New Insights on Warfarin Sodium 2 Propanol Solvate Solid- State Changes Using a Multivariate Approach

Significance 

The therapeutic window of a certain drug reflects the concentration range that provides efficacy without toxicity. Narrow therapeutic index (NTI) drugs have a narrow therapeutic window, hence doses must be titrated carefully and therapeutic monitoring is usually required. Examples of NTI-drugs: aminoglycosides, ciclosporin, carbamazepine, digoxin, digitoxin, flecainide, lithium, phenytoin, phenobarbital, rifampicin, theophylline and warfarin.

In the case of Warfarin which is one of the most commonly prescribed anticoagulant agents, it is mainly prescribed as a low dose tablet, therefore ensuring content uniformity standards is of great significance. This necessitates effective control of the NTI formulations because a small variation in the tablet formulations may result in ineffective or dangerous therapeutic consequences. As an anticoagulant, warfarin prevents blood clots in blood vessels and is useful in treating different serious and life-threatening conditions like stroke and cardiovascular diseases. In particular, warfarin sodium 2-propanol solvate (WARC) tablets, a low-dose drug products made from either amorphous or crystalline forms of warfarin sodium, have been widely preferred for treating such conditions.

The therapeutic and clinical outcome of WARC tablets has raised many concerns. Warfarin associated hemorrhage is one of the main causes of deaths amongst anticoagulant patients. Moreover, the US Food and Drug Administration removed several warfarin sodium products from the market, a move that can be attributed to poor dose performance, quality issues, as well as low dose formulations and NTI challenges. In addition to bioavailability issues, previous research has reported that multiple stages involved in the manufacturing of WARC can potentially introduce undesirable transformations that may influence the drug outcomes. Therefore, it is extremely important to ensure WARC solid-state integrity from manufacturing to patient administration.

Several techniques have been proposed to evaluate the transformation of the WARC solid-state. Nevertheless, the available methods do not provide a comprehensive characterization and understanding of the transformation of the WARC lattice structure responsible for product failure. To address this challenge, researchers from Long Island University in New York: Dr. Harsh S. Shah, Dr. Kaushalendra Chaturvedi, Dr. Rutesh Dave, Dr. Simon Bates, Dr. Rahul Haware, and Professor Kenneth Morris studied the solid form changes of the WARC considering the environmental conditions and possible manufacturing stress. Their main aim was to predict the WARC structural integrity at different storage conditions by monitoring and quantifying the real-time changes in their crystal lattice. The original research article appears in the journal, Crystal Growth and Design.

In their approach, thermal stress was studied using variable temperature powder X-ray diffraction (PXRD), allowing for real-time monitoring of WARC solid-state transformations. WARC was exposed to moisture and thermal stresses at different time durations to achieve the solid-state changes. Also, dynamic sorption-desorption isotherms were used to evaluate the sorption behavior of various WARC forms. Lastly, quantitative predictive models were developed to evaluate the impact of various parameters on the WARC structural integrity.

Results show that after prolonged exposure to high-temperature stress, WARC transformed into desolvated WARC (WARDES) and non-crystalline (WARNC­) forms. This was attributed to the 2-propanol (IPA) loss from the crystal lattice channel at high temperatures. However, at high relative humidity conditions, it directly transformed into WARNC due to increased WARC affinity for water molecules. Additionally, the solid-state transformations of the WARC were attributed to the interactions amongst the exposure time, temperature and humidity parameters. Unlike the unexposed tablets, stressed WARC tablets exhibited impaired dissolution profiles, which could potentially pose a serious WARC therapy failure, including clotting and internal bleeding.

In summary, this study is the first ever to report the crystal structure of WARC desolvated form. The predictive models enabled quantifying the IPA content, temperature, exposure time, WARC crystallinity and water content as a function of %RH. The results demonstrated the importance of achieving a good balance between the temperature, humidity and exposure time in maintaining the structural integrity of WARC at molecular level. The study provided a comprehensive understanding that may facilitate the effective design of quality dosage forms and quality control of warfarin tablets during manufacturing. In a statement to Advances in Engineering, Dr. Harsh S. Shah explained the findings will advance the development of more effective and efficient NTI WARC formulations as well as similar drug products developed in future.

New Insights on Warfarin Sodium 2 Propanol Solvate Solid- State Changes Using a Multivariate Approach - Advances in Engineering

About the author

Harsh S. Shah is a senior scientist at J-Star Research Inc. (a Member of Porton Group), Cranbury, NJ. There he leads “fit-to-purpose” research projects in drug discovery and drug product development. He is focused on helping to advance new chemical entities, develop and optimizing efficient processes and improving patient compliance using advanced analytical and computational techniques.

At J-Star Research, Harsh S. Shah has discovered a most stable form for 12 different drug molecules, thereby helping the innovator companies to advance their molecules to the next stage. The therapeutic categories of these new chemical entities included hormone replacement, anti-cancer, anti-epilepsy, anti-coagulant, lung disorders as well as cardiovascular therapies.

His prior experience includes being a Senior Analyst at Lachman Institute for Pharmaceutical Analysis at Long Island University where he participated and/or led collaborative projects with United States Food & Drug Administration (FDA), Bristol Myers Squibb, Triclinic Labs, Vertex Pharmaceuticals and Amneal Pharmaceuticals. He employs eclectic research approaches to address the challenges encountered at throughout drug product development and scale-up.

Shah has been awarded the “Research Excellence Award – 2020” by InSc, “PhD Outstanding Student Award – 2020” at Long Island University, “Academic Research Award – 2019 – 2nd place at AAPS NERDG annual conference, “Rising Stars in Analytical Chemistry and Materials Science” at Merck Symposium and “Best outgoing student – 2009” upon completion of his bachelor’s degree.

He has published 15 research papers in Peer-Reviewed Journals and more than 20 abstracts in National & International Conferences. He is an editorial board member for Asian Journal of Pharmaceutics and International Journal of Science and Pharma Innovations. He is an active member of NIPTE (National Institute for Pharmaceutical Education and Research) contributing to several of their national initiatives. He is also a member of various professional societies including AAPS, Rho-Chi, IPSE, and ACS.

About the author

Dr. Kaushalendra Chaturvedi is currently working as a Sr. Research Scientist at J-Star Research, Inc, NJ, USA. Experienced pharmaceutical scientist with the skills supporting pre-formulation and materials science activities.

He received his Ph.D. in Pharmaceutics and Drug Design from the Long Island University (LIU) in 2019 and M.S. in Pharmaceutical Sciences and Bachelor in Pharmacy from Pune University in 2011 and 2009 respectively. During his doctoral study he worked on multiple US-FDA, pharmaceutical and excipient industry sponsored projects. He has published 18 research articles in reputed peer reviewed international journals, three book chapters, and several posters presented at international conferences including conferences organized. Currently he is a member of various professional societies including AAPS, ACS, Rho-Chi, and AAPS-NERDG.

About the author

Dr. Ken Morris and has worked in the field of pharmaceutical materials science for more than 30 years. This area can be described as the study of the impact of the physico-chemical properties of formulation components on the performance of the final pharmaceutical dosage form with a focus on the use of advanced analytical techniques to follow these properties throughout the manufacturing process. He was a chemist at the U.S. EPA, a research scientist at BMS, then a Professor and associate department head in the IPPH department at Purdue University. He is a retired University Professor and Director of the Lachman Institute for Pharmaceutical Analysis at Long Island University, a Professor emeritus at the University of Hawaii at Hilo, a special government employee of the U.S. FDA-CDER-OPQ, and an adjunct Professor at Purdue University.

References

Shah, H.S., Chaturvedi, K., Dave, R., Bates, S., Haware, R., & Morris, K. (2020). New Insights on Warfarin Sodium 2-Propanol Solvate Solid-State Changes Using a Multivariate ApproachCrystal Growth & Design, 20(11), 7328-7340.

Go To Crystal Growth & Design

Shah, H. S., Chaturvedi, K., Dave, R. H., & Morris, K. R. (2021). Molecular Insights into Warfarin Sodium 2-Propanol Solvate Solid Form Changes and Disproportionation Using a Low Volume Two-Stage Dissolution Approach. Molecular Pharmaceutics18(4), 1779-1791.

Shah, H. S., Chaturvedi, K., Hamad, M., Bates, S., Hussain, A., & Morris, K. (2019). New insights on solid-state changes in the levothyroxine sodium pentahydrate during dehydration and its relationship to chemical instability. AAPS PharmSciTech20(1), 1-10.

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