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A focus on chasing pharmaceutical polyamorphs to

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Cite this: DOI: 10.1039/d4sc90250e

design better oral drug formulations
Open Access Article. Published on 27 January 2025. Downloaded on 1/27/2025 8:33:08 PM.

All publication charges for this article Ana M. Belenguer

have been paid for by the Royal Society
of Chemistry The pharmaceutical industry cares about reducing toxic side effects of drugs in oral formulation. The best
solution is to reduce the drug dose. To do so, drugs are required to have high aqueous solubility to ensure
good bioavailability. Amorphous drugs are much more water soluble than their crystalline counterparts, but
can lack physical stability. Martins and Rades, et al. (I. C. B. Martins and T. Rades et al., Chem. Sci., 2023, 14,
11447–11455, DOI: https://doi.org/10.1039/D3SC02802J) demonstrate for the first time that polyamorphs
(amorphous polymorphs) of drugs are now a reality. They demonstrated proof-of-concept, reproducible
preparation methods for 3 polyamorphs (I, II and III) of hydrochlorothiazide (HCT) that display different
glass transitions temperatures (Tg) and distinct structural relaxation profiles as excellent analytical
indicators for discriminating between the polyamorphs. HCT polyamorph-II displayed improved physical
stability with respect to the other HCT polyamorphs. A tangible benefit of polyamorphism research is the
DOI: 10.1039/d4sc90250e
opportunity to select a specific polyamorph of a drug with the desired solubility and physical stability to
rsc.li/chemical-science be incorporated in an oral formulation, a strategy that should improve drug effectiveness.

The most obvious criterion between (DSC) on the emergence of the glass
a medicinal or poisonous effect of any transition temperature Tg, as illustrated
substance is its dose. Signicantly in Fig. 1. Only below the Tg does the solid
lowering the dose of a drug in a medic- stay in the amorphous state (also named
inal formulation is the key to reducing the glass state). Above the Tg, the solid
the toxic side effects currently affecting becomes rubbery (named a supercooled
many oral formulations prepared with liquid/melt) and can even crystallise.
crystalline drugs. Good bioavailability of Crystalline solids can be rendered amor-
drugs in oral formulations requires them phous by processes such as spray drying
to present good solubility in water as (SD), quench cooling (QC) and ball
a surrogate measure of their solubility in milling (BM). BM is the most commonly
aqueous body uids. However, the solu- employed technique to prepare amor-
bility of crystalline materials is limited by phous forms, but for drugs, only those
their intermolecular long-range order, with a Tg well above the ambient
where high energy is required to disrupt temperature can become amorphized by
these interactions. BM.1 If a drug compound has a lower Tg
The research community has been than the ambient temperature, it will Fig. 1 Bottom: conceptual illustration of the
investigating a problematic but effective become crystalline upon milling.2 Since energetic and organisational behaviour of ①
solution. Drug solubility is greatly BM is typically performed at ambient crystalline and ④ amorphous solids with
improved by replacing poorly water- temperatures, and the temperature does respect to the increase in temperature.
Starting from the ① crystalline solid, the ②
soluble crystalline forms for their amor- not rise above 35 °C in long milling,2 not
melt/liquid state is obtained upon heating.
phous forms. Unlike crystalline solids all drugs can be amorphized via BM. From this ② melt/liquid state, on cooling
(Fig. 1, ①), amorphous solids lack long- Alternative techniques for amorphiza- down, a rubbery state is achieved in the ③
range order (Fig. 1, ④). Amorphous tion, including SD or QC,3–5 are currently super-cooled melt, leading on further cooling
solids are unambiguously identied the topic of research by Rades et al., as to the ④ amorphous solid. Top: differential
scanning calorimetry (DSC) profile for how
using differential scanning calorimetry well as various analytical methods for the
a controllable increase or decrease in
characterisation of the amorphous temperature produces (A) the glass transition
materials.6–8 temperature (Tg), (B) an exothermic crystal-
Yusuf Hamied Department of Chemistry, University of So, why are amorphous drugs prob- lisation temperature event (Tc), and (C) an
Cambridge, Lenseld Road, Cambridge, CB2 1EW, UK. endothermic melt temperature event (Tm).
lematic? As illustrated in Fig. 1,
E-mail: [email protected]

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amorphous materials ④ have higher amorphous materials will relax at some conventional way for amorphous mate-
energy than their crystalline counterparts point, even if they do not crystallise on rials. Powder X-ray diffraction (PXRD)
①. This results in poor physical stability the experimental time scale. scans are featureless for amorphous
over time as they may become crystalline, What is blocking the rapid develop- compounds, in comparison to crystalline
therefore offering too short a shelf-life for ment of making amorphous drugs species, which display distinct peaks (see
commercialisation. The determination of a pharmaceutical reality is the lack of Fig. 2a). While solid-state NMR can
structural relaxation of a freshly prepared suitable analytical tools to characterise provide structural information on amor-
amorphous material via isothermal their molecular-level organization. X-ray phous materials, conducting these
microcalorimetry can be considered diffraction, so helpful for determining experiments is very demanding. On the
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a surrogate indicator of its physical the molecular-level organisation of crys- other hand, pair distribution functions
Open Access Article. Published on 27 January 2025. Downloaded on 1/27/2025 8:33:08 PM.

stability against crystallisation. All talline materials, is unsuitable in its (PDFs),10 and molecular dynamics (MD)

Fig. 2 Analytical data from powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), structural relaxation and pair distribution
functions (PDFs); left column (a, d, g & j): polyamorph-I obtained by SD; middle column (b, e, h & k): polyamorph-II obtained by QC; and right
column (c, f, i & l): polyamorph-III obtained by BM. Top row (a–c): superimposed PXRD scans of HCT polyamorph stability study. Polyamorph-II
(b) has the highest physical stability while polyamorph-I (a) has the lowest, becoming crystalline 3 days after preparation. Second row down (d–f):
DSC studies for all 3 polyamorphs: I, II and III are different as they present different Tg and Tc values. Third row down (g–i): the structural relaxation
data showing significant differences between all 3 polyamorphs. Polyamorph-II (h) with the slowest relaxation sbD = 88.4 will have the highest
physical stability. Bottom row (j–l): PDF data (probability (G) of finding a pair of atoms at a given r distance), unambiguously demonstrating that for
any of the 3 polyamorphs, there is no long-range order (range of >7 Å) corresponding to the intermolecular interactions. It also excludes the
presence of crystalline and nanocrystalline material. The originals of all the graphs (ref. 9) were supplied by courtesy of Inês C. B. Martins to
modify them as felt fit for the preparation of this figure.

Chem. Sci. © 2025 The Author(s). Published by the Royal Society of Chemistry
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Commentary Chemical Science

simulations,11 are being explored to to relax, making it the most physically publication (ref. 9) to design Fig. 2 and
obtain some, though limited, under- stable HCT polyamorph.9 While PXRD for the creation and offer of the TOC
standing of the molecular-level organi- and PDF do not discriminate between the graphical abstract to be used in this focus
zation of amorphous materials. different polyamorphs, as shown in article.
Several reports show that amorphous Fig. 2, they are complementary analytical
drugs, obtained using different prepara- techniques that support that all 3 HCT
tion methods, display distinct physico- polyamorphs are fully amorphous. PXRD References
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This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.

Rades, et al. to work on dispelling the absence of nanocrystals. However, PDF E. Dudognon and V. Caron, J. Pharm.
Open Access Article. Published on 27 January 2025. Downloaded on 1/27/2025 8:33:08 PM.

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microcalorimetric analysis supplies the polyamorphism should be bright with 9 I. C. B. Martins, A. S. Larsen,
structural relaxation. These parameters safer and more affordable oral formula- A. Ø. Madsen, O. A. Frederiksen,
unmistakably differentiate between the 3 tions in the marketplace. A. Correia, K. M. Ø. Jensen,
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a Tg of 88 °C, polyamorph-II with a Tg of Author contributions Sci., 2023, 14, 11447–11455.
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117.5 °C, have very different glass transi- Article written by Ana M. Belenguer. Rev., 2022, 122, 1208–1272.
tion temperatures. A further conrma- 11 H. D. Özeren, R. T. Olsson, F. Nilsson
tion that polyamorph-II and -III are Conflicts of interest and M. S. Hedenqvist, Mater. Des.,
different is that, on further heating, pol- 2020, 187, 108387.
yamorph-II reaches a crystallisation There are no conicts to declare. 12 K. Edueng, C. A. S. Bergström, J. Gråsjö
temperature (Tc) of 189 °C while poly- and D. Mahlin, Pharmaceutics, 2019, 11,
amorph-III only reaches a Tc of 148 °C.9 Acknowledgements 425.
The differences in relaxation between 13 B. C. Hancock, E. Y. Shalaev and
the 3 polyamorphs are striking, as shown I thank Inês C. B. Martins for allowing me S. L. Shamblin, J. Pharm. Pharmacol.,
in Fig. 2. Polyamorph-II takes the longest to use the original gures from her 2002, 54, 1151–1152.

© 2025 The Author(s). Published by the Royal Society of Chemistry Chem. Sci.