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Particle engineering can be a resourceful tool to advance drug candidates by offering drug delivery innovation.
Particle engineering is a tool that has been employed within the pharmaceutical industry for some time as a way of manipulating the properties of particles to aid in effective delivery of drugs. “Particle engineering, in essence, is not a recent phenomenon,” confirms Peter York, chairman and chief scientist, CrystecPharma. “The idea of ‘particle engineering’ originates from many centuries ago in early Greek, Egyptian, and Roman times as well as later with the apothecaries in the Middle Ages who would use mortar and pestles to grind and blend their ‘concoctions’ to generate fine powders, generally botanical and mineral substances, for preparing their various medicines.”
Putting it in layman’s terms, Salvatore Mercuri, associate director, NPI & MSAT, Lonza Small Molecules, remarks that particle engineering is a means of reducing the particle size of a drug substance so that the surface area can be increased. “Now, the reason for reducing the size can vary depending on the target drug product profile,” he says. “Among those reasons can be to enhance the solubility and bioavailability of a small molecule, bring it down to a specific size to optimize it for a delivery format like a dry powder inhaler or improve content uniformity.”
Controlling the properties of drug particles for the purposes of delivery was established in the mid 20th century, York continues, when products such as metered dose inhalers and dry-powder inhalers were introduced. “Here, the key requirement was to produce formulations containing micron-sized drug particles, or which generated liquid aerosol droplets of similar size, which are required to deposit a drug for localized treatment in the lungs,” he notes. “Similar concern for particle size control, as well as the different dissolution characteristics of crystalline and amorphous forms, had already been recognized at this time for the range of insulin injection products to achieve effective treatment over different time periods for diabetic patients.”
In concurrence, Michael Morgen, R&D director, Lonza Small Molecules, stresses the importance of remembering the wide variety of activities that are incorporated in particle engineering. “[Particle engineering] is a broad and varied set of capabilities for drug development used to solve some of the more difficult problems,” he says. “This makes it a valuable toolbox of solutions for a pharma company or CDMO [contract development and manufacturing organization] to have.”
“From a high-level perspective,” Morgen continues, “[particle engineering] is an enabling capability to control the size, morphology, composition, [and] activity of particles to address various drug delivery challenges. Among other things, one potential goal is to control particle size and morphology to control in-vivo distribution (such as to the lung) or control dissolution rate. Another is to control the drug activity, as seen in spray dried dispersions.”
Even more recently, York points out that the goal of particle engineering has broadened further so that developers can deal with challenging chemicals. “The concept of engineering drug particles has catalyzed the evolution of alternative strategies, new technologies and analytical methods,” he says.
The introduction of the Biopharmaceutics Classification System (BCS) was pivotal to particle engineering as it provided recognition of the two key properties of drugs that were dowminating bioperformance, explains York. “This classification emerged from the growing awareness of the increasing frequency of poor aqueous solubility of the majority of new drug substances, many also exhibiting poor oral absorption profiles,” he says.
“The reduction of particle size of these drugs has, in many cases, aided the formation of effective, efficacious, and quality medicines,” York adds. “Within this field other important aspects of the properties of challenging drug substances have been recognized, such as variety in the solid-state properties (e.g., polymorphism, crystallinity, bioavailability) issues and drug targeting, as well as dealing with the increasing number of biotherapeutic agents.”
Building an understanding of the impact of particle properties and process variables on critical quality attributes of a drug product can be challenging, asserts Mercuri. “This understanding is important in characterizing the mechanical, physical, and/or chemical events taking place during particle formation,” he notes. “However, identifying the optimal processes for a specific API by experimentation can be very costly and time consuming. Especially for small- and mid-sized pharmaceutical companies with limited resources, these inefficiencies can be a huge setback in their commercialization strategy.”
When dealing with advanced drug delivery applications, a balance between two things needs to be made, Morgen specifies. “First, you must achieve the desired in-vivo bioperformance by using the right particle architecture and formulation compositions, which may be very difficult to design. Then, the formulation must also meet the required stability and manufacturability required for a commercial drug product, including scalability,” he explains. “Balancing performance, manufacturability, and stability is not always easy—but doable with the right subject matter experts and facilities.”
“The two most commonly used particle engineering platforms are micronization and amorphous solid dispersion (ASD),” emphasizes Mercuri. “Choosing the right technology will be determined by the API and the target drug product profile.”
ASDs find particular use in enhancing bioavailability and solubility of oral small-molecule drugs, states Morgen. This bioavailability and solubility enhancement is achieved through the conversion of the crystalline drug to the amorphous form using spray drying or hot-melt extrusion, he reveals.
“Amorphous drugs can provide [approximately] 2–100-fold higher dissolved drug levels than the crystalline solubility due to its higher free energy, making it a technology of choice for many compounds,” Morgen asserts. “Recent advances in ASD formulation architecture, such as Lonza’s high loaded dosage forms, reduce dosage form burden of ASD drug products, making them easier for patients to take.”
However, there are challenges associated with this approach, including the prevalence of high-melting point ‘brick dust’ compounds, Morgen warns. “[These compounds] require novel process approaches for formulating as ASDs by solvent-based or thermal processes,” he explains. “A number of recent process innovations have been devised for spray drying these compounds, including heated solvents and processing aids.”
Micronization is well-known and has an established track record, confirms Mercuri. “The process involves using a jet mill to reduce the particle size of APIs down to a few micrometers, thus improving solubility, dissolution rate, or processing,” he says.
The manufacturing process is required for dry powder inhaler applications, which has specific size requirements to enable drug delivery to the lungs and central airways, Mercuri adds. Beyond inhalation applications, micronization also finds use in other types of treatments. “Furthermore, it is highly flexible, can be easily scaled up, is good for substances with poor thermal stability and is easily applicable to different chemical properties,” Mercuri notes.
“A particular challenge [with micronization] is that the properties of the micronized material are different from those of non-micronized material; the increased surface area can result in poor flow and cause electrostatic charge to build up,” Mercuri specifies. “Inadequate flow can cause handling problems in downstream processes, which means that excipients (such as glidants, binders, and lubricants) may be required to improve flow properties. Material can also become more hygroscopic, so storage conditions may require humidity control. To solve these challenges, it’s important to optimize working conditions with critical process parameters.”
In addition to the issues of static, aggregation, and poor flow of materials, York also notes that changes in crystallinity of the drug, batch-to-batch variation, and loss of materials are also frequent occurrences with the ‘top down’ approach of micronization. “Over the last couple of decades, these limiting factors have generated interest in both deeper understanding of the solid state of pharmaceutical materials, drugs, and excipients, and alternative approaches to size reduction,” he says.
“The important technologies that have emerged to date operate on a ‘bottom up’ principle, where the final particle is prepared from a solution feed—essentially drying operations. These processes include spray drying, freeze drying, supercritical fluid (SCF) antisolvent precipitation, and more recently, other approaches have been introduced such as spray freezing, homogenization, liposome structures, the formation of co-crystals, as well as a number of technologies generating nanoparticles,” York asserts. “With an increasing number of biopharmaceuticals being introduced as therapeutic agents requiring particle engineering to achieve particulates suitable for drug delivery, suitable adaptions to existing processes have been made and other approaches introduced such as microfluidics.”
York singles out SCF antisolvent technologies as an approach that has proved successful for CrystecPharma in delivering engineered particles. He states that the process, which is controllable and ‘tunable’, enables the production of particles with the desired physicochemical and biopharmaceutical characteristics at high yield in a single-step scalable process. “The process can operate successfully for both biopharmaceuticals and organic chemical entities,” York says. “In addition, preparing composite particles containing drug(s) and functional excipients provide opportunities for ‘in-particle design’ with uniform particle composition.”
Additionally, as the awareness of the importance of particle engineering in drug delivery has grown, the understanding of the solid state of pharmaceuticals has deepened, York continues. “It is now important for full characterization of polymorphic/solvate/hydrate states, levels of amorphous content, and methods to control these characteristics to be understood to meet regulatory requirements in this field,” he emphasizes.
For York, the opportunity for ‘in-particle design’ is an exciting development in particle engineering as it extends the drug delivery prospects across a range of solid drug products and routes of delivery. “For example, it is possible to consider the assembly of the ‘designer’ particles in an appropriate package, such as a hard capsule, as the final product. Reduced complexity in formulation and manufacture coupled with reduced costs,” he says. “New thinking in particle engineering, underpinned by an increasing flow of knowledge on the solid state of pharmaceutical materials, will continue to address current and emerging challenges in formulation and drug delivery.”
A recent development has been the study of the internal structure of solid dosage forms containing assemblies of drug particles and formulation excipients, and engineered particles, York continues. “Recent studies using high energy X-ray beams in Synchrotron facilities and advanced computational procedures have provided comprehensive visualization of the internal architecture of various solid dosage forms, together with corresponding chemical profiles of constituents,” he says. “This approach, termed Structure Pharmaceutics, has revealed that the supposed uniformity ‘beneath the surface’ is, in many cases, not the observed situation.”
So, through this novel approach, it has been possible to identify different mechanisms and rates of drug dissolution at different locations in tablets, York explains. “For coated products and matrix-based controlled release products, alternative dissolution patterns have been observed within and between individual solid dose units from the same manufactured batch. It is clear that information from these ‘under surface’ studies will provide useful insight for the design of future, optimized solid dosage forms as well as guiding the design of engineered particles,” he specifies.
“Although [particle engineering] is an established technique, there are always opportunities for innovation,” asserts Mercuri. “Advances in computing power may help us develop more accurate models to predict gas flow or better study particle behavior. In addition, improved design, automation, and [artificial intelligence] could be applied to make the process more predictive and reliable.”
Morgen adds that enabling particle engineering approaches are key to advancing early-phase compounds from the preclinical stages to commercialization. “Having broad capability to do a broad range of engineering and to scale these processes is a valuable asset in partnering with drug innovators,” he emphasizes.
“In coming years, it is important that the benefits of drug products containing engineered particles which demonstrate targeted improvements in drug delivery are applied to address wider issues of improving global health care,” York concludes. “The successful technologies will be those which can operate at all scales following facile tech transfer, are inexpensive in cost and operation, are single step, green, and provide high reproducibility.”
Felicity Thomas is the European/senior editor for Pharmaceutical Technology Group.