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

Lu, Jennifer; Ormes, James D.; Lowinger, Michael; Xu, Wei; Mitra, Amitava; Mann, Amanda K. P.; Litster, James D.; Taylor, Lynne S.

doi:10.1021/acs.cgd.6b01664

Cited by 31 publications

(50 citation statements)

References 38 publications

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“…The basic concepts and methods were as described in our previous study. 24 The mass flow rates of telaprevir, F, are directly proportional to solute activity. The ratio of solute mass flow rate in the solution of interest to the mass flow rate of the corresponding standard state system (solute in a solution in equilibrium with crystalline state in this study) yields the fundamental supersaturation:…”

Section: Supersaturation Determinationmentioning

confidence: 99%

Maintaining Supersaturation of Active Pharmaceutical Ingredient Solutions with Biologically Relevant Bile Salts

Lu¹,

Ormes²,

Lowinger³

et al. 2017

Crystal Growth & Design

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Currently, it is of interest to improve the oral absorption of poorly water soluble therapeutic agents using supersaturating formulations. Understanding crystallization kinetics of supersaturated drug solutions is central to the design and evaluation of such formulations. Bile salts have drawn increasing attention in this context as they serve important roles in biorelevant dissolution media, in vivo, and have been shown to slow down the crystallization of active pharmaceutical ingredients. The goal of this study was to evaluate the impact of bile salt monomers and micelles on the crystallization of telaprevir, a poorly water soluble drug, from aqueous solution. To better describe the crystallization driving force in the presence of the bile salts, a side-by-side diffusion cell was used to evaluate telaprevir mass flow rate, and hence solute activity, in the absence and presence of different bile salts. The effectiveness of monomeric and miceller bile salts as crystallization inhibitors was then evaluated by performing crystallization induction time experiments at constant, activity-based supersaturation. The six most abundant biologically relevant bile salts were investigated (sodium taurocholate, sodium taurodeoxycholate, sodium taurochenodeoxycholate, sodium glycocholate, sodium glycodeoxycholate, and sodium glycochenodeoxycholate). All six bile salts exhibited nucleation inhibition properties in both homogenous supersaturated telaprevir solutions and highly supersaturated telaprevir solutions containing a second phase. The ability to retard telaprevir nucleation, however, varied amongst the bile salts and also depended on the aggregation state. Monomeric bile salts were found to be effective crystallization inhibitors. At higher bile salt concentrations, trihydroxy bile salts showed better inhibition compared to dihydroxy bile salts. These results highlight the importance of considering the composition of the test medium used to evaluate product performance, in particular in the context of evaluating crystallization kinetics.

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Section: Supersaturation Determinationmentioning

confidence: 99%

Maintaining Supersaturation of Active Pharmaceutical Ingredient Solutions with Biologically Relevant Bile Salts

Lu¹,

Ormes²,

Lowinger³

et al. 2017

Crystal Growth & Design

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“…Using the mass flow rate data for supersaturated telaprevir solutions in buffer from our previous study 16 and equation (1), the determination of telaprevir supersaturation level in different media is summarized in Figure 2. For the binary/ternary additives as well as the multicomponent media studies, = 11.5 was chosen to study telaprevir crystallization tendency in a homogeneous supersaturated solution.…”

Section: Supersaturation Determinationmentioning

confidence: 99%

“…Although various refinements have been made to the biorelevant medium composition, with the goal of improving in vitro/in vivo correlations, sodium taurocholate remains the only bile salt component used in many commercially available simulated human intestinal fluid recipes. However, it has been recently demonstrated that biologically relevant bile salts are not interchangeable from either a thermodynamic 16 or crystallization standpoint. 12,13 Therefore, it is of interest to investigate whether the current biorelevant medium used for in vitro testing might be oversimplified in the context of supersaturating dosage forms.…”

Section: Introductionmentioning

confidence: 99%

“…The goal of this study was to evaluate the impact of biorelevant testing media composition on drug crystallization kinetics from supersaturated solutions. Telaprevir was chosen as the model compound since the influence of individual biorelevant bile salts on this compound has been thoroughly studied from both a thermodynamic 16 and crystallization inhibition stand point 13,14 . In addition, the effects of binary and ternary bile salt combinations, as well as bile salt-polymer systems on telaprevir crystallization, were investigated in order to systematically evaluate the impact of multiple additives on crystallization kinetics.…”

Section: Introductionmentioning

confidence: 99%

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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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“…On the other hand, it has been suggested that the composition of aqueous media has an influence on the supersaturation behavior of a drug. 27,28 The precipitation model established by using biorelevant media, such as fasted-state/fed-state simulated intestinal fluids, 5,9 will enable prediction of drug concentrationetime profiles in intestinal fluid more accurately. In addition, information on the number (m 0,t ) and size (m 4,t /m 3,t ) of the precipitant, which is available in the population balance model, also would be beneficial in simulating the re-dissolving of the precipitant in the gastrointestinal tract.…”

Section: Parametermentioning

confidence: 99%

Population Balance Model for Simulation of the Supersaturation–Precipitation Behavior of Drugs in Supersaturable Solid Forms

Ozaki

2019

Journal of Pharmaceutical Sciences

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We developed a simulation method to describe in vitro drug concentration-time profiles under supersaturated conditions. In a nonsink dissolution test of carbamazepine polymorphic form III (CBZ), a model supersaturable solid, the concentration of carbamazepine reached a supersaturated state against its dihydrate form (CBZ). After a certain period, de-supersaturation due to the precipitation of CBZ was observed. In the simulation of this typical dissolution-precipitation profile, the precipitation process of CBZ was simulated by a population balance model in which the rates of primary/secondary nucleation and growth of CBZ were considered. Six rate constants in the precipitation model were determined from de-supersaturation profiles in unseeded isothermal crystallization experiments of CBZ. The dissolution process of CBZ was modeled on the basis of its dissolution profile under a sink condition. The simulated concentration versus time curves satisfactorily reproduced the characteristics of dissolution, supersaturation, and precipitation behavior of the model drug. The presented method will enable rational design of formulations and accurate prediction of the oral absorbability of drugs in supersaturable solid forms.

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

Cited by 31 publications

References 38 publications

Maintaining Supersaturation of Active Pharmaceutical Ingredient Solutions with Biologically Relevant Bile Salts

Maintaining Supersaturation of Active Pharmaceutical Ingredient Solutions with Biologically Relevant Bile Salts

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

Population Balance Model for Simulation of the Supersaturation–Precipitation Behavior of Drugs in Supersaturable Solid Forms

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