Freeze-Drying of tert-Butanol/Water Cosolvent Systems: A Case Report on Formation of a Friable Freeze-Dried Powder of Tobramycin Sulfate

Wittaya‐areekul, Sakchai; Needham, Gregory F.; Milton, Nathaniel; Roy, Michael L.; Nail, Steven L.

doi:10.1002/jps.10113

Cited by 37 publications

(28 citation statements)

References 12 publications

(10 reference statements)

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“…The endotherms at -14-C and -8-C are due to melting of the eutectic of TBA hydrate-ice at 20% wt/wt TBA and the melting of TBA hydrate, respectively. 11 A less sharp onset of the endotherm at -14ºC, probably indicating inhibition of TBA crystallization, 13 was seen only in the presence of both mannitol and NaHCO 3 ( Figure 3). Inhibition of TBA crystallization is probably due to the presence of amorphous Composition of the freeze-dried products: (I) EO-9 8 mg, mannitol 50 mg, NaHCO 3 20 mg; (II) EO-9 8 mg, mannitol 100 mg, NaHCO 3 20 mg; (III) EO-9 8 mg, mannitol 50 mg, PVP 50 mg, NaHCO 3 20 mg. mannitol.…”

Section: E4mentioning

confidence: 98%

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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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Section: E4mentioning

confidence: 98%

“…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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“…A single phase solution is thermodynamically favorable when the concentration of the incompatible components is low, while liquid-liquid phase separation occurs once a critical concentration of these components is reached (12,(19)(20)(21)(22). It was reported that during the freezing of a solution, the solutes can reach concentrations as high as 20-50 times of their initial concentration (23)(24)(25).…”

Section: Other Potential Mechanism: Liquid-liquid Phase Separationmentioning

confidence: 98%

“…Although most lyophiles are made from aqueous solution, lyophilization with pure organic solvent (3,4) or organic/water co-solvents (5)(6)(7)(8)(9)(10)(11)(12)(13) were reported in some cases where such solvents provided process or formulation advantages, such as improved drug stability (3,4), short drying time (6,7), and increased solubility of hydrophobic drugs (10,13).…”

Section: Introductionmentioning

confidence: 99%

Formation of Zinc–Peptide Spherical Microparticles During Lyophilization from tert-Butyl Alcohol/Water Co-solvent System

Qian

Chen

et al. 2008

Pharm Res

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A proposed mechanism of spherical particle formation of the 3:1 zinc peptide encompasses the freezing of a TBA/water solution (20-70% TBA) causing the formation of a TBA hydrate phase ("dispersed TBA hydrate"). Decreasing the temperature further causes the formation of a eutectic mixture between TBA hydrate ("eutectic TBA hydrate") and water. Due to its low aqueous solubility, the zinc peptide adduct accumulates in both of the dispersed and eutectic TBA hydrate phases to form a hydrophobic "oil" phase. Since the eutectic TBA hydrate phase is surrounded by ice, a "solid emulsion" forms to lower the interfacial energy, and gives rise to spherical zinc peptide particles upon solvent sublimation. Possibility of liquid-liquid phase separation during freeze-drying was also investigated, and no evidence was found to support this alternative mechanism.

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“…Tertiary butyl alcohol (TBA) is one of the most popular solvents used in freeze-dried formulations. Freezing and freeze-drying behavior of ingredients in solutions containing TBA has been evaluated (8)(9)(10)(11). Ni et al have demonstrated that TBA improved the stability of an antitumor drug by creating needle-shaped crystals during the freeze-drying process (8).…”

Section: Introductionmentioning

confidence: 99%

Subambient Behavior of Mannitol in Ethanol–Water Co-solvent System

2008

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Freeze-Drying of tert-Butanol/Water Cosolvent Systems: A Case Report on Formation of a Friable Freeze-Dried Powder of Tobramycin Sulfate

Cited by 37 publications

References 12 publications

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

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

Formation of Zinc–Peptide Spherical Microparticles During Lyophilization from tert-Butyl Alcohol/Water Co-solvent System

Subambient Behavior of Mannitol in Ethanol–Water Co-solvent System

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