Studying the Propensity of Compounds to Supersaturate: A Practical and Broadly Applicable Approach

Palmelund, Henrik; Madsen, Cecilie Maria; Plum, Jakob; Müllertz, Anette

doi:10.1016/j.xphs.2016.06.016

Cited by 59 publications

(120 citation statements)

References 34 publications

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“…Nucleation and crystal growth of the drug may lead to fast precipitation, unless the rates of these processes are reduced by precipitation inhibitors, such as polymers, or other substances (e.g. cyclodextrins) (Lainé et al, 2016;Palmelund et al, 2016;Williams et al, 2013). The stabilizing effect of precipitation inhibitors is called the parachute-effect ( Fig.…”

Section: Supersaturating Drug Delivery Systemsmentioning

confidence: 99%

“…The increased chemical potential of a supersaturated system (compared to the corresponding saturated or unsaturated systems) makes it thermodynamically unstable and hence, precipitation will occur at some stage (Palmelund et al, 2016). A precipitation inhibitor can be added to the system to delay or avoid drug precipitation over the required timescale.…”

Section: Mechanisms Of Precipitation Inhibitionmentioning

confidence: 99%

“…Table 1 presents the most important mechanisms of precipitation inhibition. However, it should be noted that the efficiency and mechanisms of precipitation inhibition not only depend on the inhibitor type, but also on its concentration in the media, the drug with which it is used and other excipients in the formulation (Brouwers et al, 2009;Mah et al, 2016;Palmelund et al, 2016). For example, in a study with phenytoin and different derivatives of this drug, hydroxypropylmethylcellulose (HPMC) was found to maintain drug supersaturation solely by drug crystallization inhibition, whereas PVP maintained the drug supersaturation by both a drug solubilization effect and inhibition of crystallization, depending on the drug compound (Otsuka, et al, 2015).…”

Section: Mechanisms Of Precipitation Inhibitionmentioning

confidence: 99%

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Supersaturating drug delivery systems: The potential of co-amorphous drug formulations

Laitinen

Löbmann

Priemel

et al. 2017

International Journal of Pharmaceutics

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105

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Amorphous solid dispersions (ASDs) are probably the most common and important supersaturating drug delivery systems for the formulation of poorly water-soluble compounds. These delivery systems are able to achieve and maintain a sustained drug supersaturation which enables improvement of the bioavailability of poorly water-soluble drugs by increasing the driving force for drug absorption. However, ASDs often require a high weight percentage of carrier (usually a hydrophilic polymer) to ensure molecular mixing of the drug in the carrier and stabilization of the supersaturated state, often leading to high dosage volumes and thereby challenges in the formulation of the final dosage form. As a response to the shortcomings of the ASDs, the so-called co-amorphous formulations, which are amorphous combinations of two or more low molecular weight components, have emerged as an alternative formulation strategy for poorly-soluble drugs. While the current research on co-amorphous formulations is focused on preparation and characterization of these systems, more detailed research on their supersaturation and precipitation behavior and the effect of co-formers on nucleation and crystal growth inhibition is needed. The current status of this research is reviewed in this paper. Furthermore, the potential of novel preparation methods for co-amorphous systems with respect to the current preparation methods are discussed.

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Section: Supersaturating Drug Delivery Systemsmentioning

confidence: 99%

Section: Mechanisms Of Precipitation Inhibitionmentioning

confidence: 99%

Section: Mechanisms Of Precipitation Inhibitionmentioning

confidence: 99%

See 1 more Smart Citation

Supersaturating drug delivery systems: The potential of co-amorphous drug formulations

Laitinen

Löbmann

Priemel

et al. 2017

International Journal of Pharmaceutics

Self Cite

105

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“…This has resulted in efforts to de-risk select compounds via the evaluation of supersaturation, the state at which a compound is in solution above its thermodynamically favored equilibrium solubility. 2,3 If supersaturation can be achieved and maintained, this higher concentration in the intraluminal environment has the potential for increased flux across the intestinal membrane. This can be critical for not only therapeutic success but for achieving the high concentrations required for toxicology studies and establishing a pharmacokinetic (PK)/pharmacodynamic relationship.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, it is necessary to test a range of concentrations above equilibrium. 2 Also, in vivo it is likely that supersaturation is influenced by conditions found in the intestinal environment including pH and bile composition. Therefore, test media that mimic this environment are desired such as fasted-state simulated intestinal fluid-v2 (FaSSIF-v2), fed-state simulated intestinal fluid-v2 (FeSSIF-v2), or others.…”

Section: Introductionmentioning

confidence: 99%

Automated Supersaturation Stability Assay to Differentiate Poorly Soluble Compounds in Drug Discovery

Skolnik¹,

Geraci²,

Dodd³

2018

Journal of Pharmaceutical Sciences

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Combination of co-crystal and nanocrystal techniques to improve the solubility and dissolution rate of poorly soluble drugs

2022

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Purpose Solubility and dissolution rate are essential for the oral absorption and bioavailability of poorly soluble drugs. The aim of this study was to prepare nano-co-crystals by combination of nanocrystal and co-crystal technologies, and investigate its effect, in situ, on increased kinetic solubility and dissolution rate. Methods Co-crystals of itraconazole-fumaric acid, itraconazole-succinic acid, indomethacin-saccharin and indomethacin-nicotinamide were prepared and nano-sized by wet milling. The particle size and solid state of the co-crystals were characterized by optical microscope, LD, PCS, DSC and XRPD before and after milling. Results 300-450 nm sized nano-co-crystals with a stable physical solid state were successfully prepared. Nano-co-crystals exhibited a lower crystallinity reduction than nanocrystals after wet milling. The particle size effect on the kinetic solubility of co-crystals was analysed for macro-, micro- and nano-co-crystals with in situ kinetic solubility studies. The maximum kinetic solubility of nano-co-crystals increased with excess conditions until a plateau. The highest increase was obtained with itraconazole-succinic acid nano-co-crystals with a kinetic solubility of 263.5 ± 3.9 μg/mL which was 51.5 and 6.6 times higher than the solubility of raw itraconazole and itraconazole-succinic acid co-crystal. Conclusions The synergistic effect of nanocrystals and co-crystals with regard to increased kinetic solubility and dissolution rate was proven. The combination of the advantages of nanocrystals and co-crystals is a promising formulation strategy to increase both the solubility and dissolution rate of poorly soluble drugs.

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Studying the Propensity of Compounds to Supersaturate: A Practical and Broadly Applicable Approach

Cited by 59 publications

References 34 publications

Supersaturating drug delivery systems: The potential of co-amorphous drug formulations

Supersaturating drug delivery systems: The potential of co-amorphous drug formulations

Automated Supersaturation Stability Assay to Differentiate Poorly Soluble Compounds in Drug Discovery

Combination of co-crystal and nanocrystal techniques to improve the solubility and dissolution rate of poorly soluble drugs

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