The therapeutic value of active pharmaceutical ingredients (APIs) in dosage forms such as tablets is limited by their aqueous solubility, limiting the insoluble APIs bioavailability to the cells and tissues where they’re needed most. This challenge is especially pertinent to drugs that are present in a crystalline state: While the ordered lattice structure improves the compound’s physical and chemical stability, crystalline drugs may have trouble dissolving in aqueous dissolution solutions and may not be fully absorbed.
 
To compensate for the limited bioavailability of hydrophobic APIs, manufacturers may find it necessary to include a higher concentration in the batch to deliver the desired dose. This, in turn, may pose health risks to production personnel, especially if the drug is highly potent. It may also increase the cost of medication for patients and expose them to a greater risk of adverse effect. Finally, high API concentrations can make oral medications taste unpleasant, which can reduce treatment compliance.
 
To overcome these challenges, the pharmaceutical industry has developed a technique called hot melt extrusion (HME). HME transforms the API into an amorphous form that is more soluble, thus increasing the bioavailability of the drug. This approach also forms a solid dispersion or solution composed of the API and solubility-enhancing excipients, preventing recrystallization in the long term to produce a more stable formulation. These molecular mixtures enable the manufacture of sustained, modified, time-controlled and targeted drug delivery with optimal efficacy. Additionally, the polymers used to form these structures mask the undesirable taste of the API.
 
HME is commonly used for formulating oral dosage forms such as tablets, soft gelatin capsules, and thin films, but they can also be used for subcutaneous and intraocular implants, intravaginal rings, and stick packs. HME is a viable technology for both high dose and potent compounds. The best candidate drug substances are those that are thermostable and exhibit poor solubility characteristics; however, the short processing time involved in HME does allow for the use of some less stable compounds as well.
 
How Hot Melt Extrusion Works
 
The HME technique involves pumping the API and other excipients, such as a binder and polymers, through a heated barrel at a controlled temperature. The manufacturer embeds functional excipients and the API in a carrier formulation that melts during the extrusion process, converting these components into an amorphous dispersion with a uniform shape and density. This product ultimately increases the dissolution rate, and therefore the bioavailability, of the API.
 
Though manufacturers use most of the same raw materials for HME as they do for other solid dosage forms, the nature of HME protocol limits the set of individual components that can be used to those that are thermally stable. Manufactures must be highly selective in their choice of materials since different functional excipients and complex APIs can drastically impact the success of the process and the final drug formulation. The high temperatures associated with HME processing destabilize the APIs, so the API should be monitored for thermal and oxidative drug degradation throughout the manufacturing process. Specifically, manufacturers must use stability-indicating analytical methods that will assure the identity, strength. quality and purity of the hot melt extruded pharmaceutical formulations.
 
The Advantages of Hot Melt Extrusion
 
HME offers several advantages over traditional processing techniques. For example, it doesn’t use costly and hazardous solvents, it involves fewer processing steps, and it can be operated continuously to save time. Overall, HME produces a purer, more efficient process and a more effective product.
 
Additionally, one of the unique benefits of HME is its ability to mask the bitter taste of certain APIs by embedding the API within the matrix of a polymer. Stronger drug-polymer interactions increase this taste masking effect, further demonstrating the importance of ensuring that the excipients used are compatible with the API.
 
The technique also offers some specific benefits to manufacturers who are working with highly potent drugs that can pose risks to pharmaceutical processing personnel as well as the intended patient population. The entire HME workflow is contained and controlled, reducing the pharmaceutical processing personnel’s exposure to the API and drug product. HME also produces a consistent and accurate low-dose product that can reliably deliver the desired therapeutic effect, reducing patients’ risks of dosing errors and side effects, thus increasing patient compliance with the treatment regimen and improving patient outcomes.
 
For a team of knowledgeable formulation scientists that is tasked with developing drug delivery systems and working with formulations that are thermally stable, HME is an efficient processing and production technology for solid molecular dispersion. HME can provide sustained, modified and targeted drug delivery with improved stability and bioavailability. This technique will help manufacturers save money by increasing production efficiency and reducing waste and may offer pharmaceutical manufactures, and ultimately the intended patients, access to equally effective drug products at significantly lower prices.

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Ameya Deshpande, M.S., is a Formulation Scientist at Avomeen. Avomeen’s clients benefit greatly from Ameya’s experience in pharmaceutical formulation development and his extensive knowledge of novel drug delivery systems including hot melt extrusion. His proficiency in formulation development includes the utilization of a Quality by Design (QBD) approach to develop drug products for Investigational New Drug (IND) Application and Abbreviated New Drug Application (ANDA). His expertise extends to pre-formulation testing including drug-excipient compatibility testing, physicochemical testing of drug substances and early stage drug product prototypes involving structural characterization, solubility profiling, determination of flow properties, wettability, rheological studies, impurity profiling and stability studies.