Characterization of Polymeric Excipients

Viscosity, or a fluid’s resistance to flow, is independent of the rate of shear or shear stress, at a given temperature, for Newtonian fluids. Non-Newtonian fluids such as polymer solutions often exhibit viscosity values that vary with the rate of shear or shear stress. Processability and functional performance of polymeric excipients may depend on their rheological behavior and may not be adequately reflected by the dilute solution viscosities specified in the current United States Pharmacopeia–National Formulary (USP−NF) monographs. 

To address the issues inherent to non-Newtonian fluids, and as part of its standards-setting process, the US Pharmacopeial Convention (USP) has revised the previous General Chapter on viscosity <911> (“Viscosity”) and developed a new informational General Chapter, <1911> “Rheometry”. In the past few years, USP also added four General Chapters describing several test procedures: <911> “Viscosity-Capillary Methods”, <912> “Viscosity-Rotational Methods”, <913> “Viscosity-Rolling Ball Method”, and <914> “Viscosity-Pressure Driven Methods”, all now officially adopted into the USP–NF compendia (1–12) (see Sidebar).

Along with these significant changes in the viscosity general chapters, USP developed and revised the corresponding viscosity procedures in excipient monographs to follow the revised chapter requirements, and proposed a critical labeling requirement for cases when certain viscometers are employed (see Sidebar). To obtain a more thorough characterization of macromolecular or polymeric excipients and, furthermore, to understand their variability, USP’s Excipients Expert Committee (ECX EC) recommends a future assessment of average molecular weight, or better still, the molecular weight distribution and polydispersity of the excipient. 

The General Chapter Viscosity <911> was introduced into the United States Pharmacopeia−National Formulary (USP−NF) compendia in the early 1950s to enable differentiation among commercial types or grades of an excipient and to minimize batch-to-batch variability by establishing limits for viscosity test outcomes. During the 1960s and 1970s, chapter changes were limited to the addition of two sections to <911>-Procedure for Methylcellulose and Calibration of Capillary-Type Viscometers-and the expansion of the methylcellulose procedure to include additional cellulose derivatives. No further revision proposals were published until November 2008, when two revision proposals, “Newtonian Viscosity” <911> and “Non-Newtonian Rheology” <912>, were published (1, 2). It should be noted that, in the two 2008 proposals, the terminology reverted to ‘viscometer,’ a more widely accepted term, in place of ‘viscosimeter,’ which had been adopted in the late 1970s. In 2012, the General Chapter “Viscosity” <911> that was included in USP 35−NF 30 (3) contained four sections: Introduction; Measurement of Viscosity; Procedure for Cellulose Derivatives; Calibration of Capillary-Type Viscosimeters.

[Click to Enlarge] Table: Overview of viscosity chapters.

On the basis of comments received by stakeholders during the 2011 and 2012 revisions of the viscosity general chapter, USP’s Excipients Expert Committee (EXC EC) and the General Chapters−Physical Analysis Expert Committee (GC−PA EC) proposed to reorganize the USP−NF viscosity chapters. To align with the new general chapter approach, the committees replaced the previous two proposals, “Newtonian Viscosity” <911> and “Non-Newtonian Rheology” <912> (1, 2) with proposals for two test chapters and one general informational chapter:

The test procedures from the previously proposed “Newtonian Viscosity” <911> and “Non-Newtonian Rheology” <912> (1, 2) were included in the newly proposed “Viscosity−Capillary Viscometer Methods” <911> (4) and “Rotational Rheometer Methods” <912> (5). The theories and applications from the 2008 published proposals (1, 2) were incorporated into the general information chapter “Rheometry” <1911> (6). An additional chapter was proposed in 2011--“Rolling Ball Viscometer Method” <913> (7). These changes in the viscosity general chapters affected nearly 70 USP−NF monographs (8), which were updated accordingly. 

With publication of the information chapter “Rheometry” <1911> (6) and based on input from stakeholders, specifically from several viscometer/rheometer manufacturers, the Expert Committees further updated the three viscosity test chapters (9, 10, 11) in 2013. To achieve consistency across the titles for chapters <911>, <912>, and <913>, the Expert Committees proposed the following chapter titles:

In addition to the proposed title change, the 2013 proposal for chapters <911>, <912> and <913> (9, 10, 11) included a proposed title change and added a note referencing “Rheometry” <1911>. Furthermore, the proposal was expanded to include any other type of capillary viscometer for <911>, provided that the accuracy and precision is not less than that obtained with the viscometers described in the chapter. Additionally, a new method, Method IV. Parallel Plate (or Parallel Disk) Rheometers, was introduced in the chapter <912> proposal (10). At the end of 2014, a new general chapter proposal, “Viscosity-Pressure Driven Methods” <914>, was published (12), and it was approved and adopted into USP 39-NF 34 (see Table).

References
For reference information, please refer to the References section.

Applications of viscosity in USP–NF monographs

Process ability and functional performance of polymeric excipients may depend on their rheological behavior, and may not be adequately reflected by the dilute solution viscosities specified in the current USP−NF monographs. Dilute solution viscosities are useful to specify excipient grades, but may not be relevant to applications using higher excipient concentrations. Several USP–NF general chapters such as <1059> “Excipient Performance” (13) and <3>“Topical and Transdermal Drug Products-Product Quality Tests” (13) make references to the three test chapters, <911> “Viscosity-Capillary Methods”, <912> “Viscosity-Rotational Methods”, or  <913> “Viscosity-Rolling Ball Method”, where the physical characteristics of excipients and drug products need to be assessed.

As described in the chapter <1911> “Rheometry”, liquids of high molecular weight, solutions that contain high-molecular-weight solutes, and colloidal dispersions (e.g., suspensions and emulsions) typically behave as non-Newtonian fluids. Due to the non-linear relationship between shear stress and shear rate for a non-Newtonian fluid, its rheological profile-rheogram or flow curve-will provide a more meaningful characterization than a single viscosity measurement of the apparent viscosity at a single shear rate.

Viscosity test procedures are implemented in more than 60 excipient monographs, specifically for polymeric excipients. Historical files at USP show that when a polymeric excipient monograph was established decades ago, a viscosity specification was typically used to distinguish between different types (or grades) in a polymer family monograph, due to differences in the polymer’s average molecular weight, as well as to ensure batch-to-batch consistency. It has been suggested that rheology is the most practical method for material characterization because flow behavior is responsive to variations in molecular weight and the molecular weight distribution. This has been an industry practice for many years--types (or grades) of these polymeric products are distinguished based on the viscosity label claim established by the manufacturer.

For example, hydroxypropyl cellulose, a commonly used polymeric excipient, is produced in several grades, which are determined by the intended markets (14) (see Table I). For each marketed grade, up to six viscosity types are available and are designated as H, M, G, J, L, E. Product designation is a combination of viscosity type followed by grade designation (see Table II), which shows viscosity values and the average molecular weights for hydroxypropyl cellulose (14). Viscosity values/ranges shown in Table II are dependent upon the test conditions, including instrument, type of spindle and spindle speed, test temperature, and concentration of test fluid. Without this information, the viscosity value/range alone cannot be used to characterize a specific viscosity grade.

In the Polyvinyl Alcohol USP monograph (13), the polymer is defined as a water-soluble synthetic resin represented by the formula (C₂H₄O)_n in which the average value for n is between 500 and 5000, and its average molecular weight is 22,000-220,000 g/mol. Polyvinyl alcohol is prepared by hydrolysis of polyvinyl acetate (degree of hydrolysis is 85–89%). The monograph further defines the material through a viscosity specification and includes the statement, “The apparent viscosity, in mPa•s, at 20 ∘C, of a 4% (w/w) aqueous solution is not less than 85% and not more than 115% of that stated on the label.” Average molecular weights and viscosities for several commercially available polyvinyl alcohols are summarized in Table III. As shown in Table III, the viscosity specifications were established to differentiate low, medium, and high average molecular weights.

Because the apparent viscosity of a non-Newtonian fluid is test condition dependent, USP recommended that the following labeling be incorporated in polymeric excipient monographs to ensure reproducibility among laboratories that measure viscosity of the polymer:
 

1. Labeling: Label it to indicate the viscosity, giving the viscosity measurement parameters, the concentration of the solution, and the type of equipment used.
    

Similarly, the viscosity specifications were updated for the Polyethylene Oxide NF monograph (17), which describes a nonionic homopolymer of ethylene oxide, represented as H(OCH₂CH₂)_nOH, in which n represents the average number of oxyethylene groups. The number n varies from about 2000 to 200,000. Its average molecular weight range is 88,000−8,800,000 g/mol. Again, a detailed test procedure and a labeling requirement have been added to the monograph:
 

1. Labeling: Label it to indicate the viscosity and acceptable limits, giving the viscosity measurement parameters, concentration of the solution, and the type of equipment used. Label it to indicate the name and quantity of any added antioxidant.
    

In addition to the general chapters, viscosity procedures in many excipient monographs are in the process of being developed and revised. Well-defined procedures and labeling requirements have been incorporated into the revised monographs (see Table IV). To obtain a meaningful viscosity measurement, sample solution preparation for a polymeric product is crucial. This is exemplified in the viscosity test procedure for partially-neutralized methacrylic acid and ethyl acrylate copolymer (13). Detailed sample preparation is specified in each revised monograph (see Table IV).

Viscosity specifications ideally have lower and upper limits. In some cases such as Xanthan Gum NF (13), the NF monograph specifies only a minimum apparent viscosity and no upper boundary, thus it fails to address the issue of excipient variability (18). Revision of the current “one-point” unbounded NF viscosity specification for xanthan gum is under way. In all the newly developed and updated polymeric excipient monographs listed in Table IV, viscosity acceptance criteria have been updated to include both upper and lower limits.

During the monograph updating process viscosity specifications were eliminated for several small molecule-based excipients. One of the examples is the viscosity specification for the Ethyl Oleate NF monograph (19), which was deleted in the First Supplement to USP 39–NF 34. USP believed that the introduction of identification tests and a definitive composition specification in the revised Ethyl Oleate NF monograph obviated the need for a viscosity specification.

The absence of viscosity specifications in a polymeric excipient monograph is potentially problematic. Guar Gum NF is a case in point. Acartürk and Celkan (20) evaluated the rheological behavior of 12 different multi-sourced guar gum samples intended for use in the preparation of prolonged release or colon-specific dosage forms. Their data-shown in two composite graphs (Figure 1 and 2)-clearly show substantial non-Newtonian behavior, in most instances, of 1% guar gum solutions prepared from the various samples. Furthermore, the composite figures clearly demonstrate the marked rheological variability among the samples. As the Guar Gum NF monograph has no viscosity specification at present, further research is warranted in order to provide meaningful standards that facilitate product development.

Alternative methods to assess average molecular weights and/or molecular weight distribution

Rheological characterization of polymeric excipients is a fundamental issue that USP continues to address in monograph refinement and development. Nonetheless, USP recognizes the deficiency of pharmacopeial viscosity specifications for polymeric excipients, which generally do not enable the characterization of variations in the molecular weight distribution and/or chemical composition of the polymer. The logical refinement of viscosity specifications for excipients has led USP, more recently, to work with stakeholders to better characterize polymeric excipients by introducing molecular weight limits as well as average molecular weight/molecular weight distribution specifications into the following monographs:

1. Polydextrose NF (21)
2. Hydrogenated Polydextrose NF (22)
3. Polyvinyl Acetate NF (23)
4. Chitosan NF (24)
5. Polyethylene Glycol 3350 USP (25).
    

The molecular weight limit/molecular weight distribution procedures used in these five monographs are based on gel-permeation chromatography (GPC) or size-exclusion chromatography (SEC) with either refractive index detection or viscometric detection, which are classified as secondary methods. The chemical compositions of these five polymeric excipients have also been studied, and the compendial methods in their monographs are based on SEC and/or nuclear magnetic resonance (NMR) spectroscopy.

In general, polymers consist of repeated units (monomers) in long chains of varying length and degree of branching. Usually, a polymer is not homogenous in molecular weight, but may span a broad range. Polydispersity is a measure of the distribution of molecular weight (or mass) in a given polymer sample, and can be calculated as a ratio of weight-average molecular weight and number-average molecular weight. Knowledge of the molecular weight distribution (polydispersity) of a polymer is vital for even a preliminary understanding of the relationship between structure and properties.

To determine average molecular weight and molecular weight distribution, there are two different approaches: absolute and secondary methods (26). Absolute methods such as SEC with multi angle laser light scattering detection give values that provide a direct estimate of the molecular weight. Secondary methods generate comparisons between the molecular weights of different polymers, and must be calibrated by reference to a system that has been studied by one of the absolute approaches. For the secondary methods, intrinsic viscosity and GPC or SEC are considered the faster and more routinely performed molecular weight determination methods.

In the Microcrystalline Cellulose NF, Powdered Cellulose NF, and Silicified Microcrystalline Cellulose NF monographs (13), the specification for degree of polymerization is used as one of the Identification tests. The degree of polymerization is based on measurement of intrinsic viscosity and calculation from an established relationship between degree of polymerization and intrinsic viscosity for those polysaccharides. This measurement is not an absolute method, and its use requires a prior determination of empirical relationships that relate the molecular weight or degree of polymerization to the viscosity of a polymer solution.

Weight-average molecular weights (Mw) and number-average molecular weights (Mn) for six grades of sodium alginate (pharmaceutical-grade materials) were reported based on measurements of intrinsic viscosities in aqueous solutions and calculations using the Mark-Houwink equation with the constants from the literature (27). Those grades were characterized by the manufacturer as having the same range of solution viscosities (27), but the researchers observed differences in intrinsic viscosities and in the corresponding Mw and Mn values for several grades of sodium alginate. 

It is not possible to establish unequivocally the precise molecular weight of a given polymer by means of the Mark-Houwink equation parameters cited in the literature and the intrinsic viscosity values determined experimentally in a single laboratory. Molecular weights calculated from intrinsic viscosity data, however, should be suitable for rank-order characterization, which is independent of test conditions (instrument, sample concentration, and test temperature).

SEC or GPC separates molecules of different sizes depending on the extent of their distribution into porous particles comprising the column packing. This technique is generally used to separate macromolecules such as biological molecules and synthetic polymers, and to determine their molecular weights and molecular weight distributions.

Conclusion and recommendations

Modernization of the viscosity general chapters has advanced monograph development, especially for polymeric excipients. The USP EXC EC and General Chapters-Physical Analysis Expert Committee (GC-PA EC) continue to appropriately apply those chapters to individual monographs. A few of the recommendations from the Expert Committees are provided as follows:

1. Retain viscosity tests for grade differentiation (especially polymeric or macromolecular excipients). 
2. Ensure that the viscosity tests are conducted using suitable viscometers or rheometers by following the guidelines provided in the newly developed and updated general chapters:
3. <1911> “Rheometry”
4. <911> “Viscosity−Capillary Methods”
5. <912> “Viscosity−Rotational Methods”
6. <913> “Viscosity−Rolling Ball Method”
7. <914> “Viscosity‒Pressure Driven Methods”.
8. Develop appropriate viscosity specification ranges and labeling requirements for polymeric excipient monographs.
9. As recommended by the International Conference on Harmonization, recognize the importance of molecular weight distribution, which facilitates quality by design. The EXC EC is developing a general test chapter with the expected title “Average Molecular Weight and Molecular Weight Distribution for Polysaccharides” that will be applicable to macromolecular excipients.

Authors’ note

Certain commercial equipment, instruments, vendors, or materials may be identified in this article to specify adequately the experimental procedure.  Such identification does not imply approval, endorsement, or certification by USP of a particular brand or product, nor does it imply that the equipment, instrument, vendor, or material is necessarily the best available for the purpose or that any other brand or product was judged to be unsatisfactory or inadequate.

Acknowledgments

The authors would like to thank USP summer intern Li Chen, MS (doctoral student in pharmaceutical science, Auburn University, AL) for her contributions to work currently in progress on the development of harmonized monograph procedures for the viscosity determination project.

References

1. USP, <911> “Newtonian Viscosity”, Pharmacopeial Forum 34 (6),1536-1541 (2008)
2. USP, <912> “Non-Newtonian Rheology”, Pharmacopeial Forum 34 (6),1541-1549 (2008)
3. USP, USP 35–NF 30 through First Supplement (US Pharmacopeial Convention, Rockville, MD, 2012).
4. USP, <911>“Viscosity-Capillary Viscometer Methods”, Pharmacopeial Forum 37 (4) (2011).
5. USP, <912> “Rotational Rheometer Methods”, Pharmacopeial Forum 37 (4) (2011).
6. USP, <1911> “Rheometry”, Pharmacopeial Forum 38 (6) (2012).
7. USP, <913> “Rolling Ball Viscometer Method”, Pharmacopeial Forum 37 (5) (2011).
8. Second Supplement to USP 35–NF 30 (US Pharmacopeial Convention, Rockville, MD, 2012).
9. USP, <911> “Viscosity-Capillary Methods”, Pharmacopeial Forum 39 (5) (2013).
10. USP, <912> “Viscosity-Rotational Methods”, Pharmacopeial Forum 39 (6) (2013).
11. USP, <913> “Viscosity-Rolling Ball Method”, Pharmacopeial Forum, 39 (6) (2013).
12. USP, <914> “Viscosity-Pressure Driven Method”, Pharmacopeial Forum, 40 (6) (2014).
13. USP, USP 39–NF 34 through Second Supplement (US Pharmacopeial Convention, Rockville, MD, 2016).
14. Hydroxypropyl cellulose products, www.ashland.com/file_source/Ashland/Product/Documents/Pharmaceutical/PC_11229_Klucel_HPC.pdf, accessed January 31, 2017
15. Food Chemicals Codex (US Pharmacopeial Convention, Rockville, MD, 9th ed., 2016).
16. Polyvinyl alcohol products, www.sigmaaldrich.com/catalog/search?interface=All&term=Poly(vinyl%20alcohol)&N=0&focus=product&lang=en&region=US#, accessed January 31, 2017.
17. USP, Polyethylene Oxide, Pharmacopeial Forum 36 (1), 191-193.
18. A. Thacker, et al., AAPS PharmSciTech. 11 (4), 1619-1626 (2010).
19. USP, Ethyl Oleate, Pharmacopeial Forum 41 (1) (2015).
20. F. Acartürk et al., Pharm. Dev. Technol. 14 (3), 271-277 (2009)
21. USP, Polydextrose, Pharmacopeial Forum 32 (4), 1155-1160 and 35 (5), 1206-1209 (2009).
22. USP, Hydrogenated Polydextrose, Pharmacopeial Forum 35 (5), 1210-1212 (2009)
23. USP, Polyvinyl Acetate, Pharmacopeial Forum 34 (6), 1526-1530 (2008).
24. USP, Chitosan, Pharmacopeial Forum 35 (1), 115-121 (2009)
25. USP, Polyethylene Glycol 3350, Pharmacopeial Forum 39 (6) (2013) and 41 (4) (2015)
26. H.R. Allcock et al., Contemporary Polymer Chemistry (Prentice-Hall, Upper Saddle River, NJ, 2nd ed., 1990).
27. S. Fu, et al. AAPS PharmSciTech. 11 (4), 1662-1673 (2010).

Article Details

Pharmaceutical Technology
Supplement: Solid Dosage Drug Development and Manufacturing
Vol. 41
April 2017
Pages: s33-s44

Citation

When referring to this article, please cite it as H. Wang, L. Block, and C. Sheehan, "Characterization of Polymeric Excipients," Pharmaceutical Technology Solid Dosage Drug Development and Manufacturing Supplement (April 2017).