Controlling the physical properties and performance of semi-solid formulations through excipient selection Frank Romanski, Anna V. Vladimirova, Candice Merritt, Norman Richardson and Nigel LangleyBASF Corporation, 500 White Plains Road, Tarrytown, NY 10591 frank.romanski@basf.com, anna.v.vladimirova@basf.com, norman.richardson@basf.com, nigel.langley@basf.com

IntroductionWhen developing an innovative or generic topical semi-solid product, it is standard industrial practice to identify the target performance criteria, with the ultimate objective being that it is therapeutically efficacious. The product design plan should describe what this product should accomplish and its associated attributes. These can be listed as design criteria. Some important criteria are viscosity or consistency, sensory properties, safe/non-toxic, shelf life stability, API concentration, the state of the API, API release from the formulation, and API absorption into the target compartment(s) (e.g. stratum corneum, epidermis, dermis, sebaceous glands, hair follicles, circulatory system, etc.), and all of these criteria are ultimately determined or driven by formulation inputs. [1]

In heterogeneous, semi-solid systems the performance is determined by several factors, including the list of excipients and API (Qualitative or Q1), the amount of each excipient and API (Quantitative or Q2), as well as the manufacturing process factors (e.g. temperature, temperature ramp rates, orders of addition, shear rate, etc.), packaging conditions, shelf storage time, the choice of excipients, the grade of the excipient, and the purity can all influence the final product. All of these factors (Q1 + Q2 + Processing) put together result in a final complex of microstructures, phases, and liquid and crystalline states (Q3) that influence the final product performance. These solid states, microstructures and phases need also to be reproducible in order to create a product with predictable bioavailability. Therefore, it is how all of these ingredients interact and the phases that they form that drives the performance criteria. The structures that form will affect the viscosity, stability, and sensory, as well as API solubilization, the API release, and the API absorption.

In this work, a simple semi-solid formulation consisting of two polyethylene glycols (PEGs) along with one solvent, and one API (mupirocin) was used as a model system to evaluate the effect of excipient type, properties and concentration has on the measurable microstructure and select performance criteria.

Objectives ■ To utilize a simple, three component topical ointment as a representative system for the

exploration of microstructure

■ Determine the effect of molecular weight, blend, and API on the resulting properties of a PEG-based ointment, including long term stability and syneresis

■ Establish the effects of solubilizers on the appearance, stability and drug delivery of mupirocin, as a representative API

Materials ■ All ingredients are listed in Table 1 and used as received

Trade Name (Supplier) Compendial Name Broad Classification

Pluriol® E 400 (BASF Corp.) Polyethylene Glycol (PEG), Macrogol, USP/NFSolubilizer

Pluriol® E 1450 (BASF Corp.) Polyethylene Glycol (PEG), Macrogol, USP/NFConsistency factor

Pluriol® E 6000 (BASF Corp.) Polyethylene Glycol (PEG), Macrogol, USP/NFConsistency factor

Pluriol® E 8000 (BASF Corp.) Polyethylene Glycol (PEG), Macrogol, USP/NFConsistency factor

Kollisolv® PG (BASF Corp.) Propylene Glycol, USP/NF, Ph. Eur., JP, FCC Solubilizer

Kolliphor® P 124 (BASF Corp.) Poloxamer 124, USP/NF, Ph. Eur., JPE Solubilizer

Kollisolv® GTA (BASF Corp.) Triacetin, USP/NF, Ph. Eur. Solubilizer

Mupirocin (Fischer Scientific) Mupirocin, USP API

Table 1. Trade and Compendial Names of excipients tested in this study including the broad classification used for comparative purposes

MethodsPEG-ointments were prepared by the mixture of 5 to 40 wt.% high molecular weight PEG (Pluriol® E 1450, Pluriol® E 3350, Pluriol® E 6000, and Pluriol® E 8000) with 30 to 65 wt.% low molecular weight PEG (Pluriol® E 400) and balanced with solvents propylene glycol (Kollisolv® PG), poloxamer 124 (Kolliphor® P 124), or triacetin (Kollisolv® GTA). Mixtures were heated to 75ºC, mixed and cooled under shear until a semi-solid is formed. Resulting ointments were tested using differential scanning calorimetry (from -50ºC and 100 ºC), x-ray diffraction, and polarized light microscopy. Rheology (Shear-sweep) on the ointments was completed using a TA-1 explorer rheometer. Mupirocin drug release was determined using Franz-diffusion cells (Logan FDC-6T) on a synthetic membrane (Strat-M®) and quantified using liquid chromatography for mupirocin penetration.

Results and DiscussionThe first, initial study looked at the differences between utilizing different molecular weights of solid polyethylene glycol (PEG), specifically Pluriol® E 1450, 3350, 6000 and 8000 at 30% by weight, balanced by 40% w/w liquid Pluriol® E 400 and 30% w/w Kollisolv® PG. Polarized like microscopy images are shown below in Figure 1.

Figure 1. Variations of the Solid (PEG) Phase – Visual Representation of Microstructure by varying PEG Mol. Wt. of the solid PEG phase

The images shown here were evaluated under cross-polar microscopy. It is clear that ointments produced using the 1450 weight PEG (Pluriol® E 1450) exhibited less birefringence, which is a general indicator of less overall crystallinity. In addition, small regions of interstitial liquid appear to be present. The three other ointments with increasing molecular weights of PEG exhibit higher levels of birefringence. To determine and quantify the effect of the molecular weight of the solid PEG phase, rheological studies were performed and are shown in Figure 2.

Vis

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ty (P

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1.0E-02 1.0E-01 1.0E+00 1.0E+01 1.0E+02 1.0E+03

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ess

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Pulriol E 3350 Pluriol E 1450 Pluriol E 6000 Pluriol E 8000

Figure 2. Variations of the Solid (PEG) Phase – Rheological Comparison of Ointments with varied solid PEGs

On the left hand side, it is clear that all of the ointments exhibited similar shear thinning behavior patterns, with a significant decline in viscosity as a function of shear rate. However, it is noted that while the Pluriol® E 3350, 6000 and 8000 showed nearly identical results, the overall viscosity and zero-shear viscosity of the Pluriol® E 1450 was significantly decreased. Moreover, it is shown on the right-hand portion of the plots that the shear stress, as a function of shear rate stayed relatively constant for the higher molecular weight PEGs, but exhibited an increasing trend for the Pluriol® E 1450, and one more expected by a dispersion; this indicates that the Pluriol® E 1450 ointments exhibit significantly different microstructure than the other three.

Next, the concentration of solid PEG was varied in order to elucidate the structure of the PEG-ointments. It was apparent that at solid concentrations of less than 25 wt.% result in phase separation and ultimately poor stability. This is caused by the presence of too much liquid-phase to be adequately adsorbed by the solid precipitated phase, which ultimately results in syneresis or “weeping”, commonly found as a stability failure for these types of ointments. These results are shown in Figure 3.

Figure 3. Variations of the Solid (PEG) Phase – PEG 400 and PEG 3350 ratio has an effect on microstructure (100x optical microscopy)

These formulations were also evaluated using a rheometer. As previously shown, there is a correlation between the solids content and overall crystallinity with the viscosity of the formulation. The results are shown in Figure 4.

Vis

cosi

ty (P

a s)

1.0E-01

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1.0E-02 1.0E-01 1.0E+00 1.0E+01 1.0E+02 1.0E+03

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1.0E-02 1.0E-01 1.0E+00 1.0E+01 1.0E+02 1.0E+03

40% 35% 30% 25% 20% 15% 10% 5%

Figure 4. Variations of the Solid (PEG) Phase – PEG 400 and PEG 3350 ratio has an impact on performance attributes (rheology)

Here it was found that there is a greater degree of separation between shear rate dependent viscosity for ointments with low amounts of solid PEG (<25 % w/w), while at the upper end the behavior was very similar. In addition, dispersion like behavior was also evident in the lower solid concentration PEGs, which could also be a future indicator of stability failure (syneresis).

This was corroborated further by Differential Scanning Calorimetry (DSC) data which indicates multiple phases present in the ointments and a distinct difference in the structure of the ointments at lower solids concentration. The data are shown in Figure 5.

Figure 5. Variations of the Solid (PEG) Phase – PEG 400 and PEG 3350 ratio has an impact on stability visible through differential scanning calorimetry (DSC)

Specifically, DSC peaks were found during the ramp up indicated a single suppressed melting point of the low molecular weight PEG and solvent near -10ºC, while a twin peak near the solid PEG (40ºC and 45ºC) indicated a mixed phase of PEGs together with the bulk melting of the solid PEG. The twin peaks shifted proportionally with solid PEG concentration until a single structure was evident at low concentrations. Upon cooling, ointments with lower (<25%) solid concentration clearly reorganized into a different structural arrangement, which lends evidence to the poor stability of the ointments and observed syneresis.

The XRD data confirmed a large quantity of amorphous semisolid material within each ointment complete with some crystalline solid PEG; this data is shown in Figure 6.

Figure 6. Variations of the Solid (PEG) Phase – concentration and molecular weight has impact on microstructure visible through x-ray diffraction (XRD)

Crystalline PEG was always present regardless of concentration or molecular weight, while the amount varied by concentration proportionally. Also evident is a large concentration of overall amorphous structure, which is not surprising for these ointment systems. Sharper peaks are shown for ointments containing PEG 3350 at solid ratios deemed high enough to ward off future stability issues and syneresis. In addition, several peaks are not present in the PEG 1450-based ointment, representing a lower ordered crystalline system. It should be noted that all ointments (not shown) all exhibited crystallinity down to the lowest solids concentration, and therefore the solid dispersed phase PEG is never fully dissolved within the liquid, continuous phase of the semi-solid system.

Finally, PEG ointments offer a unique anhydrous opportunity to utilize various solvents to solubilize an API and thus alter the drug delivery while maintaining a similar framework of the ointment. In order to do this, ointments were prepared using 30% w/w Kollisolv® PG (as before), Kollisolv® P 124, a poloxamer solvent/solubilizer liquid at room temperature, and Kollisolv® GTA, triacetin, a versatile pharmaceutical solvent/solubilizer. Each ointment also contained 2% mupirocin, as a common topical antibacterial API.

Figure 7. Variations of the Solvent Phase – Addition of miscible excipients affects the solubilization of APIs and ultimately the penetration rate

Each ointment was viewed at multiple magnifications for polarized light microscopy, and also evaluated qualitatively for sensory attributes. Kollisolv® PG-based ointments have the look, touch and feel of a traditional PEG ointment. The Kollisolv® P-124 significantly altered the solubility of the drug and exhibited a more opaque appearance with also tendency to be stickier. Finally, the Kollisolv® GTA based ointment had the best absorption when applied to the skin, and an overall lighter feel. Differences in crystallinity are noted in the displayed images. Clearly more crystalline material is evident in the Kollisolv® GTA-based ointments, while considerably less crystallinity is visible in the Kollisolv® P 124-based ointments.

Finally, each was characterized for drug delivery through a synthetic membrane (Strat-M®). Mupirocin permeation was evaluated by HPLC for each of these three solvent systems, the results shown in Figure 8.

Mup

iro

cin

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ease

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/cm

0.00E+00

1.50E+01

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Minutes

0 30 60 90 120

PG Poloxamer 124 Triacetin

120 minutes; 32ºC, 20% hydroalcoholic phosphate buffer, 6.8 pH, n=12

Mupirocin - PEG Ointment - Comparison

Figure 8. Variations of the Liquid Solvent Phase – Kollisolv® P124, PG and GTA have a marked difference in mupirocin penetration over two hours on a Strat-M® membrane (n=12, USP conditions)

A nominal release of mupiricon was noted for the Kollisolv® PG based ointment over two hours of cumulative release. The ointment containing Kollisolv® GTA, or triacetin showed a significant decrease in penetration; this in combination with the previously shown polarized light microscopy images indicates that the mupirocin was more crystalline, and therefore less was in solution and available for transport resulting in a low concentration gradient for diffusion. On the other hand, the Kollisolv® P124 based system, or Poloxamer 124, the penetration was significantly higher than the standard ointment; this in combination with less observed crystallinity in the polarized light microscopy images indicates that more was dissolved giving a greater concentration gradient and thus better penetration. It should be noted that the high levels of error in the ointments is expected for very high viscosity, low API concentration systems and the results were performed twice to confirm for a total of n=12.

SummaryIt was found that even a simple semi-solid model system with three primary excipients and one API still experienced significant changes to the microstructure, as well as the drug release as a result of excipient selection by type and concentration. This confirms the importance of microstructural evaluation for pharmaceutical semi-solids, both for a macroscopic and bulk property measurement, but also from a performance and in vitro release standpoint; both ultimately important for the filing of a pharmaceutical product.

Conclusions ■ A simple, three-component semi-solid formulation still exhibited significant

differences in microstructure related to both the physical properties of the ointment as well as the release properties

■ It was found that significant differences were found in microstructure related to the molecular weight of the solid PEG phase, where specifically Pluriol® E 1450 had significantly reduced viscosity and stability and would require higher use amounts

■ It was found that for Pluriol® E 3350, concentrations higher than 25% w/w would be required to ensure stability of the ointments and minimize risk of syneresis

■ It was found that crystallinity is always present in the ointments through XRD, however, DSC indicated upon cooling a rearrangement of matter if the ointment had potential to be unstable

■ Kollisolv® P124 resulted in higher dissolution of the active mupirocin and ultimately better penetration, while the opposite was found for Kollisolv® GTA

References

1 “Controlling the Physical Properties and Performance of Semi-solid Formulations through Excipient Selection”, N. Richardson, PharmaTech Whitepaper, 2015

AAPS Annual Meeting 2015, Orlando, FL – October 25 2015

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