Support Tools in Formulation Development for Poorly Soluble Drugs

Fridgeirsdottir, Gudrun Andrea; Harris, Robert; Fischer, Peter M.; Roberts, Clive J.

doi:10.1016/j.xphs.2016.05.024

Cited by 42 publications

(23 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The selection of the best technology for enhanced absorption is related to numerous factors and variables reflecting the physicochemical properties, such as Log P and melting point, as supportive tools for formulation selection. In particular, API with a high melting point has a strong crystallization tendency, which is not suitable for ASD [7], and intestinal lymphatic transport of API on LBF is not even expected at low lipophilicity, log P < 5 [45]. TAK-020 exhibits an exotherm at high temperatures of around 300 • C, including melting, and it has relatively low lipophilicity (cLogP 2.0 calculated by Daylight version 4.95).…”

Section: Pk Profiling For Determining the Optimal Drug Formmentioning

confidence: 99%

“…Known solubilized formulations, such as amorphous solid dispersion (ASD), lipid-based formulation (LBF) and cyclodextrin (CD) inclusion complex for improving the solubility; and nanocrystal (Nanocry) for improving the dissolution rate, also have limitations due to numerous concerns, such as difficulty of formulation preparation and manufacturability, inflexibility of dose, and instability of shelf life; success is not always achieved. Namely, to successfully enhance oral bioavailability of APIs, repeated trial and error is required, with these approaches still remaining a challenge [4,7]. Accordingly, other novel technologies for enhancing solubility, such as cocrystal, coamorphous, and nano-cocrystal systems have been studied to overcome the problem of low aqueous solubility in pharmaceutical drug development [5,[8][9][10].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pharmaceutical Cocrystal Development of TAK-020 with Enhanced Oral Absorption

et al. 2020

View full text Add to dashboard Cite

The objective of this study was to improve the solubility of poorly water-soluble drugs by pharmaceutical cocrystal engineering techniques and select the best pharmaceutical forms with high solubility and solubilized formulations for progress from the early discovery stage toward the clinical stage. Several pharmaceutical cocrystals of TAK-020, a Bruton tyrosine kinase inhibitor, were newly discovered in the screening based on the solid grinding method and the slurry method, considering thermodynamic factors that dominate cocrystal formation. TAK-020/gentisic acid cocrystal (TAK-020/GA CC) was selected based on a physicochemical property of enhanced dissolution rate. TAK-020/GA CC was proven to be a reliable cocrystal formation with a definitive stoichiometric ratio by a variety of analytical techniques—pKa calculation, solid-state nuclear magnetic resonance, and single X-ray structure analysis from the view of regulation. Furthermore, its absorption was remarkable and beyond those achieved in currently existing solubilized formulation techniques, such as nanocrystal, amorphous solid dispersion, and lipid-based formulation, in dog pharmacokinetic studies. TAK-020/GA CC was the best drug form, which might lead to good pharmacological effects with regard to enhanced absorption and development by physicochemical characterization. Through the trials of solid-state optimization from early drug discovery to pharmaceutical drug development, the cocrystals can be an effective option for achieving solubilization applicable in the pharmaceutical industry.

show abstract

Section: Pk Profiling For Determining the Optimal Drug Formmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pharmaceutical Cocrystal Development of TAK-020 with Enhanced Oral Absorption

et al. 2020

View full text Add to dashboard Cite

show abstract

“…It challenges formulation process and could lead to difficulties with successful therapy (1). Formulation development strategies of poorly soluble drugs include particle size reduction, crystal modification, addition of surfactants, preparation of solid dispersions, or lipid formulations (2). API dissolution profile in time is a result of complex interactions including a physical form of API, presence and chemical character of excipients in the formulation, and preparation process parameters as well.…”

Section: Introductionmentioning

confidence: 99%

Data-Driven Modeling of the Bicalutamide Dissolution from Powder Systems

et al. 2020

View full text Add to dashboard Cite

Low solubility of active pharmaceutical compounds (APIs) remains an important challenge in dosage form development process. In the manuscript, empirical models were developed and analyzed in order to predict dissolution of bicalutamide (BCL) from solid dispersion with various carriers. BCL was chosen as an example of a poor watersoluble API. Two separate datasets were created: one from literature data and another based on in-house experimental data. Computational experiments were conducted using artificial intelligence tools based on machine learning (AI/ML) with a plethora of techniques including artificial neural networks, decision trees, rule-based systems, and evolutionary computations. The latter resulting in classical mathematical equations provided models characterized by the lowest prediction error. In-house data turned out to be more homogeneous, as well as formulations were more extensively characterized than literature-based data. Thus, in-house data resulted in better models than literature-based data set. Among the other covariates, the best model uses for prediction of BCL dissolution profile the transmittance from IR spectrum at 1260 cm −1 wavenumber. Ab initio modeling-based in silico simulations were conducted to reveal potential BCL-excipients interaction. All crucial variables were selected automatically by AI/ML tools and resulted in reasonably simple and yet predictive models suitable for application in Quality by Design (QbD) approaches. Presented data-driven model development using AI/ML could be useful in various problems in the field of pharmaceutical technology, resulting in both predictive and investigational tools revealing new knowledge.

show abstract

“…Advantages of oral solid formulations are clear: high stability, dose accuracy, low production, and transportation costs, besides patient compliance. 1 Still, unsatisfactory physicochemical properties may compromise drug bioavailability. It is estimated that 75% of drug candidates to give rise to new medicines are poorly water soluble.…”

Section: Introductionmentioning

confidence: 99%