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Disappearing polymorph

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In materials science, a disappearing polymorph is a form of a crystal structure that is suddenly unable to be produced, instead transforming into a different crystal structure with the same chemical composition (a polymorph) during nucleation.[2][3] Sometimes the resulting transformation is extremely hard or impractical to reverse, because the new polymorph may be more stable.[4] It is hypothesized that contact with a single microscopic seed crystal of the new polymorph can be enough to start a chain reaction causing the transformation of a much larger mass of material.[5] Widespread contamination with such microscopic seed crystals may lead to the impression that the original polymorph has "disappeared". In a few cases such as progesterone and paroxetine hydrochloride, the disappearance is global, and it is suspected that it is because earth's atmosphere is permeated with tiny seed crystals. It is believed that seeds as small as a few million molecules (about grams) is sufficient for converting one morph to another, making unwanted disappearance of morphs particularly difficult to prevent.[3]

labeled photographs showing the differing crystal structure of two different polymorphs
Needles of two different polymorphs of metanilic acid taken under a microscope at ×20 magnification. Figure (a) shows Form II and (b) shows Form III; Form I was unable to be reproduced by researchers, an instance of a disappearing polymorph.[1]

This is of concern to the pharmaceutical industry, where disappearing polymorphs can ruin the effectiveness of their products and make it impossible to manufacture the original product if there is any contamination. There have been cases in which a laboratory that attempted to reproduce crystals of a particular structure instead grew not the original but a new crystal structure.[6] The drug paroxetine was subject to a lawsuit that hinged on such a pair of polymorphs, and multiple life-saving drugs, such as ritonavir, have been recalled due to unexpected polymorphism.[7] Although it may seem like a so-called disappearing polymorph has disappeared for good, it is believed that it is always possible in principle to reconstruct the original polymorph, though doing so may be impractically difficult.[3] Disappearing polymorphs are generally metastable forms that are replaced by more stable forms.[3]

It is hypothesized that "unintentional seeding" may also be responsible for the phenomenon in which it often becomes easier to crystallize synthetic compounds over time.[5]

Thermodynamics

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The initial polymorph is in a metastable state (1), which requires overcoming an energy threshold (2) to make it transform into a more stable polymorph with a stronger bond (3). Once (3) exists in a solution during nucleation, the resulting crystal will take the form of the more stable polymorph, making (1) nearly impossible to produce in a typical laboratory environment.

Disappearing polymorphs occur when there are two morphs of a substance, and one morph has lower Gibbs free energy, but is kinetically slower to form. Thus, when the crystal is first formed, the kinetically faster morph occurs first. Eventually, by accident or catalysis, the other morph occurs, which can then serve as seed crystal.[8][9] More abstractly stated, disappearing polymorphs are morphs that are kinetically stable but not thermodynamically stable.[3]

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In the United States, the first company to develop a drug ("pioneer") must demonstrate the drug is safe and effective by extensive and expensive trials. After that, there would be a period of exclusive rights to sell the drug, after which other companies ("generics") can market the same drug as a generic chemical under the Abbreviated New Drug Application. The pioneer companies often attempt to evergreen the patent drug by many methods. Since the appearance of generics can decrease the revenue rate of patented drugs by as much as 80%, this is very profitable.

When disappearing polymorphs are involved, it is sometimes true that the pioneer company first discovered and patented polymorph A, then polymorph B, but polymorph A inevitably converts to polymorph B when seeded with microscopic amounts of B. This then means that later companies, even if they follow all the steps specified by the pioneering patent, end up with a polymorph B. Since with disappearing polymorphism, it is practically impossible for anyone to produce the original drug without it turning into the new one, producers are effectively barred from selling generics until the patent for the new polymorph has run out.[note 1] Alternatively, they may try to argue that a new polymorph needs to undergo the same trials as new drugs, potentially delaying release of a generic for years.

Case studies

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Paroxetine hydrochloride

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Paroxetine hydrochloride was developed in the 1970s by scientists at Ferrosan and patented as US4007196A in 1976.[11] Ferrosan licensed this patent to the Beecham Group, which later merged into GSK (GlaxoSmithKline at the time).

The Paroxetine developed at that time was paroxetine anhydrate, which is a chalky powder that was hygroscopic. This made it difficult to handle. In late 1984, while scaling up the production of Paroxetine, a new crystal form (hemihydrate) suddenly appeared at two Beecham sites in the UK within a few weeks of each other. In the presence of water or humidity, mere contact with hemihydrate converts anhydrate into hemihydrate.

Alan Curzons, working for GSK, wrote down the "Paroxetine Polymorphism" memorandum on May 29, 1985, a memorandum vital to later litigations.[12]

When the patent for paroxetine anhydrate (the "original" polymorph) ran out, other companies wanted to make generic antidepressants using the chemical. The only problem was that by the time other companies began manufacturing, Earth's atmosphere was already seeded with microscopic quantities of paroxetine hemihydrate from GSK's manufacturing plants, which meant that anyone trying to manufacture the original polymorph would find it transformed into the still-patented version, which GSK refused to give manufacturing rights for. Thus, GSK sued the Canadian generic pharmaceutical company Apotex (SmithKline Beecham Corp. v Apotex Corp) for patent infringement by producing quantities of the newer paroxetine polymorph in their generic pills, asking for their products to be blocked from entering the market.[12][7]

GSK claimed that the anhydrate "inevitably" converts to hemihydrate due to the presence of seeds. Apotex rejected the seeding theory as "junk science", and "alchemy". Both the District Court and the Federal Circuit Court accepted the seeding theory of GSK, but nevertheless both judged in favor of Apotex. The District Court judged that Apotex was not responsible for unintentional presence of seeding in facility. The Federal Circuit Court invalidated the newer patent concerning the hemihydrates, on the argument of prior public use from the clinical trials.[13][14]

Later research showed that the "anhydrate" was in fact a nonstoichiometric hydrate that rapidly dehydrates and rehydrates. The hemihydrate form is more stable due to a higher number of hydrogen bonds.[15]

Paroxetine mesylate

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In order to avoid patents on paroxetine hydrochloride, some companies developed alternative salts of paroxetine. In the mid-1990s SmithKline Beecham (now a part of GSK) and Synthon independently developed paroxetine mesylate. They obtained two separate patents.

Subsequently, all attempts to produce Synthon's version of paroxetine mesylate ended up with Beecham's version. There were two possibilities: either Synthon's version is a disappearing polymorph, or Synthon's patent application contained erroneous data. Many litigations later, there was no legal consensus on which possibility was correct.[3]

Ritonavir

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Released to the public in 1996, ritonavir is an antiretroviral medication used to help treat HIV/AIDS. It has been listed on the World Health Organization's List of Essential Medicines.[16] The original medication was manufactured in the form of semisolid gel capsules, based on the only known crystal form of the drug ("Form I"). In 1998, however, a second crystal form ("Form II") was unexpectedly discovered. It had significantly lower solubility and was not medically effective.[17]

Form II was of sufficiently lower energy that it became impossible to produce Form I in any laboratory where Form II was introduced, even indirectly. Scientists who had been exposed to Form II in the past seemingly contaminated entire manufacturing plants by their presence, probably because they carried over microscopic seed crystals of the new polymorph.[3] The drug was temporarily recalled from the market. Tens of thousands of AIDS patients went without medication for their condition until ritonavir was reformulated, approved, and re-released to the market in 1999. It is estimated that Abbott, the company which produced ritonavir under the brand name Norvir, lost over $250 million USD as a result of the incident.[3]

A later study found 3 additional morphs: a metastable polymorph, a trihydrate, and a formamide solvate.[18]

Rotigotine

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Rotigotine (sold under the brand name Neupro among others) is a dopamine agonist indicated for the treatment of Parkinson's disease (PD) and restless legs syndrome (RLS).[19][20] In 2007, the Neupro patch was approved by the Food and Drug Administration (FDA) as the first transdermal patch treatment of Parkinson's disease in the United States. The drug had been established in 1980, and no prior polymorphism had been observed. In 2008, a more stable polymorph unexpectedly emerged, which was described as resembling "snow-like crystals".[3] The new polymorph did not display any observable reduction in efficacy, but nonetheless, Schwarz Pharma recalled all Neupro patches in the United States and some in Europe. Those with remaining patches in Europe were told to refrigerate their stock, since refrigeration seemed to reduce crystallization rates. The patch was reformulated in 2012, as per FDA recommendations, and was reintroduced in the United States without requiring refrigeration.[21]

Progesterone

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Progesterone is a naturally occurring steroid hormone and is used in hormone therapy and birth control pills, among other applications. There are two known forms of naturally-occurring progesterone (or nat‐progesterone), and other synthetic polymorphs of the hormone have also been created and studied.[22]

Early scientists reported being able to crystallize both forms of nat‐progesterone, and they could convert form 2 into form 1 (which is more thermodynamically stable and melts at a different temperature). When later scientists tried to crystallize form 2 from pure materials, they could not. Attempts to replicate older instructions (and variations on those instructions) for crystallization of form 2 invariably produced form 1 instead, sometimes even leading to crystals of exceptional purity but still of form 1. Researchers have tentatively suggested that form 2 became gradually harder to produce around 1975, based on a review of production difficulties documented or alluded to in existing literature.[22]

Form 2 was eventually successfully synthesized by using pregnenolone, a structurally similar compound, as an additive in the crystallization process.[3] The additive seemed to reverse the order of stability of the polymorphs. Multiple theories were proposed for why earlier research was able to produce form 2 from "pure" ingredients, ranging from the possibility that the early researchers were unintentionally working with impure materials to the possibility that seed crystals of form 1 had become more common in the atmosphere of laboratories since the 1970s.[22]

Beta-melibiose

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Pfanstiehl Chemical Company in Waukegan, Illinois, was known for isolating and purifying natural substances, including melibiose. The final step of purifying melibiose was to crystallize it. However, one day, all new melibiose crystals appeared in a different morph. The old morph was called beta-melibiose and the new morph, alpha-melibiose. The chemists theorized that tiny traces of the alpha morph in the air or on the lab equipment could be causing this change, but they never found out where the contamination was coming from. Ultimately, the company gave up. However, they suggested that if the process were attempted in a different location, where there was absolutely no trace of alpha morph, it might still be possible to successfully crystallize the beta morph.

As of 1995, this issue might still exist. According to a survey of catalogs from various chemical companies including Merck, Fluka, BDH, Aldrich, and Sigma, only the alpha-melibiose was available.

Beta-melibiose is in fact an epimer of alpha-melibiose. However, since when in solution, alpha- and beta-melibiose rapidly convert to each other, this may still be productively considered a case of crystal polymorphism.[5]

Xylitol

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Xylitol, a type of sugar, was first synthesized from beech wood chips in September 1890 in the form of syrups, but no one reported its crystal forms for 50 years. It has two different crystal morphs. One is a metastable, moisture-absorbing form that melts at 61 °C, and the other is a more stable form that melts at 94 °C. Notably, its metastable morph was prepared before the stable form, conforming to Ostwald's rule.

When a sample of xylitol in the metastable form is brought into a lab where the stable form had previously been made, the sample would change into the stable form after a few days in the open air. The structure of only the stable crystal was determined by X-ray diffraction in a 1969 publication.[23] The researchers failed to obtain the metastable form from a solution in alcohol, either at room temperature or near freezing; they invariably grew only the stable form.[23] This seems to be because once the stable form has been made in a lab, its "seeds" or nuclei can disperse in air, influencing new crystals to grow the same way.[5]

Cephadroxil

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Cefadroxil is an antibiotic. Bristol-Myers Squibb (BMS) patented the "Bouzard form" under US Patent No. 4,504,657 ('657) in 1985.[24] The patenting took 6 years due to disputes about polymorphs. An earlier patent (US Patent No. 3,781,282)[25] covered a different form, the "Micetich form". Attempts to replicate the Micetich form according to Example 19 in the '282 patent consistently yielded the Bouzard form, leading to challenges that the '657 patent was already inherent in the '282 patent, thus invalidated by prior art. BMS argued that the prevalence of the Bouzard form in manufacturing facilities led to unintentional seeding. Experimental tests of the seeding theory were ambiguous, but eventually the patent was granted.[13]

Later, Zenith Laboratories marketed a cefadroxil hemihydrate. BMS sued for "gastrointestinal infringement", claiming it converted to the patented Bouzard form in the stomach.[7][26] The case hinged on the interpretation of X-ray diffraction data, with BMS arguing it demonstrated the presence of the Bouzard form in patients who ingested Zenith's product. However, the court sided with Zenith.[13]

Ranitidine

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Ranitidine, a medicine for peptic ulcers sold under the name of Zantac, was developed by Allen & Hanburys (then a part of Glaxo Group Research, now GSK), and patented in 1978 (US4128658A, Example 32[27]). Originally, its crystals were all in Form 1, but the batch prepared on April 15, 1980 exhibited a new infrared spectrogram peak at 1045  , demonstrating that a new crystal had appeared, designated Form 2. Subsequent batches produced more and more Form 2 despite using the same procedure, until Form 1 completely disappeared. The group patented Form 2 in 1985 (US4521431A [28]) and 1987 (US4672133A[29]).[30]

Though it is very difficult to crystalize Form 1 in the presence of seeds of Form 2, once Form 1 crystals are obtained, they can coexist indefinitely with Form 2 crystals when mixed together.[3]

As the 1978 patent was nearing its 1995 expiration, many generics companies attempted to develop generics using the procedure described in 1978 patent, but they all ended up with Form 2. Some generics companies (such as Novopharm) claimed that Glaxo never produced Form 1, and thus the 1978 patent inherently anticipated Form 2, thus invalidating the 1985 and 1987 patents (since double patenting is invalid). If the argument holds, then Form 2 could be marketed as generics in 1995 at the expiration of the 1978 patent. Since an additional seven years of exclusive marketing is highly profitable, Glaxo fought back.

In order to win the first Glaxo, Inc. v. Novopharm, Ltd case,[31][32] Glaxo argued successfully that Form 1 could be produced according to the 1978 patent procedure in a carefully quarantined environment, and that Novopharm had been producing Form 2 due to disappearing polymorphs. The organic chemist Jack Baldwin, acting as a witness to Glaxo, had two of his postdoctoral researchers, for three times, produce Form 1 according to the 1978 patent procedure.[3] Consequently, the court ruled that Form 2 is covered by the 1985 patent.

Subsequent to losing the case, Novopharm attempted to bring Form 1 to market, so Glaxo sued them again in the second Glaxo, Inc. v. Novopharm, Ltd case. Glaxo argued that Novopharm could not market generics containing even trace amounts of Form 2. In particular, that means any generic Zantac containing an infrared spectrogram peak at 1045   infringes their 1985 patent. However, during the prosecution of the first case, Glaxo had already accepted that the 1985 patent covered only products containing chemicals with a specific, 29-peak infrared (IR) spectrum. This was intended to avoid double patenting—Glaxo had to emphasize the unique aspects of Form 2 to distinguish it from the invention described in the 1978 patent. Since Glaxo could not establish the presence of the 29-peak IR spectrogram in Novopharm's product, the court ruled in favor of Novopharm.[10][33]

... the claims at issue all identify Form 2 RHCl by reference to a 29-peak IR spectrum... proof of infringement requires proof that the drug alleged to infringe would exhibit all of those peaks, not a single, potentially meaningless peak.

— 110 F. 3d 1562 – Glaxo Inc v. Novopharm Ltd

In fiction

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The atoms had begun to stack and lock—to freeze—in a different fashion. The liquid that was crystallizing hadn't changed, but the crystals it was forming were, as far as industrial applications went, pure junk... The seed, which had come from God-only-knows where, taught the atoms the novel way in which to stack and lock, to crystallize, to freeze.

— Vonnegut K, Cat's Cradle, Ice-Nine

In the 1963 novel Cat's Cradle, by Kurt Vonnegut, the narrator learns about Ice-nine, an alternative structure of water that is solid at room temperature and acts as a seed crystal upon contact with ordinary liquid water, causing that liquid water to instantly freeze and transform into more Ice-nine. Later in the book, a character frozen in Ice-nine falls into the sea. Instantly, all the water in the world's seas, rivers, and groundwater transforms into solid Ice-nine, leading to a climactic doomsday scenario.[34]

Ice-nine has been described as a fictional parallel—a seed crystal triggering a chain reaction akin to the disappearing polymorph phenomenon.[5][35]

In an indirect homage to Cat's Cradle, Ice-nine and its doomsday scenario is also mentioned in the 2009 video game 999: Nine Hours, Nine Persons, Nine Doors. A character additionally describes a rumor that glycerin was not observed to crystallize until 1920, when a batch spontaneously crystallized independently of a seed crystal. From that incident forward, all glycerin globally was observed to crystallize when cooled to under 64 degrees Fahrenheit, regardless of whether it had come into contact with a seed crystal or not.[36]

See also

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Notes

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  1. ^ Legally, patents on pharmaceutical molecules usually specify the molecule by the location and amplitude of peaks in its X-ray diffraction spectrum, infrared spectrum, and other spectrographic data. The United States Pharmacopoeia states that two preparations of the same molecule usually have spectra with peaks at the same locations up to ± 0.10 degree, but relative intensities may vary up to 20%.[10]

References

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  1. ^ Rubin-Preminger JM, Bernstein J (2005-07-01). "3-Aminobenzenesulfonic Acid: A Disappearing Polymorph". Crystal Growth & Design. 5 (4): 1343–1349. doi:10.1021/cg049680y. ISSN 1528-7483.
  2. ^ Seddon KR, Zaworotko M, eds. (1999). Crystal Engineering: The Design and Application of Functional Solids. Vol. 539. Springer Science & Business Media. ISBN 978-0-7923-5905-0.
  3. ^ a b c d e f g h i j k l Bučar DK, Lancaster RW, Bernstein J (June 2015). "Disappearing polymorphs revisited". Angewandte Chemie. 54 (24): 6972–6993. doi:10.1002/anie.201410356. PMC 4479028. PMID 26031248.
  4. ^ Lowe D (November 26, 2019). "Perverse Polymorphism". In the Pipeline. American Association for the Advancement of Science. Archived from the original on July 5, 2022. Retrieved 2022-07-04.{{cite web}}: CS1 maint: bot: original URL status unknown (link)
  5. ^ a b c d e Dunitz JD, Bernstein J (1995-04-01). "Disappearing Polymorphs". Accounts of Chemical Research. 28 (4): 193–200. doi:10.1021/ar00052a005. ISSN 0001-4842.
  6. ^ Surov AO, Vasilev NA, Churakov AV, Stroh J, Emmerling F, Perlovich GL (2019). "Solid Forms of Ciprofloxacin Salicylate: Polymorphism, Formation Pathways and Thermodynamic Stability". Crystal Growth & Design. 19 (5): 2979–2990. doi:10.1021/acs.cgd.9b00185. S2CID 132854494.
  7. ^ a b c Prenol A (July 2004). "Disappearing Polymorphs and Gastrointestinal Infringement". Blakes. Archived from the original on 20 July 2012.
  8. ^ Ward MD (February 2017). "Perils of Polymorphism: Size Matters". Israel Journal of Chemistry. 57 (1–2): 82–92. doi:10.1002/ijch.201600071. ISSN 0021-2148.
  9. ^ Threlfall T (2000-09-01). "Crystallisation of Polymorphs: Thermodynamic Insight into the Role of Solvent". Organic Process Research & Development. 4 (5): 384–390. doi:10.1021/op000058y. ISSN 1083-6160.
  10. ^ a b Vure P (2011). "Polymorph patents; how strong they are really?". International Journal of Intellectual Property Management. 4 (4): 297. doi:10.1504/IJIPM.2011.043875. ISSN 1478-9647.
  11. ^ US4007196A, Christensen, Jorgen Anders & Squires, Richard Felt, "4-Phenylpiperidine compounds", issued 1977-02-08 
  12. ^ a b Abramson B (2007). The Secret Circuit: The Little-known Court where the Rules of the Information Age Unfold. Rowman & Littlefield. pp. 93–106. ISBN 978-0-7425-5281-4.
  13. ^ a b c Hilfiker R, ed. (2006). "14. Polymorphism and Patents from a Chemist's Point of View [1]". Polymorphism in the pharmaceutical industry. Weinheim: WILEY-VCH. ISBN 978-3-527-31146-0.
  14. ^ Rakoczy WA, Mazzochi DM (January 2006). "The Case of the Disappearing Polymorph: 'Inherent Anticipation' and the Impact of SmithKline Beecham Corp. v Apotex Corp. (Paxil®) on Patent Validity and Infringement by Inevitable Conversion". Journal of Generic Medicines: The Business Journal for the Generic Medicines Sector. 3 (2): 131–139. doi:10.1057/palgrave.jgm.4940110. ISSN 1741-1343.
  15. ^ Pina MF, Pinto JF, Sousa JJ, Fábián L, Zhao M, Craig DQ (December 2012). "Identification and characterization of stoichiometric and nonstoichiometric hydrate forms of paroxetine HCl: reversible changes in crystal dimensions as a function of water absorption". Molecular Pharmaceutics. 9 (12): 3515–3525. doi:10.1021/mp3003573. PMID 23051151.
  16. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  17. ^ Lowe D. "Down At the Crystal Surface". In the Pipeline. American Association for the Advancement of Science. Retrieved 2022-07-08.
  18. ^ Morissette SL, Soukasene S, Levinson D, Cima MJ, Almarsson O (March 2003). "Elucidation of crystal form diversity of the HIV protease inhibitor ritonavir by high-throughput crystallization". Proceedings of the National Academy of Sciences of the United States of America. 100 (5): 2180–2184. doi:10.1073/pnas.0437744100. PMC 151315. PMID 12604798.
  19. ^ Chen JJ, Swope DM, Dashtipour K, Lyons KE (December 2009). "Transdermal rotigotine: a clinically innovative dopamine-receptor agonist for the management of Parkinson's disease". Pharmacotherapy. 29 (12): 1452–1467. doi:10.1592/phco.29.12.1452. PMID 19947805. S2CID 40466260.
  20. ^ Davies S (September 2009). "Rotigotine for restless legs syndrome". Drugs of Today. 45 (9): 663–668. doi:10.1358/dot.2009.45.9.1399952. PMID 19956807.
  21. ^ "Neupro Patch Re-launches in the US". Archived from the original on 2016-03-23. Retrieved 2022-07-08.
  22. ^ a b c Lancaster RW, Karamertzanis PG, Hulme AT, Tocher DA, Lewis TC, Price SL (December 2007). "The polymorphism of progesterone: stabilization of a 'disappearing' polymorph by co-crystallization". Journal of Pharmaceutical Sciences. 96 (12): 3419–3431. doi:10.1002/jps.20983. PMID 17621678.
  23. ^ a b Kim HS, Jeffrey GA (1969-12-15). "The crystal structure of xylitol". Acta Crystallographica Section B: Structural Crystallography and Crystal Chemistry. 25 (12): 2607–2613. doi:10.1107/S0567740869006133. ISSN 0567-7408.
  24. ^ US4504657A, Bouzard, Daniel; Weber, Abraham & Stemer, Jacques, "Cephadroxil monohydrate", issued 1985-03-12 
  25. ^ US3781282A, Garbrecht, W., "Cephalosporin process and product", issued 1973-12-25 
  26. ^ Trask AV (2007). "An overview of pharmaceutical cocrystals as intellectual property". Molecular Pharmaceutics. 4 (3): 301–9. doi:10.1021/mp070001z. PMID 17477544.
  27. ^ US4128658A, Price, Barry J.; Clitherow, John W. & Bradshaw, John, "Aminoalkyl furan derivatives", issued 1978-12-05 
  28. ^ US4521431A, Crookes, Derek L., "Aminoalkyl furan derivative", issued 1985-06-04 
  29. ^ US4672133A, Crookes, Derek L., "Process for forming Form 2 ranitidine hydrochloride", issued 1987-06-09 
  30. ^ "{BLR 2023} Azeotroping Process – CAFC – Glaxo – Novopharm – Ranitidine". Biotechnology Law Report. 14 (3): 423–504. May 1995. doi:10.1089/blr.1995.14.423. ISSN 0730-031X.
  31. ^ Glaxo Inc. v. Novopharm Ltd., 931 F. Supp. 1280 (E.D.N.C. 1996)
  32. ^ "Glaxo Wellcome Launches Appeals Vs Novopharm Zantac Ruling". AP NEWS. Retrieved 2023-05-31.
  33. ^ 110 F. 3d 1562 – Glaxo Inc v. Novopharm Ltd. No. 96-1466. United States Court of Appeals, Federal Circuit. April 4, 1997.
  34. ^ Hicks AJ (2020-05-18). "Cat's Cradle". Posthumanism in the Novels of Kurt Vonnegut. Routledge. pp. 25–51. doi:10.4324/9780367521646-3. ISBN 9780367521646.
  35. ^ Abramson B (2007). The Secret Circuit: The Little-known Court where the Rules of the Information Age Unfold. Rowman & Littlefield. p. 92. ISBN 978-0-7425-5281-4.
  36. ^ "Game Script". Super Cheats.
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