{"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_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},"jetpack_post_was_ever_published":false},"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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At the Beilstein conference, Ian Bruno mentioned another type; \u00a0tautomeric polymorphism, where a compound can crystallise in two forms differing in the position of acidic protons. Here I explore\u2026","rel":"","context":"In "Chemical IT"","block_context":{"text":"Chemical IT","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=2"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2017\/06\/109-1024x537.jpg?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":8850,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=8850","url_meta":{"origin":17333,"position":1},"title":"Sharpless epoxidation, enantioselectivity and conformational analysis.","author":"Henry Rzepa","date":"January 3, 2013","format":false,"excerpt":"I return to this reaction one more time. Trying to explain why it is enantioselective for the epoxide product poses peculiar difficulties. Most of the substituents can adopt one of several conformations, and some exploration of this conformational space is needed. Amongst the conformational possibilities are the two rotations shown\u2026","rel":"","context":"In "Interesting chemistry"","block_context":{"text":"Interesting chemistry","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=4"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]},{"id":23434,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=23434","url_meta":{"origin":17333,"position":2},"title":"Deltamethrin – a polymorphed insecticide.","author":"Henry Rzepa","date":"March 24, 2021","format":false,"excerpt":"Deltamethin is a pyrethroid insecticide for control of malaria which has been used for a little while. Perhaps inevitably, mosquitoes are developing resistance to it. So what could be done about countering this? Well, perhaps surprisingly, form a polymorph!\u00a0These crystal structure isomers are often highly undesirable; thus\u00a0Ritonavir, which changed its\u2026","rel":"","context":"In "Interesting chemistry"","block_context":{"text":"Interesting chemistry","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=4"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2021\/03\/Screenshot-643-1024x716.jpg?resize=350%2C200&ssl=1","width":350,"height":200},"classes":[]},{"id":248,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=248","url_meta":{"origin":17333,"position":3},"title":"Conformational analysis and enzyme activity: models for amide hydrolysis.","author":"Henry Rzepa","date":"April 12, 2009","format":false,"excerpt":"The diagram below summarizes an interesting result recently reported by Hanson and co-workers (DOI: 10.1021\/jo800706y. At ~neutral pH, compound 13 hydrolyses with a half life of 21 minutes, whereas 14 takes 840 minutes. Understanding this difference in reactivity may allow us to understand why some enzymes can catalyze the hydrolysis\u2026","rel":"","context":"In "Interesting chemistry"","block_context":{"text":"Interesting chemistry","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=4"},"img":{"alt_text":"Models for peptide cleavage.","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2009\/04\/amide-cleavage.png?resize=350%2C200","width":350,"height":200},"classes":[]},{"id":21694,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=21694","url_meta":{"origin":17333,"position":4},"title":"L-Malic acid: An exercise in conformational analysis impacting upon optical rotatory dispersion (ORD).","author":"Henry Rzepa","date":"December 20, 2019","format":false,"excerpt":"My momentum of describing early attempts to use optical rotation to correlate absolute configuration of small molecules such as glyceraldehyde and lactic acid with their optical rotations has carried me to L-Malic acid (below labelled as (S)-Malic acid). The measured optical rotatory dispersion curve at low wavelengths is shown below\u2026","rel":"","context":"In "Chiroptics"","block_context":{"text":"Chiroptics","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=2644"},"img":{"alt_text":"","src":"","width":0,"height":0},"classes":[]},{"id":1856,"url":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?p=1856","url_meta":{"origin":17333,"position":5},"title":"Conformational analysis of biphenyls: an upside-down view","author":"Henry Rzepa","date":"April 2, 2010","format":false,"excerpt":"One of the (not a few) pleasures of working in a university is the occasional opportunity that arises to give a new lecture course to students. New is not quite the correct word, since the topic I have acquired is Conformational analysis. The original course at Imperial College was delivered\u2026","rel":"","context":"In "Interesting chemistry"","block_context":{"text":"Interesting chemistry","link":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/?cat=4"},"img":{"alt_text":"","src":"https:\/\/i0.wp.com\/www.ch.ic.ac.uk\/rzepa\/blog\/wp-content\/uploads\/2010\/04\/biphenyl-1.jpg?resize=350%2C200","width":350,"height":200},"classes":[]}],"jetpack_likes_enabled":false,"authors":[{"term_id":2661,"user_id":1,"is_guest":0,"slug":"admin","display_name":"Henry Rzepa","avatar_url":"https:\/\/secure.gravatar.com\/avatar\/897b6740f7f599bca7942cdf7d7914af5988937ae0e3869ab09aebb87f26a731?s=96&d=blank&r=g","0":null,"1":"","2":"","3":"","4":"","5":"","6":"","7":"","8":""}],"_links":{"self":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/17333","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=17333"}],"version-history":[{"count":13,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/17333\/revisions"}],"predecessor-version":[{"id":25041,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=\/wp\/v2\/posts\/17333\/revisions\/25041"}],"wp:attachment":[{"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=17333"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=17333"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=17333"},{"taxonomy":"author","embeddable":true,"href":"https:\/\/www.ch.ic.ac.uk\/rzepa\/blog\/index.php?rest_route=%2Fwp%2Fv2%2Fppma_author&post=17333"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}