Disappearing polymorphs

Paroxetine hydrochloride was developed in the 1970s by scientists in 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 of 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-copyrighted version, which GSK refused to give manufacturing rights for. As it is illegal to manufacture or sell anyone's patented product without their permission, GSK sued the Canadian generic pharmaceutical company Apotex 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 eventually lost the case on a technicality in the U.S. Federal Circuit Court, but many abstract legal questions were raised in the process which may not yet be fully resolved.

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.[13]

In order to avoid patent issues, 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]

Released to the public in 1996, ritonavir is an antiretroviral medication used to help treat HIV/AIDS, and has been listed on the World Health Organization's List of Essential Medicines.[14] 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, which had significantly lower solubility, and which wasn't medically effective.[15]

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.[8] The drug was temporarily recalled from the market, and 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.[8]

A later study found 3 additional morphs: a metastable polymorph, a trihydrate, and a formamide solvate.[16]

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).[17][18] 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".[8] 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.[19]

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.[20] Early scientists reported being able to crystallize both forms of nat‐progesterone, and could convert form 2 of into form 1 (which is more thermodynamically stable and melts at a different temperature). When later scientists tried to replicate the crystallization of form 2 from pure materials, they found themselves completely unable to do so. Attempts to replicate older instructions (and variations on those instructions) for crystallization of form 2 would invariably produce form 1 instead, sometimes even leading to crystals of exceptional purity—but of the wrong polymorph! 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.[20]

Form 2 was eventually successfully synthesized by using pregnenolone, a structurally similar compound, as an additive in the crystallization process.[8] The additive seemed to overturn 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.[20]

Pfanstiehl Chemical Company in Waukegan, IL 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 it 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 is 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, 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 until fifty years later. 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.

When the metastable form was brought into a lab where the stable form had previously been made, it changed into the stable form after a few days in the open air. The structure of the stable crystal was determined by.[21] They failed to obtain the metastable form from a solution of alcohol, either at room temperature or near freezing; they kept ending up with the stable form. 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]

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[22]). Originally, its crystals were all in Form 1, but in the batch prepared on April 15, 1980 exhibited a new infrared spectrogram peak at 1045 ${\displaystyle cm^{-1}}$, demonstrating that a new crystal 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 [23]) and 1987 (US4672133A[24]).[25]

Interestingly, though it's very difficult to crystalize Form 1 in the presence of seeds of Form 2, once Form 1 crystals are obtained, they can be mixed with Form 2 crystals, and both forms would coexist indefinitely.[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 it should be the 1978 patent, not the 1985 patent, that covered Form 2. Depending on which patent applies, Form 2 could be marketed as generics either in 1995 or in 2002. Since an additional seven years of exclusive marketing is highly profitable, Glaxo fought back. There were multiple cases.

In order to win the first Glaxo, Inc. v. Novopharm, Ltd case,[26][27] Glaxo successfully demonstrated that Form 1 could be produced according to the 1978 patent procedure. 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.[8] 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 ${\displaystyle cm^{-1}}$ infringes their 1985 patent. However, during the prosecution of the first case, Glaxo accepted that the 1985 patent covers only products containing chemicals with a specific, 29-peak infrared (IR) spectrum. This was intended to avoid double patenting -- Glaxo had emphasized the unique aspects of Form 2 to distinguish it from the invention described in the 1978 patent, thus avoiding a situation where they were essentially trying to patent the same invention twice. Since Glaxo could not establish the presence of the 29-peak spectrogram in Novopharm's product, the court ruled in favor of Novopharm.[9][28]

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