Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.

Cynthia A. Challener

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Highly potent drugs exhibit a combination of high toxicity and therapeutic efficacy at low doses. They also often suffer from poor aqueous bioavailability, have specific release requirements to minimize potential toxicological effects, and bitter taste. As such, they present formulation challenges, including selection of necessary and appropriate excipients such as solubility and permeation enhancers to improve bioavailability, polymeric excipients to modify release profiles and flavor compounds to mask taste, according to Marcus Jenkins, Technical Consultant with SGS.

Analysis of high-potency formulations can also be difficult. The main analytical in-vitro release tests required for pharmaceutical drug products are confirmation of identity and quantification of the drug substance and impurities, as well as performance tests, such as determination of dissolution behavior for solid-dose products. In addition to the use of numerous and varying excipients, dose-form design and solubility pose specific challenges for analytical method development and implementation for highly potent drug formulations.

SGS has worked with many different highly potent drug formulations, and each has presented its own set of challenges. Two examples include a thyroid hormone product and a highly potent drug candidate dosed in the microgram range.

For the thyroid hormone product, solid-phase extraction (SPE) technology was used to reduce excipient interference. Initially, reproducible recovery of the drug was challenging when using low rinse volumes to maintain the required concentrations for analysis, according to Marcus Jenkins, Technical Consultant with SGS, as the loss of even small amounts of drug substance during sample preparation resulted in a large percentage decrease in its assay result. “Fortunately,” he says, “SPE technology has advanced and today more reliably prepared cartridges with a wide range of stationary phases are now available that allow analysis of drug substances with different physicochemical properties.”

The drug candidate dosed in the microgram range severely limited sample dilution. In fact, a higher concentration was required for impurity analysis to maintain the necessary level of sensitivity and ensure that low-level impurities could be effectively quantified. In addition, the use of dedicated glassware was necessary to avoid contamination and ensure no additional compounds (drugs or excipients) from other ongoing projects could interfere with the analysis. Dilution was then performed prior to analysis of the drug substance assay.

There are a few main analytical challenges that developers of highly potent drug formulations face. First, the high potency and low concentration of the drug substances in these formulations make it necessary to limit sample dilution in order to achieve suitable nominal concentrations for testing. “While the limitations will depend on the physicochemical properties of each drug substance, low sample dilution typically results in high excipient contributions to samples when they are tested,” Jenkins comments.

Low sample dilution may also enable greater external interference of samples via contamination from glassware, processes, or equipment. Such an issue is generally not observed for higher-dose products because the low levels of contaminants present are often diluted out of testing concentration ranges, according to Jenkins.

A second issue is the level of sensitivity needed for effective impurity analysis. “Due to the low doses for highly potent drugs, analytical testing concentrations will often be low and thus provide a challenge to the sensitivity of any method or equipment used,” Jenkins states. The use of higher sample loading to improve the response and sensitivity for low-dose products creates the third challenge, which is that larger injection volumes increase the quantities of injected excipients.

This approach can not only result in reduced equipment lifetimes, but also require the addition of extra cleaning steps, contributing to increased equipment downtime and reduced throughput and capacity in testing laboratories, Jenkins adds. Furthermore, to minimize or eliminate excipient interference requires additional preparation steps, which lengthen the process and increase complexity, potentially leading to greater variability.

Last but not least, to ensure the safety of operators and the environment, handing of highly potent drug samples must be pursued with the proper controls in place, which can include containment such as hoods or isolators. Jenkins notes that this additional complexity can also introduce variability to testing processes.

Excipients cause concern during uniformity determination

For highly potent, low-dose drugs, ensuring the uniform distribution of the drug substance throughout the matrix is essential and often challenging. “Accurate and reliable analytical data [are] needed to enable effective and efficient product-development decisions. Should there be any doubt about the the accuracy of the analytical data regarding drug substance uniformity, development time, effort, and associated cost may be wasted trying to resolve potential formulation issues that are not real,” Jenkins observes.

The biggest issue often relates to detection difficulties due to the presence of excipients that absorb in UV wavelength regions similar to those for drug substances. One way to avoid this issue is to consider the analytical impacts of excipients during early screening and selection efforts before too much time and effort have been invested in prototype generation, according to Jenkins. Another approach is to choose alternative detection wavelengths that minimize excipient contribution, but the ability to do so depends on the absorption properties of the drug substance.

Polymeric excipients used to modify the in-vivo release of drugs can impact accurate extraction during sample preparation. “For some high-potency drug formulations it may be necessary to complete additional preparation steps to ensure full recovery of the drug substance as required to meet industry in-process checks or finished-product specifications,” Jenkins says.

Polymeric excipients may also present challenges to lab equipment such as chromatographic columns, as they can be difficult to remove and may create the need for additional cleaning/regeneration steps to return columns to optimal performance or irreversibly reduce column lifetimes, according to Jenkins. “Column deterioration during analysis can, in fact, increase the risk of an analysis failing to meet typical system suitability criteria, leading to the need to repeat analyses, thus reducing testing efficiency and cost-effectiveness,” he states.

To achieve effective analysis, all ingredients of interest in a drug formulation must be soluble in a solvent suitable for the intended method of analysis. That can be an issue for highly potent drug substances with poor water solubility, as organic solvents are typically required. “For a particular formulation, the solvent should effectively dissolve the drug substance or other ingredient of interest (e.g., preservative or anti-oxidant) but not the other formulation excipients in order to minimize excipient contributions; however, drug substances and excipients often exhibit similar properties and tend to be soluble in the same solvents,” Jenkins explains.

Careful column stationary- and mobile-phase selection can be used to separate unwanted excipient interference from peaks of interest ensuring acceptable specificity. These choices can be guided somewhat by consideration of the chemical structures of the compounds involved, according to Jenkins. “Polar functionalities in the drug substance will interact with imbedded polar groups on columns, while delocalized electron systems will interact with similar systems in certain stationary phases such as pentafluorophenyl, and alkyl chains will interact with C8 or C18 stationary phases, etc. Modern analytical columns now have combinations of these groups to allow for a wider range of stationary phases for evaluation during analytical development,” he observes.

Another approach is to use secondary or tertiary wavelength maxima to minimize interference from excipients in a highly potent drug formulation. “It is necessary, however, to consider the analysis of degradation products, as they can have different UV absorbances compared to their parent moieties,” Jenkins states. He adds that while longer wavelengths will reduce excipient contribution to the analysis, they do not prevent physical interactions of excipients with the stationary phase and the need for additional cleaning steps.

Sustained-release formulations require increased sensitivity and non-routine analyses

Highly potent drug formulations that are engineered to enable sustained release of the drug substance with targeted delivery to minimize potential toxicological effects often rely on alternative or novel excipients. These systems, according to Jenkins, reduce the initial onset and prolong the therapeutic effect window.

In-vitro release testing for such formulations requires detection of low levels of drug substances (particularly at early time points) released at slow rates. For instance, a sustained-release formulation may release 5–0% of the drug substance after 5–10 minutes, while an immediate-release formulation will typically release >45%, observes Jenkins. “Increased sensitivity achieved through use of higher-sensitivity detectors or modifications such as higher path-length flow cells or application of non-routine/non-pharmacopeial equipment, such as micro-dissolution and/or sample concentrators, is therefore often necessary. Justification of the suitability, control, and use of such equipment is, however, usually required during regulatory review,” he says.

It is not just sustained-release formulations that can cause challenges to effective dissolution analysis. For oral-dosage-form drugs formulated as capsules, during dissolution analysis certain combinations of excipients, dissolution media, and the polymers used to form the capsule shells can react to form pellicles that retard drug-substance release, according to Jenkins. “This issue is addressed either through the development of specific dissolution media to prevent crosslinking or the inclusion of the enzyme pepsin to degrade any formed pellicles,” he says. He does note, however, that these approaches are not generally applied from the outset, as often this problem does not appear until several months into
stability testing of a product.

Need for instrument innovation combined with analytical expertise

As more knowledge is gained about disease mechanisms and new drug targets are identified, the nature of highly potent drug substances continues to evolve. They are becoming steadily more potent while their solubility/permeability continues to decline. At the same time, demands for safer, easier-to-use drugs that are not only developed with patients in mind but also cost-effective are growing.

Formulation of highly potent drugs that meet those demands can be challenging, particularly given the complexity of drug formulation and analysis for these products. “The largest contribution to the cost of new, novel medicines is the time taken for development (circa 8–12 years). Improving the efficiency of development should therefore result in a reduction in the cost-per-unit and earlier availability of drugs to patients. One way to reduce development times is through introduction of more advanced analytical instruments and methods with greater sensitivity that support quick resolution of analytical challenges,” Jenkins contends.

Combining innovative systems with experienced analytical and formulation scientists using a collaborative approach would, Jenkins adds, further ensure sound scientific rationale resulting in effective development decisions. He points to, for example, consideration of the downstream impacts of formulation development decisions on required analytical methodologies. The overall result, Jenkins believes, would ultimately be expedited development timeframes for novel medicines that address unmet patient needs.

Cynthia A. Challener, PhD, is a contributing editor to 

When referring to this article, please cite it as Challener, C.A. Overcoming Analytical Challenges in High Potency Formulation. 

Articles

Sample dilution, sensitivity, excipient interference, and containment are key issues that must be addressed.

Overcoming Analytical Challenges in High Potency Formulation

Numerous pharmaceutical companies from startups to well-established firms are exploring the potential of cannabinoid-based drug substances as therapeutic agents for the treatment of a wide range of disease indications. Developmental cannabinoid medications must follow the same approval pathway established for all other small-molecule drug candidates. Early in 2023, the agency also determined that a new regulatory pathway for cannabidiol (CBD) products is needed that “balances individuals’ desire for access to CBD products with the regulatory oversight needed to manage risks” (1). “Smart companies,” says Jordan Tishler, president and CEO of inhaleMD, President of the Association of Cannabinoid Specialists, and an Instructor of Medicine at Harvard Medical School, “will see the value of following the pharmaceutical pathway and pursuing clinical trials and FDA approval, while the rest will simply make recreational products.”

Regardless of whether companies are seeking to develop therapeutics or dietary supplements based on cannabinoids, they face the challenge of realizing effective delivery of these highly hydrophobic compounds. “Cannabinoids present many of the same difficulties that other poorly soluble and/or absorbable APIs present,” states Gavin Chandler, CEO of Trokie, a company working on novel delivery systems for cannabinoids for use as dietary supplements in strict compliance with FDA and Federal Trade
Commission (FTC) rules.

In addition to being highly lipophilic molecules, cannabinoids can also undergo extensive first-pass metabolism, which creates difficulties for dosing and titration and impacts the speed of therapeutic onset, according to Chandler. He points to testosterone and triptans as being examples of other APIs that share these difficulties.

Furthermore, Tishler notes that bioavailability of cannabinoids is poor regardless of route of administration, and it is also quite variable, particularly for oral delivery. The challenge, agrees John A. MacKay, founder and CEO of Synergistic Technologies Associates, is to get nonpolar cannabinoids into some type of media or delivery vehicle that will enable sufficient quantities of them to be transported across membranes to targeted areas.

Growing numbers of patent filings and publications regarding the pharmacodynamics of cannabinoid delivery using novel technologies indicate high interest in addressing the shortcomings of cannabinoid products delivered via the standard oral routes of administration, according to Chandler. Technologies of interest include buccal, intra-nasal, and transdermal delivery systems, as well as the use of various nanoscale approaches to enable improved oral delivery.

Of the more than 120 different phytocannabinoids that have been identified, Δ9-tetrahydrocannabinol (Δ9-THC, or THC) and CBD are the most abundant and most investigated (2). Many synthetic cannabinoids have also been produced and evaluated. Most cannabinoids that have been shown to be pharmacologically active are Class II compounds under the Biopharmaceutics Classification System, which are considered to have low water solubility and high lipophilicity.

Inhalation gives best bioavailability, but presents many problems

Although inhalation of cannabis-derived products is the most common method of administration and does generally provide the best bioavailability and fast onset of action (5–10 minutes) as well bypasses first-pass metabolism (2), smoking and vaping oil extracts supply the cannabinoids in conjunction with toxic byproducts. In addition, the bioavailability still only reaches 20–30%. “The best solution to date,” says Tishler, “is a flower vaporizer, but this device is costly and the results are typically very user-dependent.”

Inhalation must be done appropriately, too, adds Mackay. “If patients don’t inhale correctly, the cannabinoids can be delivered into the mouth instead of the lungs. In addition, some people experience a gag-reflex when using an inhaler.” Due to the “stickiness” of these hydrophobic compounds, Tishler adds that it is difficult to put them in metered-dose inhalers because the devices fail after just a few uses.

Buccal and intranasal delivery could be alternatives

Buccal and intranasal delivery are other approaches to avoiding first-pass metabolism. These delivery methods also may offer reduced variability compared to oral administration of cannabinoids, according to Chandler. “We see increasing clinical evidence coming out in various publications both domestically and internationally that these types of formulations provide higher and more reliable absorption of cannabinoids that will benefit clinicians and their patients,” he observes. He does, stress, however, that there is still much work to do.

Whether one form of administration is better than another remains to be seen. In addition, Chandler remarks that cannabinoids are a diverse set of molecules, so what would be an advantage for one might be a disadvantage for another depending on the specific attributes of the cannabinoids. “On the purely theoretical side, buccal formulations are potentially easier to use because they are solids rather than liquids,” he comments.

On the other hand, intranasal delivery, based on the results with other similar APIs, could have slightly faster speed of onset at the expense of total absorption because of the washout down the throat, according to Chandler. There are concerns, however, about irritation of the nasal mucosa and mucociliary clearance, and it has been suggested that this route of administration may be most appropriate for highly potent APIs that require small dosage amounts (3).

Separately, depending on the cannabinoid, buccal or intranasal might provide for better patient tolerability, as some cannabinoids can be either very bitter or spicy, and where one technology or the other might provide a better patient experience. “We need more clinical data, but I expect there will be a place for both technologies depending on the clinical context and specific cannabinoids,” Chandler says.

For buccal formulations specifically, Chandler notes that analogous cases such as buccal delivery of testosterone show that buccal improves total absorption and reliability. Similarly, improvement of efficacy has been reported when going from oral gastric tablets of triptans to sublingual or intranasal delivery. The published literature on buccal delivery of cannabinoids, he continues, suggests that there is evidence that buccal delivery improves total absorption with pharmacokinetic (PK) profiles swinging from predominantly first-pass metabolites towards more non-metabolized actives in patients. “These papers, however,” says Chandler, “describe small trials with only a handful of patients and not powered or controlled at a level to really address the question of variability.”

Developing buccal formulations (orally disintegrating tablets, buccal mucoadhesive tablets, films and patches, sublingual disintegrating thin films, sprays, chewing gum, and lozenges) can be challenging for cannabinoids because buccal delivery comprises a group of technologies, all of which might not be suitable for all cannabinoids, according to Chandler. In addition, he notes that cannabinoids have diverse flavor profiles, which can be an issue.

“Buccal delivery tends to involve greater residence times in the mouth, and depending on the unit dose they can be highly concentrated,” Chandler explains. Furthermore, the small size of the oral cavity limits the volumes that can be comfortably delivered compared to traditional tablets/capsules. Some cannabis and hemp extract products are in development.

It is worth noting that buccal and intranasal delivery are just two forms of transmucosal drug administration, which is intended to deliver drug substances through the mucosal epithelium into systemic circulation. Others include rectal and vaginal delivery. Several different cannabinoid candidates are being developed as transmucosal products, with many of them based on THC or CBD and most as oromucosal formulations (2).

Nano products claim to tackle GI tract absorption issues

Given that oral delivery via tablets and capsules is generally the preferred route of administration due to simplicity, many developers of cannabinoid medicines are focused on overcoming the poor absorption of these molecules in the gastrointestinal (GI) tract, which is typically 15–20%. Nanoscale solutions are receiving the greatest attention, according to Tishler, but solid data has yet to be supplied, he says.

Nano-based technologies are attractive because they have the potential to not only improve solubility and bioavailability, but increase stability and provide mechanisms for controlled- and other types of modified-release profiles and taste masking (2,4).

Various solutions are being developed, including those based on lipid and polymeric nanoparticles (2,4). Other lipid-based formulations such as nanomicelles, nanoemulsions, lipid nano capsules, and nanostructured lipid carriers, self-micro emulsifying drug-delivery systems, and self-nano emulsifying drug-delivery systems are being explored, as are ethosomal systems containing phospholipids, ethanol, and water; complexation by cyclodextrins; extracellular vesicles or exosomes; mesoporous silica; and electrospun fibers (2,4).

Nanoemulsions are particularly popular, according to MacKay, with different companies using a number of different approaches to generate them. “The challenge is selecting the right emulsifiers and emulsification technology (for example, controlled cavitation) for a given cannabinoid to achieve nanoemulsions of the correct particle size that maintain their emulsified state for throughout shipment, storage, and use,” he contends.

Stability is essential, as formulations in which the emulsion has degraded will not have a consistent concentration of the cannabinoid active throughout the entire solution. The particle size is important because it not only determines how efficiently the nanoparticles will cross membranes, but which cells are targeted and how the nanoparticles interact with them, Mackay observes.

Another way to improve the solubility and bioavailability of cannabinoids is to chemically modify them in such a way as to reduce their lipophilicity without affecting the parts of the molecule involved in receptor binding and thus their pharmacological activity. Examples of modifications include adding long-chain alkyl substituents to the main ring structure to increase hydrophilicity and preparing conjugates with polar molecules.

MacKay points to the work of Alexander Makriyannis, George Behrakis Chair of Pharmaceutical Biotechnology at Northeastern University, and John W. Huffman, now deceased, previously a professor of organic chemistry at Clemson University, as being the most well known in the field. These two and many others have produced hundreds of synthetic cannabinoids with wide-ranging properties, some of which are now in preclinical or early-stage clinical development.

Cannabinoid receptors exist in the skin, and some companies are seeking to develop topical or transdermal cannabinoid formulations to skin conditions, such as psoriasis, atopic dermatitis, and acne. A common approach in this case is to generate synthetic prodrugs that can cross both the lipophilic stratum corneum and the aqueous dermis (2). Many of these formulations are also nanoscale solutions.

The key takeaway about cannabinoid drug delivery is that no one delivery approach will be effective for all natural and synthetic cannabinoids. “There is too much variability in the physicochemical characteristics of the many different pharmacologically active cannabinoids being investigated today,” MacKay states. As with other drugs, different indications and different
patient populations will require different routes of administration to meet
therapeutic, patient, and physician needs. A formulation intended to treat acute pain, which requires fast onset, will be different from one to treat chronic conditions, for which extended release will be preferable.

Woodcock, J. FDA Concludes that Existing Regulatory Frameworks for Foods and Supplements are Not Appropriate for Cannabidiol, Will Work with Congress on a New Way Forward. FDA Statement, Jan. 26, 2023.

Stella, B. et al. Cannabinoid Formulations and Delivery Systems: Current and Future Options to Treat Pain. 

 81(13): 1513–1557. doi: 10.1007/s40265-021-01579-x/

Tijani, A. O., et al., Delivering Therapeutic Cannabinoids via Skin: Current State and Future Perspectives. 

 Vol. 334, June 10, 2021, pp 427-451. https://doi.org/10.1016/j.jconrel.2021.05.005

Palrasu, M. et al., Perspectives on Challenges in Cannabis Drug Delivery Systems: Where Are We? 

 5:102–119. https://doi.org/10.1159/000525629.


Vol. 47, No. 6
June 2023
Pages: 19-20, 23

When referring to this article, please cite it as Challener, C. Overcoming the Poor Solubility of Cannabinoids. 

Nanotech-based delivery technologies are receiving significant attention.

Overcoming the Poor Solubility of Cannabinoids

Continuous manufacturing has the potential to offer benefits in terms of reduced costs, footprint, raw material consumption, and byproduct and emission generation combined with increased process consistency and product quality. Regulatory submission timelines can also be advanced by more than 12 months and approval times by three months compared to products generated via batch manufacturing (1). Not surprisingly, the US Food and Drug Administration (FDA) encourages the development of continuous processes, and these processes are slowly becoming more prevalent in both small-molecule and biologics manufacturing. It is expected, in fact, that in the near future continuous operations will be the norm rather than the exception, according to Hibreniguss Terefe, director of research and development at Catalent. As such, outsourcing providers that develop continuous manufacturing expertise and leverage this technology can establish a differentiating competitive advantage.

Editor's Note: This article was published in 

Hot-melt extrusion (HME) by its nature is a continuous process, and its integration with other continuous manufacturing operations has the potential as an amorphous solid dispersion (ASD) solution to offer more benefits than just enhanced solubility and bioavailability for poorly soluble APIs. “Given that HME is one of the best tools for enhancing solubility, linking HME processes effectively with other unit operations such as tableting/capsule filling will reduce the number of unit operations, ease scale-up to commercial production, and ultimately help patients realize earlier access to products with positive economic impacts for sponsors as well,” states Purushottam Singnurkar, vice-president and head of formulation development at Syngene International Limited.

Formulating drug substances into ASDs is a widely accepted approach to enhancing the solubility and bioavailability of poorly soluble molecules, according to Terefe. “The conversion of a crystalline API into an amorphous form by dispersing and immobilizing it in a polymeric carrier can be achieved through solvent- or fusion-based technologies. Spray drying is a solvent-based process, while HME is fusion-based technology,” he observes.

In addition to improved solubility, other benefits of using HME are good process control, scalability, and avoidance of solvents, notes Hannes Fuderer, technical operations manager with AbbVie Contract Manufacturing. “Good process control enables balancing of incoming variability into the extrusion process and reduces the variability of the extrudate itself to improve the performance of downstream processing. Good scalability provides the opportunity for faster development and transfer from
lab through pilot to commercial scale and affords flexibility to accommodate volume and extruder-scale changes during life-cycle management,” he explains.

“The ability to practically transfer material inputs continuously and have them transformed into output materials that are continuously removed leads to increased product quality assurance and enhanced product capability and control,” adds Singnurkar. He also comments that the fact that HME is a “green technology” that involves fewer processing steps than spray drying and freeze drying provides further advantages.

HME takes place in a twin-screw extruder, which is, according to Terefe, a continuous, versatile, and highly efficient self-wiping small mass mixer amenable to process analytical technology (PAT). That is why process parameters can be well controlled and HME processes can be readily scaled from R&D to commercial-scale equipment. “Once process parameters are established at a given equipment scale, the batch size is then a function of time and can be easily changed by running the process for a longer or shorter period without needing to change other process parameters,” he notes.

In addition, HME offers a high degree in flexibility and many use cases. “Based on the HME process design, there are many options to integrate an HME process into a fully continuous process or combine it with discontinuous up- and/or downstream processes if required, such as batch blending to feed the extruder or storage of extrudate intermediate prior to further (batch-wise) processing into final drug product,” Fuderer says. HME can also be used for potent compounds and due to the equipment design it typically results in high yields.

An HME unit operation is usually performed as a continuous process through a sequentially assembled equipment system consisting of powder feeder(s), optional liquid pump(s), a twin-screw extruder, a conveyor, and a pelletizer (or a chill roll flaker) working in a harmonized and continuous manner, Terefe notes. The extrudate, however, is typically handled as an intermediate and further processed as a batch, limiting HME to a semi-continuous process.

On the upstream side, the material feed can be a mixed powder blend or individual streams of different ingredients (API and excipients) fed directly. Either approach can be performed continuously, according
to Fuderer.He also notes that, based on material properties or to increase the throughput, the blend can be densified prior to extrusion by a continuous roller compactor or side-stuffer.

The extrudate, meanwhile, can be shaped into nearly any form by the design of the extruder die in combination with several cutting and shaping technologies that are also all continuous processes, Fuderer says. Common shapes are flakes, pellets, and beads depending on the downstream unit operation. “It is possible rather than collecting and buffering the shaped and cooled extrudate in containers prior to further processing, it can be dosed immediately to the next unit operation as the mass flow is still controlled,” he adds.

Integrating the extrusion process with other upstream and downstream semi-continuous unit operations such as continuous blending, milling, tablet pressing (direct compression), and tablet coating would, Terefe says, create a fully end-to-end continuous solid-oral-dosage-form manufacturing process. “Combining a continuous HME process with continuous downstream operations could be envisioned as a viable means for taking full advantage of a continuous process to manufacture solubility- and bioavailability-enhanced products,” he concludes.

One example provided by Singnurkar involves transfer of the hot extrudate directly to dies of suitable sizes for the manufacture of 3D tablets. “Integration eliminates many process steps such as cooling and milling of the extrudate and mixing with excipients, among others,” he says. Any integration of continuous operations without a centralized computer system for control and the implementation of PAT tools for constant process monitoring will, however, reduce the likelihood of success, Singnurkar stresses.

Understanding the critical material attributes (CMAs) of the API and polymer, such as the melting and glass-transition temperatures is also important for developing high-performing HME processes. “The machine settings, including the screw configuration, screw diameter-to-length-ratio, barrel-free volume, distribution of heating and cooling zones, die-orifice size and shape, and the cooling system are equality important. Critical process parameters include the barrel temperature, screw speed, residence time, and throughput,” Singnurkar from Syngene observes.

Controlling material inputs often presents the greatest challenge for HME process optimization, according to both Fuderer and Terefe. “Blend homogeneity, dosing accuracy, and risk of blend segregation during powder conveying are important issues that must be managed,” Fuderer stresses.

Inconsistent and inaccurate feeding of input material into the twin-screw extruder may be caused by poor flow properties of certain raw materials, or very low amounts of certain excipients such as plasticizers and surfactants, Terefe notes. “Feeding all of the components separately at an appropriate ratio of feed rates, as reflected in the formulation composition, would be ideal for a well-harmonized continuous
process, but this assumes that no additional pre-extrusion unit operations are necessary,” he says. Poorly flowing APIs may need to be preblended with a carrier polymer, and often, with additional flow-enhancing excipients, Terefe adds.

Fuderer does point out, though, that one advantage of the HME process is that variances in blend homogeneity and dosing are smoothened to a certain extent, and therefore, variances will not immediately impact extrudate quality.

Blend segregation, however, must be avoided during powder conveying into the extruder, according to Fuderer. This issue is particularly associated with discontinuous batch blending, as it poses higher risk for segregation at bin changes or if the upstream equipment runs empty.

In cases where the poor flow properties of the API or any excipient cannot be overcome by simple blending, Terefe observes that a pre-extrusion granulation step may be required. “Appropriate selection of the powder feeders with suitable feeder screw designs and the choice of liquid pumps for accurate liquid feeding without pulsation can help alleviate many of the input material feeding challenges,” he comments. Introducing a continuous blending process upstream of the extrusion step can also be beneficial for formulations for which simple blending cannot overcome these challenges, Terefe says.

Optimum HME processes generate extrudate with acceptable critical quality attributes (CQAs), such as amorphicity, content uniformity, and purity. Many CQAs impact downstream unit operations, according to Terefe, and thus it is crucial to have online monitoring capabilities (such as near-infrared spectroscopy for evaluating an extrudate’s crystallinity and content uniformity) to track these properties. Fortunately, says Fuderer, if HME processes are properly developed, they are robust and have good process control, and thus typically exhibit only minor variances in physical properties of extrudate intermediate that could impact downstream processing due to HME process performance.

Improper identification of critical material attributes and CQAs for HME processes can, believes Singnurkar, impact the uniformity, degradation profile, and dissolution behaviour of the final drug products. Misidentification of CPPs, meanwhile, can impact the milling of extrudates which can affect compressibility and thus make tabletting difficult. In addition, the API loading and miscibility of the API with the polymeric carrier can also, he says, significantly impact downstream processing.

It is the physical properties of the extrudate that are most important for downstream processing, Fuderer agrees. He adds, however, that they are mainly dependent on the product composition and less dependent on the HME process parameters such as the temperature profile. “As long as the product composition is controlled (e.g., blend homogeneity or ratio of solid and liquid feeds), no impact is expected on downstream processing,” he states.

In addition to product composition, Terefe emphasizes the importance of achieving consistent and controlled material throughput that is harmonized with downstream processes. For example, he points out that the material feed rate into a mill impacts particle size distribution, which may lead to inconsistency in the dissolution of the final product. Inconsistent material input into the continuous direct blending process downstream may also lead to poor blend uniformity, resulting in poor content uniformity of the final tablets.

Here again, the HME process benefits from good monitoring and control technologies. “Twin screw extruders typically have features for controlling and monitoring material throughput consistency, allowing the feed rate, extrusion load, and melt pressure to be continuously measured and monitored in real time,” Terefe explains. Any fluctuation in one of these parameters is a direct indication of material throughput inconsistency and the need to adjust the process.

Ultimately, the successful use of HME to enhance solubility and bioavailability of poorly soluble APIs manufactured in a fully continuous process, as is the case of any continuous manufacturing process, requires a well-engineered process design that can be controlled, Terefe contends. “When developing an HME process, there is a broad choice in polymers, equipment design, and development and scale-up approaches. It is important to involve appropriate subject matter experts at each stage to ensure the highest quality and most robust process for commercial manufacturing,” adds Fuderer.

The polymer and composition as well as the equipment and screw design are typically defined in early development at small extruder scale, according to Fuderer. At this stage, it is very important to understand how the material behaves in the extruder to prevent any issues to product quality or processability during scale-up because the opportunities to make changes to the composition later on are limited, he observes.

The processibility of the input material must be considered, says Terefe. For example, he highlights the need to understand the flow properties of the excipients in order to select appropriate feeders and determine pre-extrusion blending requirements.

“Investigating all possible variables that can impact product quality at the early stage can be challenging, however,” Fuderer comments. “Defining a design space that ensures product quality and processability, but also gives enough flexibility for post-development changes performed during lifecycle management (process and cost improvements, yield increases, supplier notifications for raw materials, etc.) is essential,” he concludes.

A well-planned process design that considers all technical and commercial perspectives and the company’s long-term strategy is fundamental, Terefe agrees. “The type of product(s) to be manufactured, the process flow, and unit operations need to be well understood, and the core equipment, along with necessary accessories, process control for each unit operation, and the CQAs of intermediate output material must be identified,” he states.

An effective means for achieving these goals is to use a quality-by-design (QbD) approach, according to Terefe. “A thorough risk assessment of CMAs and CPPs that impact CQAs for each unit operation must be conducted, along with identifying mitigation and control strategies,” he explains.

In addition, because continuous manufacturing aims to facilitate real-time batch release, a good understanding of each unit operation, both independently, and in combination with all other unit operations working in tandem, is essential, according to Terefe. In addition to PAT and real-time process analytics, he notes that model-based process optimization using relevant output data from sensors and processes is important.

It is also highly recommended, notes Fuderer, to keep process requirements for continuous processing in mind when developing HME processes to ensure that not only the HME process is developed to its optimum, but also that the interfaces to the up- and downstream unit operations guarantee final drug product meeting the desired quality.

Furthermore, well-organized and planned process integration into a computerized system that complies with GMP and good automated manufacturing process requirements needs to be established, as do proper IT structures and supervisory and control systems, Tenefe says. Such a centralized computer system that is integrated with various unit operations and PAT tools and provides real-time quality and process control is, in fact, essential for achieving consistent and optimum continuous HME processes, contends Singnurkar.

1. Mahesh R. An FDA Self-Audit of Continuous Manufacturing for Drug Products. FDA Podcast, 

. 28 June 2022. (Accessed March 30, 2023).

When referring to this article, please cite it as Challener, C.A. Continuous Hot-Melt Extrusion for Poorly Soluble APIs. 

Process control is essential for using continuous hot-melt extrusion to enhance solubility.

Continuous Hot-Melt Extrusion for Poorly Soluble APIs

For messenger RNA (mRNA) therapeutics and vaccines formulated as lipid nanoparticles (LNPs), the excipients receiving the most attention are the encapsulating lipids. While these compounds are crucial to the stability and delivery of mRNA-LNPs, the non-lipid excipients also play crucial roles in the function of final drug products. They impact the morphology and stability of these delivery systems, which in turn affects in vivo performance and the overall usefulness of mRNA drugs developed using nanoparticle technology.

The Real Message Behind Commercial mRNA Products

Excipients Impact Stability in mRNA-LNP Formulations

Pharmaceutical Technology’s The Real Message Behind Commercial mRNAProducts eBook

Cynthia A. Challener, PhD has been a freelance technical writer for over 20 years and contributes regularly to 


eBook: The Real Message Behind Commercial mRNA Products
April 2023
Pages: 22–25

When referring to this article, please cite it as Challener, C. A. Excipients Impact Stability in mRNA-LNP Formulations. 

Pharmaceutical Technology's The Real Message Behind Commercial mRNA Products

 This article was originally published in 

Lipids aren’t the only important ingredients influencing stability and in vivo performance.

Stability in mRNA-LNP Formulations

Oligonucleotide drug substances generally are unstable at room temperature, and some are also degraded in the presence of certain enzymes. That is why, in part, they are formulated using special delivery solutions such as lipid nanoparticles (LNPs). (These delivery technologies also facilitate entry of nucleotide APIs into target cells.) Degradation can occur via loss of terminal nucleotides or certain functional groups, oxidation, and other mechanisms. Oligonucleotide–oligonucleotide interactions that can occur at higher concentrations are an added concern. These instability issues must be managed throughout the entire manufacturing process.

The challenges are particularly great for messenger RNA (mRNA), which can be degraded by enzymes found commonly in the environment, temperature, and due to the overall shear sensitivity of the
long-chained molecule.

Managing mRNA Instability During Formulation, Manufacturing, and Shipment

 This article was previously published in 

When referring to this article, please cite it as Challener, C. A. Managing mRNA Instability During Formulation, Manufacturing, and Shipment. 

Unique solutions are required to protect inherently unstable messenger RNA.

Managing mRNA Instability

Many drug molecules, particularly biologics and vaccines, are unstable at room temperature when formulated in aqueous solutions and must be frozen or lyophilized (freeze-dried) to allow their storage and shipment. Freezing and freeze-drying involve harsh conditions that can degrade the active ingredients. Cryoprotectants and lyoprotectants are excipients used in drug product formulations to ensure that safe and efficacious products are obtained following these processes. As such, the quality of those excipients can have a direct impact on the final stability and performance of frozen and lyophilized drugs and vaccines, as explained independently by two industry experts.

Excipients used as cryoprotectants and lyoprotectants serve mainly to protect the drug substance in a formulation from degradation or disassociation during the freezing or freeze-drying process, according to Christy Eatmon, global subject matter expert, sterile drug products, in the pharma services business of Thermo Fisher Scientific. Lyoprotectants also provide a bulking effect so that the resulting dried cakes can be readily reconstituted.

Most cryoprotectants are monosaccharides (sugars), polysaccharides, or polyols, observes Virginie Le Brun, associate director of formulation development for Lonza Drug Product Services. There are limited options, she adds, because only certain excipients are suitable for use in drugs for human use, particular
 parenteral applications.

The selection of the best excipient or combination of materials and their quantity(ies) is dependent on the molecule type, according to Eatmon. She recommends the use of a design-of-experiment (DoE) approach to identify which materials work best with the target drug product.

Take a structured approach to development

Ideally, formulation compositions for drug products that must be frozen or lyophilized should be kept simple. “Whenever possible, just one excipient with sufficient ability to protect, and if necessary act as a bulking agent, should be selected,” Le Brun says. However, she adds that there might be situations where a combination is needed to achieve the most stable formulation conditions.

During formulation development, it is important, observes Heiko Nalenz, associate director of process development for Lonza Drug Product Services, to take a structured approach to development, addressing process challenges during early formulation selection. “Excipient selection should be based on the intended storage conditions and/or compatibility with the freeze-drying process. For this purpose, the thermally induced transitions of the complete product matrix (e.g., glass-transition temperature and collapse temperature) should be characterized,” he explains.

Eatmon agrees, once again underscoring the value of performing selective DoE studies to determine which excipients are most successful for the formulation and product under evaluation. “Characterization is important to understand and develop key parameters of the lyophilization cycle. For example, with a small molecule, it is important to understand whether the molecule is crystalline or amorphous. With that information in hand, the eutectic point or glass-transition temperature should be determined to enable excipient selection,” she comments.In the case of large molecules or more complex formulations, such as dispersions, Eatmon notes that the need for a combination of excipients is more likely.

Quality and purity can have multiple impacts

As with APIs, the quality and purity of lyo/cryoprotectants used in formulations that are frozen or lyophilized is important. “Impurities in materials may cause slight differences in critical attributes, which can lead to incomplete freezing or poor sublimation during the drying process,” Eatmon says. They may also negatively affect the product’s stability in the frozen or freeze-dried state, according to Nalenz. For crystallizing excipients, he points to the potential of varying impurity profiles to increase or decrease their propensity to crystallize, which might impact the quality of the drug component if it ends up in the final product in a non-desirable state.

The biggest potential impact of poor-quality cryo/lyo excipients is, according to Eatmon, for the resulting frozen or lyophilized product to fail to meet acceptance criteria, resulting in rejection of the material. “Robust quality systems should prevent the use of non-compliant materials, but if the quality issue is unexpected, timelines may be delayed while a replacement is sourced. Plans should be in place in advance to efficiently manage this type of scenario,” Eatmon emphasizes.

In addition, variability in the properties of excipients can also create challenges. “Even excipients in compliance with compendial quality specifications may have some variability in their properties or impurity profiles that may impact cryo/lyoprotective properties,” Nalenz remarks. This variability for many cryo/lyoprotectants can be attributed to the fact that they come from plant sources (e.g., starch), according to Le Brun.

Suppliers can help avoid such issues by deeply characterizing the cryo/lyo excipients they produce and obtaining knowledge of how variability might impact their products’ cryo-protective and other properties, observes Nalenz. Drug manufacturers, meanwhile, can for lyophilized products perform lyo cycle tests using different lots of lyoprotectants to ensure that batch-to-batch variability is accounted for in the final formulation, according to Eatmon. She also recommends that conservative measures be taken when developing lyophilization cycles to account for some variability in excipients, upstream drug substances, and drug-product manufacturing processes.

Excipient sourcing and characterization crucial

Appropriate sourcing of any type of excipient is essential to ensuring security of supply and the use of high-quality, compliant materials. For instance, Eatmon stresses the importance of sourcing materials that are intended for pharmaceutical use rather than nutraceutical- or food-grade materials. She also indicates that excipients classified as ultra-pure or low bioburden are preferable for use in injectable products, which comprises most frozen and freeze-dried products. In addition, given the potential for variability in excipient batches, Le Brun emphasizes the importance for formulators of understanding that variability and its impact on the properties of the drug product before selecting a specific excipient supplier.

While common cryo/lyoprotectants and bulking agents are well understood, used in a variety of commercial products, have multiple high-quality sources, and comply with a variety of compendia, there are limited
numbers of them suitable for parenteral applications, according to Eatmon. Other than the challenges related to impurities and variability, Le Brun comments that the limited options can represent a significant hurdle, particularly for newer modalities.

It is hoped that the FDA’s Pilot Program for the Review of Innovation and Modernization of Excipients (referred to as PRIME), which was launched in September 2021 (1), will lead to a regulatory pathway for approval of novel excipients and innovation in the excipients space, including new cryo- and lyoprotectants.

FDA. Center for Drug Evaluation and Research Office of New Drugs Novel Excipient Review Pilot Program. 

Cynthia A. Challener, PhD, is a contributing edtior to 

When referring to this article, please cite it as Challener, C.A. Quality Challenges Associated with Cryo/Lyoprotectants. 

Impurities and batch-to-batch variability present the biggest challenges.