A Comparison of the Crystallization Inhibition Properties of Bile Salts

Li, Na; Mosquera-Giraldo, Laura I.; Borca, Carlos H.; Ormes, James D.; Lowinger, Michael; Higgins, John; Slipchenko, Lyudmila V.; Taylor, Lynne S.

doi:10.1021/acs.cgd.6b01470

Cited by 51 publications

(59 citation statements)

References 61 publications

(103 reference statements)

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“…The significant difference between telaprevir induction times in FaSSIF and in the mixed micelles with lecithin solutions further demonstrates that STC may not be a good surrogate for human bile composition. Our results are in general agreement with those of Li et al 12 who reported a two fold increase in celecoxib induction time in mixed bile salt solutions compared to the STC only solution under constant total bile salt concentration and initial celecoxib concentration, although no lecithin was used in these studies.…”

Section: Compositions Of the Biorelevant Testing Mediasupporting

confidence: 93%

“…Most studies to date have focused on the crystallization inhibitory ability of individual bile salts. These studies revealed the potential of monomeric bile salts as nucleation [11][12][13] and/or crystal growth, 14 inhibitors. Furthermore, it was noted that bile salts showed a comparable inhibition ability to polymers for poorly water soluble drugs.…”

Section: Introductionmentioning

confidence: 97%

“…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. The goal of this study was to evaluate the impact of biorelevant testing media composition on drug crystallization kinetics from supersaturated solutions.…”

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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Section: Compositions Of the Biorelevant Testing Mediasupporting

confidence: 93%

Section: Introductionmentioning

confidence: 97%

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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“…The driving force for the common ion effect for weakly basic ionisable APIs is an increase in counterion concentration, which shifts the solubility equilibrium of the dissociated reaction to favour crystallization of the solid salt form of the API. The use of synthetic polymers, and recently of bile salts, to inhibit the crystallization of hydrophobic APIs is well described in the literature [3], [14]- [17], [21], [37], [38] This complements our previous study which shows how solution concentration and stability of CFZH + at pH 1.6 (in 25 mM HCl) depends on the presence and concentration of NaTc, lecithin, and pepsin in the system [22]. These results explain that the underlying mechanism for this manipulation of solution behaviour was through interference with the crystallization kinetics of CFZ hydrochloride from these solutions, with the exception of pepsin.…”

Section: Screening the Impact Of Polymers Bile Salts And Pepsin On Tmentioning

confidence: 99%

“…Most previous studies have focused on using polymeric additives, such as cellulose derivatives, to prolong supersaturation by inhibiting nucleation [14]- [17]. However, recently several studies have demonstrated that bile salts can also act as crystallization inhibitors for hydrophobic APIs [3], [18]- [21]. A recent systemic study of the effects of bile salts, phospholipids, and digestive peptides, on the solution concentration of the antibiotic agent clofazimine (CFZ), showed that the presence of these amphipathic compounds has a strong influence on solution behaviour i.e.…”

mentioning

confidence: 99%

Overcoming the Common Ion Effect for Weakly Basic Drugs: Inhibiting the Crystallization of Clofazimine Hydrochloride in Simulated Gastrointestinal Media

Bannigan

Verma

Hudson

2019

Crystal Growth & Design

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Bile salts, phospholipids, and digestive proteins are amphipathic compounds found naturally in the human gastrointestinal system. Therefore, it is important to consider their effects on the crystallization kinetics and solution behaviour of drugs intended for oral delivery. Supersaturating drug delivery systems that employ high energy solid forms and polymeric additives are often hailed as the gold standard for increasing drug concentration in the gastrointestinal system. However, the effects of amphiphilic compounds present in the gastrointestinal system on the crystallization behaviour of these systems are often overlooked. In this study, the effects of bile salts, phospholipids, mixtures of phospholipid and bile salts as well as digestive proteins on the crystallization kinetics of the antimicrobial agent clofazimine (CFZ) were evaluated. The crystallization inhibitory properties of these gastrointestinal amphiphiles were compared with commonly used synthetic polymers, and several of these amphipathic gastrointestinal compounds showed promise as crystallization inhibitors of clofazimine hydrochloride during induction time experiments. The best crystallization inhibitors from this induction time screening were then compared as solid physical mixtures in modified fasted state simulated gastric fluid (m-FaSSGF). Here it was found that heterogeneous nucleation of CFZ hydrochloride onto the dissolving surface of CFZ solid forms prevented these additives from inhibiting crystallization in this biorelevant media. This heterogeneous nucleation of CFZ hydrochloride was monitored in real time, using optical microscopic techniques.

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Influences of Crystal Anisotropy in Pharmaceutical Process Development

et al. 2018

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Crystalline materials are of crucial importance to the pharmaceutical industry, as a large number of APIs are formulated in crystalline form, occasionally in the presence of crystalline excipients. Owing to their multifaceted character, crystals were found to have strongly anisotropic properties. In fact, anisotropic properties were found to be quite important for a number of processes including milling, granulation and tableting. An understanding of crystal anisotropy and an ability to control and predict crystal anisotropy are mostly subjects of interest for researchers. A number of studies dealing with the aforementioned phenomena are grounded on over-simplistic assumptions, neglecting key attributes of crystalline materials, most importantly the anisotropic nature of a number of their properties. Moreover, concepts such as the influence of interfacial phenomena in the behaviour of crystalline materials during their growth and in vivo, are still poorly understood. The review aims to address concepts from a molecular perspective, focusing on crystal growth and dissolution. It begins with a brief outline of fundamental concepts of intermolecular and interfacial phenomena. The second part discusses their relevance to the field of pharmaceutical crystal growth and dissolution. Particular emphasis is given to works dealing with mechanistic understandings of the influence of solvents and additives on crystal habit. Furthermore, comments and perspectives, highlighting future directions for the implementation of fundamental concepts of interfacial phenomena in the rational understanding of crystal growth and dissolution processes, have been provided.

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A Comparison of the Crystallization Inhibition Properties of Bile Salts

Cited by 51 publications

References 61 publications

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

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

Overcoming the Common Ion Effect for Weakly Basic Drugs: Inhibiting the Crystallization of Clofazimine Hydrochloride in Simulated Gastrointestinal Media

Influences of Crystal Anisotropy in Pharmaceutical Process Development

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