Development of drug substances as mixture of polymorphs: Studies to control form 3 in casopitant mesylate

Organic Process Research and Development

Volumn 14, Issue 6, 2010, Pages 1337-1346

  Cimarosti, Zadeo ^a   Castagnoli, Carlo ^a   Rossetti, Marco ^a   Scarati, Mirka ^a   Day, Caroline ^b   Johnson, Brendan ^c   Westerduin, Pieter ^a  

^a GSK   (Italy)

^b GLAXOSMITHKLINE   (United Kingdom)

^c GLAXOSMITHKLINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CRITICAL QUALITY; CRYSTALLINE PHASIS; DRUG SUBSTANCES; GLAXO SMITHKLINE; MANUFACTURING PROCESS; MINOR COMPONENTS; PROCESS DEVELOPMENT; PRODUCT PERFORMANCE; PROJECT TEAM; QUALITY BY DESIGNS; RETROSPECTIVE ANALYSIS; SINGLE-CRYSTALLINE;

CRYSTALLINE MATERIALS; MIXTURES;

PROCESS CONTROL;

EID: 78649641378     PISSN: 10836160     EISSN: 1520586X     Source Type: Journal    
DOI: 10.1021/op100150b     Document Type: Article

References (21)

1. Guidance for Industry: ANDAs: Pharmaceutical Solid Polymorphism Chemistry, Manufacturing, and Controls Information; U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER): Rockville, MD, July 2007.
2. ICH Q6a Specifications: Test Procedures and Acceptance Criteria for New Drug Substances andNew Drug Products: Chemical Substances
3. ICH Q8 Pharmaceutical Development, (R2); U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER): Rockville, MD, Aug 2009.
4. ICH Q9 Quality Risk Management; U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER): Rockville, MD, June 2006.
5. ICH Q10 Pharmaceutical Quality System; U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER): Rockville, MD, April 2009.
6. Form 2 is not discussed in this contribution as it is not relevant. Form 2 is a metastable form only obtained from tetrahydrofuran; it is not stable on storage and quickly converts to Form 1.
7. Cimarosti, Z., Bravo, F., Castoldi, D., Tinazzi, F., Provera, S., Perboni, A., Papini, D., and Westerduin, P. Org. Process Res. Dev. 2010, 14, 805.
8. The Form 3 sample of casopitant mesylate was obtained by a combination of annealing and slurry experiments and the experimental conditions will be reported in 7.1.2 section and in the Supporting Information.
9. The microscope images of Form 1 and Form 3 were very similar, the pictures are reported in the Supporting Information.
10. SGF is the acronym of Simulated Gastric Fluid, FaSSIF of Fasted State Simulated Intestinal Fluid, FeSSIF of Fed State Simulated Intestinal Fluid.
11. DSC is the acronym of Differential Scanning Calorimetry, TGA of Thermogravimetric Analysis.
12. Irrespectively from the chemical purity of the sample used as input in the slurry, the conversion to Form 3 at 50°C in acetone reaches a plateau value and does not proceed to completion. Nevertheless some differences in the kinetic of conversion were observed in the first 14 days. All the details are available in the Supporting Information.
13. For the purpose of the regulatory submission we mainly focused the investigation on experimental conditions close to the commercial process both in terms of solvent systems and main process parameters (i.e. temperature, seed attributes).
14. Experiments were performed to get pure Form 1 by seeding the commercial process at 20°C or by performing slow evaporative crystallizations at room temperature. Moreover a DoE study explored wider process parameter ranges (temperature 0-50°C, seed amount 0.2-2% w/w, seed PSD X90 from 4 to 13 Îμm). In all these trials the lowest level of Form 3 in the drug substance obtained was 2% w/w. At-line form monitoring of the crystal formation was not feasible as the only techniques capable of discriminating the two forms are ssNMR and transmission XRPD. However, when solid samples at different stages of the crystallization process were isolated, no difference in the Form 1/Form 3 ratio was observed.
15. As said earlier in this section, Form 3 was discovered at a late stage of the process development. For this reason the selection of the most critical process parameters to be used in the second set of multivariate experiments was done with respect to the casopitant impurities and the casopitant particle size.
16. The impurities added to casopitant are drug substance-CQA, their formation and impact on the process are discussed in Cimarosti, Z., Bravo, F., Castoldi, D., Tinazzi, F., Provera, S., Perboni, A., Papini, D., and Westerduin, P. Org. Process Res. Dev. 2010, 14, 805.
17. It is worth noting that the addition rate of methanesulfonic acid was not included amongst the crystallization process parameters as particle formation is controlled by seed addition. When methanesulphonic acid is added, the degree of supersaturation is such that spontaneous nucleation is disfavoured
18. Beckmann, W. Org. Process Res. Dev. 2000, 4, 372.
19. The solubility of casopitant mesylate in ethyl acetate is very low. The full dataset generated for ethyl acetate and acetone is reported in the Supporting Information.
20. It is worth noting that PSD of the three batches of drug substance used to prepare the drug product batches submitted to dissolution was not the same, but this was not considered an issue as extensive data collected during development demonstrated that drug substance PSD has no significant impact on the dissolution rate of the drug product at the Q point (30 minutes). These considerations are based on what is observed for all the ranges on PSD of the drug substance produced (where no differences were seen when the D90 was ranging from 13 to 70 Îμm).
21. Batches 1 and 3 ranges were obtained as averages of 12 replications, while batch 2 range was an average of 6 replications.