Organic and Pharmaceutical Subcommittee Agenda and Minutes
Organic and Pharmaceutical Subcommittee
March 19, 2002
Chairman: Greg Stephenson/David Rendle
Greg Stephenson introduced two new committee members:
- Harry Brittain - worked in pharmaceutical industry and involved in pharmaceutical litigation cases
- Bob He - from Bruker
John Faber handed out information about PPXRD-2, and circulated the signature list. Terry Maguire mentioned that we had 79 attendees and 16 invited speakers at the PPXRD-I symposium.
David Rendle gave a presentation about the progress and summary of the Merck Task Group. This task group was created four years ago. It is coming to an end and achieved all that it set out to accomplish. The purpose of Merck Task group was to identify Organic and Pharmaceutical compounds, which are not in the PDF and CSD databases and pass them to the GiA. There were roughly half a dozen people in the task group and they extracted entries from the 12th edition of Merck into Excel spreadsheets. The extracted Merck entries were compared with PDF, CSD, and USP entries. A summary sheet by Shao-Fan Lin from China was shown. One example with Merck Numbers 1 to 500 was given: 546 Merck compounds empirical formulas were compared with those of the CSD database by Fangling Needham. The empirical formulas of 366 Merck entries matched those of 2644 CSD entries. These 366 Merck and 2644 CSD entries were passed to Shao-Fan Lin to match their two-dimensional structures. The number of final matches was 178 (67 unique compounds). In summary, 14% and 11% of Merck entries are in PDF and CSD databases respectively. 5% of Merck entries are in both PDF and CSD databases. David Rendle compiled a list of compounds that are not in either PDF or CSD, and are easily obtainable from Sigma and other sources. This list will be passed to GiA.
Jim Kaduk: What happens after the list is given to GiA?
Greg Stephenson: Realistically, there are half of the USP compounds not in the PDF. Do we want to appropriate funds for the next 3 or 4 years or just for one year to run these compounds? We are talking about $50,000 or $60,000 to have a comprehensive database.
Jim Kaduk: Comprehensive pharmaceutical and not comprehensive Merck?
Greg Stephenson: Right, many of them are not available - (Merck).
David Rendle: The compilation list shown here is derived from only the first 500 compounds of the Merck Index.
Harry Brittain: One compound will have many forms and the pharmaceutical industry will be interested in all the forms.
Jim Kaduk: Give us a business plan - the purpose of this subcommittee is to advise the board what to do.
Harry Brittain: If we want to target the pharmaceutical industry, perhaps the best thing to do is to identify the top 200 to 300 most important compounds and get the various forms of these compounds.
Tim Fawcett: It is a wonderful idea. Since we are targeting the pharmaceutical industry…identify the compounds and get them to the GiA committee.
Greg Stephenson: We can get together with SSCI (Solid State Characterization
Inc. West Lafayette Ind.) to buy their compounds.
They are selling powder diffraction patterns.
Brian O'Connor: This task group will be useful to give the board suggestions of this kind.
John Faber: I like the idea of taking 200 to 300 compounds. The question is how to implement it.
Harry Brittain: It is a matter of synthesis, process, and control. It should be an index-able pattern.
Greg Stephenson: In reality, 70% will not be able to be indexed. We will get the pure ones from USP first as a short-term solution and then tackle the polymorphs. We first contact SSCI to inquire about their data in their database. We will collect our own data if we are not happy the SSCI data.
Jim Kaduk: Do we have a complete list of compounds not in the PDF database?
David Rendle: No, Greg and I are working on it.
Greg Stephenson: I have started alphabetically to make the list, and have given it to GiA periodically. I am not certain GiA is the way to go.
Jim Kaduk: Maybe do a contract or contracts and just to get this stuff done…
Tim Fawcett: In defense of GiA, they get good quality patterns, good instrumentation. I am not convinced that GiA isn't the way to go. You brought up that you don't have the list on the web. We just instituted a GiA system that is web accessible so the issue may not be to get the list on the web.
Greg Stephenson: It would be nice to really put a push in before the next GiA meeting, try to get it going about that list.
Tim Fawcett: We've looked very favorably on people who have these compounds in their proposal. We let people know the available compounds are.
Greg Stephenson: We can let people know how to get compounds from the USP, other than controlled substances.
Tim Fawcett: Another question…since you have done the cross reference to the Merck Index, can we get this information to the user by telling them an entry is in the Merck Index.
Jim Kaduk: The Board needs a business or scientific plan. How much work is involved?
David Rendle: We are making lists of compounds we feel should be in the PDF database. How do we get the compounds into the database and how much will it cost?
Harry Brittain: What is in the USP would be useful to the generic drug industry. Innovators have their own list of compounds and nobody else has that list of compounds.
John Faber: In formulating a motion, one motion is to transform the information from the Merck task group into meaningful entries in the PDF. We want to prioritize the list, and suggest that these are important compounds for the generics. We need to find a way of getting them into the File. One way might be to investigate to find a collaborator to get the data, or to get the data ourselves - to go through the GiA committee.
Tim Fawcett: We know what we have on the list and we should fill in the rest. From what you said that USP is pretty important. It is better to go to the USP first for the generic reason. Is it a good summary?
Greg Stephenson: Personally, I can just see the commercial value associated with the pharmaceutical compilation.
Harry Brittain: The ones who would buy it are the generic industry. The ones with money wouldn't need it.
Harry Thielke: Who will buy it? What's the use if nobody buys it?
Tim Fawcett: Previously, we had only 25,000 compounds. We are trying
to change the game a little bit. The OEMs said that recently sales to
the pharmaceuticals have increased a lot. One of the major OEMs is putting
themselves for IPO bit.
You can go to the Securities and Exchange Commission and find out their next five years plan and there are a lot of things on pharmaceutical support. I think this is something that was not around ten years ago and is around now. The time is right and we are trying to get a product around this area.
Harry Brittain: The majority of pharmaceuticals are interested in powder patterns for litigation purposes and especially for everything in the USP that is crystalline in all easily accessible forms.
Tim Fawcett: What about excipients?
Harry Brittain: Easy… a lot are amorphous.
John Faber: Amorphous patterns should be in the database.
Harry Brittain: We are going to add about 250 compounds to the National Formulary (NF) in the next five years. Every one uses excipients. I am the chairman of the USP excipient subcommittee on monograph contents. This organization would have to get the right kind of powder patterns. For the exchange of information, USP might just give ICDD the reference standard ICDD needs.
John Faber: And we have a contact on the subcommittee who could help us on this kind of issue. Lets get a motion going.
Harry Brittain: A lot of excipients do not have polymorphs - maybe various hydrate phases, maybe some stearates have got an anhydrate and two hydrate phases. But on the other hand, it tends to be a very small number. Your product can be pharmaceutical and related products.
Tim Fawcett: Hydrates and stearates - we can get a good collection of
them and this gets back to how we set up the files.
We can have subfile. Even though we call it an organic file, do we need to have common contaminants?
John Faber: Like to develop ideas around amorphous phases.
Jim Kaduk: We need volunteers to be a contact to the USP for a joint project.
Harry Brittain: I volunteer to be the USP contact. If I can convince Roger Williams that USP can sell more reference materials by people accessing this file, he will be happy to going along with it.
Motion (Kaduk/Rendle): that ICDD contact the USP with the aim
of a joint project on the reference powder data of USP material and Harry
volunteers to be the contact.
The sense of the project is that USP will supply materials without charge, and that ICDD will arrange for the collecting of the powder data - through the Grant-in-Aid program, contract, CSSI, or other means.
Tim Fawcett moves that missing USP compounds will be entered into the PDF.
Tom Blanton: Shao-Fan Lin requests a grant for purchasing 40 pharmaceutical compounds including those from USP.
Greg Stephenson: One other point is to go through the patents and pulling data in from the patent. That would be valuable for some companies - they could be the most important information.
Harry Brittain: A list of patented crystalline forms could be the most sellable thing you have.
Tim Fawcett: Materials from the patent may not be commercially available.
John Faber: Some of our entries have patent references. Frank, do we have patent references in our database?
Frank McClune: Yes, we do.
Harry Brittain: Using the combination of keywords such as polymorphs and crystals, you can find about 75% of them.
Tim Fawcett asked Harry Brittain to give Tim Jenkins a list of keywords to search for patents.
Jim Kaduk: Shall we spend effort to generate amorphous data and fit into (PDF-3 database) a product?
Harry Brittain: Most people in the pharmaceutical industry think that all amorphous forms are the same. It would be worthwhile to educate people that there is more than one type of amorphous characteristics.
Motion (Kaduk/Faber): That information contained in the pattern
of amorphous materials is often of vital interest to many of these pharmaceutical
entries. We should engage in the process of looking for ways of finding
these patterns and get them into a database.
The sense of the motion is to extend the PDF-4/Organics to include APDF-3 patterns. By inference this could also mean including clay and polymer PDF-3 patterns in the PDF-4/Full File.
Tim Fawcett: We would not want the grantee to discount the amorphous materials.
Motion (Kaduk/Brittain): That characterization of amorphous materials is often important in pharmaceutical science. Patterns of amorphous substances should be incorporated into the PDF-4/Organic, along with characteristic physical properties (Tg, melting point, water content, etc.)
Jeff Dann: Do amorphous materials have a need for I/Ic?
Tim Fawcett: It depends on what it is.
Harry Thielke: Could you determine the density before you start?
Harry Brittain: No one actually does it.
Tim Fawcett: This database has six CDs. We do not want users to find 3000 hits. What extra information would people want?
Jim Kaduk: Melting point.
Tim Fawcett: You got it - Melting point. Do we want to think about putting information like infrared, mass spectrometry?
Harry Brittain: MP is good for calculating solubility.
John Faber: We have MP info from the Merck Task Group.
John Faber, Tim Fawcett: from 8:30 until 10 tomorrow we will have a demo for the PDF-4/organics package. There are three PCs that can be used to test this package. There is more information on the back of the agenda.
Tim Fawcett: People who would like to do the beta test should give their names to John or Fangling.
Jim Kaduk: Suggest people to write application notes for educating people at the booth.
John Faber: The 2-theta of the calculated patterns only goes up to 30 deg due to the space constraints.
Harry, Jim: most of the time 35 deg is enough.
Tim Fawcett: The point is not based on a scientific basis.
John Faber: You should sign on this committee on the list server. Give us ideas, for example d-spacing range.
Harry Brittain: We never find anything worthwhile above 35 degrees.
John Faber: Indexing is a strong recommendation from PPXRD-I and we would like you to submit ideas for the PPXRD-2 workshop.