The Origins of HME as a Solubility Enhancement Manufacturing Technology

• ExxPharma Therapeutics LLC

Background

Hot melt extrusion (HME) is currently one of the cutting-edge solubility enhancement manufacturing technologies that pharmaceutical development scientists consider when formulating poorly-soluble drug substances. A look back on how it all started and how HME became a potent and enabling solubility enhancement manufacturing technology is illuminating.

The technology was first introduced into the industry in 1991 when Warner-Lambert used HME to enhance the solubility of troglitazone, a very poorly soluble drug. Two years earlier, the company had acquired an early phase troglitazone drug product, which utilized a spray-drying process to enhance the solubility of the drug substance through the formation of an amorphous solid dispersion. Since Warner-Lambert did not have spray drying capability at the time, management asked Isaac Ghebre-Sellassie, who was Head of the Department of Technology Development at the time, and the founder and current owner of ExxPharma Therapeutics, to explore ways to convert the troglitazone spray-drying process to an alternative organic solventfree manufacturing process. The spray-drying process was originally selected by the innovator after all commonly known amorphous solid dispersion solubilization methods cited in the literature (i.e., hot melt, hot melt/solvent evaporation and solvent evaporation processes) were investigated. Both melt processes, which utilized conventional granulating equipment, led to significant degradation at the melting point of the drug and had to be abandoned in favor of the organic solvent-based spray-drying process.

HME Process Development

Given the shortcomings of the different processes evaluated earlier, an alternative novel solubility enhancement manufacturing technology, which was capable of generating an amorphous dispersion of the drug and, at the same time, eliminated organic solvents and ensured the stability of the drug substance during processing, had to be developed. Having had extensive experience in film-coating technology and several publications to their credit, Isaac and his group had an in-depth understanding of the role plasticizers play in lowering the glass transition temperatures of polymers. Using this concept, it was hypothesized that the processing temperatures could potentially be reduced by the incorporation of an appropriate plasticizer in the spray-dried formulation, the main component of which was a polymer. The next hurdle was identification of an efficient mixer that was capable of mixing the formulation components in the molten state.

Coincidentally, at about the same time, the Department of Technology Development had procured a Brabender counter-rotating twin screw extruder to investigate the potential application of hot melt extrusion in the development of melt-granulated products. Subsequent extrusion runs demonstrated that the extrudates were much more homogeneous and uniform than those granulations produced using conventional granulators, apparently due to the superior mixing capabilities of the extruder. In addition, the residence time of the product in the extruder was much shorter than that in conventional mixing equipment.

Based on these observations, Isaac and his group proceeded to evaluate HME as a solubility enhancement technology with four assumptions in mind: (a) prolonged exposure of the drug substance to elevated temperatures would be eliminated due to the short residence time of the formulation in the extruder, (b) the exclusion of air in the process section during melt extrusion would minimize oxidative degradation of the drug substance, (c) as a small mass mixer, the extruder would bring about very intimate mixing of the formulation components, and (d) an excipient that plasticizes the polymer would permit processing of the formulation at temperatures below the melting point without the reported degradation.

These assumptions were subsequently confirmed through experimentation. A granulation of the drug substance, polymer and plasticizer was prepared and extruded at temperatures 40° C below the melting point of the drug substance. The extrudates, which were glassy and brittle, were milled to provide free-flowing amorphous solid dispersion that was later blended with external tablet excipients and compressed into tablets. Pilot bioavailability data indicated that the tablets containing the solid dispersion prepared by HME and the tablets produced using the spray-dried solid dispersion were bioequivalent.

HME Process Scale-Up and Transfer

Once feasibility was demonstrated, Warner-Lambert procured and installed a 34mm Leistritz extruder, the smallest lab-size Leistritz model available at the time (since discontinued). The extrusion process was scaled up to the 34mm extruder and optimized. Interestingly, subsequent extrusion experiments conducted at the 34mm extruder demonstrated that the troglitazone formulation could actually be processed at or above the melting temperature of the drug substance without degradation. As a result, successive batches were extruded at temperatures close to the melting point of the drug substance. The HME process was successfully transferred to a Leistritz 50mm Extruder and used to manufacture registration and commercial batches. Even though the troglitazone process was the first HME-based solubility enhancement technology that was filed with the FDA, there were no regulatory issues that surfaced during pre-approval inspection and the overall approval process.

Commercial Batches

Rezulin^R (troglitazone) became the first product to be approved by the FDA in 1997 that employed HME to enhance the solubility of a drug substance (Rezulin^R was later withdrawn from the market due to unrelated liver toxicity in certain segments of the population). Despite the extensive data that was generated during development and technology transfer, manufacturing personnel were concerned initially about the reliability of the new technology, the continuous nature of the process and the significant product loss that would potentially occur if a single batch fails. As a result, it was decided, at the beginning, to limit the commercial batch sizes of the solid dispersion to 250 kg to allay the concerns. Soon after, however, due to the ruggedness of the process and the consistently highquality product manufactured at different time points during a given run-time, batch sizes were stepwise increased first to 500 kg, then to 1000 kg and finally to 5000 kg without any change to the process parameters except the extent of the run-time. Incidentally, manufacturing of the product proceeded without batch failure throughout the period the product was on the market.

Advantages of HME

HME has many important attributes that positively impact cost, quality and reproducibility of a product. The extruder has a small footprint, and the process is solvent-free, continuous, and easily scalable; in addition, the process generates densified material that can easily be blended with external tablet excipients and compressed into tablets directly, unlike spray-dried solid dispersion, which requires a densification step. The technology is also amenable to process analytical technology (PAT).

In general, HME processes are designed during development with scale-up and commercial batch flexibility in mind, and lead to much smoother tech transfer, reduced manufacturing issues, higher product quality, lower production costs and faster time-to-market.

Concerns and Misconceptions About HME

In spite of the various advantages of HME and the successful launching of Rezulin^R in 1997, it took another eight years for the next HME-enhanced product (Kaletra^R) to be introduced in the market. Even today, there are only few additional products in the market that employ HME-based solubility enhancement processes.

While the exact reasons for such a scenario may not be clear, there appear to be certain misconceptions, within the industry that at times have been dissuading development scientists and decision makers from committing to HME as a solubility enhancement manufacturing technology. Some of these reasons include:

Technology complexity: Unlike conventional large mass mixers which have simple operational parameters that are easily understood, twin screw extruders are complex mixers that require a thorough understanding of the fundamentals of twin screw extrusion technology, an expertise that may take years to master.

Thermal instability: Because HME utilizes elevated temperatures and imparts shear onto the formulation, the perception is that the process may lead to drug decomposition more often than not. However, based on experience, it is safe to assume that drug degradation could be prevented during processing by the judicious selection of tailormade formulations and optimization of critical process parameters.

Regulatory concerns: HME technology is relatively new to the industry, and as result, there has been uncertainty about the regulatory impact of the technology on drug development timeline and approval. However, given the limited number of products, which employ HME as a solubility enhancement technology that have been approved by the FDA, it could be concluded that the concerns are no longer valid.

Resistance to change: In general, the pharma industry is slow to adapt to new and unfamiliar technologies, such as HME, unless competitive market forces compel it to act. While formulation-based solubility enhancement of drug substances to improve bioavailability has been known for over five decades, it was never a priority for the industry for years since the industry has been generating drug substances that do not require solubility enhancement, or, if they do, could be rendered soluble through salt formation. Recently, however, the number of poorly-soluble drug substances in the industry pipeline has been increasing exponentially. As a consequence, the industry is now actively pursuing HME as well as other enabling solubility enhancement technologies to improve the clinical viability of poorlysoluble newly discovered drug candidates in the pipelines of pharma companies and to enhance the efficacy and improve the safety of approved poorly-soluble drug substances already in the market.

Future Trend

Approximately 90% of the drug substances in the industry pipeline are currently poorly-soluble compared to the less than 36% of the drug substances in marketed products, a significant increase in the number of active pharmaceutical ingredients that require solubility enhancement. In addition, the market value of poorly-soluble and poorly-permeable drug substances is estimated to be around $145 billion (Technology Catalysts International, 2015), a significant market opportunity for companies that possess cutting-edge solubility enhancement technologies.

As a result, overall interest in HME as a solubility enhancement technology has been growing steadily both in industry and academia in spite of the misconceptions mentioned above. The trend is expected to accelerate in the future considering the tremendous advantages the technology offers in terms of product quality, cost effectiveness and manufacturing flexibility. To meet the increased demand, some brand companies have established HME technology internally, while a select few contract development and manufacturing organizations (CDMOs) have been acquiring HME-based solubility enhancement technologies through acquisitions and strategic alliances.

A case in point is the collaboration agreement that was established between Halo Pharmaceutical and ExxPharma Therapeutics to develop and manufacture drug products for clients using ExxPharma proprietary drug delivery systems and hot melt extrusion (HME), in particular, and other twin-screw extrusion-based manufacturing technologies, in general. According to the agreement, ExxPharma is responsible for technical matters while Halo has overall responsibility for drug product manufacturing and quality control at its GMPcompliant facility in Whippany NJ (Halo Pharmaceutical, 2016).

Given the number of poorly soluble new molecular entities in pipelines, the evolving interest in HME as an enabling solubility enhancement technology by pharma companies and the CDMOs that are acquiring HME expertise, it is expected that many HME based new drug products comprising poorly-soluble new molecular entities and marketed drug substances will be approved in the coming years.

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Author Biography

Hibreniguss Terefe has more than 20 years of academic and industrial pharmaceutical research and development experience, particularly in the area of drug delivery technology. He has extensive experience in twin screw extrusion technologies, including hot melt extrusion and liquid assisted extrusion as applied to solubility enhancement, modified release and abuse deterrent formulations.