Inhibition of Crystal Nucleation and Growth by Water-Soluble Polymers and its Impact on the Supersaturation Profiles of Amorphous Drugs

Ozaki, Shunsuke; Kushida, Ikuo; Yamashita, Taro; Hasebe, Takashi; Shirai, Osamu; Kano, Kenji

doi:10.1002/jps.23588

Cited by 80 publications

(63 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PVP is also reported to inhibit and retard the recrystallization of the API via formation of a network around the drug molecules or growing crystal surface (Tantishaiyakul et al, 1999); both effects limit the molecular mobility of the API (Ozaki et al, 2013). However, use of this polymer has been limited by concerns regarding thermal degradation and hygroscopicity.…”

Section: Introductionmentioning

confidence: 98%

An investigation into the influence of drug–polymer interactions on the miscibility, processability and structure of polyvinylpyrrolidone-based hot melt extrusion formulations

Chan

Craig³

2015

International Journal of Pharmaceutics

View full text Add to dashboard Cite

While hot melt extrusion is now established within the pharmaceutical industry, the prediction of miscibility, processability and structural stability remains a pertinent issue, including the issue of whether molecular interaction is necessary for suitable performance. Here we integrate the use of theoretical and experimental drug-polymer interaction assessment with determination of processability and structure of dispersions in two polyvinylpyrrolidone-based polymers (PVP and PVP vinyl acetate, PVPVA). Caffeine and paracetamol were chosen as model drugs on the basis of their differing hydrogen bonding potential with PVP. Solubility parameter and interaction parameter calculations predicted a greater miscibility for paracetamol, while ATR-FTIR confirmed the hydrogen bonding propensity of the paracetamol with both polymers, with little interaction detected for caffeine. PVP was found to exhibit greater interaction and miscibility with paracetamol than did PVPVA. It was noted that lower processing temperatures (circa 40°C below the Tg of the polymer alone and Tm of the crystalline drug) and higher drug loadings with associated molecular dispersion up to 50% w/w were possible for the paracetamol dispersions, although molecular dispersion with the non-interactive caffeine was noted at loadings up to 20% w./w. A lower processing temperature was also noted for caffeine-loaded systems despite the absence of detectable interactions. The study has therefore indicated that theoretical and experimental detection of miscibility and drug-polymer interactions may lead to insights into product processing and extrudate structure, with direct molecular interaction representing a helpful but not essential aspect of drug-polymer combination prediction.

show abstract

Section: Introductionmentioning

confidence: 98%

An investigation into the influence of drug–polymer interactions on the miscibility, processability and structure of polyvinylpyrrolidone-based hot melt extrusion formulations

Chan

Craig³

2015

International Journal of Pharmaceutics

View full text Add to dashboard Cite

show abstract

“…The crystallization behaviour of amorphous formulations in the solid and dissolved states can be studied by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapour sorption (DVS), polarized light microscopy (PLM), powder x-ray diffraction (XRPD), Raman spectroscopy, and dissolution assays [7], [8], [11], [12], [13]. Few years ago, Alonzo and co-workers introduced the use of different experimental techniques including XRPD, microscopy, Raman spectroscopy and small-scale dissolution apparatus to study the behaviour of amorphous systems during dissolution [7] and the effect of polymers on their dissolution and precipitation behaviour [14].…”

Section: Introductionmentioning

confidence: 99%

Mechanism-based selection of stabilization strategy for amorphous formulations: Insights into crystallization pathways

Edueng

Mahlin

Larsson

et al. 2017

Journal of Controlled Release

View full text Add to dashboard Cite

We developed a step-by-step experimental protocol using differential scanning calorimetry (DSC), dynamic vapour sorption (DVS), polarized light microscopy (PLM) and a small-scale dissolution apparatus (μDISS Profiler) to investigate the mechanism (solid-to-solid or solution-mediated) by which crystallization of amorphous drugs occurs upon dissolution. This protocol then guided how to stabilize the amorphous formulation. Indapamide, metolazone, glibenclamide and glipizide were selected as model drugs and HPMC (Pharmacoat 606) and PVP (K30) as stabilizing polymers. Spray-dried amorphous indapamide, metolazone and glibenclamide crystallized via solution-mediated nucleation while glipizide suffered from solid-to-solid crystallization. The addition of 0.001%–0.01% (w/v) HPMC into the dissolution medium successfully prevented the crystallization of supersaturated solutions of indapamide and metolazone whereas it only reduced the crystallization rate for glibenclamide. Amorphous solid dispersion (ASD) formulation of glipizide and PVP K30, at a ratio of 50:50% (w/w) reduced but did not completely eliminate the solid-to-solid crystallization of glipizide even though the overall dissolution rate was enhanced both in the absence and presence of HPMC. Raman spectroscopy indicated the formation of a glipizide polymorph in the dissolution medium with higher solubility than the stable polymorph. As a complementary technique, molecular dynamics (MD) simulations of indapamide and glibenclamide with HPMC was performed. It was revealed that hydrogen bonding patterns of the two drugs with HPMC differed significantly, suggesting that hydrogen bonding may play a role in the greater stabilizing effect on supersaturation of indapamide, compared to glibenclamide.

show abstract

“…Depending upon the nature of the components and their ratio in the matrix, pharmaceutical formulations based on amorphous solid dispersions can suffer from thermodynamic instability, resulting in unexpected crystallization of the drug in the solid state during storage or during dissolution. Consequently, this causes a reduction in the amount of the drug bioavailability (4,5). …”

Section: Introductionmentioning

confidence: 99%

“…The crystallization (nucleation and crystal growth) is influenced by multiple factors such as the degree of supersaturation, the viscosity of the polymer gel, and the interfacial energy between the crystal nuclei and the solvent (7). In this context, the polymer plays an important role as it can keep the drug in the supersaturated state and therefore inhibit or delay crystallization (5) through a combination of viscosity and surface-energy effects.…”

Section: Introductionmentioning

confidence: 99%

The Combined Use of Imaging Approaches to Assess Drug Release from Multicomponent Solid Dispersions

et al. 2016

View full text Add to dashboard Cite

PurposeImaging methods were used as tools to provide an understanding of phenomena that occur during dissolution experiments, and ultimately to select the best ratio of two polymers in a matrix in terms of enhancement of the dissolution rate and prevention of crystallization during dissolution.MethodsMagnetic resonance imaging, ATR-FTIR spectroscopic imaging and Raman mapping have been used to study the release mechanism of a poorly water soluble drug, aprepitant, from multicomponent amorphous solid dispersions. Solid dispersions were prepared based on the combination of two selected polymers - Soluplus, as a solubilizer, and PVP, as a dissolution enhancer. Formulations were prepared in a ratio of Soluplus:PVP 1:10, 1:5, 1:3, and 1:1, in order to obtain favorable properties of the polymer carrier.ResultsThe crystallization of aprepitant during dissolution has occurred to a varying degree in the polymer ratios 1:10, 1:5, and 1:3, but the increasing presence of Soluplus in the formulation delayed the onset of crystallization. The Soluplus:PVP 1:1 solid dispersion proved to be the best matrix studied, combining the abilities of both polymers in a synergistic manner.ConclusionsAprepitant dissolution rate has been significantly enhanced. This study highlights the benefits of combining imaging methods in order to understand the release process.Electronic supplementary materialThe online version of this article (doi:10.1007/s11095-016-2018-x) contains supplementary material, which is available to authorized users.

show abstract

Inhibition of Crystal Nucleation and Growth by Water-Soluble Polymers and its Impact on the Supersaturation Profiles of Amorphous Drugs

Cited by 80 publications

References 31 publications

An investigation into the influence of drug–polymer interactions on the miscibility, processability and structure of polyvinylpyrrolidone-based hot melt extrusion formulations

An investigation into the influence of drug–polymer interactions on the miscibility, processability and structure of polyvinylpyrrolidone-based hot melt extrusion formulations

Mechanism-based selection of stabilization strategy for amorphous formulations: Insights into crystallization pathways

The Combined Use of Imaging Approaches to Assess Drug Release from Multicomponent Solid Dispersions

Contact Info

Product

Resources

About