Chemists work on decreasing costs of medication research
A new paper by KFU's Laboratory of New Methods of Treatment and Analysis of Materials for Medicine under Ultrafast Heating and Cooling appeared in Crystal Growth and Design.
Co-author, Lead Research Associate Valery Gorbatchuk explains, "A polymorph (a type of crystalline structure) is different crystalline arrangements of the same substance. Modern medicinal substances have rather large complex molecules that can be packaged in crystals in different ways: they form different polymorphs. It is this packaging that affects the rate of dissolution of the medication."
Thus, bioavailability—the rate of dissolution in water, and in some cases, which organ the drug will act on—depends on the crystalline packaging. For example, to treat the mucous membranes of the mouth, throat and lungs, the dissolution rate should be high, for the stomach—less, and even less for the treatment of intestinal diseases, elaborates the scientist. If the medicine for the stomach dissolves in the patient's mouth, then it simply risks not reaching the organ requiring treatment.
Polymorphs of compounds included in drugs may differ in solubility, ability to absorb moisture from the air, and be compacted into tablets without caking. Because of this, their biological activity in the body may vary, and therefore also their effectiveness in the composition of the medicine. Different polymorphs have different packaging, and, consequently, varying energies of the crystal lattice, which influences solubility speeds. That's why pharmaceutical companies need to study all the possible polymorphs of compounds used in production. Finding new polymorphs leads to mounting costs of research, changes in the manufacturing process, and even patent wars with competitors.
"When testing new drugs and bringing them to the market, pharmaceutical companies try to discover and patent all possible polymorphs. In our country, however, polymorphs of medicines are not patented. When searching—screening polymorphs, there is a problem. It is not known in advance how many of them there may be. It is believed that the number of polymorphs of a substance detected is a matter of resources spent: labor and budget," continues the interviewee.
According to the interlocutor, there are devices for automatic screening of polymorphs, which allow to go through a large number of crystallization conditions in a limited time. But there is no complete guarantee that all possible crystal forms will be detected. This is largely a matter of luck, especially for drugs that have been on the market for a long time and have been studied for many decades.
"We have developed a method for finding and preparing polymorphs that minimizes the randomness of their detection. Polymorphs are usually crystallized from solutions or melts. That is, the initial state is liquid. Here, however, all processes are solid-phase. This allows us to stabilize the crystalline forms with the least dense packing—respectively, with the highest bioavailability. That is, the solid-phase process allows us to fix the state of polymorph in the least stable form. Before our discovery of the new method, the process was carried out from solutions and melts, could not detect some forms for seemingly the most well-known and studied substances," he says.
In particular, KFU scientists prepared a new polymorph of indomethacin (a non-steroidal anti-inflammatory drug) with increased bioavailability, as well as a polymorph of this substance, previously known only in a mixture with a polymeric solvent. It should be understood that indomethacin has been studied for more than 50 years. Solid-phase processes have been studied at the Institute of Chemistry for more than 20 years. The methods and approaches have been worked out on other substances. Research on pharmaceuticals began several years ago, and the first publications appeared only this year.
"Thanks to our work, a method has emerged that makes it easier to introduce a drug into practice. When introducing new substances to the market, pharmaceutical companies try to discover all polymorphic forms. Otherwise, if the developer does not find a polymorph of a substance, a competitor may discover a polymorph and start selling the drug under its trademark, circumventing copyrights," concludes Gorbatchuk.
More information:
New Polymorph of Indomethacin: Screening by Solid-State Guest Exchange and Characterization Using Fast Scanning Calorimetry
pubs.acs.org/doi/10.1021/acs.cgd.3c00443
Provided by Kazan Federal University