Seeking Solutions in Solid-State Chemistry

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Pharmaceutical Technology Europe

Pharmaceutical Technology Europe, Pharmaceutical Technology Europe-10-01-2012, Volume 24, Issue 10

The physical form of an API is an important consideration in formulation development. Particle-engineering technologies, such as crystal design for controlling crystallisation and producing cocrystals, particle-size reduction and amorphous solid dispersions, help to optimise delivery of a drug.

The physical form of an API is important in formulation development for resolving issues in bioavailability and solubility. Particle-engineering technologies can be applied in various ways: crystal design for controlling crystallisation and producing cocrystals; particle-size reduction, achieved through jet-milling, wet polishing and nanoparticle generation; and amorphous solid dispersions, produced by several approaches, such as spray-drying, hot-melt extrusion (HME), spray-congealing and inclusion-complex generation. Pharmaceutical Technology Europe discussed these issues with Colin Minchom, vice president, Particle Design Business Unit, at Hovione.

Patricia Van Arnum


PTE: Under what type of situations would cocrystallisation be used? How does it facilitate the delivery of poorly soluble drugs?

Minchom: Interest in cocrystals has increased in recent years, and the recent FDA guidance on a proposed classification of cocrystals has prompted further discussion and counter proposals from the industry. The proposed US FDA classification of cocrystals as crystalline materials containing two or more molecules in the same crystal lattice is limited but can serve as a starting point for discussion.

The addition of a cocrystal former into the crystalline structure of the API changes its physical and chemical properties. It is possible, in some cases, to improve bioavailability to adequate levels while preserving the stability of a crystalline form. For APIs with low glass-transition temperatures, a cocrystal may be favoured over the amorphous form. As such, the use of a cocrystal may be an attractive platform to overcome the solubility limitations of Biopharmaceutics Classification System Class II and Class IV drugs. Cocrystal formation is a favoured approach for increasing apparent aqueous solubility for poorly water-soluble molecules that have no ionisable groups, and for which salt formation is not possible, or for where the physical properties of the salts formed are not desirable.

Solvates and hydrates are well-accepted crystal forms. In many ways, a cocrystal can be thought of as a solvate, but one whose components are solid at room temperature. The cocrystal will form if the resulting crystal is thermodynamically more stable than the components. Resulting cocrystal properties are dependent upon many factors, including the starting properties of the API, the physical properties of the co-former and the mechanism by which the cocrystal is formed.

To increase the probability of success, we [Hovione] recommend that at early-development stages to test other proven platforms, such as solid dispersions, micronised and nanosized crystals and inclusion complexes.

PTE: Controlling nucleation during crystallisation is an important task. What are the mechanisms for controlling crystallisation?

Minchom: Where milling techniques can be thought of as top-down sizing techniques, controlled crystallisation is where the desired particle-size distribution is achieved from the bottom up. The objectives of a crystallisation process are twofold. On the one hand, the aim is to isolate the API in the right crystal form, typically a polymorph that provides the required level of exposure and stability. On the other hand, crystallisation may also be a purification stage, whereby the impurities remain mostly dissolved in the mother liquors.


The kinetics of crystallisation (nucleation and crystal growth rates) are driven by the imposed supersaturation levels. The degree of supersaturation, temperature ramp, mixing, filtration and final drying process all contribute to the final particle-size distribution. Moreover, the relative importance of each factor can change at each scale.

Particle-size reduction

PTE: What factors determine particle size? What are the differences in particle size achieved through jet-milling, wet polishing, and nanoparticle generation?

Minchom: Particle-size reduction is not a simple phenomenon. The mechanism of generating the material of the prescribed particle size has a profound effect upon a range of physical properties that may have a significant effect on the resulting pharmaceutical behaviour. The final particle size of a material subjected to a comminution process is dictated by particle attributes, such as crystal hardness, morphology and original crystal size, as well as the size-reduction method and energy applied. Jet-milling and wet polishing may generate materials with equivalent median particle sizes; however, the resulting span from jet-milled material is likely to be wider than the wet-polished material. Amorphous material and highly reactive surfaces also may result from jet-milling while a higher level of crystallinity is maintained with wet polishing.

Dry methods, such as jet-milling, tend to be more cost-effective (mainly because they do not require sophisticated isolating techniques), but they are more aggressive, less reproducible and more limited in terms of the achievable size reduction.

Amorphous solid dispersions

PTE: What factors determine which method (i.e., spray-drying, HME, spray-congealing and inclusion-complexation generation) to use to produce the amorphous solid dispersion?

Minchom: Amorphous solid dispersions represent a tremendous opportunity for solubility enhancement of oral drugs. The resulting supersaturation levels (and hence bioavailability) and the physical stability of the final dosage form, however, depend on the manufacturing method applied. Many approaches are available to generate amorphous solid dispersions.

Spray-drying, being a solvent method, is the most versatile technique to obtain solid dispersions due to its gentle process conditions and much wider formulation options. Spray-drying is a technology that works well in nearly every compound. Another advantage of spray-drying is that it can be effectively operated using much smaller quantities of drug substance, thereby making it the most cost-effective option during early-stage development.

Melt methods, such as HME and spray-congealing, on the other hand, are more cost effective at the larger scale manufacturing and have the additional advantage of being solvent-free techniques. To use these methods, however, the compound needs to be soluble in the polymer/matrix and physically stable complexes need to be created. These methods are also limited to drug substances that can sustain relatively high heat loads. All these techniques are relatively well-established within the pharmaceutical industry, although spray-drying is a step ahead in terms of maturity.

While challenging at a very small scale, the rationale design of an HME formulation is viable when the API is available in pilot-scale quantities. Where an API has low solubility in all preferred spray-drying solvents or retains extensive solvent following drying, HME may represent the best way forward for the development of a stable amorphous solid dispersion. Spray-congealing can uses a number of lipophilic excipients, which are useful in formulating poorly water-soluble compounds that will form self emulsifying drug-delivery system (SEDD) or self micro-emulsifying drug-delivery systems (SMEDDS) on administration, as well as the polymers commonly used in spray-dried amorphous solid dispersions.

Applying acoustic levitation for elucidation of amorphous material.

Researchers at the US Department of Energy's Argonne National Laboratory have discovered a way to use sound waves to levitate individual droplets of solutions containing pharmaceuticals (1). The research facilitates the process for placing drugs from solution into an amorphous state.

The researchers applied an acoustic levitator that uses two small speakers to generate sound waves at frequencies slightly above the audible range at approximately 22 kilohertz (1). With the proper alignment of the top and bottom speakers, the speakers create two sets of sound waves that produce a standing wave. At certain points along the standing wave, there is no net transfer of energy. The acoustic pressure from the sound waves is sufficient to overcome the effect of gravity, thereby allowing light objects to levitate when placed at these points in the standing wave (1). A video showing the technology may be found at the laboratory's website (

The technology now can produce only small quantities in an amorphous state, but it is considered a useful tool in elucidating the conditions that optimise producing amorphous material.

Argonne National Laboratory's Technology Development & Commercialization Division is developing a patent for the method and is evaluating the technology for licensing for commercial development with pharmaceutical industry partners (1).

Chris Benmore, an X-ray physicist at Argonne National Laboratory, led the study and teamed with various scientists for adapting the technology for drug research. These scientists include Professors Stephen Byrn and Lynne Taylor in the Department of Industrial and Physical Pharmacy in the College of Pharmacy at Purdue University (US) and Professor Jeffrey Yarger of the Department of Chemistry and Biochemistry at Arizona State University (US) and director of the university's Magnetic Resonance Research Centre. The researchers also are now working on identifying drugs most suited to applications with the acoustic levitator.


1. J. Sagoff, "Real-world Levitation to Inspire Better Pharmaceuticals" (Argonne National Laboratory Information, Argonne, IL [US[), Sept. 12, 2012.

Advancing protein crystallisation: microgravity effects and predictive models.

Elucidating the structure and sequence of proteins is an important task in understanding the biological properties of a protein and its potential as a therapeutic target. Producing a well-ordered crystal, particularly for proteins, which can be studied through crystallography, however, is not an easy task. Recent research involves examining the effects of microgravity on protein crystallisation and a computational model for protein elucidation.

Protein crystallisation and microgravity effects

The Centre for the Advancement of Science in Space (CASIS), manager of the International Space Station (ISS) US National Laboratory, is collaborating with Merck & Co. to conduct research on protein crystallisation on board the ISS in 2013. The research will examine the effect on protein crystallisation using microgravity.

In July, CASIS announced its first request for proposals (RFP) focused on advancing protein crystallisation using microgravity. Additionally, in early September 2012, CASIS announced an RFP focused on materials testing in the extreme environment of space. Proposals for this RFP will be accepted until 24 Oct. 2012. The final agreement with Merck is dependent on approval by CASIS' evaluation and prioritisation process, a requirement for all ISS projects. If approved, the research will begin in mid-2013.

"We at Merck are excited to work with CASIS and explore the microgravity effects on several bioprocessing applications within the unique environment of the ISS National Lab," said Paul Reichert, chemistry research fellow at Merck Research Laboratories, in a September CASIS press release.

CASIS is the nonprofit organisation promoting and managing research on board the ISS US National Laboratory, which includes a solicitation for proposals in relation to advancing protein crystallisation using microgravity. The RFP seeks to identify projects within the field of crystallography that CASIS will support through grant funding, facilitation of service provider partnerships, and flight coordination to and from the ISS. Crystallography is the technique used to determine three-dimensional structures of protein molecules. Protein crystallisation, when performed in space, may produce large, better-organised crystals, thereby allowing for more focused drug development. CASIS believes that its RFP will lead to the production of better crystals in the microgravity environment than can be grown on Earth.

"CASIS has evaluated research performed to date in the life sciences and believes it is time to formally test the promising hypothesis that microgravity may produce greater internal order in protein-crystal growth," said CASIS acting Chief Scientist Timothy Yeatman, in a 26-June 2012, CASIS press release. "This could potentially lead to sharper resolution of crystals and their cognate proteins, which could produce more effective drugs for cancer and other debilitating human diseases."

In 2005, the US Congress designated the US portion of the ISS as the nation's newest national laboratory to maximise its use for improving life on Earth, promoting collaboration among diverse users, and advancing science, technology, engineering and mathematics education. The laboratory environment is available for use by other US government agencies and by academic and private institutions to provide access to the permanent microgravity setting, vantage point in low-earth orbit and varied environments of space.

Computational approaches for protein elucidation

Determining the structure and sequence of proteins is an important part of understanding the protein's biological properties and potential utility as a drug. Designing predetermined crystal structures, however, can be subtle given the complexity of proteins and the noncovalent interactions that govern crystallisation (1). Researchers at the University of Pennsylvania recently reported on a computational approach for the design or proteins that self-assemble in three dimensions to yield macroscopic crystals (1).

"People have designed crystals out of smaller, much less complex molecules than proteins, but protein design is much more subtle," said Jeffrey G Saven, associate professor of chemistry and biological and theoretical physical chemistry at the University of Pennsylvania, in a university press release. Saven conducted the research and recently reported on its results (1). Protein crystals are attractive as a nano-scale building material because their properties, particularly their exterior surfaces, are highly customisable, according to the university release.

The researchers targeted a crystal built using a relatively small protein containing a sequence of 26 amino acid positions. The researchers assigned specific amino acids to eight of the positions, but with 18 different types of amino acid to choose from for each of the remaining 18 slots, the algorithm addressed well more than 1022 potential combinations. The researchers accounted for other characteristics, such as the spacing between proteins and their orientation with respect to one another, increasing the variables being considered, according to the release.

"We worked on synthesising both of those steps, doing the characterisation of structure and the sequence at the same time," said Saven said in the university release. "As we move through this process, we eliminate things that will never work, such as proteins where atoms overlap in space or where amino acids don't fit into a given site. At the same time, we identify proteins that, as you vary the structure, are likely to yield a crystal."

Specifically, the research used a three-helix coiled-coil protein designed de novo to form a polar, layered, three-dimensional crystal having the P6 space group, which had a "honeycomb-like" structure and hexameric channels that spanned the crystal (1). The approach involved creating an ensemble of crystalline structures consistent with the targeted symmetry, characterising this ensemble to identify "designable" structures from minima in the sequence–structure energy landscape and designing sequences for these structures, and experimentally characterising candidate proteins. This approach to crystal design has potential applications to the de novo design of nanostructured materials and to the modification of natural proteins to facilitate X-ray crystallographic analysis.

The target crystal the researchers produced is a proof of concept. "There's still much we don't know about the interactions that govern crystallisation," Saven said, in the university release. "With this technique, we can explore what those interactions are or how we might take an existing protein and engineer those interactions so we get much better structures."


1. J.G. Saven et al, PNAS, 109 (19), 7304–7309 (2012).

Patricia Van Arnum is executive editor of Pharmaceutical Technology Europe.