Studying the propensity of compounds to supersaturate: a practical and broadly applicable approach

Henrik Palmelund; Cecilie Maria Madsen; Jakob Plum Christensen; Anette Müllertz; Thomas Rades

doi:10.1016/j.xphs.2016.06.016

Studying the propensity of compounds to supersaturate: a practical and broadly applicable approach

Henrik Palmelund, Cecilie Maria Madsen, Jakob Plum Christensen, Anette Müllertz, Thomas Rades

33 Citationer (Scopus)

Abstract

Supersaturating drug delivery systems can enhance the oral bioavailability of poorly soluble drug compounds. Supersaturation of such compounds has been studied in many different ways; however, a more standardized method is required. The rationale of choosing suitable concentrations of supersaturation to study has previously been very inconsistent. This makes comparisons between studies and compounds difficult, as the propensity of compounds to supersaturate varies greatly. This study presents a standardized method to study the supersaturation of drug compounds. The method allows, both, for a ranking of compounds according to their supersaturation propensity and the effectiveness of precipitation inhibitors. The time-concentration profile of supersaturation and precipitation was studied in situ for 4 different concentrations for 6 model compounds (albendazole, aprepitant, danazol, felodipine, fenofibrate, and tadalafil) in the μDISS Profiler™ in fasted-state simulated intestinal fluid. A relation between the induction time of nucleation and the initial supersaturated concentration could be established based on classical nucleation theory. The model compounds had different propensities to upersaturate. The data show that a single degree of supersaturation or concentration would not have described the different systems adequately. The method could be used in early preformulation for characterization of supersaturation propensity of novel compounds or precipitation inhibitor effects.

Originalsprog	Engelsk
Tidsskrift	Journal of Pharmaceutical Sciences
Vol/bind	105
Udgave nummer	10
Sider (fra-til)	3021-3029
Antal sider	9
ISSN	0022-3549
DOI	https://doi.org/10.1016/j.xphs.2016.06.016
Status	Udgivet - 1 okt. 2016

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10.1016/j.xphs.2016.06.016

Citationsformater

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abstract = "Supersaturating drug delivery systems can enhance the oral bioavailability of poorly soluble drug compounds. Supersaturation of such compounds has been studied in many different ways; however, a more standardized method is required. The rationale of choosing suitable concentrations of supersaturation to study has previously been very inconsistent. This makes comparisons between studies and compounds difficult, as the propensity of compounds to supersaturate varies greatly. This study presents a standardized method to study the supersaturation of drug compounds. The method allows, both, for a ranking of compounds according to their supersaturation propensity and the effectiveness of precipitation inhibitors. The time-concentration profile of supersaturation and precipitation was studied in situ for 4 different concentrations for 6 model compounds (albendazole, aprepitant, danazol, felodipine, fenofibrate, and tadalafil) in the μDISS Profiler{\texttrademark} in fasted-state simulated intestinal fluid. A relation between the induction time of nucleation and the initial supersaturated concentration could be established based on classical nucleation theory. The model compounds had different propensities to upersaturate. The data show that a single degree of supersaturation or concentration would not have described the different systems adequately. The method could be used in early preformulation for characterization of supersaturation propensity of novel compounds or precipitation inhibitor effects.",

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AB - Supersaturating drug delivery systems can enhance the oral bioavailability of poorly soluble drug compounds. Supersaturation of such compounds has been studied in many different ways; however, a more standardized method is required. The rationale of choosing suitable concentrations of supersaturation to study has previously been very inconsistent. This makes comparisons between studies and compounds difficult, as the propensity of compounds to supersaturate varies greatly. This study presents a standardized method to study the supersaturation of drug compounds. The method allows, both, for a ranking of compounds according to their supersaturation propensity and the effectiveness of precipitation inhibitors. The time-concentration profile of supersaturation and precipitation was studied in situ for 4 different concentrations for 6 model compounds (albendazole, aprepitant, danazol, felodipine, fenofibrate, and tadalafil) in the μDISS Profiler™ in fasted-state simulated intestinal fluid. A relation between the induction time of nucleation and the initial supersaturated concentration could be established based on classical nucleation theory. The model compounds had different propensities to upersaturate. The data show that a single degree of supersaturation or concentration would not have described the different systems adequately. The method could be used in early preformulation for characterization of supersaturation propensity of novel compounds or precipitation inhibitor effects.

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Studying the propensity of compounds to supersaturate: a practical and broadly applicable approach

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