Physical chemistry of supersaturated solutions and implications for oral absorption

Taylor, Lynne S.; Zhang, Geoff G. Z.

doi:10.1016/j.addr.2016.03.006

Cited by 307 publications

(314 citation statements)

References 102 publications

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“…Thus in the absence of crystallization, addition of further solute above this concentration leads to the formation of an amorphous solute-rich disperse phase. 24 Therefore, we can define the maximum achievable supersaturation ratio as:…”

Section: Discussionmentioning

confidence: 99%

“…By subsequently separating the drug-rich dispersed phase from the continuous phase, using ultracentrifugation to pellet the drug-rich phase, the composition of the continuous phase can be determined, thereby yielding one of the binodal points (at 37°C). 24 Diffusion rate measurements were also implemented to determine the concentration of telaprevir in the continuous phase following GLPS. Figure 5a shows the concentration in the receiver chamber as a function of time, from which telaprevir mass flow rate for different donor chamber concentration levels (shown in Figure 5b) can be determined from the slope.…”

Section: Crystalline Solubility and The Onset Of Glpsmentioning

confidence: 99%

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Impact of Endogenous Bile Salts on the Thermodynamics of Supersaturated Active Pharmaceutical Ingredient Solutions

Lu¹,

Ormes²,

Lowinger

et al. 2017

Crystal Growth & Design

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A variety of formulation strategies have been developed to mitigate the inadequate aqueous solubility of certain therapeutic agents. Amongst these, achieving supersaturation in vivo is a promising approach to improve the extent of oral absorption. Due to the thermodynamic instability of supersaturated solutions, inhibitors are needed to kinetically hinder crystallization. In addition to commonly used polymeric additives, bile salts, naturally present in the gastrointestinal tract, have been shown to exhibit crystallization inhibition properties. However, the impact of bile salts on solution thermodynamics is not well understood, although this knowledge is essential in order to explore the mechanism of crystallization inhibition.To better describe solution thermodynamics in the presence of bile salts, a side-by-side diffusion cell was used to evaluate solute flux for solutions of telaprevir in the absence and presence of the six most abundant bile salts in human intestinal fluid at various solute concentrations; flux measurements provide information about the solute thermodynamic activity and hence can provide an improved measurement of supersaturation in complex solutions. Trihydroxy bile salts had minimal impact on solution phase boundaries as well as solute flux, while micellar dihydroxy bile salts solubilized telaprevir leading to reduced solute flux across the membrane. An inconsistency between the concentration-based supersaturation ratio and that based on solute thermodynamic activity (the fundamental driving force for crystallization) was noted, suggesting that the activity-based supersaturation should be determined to better interpret any modification in crystallization kinetics in the presence of these additives. These findings indicate that bile salts are not interchangeable from a thermodynamic perspective, and provide a foundation for further studies evaluating the mechanism of crystallization inhibition.3

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Section: Discussionmentioning

confidence: 99%

Section: Crystalline Solubility and The Onset Of Glpsmentioning

confidence: 99%

Impact of Endogenous Bile Salts on the Thermodynamics of Supersaturated Active Pharmaceutical Ingredient Solutions

Lu¹,

Ormes²,

Lowinger

et al. 2017

Crystal Growth & Design

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“…In vivo crystallization of a drug substance is expected to diminish the solubility enhancement gained from a supersaturating system. 7 In other words, in vivo drug precipitation kinetics play an important role in affecting the bioavailability of supersaturating formulations.…”

Section: Introductionmentioning

confidence: 99%

Compositional effect of complex biorelevant media on the crystallization kinetics of an active pharmaceutical ingredient

Ormes

Lowinger

et al. 2017

CrystEngComm

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Bile salts are endogenous surfactants present in the human gastrointestinal tract in the form of mixed micelles that also contain phospholipids. Due to the inevitable encounter of oral drug formulations with bile salts, it is important to understand the impact of bile salts on the crystallization tendency of poorly soluble compounds that form supersaturated solutions in vivo in order to maximize oral drug absorption. Although there has been an increasing number of studies focusing on the role of individual bile salts on drug crystallization, the effects of mixed micelles and biorelevant media composition on crystallization kinetics have only been studied to a limited extent. In this study, we evaluated the ability of binary and ternary bile salt combinations to maintain supersaturated aqueous solutions of telaprevir. Crystallization kinetics were also compared in more complex media that also contained the phospholipid, lecithin. These included fasted state simulated intestinal fluid (FaSSIF) (a widely used medium for formulation testing which contains a single bile salt, sodium taurocholate), and media that contained several endogenous bile salts. Finally, the combined effects of a polymer, hydroxypropylmethyl cellulose acetate succinate, and the testing media on crystallization kinetics were evaluated to provide insights into supersaturation formulation design. Solution bile salt composition was found to significantly influence crystallization kinetics. However, the presence of the polymer increased induction times sufficiently that differences between media were minimized. This study suggests that when evaluating the crystallization kinetics of systems with a propensity to undergo supersaturation in vivo, attention should be paid to selecting biorelevant media.

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“…The amorphous solubility advantage for 23 compounds is shown in Fig. 4 which shows the predicted versus experimental amorphous-to-crystalline solubility (a/c) ratios using in situ generation of amorphous material (Taylor and Zhang 2016).…”

Section: Solubility Enhancement With Asdsmentioning

confidence: 99%

“…In theory, the solubility of an amorphous solid cannot exceed that of the crystalline material which is the thermodynamically stable form. However, if the crystallization is slow, then concentrations greater than the crystalline solubility can be achieved and, under some conditions, "a metastable equilibrium can exist between the amorphous material and the aqueous solution which is termed liquid-liquid equilibrium (LLE)" (Taylor and Zhang 2016). If the crystalline solubility is known, then the amorphous solubility can be estimated.…”

Section: Solubility Enhancement With Asdsmentioning

confidence: 99%

New directions in pharmaceutical amorphous materials and amorphous solid dispersions, a tribute to Professor George Zografi – Proceedings of the June 2016 Land O’Lakes Conference

Newman¹,

Hastedt

2017

AAPS Open

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The University of Wisconsin-Madison June Land O'Lakes Conference on Research and Development is held every year and is recognized worldwide as a premier teaching conference for pharmaceutical scientists. The conference held in June 2016 was a tribute to the ground-breaking work of Emeritus Professor and Dean George Zografi of School of Pharmacy, University of Wisconsin-Madison. This paper provides a summary of the wide range of topics in the areas of amorphous drugs, amorphous solid dispersions, mesophases, mesoporous supports, cocrystals, and related themes that were covered at this conference.

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Physical chemistry of supersaturated solutions and implications for oral absorption

Cited by 307 publications

References 102 publications

Impact of Endogenous Bile Salts on the Thermodynamics of Supersaturated Active Pharmaceutical Ingredient Solutions

Impact of Endogenous Bile Salts on the Thermodynamics of Supersaturated Active Pharmaceutical Ingredient Solutions

Compositional effect of complex biorelevant media on the crystallization kinetics of an active pharmaceutical ingredient

New directions in pharmaceutical amorphous materials and amorphous solid dispersions, a tribute to Professor George Zografi – Proceedings of the June 2016 Land O’Lakes Conference

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