Polymorph detection and quantification – a novel method APIs A novel method of detecting very low levels of different polymorphs using high-resolution X-ray powder diffraction with a synchrotron light source has been developed by Zach-Zambon Chemicals of Italy. Key to the project has been development of software to enable appropriate data presentation. T he issue of polymorphism in pharmaceuticals has attracted increasing attention over the past 20 years and is something to which development scientists and the regulatory authorities pay considerable attention. But why? Consider first a couple of very high profile examples from the 1990s and 2000s to see why polymorphism attracts so much attention: The case in the 1990s of Ranitidine Hydrochloride, one of the first blockbuster drugs on the market. Originally discovered and subsequently patented by (the then) Allen and Hanburys in 1978, development continued and Glaxo serendipitously discovered a new polymorph in 1980, designated Form 2, and was granted a patent in 1981 based on improved filtration and drying characteristics of Form 2 over Form 1. In 1992 the sales of Ranitidine Hydrochloride (Zantac) reached $3.44 billion so clearly an attractive proposition for the generic drugs manufacturers, especially if they could manufacture Form 1 as this came off patent So, polymorphism is important and of course can often form the basis for a generics company to attack an innovator’s patent or indeed find ways around existing patents through identification and manufacture of alternative physical forms. A report by RBC Capital Markets dated 15 January 2010, entitled Pharmaceuticals, Analyzing Litigation Success Rates comments that patent challenges remain on the rise, with 65 first-to- file lawsuits in 2009, up from 51 in 2008 and more than double the number in 2006. Not all will centre around the polymorph, but it is clearly an area of sensitivity and innovators need to be vigilant in both their scientific work and the quality of the patent itself. What is polymorphism? Polymorphism is the tendency of a solid substance to crystallise into more than one crystalline structure. These crystalline forms, although chemically identical, result from a different ordered arrangement of the molecules within the crystal lattice – a common example being two forms of carbon; graphite and diamond. Different crystal forms can have different properties, a number of which are crucial in the pharmaceuticals arena such as solubility, stability, dissolution and ultimately bioavailability. Is polymorphism common? Yes. In a survey by Stahly and co-workers, 89% of compounds screened resulted in multiple forms (based on 245 screens, see Stahly et al, Crystal Growth and Design. 2007, 7, 1007-1026). So what’s the problem? The increasing complexity of pharmaceutical molecules presents a challenge for the process chemist and engineer not only in the synthesis, but also in control of crystal form and the physical properties of the solid that are important for consistent formulation and drug delivery. In more recent years, the quest for increasingly selective (and potent) new chemical entities (NCEs) has often seen discovery chemists introducing relatively large organic side- chains, such as aromatic rings or long alkyl chains to tap into the very specific protein environment of interest, but at the expense of The Sincrotrone Elettra facility at Trieste, Italy. Zach-Zambon Chemicals worked with this company to measure down to as low as 500ppm of one polymorph in another in the solid crystalline product. January/February 2012 sp 2 Inter-Active three years earlier than Form 2. There were the inevitable infringement claims by Glaxo and patent invalidity counter-claims by the challengers. This brief example serves to demonstrate the importance of polymorphism and its understanding from the point of view of protecting intellectual property. A slightly more recent case is that of Ritonavir (Norvir) (see S R Chemburkar et al, Organic process Research and Development, 2000, 4, (5), 413) when in 1998 Abbott started to suffer many final batch lots failing specification due to lack of solubility. In short, a new thermodynamically more stable and consequently far less soluble polymorph had been generated. The failure of the lots was having a serious commercial impact as the supply of one of the formulations was depleting very rapidly. Abbott was able to recover from the situation but only after considerable effort. This very short example serves to illustrate the importance of polymorph understanding and control from the technical manufacturing point of view, which of course can impact the business.
Transcript
Polymorph detection and
quantification – a novel method
APIs
A novel method of detecting very low levels of different polymorphs using high-resolution X-ray
powder diffraction with a synchrotron light source has been developed by Zach-Zambon Chemicals of
Italy. Key to the project has been development of software to enable appropriate data presentation.
The issue of polymorphism inpharmaceuticals has attractedincreasing attention over the past 20years and is something to which
development scientists and the regulatoryauthorities pay considerable attention. But why?
Consider first a couple of very high profileexamples from the 1990s and 2000s to seewhy polymorphism attracts so much attention:
The case in the 1990s of RanitidineHydrochloride, one of the first blockbusterdrugs on the market. Originally discoveredand subsequently patented by (the then) Allenand Hanburys in 1978, developmentcontinued and Glaxo serendipitouslydiscovered a new polymorph in 1980,designated Form 2, and was granted a patentin 1981 based on improved filtration anddrying characteristics of Form 2 over Form 1.In 1992 the sales of Ranitidine Hydrochloride(Zantac) reached $3.44 billion so clearly anattractive proposition for the generic drugsmanufacturers, especially if they couldmanufacture Form 1 as this came off patent
So, polymorphism is important and ofcourse can often form the basis for a genericscompany to attack an innovator’s patent orindeed find ways around existing patentsthrough identification and manufacture ofalternative physical forms. A report by RBCCapital Markets dated 15 January 2010,entitled Pharmaceuticals, Analyzing LitigationSuccess Rates comments that patentchallenges remain on the rise, with 65 first-to-file lawsuits in 2009, up from 51 in 2008 andmore than double the number in 2006. Not allwill centre around the polymorph, but it isclearly an area of sensitivity and innovatorsneed to be vigilant in both their scientific workand the quality of the patent itself.
What is polymorphism?
Polymorphism is the tendency of a solidsubstance to crystallise into more than onecrystalline structure. These crystalline forms,although chemically identical, result from adifferent ordered arrangement of themolecules within the crystal lattice – acommon example being two forms of carbon;graphite and diamond.
Different crystal forms can have differentproperties, a number of which are crucial inthe pharmaceuticals arena such as solubility,stability, dissolution and ultimatelybioavailability.
Is polymorphism common? Yes. In a surveyby Stahly and co-workers, 89% of compoundsscreened resulted in multiple forms (based on245 screens, see Stahly et al, Crystal Growthand Design. 2007, 7, 1007-1026). So what’sthe problem? The increasing complexity ofpharmaceutical molecules presents achallenge for the process chemist andengineer not only in the synthesis, but also incontrol of crystal form and the physicalproperties of the solid that are important forconsistent formulation and drug delivery. Inmore recent years, the quest for increasinglyselective (and potent) new chemical entities(NCEs) has often seen discovery chemistsintroducing relatively large organic side-chains, such as aromatic rings or long alkylchains to tap into the very specific proteinenvironment of interest, but at the expense of
The Sincrotrone Elettra facility at Trieste, Italy. Zach-Zambon Chemicals worked with this
company to measure down to as low as 500ppm of one polymorph in another in the solid
crystalline product.
January/February 2012 sspp2 Inter-Active
three years earlier than Form 2. There werethe inevitable infringement claims by Glaxoand patent invalidity counter-claims by thechallengers. This brief example serves todemonstrate the importance of polymorphismand its understanding from the point of viewof protecting intellectual property.
A slightly more recent case is that ofRitonavir (Norvir) (see S R Chemburkar et al,Organic process Research and Development,2000, 4, (5), 413) when in 1998 Abbott startedto suffer many final batch lots failingspecification due to lack of solubility. In short,a new thermodynamically more stable andconsequently far less soluble polymorph hadbeen generated. The failure of the lots washaving a serious commercial impact as thesupply of one of the formulations wasdepleting very rapidly. Abbott was able torecover from the situation but only afterconsiderable effort. This very short exampleserves to illustrate the importance ofpolymorph understanding and control fromthe technical manufacturing point of view,which of course can impact the business.
APIs
Meet Livius Cotarca of
Zach-Zambon Chemicals
Livius Cotarca was born in Romania where hereceived his MSc in Industrial Chemistry andPhD in Organic Chemistry degrees fromPolytechnic Institute Timisoara. He also holdsa MSc degree in Chemical Engineering fromthe Polytechnic of Milan. He was successivelyAssociate Professor of Organic Chemistry atPolytechnic Institute Timisoara from 1978 to1990, Visiting Professor at the TechnicalUniversity Munich and University of Bielefeld in1991 and senior chemist and group leader atthe Caffaro Research Center in Torviscosa,Italy from 1992 to 1999. He then joinedZambon Group, currently Zach-ZambonChemicals, where he is now head of globalresearch and industrial development.
Dr Cotarca is the author of two books, 30patents and over 60 papers in the field oforganic and physical organic chemistry.
Dr Cotarca is a recipient of the Nicolae TecluAward for chemistry of the RomanianAcademy. He is a member of the AmericanChemical Society and other scientificassociations.
sp2 Inter-Active January/February 2012
solubility and sometimes, if the molecule hasmany degrees of freedom, at the expense ofcrystallinity or where crystalline, accompaniedby different polymorphic forms.
This is where there is a need for carefulscientific study of the physical form andprocesses to derive a reliable and robustmanufacturing process. The developmentteam needs access to analytical tools thathave the required sensitivity to deliver datawhich can be used to steer the developmenteffort and ensure true process and productunderstanding. It should be recognised thatcontinued efforts by the regulatory authoritiesfor drugs to be developed under theframework of Quality by Design (QbD) willcontinue to drive companies to establishgreater understanding and control.
How are polymorphs detected?
There are a host of recognised techniquesthat can be applied to the analysis of solids todetermine if they are crystalline or amorphousand to distinguish between polymorphs.Typically a combination of spectroscopictechniques (infrared, Raman, solid-statenuclear magnetic resonance and X-raypowder diffraction) with more physical studies(differential scanning calorimetry,thermogravimetric analysis, dynamic vapoursorption) are used to understand the attributesof solid samples, coupled with thorough datacomparison on samples that have beenprepared in a range of different ways toidentify the existence of different polymorphicforms.
Although opinions differ, probably the mostwidely accepted definitive technique is X-raypowder diffraction (XRPD) for routine analysisof a solid to determine its form, although oncea form is identified and characterised, simplertests are likely to be applied for routine qualitycontrol release testing (such as infraredspectroscopy). XRPD is used routinely indevelopment and analytical laboratoriesduring development. But whilst XRPD can bea work-horse for the development team, it canlack the required sensitivity for the detection ofsmall quantities of either undesired orunknown polymorphic forms, whether in acrystalline active pharmaceutical ingredient(API), amorphous API or indeed the drugproduct itself. This can be a problem, witheven very small quantities of an undesiredpolymorph ‘catalysing’ the solid stateconversion during secondary manufacture orduring API storage, for instance, to anundesired form in the drug product with
consequential lack of consistent productquality and performance reliability.
Clearly, with the technical challengesassociated with control and reliability coupledwith the intellectual property requirements foreffective protection, there is a need to acquirebetter, more sensitive, data.
What are the prospects forimproved sensitivity and control?
The scientists at Zach-Zambon Chemicalsfaced an issue with an API where polymorphiccontrol was problematic and posed a severerisk to the entire project. The solid stateexperts within the company began working onthe issue and found that conventionalmethods of polymorph detection were notsufficiently sensitive. They would analyse abatch of API and conclude it was a singlepolymorphic form, only to find that uponstorage the material would still convert to anundesired physical form.
It is well known that a synchrotron lightsource can be used to get high resolution X-ray data, including powder X-ray diffractiondata, but frequently the technique is applied toinorganic materials. Undeterred, Zach-ZambonChemicals contacted the group at SincrotroneElettra in Trieste, Italy, and initiated a projectwhich has culminated in successful resolutionof the problem. The most significant challengewas to manipulate the data so it could bepresented in a conventional format and allowready comparison with existing XRPD data.The collaboration between Zach-ZambonChemicals and Sincrotrone Elettra has beenable to quantify down to as low as 500ppm ofone polymorph in another in the solidcrystalline product. This compares veryfavourably to the commonly achieved limit ofquantification of about 0.5-1% for XRPD.
In addition to the API, one needs to controlthe solid state in the final drug product if it is asolid dosage form (tablet or capsule), creamor suspension. As an example, ZaCh Systemcompared diffractograms obtained from astandard XRPD instrument and that obtainedusing the synchrotron light source. Thisexample was chosen because it deals withsolid dosage form. For the standard XRPD thetablet had to be milled whereas for thesynchrotron analysis the whole tablet is used.
With the ability to gain very good insight intothe polymorphic form and composition,through greater understanding it is then morelikely that scientists can develop processesthat result in excellent control over solid statecomposition.
Is use of a synchrotron light source like usinga sledge hammer to crack a nut? Probablyyes, if you have an easy nut to crack, forinstance if you have an API and drug product
that show the required performance or if yourcompetitors don’t analyse your products andfind a number of forms to be present whenyour patent claims just one. However, in morecomplex situations and cases where very lowlevels of a residual (or hitherto undetected)form can negatively impact the bioavailabilityof your material after drug manufacture orstorage, then no, it is not a sledge hammer tocrack a nut. In addition, the detailedcharacterisation of API and drug productcould prove crucial in patent filings.
Scientists at Zach-Zambon Chemicals haveyet to see how universal the technique cantruly be, but believe there is great potential inusing the synchrotron light source for solidstate characterisation of APIs and theirformulated products.
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