Chemical and Physicochemical Approaches to Solve Formulation Problems

Lieberman, Harvey; Vemuri, N. Murti

doi:10.1016/b978-0-12-417205-0.00032-8

Cited by 12 publications

(12 citation statements)

References 107 publications

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“…Precipitation can be suppressed by adding excipient cosolutes (or cosolvents) that increase the solubility of active ingredients. − Generally, the solubility of solutes in water can be raised by presenting the hydrophobic molecules with a better solvent, often containing a surfactant. A much different class of solubilizing cosolutes are “hydrotropes”, first defined by Neuberg in 1916 to indicate small molecules that increase the solubility of hardly soluble molecules in water. , Typical examples of hydrotropes commonly used in pharmacological and other technological applications include small molecules such as ethanol and glycerol. , The past few years has seen a renewed surge of interest into hydrotropes due to their possible biological and technological roles as natural solubilizers of biomacromolecules. , By contrast to molecules that self-assemble in solution (such as surfactants), the contemporary definition of hydrotropes includes compounds that on their own do not form lyotropic liquid crystals or emulsions but do change their structuring upon mixing with another (hydrophobic) solute, so as to solubilize the solute . Consequently, in contrast to many surfactants, hydrotropes are usually effective only at much higher, often molar, concentrations. ,,, In drug formulations, this is often achieved by saturated solutions of the hydrotrope or even solid-phase mixtures of drug and excipient.…”

Section: Introductionmentioning

confidence: 99%

How Sugars Modify Caffeine Self-Association and Solubility: Resolving a Mechanism of Selective Hydrotropy

Shumilin¹,

Allolio²,

Harries³

2019

J. Am. Chem. Soc.

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The aggregation of drugs and nutraceuticals in aqueous media is an outstanding problem for their efficacy and bioavailability. A common solution is to add excipients or hydrotropes that increase solubility and limit aggregation. Here we study caffeine, a widely consumed drug that undergoes oligomerization and aggregation in aqueous solutions. Combining partition and solubility experiments with molecular dynamics simulations, we determined the effect of sugars (mono-and disaccharides) on caffeine selfassociation and solubility. We find that sugars selectively increase the concentration of caffeine in its monomeric state, but decrease its solubility in all oligomeric forms. Thus, we determine that, in contrast to common hydrotropes, sugars act as selective hydrotropes toward caffeine, since they differentially act on specific solvated forms of the drug. We furthermore unravel the molecular mechanism for this selectivity, and comment on the general design principles that should help develop targeted excipients for bioavailability and taste modification in drugs and foods.

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Section: Introductionmentioning

confidence: 99%

How Sugars Modify Caffeine Self-Association and Solubility: Resolving a Mechanism of Selective Hydrotropy

Shumilin¹,

Allolio²,

Harries³

2019

J. Am. Chem. Soc.

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“…Figure 2 summarizes the main strategies used to improve the bioavailability of pharmaceutical compounds as well as the several strategies applied in the pharmaceutical arena, further highlighting the use of ILs as solvents, co-solvents, and hydrotropes in the field. In opposition to approaches where pure ILs are employed as solvents, applications inspired by co-solvency or hydrotropy phenomena resort to the preparation of a mixture, where ILs are added to a major solvent (typically water) [51,52]. Co-solvents are watersoluble compounds with the ability to overcome the limited solubility of hydrophobic solutes in an aqueous solution.…”

Section: Ils Used To Improve the Solubility (Bioavailability) Of Pharmaceuticalsmentioning

confidence: 99%

“…In opposition to approaches where pure ILs are employed as solvents, applications inspired by co-solvency or hydrotropy phenomena resort to the preparation of a mixture, where ILs are added to a major solvent (typically water) [ 51 , 52 ]. Co-solvents are water-soluble compounds with the ability to overcome the limited solubility of hydrophobic solutes in an aqueous solution.…”

Section: Ils Used To Improve the Solubility (Bioavailability) Of Pharmaceuticalsmentioning

confidence: 99%

Advances Brought by Hydrophilic Ionic Liquids in Fields Involving Pharmaceuticals

et al. 2021

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The negligible volatility and high tunable nature of ionic liquids (ILs) have been the main drivers of their investigation in a wide diversity of fields, among which is their application in areas involving pharmaceuticals. Although most literature dealing with ILs is still majorly devoted to hydrophobic ILs, evidence on the potential of hydrophilic ILs have been increasingly provided in the past decade, viz., ILs with improved therapeutic efficiency and bioavailability, ILs with the ability to increase drugs' aqueous solubility, ILs with enhanced extraction performance for pharmaceuticals when employed in biphasic systems and other techniques, and ILs displaying low eco/cyto/toxicity and beneficial biological activities. Given their relevance, it is here overviewed the applications of hydrophilic ILs in fields involving pharmaceuticals, particularly focusing on achievements and advances witnessed during the last decade. The application of hydrophilic ILs within fields involving pharmaceuticals is here critically discussed according to four categories: (i) to improve pharmaceuticals solubility, envisioning improved bioavailability; (ii) as IL-based drug delivery systems; (iii) as pretreatment techniques to improve analytical methods performance dealing with pharmaceuticals, and (iv) in the recovery and purification of pharmaceuticals using IL-based systems. Key factors in the selection of appropriate ILs are identified. Insights and perspectives to bring renewed and effective solutions involving ILs able to compete with current commercial technologies are finally provided.

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“…The use of topical ERL instead of or in addition to the oral ERL tablets may be especially interesting in the control of local skin diseases, as the oral drug is known to induce side effects such as folliculitis, diarrhea, paronychia, fatigue, and hair changes [ 10 ]. However, since the change from a solid form to a solubilized form induces a significant change in the chemical environment, the drug is often much more prone to chemical instability [ 11 ]. As ERL is known to degrade upon hydrolytic and oxidative stress, with degradation products having been detected in the presence of hydrochloric acid (HCl), sodium hydroxide (NaOH), and hydrogen peroxide (H 2 O 2 ) [ 12 , 13 ], the impact of formulation change needs to be assessed.…”

Section: Introductionmentioning

confidence: 99%

Stability and Formulation of Erlotinib in Skin Creams

et al. 2022

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Recent studies have highlighted the benefit of repurposing oral erlotinib (ERL) treatment in some rare skin diseases such as Olmsted syndrome. The use of a topical ERL skin treatment instead of the currently available ERL tablets may be appealing to treat skin disorders while reducing adverse systemic effects and exposure. A method to prepare 0.2% ERL cream, without resorting to a pure active pharmaceutical ingredient, was developed and the formulation was optimized to improve ERL stability over time. Erlotinib extraction from tablets was incomplete with Transcutol, whereas dimethyl sulfoxide (DMSO) allowed 100% erlotinib recovery. During preliminary studies, ERL was shown to be sensitive to oxidation and acidic pH in solution and when added to selected creams (i.e., Excipial, Nourivan Antiox, Pentravan, and Versatile). The results also showed that use of DMSO (5% v/w), neutral pH, as well as a topical agent containing antioxidant substances (Nourivan Antiox) were key factors to maintain the initial erlotinib concentration. The proposed ERL cream formulation at neutral pH contains a homogeneous amount of ERL and is stable for at least 42 days at room temperature in Nourivan cream with antioxidant properties.

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Chemical and Physicochemical Approaches to Solve Formulation Problems

Cited by 12 publications

References 107 publications

How Sugars Modify Caffeine Self-Association and Solubility: Resolving a Mechanism of Selective Hydrotropy

How Sugars Modify Caffeine Self-Association and Solubility: Resolving a Mechanism of Selective Hydrotropy

Advances Brought by Hydrophilic Ionic Liquids in Fields Involving Pharmaceuticals

Stability and Formulation of Erlotinib in Skin Creams

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