Bridging solubility between drug discovery and development

Di, Li; Fish, Paul V.; Mano, Takamitsu

doi:10.1016/j.drudis.2011.11.007

Cited by 421 publications

(261 citation statements)

References 71 publications

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“…Di et al 5 has reviewed in detail about the various solubility measurement approaches, their usefulness and limitations in drug discovery and development.…”

Section: Methods For Solubility Estimation Of Druglike Compoundsmentioning

confidence: 99%

“…Major pharma industries, such as AstraZeneca, Novartis, Roche and Pfizer have been reported to employ semi-equilibrium techniques for high-throughput solubility measurements. 5 On the other hand, kinetic method has been employed by Boehringer Ingelheim, GSK, Pfizer & Warner-Lambert.…”

Section: Methods For Solubility Estimation Of Druglike Compoundsmentioning

confidence: 99%

“…[4][5][6] This is mainly because, most of the ligand-binding sites in the target proteins are secluded from the aqueous environment and hence hydrophobic compounds are generally preferred (or developed) in order to gain high binding affinity and activity against the target(s). 3,7 In addition, recently, the drug discovery research is also seeing a paradigm shift from enzymes to more complicated therapeutic targets, such as ion channels, protein-protein interfaces, kinases and nuclear receptors.…”

mentioning

confidence: 99%

“…3,7 In addition, recently, the drug discovery research is also seeing a paradigm shift from enzymes to more complicated therapeutic targets, such as ion channels, protein-protein interfaces, kinases and nuclear receptors. 1,5,[8][9][10] Such challenging targets generally demand more lipophilic drugs, which also involves high-crystal energies from strong intermolecular interactions.…”

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Submit Manuscript | http://medcraveonline.com been estimated that ~40% of the attrition rate of candidate-drugs has been associated with poor pharmacokinetic features and toxicity. Poor solubility is, particularly, a very significant impediment in the drug development efforts.The solubility of a drug molecule is vital for its' bioavailability. If an orally administered drug is not sufficiently soluble, then it could not be fully absorbed into the blood circulation and will be expelled from the gastrointestinal tract before reaching its' site of action. Nevertheless, hydrophobicity and innate low-water solubility are gradually becoming rather unsurprising characteristics of early hits, lead compounds and even in some market-approved drugs.3 Nearly 60%-90% of the compounds that are currently being developed exhibit poor water-soluble features 3,4 and categorized under the Biopharmaceutical Classification System (BCS) classes II (low solubility and high permeability) and IV (low solubility and low permeability). [4][5][6] This is mainly because, most of the ligand-binding sites in the target proteins are secluded from the aqueous environment and hence hydrophobic compounds are generally preferred (or developed) in order to gain high binding affinity and activity against the target(s). 3,7 In addition, recently, the drug discovery research is also seeing a paradigm shift from enzymes to more complicated therapeutic targets, such as ion channels, protein-protein interfaces, kinases and nuclear receptors. 1,5,[8][9][10] Such challenging targets generally demand more lipophilic drugs, which also involves high-crystal energies from strong intermolecular interactions.5 These factors altogether tend to adversely impact the solubility of compounds. Tackling solubility concerns in market-approved drugsIn spite of poor solubility, if a compound exhibits desirable activity (against the target protein), then it could be formulated into successful drugs with the help of various drug delivery technologies. This includes pH modification technology, co-solvent and surfactant solubilization, nanoparticle technology and micro emulsion drug delivery systems.11,12 For example, ciprofloxacin, a current fluoroquinolone-based antimicrobial agent, is weakly basic and have poor water solubility at neutral pH.11 But the solubility of this agent increases when the pH increases. As such, the currently administered formulations of ciprofloxacin contain lactic acid as a solubilizing agent (or pH modifier) and hydrochloric acid for pH adjustment. 11Imatinib, a protein-tyrosine kinase inhibitor for targeting cancers, is another example for pH-dependent soluble drugs. This drug displays very poor solubility; nevertheless, its' β-polymorphic form (i.e., imatinib salt) has showed to be very soluble at pH< 5.5.11,13 Hence, Imatinib mesylate has been orally administered for a targeted cancer therapy.11,13 Inclusion of co-solvents is also employed as a successful strategy for the formulation of insoluble drugs in the market. 14-16Ethanol, polyethylene ...

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“…Di et al 5 has reviewed in detail about the various solubility measurement approaches, their usefulness and limitations in drug discovery and development.…”

Section: Methods For Solubility Estimation Of Druglike Compoundsmentioning

confidence: 99%

Section: Methods For Solubility Estimation Of Druglike Compoundsmentioning

confidence: 99%

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“…[1,2] Consequently, many of these compounds come along with limited and often highly variable bioavailability (BA) and place a significant burden on drug development. [3] However, for many of these APIs, particularly for BCS class II compounds, there is a good chance of enhancing bioavailability and also decreasing its variability by utilizing drug delivery strategies ensuring that the API is readily and completely dissolved in the lumen of the upper gastrointestinal (GI) tract. Lipid-and surfactant-based drug delivery systems present a viable means for enhancing the oral bioavailability of some poorly water-soluble, lipophilic drugs [4,5] and represent one of the current strategies for enhancing intraluminal solubility and consequently oral BA.…”

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confidence: 99%

Enzymatically Modified Shea Butter and Palm Kernel Oil as Potential Lipid Drug Delivery Matrices

Obitte

Zorn

Oroz‐Guinea

et al. 2018

Euro J Lipid Sci & Tech

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Drug formulations based on lipids can enable a significantly better delivery of a pharmaceutically active substance and thus enhance their bioavailability. However, natural fats and oils usually have properties, which do not allow their direct use for drug delivery. Therefore, we have modified palm kernel oil (PKO) and shea butter (SB) via lipase-catalyzed transesterification using either glycerol -to create a diglyceride-enriched lipid -or using hexanoic acid via acidolysis -to alter their fatty

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Physicochemical Characterization and Oral Dosage Form Design and Selection

Dening

Amidon

et al. 2021

Burger's Medicinal Chemistry and Drug Discovery

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In order to initiate formulation development activities – that is the identification of a “marketable” product – important physical and chemical properties (physicochemical properties) as well as permeability properties need to be determined. Evaluation of these properties early in the discovery process can help discovery teams select which templates to pursue as well as identify the most promising leads. This information is also valuable “downstream” as decisions regarding dosage form design are being made. The focus of this article will be on the physicochemical properties that are most important in the evaluation of discovery leads and that provide the information needed as dosage form development is initiated and progresses. It will become apparent that the most appropriate dosage forms that make sense to consider are dictated by both the physicochemical and biopharmaceutical properties of the drug molecule. Throughout this article, there will be an emphasis on the tools and principles that will help the medicinal chemist during the drug discovery process, with particular emphasis on oral dosage forms.

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Bridging solubility between drug discovery and development

Cited by 421 publications

References 71 publications

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Enzymatically Modified Shea Butter and Palm Kernel Oil as Potential Lipid Drug Delivery Matrices

Physicochemical Characterization and Oral Dosage Form Design and Selection

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