The formulation of poorly soluble compounds for oral delivery is a growing and often daunting challenge in drug development. As innovator pipelines of developmental drugs become richer, there is a strong trend toward candidates with low aqueous solubility. Approximately 90% of drug candidates today fall into two low aqueous solubility categories of the Biopharmaceutics Classification System (BCS), Class II and Class IV.¹ Low solubility has the consequent risk of low intrinsic bioavailability, requiring additional formulation efforts that can delay the overall development process.

A specialized technology, such as hot melt extrusion (HME), presents new opportunities to improve bioavailability through solubility enhancement. Interest in HME is growing rapidly for developing bio-enhanced formulations that increase the efficacy of these compounds. We shall discuss how development-stage pharma companies can quickly evaluate the feasibility of processes such as HME for improving compound solubility and bioavailability.

Low Solubility Challenge
The bioavailability of a drug is determined by its ability to dissolve — a function of its solubility, and its permeability at the molecular level through the gut wall. The rate and extent of dissolution of the active pharmaceutical ingredient (API) in gastric or intestinal fluid is a significant factor in achieving adequate absorption. Enhancing API solubility improves absorption and therapeutic efficacy, especially for BCS Class II compounds. Poorly soluble compounds dissolve sparingly in the gut and are mostly excreted, delivering insufficient drug to the bloodstream and target tissues. Without the application of special drug delivery systems, development of clinical dosage forms with these low solubility APIs is often unsuccessful or takes more time, resulting in increased costs.

Hot Melt Extrusion to Improve Solubility
Simple approaches to increase API solubility — including the use of functional excipients or particle size reduction techniques such as milling or micronizing — are often the first approach to the low solubility problem. If these methods do not work, then one should explore hot melt extrusion to produce solid dispersions or solid solutions. An amorphous dispersion, solid dispersion or solid solution (hereafter collectively referred to as solid dispersions) exists when a drug is dispersed in a hydrophilic polymer matrix in the amorphous form or at the molecular level in a solid state. These techniques disrupt the crystal lattice of the API producing a higher energy from that has increased solubility.

HME and the Solid Dispersion
HME is an advanced technology used to disperse an API in a polymer matrix, forming a solid dispersion. The API is embedded in the hydrophilic polymeric carrier. The API must be sufficiently soluble or miscible in the carrier to achieve a solid dispersion. Interactions between the polymer and the API inhibit crystallization of the API. The higher energy state of the API increases its dissolution rate in aqueous media, allowing for formation of a supersaturated solution and thus increasing its apparent solubility. Maintenance of the supersaturated state is enhanced by interactions between the polymer and API molecules.

The HME Process
The equipment for HME consists of an extruder and its auxiliary equipment, downstream processing equipment, and monitoring tools used to evaluate performance and product quality. Processing requires a pharmaceutical-grade polymer that can be processed at a relatively low temperature (< 200°C) due to the thermal sensitivity of many drugs and the chemical decomposition points of the polymers commonly used in HME. The components must be thermally stable at the processing temperature during the short heating process, and the material must be able to deform easily inside the extruder and solidify upon exit.

The HME process involves heating, mixing, compressing and transporting a dispersion of API, plasticizers, surfactants, and other excipients in a suitable pharmaceutical-grade polymer carrier. HME is carried out in an extruder, a barrel typically utilizing rotating twin screws with various pitch designs to achieve the desired mixing and residence times in different heating and cooling sections. The material melts or softens under elevated temperature and pressure, and is forced through the orifice by screws. Twin screws are preferred over a single screw because the rotation of the intermeshing screws provides better mixing to produce a homogeneous solid containing finely dispersed API particles, or a solid solution of API in polymer. The polymer should be thermoplastic, stable at the temperatures used in the process, and chemically compatible with the API during extrusion.

The process involves:

• feeding the extruder,
• mixing, compressing, melting and plasticizing the material to reduce particle size, and
• shaping or extrusion.

The extrudates can be further processed using milling techniques such as pelletizers and cryogenic mills to give a powder that can be incorporated into oral dosage forms (tablets, capsule, etc) Alternatively, the extrudate can be shaped and cut by the die to give the final dosage form.

Differential scanning calorimetry (DSC) and thermogravimetric (TGA) analysis are important thermoanalytical techniques for characterization of API, polymer and excipient thermal properties. DSC gives information on chemical and physical changes such as melting point and glass transition temperature (softening point) as a function of temperature. TGA measures weight losses and gains as a function of temperature and can be used to determine the temperature at which chemical decomposition occurs. This knowledge allows one to set HME process conditions and limits that allow for processing of the formulation in the hot melt extruder and avoid decomposition of the API, polymer and additives during processing.

HME Carrier Systems
HME formulations consist of a polymeric carrier and possibly other excipients, such as solubilizers, surfactants and/or binders. The careful choice of a polymer is critical to achieve the desired characteristics in HME formulations, and depends mainly on the drug-polymer miscibility, polymer stability, and function of the final dosage form. The polymer should be thermoplastic, stable at the temperatures used in the process, and chemically compatible with the API during extrusion. These conditions can be evaluated on a small scale using the above- mentioned DSC and TGA thermoanalytical techniques. Polymers with low melt viscosities and high thermal conductivities exhibit a more efficient melting process.

The properties of the API can limit formulation and processing choices. The API must have sufficient solubility in the polymer formulation. Solubility guidance can be gained through application of solubility calculation models and DSC/TGA experiments with API/polymer/excipient mixtures, but definitive answers are only realized through performance of HME experiments. Ideally, the API will melt below the processing temperature to enhance incorporation of it into the solid polymer matrix. Processing must take place below the API and polymer decomposition temperatures. Interactions between the API and the polymer are important. Mobility of the API in the polymer is inhibited by the rigidity of the polymer matrix and interactions between API and polymer functional groups, which reduces the probability the API will crystallize.

We advise using an advanced extruder with a rotating intermeshing twin screw design. For initial development work, a twin-screw extruder is capable of processing small development-scale batches of finished product in ranges as low as 30-50 grams, enabling process evaluation, quality analysis, and rapid testing of formulation properties with minimum material consumption. With this system, the API and polymer can be fed as a pre-blended mixture or through separate hoppers that can provide greater control of processing parameters and the ability to vary the drug load during processing. The HME “product” is a congealed extrudate, which can be milled into a fine powder for encapsulation or tableting. For immediate formulation evaluation, a provider should also have on-site analytical equipment such as microscopy, differential scanning calorimetry, and thermal gravimetric analysis.

Balancing the Benefits of HME
When simple techniques for improving solubility — e.g., specialty excipients or particle size reduction — do not work, HME is a broadly applicable technology that has a proven track record for development of successful clinical and commercial solid oral dosage forms.

HME can be an efficient operation for the preparation of solid dispersions, resulting in little waste of API or matrix material and high product density. By dispersing APIs evenly throughout the matrix at the molecular level, the process creates dispersions of a quality comparable to solvent-based methods without using explosive, hazardous solvents or water and eliminating residual solvents and time-consuming drying steps. HME also yields high product density. However, the equipment is costly, and the judicious choice of suitable polymers, science-based formulation development and identification of processing parameters requires considerable expertise. Developers of poorly soluble compounds can benefit from partnering with a CMO with considerable expertise and experience in this field, state-of-the-art equipment and a solid reputation for high quality services.

As with any physical modification that results in a higher energy solid state, such as the production of a solid dispersion by HME, long-term stability is an important consideration. Specifically, there is a need to address recrystallization, which may occur during the product shelf life. Considerable expertise in formulation is needed to develop appropriate excipient combinations and processing for adequate long-term stability.

Hot-melt extrusion is a sophisticated technology used to develop solid dispersion dosage forms for improved drug solubility and bioavailability, a common challenge for formulation scientists in the development of drug products today. Use of this technology in the pharma industry has been steadily increasing during the past decade, as innovator pipelines trend toward candidates with poor solubility. A development approach that integrates science-based decisions and previous experience with HME is required to identify the proper excipients, processing parameters and equipment settings for successful HME formulation. Considering the cost and expertise needed for such specialized technology to improve drug solubility, it is important for development-stage companies to work with a contract formulation and manufacturing organization that has considerable experience in this area. 

References

1. Lipp R. The Innovator Pipeline: Bioavailability Challenges and Advanced Oral Drug Delivery Opportunities. American Pharmaceutical Review 2013;16(3):10-16.

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David B. Hedden, Ph.D., is senior director, Product Development at UPM Pharmaceuticals. Monthira Reodacha, ME, is formulation associate, R&D at UPM Pharmaceuticals. For more information about this article, contact sorce@upm-inc.com.