Two IISc scientists have not only demonstrated the existence of polymorphism in aspirin, but have also shown that nanoindentation has successfully been able to ferret out information that is location-specific. This could help in the development of drugs with greater efficacy and also pave the way for better drug design in the future, explains Sharath Ahuja.
It takes two to tango", they say. In the case of solving an important issue related to the common drug, aspirin, it took the coming together of two scientists from the Indian Institute of Science (IISc), Bangalore, whose expertise is in distinctly different fields, to solve the curious case of aspirin polymorphism. The scientists are Professors Upadrasta Ramamurty and Gautam R Desiraju.
Ramamurty who heads the laboratory 'Sukshma' in the Department of Materials Engineering is interested in the mechanical behaviour of materials or in simple parlance, 'examining how things break'. Crystal engineering pioneer Prof. Desiraju of the Solid State Structural Chemistry (SSCU) is a structural chemist, interested in chemical bonding and their use in designing crystals. Together, these scientists have utilised their complementary skills in solving an important scientific problem - aspirin polymorphism.
Nearly, 40,000 tons of aspirin (chemical name: acetylsalicylic acid) is used worldwide every year. Aside from its obvious chemical and pharmaceutical importance, aspirin exhibits a fascinating and perplexing structural chemistry. One of the controversial issues related to the crystal structure (the way in which the molecules are packed), has been the existence of polymorphism in aspirin.
Polymorphs are crystals of the same compound but with a different molecular arrangement. Although two crystals may appear similar in structure, they can have dramatically different properties, and many drugs only receive regulatory approval for only one form.
It was thought, for a long time, that aspirin has only one crystal structure. But recent studies indicate the possibility of another form. Ramamurty and Desiraju decided to subject the two polymorphs of aspirin to nanoindentation studies. This technique, somewhat new, allows one to literally poke a material with the tiniest of forces (of the order of tens of nano-Newton) and measure the response.
One Newton is one-tenth of a kilogram, described as the force experienced when an average sized apple falls from a height of one meter. In the current context, it is essential to use such a high resolution technique, as these are organic crystals, which are not very strong and the crystals can be grown under very careful conditions to extremely tiny dimensions (millimetre size).
Two post-doctoral fellows of Ramamurty and Desiraju—Sunil Varughese and M S R N Kiran, prepared the necessary crystals and conducted the precise experiments using a highly sophisticated state-of-the-art nanoindenter. After a short jab by the tiny indenter onto the aspirin crystal, they were able to demonstrate distinctly different mechanical signatures of the two forms of aspirin.
In addition, they could show that a crystal, which X-ray diffraction indicated a pure 'form II', does indeed contain intergrown mixture of both the forms! This 'eureka' moment not only confirmed the existence of polymorphism in aspirin, but also showed that nanoindentation has successfully been able to ferret information that is location-specific and can help resolve the finer details; as to how different crystals may be organised in compounds that exhibit complexity.
Pharmaceutical companies around the world produce billions of tablets every year of which aspirin accounts for a large percentage. The manufacture of a tablet is a complex multi-stage process under which the starting materials change their physical characteristics a number of times before the final dosage form is produced. The first step involves milling and mixing, subsequent steps include particle size reduction and sizing, blending, granulation, drying, compaction, and (frequently) coating.
Various factors associated with these processes can seriously affect content uniformity, bioavailability, or stability and most importantly, overall efficacy of the tablet. A possible change in polymorphic form of the active ingredient, rendering it less or totally inactive, or unstable, is one of the major problems that may arise if the process is not controlled properly. Another major factor is that, in the pharmaceutical industry, crystallographic techniques (both powder and single-crystal) are the tools usually used to establish phase purity and thereby claim intellectual property rights for new polymorphs.
The researchers say, "our study establishes that nanoindentation can provide ''signature'' responses for the two aspirin polymorphs, despite their very similar crystal structures, and it demonstrates also the value of the technique for application to chemical problems associated with polymorphism in the context of crystal engineering".
They further add "that the results of this scientific investigation allow the identification of the most stable polymorph, which could then be used to develop drugs with better efficacy. This could also pave the way for better drug design in the future".
Nanoindentation could have an impact on the pharmaceutical industry, which currently relies on X-ray crystallography, from amongst other analytical techniques, to establish whether or not a new drug has been made for intellectual property rights, because nanoindentation can be used to detect the presence of very small amounts of 'infringing' polymorphs.
It takes two to tango", they say. In the case of solving an important issue related to the common drug, aspirin, it took the coming together of two scientists from the Indian Institute of Science (IISc), Bangalore, whose expertise is in distinctly different fields, to solve the curious case of aspirin polymorphism. The scientists are Professors Upadrasta Ramamurty and Gautam R Desiraju.
Ramamurty who heads the laboratory 'Sukshma' in the Department of Materials Engineering is interested in the mechanical behaviour of materials or in simple parlance, 'examining how things break'. Crystal engineering pioneer Prof. Desiraju of the Solid State Structural Chemistry (SSCU) is a structural chemist, interested in chemical bonding and their use in designing crystals. Together, these scientists have utilised their complementary skills in solving an important scientific problem - aspirin polymorphism.
Nearly, 40,000 tons of aspirin (chemical name: acetylsalicylic acid) is used worldwide every year. Aside from its obvious chemical and pharmaceutical importance, aspirin exhibits a fascinating and perplexing structural chemistry. One of the controversial issues related to the crystal structure (the way in which the molecules are packed), has been the existence of polymorphism in aspirin.
Polymorphs are crystals of the same compound but with a different molecular arrangement. Although two crystals may appear similar in structure, they can have dramatically different properties, and many drugs only receive regulatory approval for only one form.
It was thought, for a long time, that aspirin has only one crystal structure. But recent studies indicate the possibility of another form. Ramamurty and Desiraju decided to subject the two polymorphs of aspirin to nanoindentation studies. This technique, somewhat new, allows one to literally poke a material with the tiniest of forces (of the order of tens of nano-Newton) and measure the response.
One Newton is one-tenth of a kilogram, described as the force experienced when an average sized apple falls from a height of one meter. In the current context, it is essential to use such a high resolution technique, as these are organic crystals, which are not very strong and the crystals can be grown under very careful conditions to extremely tiny dimensions (millimetre size).
Two post-doctoral fellows of Ramamurty and Desiraju—Sunil Varughese and M S R N Kiran, prepared the necessary crystals and conducted the precise experiments using a highly sophisticated state-of-the-art nanoindenter. After a short jab by the tiny indenter onto the aspirin crystal, they were able to demonstrate distinctly different mechanical signatures of the two forms of aspirin.
In addition, they could show that a crystal, which X-ray diffraction indicated a pure 'form II', does indeed contain intergrown mixture of both the forms! This 'eureka' moment not only confirmed the existence of polymorphism in aspirin, but also showed that nanoindentation has successfully been able to ferret information that is location-specific and can help resolve the finer details; as to how different crystals may be organised in compounds that exhibit complexity.
Pharmaceutical companies around the world produce billions of tablets every year of which aspirin accounts for a large percentage. The manufacture of a tablet is a complex multi-stage process under which the starting materials change their physical characteristics a number of times before the final dosage form is produced. The first step involves milling and mixing, subsequent steps include particle size reduction and sizing, blending, granulation, drying, compaction, and (frequently) coating.
Various factors associated with these processes can seriously affect content uniformity, bioavailability, or stability and most importantly, overall efficacy of the tablet. A possible change in polymorphic form of the active ingredient, rendering it less or totally inactive, or unstable, is one of the major problems that may arise if the process is not controlled properly. Another major factor is that, in the pharmaceutical industry, crystallographic techniques (both powder and single-crystal) are the tools usually used to establish phase purity and thereby claim intellectual property rights for new polymorphs.
The researchers say, "our study establishes that nanoindentation can provide ''signature'' responses for the two aspirin polymorphs, despite their very similar crystal structures, and it demonstrates also the value of the technique for application to chemical problems associated with polymorphism in the context of crystal engineering".
They further add "that the results of this scientific investigation allow the identification of the most stable polymorph, which could then be used to develop drugs with better efficacy. This could also pave the way for better drug design in the future".
Nanoindentation could have an impact on the pharmaceutical industry, which currently relies on X-ray crystallography, from amongst other analytical techniques, to establish whether or not a new drug has been made for intellectual property rights, because nanoindentation can be used to detect the presence of very small amounts of 'infringing' polymorphs.