Polimorphism of Active Pharmaceutical Ingredients

Teresa Paszkowska-Reymer ,  Andrzej Kutner 

Abstract

Polymorphism of active pharmaceutical ingredients is becoming an increasingly important issue in the contemporary drug development. Polymorphic form of an active pharmaceutical ingredient (API) might influence it’s kinetics of solubilization and thus affect the release of API from the finished dose of a drug. This is especially in a case for solid dosages like tablets. The release process of API from dosage form is crucial for drug bioavailability and therapeutic function. Due to the higher activity of new generation of API’s and lower doses of API in drugs (from former 200 – 600 mg down to sometimes submilligram level) the studies of polymorphic forms of API’s in finished doses have become recently a tough task. Therefore, there is a need for analytical methods to determine the polymorphic form of API not only in a plain crystalline substance but also in its finished dose. The later is to make sure that selected polymorphic form of API is preserved in a number of mechanical and thermal processes like wet granulation, fluid bed drying, grinding, mixing, sieving and tableting, in the manufacturing of a finished dose of a drug. When single crystal diffractogram for API can not be obtained a combination of several other method is to be used, as there is still no single method replacement for this analysis. In order to define a polymorphic form of API in such a quite common case standards of all existing polymorphs are to be prepared and methods developed for defining of their identity and content in mixtures of polymorphs.

In this presentation a number of examples will be discussed of determination of polymorphic forms of API’s in crystalline substances and in finished doses, carried out at Pharmaceutical Research Institute in Warsaw over the last several years. To define the polymorph of API a set of diffractometric, spectroscopic and thermal methods are used at this laboratory. First and second order spectra in FT-IR spectroscopy were used to develop a method for identification and quantitative determination of contaminating polymorph II in an API that should be present in a tablet exclusively as a polymorph I. Due to the overlapping of signals originated from API with that from excipients (placebo), selection of diagnostic regions in XRPD profiles is usually very much limited and it was successful in a very few cases that will be shown. In our examination of differences between polymorphs and pseudopolimorphs (solvates) of API the most supportive results were obtained by thermal analyses. For a number of solvates studied the additional endothermic peak in differential scaning calorimetry (DSC) is usually recorded at lower temperatures, as compared with the non-solvated substance. Combination of DSC and termogravimetric (TG) techniques allows to discriminate between a signal originated from a solvent and a signal originated from a phase transition in a DSC thermograms.

References:

[1] W. Szczepek, D. Samson-Łazińska, R. Modzelewski, U. Frączek, M. Ławecka, M. Glice, P. Cmoch, Ł. Kaczmarek, W. Szelejewski: Method of preparation of crystalline α-form of imatinib, PCT/PL2004/000024.

[2] J. Piechaczek, J. Serafin, W. Maruszak, R. Balicki, W. Szelejewski, M. Cybulski, G. Maciejewski, M. Wysoczyńska, M. Glice, K. Korczak: Method of preparation of crystalline form I of clopidogrel, PCT/PL2003/00130.

[3] A. Kutner, M. Chodyński, T. Ryznar, H. Fitak, J. Winiarski, B. Górecki, A. Burzyńska, W. Szelejewski: Method of preparation of anhydrous calcipotriol, PCT/PL2005/000087.
 

Related papers
  1. The comparison of the stability indicating  two HPLC methods and their application for the determination of bosentan in coated tablets 
  2. What modern crystallography can add to pharmaceutical research?
  3. Antiproliferative and cytotoxic effect of vitamin D3 and its derivatives on the selected cells with a higher proliferative potential
  4. Pharmaceutical  technologies  – why do they have to be innovative
  5. A novel convergent synthesis of the prostaglandin F analogues
  6. Comparative permeation studies of tacalcitol through the human skin from brand product versus generic product
  7. Vitamin D analogs enhance the activity of imatinib mesylate in human non-small cell lung cancer model
  8. Colon cancer treatment with the use of vitamin D analogs and irinotecan 
  9. Experimental and theoretical charge density studies on a model analogue of vitamin D
  10. Synthetic Technologies of Pharmaceutical Substances
  11. The influence of (24R)-1,24- dihydroxyvitamin D3 on the anticancer activity of 5-fluorouracil in human colon cancer model
  12. The use of the hyphenated LC-MS/MS technique for the characterisation of impurity profile of Quetiapine during drug development
  13. A novel synthesis of 19-nor analogs of vitamin D
  14. The influence of novel analogs of vitamin D3 on the antiproliferative activity of cisplatin or doxorubicin on human promyelocytic leukaemia cell line HL-60 
  15. The Concept of the Central Strategic Program - Innovative Medicines
  16. Isolation, structural elucidation and characterization of impurities in latanoprost
  17. New rosiglitazone salts
  18. New calcipotriol analogs, their toxicity and antitumor activity in vivo in comparison to the affinity with VDR and DBP
  19. High-yielded method of synthesis of voriconazole.
  20. CAN A QUEST FOR A NEW DRUG OF POLISH ORIGIN BE SUCCESSFUL?
  21. ROPINIROL - GENERIC DRUG FOR PARKINSON'S DISEASE
  22. SYNTHESIS OF PIOGLITAZONE HYDROCHLORIDE OF PHARMACEUTICAL PURITY AT SMALL PLANT SCALE
  23. ANTITUMOR EFFECT OF CISPLATIN OR FLUOROURACIL IN COMBINED TREATMENT WITH (24R)-1,24-DIHYDROXYVITA- MIN D3
  24. COMBINATION OF: IMATINIB, PRI-2191 AND CYTOSTATICS - THE ANTIPROLIFERATIVE EFFECTS ON HL-60 LEUKEMIA CELL LINE
  25. ANTIPROLIFERATIVE ACTIVITY IN VITRO OF DIASTEREOMERIC ANALOGUES OF VITAMIN D3 AGAINST NORMAL AND CANCER CELL LINES
  26. NEW IMPROVED METHOD OF POLYMORPHIC α FORM OF IMATINIB MESYLATE (GLEEVEC®) SYNTHESIS.
  27. NEW SYNTHESIS OF 11-(1-PIPERAZINYL)- DIBENZO[b,f][1,4]THIAZEPINE, A CRUCIAL INTERMEDIATE IN QUETIAPINE PRODUCTION.

Presentation: invited lecture at 18th Conference on Physical Organic Chemistry, Plenary session, by Teresa Paszkowska-Reymer
See On-line Journal of 18th Conference on Physical Organic Chemistry

Submitted: 2006-07-19 19:38
Revised:   2006-07-31 08:46