Drug–Polymer Solubility and Miscibility: Stability Consideration and Practical Challenges in Amorphous Solid Dispersion Development

Qian, Feng; Huang, Jun; Hussain, Munir

doi:10.1002/jps.22074

Cited by 385 publications

(316 citation statements)

References 45 publications

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“…Important factors to consider when probing the instability of amorphous dispersions of small molecules in polymers are the solubility of the API in the polymer and the position of Tg relative to the storage temperature. Based on the solubility of the API in the polymer and on the changes of Tg relative to the composition of the amorphous dispersions, it is possible to build temperature-composition diagrams in which the zones of stability and instability are defined (9)(10)(11). The solubility of the sulfonamides in PVP and Soluplus® has been determined from the T end measurement based on the work of Yu's group (29,36) and the Flory-Huggins (FH) theory (37).…”

Section: Temperature-composition Diagramsmentioning

confidence: 99%

“…The higher the Tg compared to the storage temperature, the lower the likelihood of crystallisation (8). It is critical to carefully select the components to make an amorphous dispersion so as to optimise the solubility of the API in the polymer and thus reduce the risk of phase separation in the amorphous system (9)(10)(11). An important point to consider is that attainment of a one-phase system requires the two components to be thermodynamically miscible during processing (11).…”

Section: Introductionmentioning

confidence: 99%

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Amorphous Solid Dispersions of Sulfonamide/Soluplus® and Sulfonamide/PVP Prepared by Ball Milling

Caron

Tajber

et al. 2013

AAPS PharmSciTech

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Abstract. The aim of this paper is to investigate the physicochemical properties of binary amorphous dispersions of poorly soluble sulfonamide/polymeric excipient prepared by ball milling. The sulfonamides selected were sulfathiazole (STZ), sulfadimidine (SDM), sulfamerazine (SMZ) and sulfadiazine (SDZ). The excipients were polyvinylpyrrolidone (PVP) and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co-polymer, commercially known as Soluplus®. Co-milled systems were characterised by powder X-ray diffraction and differential scanning calorimetry. PVP was shown to form amorphous dispersions over a wider composition range than Soluplus® for the four sulfonamides tested. Moreover, amorphous dispersions made with PVP were homogeneous [single glass transition (Tg)], while amorphous dispersions made from Soluplus® were heterogeneous (two Tgs). This behaviour is consistent with the fact that all the sulfonamides tested presented a lower solubility in Soluplus® than in PVP, as evidenced by Flory-Huggins parameters determined. Amorphous dispersions of SDM with Soluplus® could be produced even though SDM does not amorphise alone upon milling and Soluplus® presents Tg at a lower temperature than SDM. Amorphous dispersions of SMZ could be prepared with a lower excipient concentration compared to STZ, SDM and SDZ, which may reflect the one-dimensional H-bonding network in SMZ compared to the 2D or 3D Hbonding network found in the other sulfonamides. Stability tests (60% RH/25°C) revealed that dispersions made with Soluplus® remained dry and powdery compared to those made with PVP that formed a sticky paste in less than 2 weeks, indicating a possible advantage of using Soluplus® in terms of increased physical stability under high humidity storage conditions.

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Section: Temperature-composition Diagramsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Amorphous Solid Dispersions of Sulfonamide/Soluplus® and Sulfonamide/PVP Prepared by Ball Milling

Caron

Tajber

et al. 2013

AAPS PharmSciTech

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“…One of the main concerns to be addressed when creating amorphous dispersions is the stability of the matrix to prevent the drug from returning to its crystalline state within the delivery form before dosage (47)(48)(49). Physical stability of the drug substance can be achieved through kinetic stabilization or freezing the amorphous drug within the polymeric carrier.…”

Section: Evaluation Of Stabilitymentioning

confidence: 99%

“…It can also be achieved by thermodynamic stability which is attained by molecular interactions that hamper mobility (51). Many amorphous dispersions are formulated in a metastable region where the mode of stabilization is a combination of both kinetic and thermodynamic mechanisms (47). Drug loading also influences stability because as loading is increased, at some point miscibility is exceeded and then drug molecule proximity within the polymer matrix becomes critical.…”

Section: Evaluation Of Stabilitymentioning

confidence: 99%

Use of Polyvinyl Alcohol as a Solubility Enhancing Polymer for Poorly Water-Soluble Drug Delivery (Part 2)

Brough

Miller²,

Ellenberger

et al. 2016

AAPS PharmSciTech

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Abstract. The KinetiSol® Dispersing (KSD) technology has enabled the investigation into the use of polyvinyl alcohol (PVAL) as a concentration enhancing polymer for amorphous solid dispersions. Our previous study revealed that the 88% hydrolyzed grade of PVAL was optimal for itraconazole (ITZ) amorphous compositions with regard to solid-state properties, non-sink dissolution performance, and bioavailability enhancement. The current study investigates the influence of molecular weight for the 88% hydrolyzed grades of PVAL on the properties of KSD processed ITZ:PVAL amorphous dispersions. Specifically, molecular weights in the processable range of 4 to 18 mPa · s were evaluated and the 4-88 grade provided the highest AUC dissolution profile. Amorphous dispersions at 10, 20, 30, 40, and 50% ITZ drug loads in PVAL 4-88 were also compared by dissolution performance. Analytical tools of diffusion-ordered spectroscopy and Fourier transform infrared spectroscopy were employed to understand the interaction between drug and polymer. Finally, results from a 30-month stability test of a 30% drug loaded ITZ:PVAL 4-88 composition shows that stable amorphous dispersions can be achieved. Thus, this newly enabled polymer carrier can be considered a viable option for pharmaceutical formulation development for solubility enhancement.

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“…[9]. However, miscibility of the active ingredient in the polymer is one of the major issues in amorphous solid dispersions [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Physico-chemical characterisation of three-component co-amorphous systems generated by a melt-quench method

D’Angelo

Edgar

Hurt

et al. 2018

J Therm Anal Calorim

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The purpose of this work was to evaluate the possibility of creating a ternary co-amorphous system and to determine how the properties of a co-amorphous material are altered by the addition of a selected third component. Piroxicam and indomethacin form a stable co-amorphous with the T g above room temperature. The third component added was selected based on tendency to crystallise (benzamide, caffeine) or form amorphous (acetaminophen, clotrimazole) on cooling. Generated co-amorphous systems were characterised with TGA, HSM, DSC, FTIR and XRD. Stable ternary co-amorphous systems were successfully generated, which were confirmed using XRD, DSC and FTIR analysis. In all cases, T g of the ternary system was lower than the T g of the binary system, although higher than that of the individual third component. Upon storage for 4 weeks, all created ternary systems showed significantly smaller variation in T g compared to the binary system. Stable three-component co-amorphous systems can be generated via melt-quench method using either a crystalline or an amorphous third component. Addition of third component can alter the T g of co-amorphous system and in all cases created more stable co-amorphous system upon storage. Physical parameters may not be sufficient in predicting the resulting T g ; therefore, knowledge of chemical interaction must be brought into equation as well.

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Drug–Polymer Solubility and Miscibility: Stability Consideration and Practical Challenges in Amorphous Solid Dispersion Development

Cited by 385 publications

References 45 publications

Amorphous Solid Dispersions of Sulfonamide/Soluplus® and Sulfonamide/PVP Prepared by Ball Milling

Amorphous Solid Dispersions of Sulfonamide/Soluplus® and Sulfonamide/PVP Prepared by Ball Milling

Use of Polyvinyl Alcohol as a Solubility Enhancing Polymer for Poorly Water-Soluble Drug Delivery (Part 2)

Physico-chemical characterisation of three-component co-amorphous systems generated by a melt-quench method

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