(T1430-11-65) Unraveling the Impact of Polymeric Material Attributes in Semisolid Products: Paving the Way for Consistent Viscosity Profile Across Commercial Batches

Purpose: Semisolid dosage forms are one of the most complex drug delivery systems intended for topical applications. They contain one or more active ingredients dissolved or dispersed uniformly in the product. Viscosity modifiers are polymers used as formulation ingredients that hydrate upon interaction with solvents and impart an increase in viscosity. There are various polymers available that cater to different viscosity requirements. However, it is often difficult to choose the right grade of the polymer for the formulation and to identify the correct amount of the polymer that will produce a consistent viscosity throughout commercial batches of drug product. Most of the viscosifying polymers are hygroscopic in nature, resulting in viscosity variation of the product. In current study, our strategy is to manufacture lab scale batches with various polymers, with and without molecular weight and moisture content adjustments to achieve consistent viscosity profile, irrespective of the differences in the polymer. We hypothesize that consistent viscosity profile can be achieved with these adjustments.

Methods: Commonly used viscosifying polymers such as Carbomer, Hydroxypropyl cellulose (Klucel) and Hydroxyethyl cellulose (Natrosol) were selected for evaluation of viscosity profile. Polymeric functional group, polymer chain length and hygroscopicity are some of the Polymer Material Attributes responsible for affecting viscosity. In Carbomers, carboxylic acid functional group and hygroscopicity were identified as Polymeric Material Attributes. Carboxylic acid group contributes to increase in viscosity by unfolding the polymeric chains and forming gel matrix with an increase in pH due to deprotonation and electrostatic repulsion [1]. Typical carboxylic acid content is 56.0 – 68.0% in Carbopol 980 polymer. Three lab batches of Carbopol 980 were manufactured with different carboxylic acid content (59.0%, 60.7% and 63.0%). The carboxylic acid and moisture content calculations were performed for Carbopol 980 polymer as shown in Figure 2 [2,3]. Additionally, three more batches were manufactured without any adjustments for comparison. These batches were manufactured by taking the required quantity of purified water, Carbopol 980 was added to it under mixing and was allowed to hydrate for 1 hour, followed by neutralization using 10% NaOH solution to pH 5.5 – 6.0. Transparent gel was obtained, and viscosity was measured (Figure 1). For Hydroxypropyl cellulose, different grades such as Klucel MF, Klucel GF and Klucel LF were selected. For Hydroxyethyl cellulose, different grades such as Natrosol 250 HHX, Natrosol 250 HX and Natrosol 250 M Pharm were selected. Polymer chain length is directly proportional to its molecular weight. Thus, molecular weight and hygroscopicity are considered as Polymeric Material Attributes for cellulosic polymers. Factor calculations were done for Klucel and Natrosol grades based on molecular weight as shown in Figure 2 [2,3]. Moisture content calculations were also performed on these Klucel and Natrosol batches. Additionally, three more batches were manufactured without any adjustments for comparison of Klucel and Natrosol grades, respectively. The formulation composition of all the batches is shown in Figure 3. These batches were manufactured by taking required quantity of purified water, the polymer was added to it under mixing and was allowed to hydrate for 1 hour. Transparent gel was obtained, and viscosity was measured (Figure 1).

Results: Viscosity was measured using Brookfield RVDV-II+ Viscometer. The viscosity of batches containing Carbopol 980 manufactured with and without adjustments, measured using T-D (94) spindle at 50 RPM for 1 min, ranged from 18000 cP to 19760 cP, and from 17280 cP to 20000 cP, respectively. The viscosity for batches containing Klucel MF manufactured with and without adjustments measured using SC4-27 spindle at 7 RPM for 2 min were 12860 cP and 12460 cP. Similarly, for batches containing Klucel GF, the viscosities were 5321 cP and 214.3 cP and for batches containing Klucel LF, the viscosities were 13320 cP and 0 cP. The viscosity for batches containing Natrosol 250HHX manufactured with and without adjustments measured using SC4-21 spindle at 0.2 RPM for 7 min were 197500 cP and 189300 cP. Likewise, for batches containing Natrosol 250HX, the viscosities were 191800 cP and 58250 cP and for batches containing Natrosol 250 M Pharm, the viscosities were 72300 cP and 4000 cP.

Conclusion: Based on the results from the experimental batches, it is understood that calculations for polymeric functional group, molecular weight, and moisture content should be considered to produce consistent viscosity results. Therefore, it can be concluded that narrow and consistent viscosity profile can be achieved throughout the commercial batches using these calculations.

References: [1] Dispersing carbomers, mixing technology matters! Maarten Houlleberghs, et al., DOI: 10.1039/D2RA00176D (Paper) RSC Adv., 2022, 12, 7830-7834
[2] PC 11229 Klucel HPC, Table 2; Published by Ashland
[3] PHA18101 Natrosol 250 HEC Formulating elegant liquid and semisolid drug products, Table 1, published by Ashland


Graphical Viscosity Results


Calculations for Polymeric Material Attributes


Formulation composition for manufactured batches