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I'm an independent consultant I was told I need .be a good salesman for my business so I am an  .independent consultant however it's my pleasure to .work with fine companies like Regis who synthesize  .materials so oftentimes I'll work with CMC people .and work with chemical companies on elucidating  .the solid-state physical chemistry and determining .the relationships of different crystalline forms  .of materials during the process development .phase of chemistry of chemical development.  .Today's talk basically the outline is is I'm going .to introduce you to polymorphism the timing of  .studies that generally large Pharma uses having .worked and compared myself with other or what  .I did in my time at Eli Lilly in company along .with you know we collaborated a lot with other  .companies and much of what we do well seem to be .in common the timing and the like. I'll discuss a  .little bit of rough timing the ICH guidance to .polymorphism discussed some of the analytical  .techniques briefly. Many of which Regis has been .adding to their work so that they can support the  .solid state activities more thoroughly. Then I'll .talk about three kind of exceptional systems from  .a polymorphic standpoint but in general these .are kind of exceptional systems but in general  .if you work hand in hand process chemistry with .a person that's pretty knowledgeable with solid  .form relations you can design processes that are .very robust and can produce a single polymorph  .for product development and the for the final .product. That's what I'm going to talk about  .today. Polymorphism there's a lot of different .definitions but the purist definition is is that  .it's when you have molecules that arrange .themselves in a crystalline fashion and in  .different ways such that they have different .physical properties and in the truest sense of  .polymorphism they're chemically identical if one .was to take and dissolve those substances and run  .solution in NMR. So if you overcome the lattice .and dissolve it they're identical chemically but  .they're distinctive physically in physical forms .because of their interactions and the way that  .they pack themselves within the crystal lattice. .So polymorphism has a major impact on the or  .the physical form has a major impact on physical .properties of the active pharmaceutical ingredient  .but it can also influence a lot of the product .dosage forms performance. Many properties in  .the dosage for the final dosage form such things .as solubility particle size shape and morphology  .water sorption and desorption or roughly people .call it hygroscopicity. Chemical and physical  .stability so how much it degrades in the solid .state physically whether or not it transforms  .to another solid state form then the drying .properties purification and yield considerable you  .know the actual physical form that you're isolate .has considerable impact on this. Flow and filter  .ability commonly is impacted by the physical .form more so in the when you mix it with other  .excipients. The stability the chemical stability .can be impacted or differentiated to different  .polymorphs might have quite different chemical .stability which actually can kill projects. and  .then physical it's important that we add stand .the physical forms and are able to control the  .physical form of our API but even more so in the .final product and during throughout its shelf-life  .to ensure that we deliver a consistent and .stable product. It can impact the flow, blending,  .granulation, tableting and many other properties .that are impactful in the actual process,  .the formulation process. Dissolution: you should .be able to differentiate polymorphs based on  .dissolution and and as the FDA puts a lot of .stringent on having a robust method for discerning  .they typically push you to have very very tight .controls on your dissolution testing and you  .should you know definitely polymorphism or even .hydrate formation can have significant impact upon  .the dissolution behavior of your final product and .sometimes even bioavailability depending upon the  .solubility properties you know in the BCS class .of your compound potentially. So I'm within the  .drug development process the time that I really .the earlier the better but historically my work  .has occurred with the the salt form and selection .occurs in early lead optimization at many of the  .large pharma companies. So when you're down to .maybe five compounds in a certain program say  .doing four-day tox. Typically for me this is .out there would be about five compounds that  .are five grams of each one of those compounds .would be produced it was important enough to  .the company to provide a couple of grams for salt .selection so that we can ensure that at least the  .data that we would get in our early talks you know .four-day rodent studies that the bioavailability  .that we would get would be or the exposures that .we get and the animals would be somewhat relevant.  .So in particular crystalline versus amorphous. .we'd want to make sure that it was crystalline  .material so that or at least know what form was .dosed but during this period with the two grams  .of material would be committed to to our salt .screening and we would also they work hand in  .hand when you select a salt oftentimes you find .the you know you're trying to crystallize it  .you'll find multiple crystalline forms during .that time period but then the other three,  .so five grams would be produced two grams would .go for salt screening and then three would go for  .the tox and ADME testing. But then I'm gonna focus .mostly on the polymorphism which goes hand-in-hand  .with the salt screening but it usually follows you .know you'll initially select one or two or three  .salts and then you'll try to generate as many .forms of those salts as possible. What we would  .do is would work with the first so that first five .grams that was produced then the company would try  .to scale up larger amounts of material for more .extensive tox studies in a second species. And we  .would try to inform what polymorph, not only what .salt but what polymorphic form would be produced  .for those studies and those studies would be a .shorter but wouldn't be as long as the GLP tox  .study but they would be informative from a fact .that they would try to do some dose escalation in  .the animal and get some sort of idea and actually .would try to establish somewhat of observe some  .toxicological effect. So you'd want to be able .to obsess initially a margin of safety within  .the animal so that you would know what kind of .so you can convey to the regulatory body when you  .filed your IND what sort of safety margins you .would be operating in within your dosing regime  .in first human dose. So (during) now I would say .90% of the time so in this at that point so there  .would be a about a hundred gram scale at this .point where that those tox studies would occur,  .but we would be doing we'd select the polymorphic .form we'd make sure you know primarily we'd be  .trying to find the most stable polymorph that .we would hope to commercialize. And in doing so  .that I'd say probably 90% of the time we were .able to be successful and not have to go back  .and change form. It saves a lot of repetition of .studies. One of the things so however that happens  .so you know there's only a hundred grams here and .later when you do formulation development you're  .gonna have to scale up and have larger amounts .of material and some of these properties or the  .flow ability of materials and the like really .can't be well assessed until you get a little  .bit later into development when you're formulators .start working with materials and the like. And so  .you might uncover certain things that you don't .necessarily like about the polymorph that or the  .form they the physical form that you've chosen .there's no perfect forms you know it's rare  .that you don't hear some feedback about this or .that that should be better about your compound,  .but generally you can do a good job of selecting .the final form pretty early on and I'm talking you  .know well you know a year and a half before first .human dose. But there's certain information you  .get post or you know after you've made that .selection and one important factor is route  .selection so impurity profiles can change and it's .one of the most important factors in determining  .crystallization outcome and so because rel subs .(related substances) are the most similar to the  .drug molecule they're more likely to interact .with the growing crystal form in what forms  .nucleate. so it's an extremely important factor .and so the sooner you get your route selected  .the sooner you can be more confident that you have .the physical form and that you've identified all  .of your polymorphs. So the sooner you pin down .your chemistry the better off you are but a lot  .of that does continue you know ice processes .are developed as they're scaled up and then  .the doses aren't really established until you .start getting out into the Phase two studies  .as you refine the dose the efficacious dose and .then you start to get into formulations that are  .more representative of what you might make for .your commercial product. And so you can learn  .and periodically you may have to change like I .said less than 10 percent of the time I would say  .is when we would change forms beyond candidate .selection. Part of the importance of the salt,  .you know the most traditional means of improving .the bioavailability of a compound if you have one  .that's in the BCS class two or when it's poorly .soluble and you think that it might have to be  .a relatively high dose is salt formation. And so .it this is why traditionally it's you know salt  .versus free forms established very early on and .the solubility ratio of one versus the other can  .be as much as you know a salt form can be as much .as a thousand times more soluble than say the free  .or the neutral form of the molecule. So we try .to early on that very first step is determining  .whether or not you need a salt and in determining .whether or not you might have to enable it by  .making an amorphous form to take advantage of the .enhanced solubility of the amorphous form over the  .crystalline form. But then once you've chosen .that you look at polymorphism and and also you  .know about 30 to 40 percent of compounds will form .a hydrate and so you almost always have to deal  .with hydrates or a good percentage of the time you .have to deal with a hydrate. Where that transition  .humidity or water activity occurs and determine .which one is best for your processing and for  .control of your product but these are still .significant differences much less so in solubility  .ratio but a hydrated form versus a anhydrate .typically is about you know the hydrates about  .1/4 the solubility of the anhydrate in water. One .polymorph versus another this nice paper by Abu  .Serajuddin from Bristol-Myers Squibb in 2005. He .took a 81 different compounds and compared their  .solubility ratios to one another and determine .that you know it was a 1.76 on average full  .difference the metastable form would be one point .seven six more times more soluble than the stable  .crystalline form. And so those are significant .I mean if you go too far into development and  .you have to do a form change you're also likely .going to have to adjust your dose. Which means  .that your formulator is gonna have to change this .formulation which means you're costing yourself  .a fair amount of money and from my recollection .it was somewhere on the order of at least a half  .a million dollars to develop a good formulation .for a tablet and so it can get expensive. Early  .studies were typically done drug in capsule or .with a very simple formulation. Later studies  .are done you know in the final formulation so .you don't want to have to to develop that final  .formulation which costs a lot of money and time .so it's good to get your polymorph identified and  .defined very early. the ICH there is a conference .where they harmonize basically. There were some  .issues actually in the late 80s with carbamazepine .hydrate versus an hydrate forum where some generic  .manufacturers came out on the market and had .a compound that would convert into a hydrated  .form and the patients weren't getting efficacious .doses from what I recall and so it really brought  .the light on the importance of controlling .polymorphism. Lilly the company that I was  .blessed to work with for 30 years was very I mean .they were very well aware of this and controlled  .it I mean they had x-ray diffractometer clear .back into the 50s, and but some companies didn't  .have a full appreciation and it wasn't widely .accepted or understood within the pharma industry  .how important it actually could be but some of .those patients died in with that carbamazepine  .and so it heightened the FDA's awareness and so .the regulatory guidance came out in the mid 90s.  .Partly because of carbamazepine but it just as .being good science but that if you look at the  .guidance in Q6A on polymorphism is that basically .it's a requirement it's an expectation that you  .will deliberately search for polymorphs. It's .you need to not only monitor the batches that you  .produce and use throughout your development cycle .but you also need to deliberately try to vary the  .solvents the compositions the crystallization .conditions in order to find as many forms of  .your drug as possible and then use good science to .establish which form is best for your product and  .so that's where and they also say some of this .is a subset of the common techniques that are  .used x-ray powder diffractions been considered to .be the gold standard for identification of solid  .forms of drugs. Differential scanning calorimetry .and thermo gravimetric analysis (TGA) is widely  .employed. Microscopy much under appreciated but .extremely powerful technique is also one that's  .used in a variety of molecular spectroscopies are .used. It is it's used it's used with it's not not  .generally does a drug product get produced .in a form that's of so the question was a  .single crystal diffraction used commonly in the .screening phase that's not commonly used probably  .because of the expense of the technique and in .my lab because we grew most of the single we  .discovery chemistry ultimately gave us although .I kind of worked at the discovery interface but  .they gave us a reason because we grew most of .single crystals we acquired the single crystal  .diffractometer and did all the structural .analysis and there are some ways I'm not  .going to get into it here but it's actually quite .advantageous because you can calculate your powder  .diffraction patterns from your single crystal and .firmly establish whether or not there's a mixture  .so there's actually a really nice interplay .between single crystal and powder diffraction  .but it's generally not the final product and .the API's are generally of smaller particle  .size so it's not used as a traditional method for .distinguishing polymorphs for the screening part.yeah it's actually a requirement so yes the .polymorph screening is an expectation and  .is a part of your regulatory document you have .to explain what all you've done and basically  .convince the FDA that you've done good science .and and it ultimately factors into the control  .of your product your API as well as your product .and so they look for that in your regulatory  .submission and hopefully when they see a rover .robust package and rationale they understand  .that you have good control of your process and .product and so ultimately and you can actually  .I think there's supposed to be two identification .techniques if you ideally you'll produce out of  .your API once you've identified the forms and .understand their thermodynamic relationships  .you can get a process that will produce a single .form and then you'll have a use a qualitative  .technique oftentimes x-ray powder diffraction .you can substitute it I think usually I have  .two analytical methods for identification of your .API and you can substrate powder diffraction is  .one of those alternatively it can be FTIR which is .a little less discerning from a crystallographic  .standpoint but powder diffraction works very well .for this and so you can have high ideally you have  .a single form present and it stays that single .form and if you have multiple forms you might  .have it where you know you look for these peaks .that prove that you have the right form and then  .you ensure at this position in this position in .this position that this other form that's known  .to potentially come out of your process or that's .relevant to your process isn't present and so it's  .just a qualitative method where you just identify .the single polymorphic form but there are other  .special occasions where you might actually have a .quantitative method developed and I've done that  .on a few processes for specific reasons and I'm .not going to get into them here but you're you  .know generally you try to get into a where you .have a qualitative method for identification  .of the form of the final product API and what's .present in your which the next slide goes to that  .though is that you monitor during your stability .your accelerated stability testing to ensure that  .there's no inner conversions of forms and make .sure that the form stays the same if it doesn't  .you'll end up having an acceptance criteria which .will set specifications or limits as to how much  .is acceptable of a extraneous or a different .polymorphic form but you'll put in your analytical  .tests which high percentage of the time it'll be .IR or Raman most often though IR or x-ray powder  .diffraction to control your product this is what .I had within my lab a whole variety of techniques  .but certain ones are the most common in particular .for the screening the x-ray the conventional x-ray  .powder diffraction solid-state NMR is extremely .useful higher resolution than the other molecular  .spectroscopy but each of these have there's .no it's nice to have multiple they call them  .orthogonal techniques sometimes people refer to .them as orthogonal techniques I think it sounds  .nice but basically different techniques are more .sensitive to different types of forms oftentimes  .your thermal techniques are perhaps more or even .moisture sorption analysis might be more better  .at detecting small amounts of amorphous material .within the presence of a crystalline predominantly  .crystalline sample but basically the different .techniques they serve in a complimentary fashion  .microscopy pull the right light microscopy .is extremely powerful in particular when  .you couple it with hot stage microscope II but .to beyond there's fewer practitioners that are  .good at this but you can learn a lot just even if .you're not oh you know even if you're not really  .experienced with the thermal microscopy or with .microscopy just by looking at a sample under you  .know after you've done some crystallization if it .looks hair like chances are it's not going to flow  .very well so I can a lot of times by microscopy .I can tell you something that will won't I might  .not be able to tell you that it will flow well .but I can tell you if it won't flow well a lot  .of times and so you can quickly eliminate so .that's one of the things and I find a lot of  .labs don't do this and I've looked at a lot of .data packages from different laboratories and a  .lot of times they don't even some labs don't even .put microscopy or images in their data packages  .and then then later when you see the material that .they're producing you say yeah that stuff you're  .formulators will have a terrible time they're .gonna kill you for selecting that form for a  .product and it's just a two minute you know all .right it's the simplest technique but it tells  .you a lot and I encourage people highly - and if .if you have a contractor that is doing polymorph  .studies for you and if they don't have images .of the form that they select for development  .make them put a picture and make them give you .an image look at it and see whether or not it's  .hairy or if it's got a nice morphology that might .be if not milled you know if it's not it quant or  .if it doesn't look like it would be flowable have .them you know make sure that there's enough three  .dimensionality to it that it or have them look .until they find something that has an external  .morphology that looks like it might flow because .that I mean I've dealt with this before and it can  .be very challenging for your formulators and it .can cost a project a year or two in development  .and we use tight throughput screening and then .computational tools a variety of computation  .computational tools we had absorption modeling .within our teams but also you know a lot of times  .it's working here you were hand in hand with your .Adney and toxicology groups early on and actually  .throughout the development though with the .absorption modeling so now I'm I guess the third  .thing is is so even if you have a form change .during this period it's not a crisis you know  .it's nice the sooner you have it the sooner you .can establish your doses you know elsewise you're  .gonna have to see whether or not a form change .makes a difference and often one good place to  .do it would be during the bridging studies usually .when you go from that drug in capsule or one of  .those simple formulations usually you'll do you'll .have to bridge it to the commercial formulation to  .ensure that you know the bioavailability doesn't .change substantially and so at that same time you  .can at the same time you can actually that's a .nice time to switch polymorphs but realize you're  .varying two things simultaneously and so it's not .ideal it's nice if you have your form identified  .your physical form identified early so that this .bridging study there's only a single one involving  .the change in the two the commercial formulation .for your pivotal studies for commercialization but  .you can't combine them too that's a nice point to .do a polymorph change if you need to so the first  .system and I'll talk about a colorful one that .got around for a while it was called ROI initially  .when I started on it it was a intermediate for .a drug called zyprexa that sold widely at Lille  .that got up to over four billion dollars a year .antipsychotic but it was quite interesting because  .we had Eastman Kodak was producing a compound for .us and the intermediate and one minute it be read  .the next time it be orange next time it would .be yellow they didn't understand and classic  .polymorphism so they dissolve it solution in a .bar and it was the same material each time so  .classic polymorph true polymorph and it's a good .example because visually you know this is one of  .those few cases where polymorphism you can't you .know you can't overlook the fact that this is a  .polymorphic material if you know you know it will .form plates you know it's the same chemical entity  .in different arrangements within the crystal .lattice so we did do the crystal structures of  .all of these forms and the arrangement of the .molecules were different and also so the color  .was associated with the planarity of the aromatic .rings but it shows you very well how different  .substances can be just based upon packing within .the crystal lattice and so and you can envision  .also if you saw something like this or this .it would flow a lot differently if this were a  .product this is an intermediate fortunately but .if this had been a product these would likely  .flow much better as a powder if you micronized .it down then these needles these needles aren't  .terrible terrible in my opinion but sometimes .you'll see stuff that's hairs that there's no  .way a formulator would be if had this been a .final product these would have probably been  .more challenging from a flow perspective than .these and you could have told that very quickly  .just by looking under the microscope but you're .look at the melting point differences they're  .significant among these different forms so this .is a classic case of polymorphism and it led to  .some very good science by one of my fine well with .our group and then with one of my colleagues I had  .done some just with high throughput screening .from the early 2000s just showed where multiple  .crystals would crystallize simultaneously .from the same exact crystallization and there  .is little control over what form would come out .you'd get mixtures of forms a friend of mine who  .unfortunately passed this past year Joel Bernstein .great scientist and that's one of the one thing  .wonderful things about this field it's kind of a .small field then you have a few people and then  .you kind of come from similar lineages and we .all kind of connect internationally you and but  .Joel's Bernstein was very prominent in the field .and he had termed this concomitant polymorphs when  .multiple polymorphic forms grow simultaneously .and Leanne knew in a nice accounts of chemical  .research in 2010 I believe it was a cover article .but he had done he continued to do very good work  .and went on to University of Minnesota one of .his graduate former graduate students is here  .and there Wisconsin I'm sorry yes University .of Wisconsin and he continued to study this  .interesting system and I think actually there's .nine or ten forms by now of which I think seven  .we have crystal structures of but at this time .they use a combination of thermal analysis at the  .melting points and their enthalpies of fusion to .relative to the room temperature the yellow form  .which was stable at room temperature he could .infer the free energy or measure the energy  .difference between the different polymorphs and .then by melting with miscible the same miscible  .substance he could measure the enthalpy of fusion .and the melting point depression and used the  .heat capacity changes to again at different .temperatures with different amounts of that  .eutectic forming substance could calculate at .different temperatures the energy difference  .relative to the room temperature stable form and .I took the liberty of extending that a little bit  .or extending those lines down to room temperature .to get the Gibbs free energy difference between  .those forms approximately so that I could use that .in comparison with some other data that had been  .plotted for polymorphic forms so this nice little .thing that a booster should and did and trends and  .solubilities of polymorphs that he published she .took 81 different polymorphic forms and ranked  .the solubility ratio of the metastable form versus .the stable form as polymorphic pairs and he took  .81 different substances or different polymorphic .pairs and plotted those and he found actually the  .solubility the you know the metastable form was .about one point seven six times more soluble than  .the stable form so there's some scatter in the .data but the average was actually pretty tight  .and I was using like the free energy difference .that LeAnn had measured and extrapolating it down  .the room temperature this data was determined .by solubility analysis and Hoffman you can use  .a Hoffman equation to a first approximation .it's actually activities here but you can  .use solubilities to the first approximation and .so I can take the free energy differences from  .Roy the Roy system based on LeAnn's data and then .calculate what that would be that solubility ratio  .and then compare it to the average polymorphic .system so the average polymorphic system if you  .calculate based on this number it's actually I .convert it in a kcal instead of what Leeanne had  .which was the Kate kilojoules per mole but it's .0.33 kcal per mole is on average the difference  .for these polymorphic pairs but with these with .the ROI compound it's actually much tighter in  .quite a bit lower so it was 0.14 kcal per .mole which is significantly different and  .pretty tight and probably explains a little bit I .guess the conclusion I had or inference I have is  .that then I think I think there's enough data out .there to it's basically that poly Moore's a very  .similar energy in particularly those concomitant .ones there's competition of nucleation rate and  .growth rates that result mixtures of polymorphic .forms and they're very difficult to control if you  .want to control what polymorphic form comes out .you have to control the super saturation their  .ratio is very tightly in order to do so and really .with ROI it was pretty difficult to because they  .were so tight it was pretty difficult to .we were fortunate that it wasn't the final  .product because it would have been a little .bit it would have been a challenging system  .we might have ended up having to use some sort .of or you know a quantitative method if it had  .been a final product but it was much more it was .a difficult system to control what form came out.that is not on here that's actually in a different .paper by and I referenced it earlier but it's as  .much as a thousand times way out there yeah yeah .yes yeah it's but I did have there's a reference  .in there which fortunately was done by a Bruno .Hancock has one but it can be up to a thousand  .times different yeah and that's why people for .the longest time were very hesitant to go with  .amorphous forms when a crystalline form was known .was because there was so much driving force or  .energy and then we got into solid dispersions .where you could inhibit that from happening but  .I'm focusing on you know the polymorphic systems .I'll go Paul Ratana beers kind of the been known  .over the years is one of the more famous cases .with Abbott they had a form that appeared after  .they've been on the market for a year or two with .their semi-solid capsules in there and all of a  .sudden a new form started to appear in their .product so a new crystal form was found in the  .formulated product a team of scientists went to .investigate if any significant changes have been  .made in their manufacturing process until this .time no detectable quantities of form to have  .been tected in the bulk drug Lots soon after .visiting the facility manufacturing facility  .form two started showing up in their bulk drug .production facilities as well so they moved the  .seeds from the product and then they seeded their .process and then all of a sudden they had trouble  .controlling their final process they're off the .market I believe you know this was first in class  .I believe of one of the protease inhibitors and .obviously there was a lot of it was growing in  .sales very rapidly and all of a sudden they .had to come off withdrawal from the market  .while they reformulated they theorized that the .compound adopted and energetically dis favorable  .conformation in the stable crystal structure .and that's why I didn't nucleate very well  .to be honest the data wasn't really good behind .this I mean it was kind of a little hand waving  .which is kind of what you find with love times .with these polymorphic forms they don't didn't  .know I mean they theorized but there wasn't an .absolute answer as to what was going on but they  .theorized that a heterogeneous nucleation occurred .by a related substance that had that unfavorable  .conformation nucleated it this was by baauer .who was in a different area but at the same time  .though the guys in process chemistry published a .paper and they said the origin of form - remains  .debatable the fact was that this issue had to be .addressed as soon as possible and so there was a  .lot of urgency and I knew enough of the guys from .around there to know that yeah they were working  .a lot of hours and what was interesting though is .right if you took it it was a part of this study  .that Sara soon had had done and it was at one .of the ones that's at extreme of differences in  .solubility ratio and it was if you calculated .it was about 0.8 kcals per mole theoretically  .with polymorphs they say that Polly Morris will .fall within one kcal per mole of one another but  .the reality is most of them fall within point .three three kcal per mole so that brings me to  .my final system that is somewhat extraordinary .when I so I called it the missing polymorph of  .melatonin agonist but basically if you remember .pastors experiments where he kind of led to some  .of our increased understanding of chirality in .using tartaric acid where he noticed under the  .microscope that these that there are half of .the crystallites were of mirror image to the  .other half you know non superimposable and .it helped him infer you know basically that  .they had you know chirality associated with the .chemical entity of tartaric acid but in theory  .if you took D&L tartaric acid and separate you .know crystallize them separately you could get  .the same forms out of each enantiomer you know .it's a mirror image so they they'd be mirror  .image crystals but theoretically you could get the .exact same packing out of them because there's the  .same molecules they have the same conformational .freedom and flexibility they should produce the  .same forms but in this case the act of any antemer .was produced by discovery Kimmy decided that they  .would use the this was in the mid to early 90s and .they went with the act of enantiomer and provided  .for and they've had this happen more than once .where to say it to conserve the act of molecule  .we know biologically biological systems are .very sensitive to chirality crystallization  .usually you do an a chiral or non chiral media .and so theoretically you should be able to learn  .what you need to from the inactive enantiomer .and so they in the study of the inactive in  .enantiomer while they were off doing their talk .studies and the like throughout for the initial  .batches that were provided were metastable form .line the fourth batch resulted in this much more  .dramatically stable form to it was extremely .difficult to produce this metastable form after  .the discovery of the stable form too and in fact I .only produced was able to go back and produce the  .metastable form one time not surprisingly that it .came out of that it was from the oil where I was  .actually able to get it to nucleate out as form .one but it was much more difficult to get form one  .once the more stable form was produced and that's .not all that uncommon I've seen it a few different  .times where you'd produce one form and then a .next form then an X form and then ultimately you  .couldn't go back to the prior forms it's been .Joel Bernstein again referred to that as being  .disappearing polymorphs but it's been noted over .history that this is not uncommon there's a number  .of good papers where this has occurred and some .people say with ranitidine hydrochloride which  .had a big patent dispute over it but that was the .case with Rena Denney ranitidine hydrochloride so  .they had so I had a disappearing polymorph in .that in that case with the inactive enantiomer  .but when I got the act of enantiomer to work with .we never could reproduce the stable polymorphic  .form to that had been that we you existed from the .inactive enantiomer even though we did thousands  .of recrystallization experiments and more than .ten multi kilogram scale Lots each one of those  .produce the metastable form one which was .quite surprising so in that case I called  .that the missing polymorph because we knew I had .to exist but we couldn't produce it so the what  .happens sometimes is you run into a big problem .and sometimes attrition takes care of the problem  .for you and that molecule we stopped developing .it it was in Phase two clinical trials I believe  .we stopped developing it but it took we actually .out licensed it and then finally the company that  .was actually working with it gave us after the .patent had expired I got approval from Lee the  .on the chemical entity unlegal to go ahead and and .actually the company that had purchased it from us  .went out of business and legal finally said I .could publish on it and so I had had to wait 14  .years but ultimately if you wait long enough you .can publish it that's but these were purified so  .they actually the very final step was a chiral .producing step yes well that's interesting you  .know I'm not going to actually be able to go .into that in detail but yeah you would think  .that like fast yours experiment that it would be .a conglomerate but it we will have time enough  .to go into that here but there's some yeah here .if you have interest in this kind of thing read  .the paper I went to a lot probably more detail .than I should have but it was it's an interesting  .really interesting system but so after 14 years .I thought that my mind you know I'm that really  .wasn't that way was it and you know my mind .was just there's no way in the world it would  .still behave that way but I it was one of those .that just stuck in my mind and so once I got the  .approval first thing I did was actually I got a .research stores I got like 30 some lots of the  .active in antemer and and looked at them all and .they had all stayed stable and they had stayed in  .that metastable crystalline form for 14 years .and I was pretty surprised with that and then  .I looked at the so then I took the two primary .Lots you know one of the active enantiomer and  .one of the inactive enantiomer and then I just .recrystallized them against I believe it was like  .23 different solvents and separate experiments .and surprisingly enough you know the act of  .enantiomer melted or formed that the metastable .form the one that melted one hundred and twenty  .seven point nine degrees C each time and the .inactive enantiomer always crystallized out  .at the as a higher melting point in crystalline .form I didn't expect this to happen I thought it  .was I I was amazed that that would occur yeah .I did yeah it's I'll reference it in here but.they should you're absolutely yeah you would think .they would be but they weren't and so I studied it  .and I'm not going to go into all the details but .the but part of it was you know obviously related  .substances being most similar to the drug itself .are the most likely culprit and but in this case  .I I mean I the purity was almost identical you .know they're both you know one's 99.3% pure the  .others 99.5% they had the same related substance .profile just slight very small differences in  .the rel subs nucleation is one let's say is very .interesting and we still don't fully understand  .it I was able to take the two individual forms .and make her a summate but I did I did a lot of  .other studies that are published here trying to .understand that it does crystallize as a recipe  .yes it does yeah hey yeah and so I actually so .that actually makes some pretty nice cover art  .so this is the if you actually do the experiment .all I should have left the experimental points on  .there probably but it doesn't look as pretty if .you do that I measured the actual thermo phase  .diagram but so in the one case because it's the .lower melting point when I did the melt eutectic  .it had a different eutectic because it was a .different polymorph mixed in with the racemic and  .when i did the but your lower melting point form .has a polymorph that's obviously missing because  .we know that it should form that polymorph but in .the other hand we had with the inactive once you  .formed the stable polymorph the one that may have .melted so much higher you couldn't form other than  .the one time where I did it from the the melt or .where I from the viscous liquid super saturated  .liquid was able to get it but essentially you had .a disappeared polymorph it would become much more  .difficult to form that metastable form and so .I did publish it a couple of there's some but  .this is the primary paper but there's a lot of .detail in there cuz I hope somebody would go  .back and try to reproduce the work for themselves .and actually find that missing polymorph we you  .you know I used the variety of techniques but I .did want to relate again through solubility and  .through calorimetry the phase diagrams and also .the solubility analysis two main point to get  .to the main point basically is that it was almost .like Ratana beer also where that metastable form  .was four full times more soluble than the stable .poly more so is pretty exceptional so these ones  .that are really hard to nucleate oftentimes are .the ones that have the highest difference in  .energy the ones that nucleate the most I'll .get that in a second the ones that nucleate  .more readily or the first appearing ones are the .ones that are metastable and that's been known  .for years but basically melatonin ritonavir the .late appearing polymorphs were difficult appearing  .polymorphs if you will were different by 0.8 kcals .per mole so they lie they are at the extreme for  .polymorphs Roy was 0.14 kcal per mole that's the .concomitant one where we had difficult controlling  .which form would grow so late appearing polymorphs .or nearly four standard deviations away from the  .average energy difference of the average organic .polymorphic systems and so I did do these energy  .diagrams using a combination of thermal analysis .and solubility analysis across the wide variety of  .energies per of temperatures but I'm just going .to boil it down to you know with when it comes  .to polymorphism it's all about nucleation and .getting different conditions and getting forms  .to nucleate and the classic nucleation theory .which there's other you know nucleation theory  .he's out there density fluctuations and the .like but to be honest is still one of the most  .practical descriptions of nucleation processes .and but typically you'll break down the energy  .of the nucleation process into two separate .terms the initial term that is dis favorable  .is associated with interfacial tension and then .there's this other term which is associated with  .volume growth of the actual crystal and this so .that interfacial energy term is dis favorable and  .that's because as so right here as the radius of .clusters of molecules as they come together and  .form larger and larger clusters its disfavored as .they separate themselves from solution there's an  .interfacial tension that occurs but then once .you get enough molecules together beyond that  .it actually the bulk growth becomes dominant and .further growth and the crystallization the overall  .crystallization process becomes favorable and .crystallization occurs but some people say primary  .nucleation doesn't exist I've heard that before .from some pretty good scientists but secondary  .nucleation whether you consider it by seeds which .is something we use to our advantage in processes  .lots of people you know it'd be preferable that .you wouldn't have to use seeds but it's your best  .way to control crystallization of a process and .it's always prudent to write in a seeding step you  .might not have to use it but right in provisions .for a seeding step in your final crystallization  .for control purposes but if you remove that .inter facial pension through seeding you can  .direct the crystallization to the form that you .desire and so if you have seen crystals you buy  .fit bypass the disfavored process of nuke and so .there's a if you do the inverse of that which is  .nucleation rate basically the more the bigger the .energy difference or the between the crystalline  .forms the higher basically this nucleation .activation energy and so your metastable  .forms tend to nucleate at a faster rate than your .stable crystalline forms and so in the end and  .the absence of seeds when the energy difference .between polymorphs are small their nucleation  .rates are likely to be similar and concomitant .polymorphs more likely in the absence of seeds  .very large energy differences may result in very .large differences in nucleation rates and so the  .overall conclusions this is kind of a reiteration .of the earlier thing but for the melatonin agonist  .i'm my inference is that there was basically .a heterogeneous impurity likely not the drug  .substance itself because both of them were exposed .to the same in you know the same environment  .they were grown in the same labs with the same .equipment but it's likely that a chiral impurity  .enabled one enantiomer you know heterogeneous .li nucleated one whereas the other one was  .never exposed to the that same mirror image chiral .substance that had caused heterogeneous nucleation  .to occur in crystallization of its stable form .but with that i'd like to acknowledge my coworkers  .Craig Wolfe angle Jennifer Runyan and Dave .Jackson for their analytical support professor  .frank lucien who passed away unfortunately way .too young and john Kendrick who worked with me  .on the ab initio calculations and which I didn't .present today but our in the paper thank you  .for your time and listening to my presentation .that's Pharma form finders comm is the company  .that I work for as an independent consultant and I .thank very much regis chemicals for giving me the  .opportunity to speak today can I get her first .she does up quicker uh-huh you know what you're  .right this is this is not a chiral method oh they .would result yeah now I at the time we were doing  .it but when I went back and visited I did not have .access to the resources so I didn't have that data  .to include yes I would have liked to have had that .it is it is although although it should have the  .same chromophore right but one of it one of the in .the same entities were present there but yes that  .would be worth knowing if one of those were chiral .I should have yeah it's been a while yeah yes so  .an hydrates sometimes it depends on the nucleation .how well it nucleate so the question was would  .an hydrate and hydrate if you're doing the vapor .sorption desorption so changing the water activity  .in that piece of equipment it I find that if .it's very soluble that the interconversion can  .oftentimes be absorbed on or be observed in the .vapor sorption experiment sometimes I think if you  .really want to be safe you're better off putting .it into because of expensive piece of equipment  .it takes a long time to make the measurement .or you're tying up a piece of equipment it may  .take a while for it to nucleate to hydrate forty .percent thirty to forty percent of the molecules  .will form a hydrated form it's been shown three .or four at least three or four good publications  .so and they always come up with about the same .you know the thirty to forty percent of the time  .so you should always almost always expect that .you're gonna find a hydrate you want to choose  .the form that is stable from say thirty to seventy .percent relative humidity it's nice if it doesn't  .interconvert but to really be certain of whether .or not a hydrate exists DBS is extremely useful  .for understanding how your hikers got busy and .whether or not it happens quickly changes from  .one form to another but it's also nice to use .like to place the sample over water at different  .water activities it is different I'm not gonna say .either of more typical I've experienced probably  .half the time it's one where and we oftentimes .refer to those so the question yeah so the  .question was you know there's certain hydrates .where the water molecule is an intimate part of  .structure and and if you remove it the structural .collapse and there's other cases where you can  .remove the water by exposing it to low humidity .or atmospheres of low water activity and in those  .cases usually there's a change in the lattice it .can be very small but usually there's a change in  .the lattice and usually there's actually fracture .so you can see it under microscopy but sometimes  .the peaks stay almost exactly the same location .so you don't get a collapse of the structure and  .those we call variable hydrates and usually when .we're doing our screening process we try to stay  .away from those because it's more of a challenge .analytically and other ways of controlling the  .potency because you got to include water in the .potency so usually we try to stay away from those  .types from selecting those as final products .but your cephalexin which was called monohydrate  .and then they made us change it to suffle X and .hydrate because it same thing with seafloor lots  .of lots of molecules do that variable hydrate sort .of behavior it's just a little more challenging  .sometimes you have no choice it's the only form .you have but other times yeah but I wouldn't say  .one is more common than the other I would say .you're I'd say you're probably right if you have  .a nice distinct step usually that's a physical .form change as opposed to like with cefalexin  .or it changes Chi yeah it's you get hysteresis .but it's not a real discrete change in the DVS.usually it's a good atom that means it's .a nice discreet change the only thing is  .is if you have hysteresis between them .it's a nice step and you have hysteresis  .between them it's you know there's an inner .conversion you just don't know we're in that  .humidity range that occurs but there's that's .when we go on to slurries and solvents with  .water and determine what that critical .water activity is to pin it down closer.oh this this laughs so to use so the question .is if you know that that form is more stable  .but you can't get it are you going to market the .metastable form because you can't get it you know  .I think that's what you would do if you had to .but I can tell you that if we had gone beyond  .phase 2 clinical trials I can't imagine how many .people in our company we had a significant number  .of people working on it but it we would have .had all the king's horses and all the king's  .men trying to find that polymorph I promise you .because somebody else could have patented that  .other form and we couldn't make that form so .there's no way we can patent it possibly that  .that possible you know that I'm sure we would .have considered that yes it actually happened  .before people really went to doing more of those .but yeah that would have been a good option.you'll have to go through the ice eh guidelines .yes you can go with metastable forms there have  .been plenty of metastable forms that have been .marketed and then they later found stable forms  .but as long as they can continue to produce the .same form even if it's a metastable form there's  .nothing that precludes you from developing that .metastable form but there's a risk I you know I  .think that's good science and that'll be dialogue .between you and the FDA or the you and the  .regulatory body but you could rationalize through .modeling and other things whether or not there's  .an omelet yeah so then you have a different .way in parts sort of like an h1 by tourism yeah.you could I mean you can rationalize that but .that would be available to either one of them  .that's well okay yeah you're saying yeah .it's possible cause if it's a high enough  .energy barrier I don't think in this case .I don't think in this case you have a high  .enough energy barrier that I mean those .are single bonds I doubt it but I read  .the paper think about it send me an email .it is as a unique yeah yeah and I think  .that's polymorphisms unique and nucleation still .fascinating today as it was a hundred years ago.yeah point therefore no no no but I don't .think that's your explanation like anyway  .if there's any other questions .if not I'll let you guys eat.you.

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