On The Bioavailability of Drugs Containing the Active Pharmaceutical Ingredient (API) Under the INN Darunavir
Goizman MS1*, Zotova OA1, Korlyukov AA2, Suponitsky KYu3, Chernobrovkin MG and Akopyan LV1
1Drugs Technology LLC, Russia
2Nesmeyanov Institute of Organoelement Compounds, Russia
Submission: April 06, 2017; Published: October 03, 2017
*Corresponding author: Goizman MS, Drugs Technology LLC, Khimki, Moscow Region, Rabochaya Str. 2A, Russia, Email: goizmanmi@gmail.com
How to cite this article: Goizman M, Zotova O, Korlyukov A, Suponitsky KYu, Chernobrovkin MG, et al. On The Bioavailability of Drugs Containing the Active Pharmaceutical Ingredient (API) Under the INN Darunavir. Mod Appl Bioequiv Availab. 2017; 2(4): 555593 DOI: 10.19080/MABB.2017.02.555593
Mini Review
Presently,thecompound[(3R,3aS,6aRJ-hexahydrofuro[2,3-b] furan-3-ol](1S,2R)-3-[[(4- minophenyl]sulphonyl](isobutyl]amino]-1-benzyl-2- hydroxypropylcarbamate (herein after the Compound I) is one of the best HIV-protease inhibitors known under the International Non-proprietary Name (INN) Darunavir Darunavir API is contained in both tablet drugs PREZISTA and KEMERUVIR; for the first drug in form of crystalline Darunavir Ethanolate, for the second in the form of Darunavir Amorphous.
As HIV-protease inhibitor the Compound I, its chemical structure and synthesis were described in the patent "hydroxyethlamino sulphon-amides useful as retroviral protease inhibitors” [1] which has had conventional priority since August 24, 1993. Later the INN Darunavir was suggested for Compound I to honor Prof. Arun K. Ghosh, the author of the original research paper [2]. It is noteworthy to mention that the method of synthesis of Darunavir Amorphous from Ethanolate was disclosed in the patent "Polymorphs of Darunavir” [3] having conventional priority as of January 29, 2009.
Subsequently, considering the start [4] of clinical studies of compound I under the code name of TMC 114 [5], the patent [1] and the decision by FDA USP dated June 23, 2006 authorizing the use of PREZISTA® tablets containing specifically Darunavir Ethanolate as API, we are to conclude that the API used in clinical studies ought to have been the crystalline Ethanolate of compound I.
The dosage of PREZISTA® tablets is naturally indicated in units, equivalent to that of compound I, which presently is known under INN Darunavir. Despite all of the above-mentioned a patent application No 02076929.5 was filed on May 16, 2002 with a title containing no specific information- "Pseudopoly-morphic forms of a HIV protease inhibitor” [6]. In the text of this application, instead of INN Darunavir or TMS 114 code, the chemical name of compound I as HIV-protease inhibitor is used, which de facto gave the applicants the opportunity to claim a number of solvates (pseudopolymorphsj of compound I as part of patented text. This included, in particular, Darunavir Ethanolate which at the time was already being clinically tested and the intermediate results of the tests were published in 2001 in [4].
In light of the above said and taking into consideration the paper [7] we deemed it necessary, with the intention of additional assessment of the data presented in the work [6], to carry out an XRD analysis of preliminarily fragmented PREZISTA tablets (API Darunavir Ethanolate) and KEMERUVIR (API Darunavir Amorphousj, as well as to experimentally evaluate the possibility of synthesizing Darunavir Ethanolate or Dihydrate through the interaction of Darunavir Amorphous powder with stoichiometric quamtities of ethanol or water Diffractograms in Bragg-Brentano geometry were obtained with the help of Bruker D8 Advance diffract meter equipped with x-ray tube with a copper anode and a position-sensitive detector. The filming step was 0.02° 20 and filming time lapse was 4, 0-60, 0° 20 (adjusted by Rietveld method in the program TOPAS4-2).
We found that the content of crystalline Darunavir Ethanolate was no less than 90% and the content of Darunavir Amorphous was no more than 10% of the total solids in PREZISTA tablets from three different batches released at three different times. These data matched well to the findings obtained by using UV spectrophotometry and gas-liquid chromatography methods applied respectively for the determination of contents of Darunavir and ethanol in the same tablets. This leads us to believe that it is exactly because of the assumption of the possibility of partial loss of ethanol that the regulatory documents in regard to PREZISTA tablets provide neither qualitative nor quantitative determination of ethanol content in them.
Diffractograms of KEMERUVIR prove that only unsolvated Amorphous Darunavir is present in it as API, the content of which as determined independently by using a UV spectrophotometry method matches the expected nominal value. Therefore, no modification of the structure of API by ethanol has been carried out within the framework of the technological process related to the production of this drug, even though it is quite easy to implement, since as it was demonstrated by X-ray diffraction method, the contact of Amorphous Darunavir with equimolar quantity of ethanol at room temperatures leads to the formation of crystal Darunavir Ethanolate as fast as within 15 seconds.
Under similar conditions, while processing Amorphous Darunavir by water no formation of the respective pseudopolymorphouso hydrate described in the patent [6] is detected-the substance remains amorphous, which is indicative of the low rate of formation of the crystallohydrate of Darunavir and proves the high probability of the fact that the water contained in PRE-ZISTA and KEMERUVIR tablets is hygroscopic.
Based on the evidence found, we may assert that as API the crystalline Darunavir Ethanolate and Darunavir Amorphous have no substantial advantages over each other.
References
- Mueller RA, Stonegate TG, Talley JJ (1995) PCT Pab 95(06030).
- Ghosh AK, Kincaid JF, Cho W (1998) Bioorganic & Medicinal Chemistry Letters 8(6): 687-690.
- Ehud Marom (2014) Patents by Inventor Ehud Marom, USA.
- De Béthune MP, Wigerinck P, Jonckheere H (2001) Abstr F-1677. 41st International Conference on Antimicrobial Agents and Chemotherapy, Chicago, USA.
- Koh Y, Nakata H, Maeda K (2003) Antimicrobial Agents and Chemotherapy 47: 3123-3129.
- Pseudopolymorphic forms of a HIV protease inhibitor, Tibotec Pharmaceuticals Ltd., USA.
- Gyseghema VE, Stokbroekx S, Armas H (2009) European J of Pharm Sciences 38: 489-497.