Organic and Pharmaceutical Subcommittee Agenda and Minutes

Organic and Pharmaceutical Subcommittee
Chairman: Greg Stephenson
Time/Date: 13:00 24-March-2004
Location: Conference A, ICDD

Greg Stephenson called the meeting to order and circulated the attendance sign-up sheet. The attendance sheet is on file at ICDD headquarters. Greg mentioned that the subcommittee had done a lot of work during the past year. Several reports follow:

Board of Directors Liaison Report (David Rendle)

There were two motions from the ICDD spring meeting last year. The first was that the detergent subfile classification should be removed from the PDF database, because it was populated only by about six or seven entries. The second motion was that the European Pharmacopeia and United States Pharmacopeia/National Formulary should be used as the source for excipients as part of the pharmaceutical descriptions. The headquarter’s response to this was to carry out the work. The PDF4/Full File now contains about eight hundred and the PDF4/Organics about eleven hundred excipients.

Greg stated that the motion to clean up the detergent subfile is a good idea.

Product Use and Developments Report (Tim Fawcett)

Tim Fawcett showed slides that he had worked on with John Faber and Camden Hubbard last year. The focus was on the capability of the ICDD PDF4 databases. ICDD staff added data from the Cambridge database for the PDF-4/Organics database. They also added excipients and the common salts to the PDF4 databases in response to the Organic and Pharmaceutical Subcommittee’s suggestion last year. The excipients classification is a strong addition. The PDF-4/Organics has the PCSIWIN search index integrated with the product. The ICDD editorial process had extensive review for the calculated CSD data as well as the experimental data. Due to the disorder properties of the CSD data, about 50,000 CSD entries were not calculated. These 50,000 disordered entries have good crystal data for the CSD structure display, but are not appropriate for calculating powder patterns. Bernard Squires and Camden Hubbard produced the powder patterns of fourteen over-the-counter/prescription drugs and one fertilizer. With PCSIWIN’s intelligent text reader, Fink search, long line search, and other options, all major phases were identified. Although, the major component of the PDF-4/Organics database came from the CSD database, many of the hits came from the ICDD experimental database, which was populated with excellent organic compounds through the GIA program. This proves that PDF-4/Organics works very well in identifying pharmaceutical compounds. The ability of different software programs to identify and removing microcrystalline materials, such as cellulous and starch, will greatly enhance the success of this type of analysis.

Robert Snyder: An accurate powder pattern will be obtained by using the partial occupancy at the disorder site for the calculation. (Note: Absolutely true the problem being that many site occupancies are
not full described or data available for calculation.)

Tim Fawcett: We might be able to get the partial occupancy information by going back to the original literature reference.

Greg Stephenson: This represents the opportunity for volunteers’ effort.

Tim Fawcett: We need the members to identify which of the missing entries from the database are important to the industry. They are potential GiA patterns. In order to get the 50,000 mid-quality patterns into the PDF database, we can also use a quality mark system to address this issue.

Status of Ongoing CSD Efforts (Suri Kabekkodu)

Suri Kabekkodu gave the report on the status of the calculated patterns from CSD and some future plans. There are about 275,000 patterns calculated from CSD. In addition to the calculation, some properties such as habit, polymorphism, isomorphic, bioactivity and sensitivity were flagged for searching purposes. There are about 50,000 entries from the CSD version 5.25 that were not calculated due to the disordered structures. About 100 entries with disordered structures were calculated. The Merck task group specified these entries as compounds valuable to users. The editorial subcommittee meeting proposed a solution to the missing entries due to the disordered structures. The proposal is to use quality marks to rate the quality of the calculated patterns according to their missing electron density. Members of this committee will view a list of compounds with missing electron densities and prioritize the list according to their significance.

Greg Stephenson: It is important to get this list to the volunteers, but probably a lot of this type of compounds.

Tim Fawcett: We can start out with compounds with drug activities.

Merck Task Group Final Report (David Rendle)

David Rendle reported that the Merck project started in 1998 and finally completed after six years. The purpose of the task was to identify those organic compounds in the Merck Index whose powder diffraction patterns are not currently in the Organic PDF and to develop a strategy for acquiring their diffraction data. The strategy was to abstract information on all the solid organic compounds listed in the 12th Edition of the Merck Index and store it in an Excel Spreadsheet. This spreadsheet information was then compared with the Organic PDF, the Cambridge Structural Database, and the United States Pharmacopeia (USP). The task group output a list of organic compounds (including pharmaceuticals) regarded as important, with suggested sources and purchase prices. This list will be forwarded to the Grant-in-Aid Committee via the Organic & Pharmaceutical Subcommittee. There were 12,839 entries generated from the Merck Index. They are organic solids and their derivatives with melting point greater than 20°C. Fourteen percent of them are in the PDF, eleven percents in the CSD, and six percent in both PDF and CSD. As a result of the project, a total of 1,217 compounds have been named as potential Grant-in-Aid compounds. An example of this was shown.

Tim Fawcett: Why don’t the numbers do add up?

David Rendle: Some are inorganic, and/or liquids. The majority of the discrepancy was due to the unavailability commercially.

(Fawcett: The PDF has a majority (1,554) of Merck Index solid materials. The GiA committee is targeting another 1,217 that we believe to be available)

Greg Stephenson: Some of them do not have commercial value.

Tim Fawcett: This committee may have more insight about important inorganic salts from this list for us to complete our appropriate addition to the database.

John Faber: This subcommittee gave us a reference book on salts last year. We are wondering whether it is just that.

Greg Stephenson: It is just that on the salts.

Tom Blanton: Will this committee prioritize the list for the GIA program?

David Rendle: We were concerned that several GIA grantees might select the top entries on the prioritized list at the same time. Wouldn’t it be better to just circulate the list?

Tim Fawcett: Is there any way to judge the commercial significance of the compounds on the list?

Greg Stephenson: Name recognition.

Strategic Growth of the PDF-4 Organics (Jim Kaduk)

Jim Kaduk stated that he got a flyer last week on the Organic databases. He emphasized that one of the five strategic priorities for ICDD for next year is the growth of the PDF-4/Organics as a self-sustaining product. The subcommittee could give ICDD some advice to make this product more valuable to users. The other goal is to devise an executable plan to take advantage of the Cambridge, MPDS, and ICSD’s classification systems for the PDF-4/Organics common-name and subfile features. This subcommittee is one of the responsible parties for this activity. One other plan is to clean up the fifty thousand entries from the CSD. Part of this plan requires going back and re-abstracting the original literature.

Tony DeCamp: The pharmaceutical subfile indicators should be carried over to the replacing patterns from the deleted ones.

PPXRD3 Brief Report (Greg Stephenson)

We just completed our third PPXRD symposium. It was very successful with about sixty attendees. It is somewhat unique for the pharmaceutical industry. Basically all the reviews were very favorable and we should continue this type of symposium. Next year we plan to have one in Europe. The plan is to rotate the symposium back and forth between the United States and Europe every other year. Although attendees would like to see more industrial applications in the future, the response was overwhelmingly positive.

Need for Establishment of Organic Intensity Standard-Not enough time (Greg Stephenson)
The need is certainly there.

John Faber: Intensity or d-spacing standard?

Greg Stephenson: Intensity standard. Silver behenate is a pretty good d-spacing standard.

Larry Bernstein: Not many organic compounds contain silver.

Tim Fawcett: I have been approached about three types of standards: internal standard for quantitation of organics (light element matrix), d-spacing standard for calibrating low angle, and low angle calibration standard for SAX units. ICDD and NIST will cooperate in this project. If anyone has good ideas about this task, please bring them to my or Greg’s attention.