Disappearing polymorph
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 during nucleation. Sometimes the resulting transformation is extremely hard or impractical to reverse, because the new polymorph may be more stable. That is, they are metastable forms that have been replaced by more stable forms.
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. 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 gradually spread across the world, and it is suspected that it is because Earth's atmosphere has over time become permeated with tiny seed crystals. It is believed that seeds as small as a few million molecules is sufficient for converting one morph to another, making unwanted disappearance of morphs particularly difficult to prevent. It is hypothesized that "unintentional seeding" may also be responsible for a related phenomenon, where a previously difficult-to-crystallize compound becomes easier to crystallize over time.
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 with a lab that has not been contaminated by the new morph. This was demonstrated in the ranitidine case. However, doing so is usually impractical or uneconomical. In some cases, the original morph can be reconstructed by a different pathway with different chemical kinetics, as in the case of progesterone.
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. 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.
Thermodynamics
The Gibbs phase rule states that under most thermodynamic conditions, for each chemical species, only one phase is thermodynamically stable, except on certain boundaries, such as the coexistence of ice and water right at the freezing point. In particular, since each crystal morph is a phase of matter, this implies that under normal circumstances, there exists only a single crystal morph at thermodynamic equilibrium. However, some phases may be kinetically stable, even if not energetically so.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. More abstractly stated, disappearing polymorphs are morphs that are kinetically stable but not thermodynamically stable.
In detail, consider the classical nucleation theory of crystallization of water into ice. When liquid water is held just below the freezing point, the relative change in Gibbs free energy for a sphere of ice with radius iswhere is the change in free energy per volume, and is the change in free energy per surface area. The term is usually positive, since there is an energy penalty for the boundary between two different phases of matter. However, as water crosses from above to below freezing point, turns from negative to positive.
The critical radius is, which satisfies. A ball of ice with tends to shrink, but a ball of ice with tends to grow. A perfectly homogeneous liquid water below the freezing point may thus remain indefinitely liquid, until a single "seed crystal" of ice appears with, after which it would grow without limit. Similarly, dirt within the water that is attracted to ice would have a negative interfacial energy with ice, which allows an initial seed crystal to form around dirt particles. This competition between kinetics and stability allows the supercooling effect, whereby a clean liquid water without dirt or seed crystals may remain indefinitely in a liquid state. It also allows cloud seeding.
When there are two morphs, it is possible for the curves to cross over at different points, as illustrated. In this case, morph B crystals are energetically favored when it is small, but for a large enough crystal, morph A is energetically favored. This means that during crystallization, morph B tends to appear first, which then may grow without bound. That is, morph B is kinetically favored. However, it is a metastable crystal. If a seed crystal of morph A above the crossover radius is already present, morph A would outcompete morph B.
Benzamide illustrates this process. Justus von Liebig and Friedrich Wöhler observed that when a boiling water solution of benzamide is cooled slowly, a metastable morph appears as a "white mass of silky needles". Later, a different crystal morph would appear within as small cavities, and expand into the entire mass after a few days.
Pharmaceutical and legal impact
In the United States, the first company to develop a drug 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 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. 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
Paroxetine hydrochloride
was developed in the 1970s by scientists at Ferrosan and patented as US4007196A in 1976. Ferrosan licensed this patent to the Beecham Group, which later merged into GSK.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 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.
When the patent for paroxetine anhydrate 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 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.
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.
Later research showed that the "anhydrate" was in fact a non-stoichiometric hydrate that rapidly dehydrates and rehydrates. The hemihydrate form is more stable due to a higher number of hydrogen bonds.
Paroxetine mesylate
In order to avoid patents on paroxetine hydrochloride, some companies developed alternative salts of paroxetine. In the mid-1990s SmithKline Beecham 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 is still no legal consensus on which possibility is correct.
Ritonavir
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. The original medication was manufactured in the form of semisolid gel capsules, based on the only known crystal form of the drug. In 1998, however, a second crystal form was unexpectedly discovered. It had significantly lower solubility and was not medically effective. Subsequent research showed that the two forms are conformational polymorphs, with Form II more thermodynamically stable since "all of the strong hydrogen bond donors and acceptors have been satisfied".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. The drug was temporarily recalled from the market. Tens of thousands of AIDS patients went without medication for their condition until ritonavir was reformulated as a capsule, 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.
It was a serious public relations problem for Abbott, so the company held interviews and press conferences, at which senior Abbott officials answered questions. The transcripts are archived at .
A later study found 3 additional morphs: a metastable polymorph, a trihydrate, and a formamide solvate.