A refined phase diagram of the tert-butanol-water system and implications on lyophilization process optimization of pharmaceuticals.

While water is the solvent of choice for the lyophilization of pharmaceuticals, tert-butyl alcohol (TBA) along with water can confer several advantages including increased solubility of hydrophobic drugs, decreased drying time, improved product stability and reconstitution characteristics. The goal of this work was to generate the phase diagram and determine the eutectic temperature and composition in the "water rich" region (0.0 to 25.

Investigation of PEG crystallization in frozen and freeze-dried PEGylated recombinant human growth hormone-sucrose systems: implications on storage stability.

The objectives of the current study were to investigate (i) the phase behavior of a PEGylated recombinant human growth hormone (PEG-rhGH, ∼60 kDa) during freeze-drying and (ii) its storage stability. The phase transitions during freeze-thawing of an aqueous solution containing PEG-rhGH and sucrose were characterized by differential scanning calorimetry. Finally, PEG-rhGH and sucrose formulations containing low, medium, and high polyethylene glycol (PEG) to sucrose ratios were freeze-dried in dual-chamber syringes and stored at 4°C and 25°C.

Determination of the influence of primary drying rates on the microscale structural attributes and physicochemical properties of protein containing lyophilized products.

This work investigated the impact of primary drying conditions on the microstructure and protein stability of bovine serum albumin (BSA) containing lyophilized cakes. Two primary drying conditions were employed (termed 'conservative', slower drying rate and 'aggressive', higher drying rate) at two protein loadings (5 and 50 mg mL(-1)). The cake attributes were characterized using micro-X-ray computed tomography (micro-CT), scanning electron microscopy, manometric temperature measurements, Fourier transform infrared spectroscopy (FTIR) and size exclusion chromatography (SEC).

Investigation of PEG crystallization in frozen PEG-sucrose-water solutions: II. Characterization of the equilibrium behavior during freeze-thawing.

Our objective was to characterize, by DSC and XRD, the equilibrium thermal behavior of frozen aqueous solutions containing polyethylene glycol (PEG) and sucrose. Aqueous solutions of (i) PEG (2.5-50% w/w), (ii) sucrose (10% w/v) with different concentrations of PEG (1-20% w/v), and (iii) PEG (2% or 10% w/v) with different concentrations of sucrose (2-20% w/v), were cooled to -70 ° C at 5 ° C/min and heated to 25 ° C at 2 ° C/min in a DSC.

Comparative evaluation of disodium edetate and diethylenetriaminepentaacetic acid as iron chelators to prevent metal-catalyzed destabilization of a therapeutic monoclonal antibody.

Understanding the effect of metal chelators with respect to their ability to inhibit metal-catalyzed degradation in biologic products is a critical component for solution formulation development. Two metal chelators, disodium edetate (Na(2)EDTA) and diethylenetriaminepentaacetic acid (DTPA), were evaluated for their ability to stabilize IgG2 mAb in solution formulations spiked with various levels of iron. Real-time stability attributes such as oxidation, soluble aggregate formation, deamidation, and fragmentation demonstrated that DTPA was equivalent to Na(2)EDTA with respect to inhibiting iron-induced degradation over the range of iron concentrations studied.

Investigation of PEG crystallization in frozen PEG-sucrose-water solutions. I. Characterization of the nonequilibrium behavior during freeze-thawing.

Our objective was to characterize the nonequilibrium thermal behavior of frozen aqueous solutions containing PEG and sucrose. Aqueous solutions of (i) sucrose (10%, w/v) with different concentrations of PEG (1-20%, w/v), and (ii) PEG (10%, w/v) with different concentrations of sucrose (2-20%, w/v), were cooled to -70 degrees C at 5 degrees C/min and heated to 25 degrees C at 2 degrees C/min in a differential scanning calorimeter. Annealing was performed at temperatures ranging from -50 to -20 degrees C for 2 or 6 h.

Determination by NMR of the binding constant for the molecular complex between alprostadil and alpha-cyclodextrin. Implications for a freeze-dried formulation.

A binding constant was determined for the complexation reaction between alprostadil (PGE1) and alpha-cyclodextrin (alpha-CD). This constant was used to calculate the fraction PGE1 free upon reconstitution of Caverject dual chamber syringe, indicated for the treatment of erectile dysfunction. The determination was based on the measurement of the chemical shift of the C20 methyl protons of PGE1.

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

Non-aqueous co-solvent systems have been evaluated for their potential use in the freeze-drying of pharmaceutical products. The advantages of using these non-aqueous solvent systems include: increased drug wetting or solubility, increased sublimation rates, increased pre-dried bulk solution or dried product stability, decreased reconstitution time, and enhancement of sterility assurance of the pre-dried bulk solution. Conversely, the potential disadvantages and issues which must be evaluated include: the proper safe handling and storage of flammable and/or explosive solvents, the special facilities or equipment which may be required, the control of residual solvent levels, the toxicity of the remaining solvent, qualification of an appropriate GMP purity, the overall cost benefit to use of the solvent, and the potential increased regulatory scrutiny.