What’s Old Is New: The Rebirth of Polyvinyl Alcohol for Enhanced Solubility and Sustained Release Formulations

• MilliporeSigma

Introduction

The increasing interest in complex, specialized medicines with specific targets and functionality presents a multitude of considerations to make and hurdles to clear before successfully launching your final drug product. Achieving formulation stability, bioavailability of active pharmaceutical ingredients (APIs), and the desired release kinetics, even in low dosage formulations, are a great challenge that must be overcome for maximal effectiveness.

Innovative excipients and technologies offer possible solutions. However, these can present hurdles of their own. In vitro and in vivo safety assessments, along with in-depth regulatory review, are required for novel excipients. These assessments can lead to extra costs and delays, while complicating the risk profile of bringing the drug to market.

We often think of innovation as the creation of novel materials. However, finding new ways to use tried-and-true materials can be equally innovative - and advantageous. Prior experience saves time and cost in formulation development and manufacturing, while the use of proven, reliable ingredients increases confidence and lowers risk.

In pharmaceuticals, polyvinyl alcohol (PVA or PVOH) is one material that is not new but can be used in novel ways. This synthetic polymer produced by the polymerization of vinyl acetate and partial hydrolysis of the resulting esterified polymer is a widely used excipient that shows great promise for new formulation approaches and solutions to bioavailability, stability, and release challenges.

Finding an approach that increases the API’s solubility is one way to boost a drug’s bioavailability: The use of specific solubility enhancing techniques and excipients can improve absorption of the API into the body, increasing its therapeutic benefits in vivo.

Furthermore, solutions that enable controlled release of APIs can also enhance bioavailability and drug performance. Adapting the release pattern to the therapeutic need facilitates optimization of the dosing regimen for greater convenience, patient adherence, and efficacy-to-safety ratio¹ - all important considerations, especially in long-term therapy.

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This article examines how PVA can help formulators solve solubility and controlled-release challenges while minimizing requirements for in vitro and in vivo safety assessments and in-depth regulatory review. Utilizing PVA, which is generally recognized as safe (GRAS) by the U.S. Food and Drug Administration (FDA),² can prevent the potential unplanned costs, delays, and higher risk of bringing a drug to market with a novel excipient.

Understanding PVA Grades is the First Key to Formulation Success

Nomenclature

The typical, two-figure PVA nomenclature indicates the viscosity of a 4% solution at 20^° C and the degree of hydrolysis of the polymer. For example, PVA 5-88 is a PVA grade with a viscosity of 5 mPa · s that is 88% hydrolyzed. This classification system is used because these two parameters affect polymer performance significantly.

Why hydrolysis (saponification) matters

With increasing hydrolysis, hydrogen bonding between chains also increases. Stronger bonding means more crystallinity, a higher melting temperature, and greater mechanical strength. A lower hydrolysis grade is typically more soluble in water and more compatible with other excipients. Why hydrolysis (saponifi cation) matters With increasing hydrolysis, hydrogen bonding between chains also increases. Stronger bonding means more crystallinity, a higher melting temperature, and greater mechanical strength. A lower hydrolysis grade is typically more soluble in water and more compatible with other excipients.

Why viscosity matters

As PVA polymer chain length rises - and with it, the molecular weight (MW) - the viscosity in solution also increases. All PVAs are water-soluble, but MW has a strong eff ect on solution performance. Rising MW increases the time required for dissolution and decreases the maximum soluble amount.

Global pharmacopoeia requirements vary

The European Pharmacopoeia (Ph. Eur.) and Japanese Pharmaceutical Excipients (JPE) hydrolysis grades are >72.2% or 78–96% and >97%, respectively. However, the U.S. Pharmacopoeia (USP) specifi es a narrower range: 85–89%. Therefore, only PVA grades with hydrolysis of 85–89% conform to all three of these major pharmacopoeias. The specified range for the compendial material allows developers to fine-tune their formulations by selecting the appropriate PVA grade, additional excipients, and formulation conditions for the task at hand.

PVAs Tailored for Sustained Release and Solubility Enhancement Exist

Certain PVA-based excipients have been characterized and introduced into the market specifically for oral sustained release and solubility enhancement via hot melt extrusion. These compendial PVAs surpass the requirements of the above pharmacopoeias by specifying additional parameters relevant for these applications. The following sections present experimental work investigating the performance potential of these materials in sustained release and enhanced-solubility formulations.

PVAs for sustained release formulations

Many approaches for altering the rate of a drug’s release and/or place of liberation are available.³ Delayed, sustained, multiphasic/programmed, site-specific/targeted, and triggered drug release can all be leveraged for significant therapeutic benefits, such as better efficacy, reduced side effects, more convenient dosing, and improved patient adherence.

When deciding on an approach, factors such as API properties, required dose, desired release profile, clinical and market needs, the size of the dosage form, development time, cost, and available equipment all come into play. And while advances have been made in techniques, materials, and rational design of modified release formulations, challenges remain. Finding suitable materials and/or techniques to consistently achieve the desired release profile, prevent dose-dumping, and facilitate the formulation of high-dose and high-solubility compounds is far from straightforward.

Sustained release systems are extremely useful and prevalent in the pharmaceutical market. Monolithic matrix systems - either hydrophilic or hydrophobic - are used extensively for these formulations.

In hydrophilic matrix systems, the API is homogeneously dispersed in a polymer-based matrix. When the polymer contacts the gastrointestinal medium, it hydrates and swells, forming a gel surface layer. The API is released via diffusion through this viscous layer, as well as through slow erosion of the polymer matrix. Hydrophobic matrices, on the other hand, allow the surrounding medium to penetrate. The drug dissolves and diffuses out through pores. This difference in functionality means that while hydrophilic matrices can work with either insoluble or soluble APIs, hydrophobic matrices are limited to soluble APIs.¹

An important benefit of sustained release matrix systems is a reduced risk of dose-dumping compared to single-unit coated formulations in which the only material preventing API release is a surface fi lm coating. Any defect in this coating layer (or division of the tablet) may mean that instead of being released gradually, the API is released all at once, possibly resulting in serious adverse or toxic effects. In monolithic matrix systems, the active ingredient is homogeneously mixed with the release rate-controlling material, so dose-dumping is far less likely.

Since PVA is fully synthetic, its physicochemical and functional characteristics can be tightly controlled, enabling robust and reproducible manufacturing processes, with reliable final product performance. In contrast, natural or semi-synthetic materials such as HMPC are subject to limitations. While formulation with HPMC is cost-effective and straightforward, potentially making it the most commonly used excipient for controlled release matrices, its semi-synthetic nature makes it prone to difficulties such as batch-to-batch variation, which can diminish product performance. ^4-5

PVA’s suitability for sustained release formulations has been confirmed in applications targeted at non-oral administration routes.^6-8 But what about oral routes?

There is a PVA-based excipient specifi cally designed for oral applications and intended to off er easy handling and good reproducibility in terms of sustained API release and direct compression manufacturability. To test these features, we formulated this excipient with 32.0% (w/w) propranolol

HCl as the model API. The formulation and dissolution profi le are shown in Figure 1.

• The formulation demonstrated very good compressibility - up to a hardness of 318 N from 30 kN compression, for a 500 mg tablet. Ejection forces remained constant over virtually the entire test interval (5, 10, 20, and 30 kN) with friability (Ph. Eur./USP test method) of 0.7% at 5 kN and 0.0% at ≥10 kN, suggesting this excipient is wellsuited for high-throughput, direct compression processes.
• In vitro tablets of varying hardness were shown to dissolve consistently, indicating a robust manufacturing process.
• The effect of pH on drug release was shown to be insignificant (Figure 2A).
• In media with up to 40% (v/v) ethanol, no dose-dumping effect was observed (Figure 2B).
• Stability studies in long-term and accelerated conditions, using closed and opened containers, confirmed no change in the drug dissolution profile over 12 months.

PVA is well-suited for use in oral modified release as the dissolution profile is unaffected by pH or alcohol. Overall, the PVA-based excipient tailored for solid oral sustained release formulations was used successfully for that purpose, providing consistent, sustained drug delivery over long release periods. Its very good compressibility makes it ideal for direct compression processes, while stability studies and dissolution testing in media of different pH and ethanol content confirmed the system’s robustness. Constant release behavior over a broad range of compression forces and tablet hardness levels are further evidence of the system’s robustness. PVA is well-suited for use in oral modified release as the dissolution profile is unaffected by pH or alcohol.

PVA for Solubility Enhancement

An API with poor solubility in water is a challenge for drug formulation. One technique that can help is hot melt extrusion (HME). In HME, the API is molecularly dispersed using elevated heat and shear force, forming a solid dispersion of the API in a polymeric matrix.

Considerations for HME include: API and excipient degradation temperatures, thermoplastic suitability of the polymer, and the solubilization capacity of the polymer with respect to the API. Recently, PVA has been highlighted as a polymer well-suited to HME.^9-10

We tested a PVA-based excipient that was developed specifically for HME application, taking into consideration aspects such as flowability, melt viscosity, thermostability, API compatibility, and stability of the extrudate under stress conditions. A selection of low-solubility model APIs with diverse physicochemical properties were extruded with this polymer, and the extrudates were assessed with respect to drug load and solubility enhancement (Table 1).

• Significant increases in API solubility were seen; from two-fold to over 150-fold increases, compared to the solubility of the crystalline drug alone. As for API loading, seven of nine extrudates carried a minimum API load of 30% (w/w), with some holding as much as 55% (w/w) (Table 1). In contrast, many drug products on the market are limited to 10–15% (w/w).
• Dissolution of tablets made with the HME-optimized PVA excipient and itraconazole as the model API demonstrated 20% more dissolved API compared to other marketed polymer extrudates of similar drug load and a marketed, solid dispersion-based product (Figure 3).
• Stability testing was performed: After storage for 12 months, dissolution, differential scanning calorimetry, and high performance liquid chromatography were employed to assess the effect of storage at low temperature and under long-term and accelerated conditions. No recrystallization or degradation of the API was observed.
• The HME-optimized PVA excipient can be formulated into sustained and immediate release formulations, making it a very versatile HME excipient. With itraconazole as a model API, the extrudate was pelletized and then filled into capsules, directly compressed into tablets and directly shaped into tablets.

The capsule’s dissolution profile is immediate release. Compressed tablets formulated using milled extrudate achieved both immediate and sustained release profiles, depending on the overall formulation. The directly shaped tablets demonstrated sustained release kinetics, as shown in Figure 4.

• It was also shown that no significant changes in the release profiles occur (no dose-dumping) with 10–40% ethanol added, an FDA requirement for sustained release formulations.

Conclusion

Polyvinyl alcohol, a multicompendial, pharmaceutical-grade polymer with a low risk profile, has been applied in the pharmaceutical sector for decades in numerous applications.

PVA’s suitability for oral sustained release dosage forms was demonstrated, including benefits such as minimal susceptibility to pH-dependent or alcohol-induced dose-dumping. A thermostable polymer, it was also successfully used in HME to formulate poorly water-soluble APIs into stable amorphous solid dispersions. A solubility enhancement of up to 150-fold compared to the crystalline API and high drug loadings of up to 55% (w/w) were demonstrated.

Because of its fully synthetic nature, PVA is well-suited for quality by design approaches. Synthetic polymers exhibit high batch-to batch consistency, and additional specifications outside of the compendia can be established with the final application in mind.

As a well-known polymer in the pharmaceutical sector, PVA is increasingly gaining momentum in new technologies for drug delivery. Recent publications indicate that PVA is suitable not only for the applications in HME and sustained release discussed above, but also for other technologies emerging in the pharmaceutical sector, such as microneedles for transdermal delivery and 3D printing.^11-14 The example of PVA clearly demonstrates that the exploration of new formulation technologies does not always necessitate the development of a novel polymer, but that it is often worthwhile to first consider the polymers already on the shelves.

Author Biogrphaphies

Dr. Adela Kasselkus is Technical Communication Manager at Merck KGaA, Darmstadt, Germany. She holds a doctorate in pharmaceutical technology from the University of Duesseldorf and has broad experience in solid formulation development with a focus on bioavailability enhancing technologies. In her previous role in technical marketing at Merck KGaA, she was responsible for the development of the product portfolio and supporting customers in questions of application, already with a focus on PVA.

Erica Weiskircher-Hildebrandt is the Associate Director of Business Development for Formulation for MilliporeSigma. She holds a Master of Science degree in biochemistry, microbiology, and molecular biology from Pennsylvania State University. With a career spanning over 10 years in the pharmaceutical industry from R&D to operations to marketing/sales, Weiskircher-Hildebrandt joined the global organization of Merck KGaA, Darmstadt, Germany, in 2015 as a technical product manager. In her current position, she and her team are responsible for technical sales for new innovative products in the Americas.

Dr. Eva Schornick is Global Technical Product Manager of an excipient portfolio for solid dose formulations in the Life Science Business of Merck KGaA, Darmstadt, Germany. She has eight years of experience in the pharmaceutical industry, working in various positions since 2011. She is a pharmacist by education and holds a PhD in pharmaceutical technology.

Dr. Finn Bauer is Director for Solid Formulations R&D at Merck KGaA, Darmstadt, Germany, which recently launched two PVA-based excipients for sustained release and solubility enhancement through hot melt extrusion. A biochemist by education, he holds a doctoral degree from the University of Bayreuth, Germany, and an MBA from Ashridge Executive Education, UK. With broad experience in managing product and application development projects, Bauer has held positions from quality control and project management, to R&D and site manager in the US subsidiary.

Dr. Mengyao Zheng is Technical Product Manager of Solid Excipients for Formulation Franchise (Global Marketing) at Merck KGaA, Darmstadt, Germany. Zheng has six years of experience in the pharmaceutical industry, covering positions from lab head in R&D to technical product manager in marketing, with a focus on formulation technology and innovative excipients. Zheng formerly was the technical lead for launching PVA excipients specifically designed for applications in hot melt extrusion technology.

References

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