Advanced screening assays to rapidly identify solubility-enhancing formulations: High-throughput, miniaturization and automation

Dai, Wei; Pollock-Dove, Crystal; Liang, Dong; Li, Shu

doi:10.1016/j.addr.2007.10.017

Cited by 56 publications

(43 citation statements)

References 48 publications

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“…Often, the medicinal chemist can only share a few milligrams. A preformulation laboratory must develop expertise, experience, and innovative approaches to generate meaningful and required data with the minimum amount of API available (7). For instance, we have optimized the procedure and perform important physicochemical characterization using only about 25 mg of the API (8).…”

Section: Preformulationmentioning

confidence: 99%

Preclinical Formulations: Insight, Strategies, and Practical Considerations

et al. 2014

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Abstract. A lot of resources and efforts have been directed to synthesizing potentially useful new chemical entities (NCEs) by pharmaceutical scientists globally. Detailed physicochemical characterization of NCEs in an industrial setup begins almost simultaneously with preclinical testing. Most NCEs possess poor water solubility posing bioavailability issues during initial preclinical screening, sometimes resulting in dropping out of an NCE with promising therapeutic activity. Selection of right formulation approach for an NCE, based on its physicochemical properties, can aid in improving its solubility-related absorption and bioavailability issues. The review focuses on preclinical formulations stressing upon different preclinical formulation strategies and deciphers the understanding of formulation approaches that could be employed. It also provides detailed information related to a vast pool of excipients available today, which is of immense help in designing preclinical formulations. Few examples mentioned, throw light on key aspects of preclinical formulation development. The review will serve as an important guide for selecting the right strategy to improve bioavailability of NCEs for academic as well as industrial formulation scientists.

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Section: Preformulationmentioning

confidence: 99%

Preclinical Formulations: Insight, Strategies, and Practical Considerations

et al. 2014

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“…The pharmacokinetic (PK) results in rat (Dai et al, 2007a) and dog (Dai et al, 2007b) studies showed that no-precipitation formulations in the microscreening testing had a significantly improved bioavailability compared with those which exhibited drug precipitation in the in vitro assay. In particular, the assay is useful in assessing precipitation potential of weak basic drugs that are solubilized in the acidic gastric fluid and are very likely to precipitate after the solution empties from the stomach into the small intestine (Dai et al, 2008b).…”

Section: Microscreening Precipitation Assaymentioning

confidence: 99%

“…Moreover, the microscreening assay is applicable to evaluate drug precipitation of various formulations such as micelle, microemulsion, lipid and supersaturatable lipid formulation, complexation, and solid solu- tion/solid dispersion using small quantities of compounds (Dai et al, 2008b), something that would be difficult to do manually. Despite some advantages, solvent casting could bring a concern that drug may change its polymorph in the excipient matrix after solvent removal.…”

Section: Microscreening Precipitation Assaymentioning

confidence: 99%

“…Several studies have demonstrated correlation results between high-throughput/miniaturized assays and bench-scale precipitation assays Chen and Venkatesh, 2004;Dai et al, 2007a,b;Mansky et al, 2007;Wyttenbach et al, 2007). In fact, such high-throughput precipitation assays are often used to rapidly screen out formulations with the highest precipitation potential, then conventional bench-scale precipitation methods are applied to further optimize or refine lead formulation choices for preclinical testing or initial clinical assessment (Chen et al, 2005(Chen et al, , 2003Dai et al, 2007aDai et al, , 2008b. Generally speaking, these new assays are more suited for screening solubility-enhancing formulations in drug discovery or early drug development because they usually do not focus on the long-term stability of such formulations.…”

Section: Other Assaysmentioning

confidence: 99%

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In vitro methods to assess drug precipitation

Dai

2010

International Journal of Pharmaceutics

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“…The solution is then allowed to equilibrate for a predetermined time in which the drug may precipitate. After filtration, the drug remaining in solution is measured using an UV plate reader (2). This kinetic solubility approach provides for a rapid result, but even when using buffers of physiological pH values, the results are altered by the presence of the organic solvent and, thus, the solubility is often overestimated (3).…”

Section: Introductionmentioning

confidence: 99%

Miniaturized Transfer Models to Predict the Precipitation of Poorly Soluble Weak Bases upon Entry into the Small Intestine

Klein

Buchanan

2012

AAPS PharmSciTech

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Abstract. For poorly soluble weak bases, the possibility of drug precipitation upon entry into the small intestine may affect the amount of drug available for uptake through the intestinal mucosa. A few years ago, a transfer model was introduced which has been developed to simulate the transfer of a dissolved drug out of the stomach into the small intestine. However, this setup requires the use of clinically relevant doses of the drug, which are typically not available in the early stages of formulation development. The present series of tests was performed to check whether it is possible to create a miniaturized but physiologically relevant transfer model that can be applied in the early formulation development. Experiments were performed with two miniaturized setups: a 96-well plate model and a mini-paddle transfer system. Itraconazole and tamoxifen were used as model drugs. An appropriate amount of each drug formulation was dissolved in simulated gastric fluid and then transferred into an acceptor phase consisting of fasted/fed state simulated small intestinal fluid. The amount of drug dissolved in the acceptor phase was monitored over a period of 4 h. Results from both setups were very similar. The tamoxifen preformulation did not precipitate, whereas the itraconazole formulation precipitated to the same extent in both setups. Due to the possibility of generating physiologically relevant results but using smaller sample sizes and smaller volumes of media, both miniaturized transfer systems offer various advantages in terms of substance and analytical and material cost savings when evaluating the precipitation potential of poorly soluble weakly basic drug candidates.

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Advanced screening assays to rapidly identify solubility-enhancing formulations: High-throughput, miniaturization and automation

Cited by 56 publications

References 48 publications

Preclinical Formulations: Insight, Strategies, and Practical Considerations

Preclinical Formulations: Insight, Strategies, and Practical Considerations

In vitro methods to assess drug precipitation

Miniaturized Transfer Models to Predict the Precipitation of Poorly Soluble Weak Bases upon Entry into the Small Intestine

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