{"id":17333,"date":"2017-01-02T09:55:17","date_gmt":"2017-01-02T09:55:17","guid":{"rendered":"http:\/\/www.ch.imperial.ac.uk\/rzepa\/blog\/?p=17333"},"modified":"2022-04-10T08:03:13","modified_gmt":"2022-04-10T07:03:13","slug":"ritonavir-a-look-at-a-famous-example-of-conformational-polymorphism","status":"publish","type":"post","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=17333","title":{"rendered":"Ritonavir: a look at a famous example of conformational polymorphism."},"content":{"rendered":"
\n

Here is an inside peek at another one of Derek Lowe’s 250 milestones in chemistry, the polymorphism of Ritonavir<\/strong>.[1]<\/a><\/span>\u00a0The story in a nutshell concerns one of a pharma company’s worst nightmares; a drug which has been successfully brought to market unexpectedly\u00a0“changes” after a few years on market to a less effective form (or to use the drug term, formulation). This can happen via<\/em> a phenomenon known as polymorphism, where the crystalline structure of a molecule can have more than one form.[2]<\/a><\/span>,[3]<\/a><\/span>,[4]<\/a><\/span> In this case, form I<\/strong> 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<\/em>“[1]<\/a><\/span><\/p>\n

The structure of the original form I<\/strong> is shown below (3D DOI:\u00a010.5517\/CCRVC75<\/a>). The compound has three HN-CO peptide linkages, all of which are in the stereoelectronically favoured s-cis<\/i> form<\/a>, with a dihedral angle of 180\u00b0 across the H-N and C=O vectors.<\/p>\n

\"\"<\/a>

Click for 3D<\/p><\/div>\n

To show how favourable this s-cis<\/i> form is, here is a search of the Cambridge structural database for acyclic<\/b> HN-C=O bonds; of the ~8200 examples, only\u00a05 have an s-trans<\/i>\u00a0torsion of\u00a0~180\u00b0. 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\u00b0 (artefacts?).<\/p>\n

\"\"<\/p>\n

The new type-II form that emerged has only two s-cis<\/em> peptide linkages, and the third has isomerised to this higher energy\u00a0s-trans<\/em> form (3D DOI: 10.5517\/CCRVC97<\/a>)<\/p>\n

\"\"<\/a>

Click for 3D<\/p><\/div>\n

This has various knock-on effects on the conformation of the actual molecule itself.<\/p>\n

    \n
  1. The cis-trans<\/em> isomerisation of a peptide or amide bond is a relatively high energy process, since the C=N bond order is higher than 1<\/strong>. For example, in the 1<\/sup>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\u00a0rotation about the C=N bond.<\/li>\n
  2. A pedant might query whether this isomerism is correctly termed a conformational<\/strong> or a configurational<\/strong> change? High-energy rotations that result in cis\/trans<\/strong> isomerisms are normally referred to as a configurational changes, whereas low energy rotations about e.g.<\/em> single bonds are known as conformational changes (thus the conformational changes in cyclohexane). There is a grey region\u00a0such as this one, where the boundary between the two terms is encountered.\u00a0<\/li>\n
  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\u00a0in form I to +51 in form II<\/strong>.<\/li>\n
  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.<\/li>\n
  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\u00a0 from the diagrams of the single molecules shown above.<\/li>\n
  6. Overall, the free energy of the lattice is lower, despite the higher energy of the s-trans<\/em> peptide bond.\u00a0<\/li>\n
  7. Clearly, the dynamics of crystallisation initially favoured form I<\/strong> (despite the higher energy of the crystallised outcome), but if a tiny seed of form II<\/strong> is present (or perhaps other impurities) this can dramatically (but unpredictably) change these crystallisation dynamics.<\/li>\n<\/ol>\n

    I suspect that since 1998 when this story unfolded, all new drugs in which one or more s-cis<\/strong> peptide bonds are present have caused anxiety. In the system above for example, one might ask whether\u00a0cis\/trans<\/em> isomerisation of instead either of the other two peptide bonds present might\u00a0have similar results? Or hypothesize whether inhibiting the associated rotation of the\u00a0C-C single bond noted above by appropriate “tethering” might prevent form I <\/strong>from converting to form II.<\/strong>\u00a0Since 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.[5]<\/a><\/span> Perhaps, if such a method were found, it might be too commercially valuable to share?<\/p>\n

    References<\/h2>\n
    1. J. Bauer, S. Spanton, R. Henry, J. Quick, W. Dziki, W. Porter, and J. Morris, \"Ritonavir: An Extraordinary Example of Conformational Polymorphism\", Pharmaceutical Research<\/i>, vol. 18, pp. 859-866, 2001. https:\/\/doi.org\/10.1023\/a:1011052932607<\/a>\n\n<\/li>\n
    2. J.D. Dunitz, and J. Bernstein, \"Disappearing Polymorphs\", Accounts of Chemical Research<\/i>, vol. 28, pp. 193-200, 1995. https:\/\/doi.org\/10.1021\/ar00052a005<\/a>\n\n<\/li>\n
    3. D. Bu\u010dar, R.W. Lancaster, and J. Bernstein, \"Disappearing Polymorphs Revisited\", Angewandte Chemie International Edition<\/i>, vol. 54, pp. 6972-6993, 2015. https:\/\/doi.org\/10.1002\/anie.201410356<\/a>\n\n<\/li>\n
    4. G.J.O. Beran, I.J. Sugden, C. Greenwell, D.H. Bowskill, C.C. Pantelides, and C.S. Adjiman, \"How many more polymorphs of ROY remain undiscovered\", Chemical Science<\/i>, vol. 13, pp. 1288-1297, 2022. https:\/\/doi.org\/10.1039\/d1sc06074k<\/a>\n\n<\/li>\n
    5. S.R. Chemburkar, J. Bauer, K. Deming, H. Spiwek, K. Patel, J. Morris, R. Henry, S. Spanton, W. Dziki, W. Porter, J. Quick, P. Bauer, J. Donaubauer, B.A. Narayanan, M. Soldani, D. Riley, and K. McFarland, \"Dealing with the Impact of Ritonavir Polymorphs on the Late Stages of Bulk Drug Process Development\", Organic Process Research & Development<\/i>, vol. 4, pp. 413-417, 2000. https:\/\/doi.org\/10.1021\/op000023y<\/a>\n\n<\/li>\n<\/ol>\n\n<\/div> ","protected":false},"excerpt":{"rendered":"

      Here is an inside peek at another one of Derek Lowe’s 250 milestones in chemistry, the polymorphism of Ritonavir.\u00a0The story in a nutshell concerns one of a pharma company’s worst nightmares; a drug which has been successfully brought to market unexpectedly\u00a0“changes” after a few years on market to a less effective form (or to use […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"jetpack_post_was_ever_published":false,"_jetpack_newsletter_access":"","_jetpack_dont_email_post_to_subs":true,"_jetpack_newsletter_tier_id":0,"_jetpack_memberships_contains_paywalled_content":false,"_jetpack_memberships_contains_paid_content":false,"activitypub_content_warning":"","activitypub_content_visibility":"","activitypub_max_image_attachments":5,"activitypub_interaction_policy_quote":"anyone","activitypub_status":"","footnotes":"","jetpack_publicize_message":"","jetpack_publicize_feature_enabled":true,"jetpack_social_post_already_shared":true,"jetpack_social_options":{"image_generator_settings":{"template":"highway","default_image_id":0,"font":"","enabled":false},"version":2}},"categories":[4],"tags":[1974,1395,1313,40,1985,1983,68,1988,1982,1987,1980,1984,1986,1981,1979,1978,1972,1976,1975,1657,1971,1977,1973],"ppma_author":[2661],"class_list":["post-17333","post","type-post","status-publish","format-standard","hentry","category-interesting-chemistry","tag-carbamates","tag-chemistry","tag-derek-lowe","tag-free-energy","tag-high-energy-process","tag-high-energy-rotations","tag-higher-energy","tag-higher-energy-s-trans-form","tag-hydrogen-bonding-network","tag-later-manufacturing","tag-lipid-polymorphism","tag-low-energy-conformational-effects","tag-low-energy-rotations","tag-lower-energy-rotation","tag-peek","tag-polymorphism","tag-protease-inhibitors","tag-ritonavir","tag-rtt","tag-sn","tag-software-engineering","tag-thiazoles","tag-ureas"],"yoast_head":"\nRitonavir: a look at a famous example of conformational polymorphism. - 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