Imperial College London

Henry Rzepa

Here is an inside peek at another one of Derek Lowe's 250 milestones in
chemistry, the polymorphism of
**Ritonavir**.\[cite\]10.1023/A:1011052932607\[/cite\] The story in a
nutshell concerns one of a pharma company's worst nightmares; a drug
which has been successfully brought to market unexpectedly "changes"
after a few years on market to a less effective form (or to use the drug
term, formulation). This can happen *via* a phenomenon known as
polymorphism, where the crystalline structure of a molecule can have
more than one
form.\[cite\]10.1021/ar00052a005\[/cite\],\[cite\]10.1002/anie.201410356\[/cite\],\[cite\]10.1039/D1SC06074K\[/cite\]
In this case, form **I** was formulated into soluble tablets for oral
intake. During later manufacturing, a new less-soluble form appeared and
"*within weeks this new polymorph began to appear throughout both the
bulk drug and formulation
areas*"\[cite\]10.1023/A:1011052932607\[/cite\]

The structure of the original form **I** is shown below (3D
DOI: [10.5517/CCRVC75](https://doi.org/10.5517/CCRVC75){target="_blank"
rel="noopener noreferrer"}). The compound has three HN-CO peptide
linkages, all of which are in the [stereoelectronically favoured *s-cis*
form](http://www.ch.imperial.ac.uk/rzepa/blog/?p=9459), with a dihedral
angle of 180° across the H-N and C=O vectors.

::: {#attachment_17336 .wp-caption .aligncenter style="width: 510px"}
[![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2017/01/071.jpg){.size-full
.wp-image-17336 decoding="async"
aria-describedby="caption-attachment-17336" width="400"
srcset="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2017/01/071.jpg 726w, https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2017/01/071-300x231.jpg 300w"
sizes="(max-width: 726px) 100vw, 726px"}](https://doi.org/10.5517/CCRVC75){target="_blank"
rel="noopener noreferrer"}

Click for 3D
:::

To show how favourable this *s-cis* form is, here is a search of the
Cambridge structural database for **acyclic** HN-C=O bonds; of the
\~8200 examples, only 5 have an *s-trans* torsion of \~180°. It is I
feel statistically not entirely correct to convert this ratio of K=1640
to a free energy, but if one does, then at 298K, RTlnK works out to 4.4
kcal/mol. Note also that two compounds show an angle of \~90°
(artefacts?).

![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2017/01/073.jpg){.aligncenter
.size-full .wp-image-17343 decoding="async" width="450"
srcset="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2017/01/073.jpg 761w, https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2017/01/073-300x205.jpg 300w"
sizes="(max-width: 761px) 100vw, 761px"}

The new type-II form that emerged has only two *s-cis* peptide linkages,
and the third has isomerised to this higher energy *s-trans* form (3D
DOI: [10.5517/CCRVC97](https://doi.org/10.5517/CCRVC97){target="_blank"
rel="noopener noreferrer"})

::: {#attachment_17339 .wp-caption .aligncenter style="width: 510px"}
[![](http://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2017/01/072.jpg){.size-full
.wp-image-17339 decoding="async"
aria-describedby="caption-attachment-17339" width="400"
srcset="https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2017/01/072.jpg 704w, https://www.ch.ic.ac.uk/rzepa/blog/wp-content/uploads/2017/01/072-300x198.jpg 300w"
sizes="(max-width: 704px) 100vw, 704px"}](https://doi.org/10.5517/CCRVC97)

Click for 3D
:::

This has various knock-on effects on the conformation of the actual
molecule itself.

1.  The *cis-trans* isomerisation of a peptide or amide bond is a
    relatively high energy process, since the C=N bond order is higher
    than **1**. For example, in the ^1^H NMR spectrum of N,N-dimethyl
    formamide at room temperature, one can famously observe two methyl
    resonances and it is only at higher temperatures that the two
    signals coalesce due to more rapid rotation about the C=N bond.
2.  A pedant might query whether this isomerism is correctly termed a
    **conformational** or a **configurational** change? High-energy
    rotations that result in **cis/trans** isomerisms are normally
    referred to as a configurational changes, whereas low energy
    rotations about *e.g.* single bonds are known as conformational
    changes (thus the conformational changes in cyclohexane). There is a
    grey region such as this one, where the boundary between the two
    terms is encountered. 
3.  This isomerism has the knock-on effect of inducing a much lower
    energy rotation of a C-C single bond (on the left hand side of the
    representations above), rotating from a dihedral angle of +193 in
    form I to +51 in form **II**.
4.  More minor affects are seen in the conformation of the central
    benzyl group and the S/N heterocyclic ring on the right hand side.
5.  All these low energy conformational effects occur because a better
    hydrogen bonding network can then be set up in the crystal lattice,
    something not easily predictable  from the diagrams of the single
    molecules shown above.
6.  Overall, the free energy of the lattice is lower, despite the higher
    energy of the *s-trans* peptide bond. 
7.  Clearly, the dynamics of crystallisation initially favoured form
    **I** (despite the higher energy of the crystallised outcome), but
    if a tiny seed of form **II** is present (or perhaps other
    impurities) this can dramatically (but unpredictably) change these
    crystallisation dynamics.

I suspect that since 1998 when this story unfolded, all new drugs in
which one or more **s-cis** peptide bonds are present have caused
anxiety. In the system above for example, one might ask
whether *cis/trans* isomerisation of instead either of the other two
peptide bonds present might have similar results? Or hypothesize whether
inhibiting the associated rotation of the C-C single bond noted above by
appropriate "tethering" might prevent form **I** from converting to form
**II.** Since 1998, I am sure trying to predict the solid form of an
organic molecule from its isolated structure using computational methods
has dramatically increased, although I have not found in SciFinder any
reported instances of such modelling for Ritonavir
itself.\[cite\]10.1021/op000023y\[/cite\] Perhaps, if such a method were
found, it might be too commercially valuable to share?

::: {.wp_orcid_field}
[https://orcid.org/0000-0002-8635-8390](https://orcid.org/0000-0002-8635-8390){target="_blank"
rel="author"}
:::


Here is an inside peek at another one of Derek Lowe’s 250 milestones in chemistry, the polymorphism of
<strong>
 Ritonavir
</strong>
.[cite]10.1023/A:1011052932607[/cite] The story in a nutshell concerns one of a pharma company’s worst nightmares;

Publicaciones de Rogue Scholar

Ritonavir: a look at a famous example of conformational polymorphism.