Print Developing Amorphous Pharmaceuticals: Opportunity and Necessity | American Ph...

Page 1 of 11

Developing Amorphous Pharmaceuticals: Opportunity

and Necessity
Tuesday, August 21, 2012

• Print

Anne Kavanagh, Ph.D.

Ian McConvey, Ph.D.
Jim McCabe, Ph.D.
Helen Blade, Ph.D.
Steve Cosgrove, Ph.D.

• AstraZeneca Pharmaceuticals

Introduction

Amorphous pharmaceuticals represent both opportunity and necessity in pharmaceutical development. The opportunity
arises from the potential to improve bioavailability via use of an amorphous form, rather than a crystalline form. On the
other hand, it is sometimes the case that no crystalline form is available, in which case it is necessary to deal with the
amorphous form. This article will discuss the development of amorphous pharmaceuticals, with reference to three case
studies from within AstraZeneca.

The use of high throughput methods in drug discovery has led to compounds with more lipophilic properties and hence
poor aqueous solubility [1,2], resulting in drugs with dissolution-limited bioavailability. In the case of poorly soluble but
well-permeable drugs (BCS class II), high free energy states such as the amorphous form can significantly improve
‘apparent’ solubility [3,4], often leading to large increases in dissolution rate in the gastro-intestinal tract, thus increasing
the bioavailability. However, since the amorphous form is a highly metastable state, there is a thermodynamic drive
towards crystallization; in some cases even at temperatures below the glass transition temperature (Tg) [5]. In cases
where a crystalline drug has been rendered amorphous, it is common practice to prepare a dispersion of the drug in a
pharmaceutically-acceptable polymer in order to stabilize against crystallization [6]. In some cases, the use of a
dispersion may have a further role in acting as a crystallization inhibitor in vivo [7].

It is sometimes the case that no crystalline form, including salts, co-crystals or pharmaceutically-acceptable solvates, is
available. The amorphous drug may be isolated by a variety of methods including precipitation or desolvation of a
solvate, and the ease of isolation will be affected by the glass transition temperature (Tg) and the extent to which the Tg
is lowered by residual solvent [8]. In some cases, amorphous salts have been found to have a higher Tg than the free
acid or base [9,10], and amorphous dispersions may also be used to improve the physical properties.

http://www.americanpharmaceuticalreview.com/Featured-Articles/119521-Developing-A... 04-10-2012
Print Developing Amorphous Pharmaceuticals: Opportunity and Necessity | American Ph... Page 2 of 11

A brief overview of the preparation and characterization of amorphous pharmaceuticals will be followed by case studies
of (A) an amorphous drug requiring no stabilization, (B) a poorly-soluble drug (BCS class II) in which an amorphous
dispersion is used to achieve improved bioavailability and maintain physical stability and (C) an amorphous drug for
which no crystalline forms are known.

Preparation and Characterization of Amorphous Pharmaceuticals

Amorphous materials can be made in a variety of ways including mechanical treatment, heating (quench cooling or
desolvation) and various solvent-based processes (including rotary evaporation, lyophilization, precipitation and spray-
drying). The case studies here all used spray-drying to produce amorphous API or solid dispersions in quantities ranging
from a few grams to tens of kilograms [11]. Spray-drying has the benefit of exposing the sample to a high temperature
for only a very short time and of providing samples in powdered form requiring no particle size reduction. On the other
hand, spray-drying requires some process development to achieve high yields, and it can sometimes be difficult to find a
solvent suitable for both the drug and the polymer(s) of interest. In assessing the quality of spray-dried material, an
initial, qualitative assessment will typically be based on examination by Polarized Light Microscopy (PLM), Powder X-
Ray Diffraction (XRPD) and Differential Scanning Calorimetry (DSC). These analytical techniques can rule out materials
which clearly contain crystalline drug. Further development of an amorphous form may require quantification of the level
of crystallinity, in particular to determine the level of detection and set a specification for manufacture (described here for
Compound B).

XRPD and vibrational spectroscopy have been used to quantify the amount of crystalline in amorphous drug [12-15],
with levels of detection as low as 0.5 and 1%, depending on the system investigated and the method used, and
detection limits of 0.2% have been achieved by XRPD with synchrotron radiation [16]. Solid State Nuclear Magnetic
Resonance (ssNMR) has also been used to analyze crystalline and amorphous content [17-19].

For both XRPD and vibrational spectroscopy it is necessary to prepare a calibration set by mixing crystalline API with a
suitable amorphous matrix, and this itself is not a trivial exercise. Some of the difficulties which may be encountered
include: ensuring that the crystalline standard is representative of the crystalline material present in the samples,
achieving homogeneity of standards and the physical stability of the standards. ssNMR has the advantage of being a
standardless method; the amount of crystalline material is given by the relative areas of the sharp peaks due to the
crystalline content and the broad peaks of the amorphous component.

Understanding whether an amorphous drug or dispersion is stable with respect to crystallization in the long term is
difficult to address. Storage under stressed conditions such as 40oC/75%RH is often used in order to quickly rule out
drugs or dispersions that are unstable. However, it is recognized that these conditions may not relate to the long-term
storage conditions, particularly since a sample may be taken above the Tg by a combination of moisture sorption and
elevated temperature. In the case of dispersions, phase separation may indicate a lack of long- term stability, and this
may be indicated by the presence of more than one Tg in DSC measurements (for instance, that of the pure drug as well
as that of the dispersion).

A recent addition to the tools available for characterization of amorphous drugs and dispersions is the pair-wise
distribution function approach (PDF). This takes into account all the scattered radiation, including the “halo” observed for
X-ray amorphous samples [20] and describes the probability of finding two atoms separated by a certain distance, r. The
method provides information on short-range order as well as long-range, which makes it of particular value in
understanding amorphous materials. Historically the PDF method has been applied to inorganic materials using

http://www.americanpharmaceuticalreview.com/Featured-Articles/119521-Developing-A... 04-10-2012
Print Developing Amorphous Pharmaceuticals: Opportunity and Necessity | American Ph... Page 3 of 11

synchrotron X-Ray sources, but recently interest has focused on the application to pharmaceutical materials using
laboratory X-Ray sources [21,22].

Figure 1 compares the PDF traces of crystalline, amorphous and nanocrystalline forms of a compound; the XRPD’s
were simulated from the crystal structure using a modeling and simulation application and then the PDF traces were
calculated using PDFGetX2 [23]. It can be seen that for the amorphous example, the PDF indicates the length range
over which the sample is ordered; in this case 10A, while the powder pattern simply shows that the sample is
amorphous.

Case studies

Compound A: An Amorphous API Not Requiring Stabilization

Compound A is an amorphous HCl salt, prepared by spray-drying a crystalline solvate of the salt. Following small-scale
lab trials, the compound was spray-dried at the 50g scale, using methanol as the solvent and achieving a yield of 83%.
Secondary drying was carried out and this achieved a residual methanol content of between 0.05% and 0.8%,
depending on batch and scale of manufacture.

http://www.americanpharmaceuticalreview.com/Featured-Articles/119521-Developing-A... 04-10-2012
Print Developing Amorphous Pharmaceuticals: Opportunity and Necessity | American Ph... Page 4 of 11

The dry Tg of the compound was 127oC (measured

after in-situ drying in the DSC). However, the presence of residual solvent lowered the Tg to values between 68 and
80oC; the exact value varied from batch to batch depending on the amount of residual solvent.

An investigation was carried out into the effect of relative humidity and moisture sorption on the Tg and handling
properties. This was achieved by storing samples over saturated salt solutions for several days and then measuring
moisture content and Tg; results are shown in Figure 2.

This study demonstrated that the drug should be stored with dessicant, and confirmed that secondary drying should aim
to reduce the solvent content as low as practicable in order to maintain the Tg as high as possible. Given the degree of
the plasticization effect of moisture on the compound, the question of whether the compound could be handled under
ambient conditions and still remain a freeflowing powder was addressed with further testing. A sample was held at
25oC/60%RH for 17 days, (at which point the Tg was measured as 52oC); microscopy showed that the morphology of
the particles had not changed and the sample remained a powder, giving an indication that it would be possible to
handle the compound under ambient conditions.

The spray-dried material was of high purity and chemical stability testing demonstrated that storage at room temperature
with desiccant would give an adequate shelf-life. In this case, the amorphous compound is relatively straightforward to
develop for several reasons: the immediate precursor is crystalline (which helps to provide high purity), the isolation
route is a straightforward desolvation by spraydrying, and the Tg of the material is sufficiently high that problems in
handling are avoided.

Compound B: Improving the Bioavailability of a Poorly-soluble Crystalline Drug

The second study, compound B, is a crystalline drug in BCS Class II, i.e. bioavailability limited by dissolution; at doses
higher than 50mg, bioavailability is variable and non-linear, and so use of amorphous drug was investigated. The
amorphous drug had a Tg of 54oC, (prepared by quench-cooling in the DSC and measured under dry conditions), and
crystallization was seen to commence, at room temperature, very soon after amorphous preparation. It was therefore
clearly necessary to stabilize the amorphous drug against crystallization.

A series of dispersions of Compound B with various polymers was prepared at drug loadings of 20 to 50% drug w/w.
These were initially examined by XRPD and DSC, to rule out dispersions which were clearly not effective; for instance,

http://www.americanpharmaceuticalreview.com/Featured-Articles/119521-Developing-A... 04-10-2012
Print Developing Amorphous Pharmaceuticals: Opportunity and Necessity | American Ph... Page 5 of 11

those with a relatively high drug loading were seen to crystallize on heating during DSC measurement, or gave

crystalline XRPD peaks after a short storage time.

The remaining dispersions were evaluated by stability testing, in which samples were stored at a range of conditions
including forced degradation conditions. Samples were tested for physical stability by XRPD and DSC, and dissolution
testing was carried out to confirm that amorphous dispersions did confer advantages over the crystalline form. The lead
dispersion that emerged from this work was a dispersion with HPMCP (hydroxypropyl methyl cellulose phthalate) with a
drug loading of 25% w/w.

The dispersion was manufactured by spray-drying from a solution of acetone containing approximately 12% solids (drug
and polymer combined). Secondary drying was necessary to achieve acceptable solvent levels, and roller compaction
was used to densify the dispersion for formulation. Figure 3 shows the morphology of the dispersion before and after
roller compaction.

Quantitative methods for the detection of

crystalline drug in dispersion were developed for the spray-dried powder. A set of standards containing 1, 2, 3, 5 and
10% crystalline drug by weight was prepared. Using this set of standards, it was possible to devise an XRPD method
with a level of detection of 1% crystalline drug. A NIR method was also developed; this method was in good agreement
with XRPD, had a slightly lower limit of detection than XRPD and has the potential to determine water and acetone
content at the same time as crystallinity. 19F ssNMR was also run on these standards, and it was demonstrated that 1%
crystallinity could be detected. Note that the limit of detection of 1% crystalline is relative to the dispersion and not the
drug; since the drug is 25% of the dispersion, then the level of detection, expressed as a fraction of the drug, is 4%.

Analysis of stability samples showed that crystallization occurred under forced degradation conditions but not at
25oC /60%RH (up to six months). Dissolution testing showed that dissolution failures correlated with the presence of
crystalline material. However, a problem with stability testing was recognized: under forced degradation conditions the

http://www.americanpharmaceuticalreview.com/Featured-Articles/119521-Developing-A... 04-10-2012
Print Developing Amorphous Pharmaceuticals: Opportunity and Necessity | American Ph... Page 6 of 11

polymer was not stable and suffered from impurity growth and a reduction in molecular weight distribution. It is therefore
possible that in this case, accelerated stability testing is inappropriate.

Dissolution testing showed that the amorphous dispersion gave higher solution concentrations at high-dose than did
formulations of the crystalline drug (Figure 5). The impact on bioavailability was that the exposure achieved by the
amorphous dispersion was higher than that from the crystalline drug, and continued to increase as dose increased.

We have retrospectively made simple dispersions of Drug B with various polymers, and applied the PDF analysis

method, with promising results. Examination of the

freshly-prepared dispersion by standard XRPD shows little distinction between the two dispersions while the PDF
suggests that the local order in the second dispersion extends to a slightly longer scale than in the first dispersion. The
dispersions were then held at 40oC/75%RH for 15 days. Optical microscopy (imaged under crossed-polars) shows
crystallization has occurred in the second dispersion, while the first dispersion has remained largely free from
crystallization.

This example of Compound B illustrates that it is possible to stabilize a drug with a low Tg and high propensity to
crystallize. However, this requires a rather high carrier to drug ratio, which may be problematic if a high dose is required.

Compound C Case Study: An Unstable Amorphous Compound without a Crystalline Form

In some cases it is necessary to develop an amorphous pharmaceutical because no crystalline forms can be identified.
As mentioned above, the ease of development of such a compound will be critically dependant on the Tg, both in the dry

http://www.americanpharmaceuticalreview.com/Featured-Articles/119521-Developing-A... 04-10-2012
Print Developing Amorphous Pharmaceuticals: Opportunity and Necessity | American Ph... Page 7 of 11

state and at typical levels of solvent. Compound C is

an amorphous compound which had been subject to many attempts to find a crystalline form, whether the free base or
as a salt, but all attempts were unsuccessful. The drug had a Tg of 70oC when dry but at typical levels of solvent this
could drop to 15oC, and this led to difficulties in isolating and handling the amorphous free base.

Initial precipitation attempts failed to isolate the amorphous solid from the liquors, since the precipitated particles
deliquesced on the filter. However, a low temperature precipitation method was developed in which moisture was
excluded and the solid maintained at a temperature below the Tg during all stages of precipitation and isolation. In this
process, a solution of the drug was added to an anti-solvent at -15°C, during which time particles were formed. The
solvents were then distilled off before filtering the slurry under cold nitrogen.

Spray-drying of the drug was successful on the lab-scale, although the low Tg of the compound limited the choice of
solvent, but the yield was low and the process likely to be impractical at a manufacturing scale since it required ‘open

http://www.americanpharmaceuticalreview.com/Featured-Articles/119521-Developing-A... 04-10-2012
Print Developing Amorphous Pharmaceuticals: Opportunity and Necessity | American Ph... Page 8 of 11

loop’ conditions, i.e. use of fresh, rather than recirculated N2 gas, in order to dry the material effectively.

Some success in improving the ease of precipitation and physical properties was achieved by forming amorphous salts.
The salts prepared, and their Tg values are given in Table 1. Although these salts generally gave an increase in Tg
compared to the free base, they did not achieve adequate chemical stability and so were not progressed further.

Dispersions of the drug with a range of polymers and cyclodextrins (β-CD and HPβCD) were prepared by spray-drying.
The polymers used included: HPMCP, PVP, PVA and copovidone, and these were spray-dried at a drug loading of 10%
w/w, while the cyclodextrins were spray-dried at stoichiometric ratios. Despite generally improving the physical
properties of the compound, most dispersions failed to give an improvement in chemical stability. However, three
dispersions were found to combine an improvement in physical properties with acceptable chemical stability; these were
PVA and the cyclodextrins.

This case study demonstrates the burden placed on the drug development process by a ‘difficult’ amorphous compound.
In the case of Compound C, there is no crystallization process immediately prior to isolation of the amorphous free base
to confer purity, the compound has poor chemical stability, low Tg, has an affinity for solvent and is

hygroscopic. These properties led to difficulties

in isolating the AFB itself, even at small scale, ruled out amorphous salts because of their poor chemical stability, and
severely restricted the carriers that could be used in spray-drying. This particular compound however, did have one
advantage, and that was its low dose, which would allow a low drug loading in a dispersion.

Conclusion

Amorphous pharmaceuticals present the industry with a mixture of opportunities and challenges, ranging from
improvements in the bioavailability of poorly soluble drugs to the isolation and formulation of compounds which will not
crystallize and have poor physical properties. These three case studies demonstrate the range of difficulties associated
with the development of amorphous API with a range of behaviors from ‘well-behaved’ to ‘badly-behaved’.

http://www.americanpharmaceuticalreview.com/Featured-Articles/119521-Developing-A... 04-10-2012
Print Developing Amorphous Pharmaceuticals: Opportunity and Necessity | American Ph... Page 9 of 11

‘Well-behaved’ compounds with an acceptably high Tg, good chemical stability and straightforward isolation route, such
as Compound A should be relatively easy to develop, while at the other extreme, compounds such as C, with low Tg,
poor chemical stability and a complex isolation route will present many challenges. Compounds in which a crystalline
material is rendered amorphous and possibly stabilized by a carrier (Compound B) represent the intermediate case; the
challenge here is clearly to prevent crystallization and ensure that the solubility advantage is maintained and translated
into a biopharmaceutical advantage.

Acknowledgements

The authors are grateful to Steve Cosgrove, David Gray, Dedong Wu, Paul Stott, Steve Holland, Alessia Portieri, Liz
Meehan, Jan Cherryman, Richard Storey (AstraZeneca) and Sarah Gibson (Cambridge University) for sharing data and
helpful discussions.

References

1. G. M. Keseru and G. M. Makara, ‘The Infl uence of Lead discovery Strategies on the Properties of drug Candidates.’
Nature Reviews, Drug Discovery, 8 (2009) 203.

2. C. A. Lipinski, Journal of Pharmacological and Toxicological Methods, 44 (2000), 235

3. B. C. Hancock and M. Parks, ‘What is the true solubility advantage for amorphous pharmaceuticals?’ Pharm Res 17
(2000) 397.

4. B. C. Hancock and G. Zografi , ‘Characteristics and Signifi cance of the Amorphous state’, J. Pharm. Sci., 86, 1997,
pp1-12.

5. T. Wu and L. Yu, ‘Surface Crystallization of Indomethacin Below Tg’. Pharm Res 23 (2006) 2350

6. K. Nagapudi and J. Jona, ‘Amorphous Active Pharmaceutical Ingredients in Preclinical Studies: Preparation,
Characterization and Formulation’, Current Bioactive Compounds, 4 (2008) 213

7. H. R. Guzman, M. Tawa, Z. Zhang, P. Ratanabanangkoon, P. Shaw, C. Gardner, H. Chen, J Moreau, O. Almarsson

and J. F. Remenar, ‘Combined use of crystalline salt forms and precipitation inhibitors to improve oral absorption of
celecoxib from solid oral formulations’ J. Pharm. Sci., 96(10) (2007) 2686.

8. B.C. Hancock and G. Zografi , ‘The Relationship Between the Glass Transition Temperature and the Water Content of
Amorphous Pharmaceutical Solids’, Pharm. Res. 11(4) (1994) 471

9. C.S.Towler, T. Li., H. Wikstrom, D. M. Remick, M. V. Sanchez and L. S. Taylor, ‘An Investigation into the Properties of
Some Amorphous Organic Salts’ Molecular Pharmaceutics, 5 (2008) 946

10. P. Tong, L.S. Taylor and G.Zografi , ‘Influence of Alkali Metal Counterions on the Glass Transition Temperature of
Amorphous Indomethacin Salts’, Pharm Res, 2002 (19) 649

11. I. McConvey, M. Hoyle and O. Nulty, 2009, ‘Reducing the hazards associated with spray drying from laboratory
through to larger scale including considerations for outsourcing and secondary containmentI IChemE Symposium
Series, Hazards XXI

http://www.americanpharmaceuticalreview.com/Featured-Articles/119521-Developing-A... 04-10-2012
Print Developing Amorphous Pharmaceuticals: Opportunity and Necessity | American ... Page 10 of 11

12. L.S. Taylor and G. Zografi , ‘The Quantitative Analysis of Crystallinity Using FT-Raman Spectroscopy’ , Pharm Res,
15(5) (1998) 755

13. R. Surana and R. Suryanarayanan, ‘Quantitation of Crystallinity in Substantially Amorphous Pharmaceuticals and
Study of Crystallization Kinetics by X-Ray Powder Diffractometry’, Powder Diffraction 15(1) (2000) 2

14. I. Fix and K-J. Steffens, ‘Quantifying Low amorphous or Crystalline Amounts of Alpha- Lactose-Monohydrarte Using
X-Ray Powder Diffraction, Near Infrared Spectroscopy and Differential Scanning Calorimetry’ Drug Dev Ind Pharm, 30
(5) (2004) 513

15. C. Clunes, A. Mahendrasingram and R Suryanarayanan, ‘Quantification of Crystallinity in Substantially Amorphous

Materials by Synchrotron X-Ray Powder Diffractometry’ Pharm Res, 22(11) (2005) 1942

16. A. Heinz, C.J. Strachan, K.C. Gordon and T. Rades, ‘Analysis of Solid State Transformations of Pharmaceutical
Compounds Using Vibrational Spectroscopy’ J. Pharm. Pharmacol, 61 (2009) 971

17. R. Lefort, A. De Gusseme, J-F Wilart, F. Danede, and M. Descamps, ’Solid state NMR and DSC Methods for
Quantifying the Amorphous Content in Solid Dosage Forms: an Application to Ball- Milling of Trehalose’ I. J. Pharma 280
(2004) 209.

18. R.K. Harris, ’NMR Studies of Organic Polymorphs and Solvates’, The Analyst, 131 (2006) 351

19. S.J. Byard, S. L. Jackson, A. Smail, M. Bauer, D.C. Apperley, ’Studies on the Crystallinity of a Pharmaceutical
Development Drug Substance’ J. Pharm. Sci. 94 (2005) 1321

20. T. Egami and S. J. L. Billinge, Underneath the Bragg Peaks: Structural Analysis of Complex Materials, Elsevier
Science, Oxford, 2004.

21. S. Bates, G. Zografi , D. Engers, K. Morris, K. Crowley and A. Newman, Analysis of Amorphous and Nanocrystalline
Solids from their X-Ray Diff raction Patterns’ Pharm Res, 23 (2006) 2333

22. A. Newman, D. Engers, S.Bates, I. Ivanisevic, R.C. Kelly and G. Zografi , ‘Characterization of Amorphous
API:Polymer Mixtures Using X-Ray Powder Diff raction’, J. Pharm. Sci, 97 (2008) 4840

23. X. Qiu, J. W. Thompson, and S. J. L. Billinge, ’PDFgetX2: A GUI driven program to obtain the pair distribution
function from X-ray powder diff raction data’, J. Appl. Cryst 37 (2004) 678 Copyright ⓒ International Union of
Crystallography.

Author Biographies

Dr. Anne Kavanagh joined AstraZeneca in 2000, initially in the fi eld of solid state characterization, and more recently
as a Crystallization Scientist. She is particularly interested in exploiting and tailoring the properties of the solid form,
whether crystalline or amorphous, to achieve desirable properties, such as improved bioavailability, ease of handling,
formulation and process robustness.

Dr. Helen Blade (né Hughes) is a Senior Scientist at AstraZeneca. She joined the company in 2007 having gained a
Ph.D. with Professor Matt Rosseinsky at University of Liverpool, UK. Since then she has supported a range of early to
mid-phase projects. Helen has been instrumental in the development of pairwise distribution function with AZ.

http://www.americanpharmaceuticalreview.com/Featured-Articles/119521-Developing-A... 04-10-2012
Print Developing Amorphous Pharmaceuticals: Opportunity and Necessity | American ... Page 11 of 11

Dr. Jim McCabe Astrazeneca joined AstraZeneca Macclesfield 11 years ago, having previously worked for Merck Sharp
and Dohme. His areas of interest include solid-state characterization of pharmaceutical materials, rational screening of
solid forms (polymorphs, solvates and salts), crystallization strategies for poorly crystalline materials, structural aspects
of crystallization from solution and stabilization of amorphous materials.

Dr. Ian McConvey is now an independent Process Consultant. For the past 31 years he has worked in industry and
academia and is a Fellow of the Institution of Chemical Engineers. Whilst at AstraZeneca one of his activities was to
support the early development of spray-drying technology and the subsequent externalization to contract manufacturers.

Dr. Steve Cosgrove has over 17 years experience in the solid state field and has applied this to a wide range of
pharmaceutical projects from very early phase to late phase III. Over this time he has held a number of scientific and
managerial positions relating to commercial development across the UK-US region of AstraZeneca.

http://www.americanpharmaceuticalreview.com/Featured-Articles/119521-Developing-A... 04-10-2012