Organic Process Research & Development 2010, 14, 805–814
Application of the QbD Principles in the Development of the Casopitant Mesylate Manufacturing Process. Process Research Studies for the Definition of the Control Strategy of some Drug Substance-CQAs for Stages 2a, 2b, and 2c Zadeo Cimarosti,*,† Fernando Bravo,† Damiano Castoldi,† Francesco Tinazzi,† Stefano Provera,‡ Alcide Perboni,† Damiano Papini,† and Pieter Westerduin† Chemical DeVelopment, Medicines Research Center, GlaxoSmithKline, Verona, Italy, and Molecular DiscoVery Research, Medicines Research Center, GlaxoSmithKline, Verona, Italy
Abstract: Casopitant was identified as a potent NK1 antagonist by GlaxoSmithKline (GSK). It was selected as part of a wide drug discovery programme within GSK for its potential activities on a number of therapeutic targets such as inflammatory bowel disease, overactive bladder, CNS disorders, and others. The mesylate salt of casopitant was selected for full development. The manufacturing process to casopitant mesylate was developed and optimised by following a Quality by Design approach, whereby a control strategy was developed, underpinned by process understanding and risk analysis, for an enhanced level of quality assurance. Quality process parameters and specifications levels for the Stages 2a, 2b, and 2c are the elements of the control strategy of the manufacturing process discussed in detail in this paper. The Design of Experiment approach has been extensively used to support the definition of the proven acceptable ranges for the process. The aim is to show the process development studies carried out to ensure quality control for the final drug substance.
1. Introduction In the past years, a number of regulatory guidelines (ICH Q8, ICH Q9, and ICH Q10)1 have been issued, describing a new approach to process development where the quality is builtin rather than tested in the product. This approach is called “Quality by Design” (QbD). These guidelines are focused on different aspects of QbD.1 For example, ICH Q8 describes an enhanced approach by the use of process understanding. ICH Q9 describes the risk management tools that can be used to successfully manage the risk, and ICH Q10 introduced the concept of a control strategy, defined as a set of controls, derived from current product and process understanding that assures process performance and obtaining drug substance that meets the critical quality attributes (drug substance-CQAs, the measurable properties that are critical to ensuring patient safety and efficacy). The development of a robust control strategy supported by process understanding and by using the appropriate risk * To whom correspondence
[email protected]. † Chemical Development. ‡ Molecular Discovery Research.
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E-mail:
(1) ICH Q8 Pharmaceutical DeVelopment; ICH Q9 Quality Risk Management; ICHQ 10 Pharmaceutical Quality System. 10.1021/op1000622 2010 American Chemical Society Published on Web 05/25/2010
assessment tools is therefore key to ensuring that the quality of the drug substance or drug product is appropriate and consistent. Regulatory agencies2 fully support this approach and encourage its adoption during the development of drug substance and drug product manufacturing processes. More details on this approach as applied by GSK have been recently reported in a previous paper,3 where a detailed description of the elements of control (the attributes of the input materials, the process parameters, and the procedure) is also given. A QbD approach has recently been applied to the development of the manufacturing process for casopitant mesylate 1, a potent neurokinin receptor (NK1) antagonist. In this contribution, some of the process understanding studies carried out on Stages 2a, 2b, and 2c for the definition of the control strategy are described. The elements of control discussed are the quality process parameters (the parameters that have an impact on drug substance-CQAs) and the specifications levels for starting materials and one intermediate of the manufacturing process. The Design of Experiment (DoE) approach has been extensively used to support the development work in all the stages and in particular in the definition of the proven acceptable ranges (PARs) (the upper and/or lower limits for process parameter between which the parameter is known to produce a process output that meets the CQAs) for Stage 2a. For the reader’s benefit, a Glossary with the definitions of the terms used within this text is included. 2. Synthetic Route The commercial process to synthesise casopitant mesylate 1, is a multistage convergent process, summarised in Scheme 1. In Stage 1, the dihydropyridone 10 is converted into the piperidone 8 by reduction of the double bond and hydrogenolysis of the carbobenzyloxy protecting group. The piperidone 8 is resolved Via dynamic kinetic resolution (DKR) using Lmandelic acid to yield the (R)-piperidone as the L-mandelate salt 7. In Stage 2, the (R)-amine 5 is converted into the carbamoyl chloride 4 by reaction with carbon dioxide and thionyl chloride. (2) See for example: Pharmaceutical cGMPs for the 21st century - A risk based approach, Final Report; U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER): Silver Spring, MD, U.S.A., 2004. (3) Cimarosti, Z.; Bravo, F.; Stonestreet, P.; Tinazzi, F.; Vecchi, O.; Camurri, G. Org. Process Res. DeV. ASAP - DOI: 10.1021/op900242x. Vol. 14, No. 4, 2010 / Organic Process Research & Development
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Scheme 1. Commercial route for casopitant mesylatea
a Stage 1a: ethyl acetate, Rh/C, hydrogen. Stage 1b: ethyl acetate, Pd/C, hydrogen. Stage 1c: i) 2-propanol, water, L-mandelic acid; ii) 7 seed; iii) 2-propanol, cyclohexane. Stage 2e: i) ethyl acetate, carbon dioxide, triethylamine; ii) chloro(trimethyl)silane; iii) pyridine; iv) thionyl chloride; v) malic acid (aq); vi) water; vii) Na2CO3 (aq) or K2HPO4 (aq); viii) ethyl acetate. Stage 2a: i) ethyl acetate; ii) Na2CO3 (aq); iii) NaCl (aq) or water; iv) ethyl acetate. Stage 2b: i) triethylamine; ii) 1-acetylpiperazine; iii) malic acid (aq); iv) Na2CO3 (aq); v) NaCl (aq) or water; vi) acetonitrile. Stage 2c: i) acetonitrile, 1-acetylpiperazine, NaBH(OAc)3/HCOOH; ii) ethyl acetate; iii) NH4OH (aq); iv) Na2CO3 (aq); v) NaCl (aq) or water or K2HPO4 (aq); vi) ethyl acetate. Stage 2d: i) ethyl acetate; ii) acetone; iii) methanesulfonic acid; iv) casopitant mesylate seed; v) isooctane; vi) ethyl acetate.
Scheme 2. Formation of casopitant stereoisomers
Acylation of the (R)-piperidone 6 (obtained by basification of its corresponding L-mandelate salt 7) with an excess of the carbamoyl chloride 4 yields the piperidone-urea 3, followed by addition of l-acetylpiperazine to react with the excess of carbamoyl chloride. The piperidone-urea 3 is subjected to reductive amination with additional 1-acetylpiperazine in the presence of the reducing system sodium triacetoxyborohydride [NaBH(OAc)3]/formic acid to afford a mixture of casopitant 2 and its anti-isomer 11 (showed in 806
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Scheme 2) in a ratio of approximately 2:1. Casopitant mesylate 1 is obtained after a seeded, selective precipitation by addition of methanesulfonic acid in a mixture of ethyl acetate, acetone, and isooctane. In this contribution the process research studies carried out for the definition of the control strategy for Stages 2a, 2b, and 2c of some drug substance-CQAs are reported. 3. Drug Substance-CQAs Discussed for Stages 2a, 2b, and 2c The drug substance-CQAs discussed in this paper in the context of Stages 2a, 2b, and 2c are impurities with the potential to contaminate the drug substance, and they are the stereoisomers of the casopitant and the impurities coming from the contaminants of the starting material 1-acetylpiperazine. The structures and the rationale for their formation are reported below. 3.1. Casopitant Stereoisomers. The synthetic route introduces three stereogenic centres, so that in principle a total of eight stereoisomers can be formed. In addition to casopitant mesylate 1 and its enantiomer, there are six other isomers: three diastereoisomers and each diastereoisomer can exist as an enantiomeric pair. The formation of each individual stereoisomer is summarised in Scheme 2 and Table 1; all of them might be present in the drug substance. For this reason all of them are drug substance-CQAs, and their control has to be ensured according to the ICH guideline on impurities. Considering Stages 2a, 2b, and 2c that are discussed in this contribution, the sources of these stereoisomers are in the
Table 1. Formation of casopitant stereoisomers
a
The configuration of the stereocentres according to Scheme 2 is reported.
Scheme 3. Drug substance-CQAs from 1-acetylpiperazine impurities
It is worth noting that the compounds belonging to the following pairs 11 and 15, 16 and 18, 17 and 19 and casopitant and 14 are enantiomers. 3.2. 1-Acetylpiperazine Impurities. Process understanding studies highlighted also that one of the reagents, 1-acetylpiperazine, could contain piperazine, 1-propanoylpiperazine, and N-(2-aminoethyl)acetamide as impurities. Process understanding studies showed that these impurities could react in Stage 2c chemistry by generating three impurities with the potential to contaminate the drug substance (compounds 20, 21, and 22). These potential impurities were defined drug substance-CQAs. Details of their formation are given in Scheme 3 and Table 2. 4. Setting of the Appropriate Specification Limits for the Key Input Materials of Stages 2a, 2b, and 2c The experiments that allowed the definition of the specification for the (R)-piperidone 6, the (R)-amine 5, and 1-acetylpiperazine are reported in this section. These data in combination with the chemical data reported in the following sections allowed the definition of the control strategy for Stages 2a, 2b, and 2c with respect to the drug substance-CQA to be introduced. 4.1. (R)-Piperidone 6 and (R)-Amine 5. These input materials are considered together as they are both linked with the drug substance-CQA reported in Scheme 2 (casopitant stereoisomers 11, 14, 15, 16, 17, 18, and 19). Thus, a spiking study by using (R)-piperidone mandelate salt 7 [contaminated with 2% a/a of (S)-piperidone 13], and (R)-amine 5 [contaminated with 0.9% a/a of the (S)-amine 12] was carried out. The final casopitant mesylate was within specification as shown in Table 3. Table 3. Spiking experiment for the definition of the specification limits for 5 and 6
Table 2. Structures of the 1-acetylpiperazine impurities
impurity (S)-piperidone 13 in (R)-piperidone salt 7 (S)-amine 12 in (R)-amine 5
specification level of drug limit of drug substance-CQA substance-CQA level of in the drug in the drug substance impurity substance (% w/w) (% a/a) (% w/w)a 2 0.9
16 and 18
0.25
NGTb 0.4
17 and 19
