Managing risk associated with crystal polymorphism in pharmaceutical development
Submitting InstitutionUniversity of Greenwich
Unit of AssessmentChemistry
Summary Impact TypeTechnological
Research Subject Area(s)
Chemical Sciences: Analytical Chemistry, Inorganic Chemistry, Physical Chemistry (incl. Structural)
Summary of the impact
Nearly all solid dosage forms contain drugs in crystalline form; and all
crystals have the potential to `morph', suddenly, into different forms
which can affect the safety and efficacy of the medicinal product. A
number of high-profile cases in which marketed medicines had to be
withdrawn [Lee, et al., Annu. Rev. Chem. Biomol. Eng. 2011,
2, 259-280] led multinational drug company Pfizer to conclude that
a greater understanding of polymorphism was required to enable drug
product design for the 21st Century. The University of
Greenwich pioneered methods to predict crystal behaviour on the shelf and
during manufacture that were affordable, timely and effective. It enabled
Pfizer to select the optimal polymorphic drug form and manage risk
associated with uncontrolled solid-state transformations, thereby
safeguarding patients and avoiding huge costs.
Polymorphism is a phenomenon where drug molecules can adopt multiple
crystalline packing arrangements or conformations in the solid state. It
affects manufacturing performance, the stability of formulated medicines
and the extent of oral absorption and hence the dose. An optimal
polymorphic drug form must be selected that is thermodynamically stable.
Pfizer did not have the analytical tools to provide a deep knowledge of
the emerging importance of polymorphism. Pfizer identified Martin
Snowden, with expertise in surface and colloid chemistry, and John
Mitchell, a physical organic chemist, to lead research to develop
the technology in four areas. Stephen Wicks, Vice President of
Pharmaceutical Science and Technology and UK Development Director at
Pfizer, led the technology transfer project.
2.1 Production of highly pure crystals for physical and mechanical
Flash-Liquid Chromatography is a purification method of choice for
preparative separations of drug molecules. Flash-LC had limited ability to
produce pure fractions for routine solid-state characterisation because of
its reliance on UV detection: important organic solvents used to achieve
high purity levels had high UV cut-offs; many new drug candidates lacked
significant chromophores. The Evaporative Light Scattering Detector (ELSD)
was adapted for use with Flash-LC to allow the routine preparation of
Active Pharmaceutical Ingredients (APIs) for materials science analysis
when UV detection was not possible. [3.1.1 and 3.1.2]
2.2 Characterisation of crystal disorder to predict catastrophic
Single-crystal X-ray diffraction produces a complete model of a
material's molecular and solid-state structure. Ab.initio
prediction of crystal structure is also possible. The practice was
considered using a combination of structural information and structure
prediction methodologies to develop powerful structure prediction
procedures for drug crystals and more complex solid-state forms, e.g.
2.3 Prediction of processing properties of pharmaceutical powders
using single crystals
Manufacturing processes can be problematic when drug crystals deform
elastically in production machinery. Particle physics investigations
required large quantities of pure, expensive crystalline drug.
Consequently such studies were deferred to a point in the development
programme where change, however desirable, was impractical. Indentation
techniques were developed using highly purified single crystals to
investigate the processing performance of drug candidate crystals, very
early in the development process, to provide the opportunity to engineer
and substitute improved solid-state variants to avoid processing problems.
2.4 Chemical imaging of pharmaceutical products
Conventional analytical techniques sample the average bulk
characteristics of pharmaceutical products. It is possible to determine
the total drug content in a tablet but not the distribution of particles
within a matrix formed with other formulation excipients. With spatial and
chemical information, obtained using near infrared and Raman spectroscopy,
it is possible to generate chemical images of each ingredient within the
formulation. The physicochemical form of drug, in the presence of
excipient particles, in the sample can be determined along with the size
of any material clustering and spatial position relative to other
components. The interface with processing machinery can also be
determined. This research increased process understanding and material
attributes associated with the clinical performance of the product.
References to the research
3.1.1 Mathews, B. T., Higginson, P. D., Lyons, R., Mitchell, J. C.,
Sach, N. W., Snowden, M. J., Taylor, M. R., & Wright, A.G.
(2004). Improving Quantitative Measurements for the Evaporative Light
Scattering Detector. Chromatographia, 60(11-12), 625-633.
3.1.2 Dubant, S., Mathews, B., Higginson, P., & Crook, R., Snowden
M.J., Mitchell, J.C., (2008). Practical solvent system selection for
counter-current separation of pharmaceutical compounds. Journal of
Chromatography A, 1207(102), 190-192.
3.3.1 Taylor L. J., Papadopoulos D. G., Dunn P. J., Bentham A. C., Dawson
N. J., Mitchell J. C. & Snowden M. J. (2004).
Predictive milling of pharmaceutical materials using nanoindentation of
single crystals, Organic Process Research & Development, 8(4),
3.3.2 Taylor L. J., Papadopoulos D. G., Dunn P. J., Bentham A. C., Mitchell
J. C., & Snowden M. J. (2004), Mechanical
characterisation of powders using nanoindentation, Powder Technology,
143-144, 179-185. http://dx.doi.org/10.1016/j.powtec.2004.04.012
3.4.1 Šašić, S., Clark, D. A., Mitchell, J. C., & Snowden,
M. J. (2005). Raman line mapping as a fast method for analyzing
pharmaceutical bead formulations. Analyst, 130(11),
3.4.2 Šašić, S., Clark D. A., Mitchell, J. C. and Snowden M.
J., (2005). Analysing Raman images of pharmaceutical products by
sample-sample 2D correlation, Appl. Spec., 59, (5),
3.4.3 Šašić, S., Clark, D. A., Mitchell, J. C., & Snowden,
M. J. (2004). A comparison of Raman chemical images produced by
univariate and multivariate data processing—a simulation with an example
from pharmaceutical practice. Analyst, 129(11), 1001-1007.
3.4.4 Brody, R.H., Kierstan, K.T.E., Clark, D.A., Mitchell, J.C.
& Snowden, M.J. (2003). Analysis of challenging pharmaceutical
samples using chemical and elemental images. Microscopy and
Microanalysis, 9 (Suppl. 02), 1108-1109.
Details of the impact
Nearly all solid medicines like tablets and capsules contain drugs in
crystalline form; and all crystals have the potential to `morph' into not
one but many alternative forms. The likelihood of the crystals actually
changing and becoming a danger to patients is very small but it can and
does happen, with catastrophic consequences.
In 1988, a clinical failure of Tegretol (carbamazepine) tablets, the
anticonvulsant widely used with epilepsy, was observed. It was believed to
be caused by a phase conversion from the anhydrate to dehydrate form. In
1998 Abbott Laboratories withdrew Norvir (ritonavir), essential at that
time in the treatment of HIV/AIDS, because the capsules unexpectedly
failed dissolution tests. The public were without an essential drug while
researchers investigated. They finally identified that the drug crystals
had changed into a more stable, less soluble polymorph which contaminated
laboratories and effectively halted production processes. They had to
completely reformulate the drug and develop a new capsule product. The
case cost Abbott hundreds of millions of dollars and over 600 scientists
working for nearly a year to resolve the issue. The estimated loss in
sales in 1998 alone is $250m.
Pfizer experienced similar problems with two drugs in development and
concluded that a deeper scientific knowledge of polymorphism was an
emerging need in the pharmaceutical industry. The consequences were
typically catastrophic, hard to predict, clinically and economically
unacceptable, and damaging to patients' trust in the company to produce
the quality products they relied on.
Pfizer identified internal and external drivers for the need to
understand polymorphism on a more scientifically rigorous basis. These
- emphasis on the chemical rather than physical attributes of drugs and
- the instrumentation used to characterise polymorphism was relatively
simplistic and unable to predict the potential for phase transition;
- the existing protocols to test physical performance required large
quantities of expensive pure solid drug, and occurred too late in the
development process to stimulate the re-engineering of defective
crystalline drug forms;
- an industry-wide drive for more rapid drug development and clinical
Pfizer turned to the University of Greenwich to develop the scientific
- produce small quantities of highly purified drug crystals, alone and
in drug product matrices, from side streams of conventional pilot
- use the pure drugs to develop tests on single crystals, a process
which is much cheaper and can be performed at the start rather than end
of the drug development process;
- develop tests that could predict polymorph instability and how they
behave during manufacture, and in turn allow the engineering and
understanding of new solid-state forms for development.
Since 2008 Pfizer has been able to apply the resulting methodologies,
systematically to the development of crystalline APIs for use in solid
oral and inhalation dosage forms. The company has also applied them to
understand the risk for products licensed from other companies not using
this scientific paradigm. Pfizer has invested £2.4m in the university to
date. The programme has resulted in critical technology and human resource
transfer to the company as well as 27 refereed publications. To date 24
researchers have progressed through the scheme; 40% have taken up posts
within Pfizer and 42% with other leading pharmaceutical companies.
The larger impacts are that Pfizer has vastly reduced the risk of
polymorphism in its drugs, increasing the confidence of patients and
health professionals. Examples of what might have happened without the
university's pioneering research abound, for instance to UCB with
Parkinson's disease drug rotigotine. Filed in 2003 as a drug that did not
exhibit polymorphism, rotigotine was delivered through Neupro skin patches
and many patients experienced an improved quality of life. In 2008,
dendritic structures were observed: a new form polymorph had crystallised
which reduced the patches' efficacy. The product was withdrawn in the US
in 2008 and did not return to the market until 2012. Similarly, in 2010
BMS withdrew 64 million Avalide tablets (hydrochlorthiazide and
irbesartan) over concerns that irbesartan crystals had converted to a less
soluble polymorph. Avalide sales were calculated to be $310 million in the
first nine months of 2010. Pfizer is able to safeguard its patients and
avoid the cost associated with recalls and the redevelopment and relaunch
of clinically essential products.
Sources to corroborate the impact
5.1 Letter of Corroboration from Pfizer Inc. A
corroborating letter is available from the R&D Director, Pfizer Ltd.
The contact for communication the Senior Director and Head of Materials
Science Pfizer Ltd.
5.2 Corroborating Pfizer Publications. The following
publications, by Pfizer lead authors, confirm the application and
development of the tools and techniques developed by the Pfizer-University
of Greenwich partnership.
5.2.1. Extracting process-related information from pharmaceutical
dosage forms using near infrared microscopy, Fiona Clarke,
Vibrational Spectroscopy 2004 34 25-35
5.2.2. Evaluating particle hardness of pharmaceutical solids using AFM
nanoindentation Victoria M. Masterson, Xiaoping Cao International
Journal of Pharmaceutics 2008 362 163-171.
5.2.3. Chemical imaging of pharmaceutical granules by Raman global
illumination and near- infrared mapping platforms Slobodan Sasic
Analytica Chimica Acta 2008 611 73-79.
5.2.4. Scalable Technology for the Extraction of Pharmaceutics
(STEP): The transition from academic know how to industrial reality,
Ian Sutherland, Svetlana Ignatova, Peter Hewitson, Lee Janaway, Philip
Wood, Neil Edwards, Guy Harris, Hacer Guzlek, David Keay, Keith Freebairn,
David Johns, Nathalie Douillet, Chris Thickitt, Elsa Vilminot, Ben
Mathews, Journal of Chromatography A, 2011 1218 6114- 6121.