Enhancing the Solubility of Active Pharmaceutical Ingredients Using Hot Melt Extrusion and Polyvinyl Alcohol

Figure 7. A wide range of polymer extrudates can be processed into various dosage forms.

Solubility of the active pharmaceutical ingredient (API) in an oral formulation is critical for absorption from the gastrointestinal (GI) tract and the intended therapeutic effect. Ensuring that an API has the necessary solubility can be challenging for drug developers and formulators. If limitations in solubility cannot be successfully addressed, a new chemical entity (NCE) is unlikely to advance in the development pipeline. Addressing this potential roadblock to clinical success is becoming increasingly important as NCEs continue to become larger and more lipophilic and, as a result, less soluble.1

Figure 1. Current distribution of marketed drug substances (A) and drug substances in the pipeline (B) classified in the different BCS classes.

The importance of solubility is reflected in the biopharmaceutics classification system (BCS).1 The BCS correlates in vitro solubility and permeability with the potential in vivo performance of drug molecules and categorizes them in four classes. BCS Class I, for example, includes molecules that have both high solubility and permeability and are expected to have good absorption in the GI tract. BCS Class II compounds have low solubility and high permeability, while BCS Class III molecules have high solubility and low permeability. The most challenging class of molecules are those categorized as BCS Class IV which have both low solubility and permeability. The BCS was originally used by the US Food and Drug Administration (FDA) as a regulatory tool for the basis for biowaiver applications for immediate release formulations to reduce the need for additional in vivo studies for bioavailability and bioequivalence.2

As shown in Figure 1, approximately 70–90% of pipeline candidates/NCEs and about 40% of marketed APIs have solubility issues.3

Expanding upon the BCS, the developability classification system (DCS) introduced key modifications to improve applicability to formulation development.4 The system helps formulators address poorly soluble APIs by identifying root causes and providing guidance on solubility enhancing techniques such as the use of excipients. Dissolution rate can be enhanced by the use of an excipient, while solubility can be enhanced via solid-state modification.

As part of the DCS, BCS Class II molecules were divided into two sub-categories: DCS Class IIa and DCS Class IIb. DCS Class IIa molecules are dissolution-limited while DCS Class IIb molecules have such low solubility that no matter how quickly the drug gets into solution, there will not be a measurable impact on absorption.

For a detailed exploration of the DCS and recommendations for addressing dissolution limited DCS IIa molecules, please refer to our white papers entitled The Developability Classification System (DCS): Enabling an Optimized Approach for Formulation of Poorly Soluble Molecules5 and Poloxamer: A Simple and Powerful Solution for Accelerating Dissolution.6

This white paper describes how hot melt extrusion (HME) and a specially-engineered grade of polyvinyl alcohol (Parteck® MXP polyvinyl alcohol 3-82 Emprove® Essential Ph Eur; referred to in this publication as Parteck® MXP 3-82 PVA by Merck) can be used to increase the solubility of DCS IIb molecules.

Use of Polyvinyl Alcohol in HME for Stability and to Inhibit Precipitation

HME has a broad set of applications, including modification of the physical state of APIs with the aim of enhancing solubility. In HME processes, the API is mixed with a matrix polymer, converting the poorly soluble crystalline form of the drug into a more soluble amorphous solid dispersion (ASD; Figure 2). During this process, it is essential that the components are mixed under elevated temperature which induces melting and mixing at a molecular level. HME stabilizes the API in the amorphous form and allows a supersaturated state of the API in solution by inhibiting precipitation which could otherwise interfere with dissolution and efficacy of the drug.

Figure 2. Simplified schematic of the HME process, visualizing the transition of API and matrix polymer from feeder to extruder die.

Selection of the matrix polymer for use in HME is driven by the intended release profile, thermal characteristics of the API and polymer (e.g., melting point/ glass transition temperature), and whether it is suitable to stabilize the API in the ASD and in solution. In addition to increasing the solubility of APIs, HME offers a number of other benefits. HME is suitable for continuous manufacturing and is solvent-free, which contributes to sustainability goals of the manufacturer
and is safer for employees to handle.

When using HME, the suitability of the API and the specific type of matrix polymer must be determined. Key considerations regarding the polymer include degradation temperature, thermoplasticity, and solubilization capacity of the polymer with respect to the API to ensure high drug loadings. Various polymers can be used in HME processes, including polyvinyl alcohol (PVA), cellulose derivatives, polyacrylates and polymethacrylates, polyethylene glycols, and polyvinyl pyrrolidone.7

PVA is ideal for use as the polymer in HME due to its ability to enhance solubility, stabilize amorphous APIs, and inhibit precipitation (Figure 3). PVA is well-known and frequently used in oral solid dosage forms in the pharmaceutical industry and categorized as Generally Recognized as Safe (GRAS) by the FDA. Read more about PVA in our white paper entitled Polyvinyl Alcohol: Revival of a Long-Lost Polymer.8

Figure 3. Structure of a partially hydrolyzed polyvinyl alcohol.

PVA is a thermostable polymer available in different grades, suitable for a variety of applications and follows a common naming convention. Parteck® MXP 3-82 PVA was developed specifically to address challenges in HME with its properties tailored to yield the desired performance and the name reflecting its viscosity and degree of hydrolysis:

The first number (in this case, 3) specifies the apparent viscosity in mPa·s of a 4% aqueous solution at 20 °C which is also linked to the relative molecular weight of the polymer chain. PVA with a relatively low molecular weight is essential for HME as it will also provide a low melt viscosity during processing.
The second number (in this case, 82) is the hydrolysis grade which refers to the percentage of acetate groups on the PVA backbone that are hydrolyzed (i.e., have a hydroxyl group) rather than hydrophobic regions (i.e., having an acetate group). This number reflects the ability of the polymer to interact with and stabilize the API and inhibits precipitation.

Parteck® MXP 3-82 PVA has a relatively low viscosity and low molecular weight and its PVA backbone contains 82% hydroxyl groups and 18% acetate groups. This amphiphilic molecular design allows it to form strong interactions with hydrophobic drug molecules, both in solid state and in solution.

These interactions improve stabilization and precipitation inhibition of ASDs, and maintain supersaturation throughout physiologically relevant timescales, even for the most challenging DCS Class IIb APIs.

Parteck® MXP 4-88 PVA contains 88% hydroxyl groups and 12% acetate groups. This higher hydrolysis grade makes it more hydrophilic and highly suitable for amorphous stabilization of certain challenging molecules. Due to its uniquely high thermal application range, Parteck® MXP 4-88 excipient can be used for solubility enhancement across a very broad melting temperature range, including APIs with very high melting points that are typically considered as unsuitable for HME.9

Additional Benefits of Parteck® MXP 3-82 PVA in HME

With an optimized chemical structure, Parteck® MXP 3-82 PVA has an advanced broad processing window supporting HME from 130 °C to 210 °C without chemical degradation of the polymer (Figure 4). Even when heated to the temperatures in this range, the polymer retains good viscosity and performance. The purple line in Figure 4 represents the melt viscosity of the polymer as it goes through the extrusion process while the dotted pink line is the threshold at which the process is able to proceed; a viscosity above the pink line will prove difficult for the HME process. Only when temperatures go above 210 °C does the desirable elastic behavior of the polymer change and become more viscous.

Figure 4. The thermal behavior of Parteck® MXP 3-82 PVA ensures a broad processing range during the HME process.

ThermoFisher Scientific Haake Mars Rheo60; temperature ramp from 170 °C to 230 °C ΔT/t = 2°/min, oscillating shear stress, CD, ɣ₀ = 0.1%, f = 1.0 Hz, gap = 1.00 mm, Measuring geometry = D P25/Al + adapter Px.

The elasticity of the polymer is represented by the storage modulus G’ and the plastic behavior is represented by the loss module G’’. Both parameters are related by tan delta. Overall, a viscoelastic melt behavior was observed for the polymer in the molten state with G’’ slightly above G’. A crossover point is observed at about 215 °C indicating changes in the melt. The pseudoplastic melt behavior of the melt provides a shear thinning effect allowing an effective down-streaming also in tiny nozzle geometries therefore expanding the downstream flexibility for creation of final dosage forms.

Figure 5 shows the melt behavior of Parteck® MXP 3-82 PVA and its effect on processability. Data confirm that process relevant parameters remain steady and within desirable ranges with use of Parteck® MXP 3-82 PVA. Consistency across these parameters provides a broad application range and ensures an efficient process and final product uniformity. There are relatively few variations in melt temperature which is indicative of a consistent and stable melting process, and torque remains relatively low indicating the equipment is not straining.

Feeder and extruder speed are constant throughout the duration of the HME process, as well as the pressure at which the material comes out of the extruder. If the pressure is too high, material must be forced through the die; if the pressure is too low, material is leaking out like a liquid.

Figure 5. Process conditions of Parteck® MXP 3-82 PVA throughout an exemplary HME process.

Most polymers, including PVA, are hygroscopic, changing mass upon exposure to water vapor. Because
Parteck® MXP 3-82 PVA shows a low hysteresis between absorption and desorption, concerns related
to hygroscopicity are reduced. The dynamic vapor absorption results (Figure 6) show that the absorption
and desorption curves practically overlap. This indicates that the uptake of water, due to increasing humidity,
is reversible and does not affect the internal structure of the substance which would have a significant and
unforeseeable impact on the performance in process and final formulation.

See the full white paper on “Enhancing the Solubility of Active Pharmaceutical Ingredients” here

(click the picture to download the white paper)

Source: Merck white paper “Enhancing the Solubility of Active Pharmaceutical Ingredients”