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kilomentor | 21 June, 2008 18:10
The objective of the Kilomentor Blog is education. One can learn the basis for chemical process development and organic synthesis in schools, either technical or university undergraduate. One can build upon these with chemistry or engineering postgraduate training, but there is no path onward from there, which is widely accessible. This may be because of a person’s location on the planet or financial means. The careers that spring up from these roots are fun and useful to society. They should be open to the best minds on the planet; to whoever is intrigued to practice these arts. I write what has been useful to me and what I have learned slowly and painstakingly over 40 years. Wherever you are, all you need is access to the internet and you can share for free my experience, my insights, and yes, my errors. My goal is to provide a level playing field world-wide for organic process scientists.
A month ago my fiftieth blog article was published. The number of viewings for Kilomentor has passed 27,000. Several months ago the Kilomentor Blog was for several weeks the first ranked article on Google when the search terms: chemical process development’ organic synthesis, were entered.
Writing for Kilomentor has encouraged me to read more widely and try to put in perspective what I read. It has driven me to ask myself what the core knowledge in this profession is. It has enabled me to work together with some of you, solving problems together.
Thanks for reading.
Clarke Slemon PhD
The Kilomentor
kilomentor | 10 June, 2008 17:30
A powerful idea for pharmaceutical product development is contained in an article titled, Consider a new approach to pharmaceutical development, authored by Pradir Ki Basu, Ronald A Mack, ,and Jonathan M. Vinson available at
http://findarticles.com/p/articles/mi_qa5350/is_199908/ai_n21444525
Hereunder, Kilomentor discusses aspects of their core idea, but these comments can only be followed after reading the original article.
Much of the article presents arguments supporting the importance of cost efficiently discovering a synthetic method, scaling it up and putting into production a process for manufacturing a new pharmaceutical. This is the pharmaceutical business with the actual marketing and selling stripped away. Its importance to profitability does not need to be debated.
The present authors are concerned about the efficient execution of the plan that starts after the identification of a biologically active target that is a candidate to be a commercial drug and proceeds to the validation of manufacture that molecule at commercial scale.
The new approach that they propose positions ‘process vision’ as the core concept. It is the definition and exemplification of ‘process vision’ which is the article’s most significant accomplishment. The authors identify the defining characteristics of the process vision at different places in the article but for me, I cannot say I adequately understood it until I drew particular phrases together in my notes.
· “The process vision satisfies all essential requirements, including those for safety, quality, waste minimization, cost, time, and operability.”
· “The process vision is neither the process with maximum yield nor the one that gives maximum product purity…..it is neither a chemist’s vision, nor an engineer’s vision; it is not even the vision of the chemists and engineers together.”
· “It is a vision a vision that all stakeholders in development, manufacturing and marketing can share…..”
Reading between the lines and amplifying certain aspects, the process vision might be a policy statement that provides as a starting point, desirable standards by which team members of each stage of the plan (laboratory process, kilo lab, pilot plant, and manufacturing facility) strive to meet their downstream colleagues’ concerns from the outsell of their work.
The authors make this clearer with specific examples of the unique orientation and emphasis that players at the different stages have and which they want to bring into early assessment, early inevitable cross purposes, and early compromise or conflict resolution. They write, “Chemists think in terms of steps, reactions, yield, purity, and so on; engineers in terms of unit operations, physical properties, heat load, and the like; manufacturing personnel in terms of unit operations, in terms of throughput, waste, control issues and plant modifications that may be required to run a process; and marketing people in terms of net present value of the product, how much it can sell for etc.”
For me, what the authors are somewhat ambiguous about is the mechanism they recommend for achieving this ‘process vision’ even though over and over again in the article they return to this same theme:
“It is important ….to get stakeholders to develop….agreed-upon objectives of process development.”
“communication among….personnel is critical during process development.”
“We need to…. provid[e] development team members with systems or tools to facilitate communications among different disciplines.”
“Unless the manufacturing team is involved in the process development, they will not have confidence in the scale-up”.
“…manufacturing and commercial input at this stage [late stage discovery] is essential for choosing the optimum processing route”.
“Team members need to be involved setting targets for cost, manufacturability, waste and emission loads, development time….”
“These alternatives must be evaluated based on….criteria agreed upon by all stakeholders….”
“If stakeholders are involved in planning experiments, it’s likely that more useful data could be collected from fewer experiments.”
For me these snippets hint at or outright propose two different strategies.
One can try to bring a diverse project team, with participation beginning with late stage R&D and including representatives all the way up to marketing, together frequently enough to work out priorities and make decisions even at the experimental program level.
Alternatively, one can establish some sort of median or normal or starting-point performance criteria addressing the main, recurring concerns of process development, manufacturing, and marketing which will serve as a process vision statement that will act as a proxy for the multiform interests of the entire downstream project team and continuously represent their standard concerns to upstream collaborators.
According to this meaning, a process vision statement would be a tool commanding corporate authority that would continuously challenging upstream groups with the standard core concerns of the downstream members.
The authors marvelously illustrate this challenging throughout their article. What I interpret them to be saying is that the problem is not that different elements of the project team have concerns which inevitably seem to operate at cross purposes; but that the team members will reach solutions that satisfy all parties, so long as the area of tension is discovered early enough.
Kilomentor has a strong preference for the second alternative. Use of a process vision statement as a proxy for the perspectives and concerns of downstream project groups seems preferable to using meetings of a large group with the frequency needed to actually direct even the collection of particular data. For a company’s drug product projects to be successful and on-time, any process’s strategy must not conflict too greatly with the psychological needs and private professional goals of the individual team members. The people downstream in the project, whether they be in process development, manufacturing, or marketing, simply will not give a project the attention it needs until it arrives at the phase where they are being held singly and personally responsible. They are too busy concentrating their attention on what is on their plate already and extinguishing the fat that is already in the fire. This is human nature! Besides, pharmaceutical product projects can go on so long that some participants can realistically expect to no longer be involved when a late-stage discovery project limps into manufacturing or marketing. People may hope or plan to outrun the difficulties.
Equally problematically, the up stream professionals, working at a particular phase of the work on their own turf, would require an uncommon personal modestly to accept without rancor face-to-face demands that particular questions be answered on a priority basis.
A corporate ‘process vision’ statement takes the personalities and egos out. At the same time, the standards proposed by a process vision statement would command authority and yet not be carved in stone. They would exist to bring a persistent awareness of particular concerns. They would bring those different needs, which may be pulling at cross purposes to early attention, and they can be expected to bring the affected team members together to create or negotiate a solution.
This excellent thought provoking article by Basu, Mack and Vinson contains other important ideas which I hope to look at in later blogs.
kilomentor | 03 June, 2008 17:39
Kilomentor continues with his review of the properties and procedures for the manufacture of pharmaceutical salts. The procedures are among the most import in chemical process development and organic synthesis.
It would seem from looking at the names of pharmaceutical products that phosphate anion is a fairly frequently used pharmaceutical salt former, but closer examination reveals that there are actually very few ionic pharmaceutical phosphate salts. Among drug substances called phosphates, the majority are covalent phosphate esters of an alcohol functional group.
Nevertheless, there is a place for the phosphate salts because the monophosphate is probably the most hydrophilic anion used to make pharmaceutical salts. Dihydrogen phosphate anion contains two very polarized hydrogen-oxygen bonds that energetically prefer to exist in a hydrogen bonding, high dielectric medium. When this hydrophilic anion is combined with a large hydrophobic cation, the result is almost always an insoluble salt. To balance this advantage the following disadvantages must be weighed:
· These salts have a high propensity to give several different hydrate pseudopolymorphs.
· phosphoric acid as a viscous oil or very low melting solid that is difficult to manipulate quantitatively.
· phosphoric acid is not miscible with the non-polar organic solvents which are the preferred media for the hydrophobic base partner
· the acid’s hygroscopicity makes weighing more difficult.
Evidence of the hydrophilicity of phosphate is provided by its selection for use in a standard procedure for making those acid addition salts of acids, which are themselves in the neutral form poorly stable, such as nitrates, thiocyanates, perchlorates and fluoroborates.
The procedure is taken from Brandstrom and Gustavii, Acta Chemica Scandinavica 23 (1969) 1215-1218.
To a two phase mixture of 1M aqueous phosphoric acid and methylene chloride or chloroform, add the free base which thereupon dissolves in the aqueous acid. Add sodium nitrate, sodium thiocyanate, sodium perchlorate or sodium terafluoroborate; mix the phases and extract the salt, anion and protonated base, into the organic layer quantitatively. Because the phosphoric acid monoanion is so hydrophilic it does not compete with these anions for extraction into the lipophilic organic layer even though it is present in enormous excess. That phosphoric acid is the bulk acidifying agent used testifies to its preference for the aqueous phase. The pKas of phosphoric acid are K1 =7.107 x 10-3 ; K2 =7.99 x 10-8; K3= 4.8 x 10-13.
The literature provides another piece of evidence that ionic phosphates may be good choices for giving solid crystalline salts for a wide range of bases. Helene Perrier and Marc Labelle found the phosphates the second most preferred salts for isolating as salts a wide range of intermediates containing the 3-acylquinoline moiety [J. Org. Chem. (1999), 64, 2110-2113.
Some corroborative information about crystalline phosphate salts comes from an article analyzing salts found in the Cambridge structural Database. http://www.msm.cam.ac.uk/pfizer/pdf/Publications/P03%20(02)%20-%20Occurrence%20of%20Pharmaceutically%20Acceptable%20Anions%20and%20Cations%20in%20the%20Cambridge%20Structural%20Database.pdf
The phosphate dianion was found to have the highest percentage of its salts as hydrates of all the salts examined. According to the authors’ interpretation this suggests that increasing charge on a single ion leads to increasing hydrate formation. They reference another paper that suggests that hydrate formation is a result of an imbalance between the number of hydrogen bond donors and acceptors in a crystal. [Infantes l., Chisholm J. Motherwell S. Cryst. Eng. Comm. 2003, 5: 480-486.]
Some specific examples of procedures are given in the extended text below.
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