Amorphous Stabilization and Dissolution Enhancement of Amorphous Ternary Solid Dispersions: Combination of Polymers Showing Drug–Polymer Interaction for Synergistic Effects

Prasad, Dev; Chauhan, Harsh; Atef, Eman

doi:10.1002/jps.24137

Cited by 108 publications

(79 citation statements)

References 41 publications

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“…The rule of thumb for estimating miscibility reported in literature is a difference in solubility parameter (Δδ) of less than 7 (MJ/m 3 ) ½ indicates that the substances are miscible; a Δδ value more than 10 (MJ/m 3 ) ½ predicts unfavourable interaction and immiscibility between the components of the blend leading to phase separation. A Δδ value of 7-10 (MJ/m 3 ) ½ indicates partial miscibility of the ingredients [21,27]. As seen in Table 3, the calculated solubility parameters for Soluplus and the processing aid materials, PEG, PEO and Tween 80, are nearly identical, indicating excellent miscibility of all excipients in CMS placebo.…”

Section: Prediction Of Excipient-excipient and Drug-excipient Miscibimentioning

confidence: 92%

An investigation into the use of polymer blends to improve the printability of and regulate drug release from pharmaceutical solid dispersions prepared via fused deposition modeling (FDM) 3D printing

Alhijjaj

Belton

2016

European Journal of Pharmaceutics and Biopharmaceutics

236

134

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FDM 3D printing has been recently attracted increasing research efforts towards the production of personalized solid oral formulations. However, commercially available FDM printers are extremely limited with regards to the materials that can be processed to few types of thermoplastic polymers, which often may not be pharmaceutically approved materials nor ideal for optimizing dosage form performance of poor soluble compounds. This study explored the use of polymer blends as a formulation strategy to overcome this processability issue and to provide adjustable drug release rates from the printed dispersions. Solid dispersions of felodipine, the model drug, were successfully fabricated using FDM 3D printing with polymer blends of PEG, PEO and Tween 80 with either Eudragit E PO or Soluplus. As PVA is one of most widely used polymers in FDM 3D printing, a PVA based solid dispersion was used as a benchmark to compare the polymer blend systems to in terms processability. The polymer blends exhibited excellent printability and were suitable for processing using a commercially available FDM 3D printer. With 10% drug loading, all characterization data indicated that the model drug was molecularly dispersed in the matrices.During in vitro dissolution testing, it was clear that the disintegration behavior of the formulations significantly influenced the rates of drug release. Eudragit EPO based blend dispersions showed bulk disintegration; whereas the Soluplus based blends showed the 'peeling' style disintegration of strip-by-strip. The results indicated that interplay of the miscibility between excipients in the blends, the solubility of the materials in the dissolution media and the degree of fusion between the printed strips during FDM process can be used to manipulate the drug release rate of the dispersions. This brings new insight into the design principles of controlled release formulations using FDM 3D printing.

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Section: Prediction Of Excipient-excipient and Drug-excipient Miscibimentioning

confidence: 92%

An investigation into the use of polymer blends to improve the printability of and regulate drug release from pharmaceutical solid dispersions prepared via fused deposition modeling (FDM) 3D printing

Alhijjaj

Belton

2016

European Journal of Pharmaceutics and Biopharmaceutics

236

134

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“…Binary or ternary solid dispersions have been reported to be more successful since they provide physical stability and prevents recrystallization of drug (4,(6)(7)(8)(9). Use of surfactant with carrier enhances the wettability and solubilization of the drug and also assists in drug release (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Effervescence Assisted Fusion Technique to Enhance the Solubility of Drugs

et al. 2015

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Abstract. The solubility of five poorly soluble drugs was enhanced by using an effervescence assisted solid dispersion (EASD) technique. EASDs were prepared by using modified fusion method. Drug and hydrophilic carrier were melted, and in this molten mixture, effervescence was generated by adding effervescence couple comprising organic acid (citric acid) and carbonic base (sodium bicarbonate). Solubility of drug powders, solid dispersions, and EASDs was determined at 25°C using shake flask method. Atorvastatin calcium, cefuroxime axetil, clotrimazole, ketoconazole, and metronidazole benzoate were estimated using a spectrophotometer at 246, 280, 260, 230, and 232 nm (λ max ), respectively. Solubility of atorvastatin calcium (from 100 to 345 μg/ml), cefuroxime axetil (from 441 to 1948 μg/ml), clotrimazole (from 63 to 677 μg/ml), ketoconazole (from 16 to 500 μg/ml), and metronidazole benzoate (from 112 to 208 μg/ml) in EASDs was enhanced by 3.45-, 4.4-, 10.7-, 31.2-, and 1.8-fold, respectively. Scanning electron micrographs of drug powder, solid dispersion, and EASDs were compared. Scanning electron micrographs of EASDs showed a uniform distribution of drug particles in the carrier matrix. Morphology (size and shape) of cefuroxime axetil particles was altered in solid dispersion as well as in EASD. EASDs showed better solubility enhancement than conventional solid dispersions. The present technique is better suitable for drugs having a low melting point or melt without charring. Effervescence assisted fusion technique of preparing solid dispersions can be employed for enhancing solubility, dissolution, and bioavailability of poorly soluble drugs.

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“…Due to the advancement in basic physicochemical understanding of amorphous systems, the utilization of this techniques has immensely increased in enabling the delivery of the difficult to solubilize compounds. Traditional binary solid dispersions contain a drug dispersed in a single polymer matrix, whereas in recently developed ternary solid dispersions three components i.e., API, polymer, and an additive are present [1][2][3][4][5][6][7].…”

Section: Editorialmentioning

confidence: 99%

Ternary Amorphous Solid Dispersions

Prasad¹,

Lande²,

Chauhan³

et al. 2017

J Dev Drugs

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EditorialAmorphous solid dispersion is one of the techniques used in the formulation development of poorly soluble compounds. Due to the advancement in basic physicochemical understanding of amorphous systems, the utilization of this techniques has immensely increased in enabling the delivery of the difficult to solubilize compounds. Traditional binary solid dispersions contain a drug dispersed in a single polymer matrix, whereas in recently developed ternary solid dispersions three components i.e., API, polymer, and an additive are present [1][2][3][4][5][6][7].In both the systems, API is present in amorphous form and polymer is used for the stabilization of this amorphous form via decrease in molecular mobility or via drug-polymer molecular interactions. The third component is usually a surface-active agent or another polymer depending on the desired dissolution/stability profiles of the drug. For example, if the faster dissolution is desired then surfactant would be a better choice and if the prevention of re-crystallization is needed then another polymer with higher Tg may be used in developing the ternary solid dispersions.One of the challenges associated with developing ternary dispersion is the selection of appropriate polymers/surfactant and their combinations. In those cases, solution studies can be successfully used to distinguish the ability of individual polymer vs. combined polymers for synergistic effect in terms of dissolution enhancement or amorphous stabilization or both [2]. The parameters studied in such solution state screening studies usually are the ability of polymers or their combinations to inhibit precipitation and maintaining supersaturation (Figure 1). The prepared ternary solid dispersions can be characterized by technique such as DSC/MDSC, PXRD, and FTIR. These techniques are used to determine important parameters such as the glass-transition temperature of amorphous components, the crystallinity of the drug and the molecular interaction between drug and excipients.The future research focusing on the 1) combination of polymers to tailor the release profile and stability, 2) advance characterization techniques such as small angle X-ray scattering and solid-state NMR and 3) improvement in manufacturing of amorphous solid dispersions will progress the application of ternary solid dispersions strategy in resolving the challenges of current drug development program. The advancement of dedicated CROs for amorphous dispersions development and recent success of drugs such as Telaprevir (Incivek®) and Ivacaftor (Kalydeco®) suggests that this technique is capable of providing the desired approach for the development of poorly soluble compounds.Finally, the fact that almost 40% of the new chemical entities are poorly water soluble in nature implies that studies with ternary solid dispersions will continue, and with increase understanding of these systems, more drug compounds formulated as solid dispersions will reach the market in the future.

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Amorphous Stabilization and Dissolution Enhancement of Amorphous Ternary Solid Dispersions: Combination of Polymers Showing Drug–Polymer Interaction for Synergistic Effects

Cited by 108 publications

References 41 publications

An investigation into the use of polymer blends to improve the printability of and regulate drug release from pharmaceutical solid dispersions prepared via fused deposition modeling (FDM) 3D printing

An investigation into the use of polymer blends to improve the printability of and regulate drug release from pharmaceutical solid dispersions prepared via fused deposition modeling (FDM) 3D printing

Effervescence Assisted Fusion Technique to Enhance the Solubility of Drugs

Ternary Amorphous Solid Dispersions

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