Translation. Region: Russian Federation –
Source: Novosibirsk State University –
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A first-year master's student at the Department of Solid State Chemistry (SSC) is conducting a study on the stability of the antiviral compound tecovirimat. Faculty of Natural Sciences (FNS) of Novosibirsk State University Alexander Ivlev, under the scientific supervision of Sergey Arkhipov, a senior lecturer in the Solid State Chemistry Department at the NSU Natural Sciences Department and a candidate of chemical sciences, and Dmitry Kolybalov, an assistant at the Solid State Chemistry Department at the NSU Natural Sciences Department. As part of their work, the scientists addressed the problem of the lack of reproducibility in experiments to obtain solid forms of the active ingredient in an anti-smallpox drug. They proposed new methods for producing several solid forms, one of which is currently undergoing patenting.
— It is generally accepted that humanity has conquered the smallpox virus (VARV). The eradication of the deadly disease it causes was confirmed in 1980 at a meeting of the World Health Assembly. There, a decision was made to halt mass vaccination against this virus, which ultimately led to a significant decline in the population's immunity to all orthopoxviruses—a large family of DNA viruses that include the causative agents of diseases such as smallpox, cowpox, and monkeypox (MPXV). Smallpox is transmitted only from person to person, but other orthopoxviruses can be transmitted from animals to humans. One such virus is monkeypox. In 2022, the World Health Organization (WHO) declared the monkeypox outbreak a public health emergency of international concern. According to the WHO, from January 1, 2022, to April 30, 2025, a total of 142,141 laboratory-transmitted cases of MPXV infection were recorded, 328 of which were fatal. Work is currently underway to develop and improve vaccines, diagnostic tests, and drugs to combat the monkeypox virus. And with our research, we are contributing to solving this global problem, said Alexander Ivlev.
Tecovirimat is a chemical compound with antiviral activity against orthopoxviruses. In January 2022, the European Medicines Agency approved TPOXX®, whose active ingredient is tecovirimat, for the treatment of monkeypox virus disease. In 2023, NIOH-14, a prodrug of tecovirimat, was introduced into the Russian Federation. Tecovirimat exhibits exceptional activity against smallpox, monkeypox, cowpox, vaccinia, and other orthopoxviruses while exhibiting low toxicity. It acts by targeting the viral protein p37, which prevents the release of the virus from the infected cell and ultimately prevents its spread throughout the body. Two dosage forms of tecovirimat are currently available: capsules for oral administration and powder for intravenous injection.
Each dosage form has its own limitations and storage temperature requirements. Capsules must be stored at a temperature of 20°C to 25°C, but a temperature range of 15°C to 30°C is acceptable. Injectable powder must be stored at a temperature of 2°C to 8°C; short-term storage (up to 24 hours) at ambient temperature is permitted; freezing is not permitted. The development of this dosage form has expanded the scope of tecovirimat's use.
This drug is patented by the American company SIGA technologies. The crystal structure of tecovirimat monohydrate (solid form III) has been determined and deposited in the Cambridge Crystallographic Data Center. To date, SIGA technologies has discovered six structurally distinct solid forms of tecovirimat: two monohydrates, one hemihydrate, and three anhydrous forms. However, the crystal structure has only been determined for tecovirimat monohydrate, which is solid form III, which is easily prepared but is metastable at room temperature and gradually converts to solid form I. The crystal structures of the remaining solid forms remain unknown.
"We are studying the stability of solid forms of tecovirimat under changing environmental conditions. During the previous phase of the study, supported by the Priority 2030 program, we identified conditions for the reproducible production of solid forms of tecovirimat, determined the crystal structures of five of the six known solid forms, and identified differences in their structures. Different solid forms containing the same compound can differ significantly in their physicochemical properties (in particular, apparent solubility and dissolution rate), so this information is crucial for identifying existing solid forms and searching for new solid forms of tecovirimat, as well as developing methods for their production. Equally important is data on the stability and interconversion of different solid forms of tecovirimat, as this directly impacts the storage conditions of the dosage forms," explained Alexander Ivlev.
In a new phase of their research, the scientists addressed the critical issue of the lack of reproducibility in experiments producing solid forms of tecovirimat. They identified previously undescribed methods for producing these forms, one of which is currently undergoing patenting. A reproducible method for producing a desired solid form allows the scientists to synthesize the required quantity of the desired form, fully characterize the properties of the resulting compound, grow crystals, and determine its spatial structure and properties. The method chosen for patenting has significant potential for scalability.
Currently, the scientists have produced sufficient quantities of each solid form of tecovirimat for study, and for each, they have obtained powder diffraction profiles of higher quality than those presented in the SIGA technologies patent. For three solid forms of tecovirimat, the scientists have already demonstrated stability at low temperatures. Such data for the solid forms under study have not previously been described in the literature. Experiments are currently underway to study the stability of solid forms of tecovirimat in high-humidity environments. Combined with experiments on the effects of temperature, this will allow conclusions to be drawn regarding the feasibility of their use in the development of new dosage forms of the smallpox drug based on a metastable solid form.
To study the structures and properties of various forms of tecovirimat, the young scientist employed several methods: X-ray diffraction analysis, X-ray structural analysis, and differential scanning calorimetry. Using powder X-ray diffraction (XRD), diffraction patterns unique to each solid form were obtained and the phase purity of the crystalline product was assessed. The crystal structure of the studied substances was deciphered using single-crystal X-ray diffraction (XRD). The response of the studied forms of tecovirimat to temperature changes was determined using differential scanning calorimetry (DSC). Based on the nature of the effects upon heating or cooling the sample, they determined which solid form was more stable and determined the temperature at which one form could transform into the other, altering its crystalline structure.
Currently, the young researcher is working to determine the structure of the final, sixth, solid form of tecovirimate. The method for its production has already been discovered; the conditions for producing crystals remain to be determined. Next, they plan to search for new solid forms of tecovirimate and study their physicochemical properties. The next stage of the project will involve mechanochemical studies.
"In production, mechanical action is used to grind particles of pharmaceutical substances, but this can also lead to the transition of one solid form to another. That is, a solid form of a substance can change its crystalline structure and transform into another solid form of the same compound. And since powders of future drug substances can be subject to mechanical action in industrial settings, it is crucial to know in advance what consequences this technical process may cause," explained Alexander Ivlev.
The final stage of the work involves cocrystallizing the active ingredient of TPOXX® with other compounds to produce solid forms in which the tecovirimat molecule will be bound to other molecules via intermolecular interactions. Such experiments are necessary to obtain new solid forms with improved properties, which should ultimately improve the properties of the final product, such as its solubility or temperature stability.
"I hope that our work will ultimately lead to improved efficacy of the drug and help doctors in their work," said Alexander Ivlev.
This work is being carried out with the support of the Priority 2030 program within the framework of the youth research project competition “X-ray, synchrotron, and neutron methods of interdisciplinary research.”
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