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Poly(D,L-lactic acid) (PLA) has been widely used in pharmaceutics and medicine. Low molecular weight (LMW) PLA is especially useful for rapidly degrading biomaterials such as those used for short-duration drug delivery systems. There is scant information available in the literature regarding the purification and analysis of LMW PLA. In this paper we report (1) a convenient and effective polymer purification/fractionation technique to produce LMW PLA with narrow molecular weight distribution (MWD) and (2) analyses that were used to characterize the molecular weight and MWD of these polymers. A novel, convenient and effective temperature-induced solution-phase separation method was developed to produce narrow MWD, LMW (600–2000 g mol−1) PLA. Molecular weights determined using gel permeation chromatography (GPC) with universal calibration, unlike those determined with the commonly used conventional calibration, showed good agreement with those obtained using several independent direct techniques. The phase separation induced by temperature reduction of a polymer in a single solvent system provided a simple and effective technique to produce narrow MWD, LMW PLA polymers. Additional advantages of this technique are: (1) only one solvent is required; (2) the risk of local complete solid polymer precipitation is eliminated; (3) it is reversible and not dependent on the rate of cooling; and (4) use of chlorinated solvents is avoided. This technology may open up a new opportunity for manufacturing LMW polymers with narrow MWD. We also found that GPC with universal calibration is a more accurate method than GPC with the commonly used conventional calibration for characterizing these polymers, and is straightforward to use especially now that on-line viscosity detectors are widely available. Copyright © 2010 Society of Chemical Industry

This study evaluated the effect of the imaginary component of the refractive index on laser diffraction particle size data for pharmaceutical samples.Excipient particles 1-5 microm in diameter (irregular morphology) were measured by laser diffraction. Optical parameters were obtained and verified based on comparison of calculated vs. actual particle volume fraction.Inappropriate imaginary components of the refractive index can lead to inaccurate results, including false peaks in the size distribution. For laser diffraction measurements, obtaining appropriate or "effective" imaginary components of the refractive index was not always straightforward. When the recommended criteria such as the concentration match and the fit of the scattering data gave similar results for very different calculated size distributions, a supplemental technique, microscopy with image analysis, was used to decide between the alternatives. Use of effective optical parameters produced a good match between laser diffraction data and microscopy/image analysis data.The imaginary component of the refractive index can have a major impact on particle size results calculated from laser diffraction data. When performed properly, laser diffraction and microscopy with image analysis can yield comparable results.

A novel application of oscillatory shear rheology was used to directly monitor global phase behavior of protein formulations in the frozen state and study its correlation with physical instability of frozen protein formulations.Oscillatory rheology was used to measure changes in rheological parameters and to identify mechanical softening temperature (Ts*) and related properties of an IgG2 mAb formulation. Rheological measurements were compared to DSC/MDSC. Physical stability of IgG2 formulations was monitored by SE-HPLC.Rheological parameters and Ts* of an IgG2 formulation were sensitive to physical/morphological phase changes during freezing and thawing. Ts* of the frozen formulation was a function of concentration of protein and excipient. Complex modulus, G*, and phase angle, δ, for IgG2 at 70 mg/mL in a sucrose-containing formulation showed the system was not completely frozen at -10°C, which correlated to stability data consistent with ice-induced protein aggregation.We report the first application of oscillatory shear rheology to study phase behavior of IgG2 in a sucrose-containing formulation and its correspondence with physical stability not explained by glass transition (Tg'). We provide a mechanism and data suggesting that protein instability occurs at the ice/water interface.

Accurate values for the apparent oxygen permeability of "superpermeable" silicone rubber were obtained using a polaro-graphic oxygen sensor in conjunction with measuring gases of low oxygen partial pressure. This method reduces errors that result from the nonlinear response of the polarographic cell to high oxygen flux and may call into question all papers measuring highly transmissible samples by the polarographic technique. Data collected with gases of 2–10% oxygen were extrapolated to 0% oxygen in order to correct for electrode nonlinearity. To confirm the accuracy of these apparent permeabilities, we performed thickness analyses of the estimates to eliminate the effect of liquid (boundary) layer resistance. When data for materials of greater than 0. 054 cm thickness were used in the calculation, the final extrapolated value tended to exceed the literature oxygen permeability (Dk) of 600 barrers (one barrer is equivalent to 10 −11 mlO 2 (STP) cm/second cm 2 mmHg). However, it was found that such thick sample data were subject to high edge and geometrical effects. When the thick sample data were excluded, Dk values of 561 and 618 barrers were obtained, depending on the thickness analysis used; these values closely match gas/gas results (although with sizable precision errors) and thus independently corroborate our technique. This extension of the usefulness of the polarographic oxygen sensor to superpermeable silicone rubber may also apply to other superpermeable polymers and contact lenses.

We determined the cytotoxicity of some artemisinin derivatives against EN2 tumor cells using the MTT assay. Artemisinin (1) was clearly more cytotoxic than deoxyartemisinin (2), which lacks the endoperoxide bridge. Ether-linked dimers of dihydroartemisinin with defined stereochemistry were found to differ in the extent of cytotoxic effect on EN2 cells. The nonsymmetrical dimer (3) was more cytotoxic than the symmetrical dimer (4). The nonsymmetrical dimer of dihydrodeoxyartemisinin (5) lacking the endoperoxide bridges was also effective in the MTT assay, although less cytotoxic than 3 and 4. Similarly, the symmetrical dimer (6) was less effective than 5. Epoxides of artemisitene also showed that stereochemistry was an important factor for cytotoxicity. The results suggested that the endoperoxide bridge was not crucial for cytotoxicity to the tumor cells, but contributed to the cytotoxic effect apparently exerted by the ether linkage of the dimers. Flow cytometry data indicated that the dimers 3 and 4 caused an accumulation of the cells in the G(1)-phase of the cell cycle. In contrast, artemisinin (1) caused a slight increase of S-phase cells.