Exploring the Role of Surfactants in Enhancing Drug Release from Amorphous Solid Dispersions at Higher Drug Loadings

Saboo, Sugandha; Bapat, Pradnya; Moseson, Dana E.; Kestur, Umesh S.; Taylor, Lynne S.

doi:10.3390/pharmaceutics13050735

Cited by 44 publications

(21 citation statements)

References 47 publications

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“…Oral administration formulations of poorly soluble drugs generally contain various additives such as surfactants and polymers. Furthermore, the addition of a surfactant to an amorphous solid dispersion can improve the release performance of the drug and support the formation of amorphous drug-rich nanodroplets. , Thus, the mixing of a surfactant in supersaturated formulations sometimes has an advantage in improving drug absorption in vivo . When a solubilizer is present, the concentration-based supersaturation estimates using apparent crystalline/amorphous solubilities prove to be inaccurate. , Thus, the apparent amorphous solubility is no longer a good indicator of the supersaturation advantage, which is consistent with the present study.…”

Section: Discussionsupporting

confidence: 76%

“…Furthermore, the addition of a surfactant to an amorphous solid dispersion can improve the release performance of the drug and support the formation of amorphous drug-rich nanodroplets. 45,46 Thus, the mixing of a surfactant in supersaturated formulations sometimes has an advantage in improving drug absorption in vivo. 47 When a solubilizer is present, the concentration-based supersaturation estimates using apparent crystalline/amorphous solubilities prove to be inaccurate.…”

Section: ■ Discussionmentioning

confidence: 99%

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Unusual Correlation between the Apparent Amorphous Solubility of a Drug and Solubilizer Concentration Revealed by NMR Analysis

2022

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Herein, we investigated the effect of the solubilizers, cetyltrimethylammonium bromide (CTAB) and amino methacrylate copolymer (Eudragit E PO, EUD-E), on the apparent amorphous solubility of ketoprofen (KTP) and free KTP concentrations in an aqueous phase when a KTP-rich phase was generated by liquid–liquid phase separation. Quantitative analysis by solution nuclear magnetic resonance (NMR) revealed that the apparent amorphous solubility of KTP increased with increasing EUD-E concentrations by the solubilization of KTP into the EUD-E micelles; this was reminiscent of the improvement in the apparent crystalline solubility of KTP observed when EUD-E was added. In contrast, the apparent amorphous solubility of KTP decreased with increasing CTAB concentrations, although the solubilizing ability of CTAB was stronger than that of EUD-E when the KTP-rich phase was absent. NMR analysis revealed that CTAB was distributed into the KTP-rich phase to a relatively large extent. This resulted in a significant reduction of the chemical potential of KTP in the KTP-rich phase in the CTAB solution. Thus, the maximum free KTP concentration in the aqueous phase was reduced more significantly in the CTAB solution than in the EUD-E solution. Moreover, the solubilization effect of KTP by the CTAB micelles in the aqueous phase was drastically diminished due to the distribution of CTAB into the KTP-rich phase. As a result, the apparent amorphous solubility of KTP reached a minimum at a CTAB concentration of 200 μg/mL. A further increase in the CTAB concentration resulted in an improvement in the apparent amorphous solubility of KTP due to the solubilization effect of CTAB remaining in the aqueous phase. The present study highlights the impact of solubilizer selection on the apparent amorphous solubility and attainable supersaturation of the drug, which should be considered during the development of supersaturating formulations to obtain preferable oral absorption.

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Section: Discussionsupporting

confidence: 76%

Section: ■ Discussionmentioning

confidence: 99%

Unusual Correlation between the Apparent Amorphous Solubility of a Drug and Solubilizer Concentration Revealed by NMR Analysis

2022

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“…The impact of the presence of surfactants on the R3m model has not yet been studied. The presence of this tertiary component likely impacts the factors that influence dispersability . The original R3m dispersability model was based on very specific compositions and processing conditions.…”

Section: Discussionmentioning

confidence: 99%

Interpreting the Physicochemical Meaning of a Molecular Descriptor Which Is Predictive of Amorphous Solid Dispersion Formation in Polyvinylpyrrolidone Vinyl Acetate

et al. 2021

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A molecular descriptor known as R3m (the R-GETAWAY third-order autocorrelation index weighted by the atomic mass) was previously identified as capable of grouping members of an 18-compound library of organic molecules that successfully formed amorphous solid dispersions (ASDs) when co-solidified with the co-polymer polyvinylpyrrolidone vinyl acetate (PVPva) at two concentrations using two preparation methods. To clarify the physical meaning of this descriptor, the R3m calculation is examined in the context of the physicochemical mechanisms of dispersion formation. The R3m equation explicitly captures information about molecular topology, atomic leverage, and molecular geometry, features which might be expected to affect the formation of stabilizing non-covalent interactions with a carrier polymer, as well as the molecular mobility of the active pharmaceutical ingredient (API) molecule. Molecules with larger R3m values tend to have more atoms, especially the heavier ones that form stronger non-covalent interactions, generally, more irregular shapes, and more complicated topology. Accordingly, these molecules are more likely to remain dispersed within PVPva. Furthermore, multiple linear regression modeling of R3m and more interpretable descriptors supported these conclusions. Finally, the utility of the R3m descriptor for predicting the formation of ASDs in PVPva was tested by analyzing the commercially available products that contain amorphous APIs dispersed in the same polymer. All of these analyses support the conclusion that the information about the API geometry, size, shape, and topological connectivity captured by R3m relates to the ability of a molecule to interact with and remain dispersed within an amorphous PVPva matrix.

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“…A polymer can inhibit the crystallization of an amorphous drug, improve its tabletability, and maintain supersaturation during dissolution . A surfactant is introduced to improve wetting and dissolution − and to lower the processing temperature for melt-extruded formulations Table lists several marketed ASDs and the excipients therein.…”

Section: Introductionmentioning

confidence: 99%

Surfactants Accelerate Crystallization of Amorphous Nifedipine by Similar Enhancement of Nucleation and Growth Independent of Hydrophilic–Lipophilic Balance

Yao¹,

Benson²,

Gui³

et al. 2022

Mol. Pharmaceutics

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Amorphous formulations, increasingly employed to deliver poorly soluble drugs, generally contain surfactants to improve wetting and dissolution. These surfactants are often liquids and can potentially increase the mobility of the drug and reduce its stability, but little is known about this effect. Here we investigate the effect of four common nonionic surfactants (Tween 80, Span 80, Triton X-100, and Poloxamer 407) on the crystallization of amorphous nifedipine (NIF). We find that the surfactants significantly enhance the rates of crystal nucleation and growth even at low concentrations, by up to 2 orders of magnitude at 10 wt %. The surfactants tested show similar enhancement effects independent of their structural details and hydrophilic–lipophilic balance (HLB), suggesting that surfactant adsorption at solid/liquid interfaces does not play a major role in crystal nucleation and growth. Importantly, the surfactants accelerate crystal nucleation and growth by a similar factor. This result mirrors the previous finding that a polymer dopant in a molecular glass-former causes similar slowdown of nucleation and growth. These results indicate that nucleation and growth in a deeply supercooled liquid are both mobility-limited, and a dopant mainly functions as a mobility modifier (enhancer or suppressor depending on the dopant). The common surfactants tested are all mobility enhancers and destabilize the amorphous drug, and this negative effect must be managed using stabilizers such as polymers. The effect of surfactants on nucleation can be predicted from the effect on crystal growth and the crystallization kinetics of the pure system, using the same principle previously established for drug–polymer systems. We show how the independently measured nucleation and growth rates enable predictions of the overall crystallization rates.

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Exploring the Role of Surfactants in Enhancing Drug Release from Amorphous Solid Dispersions at Higher Drug Loadings

Cited by 44 publications

References 47 publications

Unusual Correlation between the Apparent Amorphous Solubility of a Drug and Solubilizer Concentration Revealed by NMR Analysis

Unusual Correlation between the Apparent Amorphous Solubility of a Drug and Solubilizer Concentration Revealed by NMR Analysis

Interpreting the Physicochemical Meaning of a Molecular Descriptor Which Is Predictive of Amorphous Solid Dispersion Formation in Polyvinylpyrrolidone Vinyl Acetate

Surfactants Accelerate Crystallization of Amorphous Nifedipine by Similar Enhancement of Nucleation and Growth Independent of Hydrophilic–Lipophilic Balance

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