Strategic drug analysis in fed-state gastric biorelevant media based on drug physicochemical properties

Baxevanis, Fotios; Kuiper, Jesse; Fotaki, Nikoletta

doi:10.1016/j.ejpb.2018.03.001

Cited by 11 publications

(29 citation statements)

References 83 publications

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“…The generated models were assessed in terms of goodness of prediction (Q 2 ) and goodness of fit (R 2 ). Q 2 > 0.5 26 and R 2 and Q 2 values with a difference not greater than 0.2e0.3 27 were indications of acceptable models. The number of PLS components (lines on the X-space which best approximate and correlate with the Y-vector) was selected as described previously.…”

Section: Discussionmentioning

confidence: 94%

Affinity of Lipophilic Drugs to Mixed Lipid Aggregates in Simulated Gastrointestinal Fluids

Fagerberg¹,

Zarmpi²,

Jabbar

et al. 2021

Journal of Pharmaceutical Sciences

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Mixed lipid aggregates, comprising of bile salts and phospholipids, present in the small intestine assist in drug solubilization and subsequent drug dissolution and absorption through the intestinal epithelium. The increased variability in their levels, observed physiologically, may create challenges not only for in vivo bioavailability and bioequivalence studies, but also for in vitro bio-predictive studies as correlations between in vitro and in vivo data are not always successful. The current study investigated the impact of biorelevant dissolution media, with physiologically relevant sodium taurocholate and lecithin levels, on the apparent solubility and affinity of lipophilic compounds with a wide range of physicochemical properties (drug ionization, drug lipophilicity, molecular weight) to mixed lipid aggregates. Apparent solubility data in biorelevant dissolution media for the studied neutral drugs, weak bases and weak acids were compared against a phosphate buffer pH 6.5 in the absence of these lipidic components. Presence of mixed lipid aggregates enhanced the apparent solubility of the majority of compounds and the use of multivariate data analysis identified the significant parameters affecting drug affinity to mixed lipid aggregates based on the chemical class of the drug. For neutral drugs, increasing bile salt concentrations and/or drug lipophilicity resulted in greater enhancement in apparent solubility at 24-hr. For weak bases and weak acids, the effect of increasing bile salt levels on apparent solubility depended mostly on an interplay between drug lipophilicity and drug ionization.

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Section: Discussionmentioning

confidence: 94%

Affinity of Lipophilic Drugs to Mixed Lipid Aggregates in Simulated Gastrointestinal Fluids

Fagerberg¹,

Zarmpi²,

Jabbar

et al. 2021

Journal of Pharmaceutical Sciences

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“…The model quality was evaluated on the square of the coefficient of determination (R 2 ) and goodness of prediction (Q 2 ). R 2 and Q 2 values close to 1 represent (1) log SP = c + eE + sS + aA + bB + vV a good model fit and a high predictive power, respectively (8). The number of principal components for each model was selected based on the model's optimum Q 2 value.…”

Section: Methodsmentioning

confidence: 99%

Evaluating pediatric and adult simulated fluids solubility: Abraham solvation parameters and multivariate analysis

et al. 2021

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Purpose To understand drug solubilization as a function of age and identify drugs at risk of altered drug solubility in pediatric patients. To assess the discrimination ability of the Abraham solvation parameters and age-related changes in simulated media composition to predict in vitro drug solubility differences between pediatric and adult gastrointestinal conditions by multivariate data analysis. Methods Differences between drug solubility in pediatric and adult biorelevant media were expressed as a % pediatric-to-adult ratio [Sp/Sa (%)]. Solubility ratios of fourteen poorly water-soluble drugs (2 amphoteric; 4 weak acids; 4 weak bases; 4 neutral compounds) were used in the analysis. Partial Least Squares Regression was based on Abraham solvation parameters and age-related changes in simulated gastrointestinal fluids, as well as their interactions, to predict the pediatric-to-adult solubility ratio. Results The use of Abraham solvation parameters was useful as a theory-informed set of molecular predictors of drug solubility changes between pediatric and adult simulated gastrointestinal fluids. Our findings suggest that the molecular solvation environment in the fasted gastric state was similar in the pediatric age-groups studied, which led to fewer differences in the pediatric-to-adult solubility ratio. In the intestinal fasted and fed state, there was a high relative contribution of the physiologically relevant surfactants to the alteration of drug solubility in the pediatric simulated conditions compared to the adult ones, which confirms the importance of an age-appropriate composition in biorelevant media. Conclusion Statistical models based on Abraham solvation parameters were applied mostly to better understand drug solubility differences in adult and pediatric biorelevant media.

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“…For the quantitative analysis of nifedipine, HPLC combined with UV detection was used. The method was adapted from the method previously reported by Vertzoni et al . Nifedipine was separated on an analytical C 18 column (Thermo Hypersil GOLD, 5 μm, 250 × 4.6 mm) with UV detection at 238 nm, a column temperature of 30°C, mobile phase of a 60:40 mixture ( v /v) of methanol and water (Milli‐Q), a flow rate of 1.0 mL/min, and injection volume of 50 μL.…”

Section: Methodsmentioning

confidence: 99%

Potential prediction of formulation performance in paediatric patients using biopharmaceutical tools and simulation of clinically relevant administration scenarios of nifedipine and lorazepam

Vossen

Hanff

Vulto

et al. 2019

Brit J Clinical Pharma

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Aims: This study explores the impact of paediatric patient related factors and choice of formulation on the dissolution characteristics of nifedipine and lorazepam, 2 drug substances regularly applied in very young patients and in compounded formulations.Methods: Dissolution experiments were designed to reflect clinical practice in a paediatric hospital, with respect to dosage forms, feeding regimens and methods of administration. Solubility studies addressed the influence of age and prandial state.Drug solubility and dissolution experiments were conducted in biorelevant media and adapted age-specific (neonate and infant) media. Dissolution studies were performed with the mini-paddle apparatus and the flow-through cell apparatus.Results: Dissolution of nifedipine formulations was not affected by age-related changes of the fasted state simulated gastrointestinal fluids, and by disintegration of the formulation before administration. However, a significant difference in nifedipine's dissolution rate from commercial tablets and compounded capsules was observed. The dissolution of lorazepam tablets was affected by fasted-vs fed-state media, but it was deemed less likely to be clinically relevant. The significant effect of fed-state media on nifedipine's solubility was considered to have possible clinical relevance since very young patients are almost continuously in a fed state. Conclusion:The in vitro results obtained from these studies reveal the potential of biorelevant solubility and dissolution studies reflecting clinical practice to predict drug performance in paediatric patients.

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Strategic drug analysis in fed-state gastric biorelevant media based on drug physicochemical properties

Cited by 11 publications

References 83 publications

Affinity of Lipophilic Drugs to Mixed Lipid Aggregates in Simulated Gastrointestinal Fluids

Affinity of Lipophilic Drugs to Mixed Lipid Aggregates in Simulated Gastrointestinal Fluids

Evaluating pediatric and adult simulated fluids solubility: Abraham solvation parameters and multivariate analysis

Potential prediction of formulation performance in paediatric patients using biopharmaceutical tools and simulation of clinically relevant administration scenarios of nifedipine and lorazepam

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