodology is necessitated. The major goals of in vitro dissolution are to ensure the performance of oral drug products and the support of drug formulation design, including bioequivalence (BE). Orally administered anticancer drugs, such as dasatinib and erlotinib (tyrosine kinase inhibitors), are used to treat various types of cancer. These drugs are weak bases that exhibit pH-dependent and high solubility in the acidic stomach and low solubility in the small intestine (>pH 6.0). Therefore, these drugs supersaturate and/or precipitate when they move from the stomach to the small intestine. Also of importance, gastric acidity for cancer patients may be altered with aging (reduction of gastric fluid secretion) and/or co-administration of acid-reducing agents. These may result in changes to the dissolution profiles of weak base and the reduction of drug absorption and efficacy. In vitro dissolution methodologies that assess the impact of these physiological changes in the GI condition are expected to better predict in vivo dissolution of oral medications for patients and, hence, better assess efficacy, toxicity and safety concerns. The objective of this present study is to determine the initial conditions for a mini-Gastrointestinal Simulator (mGIS) to assess in vivo dissolution of BCS class IIb drugs, dasatinib as a model drug, including the different gastric condition. The maximum dissolution of dasatinib with USP dissolution apparatus II was less than 1% in pH 6.5 SIF, while the one with mGIS (pH 1.2 SGF/pH 6.5 SIF) reached almost 100%. The supersaturation and precipitation of dasatinib were observed in the in vitro dissolution studies with mGIS but not with USP apparatus II. Additionally, dasatinib dissolution with mGIS was reduced to less than 10% when the gastric pH was elevated, suggesting the co-administration of acid reducing agents will decrease the oral bioavailability of dasatinib. Accurate prediction of in vivo drug dissolution would be beneficial for assuring product safety and efficacy for patients. To this end, we have created a new in vitro dissolution system, mGIS, to predict the in vivo dissolution phenomena of a weak base drug, dasatinib. The experimental results when combined with in silico simulation suggest that the mGIS predicted the in vivo dissolution well due to the elevation of gastric pH. Thus, mGIS might be suitable to predict in vivo dissolution of weak basic drugs. This mGIS methodology is expected to significantly advance the prediction of in vivo drug dissolution. It is also expected to assist in optimizing product development and drug formulation design in support of Quality by Design (QbD) initiatives.
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PMID:In vitro dissolution methodology, mini-Gastrointestinal Simulator (mGIS), predicts better in vivo dissolution of a weak base drug, dasatinib. 2597 75

This study aimed to gain further insight into the gastrointestinal disposition of the weakly acidic BCS class II drug diclofenac and the implications for systemic drug exposure in humans under fasted and fed state conditions. For this purpose, gastrointestinal and blood samples were collected from healthy volunteers after oral intake of a commercially available tablet of the potassium salt of diclofenac (i.e., Cataflam) in different prandial states. Subsequently, these in vivo data served as a reference for the evaluation of in vitro tools with different levels of complexity, i.e., a conventional USP II dissolution apparatus, a modified version of the dynamic open flow through test apparatus, and the TNO gastrointestinal model equipped with the recently developed advanced gastric compartment (TIMagc). In vivo data suggested impaired drug dissolution and/or immediate precipitation in the fasted stomach, linked to the acidity of the gastric environment. Similarly, a vast presence of solid drug material in the stomach was observed under fed state conditions, which could be attributed to a marked delay in intragastric tablet disintegration after drug intake with a meal. Emptying of solid drug from the stomach into the duodenum generally resulted in rapid intestinal drug (re)dissolution in both test conditions, explaining the absence of a food effect on the extent of overall systemic exposure for diclofenac. In vitro tools were found to be capable of predicting in vivo intraluminal (and systemic) disposition of this compound, the extent of which depended on the degree to which the dynamic nature of the gastrointestinal process(es) to be investigated was simulated.
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PMID:Gastrointestinal and Systemic Disposition of Diclofenac under Fasted and Fed State Conditions Supporting the Evaluation of in Vitro Predictive Tools. 2862 52

Poor solubility and low dissolution rate of pharmaceuticals in many cases largely limit their bioavailability and efficacy. One of the promising approaches to improve dissolution behavior is to develop new multicomponent solid forms. Herein we use this strategy to synthesize new multicomponent solids of dapsone (DAP), which belongs to BCS class IV, with a series of hydroxybenzoic acid coformers. A new salt of DAP with 2,6-dihydroxybenzoic acid (26DHBA) and 4 eutectics with other hydroxybenzoic acids were reported through comprehensive characterizations using powder X-ray diffraction DSC, and vibrational spectroscopy techniques. The salt formation was evidenced by the presence of ionic interactions detected using FT-IR and Raman spectroscopy, and the stoichiometric ratio was determined to be 1:1. Binary phase diagrams were established to determine the composition of eutectics. The cause for salt and eutectic selection was further understood by computing molecular electrostatic potential (MEP) surface where 26DHBA shows the greatest acidity. Moreover, the powder dissolution study and microenvironment pH measurement reveal that both salt and eutectics of DAP display improvements on the dissolution rate and equilibrium concentration in which the acidity of coformers plays a dominant role. Our findings provide a direction for future coformer screening of multicomponent solids with improved pharmaceutical properties.
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PMID:Eutectics and Salt of Dapsone With Hydroxybenzoic Acids: Binary Phase Diagrams, Characterization and Evaluation. 3229 58