In response to our recommendations to the USP that specifications for number average molecular weight (Mn), in addition to those for weight average molecular weight (Mw), be included in the draft monographs for Dextran 70 and Dextran 40, some clinicians stated that the oncotic effect of dextrans does not relate to Mn (or to Mw) but rather to a water retaining (binding) capacity of dextran. In view of the foregoing, we have carried out calculations in order to demonstrate that the colligative properties of dextran, deriving from Mn, are responsible for the oncotic effect as with other polydisperse colloids. The dextrans for which osmotic pressures were considered range in Mn from 24,000 to 375,000, and except for Dextran 40 (Mn approximately 23,500) and Dextran 70 (Mn approximately 39,600), all data are from the literature. Three osmotic coefficients (Mn, B2, and B3) are found to provide a sufficient mathematical representation of the oncotic properties of each of these dextrans alone. Furthermore, a global, non-linear least squares fit of the osmotic pressure data shows that B2 can be expressed as a function of (Mn)-2, in accord with theory, whereas B3 is independent of Mn. Thus, these correspond to universal values for B2 and B3. These universal virial coefficients in conjunction with the appropriate values of Mn successfully reproduce experimental osmotic pressures for all these dextrans over a concentration range of 5- 60 mg/mL with a small RMS deviation thereby justifying our recommendations to the USP. Since most osmotic pressure data used to determine B2 and B3 are from the literature, we plan to make additional osmotic pressure measurements - in particular on mixtures of dextrans with extreme Mn values - in order to confirm that the universal virial coefficients afford accurate predictions of oncotic pressure. In the proposed USP Monographs for Dextran 70 and Dextran 40, a SEC-HPLC technique is described for obtaining the molecular weight distribution of these products thereby permitting the computation of any type of molecular weight Recently, we obtained from the USP two sets of dextran molecular weight standards to be used in conjunction with SEC-HPLC to obtain Mw and Mn values. We plan to utilize these standards to evaluate several different proposed SEC-HPLC methodologies for accuracy and ease of use. Adoption of these monographs by the USP will provide substantial regulatory relief to the Agency since these will define the corresponding drug substances and drug products. We also plan to pursue an earlier observation that Mw and Mn values for a lot of Dextran 70 or Dextran 40 permit a reasonable prediction of the molecular weight distribution of constitutive species since the experimental distributions tend to be very nearly normal distributions.
