Practical aspects of lyophilization using non-aqueous co-solvent systems

Teagarden, Dirk L.; Baker, David

doi:10.1016/s0928-0987(01)00221-4

Cited by 164 publications

(104 citation statements)

References 19 publications

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“…Comparison of all dissolution profiles was carried out in both release medias (borate buffer pH 9 and sodium orthophosphate buffer pH 12). At different time intervals (5,10,15,30,45, and 60 minutes), 3 mL samples were withdrawn and filtered using a Millipore filter (0.22 micrometer), followed by compensation with the same volume of fresh dissolution medium. Samples (in triplicates) were then measured spectrophotometrically at a wavelength of 266 nm using the corresponding proper buffer containing the corresponding SPC ratio as a blank.…”

Section: In Vitro Release Studymentioning

confidence: 99%

“…TBA possesses a high vapor pressure (41.25 mmHg at 25°C), a high melting point (24°C) and has a low toxicity. 30 Moreover, adding TBA to the lyophilization process was reported to produce large needle-shaped crystals with a high surface area and porosity that can facilitate sublimation. All these factors suggested TBA as an ideal freeze-drying medium that could be removed rapidly and completely by lyophilization.…”

Section: Co-solvent Typementioning

confidence: 99%

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Lyophilized phytosomal nanocarriers as platforms for enhanced diosmin delivery: optimization and ex vivo permeation

Freag¹,

Elnaggar²,

Abdallah³

2013

IJN

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Diosmin (DSN) is an outstanding phlebotonic flavonoid with a tolerable potential for the treatment of colon and hepatocellular carcinoma. Being highly insoluble, DSN bioavailability suffers from high inter-subject variation due to variable degrees of permeation. This work endeavored to develop novel DSN loaded phytosomes in order to improve drug dissolution and intestinal permeability. Three preparation methods (solvent evaporation, salting out, and lyophilization) were compared. Nanocarrier optimization encompassed different soybean phospholipid (SPC) types, different solvents, and different DSN:SPC molar ratios (1:1, 1:2, and 1:4). In vitro appraisal encompassed differential scanning calorimetry, infrared spectroscopy, particle size, zeta potential, polydispersity index, transmission electron microscopy, drug content, and in vitro stability. Comparative dissolution studies were performed under sink versus non-sink conditions. Ex vivo intestinal permeation studies were performed on rats utilizing noneverted sac technique and high-performance liquid chromatography analysis. The results revealed lyophilization as the optimum preparation technique using SPC and solvent mixture (Dimethyl sulphoxide:t-butylalchol) in a 1:2 ratio. Complex formation was contended by differential scanning calorimetry and infrared data. Optimal lyophilized phytosomal nanocarriers (LPNs) exhibited the lowest particle size (316 nm), adequate zeta-potential (-27 mV), and good in vitro stability. Well formed, discrete vesicles were revealed by transmission electron microscopy, drug content, and in vitro stability. Comparative dissolution studies were performed. LPNs demonstrated significant enhancement in DSN dissolution compared to crude drug, physical mixture, and generic and brand DSN products. Permeation studies revealed 80% DSN permeated from LPNs via oxygenated rat intestine compared to non-detectable amounts from suspension. In this study, LPNs (99% drug loading) could be successfully tailored for DSN with improved dissolution and permeation characteristics, which is promising for lowering the influence of exogenous factors and increasing drug delivery.

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Section: In Vitro Release Studymentioning

confidence: 99%

Section: Co-solvent Typementioning

confidence: 99%

Lyophilized phytosomal nanocarriers as platforms for enhanced diosmin delivery: optimization and ex vivo permeation

Freag¹,

Elnaggar²,

Abdallah³

2013

IJN

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“…However, as the H69 and NANOEDGE technologies involve the precipitation of particles in liquid media that usually contain organic solvents, these nanosuspensions are not ready to be used further. Extra drying steps need to be performed to eliminate the organic solvent content, which makes the process longer, more expensive, and more complicated regarding regulatory aspects (Shegokar and Muller, 2010;Teagarden and Baker, 2002). On the contrary, when employing the H42 and H96 technologies, the organic solvent necessary to dissolve the poorly soluble drugs is eliminated during the bottom-up step.…”

Section: Cryogenic Millingmentioning

confidence: 99%

Drug Nanonization: An Overview of Industrially Feasible Top-Down Technologies for Nanocrystal Production

Dahiya¹

2017

Bull. Pharm. Res.

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Many drugs are associated with one or more problems in their delivery including, poor bioavailability, in vivo stability, solubility, intestinal absorption, sustained and targeted delivery to site of action, therapeutic effectiveness, side effects and plasma fluctuations of drugs which either fall below the minimum effective concentrations or exceed the safe therapeutic concentrations. Extensive research efforts have been reported including micronization, salt formation, pH modification, solid dispersions, complexation, solubilization, hydrotropy etc for addressing one or more of these challenges in order to achieve desired formulation performance. Many of these techniques have been commercialized and still under continuous research. In spite of their potential for improved drug delivery, they suffer from one or more limitations and could not be exploited fully. Recently, various nanonization strategies have emerged to increase the dissolution rates and bioavailability of numerous drugs that are poorly soluble in water. These technologies have been proved to be highly effective not only for improving poor aqueous solubility and bioavailability problems but also in dealing with other formulation challenges. This article overviews the potential of nanonization to overcome many problems associated with modern drug delivery and addresses the salient features of the industrially feasible top-down technologies involved in production of nanocrystals.

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“…5 Organic solvents have positive effects on these 3 items. 9 TBA is one of the organic solvents that has been used often in freeze drying. [9][10][11][12][13][14][15] The benefits of TBA are shorter freeze-drying times and significantly higher specific surface areas of freeze-dried products.…”

Section: Solubility and Stability Of Eo-9mentioning

confidence: 99%

Development of a bladder instillation of the indoloquinone anticancer agent EO-9 using tert-butyl alcohol as lyophilization vehicle

et al. 2007

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The purpose of this research was to develop a stable bladder instillation of EO-9 for the treatment of superficial bladder cancer. First, stability and dissolution studies were performed. Subsequently, the freeze-drying process was optimized by determination of the freeze-drying characteristics of the selected cosolvent/water system and differential scanning calorimetry analysis of the formulation solution. Furthermore, the influence of the freeze-drying process on crystallinity and morphology of the freeze-dried product was determined with x-ray diffraction analysis and scanning electron microscopy, respectively. Subsequently, a reconstitution solution was developed. This study revealed that tert-butyl alcohol (TBA) can be used to both dramatically improve the solubility and stability of EO-9 and to shorten the freeze-drying cycle by increasing the sublimation rate. During freeze drying, 3 TBA crystals were found: TBA hydrate-ice crystals, crystals of TBA hydrate, and a third crystal, probably composed of TBA hydrate crystals containing~90% to 95% TBA. Furthermore, it was shown that crystallization of TBA hydrate was inhibited in the presence of both sodium bicarbonate (NaHCO 3 ) and mannitol. Addition of an annealing step resulted in a minor increase in the crystallinity of the freeze-dried product and formation of the δ-polymorph of mannitol. A stable bladder instillation was obtained after reconstitution of the freeze-dried product (containing 8 mg of EO-9, 20 mg of NaHCO 3 , and 50 mg of mannitol per vial) to 20 mL with a reconstitution solution composed of propylene glycol/water for injection (WfI)/NaHCO 3 /sodium edetate 60%/40%/2%/0.02% vol/ vol/wt/wt, followed by dilution with WfI to a final volume of 40 mL.

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Practical aspects of lyophilization using non-aqueous co-solvent systems

Cited by 164 publications

References 19 publications

Lyophilized phytosomal nanocarriers as platforms for enhanced diosmin delivery: optimization and ex vivo permeation

Lyophilized phytosomal nanocarriers as platforms for enhanced diosmin delivery: optimization and ex vivo permeation

Drug Nanonization: An Overview of Industrially Feasible Top-Down Technologies for Nanocrystal Production

Development of a bladder instillation of the indoloquinone anticancer agent EO-9 using tert-butyl alcohol as lyophilization vehicle

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