Improving API Solubility Using Hot Melt Extrusion Formulation With Polyvinyl Alcohol

Poor solubility of active pharmaceutical ingredients (APIs) is a critical challenge in drug development. There are many avenues to improving API solubility including promoting API dissolution, API processing, and formulation approaches. One formulation technique to increase solubility and, consequently, improve bioavailability of drugs is Hot Melt Extrusion (HME).

WHAT IS HOT MELT EXTRUSION?

During Hot Melt Extrusion, the API is dispersed, often down to the molecular level, into a polymer matrix to form an amorphous solid dispersion (Figure 1). It is a solvent-free process that is applicable to a broad range of poorly soluble APIs, making it suitable for various solid dosage formulations.

Improving API Solubility Using Hot Melt Extrusion Formulation With Polyvinyl Alcohol_Figure 1.The API is melted and mixed with a matrix polymer in the extruder to enable homogeneous dispersion of the API within the polymer. — Figure 1.The API is melted and mixed with a matrix polymer in the extruder to enable homogeneous dispersion of the API within the polymer.

In this article, we’ll discuss the basics of Hot Melt Extrusion and how it can be used for enhancing API solubility, and share solubility data based on our PVA-based Parteck^® MXP excipients (Parteck^® MXP 4-88 and Parteck^® MXP 3-82) which are developed for HME.

When developing an HME formulation, the suitability of the API and polymer for the process must be considered. Characteristics such as polymer degradation temperatures are often limiting factors. Good thermoplasticity of the polymer, stabilization of the API, and precipitation inhibition are also prerequisites for HME. A high solubilization capacity of the polymer with respect to the API is also desirable, as this allows for high drug loadings. Recent work has expanded upon analytical and in silico tools to assess the compatibility of drugs with polymers which can also be applied to the HME formulation.^1,2

WHAT ARE THE ADVANTAGES OF HOT MELT EXTRUSION?

Advantages of HME include enhanced solubility and bioavailability of the API; flexibility in drug release kinetics allowing for both immediate and sustained release; good scalability; and compatibility with continuous manufacturing.

HME also provides great versatility; potential downstream options include direct shaping of the extrudate into tablets or other downstream processing of the extrudate such as pelletizing, milling, and direct tablet compression. In contrast to other solid dispersion technologies, HME is a solvent-free process.

WHAT POLYMERS CAN BE USED IN HOT MELT EXTRUSION?

Various polymers can be used in HME processes including cellulose derivatives, polyacrylates and polymethacrylates, polyethylene glycols, and polyvinyl pyrrolidone (PVP). Recently, polyvinyl alcohol (PVA) has been highlighted as a polymer particularly well-suited for HME.³

POLYVINYL ALCOHOL (PVA) AS A HME POLYMER

PVA is a synthetic polymer produced by polymerization of vinyl acetate and partial hydrolysis of the resulting ester-based polymer. First discovered in 1924,⁴PVA has been used in approved drug products for decades⁵ and is generally recognized as safe by the US Food and Drug Administration (FDA).⁶ Furthermore, there is a body of scientific literature on the suitability of PVA for oral ingestion. The acceptable daily intake (ADI) for humans is 50 mg/kg of body weight as identified by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) in 2003.⁷ To summarize, there is well-founded scientific evidence for the safety of PVA.⁸

PVA is a thermoplastic polymer, which shows a pseudo-plastic viscosity behavior; with an increased shear rate, the viscosity drops slightly which benefits the HME process. The higher the shear forces, the easier the extrusion – including high throughput rates, improved downstream processing, optimized melt flow through the channels and extended process ranges. By adding plasticizers, the application range of HME using PVA as carrier polymer can be extended to APIs with high and low melting temperatures.

The PVA-based Parteck^® MXP excipients are specifically developed for use in HME. Their flowability allows for constant feed into the extruder which prevents negative impacts on reproducibility and continuous manufacturing processes. PVA-based polymers are suitable for a wide range of different APIs with different melting temperatures and APIs with high and stable drug loads (Table 1). They also enable a simple formulation design involving the excipient, API, and, if needed, plasticizer for extrusion.

Improving API Solubility Using Hot Melt Extrusion Formulation With Polyvinyl Alcohol_Table 1.Exemplary data for Parteck® MXP 4-88 excipient loading capacity and solubility enhancement using nine different model APIs. — Table 1.Exemplary data for Parteck® MXP 4-88 excipient loading capacity and solubility enhancement using nine different model APIs.

As there is no one-size-fits-all approach in formulation, we created two Parteck^® MXP polymer grades. A lower degree of hydrolysis polyvinyl alcohol grade (Parteck^® MXP 3-82) forms stronger interactions with hydrophobic molecules and acts as a precipitation inhibitor, while a higher degree of hydrolysis polyvinyl alcohol grade (Parteck^®MXP 4-88) has a very broad application range, including APIs that are typically not considered for HME due to their high melting points. Table 2 summarizes the key properties of the Parteck^® MXP polymers.