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The oral route remains the most preferred method for delivering drugs. It offers good patient compliance due to its acceptability, convenience, and ease of administration. Moreover, the overall production costs for oral formulations are less expensive because they do not require sterile manufacturing conditions. The development of a successful and effective oral dosage form, however, is often faced with a number of challenges such as drug instability in the acid or alkaline environments of the gastrointestinal (GI) tract and unsatisfactory absorption of compounds with poor physicochemical properties. Solubility, dissolution, and the ability of a drug molecule to permeate the GI membrane are fundamental parameters for effective delivery of oral formulations.

Advances in combinatorial chemistry and high-throughput screening have led to an increasing number of poorly soluble drugs in the development pipeline and the need to develop technologies that address solubility issues has never been more crucial. One approach that is becoming increasingly popular is the use of amorphous solid dispersions because of their broad applicability, observes Kevin O’Donnell, PhD, senior chemist at Dow Pharma & Food Solutions. Traditional methods rely on certain API properties to be successful, according to O’Donnell. “For example, salt formation requires the API to be ionizable and complexing agents such as cyclodextrins require the drug to fit within the complexing ring.”

“For solid dispersions, it is a matter of rendering and maintaining the drug in the amorphous state and/or adequately dispersing it within a carrier matrix using one of many available technologies,” O’Donnell explains. “While drug-carrier incompatibilities may exist, requiring careful excipient selection, there is no distinct property required of the API for formulation into a solid dispersion. In addition to this breadth, solid dispersions can often provide a significant increase in solubility compared to other formulation approaches. This advantage is largely due to the amorphous state of the API and to the hydrophilic nature of the surrounding matrix material that can aid in wetting once exposed to the aqueous biological media. Furthermore, solid dispersions allow for unique intellectual property to be obtained, thereby aiding in the lifecycle management of existing compounds and maximizing a drug’s economic potential.”

The number of commercial products based on solid dispersion technologies is growing–for example, Kaletra (AbbVie) and Sporanox (Janssen)–which means that the technologies are becoming more established and the regulators are becoming more comfortable with such formulations,” notes Ian Barker, PhD, project scientist at Molecular Profiles. “The amorphous solid dispersion strategy for enhancing drug solubility is attractive for several reasons,” he continues. “The formulation is relatively simple, consisting of principally the drug and a polymer, and potentially suitable for a wide range of drug compounds and drug loadings. This approach is well suited for downstream processing into conventional oral dosage forms, such as capsules or tablets.”

Solid dispersions for solubility enhancement
“Amorphous solid dispersions can be produced with various technologies, such as hot-melt extrusion (HME) and spray drying,” explains Min Park, group product manager, Advanced Delivery Technologies, Catalent Pharma Solutions. “These amorphous technologies offer a lot of flexibility in terms of use of polymers/excipients and process parameters that suit the physicochemical properties of a particular water-insoluble API. HME and spray drying are also scalable technologies, meaning that they are ideally suited for use in the production of solid dispersions.

Spray drying seems to be more popular and available than HME, observes Paul Titley, business development director of Aesica Pharmaceuticals, “but time may even the score,” he adds. “Both technologies can produce the amorphous materials desired but they expose the API to very different processing conditions. HME applies more heat to the API than spray drying. The API in an extruder will be heated to high temperatures (approaching 200 °C) and remain there for longer than in a spray drier. This is not a problem for robust APIs, but some will degrade at the high temperatures inside an HME.” Titley points out that spray driers also operate at high temperatures, but the API exposure is for a fraction of the time in an HME.

“The physical forms of the amorphous products are very different,” Titley explains. “Spray drying creates a fine powder, whereas HME creates a granular crumb, and therefore, different dosage form options. But both approaches can produce tablets or capsules. Spray drying always requires a solvent, sometimes water, but often organic and even flammable organic solvents. Such solvents must be scrubbed from the exhaust gas (air or nitrogen) at not inconsiderable expense. Processing costs of HME center on the heating and cooling of the extrusion barrel. Ultimately, the physical size of the equipment will need to be addressed. A large spray drier is a significant installation (similar to installing a fluid bed drier), and they are not portable. A large HME is hardly portable but need not be as permanent a fixture. Both technologies are offered by CDMOs and concerns over installation can be outsourced.”

Key considerations in the method selection process
The selection of a particular technology will mainly depend on the physicochemical characteristics of the given drug and the drug loading required for the formulation, says Park. “The low solubility of the API in solvents, the melting point, and the glass transition temperature of the API (lower than 220 °C) will dictate the use of HME technology in producing solid dispersions. The lipophilicity of the API is also an important factor in selecting the technology, as higher log P leads to lower drug loading in the formulation.”

According to O’Donnell, HME is unlikely to be a successful option for drugs that display thermal and shear instabilities, and the formulator should consider an alternative technology such as spray drying. “This may also be true for APIs with very high melting points as it may be difficult to process into a solid dispersion while operating at temperatures at which pharmaceutical polymers are stable,” he adds. “Conversely, drugs that are poorly soluble in solvent systems reasonable for use in the pharmaceutical industry are inappropriate for spray drying. In such a case, the solids load in the feed solution may be too low for the process to be economically viable or an undesirable solvent may be employed creating regulatory concerns.”

O’Donnell notes that the limited quantities of API available in early development often leads formulators towards spray drying because laboratory-scale equipment consumes a minimal amount of product. However, he points out that recent advances by manufacturers to miniaturize hot-melt extruders are allowing formulators to utilize HME at much earlier stages in development and assess it as a potential path forward. “The formulator’s experience/expertise and in-house capabilities may directly influence which method is chosen,” says O’Donnell. “Overall, the preferred method will be one that allows for successful formulation of the API into a commercial product.”

Barker explains that the initial screening exercise would typically focus on determining the miscibility and stability of the drug substance in a range of polymers, often using a film-casting approach to prepare the samples (pre-dissolving drug and polymer in a common solvent and then evaporating off the solvent). “This process is similar to what happens in a spray-drying process, so arguably spray-drying is always the first option evaluated. However, if a drug has relatively low melting point (< 180 °C) and is chemically stable when heated to its melting point, then HME is considered as an alternative process for producing the amorphous drug/polymer intermediate.” According to Barker, HME is often the favored option because it is a simple manufacturing process that is suitable for continuous processing and is therefore cost efficient. It produces a dense, granular material that is easily further processed into capsule or tablet dosage forms; and it involves no use of solvents.

Weighing the pros and cons of each technology
Spray drying is a physically gentle process but it involves the use of solvents, says Titley. The API must first be dissolved in the spray-drying solvent (usually organic), and the range of solvents available increases the likelihood that a solution can be produced. According to Titley, the expected dose and the amount of API available will influence the method selection. “Spray drying can be carried out using extremely small amounts of API as low as 100 mg, whereas HME requires sufficient material to fill the extruder (even a small one) and consumes a few grams.”

HME, however, is a solvent-free process, and this attribute in itself is a huge advantage in formulation development and manufacturing. “Being a solvent-free process not only allows formulators to work with APIs that are poorly soluble in pharmaceutical solvent systems but eliminates certain issues such as potential residual solvent in the final product, which can reduce the physical stability of an amorphous solid dispersion and may create regulatory concerns. Additionally, the removal of solvents from the process decreases costs and increases worker safety,” O’Donnell points out. “Furthermore, it is a continuous process, which minimizes production downtime, decreases product variability, and lowers costs. HME is more flexible in terms of the final product as well as it can directly produce strands, pellets, films, tubes, core/shell systems, granules, and various shapes allowing the manufacture of a wide variety of dosage forms to deliver a solid dispersion,” O’Donnell continues.

In HME, the API is dissolved or melted in the host polymer, explains Titley. “The API may not withstand the heat and may not dissolve completely in the desired excipient. Therefore, in early development, where API is scarce and the number of experimental batches may be high, spray drying may be the only choice. In later development stages, however, if the API exposure conditions permit, HME has advantages of lower energy and lower waste costs. Moreover, the HME equipment occupies a much smaller footprint than equivalent spray driers.”

Park adds that HME offers a lot of flexibility with the use of excipients and process parameters to achieve the desired drug loading with good physical stability. One disadvantage with HME is the degradation of APIs that have a degradation profile close to their melting point, Park notes. “At Catalent Pharma Solutions, our Optimelt platform is capable of dealing with the challenges presented by such APIs using a unique approach to the development of oral solid dosage forms,” says Park. “It encompasses integrating the preformulation characteristics of the API with melt extrusion process parameters through the help of key indicators, such as the specific mechanical energy input, the residence time distribution, and the degree of fill, among others.”

O’Donnell agrees that the production of solid dispersions of thermally or shear-sensitive APIs is a problem with HME that spray drying does not have. “The formulator will also see greater success using spray drying for drugs with high melting points as temperatures capable of generating the amorphous dispersions of these drugs may degrade the polymeric carrier or other formulation components,” observes O’Donnell. “Additionally, spray-dried dispersions have a very small particle size, thereby increasing the surface area significantly, which greatly increases the dissolution rate of the formulation. Similar particle sizes may be obtained following HME through milling. However, this may induce recrystallization of the drug resulting in a detrimental change in the dissolution rate of the final formulation,” he adds.

Scale-up challenges
Scale up of spray drying has the objective of maintaining the particle characteristics and maximizing the yield of the process, according to Titley. “Spray driers can be constructed with either single-pass or closed-loop airflow. The practicalities of the process do not change–if nozzles didn’t block at small scale, they should not block at larger scale. However, the distance between the nozzle and the collection chamber wall will be greater, hence the dried particle will also tend to be bigger.”

Titley explains that subtle changes to the processing conditions can be made following calculations of input temperature and air volume to reproduce the original (small-scale) drying or residence time of the droplets. “The increased particle size may be marginal and the crucial test is the rate of dissolution,” he points out. “Residual solvents must be assayed and processing conditions adjusted to reduce them to a minimum. The large volumes of liquid, size of vessels, assembly/disassembly of a large spray drier, and safe collection of the powder need serious consideration.”

HME is an efficient and versatile process, observes Barker. “Increasing the batch size is often simply a case of feeding more material into the extruder and running it for longer,” he explains. In scaling up from development or pilot scale to commercial scale, consideration needs to be given to determining the required processing parameters (e.g., temperature and shear rate) on a larger extruder to produce satisfactory extrudate, according to Barker.

O’Donnell adds that the exposure to temperature in terms of residence time distribution and heat transfer (as well as mass transfer) must be well understood. “Shear exposure is also crucial in regards to both dispersive and distributive mixing. Simplifying these, the former requires the same number of divisions per kilogram be maintained while the latter requires the same stress rate be applied,” O’Donnell says. “Devolatilization must also be considered when scaling up to ensure proper removal of any off-gassed byproducts or water vapor. Each of these aspects presents a unique challenge to the formulator; however, adjustment based on scale can be made through empirical calculation with some assumptions being made.”

Recent advances in the manufacture of solid dispersions
In recent years, the most notable advancement in pharmaceutical extrusion equipment has been the miniaturization of the systems, observes O’Donnell. “Prior to this, HME was limited in adoption at early stages of development due to the large quantity of API required for the trials,” O’Donnell comments. “Today, new laboratory-scale extruders, such as the Leistritz Nano 16 and Nano 12, Thermo Pharma 11, and Steer OMicron 12, require significantly less material for individual trials, thereby allowing for rapid process and formulation development of early stage pipeline compounds.”

For Barker, the greatest progress in HME has been in the types of excipients available for the formulation development of solid dispersions. “Whilst the principles of HME have remained relatively constant, considerable changes in the excipients used have been observed,” Barker remarks. These excipients include AFFINISOL HPMC HME (Hypromellose) from The Dow Chemical Company and BASF’s polyvinyl caprolacta-polyvinyl acetate-polyethylene glycol graft copolymer, Soluplus. “Notably, the introduction of functional polymers has widened the pool of matrices available, providing a greater chemical tool kit to solve difficult formulation challenges,” says Barker. “The increased processability of these materials allows for extrusion over a broad range of operating conditions, facilitating solid dispersion manufacture for a wide variety of APIs,” adds O’Donnell.

Quality by design
As amorphous solid dispersions are often formulated for Biopharmaceutics Classification System (BCS) Class II and Class IV APIs, the critical quality attributes (CQAs) for a product in development are dissolution, bioavailability, and solid-state stability, explains O’Donnell. “The acceptable target for each CQA should be identified early in development to define what the final product will be in terms of ideal performance,” O’Donnell points out. “Once identified, a design of experiments (DoE) can be employed to determine the influence of the process parameters on the CQAs. The understanding of the process variables on the CQAs allows the formulator to identify the design space acceptable for consistent product quality thereby implementing quality by design (QbD).”

The development of a spray-dried product is a relatively straightforward process that can be split into several distinct sections, according to Titley. “This stepwise nature lends itself to a measured QbD approach,” observes Titley. Once the solvent system and formulation is settled, the process can be examined using the following:

  • Critical process parameters (CPPs): inlet temperature, solution flow, and gas flow (aspiration) rates.
  • CQAs: particle size, moisture content, percent yield, and crystallinity.

Titley refers to Kumar et al. who recorded these findings for their subject formulation by following a QbD protocol. The study identified inlet temperature as the only significant factor to affect dry powder particle size. Higher inlet temperatures caused drug surface melting and hence aggregation of the dried nanocrystalline powders. Aspiration and solution flow rates were identified as significant factors affecting yield. Higher yields were obtained at higher aspiration and lower solution flow rates (1).

For HME processes, the main CPPs to be considered in the design space are screw speed, barrel temperature, and degree of fill, says Park. “These scale-independent process parameters affect the product quality attributes, such as residence time distribution, specific energy, and melt temperature,” he adds. “Process analytical technology (PAT) tools can be used for measuring residence time distribution to design experiments in the QbD space. A set of DoE studies are used to determine the process response parameters that are critical to product quality, as well as to define the optimal process parameters that will guide the long-term process development and prove to be necessary to establish a reproducible process. The determined link between process responses and quality attributes of a drug product will be useful, regardless of equipment scale or brand,” Park concludes.

1. S. Kumar et al., Int J Pharm 464 (1-2) 234-242 (2014).

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